TY - JOUR A1 - Weidner, Christopher A1 - Rousseau, Morten A1 - Plauth, Annabell A1 - Wowro, Sylvia J. A1 - Fischer, Cornelius A1 - Abdel-Aziz, Heba A1 - Sauer, Sascha T1 - Iberis amara Extract Induces Intracellular Formation of Reactive Oxygen Species and Inhibits Colon Cancer JF - PLoS ONE N2 - Massively increasing global incidences of colorectal cancer require efficient treatment and prevention strategies. Here, we report unexpected anticancerogenic effects of hydroethanolic Iberis amara extract (IAE), which is known as a widely used phytomedical product for treating gastrointestinal complaints. IAE significantly inhibited the proliferation of HT-29 and T84 colon carcinoma cells with an inhibitory concentration (IC\(_{50}\)) of 6 and 9 μg/ml, respectively, and further generated inhibitory effects in PC-3 prostate and MCF7 breast cancer cells. Inhibition of proliferation in HT-29 cells was associated with a G2/M phase cell cycle arrest including reduced expression of various regulatory marker proteins. Notably, in HT-29 cells IAE further induced apoptosis by intracellular formation of reactive oxygen species (ROS). Consistent with predictions derived from our in vitro experiments, bidaily oral gavage of 50 mg/kg of IAE over 4 weeks resulted in significant inhibition of tumor growth in a mouse HT-29 tumor xenograft model. Taken together, Iberis amara extracts could become useful alternatives for preventing and treating the progression of colon cancer. KW - iberis amara extract KW - colorectal cancer KW - treatment KW - prevention Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167044 VL - 11 IS - 4 ER - TY - JOUR A1 - Vaze, Koustubh M. A1 - Helfrich-Förster, Charlotte T1 - Drosophila ezoana uses an hour-glass or highly damped circadian clock for measuring night length and inducing diapause JF - Physiological Entomology N2 - Insects inhabiting the temperate zones measure seasonal changes in day or night length to enter the overwintering diapause. Diapause induction occurs after the duration of the night exceeds a critical night length (CNL). Our understanding of the time measurement mechanisms is continuously evolving subsequent to Bünning’s proposal that circadian systems play the clock role in photoperiodic time measurement (Bünning, 1936). Initially, the photoperiodic clocks were considered to be either based on circadian oscillators or on simple hour-glasses, depending on ‘positive’ or ‘negative’ responses in Nanda–Hamner and Bünsow experiments (Nanda & Hammer, 1958; Bünsow, 1960). However, there are also species whose responses can be regarded as neither ‘positive’, nor as ‘negative’, such as the Northern Drosophila species Drosophila ezoana, which is investigated in the present study. In addition, modelling efforts show that the ‘positive’ and ‘negative’ Nanda–Hamner responses can also be provoked by circadian oscillators that are damped to different degrees: animals with highly sustained circadian clocks will respond ‘positive’ and those with heavily damped circadian clocks will respond ‘negative’. In the present study, an experimental assay is proposed that characterizes the photoperiodic oscillators by determining the effects of non-24-h light/dark cycles (T-cycles) on critical night length. It is predicted that there is (i) a change in the critical night length as a function of T-cycle period in sustained-oscillator-based clocks and (ii) a fxed night-length measurement (i.e. no change in critical night length) in damped-oscillator-based clocks. Drosophila ezoana flies show a critical night length of approximately 7 h irrespective of T-cycle period, suggesting a damped-oscillator-based photoperiodic clock. The conclusion is strengthened by activity recordings revealing that the activity rhythm of D. ezoana flies also dampens in constant darkness. KW - photoperiodic time mesurement KW - wyeomyia smithii KW - protophormia terraenovae KW - immunoreactive neurons KW - geographical variation KW - reproductive diapause KW - rhythmic components KW - locomotor activity KW - circadian clock KW - damped-oscillator-model of photoperiodic clock KW - diapause KW - Drosophila KW - hour-glass KW - pitcher-plant mosquito KW - bug riptortus-pedestris KW - Nanda-Hamner KW - photoperiodism Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-204278 VL - 41 IS - 4 ER - TY - JOUR A1 - Beer, Katharina A1 - Steffan-Dewenter, Ingolf A1 - Härtel, Stephan A1 - Helfrich-Förster, Charlotte T1 - A new device for monitoring individual activity rhythms of honey bees reveals critical effects of the social environment on behavior JF - Journal of Comparative Physiology A N2 - Chronobiological studies of individual activity rhythms in social insects can be constrained by the artificial isolation of individuals from their social context. We present a new experimental set-up that simultaneously measures the temperature rhythm in a queen-less but brood raising mini colony and the walking activity rhythms of singly kept honey bees that have indirect social contact with it. Our approach enables monitoring of individual bees in the social context of a mini colony under controlled laboratory conditions. In a pilot experiment, we show that social contact with the mini colony improves the survival of monitored young individuals and affects locomotor activity patterns of young and old bees. When exposed to conflicting Zeitgebers consisting of a light-dark (LD) cycle that is phase-delayed with respect to the mini colony rhythm, rhythms of young and old bees are socially synchronized with the mini colony rhythm, whereas isolated bees synchronize to the LD cycle. We conclude that the social environment is a stronger Zeitgeber than the LD cycle and that our new experimental set-up is well suited for studying the mechanisms of social entrainment in honey bees. KW - Social entrainment KW - Foragers KW - Nurses KW - Locomotor activity KW - Temperature rhythms Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188030 VL - 202 IS - 8 ER - TY - JOUR A1 - Kapp, Markus A1 - Kosmala, Aleksander A1 - Kircher, Stefan A1 - Luber, Verena A1 - Kunzmann, Volker T1 - Exceptional Response to Nanoparticle Albumin-Bound Paclitaxel and Gemcitabine in a Patient with a Refractory Adenocarcinoma of the Ampulla of Vater JF - Case Reports in Oncology N2 - Ampullary carcinoma is a rare tumor and evidence on the treatment of recurrent metastatic disease is scarce. We report the case of a 60-year-old patient with an R0-resected node-positive adenocarcinoma of the papilla of Vater of an initially diagnosed intestinal subtype who developed pulmonary metastases 2 months after adjuvant gemcitabine chemotherapy and, subsequently, liver metastases. Palliative combination chemotherapy with standard regimens for intestinal-type adenocarcinoma (FOLFOX and FOLFIRI) failed. However, subsequent combination chemotherapy with nanoparticle albumin-bound paclitaxel and gemcitabine, a regimen with proven efficacy in metastatic adenocarcinoma of the pancreas, resulted in a durable, very good partial remission. Treatment was manageable and well tolerated. Primary tumor and metastatic tissue were reassessed by immunohistochemistry and had to be reclassified to a mixed phenotype containing predominant elements of the pancreatobiliary subtype. Our case suggests that combination chemotherapy with nanoparticle albumin-bound paclitaxel and gemcitabine could represent a promising option for the treatment of this rare disease and warrants further investigation within controlled clinical trials. Moreover, thorough characterization of ampullary carcinomas by histomorphology and additional immunohistochemistry should become mandatory in order to start a chemotherapeutic regimen tailored for the definitive subtype. KW - adenocarcinoma of the ampulla of Vater KW - intestinal-type adenocarcinoma KW - pancreatobiliary type KW - FOLFOX KW - FOLFIRI KW - gemcitabine KW - nanoparticle albumin-bound paclitaxel Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-168358 VL - 9 IS - 1 ER - TY - JOUR A1 - Ben Ami, Tal A1 - Tong, Yuehong A1 - Bhuiyan, Alauddin A1 - Huisingh, Carrie A1 - Ablonczy, Zsolt A1 - Ach, Thomas A1 - Curcio, Christine A. A1 - Smith, R. Theodore T1 - Spatial and Spectral Characterization of Human Retinal Pigment Epithelium Fluorophore Families by Ex Vivo Hyperspectral Autofluorescence Imaging JF - Translational Vision Science & Technology N2 - Purpose: Discovery of candidate spectra for abundant fluorophore families in human retinal pigment epithelium (RPE) by ex vivo hyperspectral imaging. Methods: Hyperspectral autofluorescence emission images were captured between 420 and 720 nm (10-nm intervals), at two excitation bands (436–460, 480–510 nm), from three locations (fovea, perifovea, near-periphery) in 20 normal RPE/Bruch's membrane (BrM) flatmounts. Mathematical factorization extracted a BrM spectrum (S0) and abundant lipofuscin/melanolipofuscin (LF/ML) spectra of RPE origin (S1, S2, S3) from each tissue. Results: Smooth spectra S1 to S3, with perinuclear localization consistent with LF/ML at all three retinal locations and both excitations in 14 eyes (84 datasets), were included in the analysis. The mean peak emissions of S0, S1, and S2 at λ\(_{ex}\) 436 nm were, respectively, 495 ± 14, 535 ± 17, and 576 ± 20 nm. S3 was generally trimodal, with peaks at either 580, 620, or 650 nm (peak mode, 650 nm). At λ\(_{ex}\) 480 nm, S0, S1, and S2 were red-shifted to 526 ± 9, 553 ± 10, and 588 ± 23 nm, and S3 was again trimodal (peak mode, 620 nm). S1 often split into two spectra, S1A and S1B. S3 strongly colocalized with melanin. There were no significant differences across age, sex, or retinal location. Conclusions: There appear to be at least three families of abundant RPE fluorophores that are ubiquitous across age, retinal location, and sex in this sample of healthy eyes. Further molecular characterization by imaging mass spectrometry and localization via super-resolution microscopy should elucidate normal and abnormal RPE physiology involving fluorophores. Translational Relevance: Our results help establish hyperspectral autofluorescence imaging of the human retinal pigment epithelium as a useful tool for investigating retinal health and disease. KW - spectral characterization KW - human retinal pigment epithelium KW - fluorophores KW - hyperspectral autofluorescence imaging Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-168328 VL - 5 IS - 3 ER - TY - JOUR A1 - Harkin, David J. A1 - Broch, Katharina A1 - Schreck, Maximilian A1 - Ceyman, Harald A1 - Stoy, Andreas A1 - Yong, Chaw-Keong A1 - Nikolka, Mark A1 - McCulloch, Ian A1 - Stingelin, Natalie A1 - Lambert, Christoph A1 - Sirringhaus, Henning T1 - Decoupling charge transport and electroluminescence in a high mobility polymer semiconductor JF - Advanced Materials N2 - Fluorescence enhancement of a high-mobility polymer semiconductor is achieved via energy transfer to a higher fluorescence quantum yield squaraine dye molecule on 50 ps timescales. In organic light-emitting diodes, an order of magnitude enhancement of the external quantum efficiency is observed without reduction in the charge-carrier mobility resulting in radiances of up to 5 W str\(^{-1}\) m\(^{-2}\) at 800 nm. KW - Light-emitting diodes KW - Fiels-effect transistors KW - Energy transfer KW - Conjugated polymers KW - High performance KW - High efficiency KW - Perovskite KW - Amplification KW - Fluorescence KW - Emission Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187670 VL - 28 IS - 30 ER - TY - JOUR A1 - Suliman, Salwa A1 - Mustafa, Kamal A1 - Krueger, Anke A1 - Steinmüller-Nethl, Doris A1 - Finne-Wistrand, Anna A1 - Osdal, Tereza A1 - Hamza, Amani O. A1 - Sun, Yang A1 - Parajuli, Himalaya A1 - Waag, Thilo A1 - Nickel, Joachim A1 - Johannessen, Anne Christine A1 - McCormack, Emmet A1 - Costea, Daniela Elena T1 - Nanodiamond modified copolymer scaffolds affects tumour progression of early neoplastic oral keratinocytes JF - Biomaterials N2 - This study aimed to evaluate the tumorigenic potential of functionalising poly(LLA-co-CL) scaffolds. The copolymer scaffolds were functionalised with nanodiamonds (nDP) or with nDP and physisorbed BMP-2 (nDP-PHY) to enhance osteoinductivity. Culturing early neoplastic dysplastic keratinocytes (DOK\(^{Luc}\)) on nDP modified scaffolds reduced significantly their subsequent sphere formation ability and decreased significantly the cells' proliferation in the supra-basal layers of in vitro 3D oral neoplastic mucosa (3D-OT) when compared to DOK\(^{Luc}\) previously cultured on nDP-PHY scaffolds. Using an in vivo non-invasive environmentally-induced oral carcinogenesis model, nDP scaffolds were observed to reduce bioluminescence intensity of tumours formed by DOK\(^{Luc}\) + carcinoma associated fibroblasts (CAF). nDP modification was also found to promote differentiation of DOK\(^{Luc}\) both in vitro in 3D-OT and in vivo in xenografts formed by DOKLuc alone. The nDP-PHY scaffold had the highest number of invasive tumours formed by DOK\(^{Luc}\) + CAF outside the scaffold area compared to the nDP and control scaffolds. In conclusion, in vitro and in vivo results presented here demonstrate that nDP modified copolymer scaffolds are able to decrease the tumorigenic potential of DOK\(^{Luc}\), while confirming concerns for the therapeutic use of BMP-2 for reconstruction of bone defects in oral cancer patients due to its tumour promoting capabilities. KW - Bone morphogenetic protein-2 KW - Sinus floor augmentation KW - Marrow stromal cells KW - Growth; BMP-2 KW - Tumorigenicity KW - Biodegradable polymer scaffolds KW - Mandibular continuity defects KW - Squamous-cell carcinoma KW - In-vitro KW - Mesenchymal transition KW - BMP-2 KW - Bone tissue engineering KW - Biocompatibility KW - Microenvironment KW - Oral squamous cell carcinoma Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188287 VL - 95 ER - TY - JOUR A1 - Seifert, Sabine A1 - Shoyama, Kazutaka A1 - Schmidt, David A1 - Würthner, Frank T1 - An electron-poor C\(_{64}\) nanographene by palladium-catalyzed cascade C-C bond formation: one-pot synthesis and single-crystal structure analysis JF - Angewandte Chemie-International Edition N2 - Herein, we report the one-pot synthesis of an electron-poor nanographene containing dicarboximide groups at the corners. We efficiently combined palladium-catalyzed Suzuki-Miyaura cross-coupling and dehydrohalogenation to synthesize an extended two-dimensional pi-scaffold of defined size in a single chemical operation starting from N-(2,6-diisopropylphenyl)-4,5-dibromo-1,8-naphthalimide and a tetrasubstituted pyrene boronic acid ester as readily accessible starting materials. The reaction of these precursors under the conditions commonly used for Suzuki-Miyaura cross-coupling afforded a C\(_{64}\) nanographene through the formation of ten C-C bonds in a one-pot process. Single-crystal X-ray analysis unequivocally confirmed the structure of this unique extended aromatic molecule with a planar geometry. The optical and electrochemical properties of this largest ever synthesized planar electron-poor nanographene skeleton were also analyzed. KW - Graphene nanoribbons KW - Liquid-crystalline KW - dyes/pigments KW - polycyclic aromatic hydrocarbons KW - two-dimensional nanostructures KW - Aromatic-hydrocarbon KW - Carbon KW - Dyes KW - Functionalization KW - cascade reactions KW - nanographene Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188889 VL - 55 IS - 22 ER - TY - JOUR A1 - Thormann, Birthe A1 - Ahrens, Dirk A1 - Armijos, Diego Marín A1 - Peters, Marcell K. A1 - Wagner, Thomas A1 - Wägele, Johann W. T1 - Exploring the Leaf Beetle Fauna (Coleoptera: Chrysomelidae) of an Ecuadorian Mountain Forest Using DNA Barcoding JF - PLoS ONE N2 - Background Tropical mountain forests are hotspots of biodiversity hosting a huge but little known diversity of insects that is endangered by habitat destruction and climate change. Therefore, rapid assessment approaches of insect diversity are urgently needed to complement slower traditional taxonomic approaches. We empirically compare different DNA-based species delimitation approaches for a rapid biodiversity assessment of hyperdiverse leaf beetle assemblages along an elevational gradient in southern Ecuador and explore their effect on species richness estimates. Methodology/Principal Findings Based on a COI barcode data set of 674 leaf beetle specimens (Coleoptera: Chrysomelidae) of 266 morphospecies from three sample sites in the Podocarpus National Park, we employed statistical parsimony analysis, distance-based clustering, GMYC- and PTP-modelling to delimit species-like units and compared them to morphology-based (parataxonomic) species identifications. The four different approaches for DNA-based species delimitation revealed highly similar numbers of molecular operational taxonomic units (MOTUs) (n = 284–289). Estimated total species richness was considerably higher than the sampled amount, 414 for morphospecies (Chao2) and 469–481 for the different MOTU types. Assemblages at different elevational levels (1000 vs. 2000 m) had similar species numbers but a very distinct species composition for all delimitation methods. Most species were found only at one elevation while this turnover pattern was even more pronounced for DNA-based delimitation. Conclusions/Significance Given the high congruence of DNA-based delimitation results, probably due to the sampling structure, our study suggests that when applied to species communities on a regionally limited level with high amount of rare species (i.e. ~50% singletons), the choice of species delimitation method can be of minor relevance for assessing species numbers and turnover in tropical insect communities. Therefore, DNA-based species delimitation is confirmed as a valuable tool for evaluating biodiversity of hyperdiverse insect communities, especially when exact taxonomic identifications are missing. KW - leaf beetle KW - Coleoptera: Chrysomelidae KW - Podocarpus National Park KW - DNA-based species delimitation KW - biodiversity Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167253 VL - 11 IS - 2 ER - TY - JOUR A1 - Rech, Juergen A1 - Hueber, Axel J. A1 - Finzel, Stephanie A1 - Englbrecht, Matthias A1 - Haschka, Judith A1 - Manger, Bernhard A1 - Kleyer, Arnd A1 - Reiser, Michaela A1 - Cobra, Jayme Fogagnolo A1 - Figueiredo, Camille A1 - Tony, Hans-Peter A1 - Kleinert, Stefan A1 - Wendler, Joerg A1 - Schuch, Florian A1 - Ronneberger, Monika A1 - Feuchtenberger, Martin A1 - Fleck, Martin A1 - Manger, Karin A1 - Ochs, Wolfgang A1 - Schmitt-Haendle, Matthias A1 - Lorenz, Hanns-Martin A1 - Nuesslein, Hubert A1 - Alten, Rieke A1 - Henes, Joerg A1 - Krueger, Klaus A1 - Schett, Georg T1 - Prediction of disease relapses by multibiomarker disease activity and autoantibody status in patients with rheumatoid arthritis on tapering DMARD treatment JF - Annals of the Rheumatic Diseases N2 - Objective To analyse the role of multibiomarker disease activity (MBDA) score in predicting disease relapses in patients with rheumatoid arthritis (RA) in sustained remission who tapered disease modifying antirheumatic drug (DMARD) therapy in RETRO, a prospective randomised controlled trial. Methods MBDA scores (scale 1-100) were determined based on 12 inflammation markers in baseline serum samples from 94 patients of the RETRO study. MBDA scores were compared between patients relapsing or remaining in remission when tapering DMARDs. Demographic and disease-specific parameters were included in multivariate logistic regression analysis for defining predictors of relapse. Results Moderate-to-high MBDA scores were found in 33% of patients with RA overall. Twice as many patients who relapsed (58%) had moderate/high MBDA compared with patients who remained in remission (21%). Baseline MBDA scores were significantly higher in patients with RA who were relapsing than those remaining in stable remission (N=94; p=0.0001) and those tapering/stopping (N=59; p=0.0001). Multivariate regression analysis identified MBDA scores as independent predictor for relapses in addition to anticitrullinated protein antibody (ACPA) status. Relapse rates were low (13%) in patients who were MBDA-/ACPA-, moderate in patients who were MBDA+/ACPA- (33.3%) and MBDA-ACPA+ (31.8%) and high in patients who were MBDA+/ACPA+ (76.4%). Conclusions MBDA improved the prediction of relapses in patients with RA in stable remission undergoing DMARD tapering. If combined with ACPA testing, MBDA allowed prediction of relapse in more than 80% of the patients. Trial registration number EudraCT 2009-015740-42. KW - Drug-free remission KW - Clinical remission KW - Validation KW - Synovitis Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187519 VL - 75 IS - 9 ER - TY - JOUR A1 - Audehm, P. A1 - Schmidt, M. A1 - Brück, S. A1 - Tietze, T. A1 - Gräfe, J. A1 - Macke, S. A1 - Schütz, G. A1 - Goering, E. T1 - Pinned orbital moments - A new contribution to magnetic anisotropy JF - Scientific Reports N2 - Reduced dimensionality and symmetry breaking at interfaces lead to unusual local magnetic configurations, such as glassy behavior, frustration or increased anisotropy. The interface between a ferromagnet and an antiferromagnet is such an example for enhanced symmetry breaking. Here we present detailed X-ray magnetic circular dichroism and X-ray resonant magnetic reflectometry investigations on the spectroscopic nature of uncompensated pinned magnetic moments in the antiferromagnetic layer of a typical exchange bias system. Unexpectedly, the pinned moments exhibit nearly pure orbital moment character. This strong orbital pinning mechanism has not been observed so far and is not discussed in literature regarding any theory for local magnetocrystalline anisotropy energies in magnetic systems. To verify this new phenomenon we investigated the effect at different temperatures. We provide a simple model discussing the observed pure orbital moments, based on rotatable spin magnetic moments and pinned orbital moments on the same atom. This unexpected observation leads to a concept for a new type of anisotropy energy. KW - pinned orbital moments KW - ferromagnet KW - antiferromagnet KW - anisotropy energy Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167727 VL - 6 IS - 25517 ER - TY - JOUR A1 - Telorac, Jonas A1 - Prykhozhij, Sergey V. A1 - Schöne, Stefanie A1 - Meierhofer, David A1 - Sauer, Sascha A1 - Thomas-Chollier, Morgane A1 - Meijsing, Sebastiaan H. T1 - Identification and characterization of DNA sequences that prevent glucocorticoid receptor binding to nearby response elements JF - Nucleic Acids Research N2 - Out of the myriad of potential DNA binding sites of the glucocorticoid receptor (GR) found in the human genome, only a cell-type specific minority is actually bound, indicating that the presence of a recognition sequence alone is insufficient to specify where GR binds. Cooperative interactions with other transcription factors (TFs) are known to contribute to binding specificity. Here, we reasoned that sequence signals preventing GR recruitment to certain loci provide an alternative means to confer specificity. Motif analyses uncovered candidate Negative Regulatory Sequences (NRSs) that interfere with genomic GR binding. Subsequent functional analyses demonstrated that NRSs indeed prevent GR binding to nearby response elements. We show that NRS activity is conserved across species, found in most tissues and that they also interfere with the genomic binding of other TFs. Interestingly, the effects of NRSs appear not to be a simple consequence of changes in chromatin accessibility. Instead, we find that NRSs interact with proteins found at sub-nuclear structures called paraspeckles and that these proteins might mediate the repressive effects of NRSs. Together, our studies suggest that the joint influence of positive and negative sequence signals partition the genome into regions where GR can bind and those where it cannot. KW - DNA sequencing KW - glucocorticoid receptor KW - DNA binding KW - transcription factors Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166330 VL - 44 IS - 13 ER - TY - JOUR A1 - Lenders, Malte A1 - Weidemann, Frank A1 - Kurschat, Christine A1 - Canaan-Kühl, Sima A1 - Duning, Thomas A1 - Stypmann, Jörg A1 - Schmitz, Boris A1 - Reiermann, Stefanie A1 - Krämer, Johannes A1 - Blaschke, Daniela A1 - Wanner, Christoph A1 - Brand, Stefan-Martin A1 - Brand, Eva T1 - Alpha-Galactosidase A p.A143T, a non-Fabry disease-causing variant JF - Orphanet Journal of Rare Diseases N2 - Background Fabry disease (FD) is an X-linked multisystemic disorder with a heterogeneous phenotype. Especially atypical or late-onset type 2 phenotypes present a therapeutical dilemma. Methods To determine the clinical impact of the alpha-Galactosidase A (GLA) p.A143T/ c.427G > A variation, we retrospectively analyzed 25 p.A143T patients in comparison to 58 FD patients with other missense mutations. Results p.A143T patients suffering from stroke/ transient ischemic attacks had slightly decreased residual GLA activities, and/or increased lyso-Gb3 levels, suspecting FD. However, most male p.A143T patients presented with significant residual GLA activity (~50 % of reference), which was associated with normal lyso-Gb3 levels. Additionally, p.A143T patients showed less severe FD-typical symptoms and absent FD-typical renal and cardiac involvement in comparison to FD patients with other missense mutations. Two tested female p.A143T patients with stroke/TIA did not show skewed X chromosome inactivation. No accumulation of neurologic events in family members of p.A143T patients with stroke/transient ischemic attacks was observed. Conclusions We conclude that GLA p.A143T seems to be most likely a neutral variant or a possible modifier instead of a disease-causing mutation. Therefore, we suggest that p.A143T patients with stroke/transient ischemic attacks of unknown etiology should be further evaluated, since the diagnosis of FD is not probable and subsequent ERT or chaperone treatment should not be an unreflected option. KW - Fabry disease KW - genotype KW - lyso-Gb3 KW - variant of unknown significance KW - GLA mutation KW - late-onset KW - stroke Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166559 VL - 11 IS - 54 ER - TY - JOUR A1 - Marx, Gernot A1 - Schindler, Achim W. A1 - Mosch, Christoph A1 - Albers, Joerg A1 - Bauer, Michael A1 - Gnass, Irmela A1 - Hobohm, Carsten A1 - Janssens, Uwe A1 - Kluge, Stefan A1 - Kranke, Peter A1 - Maurer, Tobias A1 - Merz, Waltraut A1 - Neugebauer, Edmund A1 - Quintel, Michael A1 - Senninger, Norbert A1 - Trampisch, Hans-Joachim A1 - Waydhas, Christian A1 - Wildenauer, Rene A1 - Zacharowski, Kai A1 - Eikermann, Michaela T1 - Intravascular volume therapy in adults guidelines from the association of the scientific medical societies in Germany JF - European Journal of Anaesthesiology N2 - No abstract available. KW - Predict fluid responsiveness KW - Randomized controlled-trial KW - 6-percent hydroxyethyl starch KW - Central venous-pressure KW - Elective cesarean-section KW - Critically-ill patients KW - Puls-pressure variation KW - Lactated ringers solution KW - Hypertonic saline 7.5-percent KW - Major abdominal surgery Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188223 VL - 33 IS - 7 ER - TY - JOUR A1 - Schmidt-Hieber, M. A1 - Silling, G. A1 - Schalk, E. A1 - Heinz, W. A1 - Panse, J. A1 - Penack, O. A1 - Christopeit, M. A1 - Buchheidt, D. A1 - Meyding-Lamadé, U. A1 - Hähnel, S. A1 - Wolf, H. H. A1 - Ruhnke, M. A1 - Schwartz, S. A1 - Maschmeyer, G. T1 - CNS infections in patients with hematological disorders (including allogeneic stem-cell transplantation)-Guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) JF - Annals of Oncology N2 - Infections of the central nervous system (CNS) are infrequently diagnosed in immunocompetent patients, but they do occur in a significant proportion of patients with hematological disorders. In particular, patients undergoing allogeneic hematopoietic stem-cell transplantation carry a high risk for CNS infections of up to 15%. Fungi and Toxoplasma gondii are the predominant causative agents. The diagnosis of CNS infections is based on neuroimaging, cerebrospinal fluid examination and biopsy of suspicious lesions in selected patients. However, identification of CNS infections in immunocompromised patients could represent a major challenge since metabolic disturbances, side-effects of antineoplastic or immunosuppressive drugs and CNS involvement of the underlying hematological disorder may mimic symptoms of a CNS infection. The prognosis of CNS infections is generally poor in these patients, albeit the introduction of novel substances (e.g. voriconazole) has improved the outcome in distinct patient subgroups. This guideline has been developed by the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) with the contribution of a panel of 14 experts certified in internal medicine, hematology/oncology, infectious diseases, intensive care, neurology and neuroradiology. Grades of recommendation and levels of evidence were categorized by using novel criteria, as recently published by the European Society of Clinical Microbiology and Infectious Diseases. KW - Central nervous system KW - Polymerase chain raction KW - Herpes simplex encephalitis KW - Invasive fungal-infections KW - Clinical practice guidelines KW - Liposomal amphotericin-B KW - Immunocompromised patient KW - Progressive multifocal leukoencephalopathy KW - Varicella-zoster-virus KW - Diagnosis KW - Treatment KW - Bone-marrow-transplantation KW - Real-time PCR KW - Guideline KW - Central nervous system infection Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188210 VL - 27 IS - 7 ER - TY - JOUR A1 - Brevik, Erlend J A1 - van Donkelaar, Marjolein M. J. A1 - Weber, Heike A1 - Sánchez-Mora, Cristina A1 - Jacob, Christian A1 - Rivero, Olga A1 - Kittel-Schneider, Sarah A1 - Garcia-martinez, Iris A1 - Aebi, Marcel A1 - van Hulzen, Kimm A1 - Cormand, Bru A1 - Ramos-Quiroga, Josep A A1 - Lesch, Klaus-Peter A1 - Reif, Andreas A1 - Ribases, Marta A1 - Franke, Barbara A1 - Posserud, Maj-Britt A1 - Johansson, Stefan A1 - Lundervold, Astri J. A1 - Haavik, Jan A1 - Zayats, Tetyana T1 - Genome-wide analyses of aggressiveness in attention-deficit hyperactivity disorder JF - American Journal of Medical Genetics Part B-Neuropsychiatric Genetics N2 - Aggressiveness is a behavioral trait that has the potential to be harmful to individuals and society. With an estimated heritability of about 40%, genetics is important in its development. We performed an exploratory genome-wide association (GWA) analysis of childhood aggressiveness in attention deficit hyperactivity disorder (ADHD) to gain insight into the underlying biological processes associated with this trait. Our primary sample consisted of 1,060 adult ADHD patients (aADHD). To further explore the genetic architecture of childhood aggressiveness, we performed enrichment analyses of suggestive genome-wide associations observed in aADHD among GWA signals of dimensions of oppositionality (defiant/vindictive and irritable dimensions) in childhood ADHD (cADHD). No single polymorphism reached genome-wide significance (P<5.00E-08). The strongest signal in aADHD was observed at rs10826548, within a long noncoding RNA gene (beta = -1.66, standard error (SE) = 0.34, P = 1.07E-06), closely followed by rs35974940 in the neurotrimin gene (beta = 3.23, SE = 0.67, P = 1.26E-06). The top GWA SNPs observed in aADHD showed significant enrichment of signals from both the defiant/vindictive dimension (Fisher's P-value = 2.28E-06) and the irritable dimension in cADHD (Fisher's P-value = 0.0061). In sum, our results identify a number of biologically interesting markers possibly underlying childhood aggressiveness and provide targets for further genetic exploration of aggressiveness across psychiatric disorders. KW - Large multicenter ADHD KW - Antisocial behavior KW - Diagnostic approach KW - Rating scale KW - Gene KW - Deficit/hyperactivity disorder KW - Susceptibility loci KW - Conduct disorder KW - Association KW - Adult KW - ADHD KW - Aggression KW - GWAS Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188116 VL - 171B IS - 5 ER - TY - JOUR A1 - Leibold, NK A1 - van den Hove, DLA A1 - Viechtbauer, W A1 - Buchanan, GF A1 - Goossens, L A1 - Lange, I A1 - Knuts, I A1 - Lesch, KP A1 - Steinbusch, HWM A1 - Schruers, KRJ T1 - CO\(_{2}\) exposure as translational cross-species experimental model for panic JF - Translational Psychiatry N2 - The current diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders are being challenged by the heterogeneity and the symptom overlap of psychiatric disorders. Therefore, a framework toward a more etiology-based classification has been initiated by the US National Institute of Mental Health, the research domain criteria project. The basic neurobiology of human psychiatric disorders is often studied in rodent models. However, the differences in outcome measurements hamper the translation of knowledge. Here, we aimed to present a translational panic model by using the same stimulus and by quantitatively comparing the same outcome measurements in rodents, healthy human subjects and panic disorder patients within one large project. We measured the behavioral–emotional and bodily response to CO\(_{2}\) exposure in all three samples, allowing for a reliable cross-species comparison. We show that CO\(_{2}\) exposure causes a robust fear response in terms of behavior in mice and panic symptom ratings in healthy volunteers and panic disorder patients. To improve comparability, we next assessed the respiratory and cardiovascular response to CO\(_{2}\), demonstrating corresponding respiratory and cardiovascular effects across both species. This project bridges the gap between basic and human research to improve the translation of knowledge between these disciplines. This will allow significant progress in unraveling the etiological basis of panic disorder and will be highly beneficial for refining the diagnostic categories as well as treatment strategies. KW - translational panic model KW - CO\(_{2}\) exposure KW - humans KW - mice KW - panic disorder KW - cross-species comparison KW - fear response Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-168308 VL - 6 IS - e885 ER - TY - JOUR A1 - Berges, Carsten A1 - Kerkau, Thomas A1 - Werner, Sandra A1 - Wolf, Nelli A1 - Winter, Nadine A1 - Hünig, Thomas A1 - Einsele, Hermann A1 - Topp, Max S. A1 - Beyersdorf, Niklas T1 - Hsp90 inhibition ameliorates CD4\(^{+}\) T cell-mediated acute Graft versus Host disease in mice JF - Immunity, Inflammation and Disease N2 - Introduction: For many patients with leukemia only allogeneic bone marrow transplantion provides a chance of cure. Co‐transplanted mature donor T cells mediate the desired Graft versus Tumor (GvT) effect required to destroy residual leukemic cells. The donor T cells very often, however, also attack healthy tissue of the patient inducing acute Graft versus Host Disease (aGvHD)—a potentially life‐threatening complication. Methods: Therefore, we used the well established C57BL/6 into BALB/c mouse aGvHD model to evaluate whether pharmacological inhibition of heat shock protein 90 (Hsp90) would protect the mice from aGvHD. Results: Treatment of the BALB/c recipient mice from day 0 to +2 after allogeneic CD4\(^{+}\) T cell transplantation with the Hsp90 inhibitor 17‐(dimethylaminoethylamino)‐17‐demethoxygeldanamycin (DMAG) partially protected the mice from aGvHD. DMAG treatment was, however, insufficient to prolong overall survival of leukemia‐bearing mice after transplantation of allogeneic CD4\(^{+}\) and CD8\(^{+}\) T cells. Ex vivo analyses and in vitro experiments revealed that DMAG primarily inhibits conventional CD4\(^{+}\) T cells with a relative resistance of CD4\(^{+}\) regulatory and CD8\(^{+}\) T cells toward Hsp90 inhibition. Conclusions: Our data, thus, suggest that Hsp90 inhibition might constitute a novel approach to reduce aGvHD in patients without abrogating the desired GvT effect. KW - Hsp90 KW - leukemia KW - acute Graft versus Host Disease KW - Graft versus Tumor Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-168318 VL - 4 IS - 4 ER - TY - JOUR A1 - Reynolds, David L. A1 - Hofmeister, Brigitte T. A1 - Cliffe, Laura A1 - Siegel, T. Nicolai A1 - Andersson, Britta A. A1 - Beverley, Stephen M. A1 - Schmitz, Robert J. A1 - Sabatini, Robert T1 - Base J represses genes at the end of polycistronic gene clusters in Leishmania major by promoting RNAP II termination JF - Molecular Microbiology N2 - The genomes of kinetoplastids are organized into polycistronic gene clusters that are flanked by the modified DNA base J. Previous work has established a role of base J in promoting RNA polymerase II termination in Leishmania spp. where the loss of J leads to termination defects and transcription into adjacent gene clusters. It remains unclear whether these termination defects affect gene expression and whether read through transcription is detrimental to cell growth, thus explaining the essential nature of J. We now demonstrate that reduction of base J at specific sites within polycistronic gene clusters in L. major leads to read through transcription and increased expression of downstream genes in the cluster. Interestingly, subsequent transcription into the opposing polycistronic gene cluster does not lead to downregulation of sense mRNAs. These findings indicate a conserved role for J regulating transcription termination and expression of genes within polycistronic gene clusters in trypanosomatids. In contrast to the expectations often attributed to opposing transcription, the essential nature of J in Leishmania spp. is related to its role in gene repression rather than preventing transcriptional interference resulting from read through and dual strand transcription. KW - Trypanosoma-brucei KW - Transcription initiation KW - Messenger RNA KW - DNA KW - Genome KW - Cruzi KW - Hydroxymethyluracil KW - Expression KW - Parasite KW - Glucosyltransferase Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187727 VL - 101 IS - 4 ER - TY - JOUR A1 - Maiellaro, Isabella A1 - Lohse, Martin J. A1 - Kitte, Robert J. A1 - Calebiro, Davide T1 - cAMP Signals in Drosophila Motor Neurons Are Confined to Single Synaptic Boutons JF - Cell Reports N2 - The second messenger cyclic AMP (cAMP) plays an important role in synaptic plasticity. Although there is evidence for local control of synaptic transmission and plasticity, it is less clear whether a similar spatial confinement of cAMP signaling exists. Here, we suggest a possible biophysical basis for the site-specific regulation of synaptic plasticity by cAMP, a highly diffusible small molecule that transforms the physiology of synapses in a local and specific manner. By exploiting the octopaminergic system of Drosophila, which mediates structural synaptic plasticity via a cAMP-dependent pathway, we demonstrate the existence of local cAMP signaling compartments of micrometer dimensions within single motor neurons. In addition, we provide evidence that heterogeneous octopamine receptor localization, coupled with local differences in phosphodiesterase activity, underlies the observed differences in cAMP signaling in the axon, cell body, and boutons. KW - cAMP KW - synaptic plasticity KW - PDE KW - octopamine KW - FRET KW - active zone KW - dunce KW - GPCR Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-162324 VL - 17 IS - 5 ER - TY - JOUR A1 - Siegmund, Daniela A1 - Kums, Juliane A1 - Ehrenschwender, Martin A1 - Wajant, Harald T1 - Activation of TNFR2 sensitizes macrophages for TNFR1-mediated necroptosis JF - Cell Death & Disease N2 - Macrophages express TNFR1 as well as TNFR2 and are also major producers of tumor necrosis factor (TNF), especially upon contact with pathogen-associated molecular patterns. Consequently, TNF not only acts as a macrophage-derived effector molecule but also regulates the activity and viability of macrophages. Here, we investigated the individual contribution of TNFR1 and TNFR2 to TNF-induced cell death in macrophages. Exclusive stimulation of TNFR1 showed no cytotoxic effect whereas selective stimulation of TNFR2 displayed mild cytotoxicity. Intriguingly, the latter was strongly enhanced by the caspase inhibitor zVAD-fmk. The strong cytotoxic activity of TNFR2 in the presence of zVAD-fmk was reversed by necrostatin-1, indicating necroptotic cell death. TNFR1- and TNF-deficient macrophages turned out to be resistant against TNFR2-induced cell death. In addition, the cIAP-depleting SMAC mimetic BV6 also enforced TNF/TNFR1-mediated necroptotic cell death in the presence of zVAD-fmk. In sum, our data suggest a model in which TNFR2 sensitizes macrophages for endogenous TNF-induced TNFR1-mediated necroptosis by the known ability of TNFR2 to interfere with the survival activity of TRAF2-cIAP1/2 complexes. KW - TNFR2 Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-162317 VL - 7 ER - TY - JOUR A1 - Robertson, Kevin A. A1 - Hsieh, Wei Yuan A1 - Forster, Thorsten A1 - Blanc, Mathieu A1 - Lu, Hongjin A1 - Crick, Peter J. A1 - Yutuc, Eylan A1 - Watterson, Steven A1 - Martin, Kimberly A1 - Griffiths, Samantha J. A1 - Enright, Anton J. A1 - Yamamoto, Mami A1 - Pradeepa, Madapura M. A1 - Lennox, Kimberly A. A1 - Behlke, Mark A. A1 - Talbot, Simon A1 - Haas, Jürgen A1 - Dölken, Lars A1 - Griffiths, William J. A1 - Wang, Yuqin A1 - Angulo, Ana A1 - Ghazal, Peter T1 - An Interferon Regulated MicroRNA Provides Broad Cell-Intrinsic Antiviral Immunity through Multihit Host-Directed Targeting of the Sterol Pathway JF - PLoS Biology N2 - In invertebrates, small interfering RNAs are at the vanguard of cell-autonomous antiviral immunity. In contrast, antiviral mechanisms initiated by interferon (IFN) signaling predominate in mammals. Whilst mammalian IFN-induced miRNA are known to inhibit specific viruses, it is not known whether host-directed microRNAs, downstream of IFN-signaling, have a role in mediating broad antiviral resistance. By performing an integrative, systematic, global analysis of RNA turnover utilizing 4-thiouridine labeling of newly transcribed RNA and pri/pre-miRNA in IFN-activated macrophages, we identify a new post-transcriptional viral defense mechanism mediated by miR-342-5p. On the basis of ChIP and site-directed promoter mutagenesis experiments, we find the synthesis of miR-342-5p is coupled to the antiviral IFN response via the IFN-induced transcription factor, IRF1. Strikingly, we find miR-342-5p targets mevalonate-sterol biosynthesis using a multihit mechanism suppressing the pathway at different functional levels: transcriptionally via SREBF2, post-transcriptionally via miR-33, and enzymatically via IDI1 and SC4MOL. Mass spectrometry-based lipidomics and enzymatic assays demonstrate the targeting mechanisms reduce intermediate sterol pathway metabolites and total cholesterol in macrophages. These results reveal a previously unrecognized mechanism by which IFN regulates the sterol pathway. The sterol pathway is known to be an integral part of the macrophage IFN antiviral response, and we show that miR-342-5p exerts broad antiviral effects against multiple, unrelated pathogenic viruses such Cytomegalovirus and Influenza A (H1N1). Metabolic rescue experiments confirm the specificity of these effects and demonstrate that unrelated viruses have differential mevalonate and sterol pathway requirements for their replication. This study, therefore, advances the general concept of broad antiviral defense through multihit targeting of a single host pathway. KW - microRNA KW - sterol pathway KW - multihit targeting KW - interferon signaling Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166666 VL - 14 IS - 3 ER - TY - JOUR A1 - Klement, Rainer J. A1 - Champ, Colin E. A1 - Otto, Christoph A1 - Kämmerer, Ulrike T1 - Anti-Tumor Effects of Ketogenic Diets in Mice: A Meta-Analysis JF - PLoS ONE N2 - Background Currently ketogenic diets (KDs) are hyped as an anti-tumor intervention aimed at exploiting the metabolic abnormalities of cancer cells. However, while data in humans is sparse, translation of murine tumor models to the clinic is further hampered by small sample sizes, heterogeneous settings and mixed results concerning tumor growth retardation. The aim was therefore to synthesize the evidence for a growth inhibiting effect of KDs when used as a monotherapy in mice. Methods We conducted a Bayesian random effects meta-analysis on all studies assessing the survival (defined as the time to reach a pre-defined endpoint such as tumor volume) of mice on an unrestricted KD compared to a high carbohydrate standard diet (SD). For 12 studies meeting the inclusion criteria either a mean survival time ratio (MR) or hazard ratio (HR) between the KD and SD groups could be obtained. The posterior estimates for the MR and HR averaged over four priors on the between-study heterogeneity τ\(^{2}\) were MR = 0.85 (95% highest posterior density interval (HPDI) = [0.73, 0.97]) and HR = 0.55 (95% HPDI = [0.26, 0.87]), indicating a significant overall benefit of the KD in terms of prolonged mean survival times and reduced hazard rate. All studies that used a brain tumor model also chose a late starting point for the KD (at least one day after tumor initiation) which accounted for 26% of the heterogeneity. In this subgroup the KD was less effective (MR = 0.89, 95% HPDI = [0.76, 1.04]). Conclusions There was an overall tumor growth delaying effect of unrestricted KDs in mice. Future experiments should aim at differentiating the effects of KD timing versus tumor location, since external evidence is currently consistent with an influence of both of these factors. KW - anti-tumor effects KW - ketogenic dients KW - mice Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167036 VL - 11 IS - 5 ER - TY - JOUR A1 - Steigerwald, Frank A1 - Müller, Lorenz A1 - Johannes, Silvia A1 - Matthies, Cordula A1 - Volkmann, Jens T1 - Directional deep brain stimulation of the subthalamic nucleus: a pilot study using a novel neurostimulation device JF - Movement Disorders N2 - Introduction A novel neurostimulation system allows steering current in horizontal directions by combining segmented leads and multiple independent current control. The aim of this study was to evaluate directional DBS effects on parkinsonian motor features and adverse effects of subthalamic neurostimulation. Methods Seven PD patients implanted with the novel directional DBS system for bilateral subthalamic DBS underwent an extended monopolar review session during the first postoperative week, in which current thresholds were determined for rigidity control and stimulation-induced adverse effects using either directional or ring-mode settings. Results Effect or adverse effect thresholds were modified by directional settings for each of the 14 STN leads. Magnitude of change varied markedly between leads, as did orientation of optimal horizontal current steering. Conclusion Directional current steering through chronically implanted segmented electrodes is feasible, alters adverse effect and efficacy thresholds in a highly individual manner, and expands the therapeutic window in a monopolar review as compared to ring-mode DBS. KW - deep brain stimulation KW - Parkinson's disease Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187683 VL - 31 IS - 8 ER - TY - JOUR A1 - Horikiri, Tomoyuki A1 - Yamaguchi, Makoto A1 - Kamide, Kenji A1 - Matsuo, Yasuhiro A1 - Byrnes, Tim A1 - Ishida, Natsuko A1 - Löffler, Andreas A1 - Höfling, Sven A1 - Shikano, Yutaka A1 - Ogawa, Tetsuo A1 - Forchel, Alfred A1 - Yamamoto, Yoshihisa T1 - High-energy side-peak emission of exciton-polariton condensates in high density regime JF - Scientific Reports N2 - In a standard semiconductor laser, electrons and holes recombine via stimulated emission to emit coherent light, in a process that is far from thermal equilibrium. Exciton-polariton condensates–sharing the same basic device structure as a semiconductor laser, consisting of quantum wells coupled to a microcavity–have been investigated primarily at densities far below the Mott density for signatures of Bose-Einstein condensation. At high densities approaching the Mott density, exciton-polariton condensates are generally thought to revert to a standard semiconductor laser, with the loss of strong coupling. Here, we report the observation of a photoluminescence sideband at high densities that cannot be accounted for by conventional semiconductor lasing. This also differs from an upper-polariton peak by the observation of the excitation power dependence in the peak-energy separation. Our interpretation as a persistent coherent electron-hole-photon coupling captures several features of this sideband, although a complete understanding of the experimental data is lacking. A full understanding of the observations should lead to a development in non-equilibrium many-body physics. KW - side-peak emission KW - exciton-polariton condensates KW - standard semiconductor laser Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167711 VL - 6 IS - 25655 ER - TY - JOUR A1 - Canessa, Andrea A1 - Pozzi, Nicolò G. A1 - Arnulfo, Gabriele A1 - Brumberg, Joachim A1 - Reich, Martin M. A1 - Pezzoli, Gianni A1 - Ghilardi, Maria F. A1 - Matthies, Cordula A1 - Steigerwald, Frank A1 - Volkmann, Jens A1 - Isaias, Ioannis U. T1 - Striatal Dopaminergic Innervation Regulates Subthalamic Beta-Oscillations and Cortical-Subcortical Coupling during Movements: Preliminary Evidence in Subjects with Parkinson's Disease JF - Frontiers in Human Neuroscience N2 - Activation of the basal ganglia has been shown during the preparation and execution of movement. However, the functional interaction of cortical and subcortical brain areas during movement and the relative contribution of dopaminergic striatal innervation remains unclear. We recorded local field potential (LFP) activity from the subthalamic nucleus (STN) and high-density electroencephalography (EEG) signals in four patients with Parkinson’s disease (PD) off dopaminergic medication during a multi-joint motor task performed with their dominant and non-dominant hand. Recordings were performed by means of a fully-implantable deep brain stimulation (DBS) device at 4 months after surgery. Three patients also performed a single-photon computed tomography (SPECT) with [123I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane (FP-CIT) to assess striatal dopaminergic innervation. Unilateral movement execution led to event-related desynchronization (ERD) followed by a rebound after movement termination event-related synchronization (ERS) of oscillatory beta activity in the STN and primary sensorimotor cortex of both hemispheres. Dopamine deficiency directly influenced movement-related beta-modulation, with greater beta-suppression in the most dopamine-depleted hemisphere for both ipsi- and contralateral hand movements. Cortical-subcortical, but not interhemispheric subcortical coherencies were modulated by movement and influenced by striatal dopaminergic innervation, being stronger in the most dopamine-depleted hemisphere. The data are consistent with a role of dopamine in shielding subcortical structures from an excessive cortical entrapment and cross-hemispheric coupling, thus allowing fine-tuning of movement. KW - beta oscillations KW - Parkinson’s disease KW - motor control KW - movement disorders KW - imaging KW - subthalamic nucleus KW - coherence analysis Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164061 VL - 10 IS - 611 ER - TY - JOUR A1 - Banales, Jesus M. A1 - Cardinale, Vincenzo A1 - Carpino, Guido A1 - Marzioni, Marco A1 - Andersen, Jesper B. A1 - Invernizzi, Pietro A1 - Lind, Guro E. A1 - Folseraas, Trine A1 - Forbes, Stuart J. A1 - Fouassier, Laura A1 - Geier, Andreas A1 - Calvisi, Diego F. A1 - Mertens, Joachim C. A1 - Trauner, Michael A1 - Benedetti, Antonio A1 - Maroni, Luca A1 - Vaquero, Javier A1 - Macias, Rocio I. R. A1 - Raggi, Chiara A1 - Perugorria, Maria J. A1 - Gaudio, Eugenio A1 - Boberg, Kirsten M. A1 - Marin, Jose J. G. A1 - Alvaro, Domenico T1 - Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA) JF - Nature Reviews Gastroenterology & Hepatology N2 - Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies with features of biliary tract differentiation. CCA is the second most common primary liver tumour and the incidence is increasing worldwide. CCA has high mortality owing to its aggressiveness, late diagnosis and refractory nature. In May 2015, the "European Network for the Study of Cholangiocarcinoma" (ENS-CCA: www.enscca.org or www.cholangiocarcinoma.eu) was created to promote and boost international research collaboration on the study of CCA at basic, translational and clinical level. In this Consensus Statement, we aim to provide valuable information on classifications, pathological features, risk factors, cells of origin, genetic and epigenetic modifications and current therapies available for this cancer. Moreover, future directions on basic and clinical investigations and plans for the ENS-CCA are highlighted. KW - primary sclerosing cholangitis KW - growth-factor-receptor KW - biliary-tract cancer KW - epithelial-mesenchymal transition KW - fine-needle-aspiration KW - human intrahepatic cholangiocarcinoma KW - induce cyclooxygenase-2 expression KW - human cholangiocellular carcinoma KW - nucleoside transporter KW - hepatic stellate cells Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-189077 VL - 13 IS - 5 ER - TY - JOUR A1 - Lenders, Malte A1 - Hennermann, Julia B. A1 - Kurschat, Christine A1 - Rolfs, Arndt A1 - Canaan-Kühl, Sima A1 - Sommer, Claudia A1 - Üçeyler, Nurcan A1 - Kampmann, Christoph A1 - Karabul, Nesrin A1 - Giese, Anne-Katrin A1 - Duning, Thomas A1 - Stypmann, Jörg A1 - Krämer, Johannes A1 - Weidemann, Frank A1 - Brand, Stefan-Martin A1 - Wanner, Christoph A1 - Brand, Eva T1 - Multicenter Female Fabry Study (MFFS) - clinical survey on current treatment of females with Fabry disease JF - Orphanet Journal of Rare Diseases N2 - Background The aim of the present study was to assess manifestations of and applied treatment concepts for females with Fabry disease (FD) according to the current European Fabry Guidelines. Methods Between 10/2008 and 12/2014, data from the most recent visit of 261 adult female FD patients from six German Fabry centers were retrospectively analyzed. Clinical presentation and laboratory data, including plasma lyso-Gb3 levels were assessed. Results Fifty-five percent of females were on enzyme replacement therapy (ERT), according to recent European FD guidelines. Thirty-three percent of females were untreated although criteria for ERT initiation were fulfilled. In general, the presence of left ventricular hypertrophy (LVH) seemed to impact more on ERT initiation than impaired renal function. In ERT-naïve females RAAS blockers were more often prescribed if LVH was present rather than albuminuria. Affected females with missense mutations showed a similar disease burden compared to females with nonsense mutations. Elevated plasma lyso-Gb3 levels in ERT-naïve females seem to be a marker of disease burden, since patients showed comparable incidences of organ manifestations even if they were ~8 years younger than females with normal lyso-Gb3 levels. Conclusion The treatment of the majority of females with FD in Germany is in line with the current European FD guidelines. However, a relevant number of females remain untreated despite organ involvement, necessitating a careful reevaluation of these females. KW - Fabry disease KW - females KW - lyso-Gb3 KW - enzyme replacement therapy KW - guidelines Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166543 VL - 11 IS - 88 ER - TY - JOUR A1 - Schupp, Nicole A1 - Stopper, Helga A1 - Heidland, August T1 - DNA Damage in Chronic Kidney Disease: Evaluation of Clinical Biomarkers JF - Oxidative Medicine and Cellular Longevity N2 - Patients with chronic kidney disease (CKD) exhibit an increased cancer risk compared to a healthy control population. To be able to estimate the cancer risk of the patients and to assess the impact of interventional therapies thereon, it is of particular interest to measure the patients’ burden of genomic damage. Chromosomal abnormalities, reduced DNA repair, and DNA lesions were found indeed in cells of patients with CKD. Biomarkers for DNA damage measurable in easily accessible cells like peripheral blood lymphocytes are chromosomal aberrations, structural DNA lesions, and oxidatively modified DNA bases. In this review the most common methods quantifying the three parameters mentioned above, the cytokinesis-block micronucleus assay, the comet assay, and the quantification of 8-oxo-7,8-dihydro-2′-deoxyguanosine, are evaluated concerning the feasibility of the analysis and regarding the marker’s potential to predict clinical outcomes. KW - chronic kidney disease KW - cancer risk KW - DNA damage KW - biomarkers Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166569 VL - 2016 IS - 3592042 ER - TY - JOUR A1 - Ahmed, Zeeshan A1 - Zeeshan, Saman A1 - Dandekar, Thomas T1 - Mining biomedical images towards valuable information retrieval in biomedical and life sciences JF - Database - The Journal of Biological Databases and Curation N2 - Biomedical images are helpful sources for the scientists and practitioners in drawing significant hypotheses, exemplifying approaches and describing experimental results in published biomedical literature. In last decades, there has been an enormous increase in the amount of heterogeneous biomedical image production and publication, which results in a need for bioimaging platforms for feature extraction and analysis of text and content in biomedical images to take advantage in implementing effective information retrieval systems. In this review, we summarize technologies related to data mining of figures. We describe and compare the potential of different approaches in terms of their developmental aspects, used methodologies, produced results, achieved accuracies and limitations. Our comparative conclusions include current challenges for bioimaging software with selective image mining, embedded text extraction and processing of complex natural language queries. KW - humans KW - software KW - image processing KW - animals KW - computer-assisted KW - data mining/methods KW - natural language processing Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-162697 VL - 2016 ER - TY - JOUR A1 - Paknia, Elham A1 - Chari, Ashwin A1 - Stark, Holger A1 - Fischer, Utz T1 - The Ribosome Cooperates with the Assembly Chaperone pICln to Initiate Formation of snRNPs JF - Cell Reports N2 - The formation of macromolecular complexes within the crowded environment of cells often requires aid from assembly chaperones. PRMT5 and SMN complexes mediate this task for the assembly of the common core of pre-mRNA processing small nuclear ribonucleoprotein particles (snRNPs). Core formation is initiated by the PRMT5-complex subunit pICln, which pre-arranges the core proteins into spatial positions occupied in the assembled snRNP. The SMN complex then accepts these pICln-bound proteins and unites them with small nuclear RNA (snRNA). Here, we have analyzed how newly synthesized snRNP proteins are channeled into the assembly pathway to evade mis-assembly. We show that they initially remain bound to the ribosome near the polypeptide exit tunnel and dissociate upon association with pICln. Coincident with its release activity, pICln ensures the formation of cognate heterooligomers and their chaperoned guidance into the assembly pathway. Our study identifies the ribosomal quality control hub as a site where chaperone-mediated assembly of macromolecular complexes can be initiated. KW - ribosome KW - snRNPs KW - assembly chaperone KW - pICln Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-162420 VL - 16 IS - 12 ER - TY - JOUR A1 - Bert, Bettina A1 - Chmielewska, Justyna A1 - Bergmann, Sven A1 - Busch, Maximilian A1 - Driever, Wolfgang A1 - Finger-Baier, Karin A1 - Hößler, Johanna A1 - Köhler, Almut A1 - Leich, Nora A1 - Misgeld, Thomas A1 - Nöldner, Torsten A1 - Reiher, Annegret A1 - Schartl, Manfred A1 - Seebach-Sproedt, Anja A1 - Thumberger, Thomas A1 - Schönfelder, Gilbert A1 - Grune, Barbara T1 - Considerations for a European animal welfare standard to evaluate adverse phenotypes in teleost fish JF - The EMBO Journal N2 - No abstract available. KW - Danio-rerio KW - Zebrafish KW - Pain Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188783 VL - 35 IS - 11 ER - TY - JOUR A1 - Neufang, S. A1 - Akhrif, A. A1 - Herrmann, C.G. A1 - Drepper, C. A1 - Homola, G.A. A1 - Nowak, J. A1 - Waider, J. A1 - Schmitt, A.G. A1 - Lesch, K.-P. A1 - Romanos, M. T1 - Serotonergic modulation of 'waiting impulsivity' is mediated by the impulsivity phenotype in humans JF - Translational Psychiatry N2 - In rodents, the five-choice serial reaction time task (5-CSRTT) has been established as a reliable measure of waiting impulsivity being defined as the ability to regulate a response in anticipation of reinforcement. Key brain structures are the nucleus accumbens (NAcc) and prefrontal regions (for example, pre- and infralimbic cortex), which are, together with other transmitters, modulated by serotonin. In this functional magnetic resonance imaging study, we examined 103 healthy males while performing the 5-CSRTT measuring brain activation in humans by means of a paradigm that has been widely applied in rodents. Subjects were genotyped for the tryptophan hydroxylase-2 (TPH2; G-703T; rs4570625) variant, an enzyme specific for brain serotonin synthesis. We addressed neural activation patterns of waiting impulsivity and the interaction between the NAcc and the ventromedial prefrontal cortex (vmPFC) using dynamic causal modeling. Genetic influence was examined via interaction analyses between the TPH2 genotype (GG homozygotes vs T allele carriers) and the degree of impulsivity as measured by the 5-CSRTT. We found that the driving input of the vmPFC was reduced in highly impulsive T allele carriers (reflecting a reduced top-down control) in combination with an enhanced response in the NAcc after correct target processing (reflecting an augmented response to monetary reward). Taken together, we found a high overlap of our findings with reports from animal studies in regard to the underlying cognitive processes, the brain regions associated with waiting impulsivity and the neural interplay between the NAcc and vmPFC. Therefore, we conclude that the 5-CSRTT is a promising tool for translational studies. KW - Clinical Genetics Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164418 IS - 6 ER - TY - JOUR A1 - Wandrey, Georg A1 - Wurzel, Joel A1 - Hoffmann, Kyra A1 - Ladner, Tobias A1 - Büchs, Jochen A1 - Meinel, Lorenz A1 - Lühmann, Tessa T1 - Probing unnatural amino acid integration into enhanced green fluorescent protein by genetic code expansion with a high-throughput screening platform JF - Journal of Biological Engineering N2 - Background Genetic code expansion has developed into an elegant tool to incorporate unnatural amino acids (uAA) at predefined sites in the protein backbone in response to an amber codon. However, recombinant production and yield of uAA comprising proteins are challenged due to the additional translation machinery required for uAA incorporation. Results We developed a microtiter plate-based high-throughput monitoring system (HTMS) to study and optimize uAA integration in the model protein enhanced green fluorescence protein (eGFP). Two uAA, propargyl-L-lysine (Plk) and (S)-2-amino-6-((2-azidoethoxy) carbonylamino) hexanoic acid (Alk), were incorporated at the same site into eGFP co-expressing the native PylRS/tRNAPyl CUA pair originating from Methanosarcina barkeri in E. coli. The site-specific uAA functionalization was confirmed by LC-MS/MS analysis. uAA-eGFP production and biomass growth in parallelized E. coli cultivations was correlated to (i) uAA concentration and the (ii) time of uAA addition to the expression medium as well as to induction parameters including the (iii) time and (iv) amount of IPTG supplementation. The online measurements of the HTMS were consolidated by end point-detection using standard enzyme-linked immunosorbent procedures. Conclusion The developed HTMS is powerful tool for parallelized and rapid screening. In light of uAA integration, future applications may include parallelized screening of different PylRS/tRNAPyl CUA pairs as well as further optimization of culture conditions. KW - protein engineering KW - amber codon suppression KW - online monitoring system KW - high-throughput screening KW - unnatural amino acid KW - bio-orthogonal chemistry Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166304 VL - 10 IS - 11 ER - TY - JOUR A1 - Schuster, Ann-Christin A1 - Burghardt, Markus A1 - Alfarhan, Ahmed A1 - Bueno, Amauri A1 - Hedrich, Rainer A1 - Leide, Jana A1 - Thomas, Jacob A1 - Riederer, Markus T1 - Effectiveness of cuticular transpiration barriers in a desert plant at controlling water loss at high temperatures JF - AoB Plants N2 - Maintaining the integrity of the cuticular transpiration barrier even at elevated temperatures is of vital importance especially for hot-desert plants. Currently, the temperature dependence of the leaf cuticular water permeability and its relationship with the chemistry of the cuticles are not known for a single desert plant. This study investigates whether (i) the cuticular permeability of a desert plant is lower than that of species from non-desert habitats, (ii) the temperature-dependent increase of permeability is less pronounced than in those species and (iii) whether the susceptibility of the cuticular permeability barrier to high temperatures is related to the amounts or properties of the cutin or the cuticular waxes. We test these questions with Rhazya stricta using the minimum leaf water vapour conductance (gmin) as a proxy for cuticular water permeability. gmin of R. stricta (5.41 × 10\(^{-5}\) m s\(^{-1}\) at 25 °C) is in the upper range of all existing data for woody species from various non-desert habitats. At the same time, in R. stricta, the effect of temperature (15-50 °C) on gmin (2.4-fold) is lower than in all other species (up to 12-fold). Rhazya stricta is also special since the temperature dependence of gmin does not become steeper above a certain transition temperature. For identifying the chemical and physical foundation of this phenomenon, the amounts and the compositions of cuticular waxes and cutin were determined. The leaf cuticular wax (251.4 μg cm\(^{-2}\)) is mainly composed of pentacyclic triterpenoids (85.2% of total wax) while long-chain aliphatics contribute only 3.4%. In comparison with many other species, the triterpenoid-to-cutin ratio of R. stricta (0.63) is high. We propose that the triterpenoids deposited within the cutin matrix restrict the thermal expansion of the polymer and, thus, prevent thermal damage to the highly ordered aliphatic wax barrier even at high temperatures. KW - conductance KW - triterpenoids KW - aliphatic compounds KW - cuticular transpiration KW - cuticular wax KW - cutin KW - desert KW - minimum KW - plant cuticle KW - temperature KW - transition temperature Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-160963 VL - 8 ER - TY - JOUR A1 - Mavratzakis, Aimee A1 - Herbert, Cornelia A1 - Walla, Peter T1 - Emotional facial expressions evoke faster orienting responses, but weaker emotional responses at neural and behavioural levels compared to scenes: a simultaneous EEG and facial EMG study JF - NeuroImage N2 - In the current study, electroencephalography (EEG) was recorded simultaneously with facial electromyography (fEMG) to determine whether emotional faces and emotional scenes are processed differently at the neural level. In addition, it was investigated whether these differences can be observed at the behavioural level via spontaneous facial muscle activity. Emotional content of the stimuli did not affect early P1 activity. Emotional faces elicited enhanced amplitudes of the face-sensitive N170 component, while its counterpart, the scene-related N100, was not sensitive to emotional content of scenes. At 220-280 ms, the early posterior negativity (EPN) was enhanced only slightly for fearful as compared to neutral or happy faces. However, its amplitudes were significantly enhanced during processing of scenes with positive content, particularly over the right hemisphere. Scenes of positive content also elicited enhanced spontaneous zygomatic activity from 500-750 ms onwards, while happy faces elicited no such changes. Contrastingly, both fearful faces and negative scenes elicited enhanced spontaneous corrugator activity at 500-750 ms after stimulus onset. However, relative to baseline EMG changes occurred earlier for faces (250 ms) than for scenes (500 ms) whereas for scenes activity changes were more pronounced over the whole viewing period. Taking into account all effects, the data suggests that emotional facial expressions evoke faster attentional orienting, but weaker affective neural activity and emotional behavioural responses compared to emotional scenes. KW - Emotion KW - Affective processing KW - Faces and scenes KW - Electroencephalography KW - Spontaneous facial EMG KW - N170 KW - N100 KW - Early posterior negativity Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-191535 VL - 124 IS - Part A ER - TY - JOUR A1 - Diessner, Joachim A1 - Wischnewsky, Manfred A1 - Stüber, Tanja A1 - Stein, Roland A1 - Krockenberger, Mathias A1 - Häusler, Sebastian A1 - Janni, Wolfgang A1 - Kreienberg, Rolf A1 - Blettner, Maria A1 - Schwentner, Lukas A1 - Wöckel, Achim A1 - Bartmann, Catharina T1 - Evaluation of clinical parameters influencing the development of bone metastasis in breast cancer JF - BMC Cancer N2 - Background The development of metastases is a negative prognostic parameter for the clinical outcome of breast cancer. Bone constitutes the first site of distant metastases for many affected women. The purpose of this retrospective multicentre study was to evaluate if and how different variables such as primary tumour stage, biological and histological subtype, age at primary diagnosis, tumour size, the number of affected lymph nodes as well as grading influence the development of bone-only metastases. Methods This retrospective German multicentre study is based on the BRENDA collective and included 9625 patients with primary breast cancer recruited from 1992 to 2008. In this analysis, we investigated a subgroup of 226 patients with bone-only metastases. Association between bone-only relapse and clinico-pathological risk factors was assessed in multivariate models using the tree-building algorithms “exhausted CHAID (Chi-square Automatic Interaction Detectors)” and CART(Classification and Regression Tree), as well as radial basis function networks (RBF-net), feedforward multilayer perceptron networks (MLP) and logistic regression. Results Multivariate analysis demonstrated that breast cancer subtypes have the strongest influence on the development of bone-only metastases (χ2 = 28). 29.9 % of patients with luminal A or luminal B (ABC-patients) and 11.4 % with triple negative BC (TNBC) or HER2-overexpressing tumours had bone-only metastases (p < 0.001). Five different mathematical models confirmed this correlation. The second important risk factor is the age at primary diagnosis. Moreover, BC subcategories influence the overall survival from date of metastatic disease of patients with bone-only metastases. Patients with bone-only metastases and TNBC (p < 0.001; HR = 7.47 (95 % CI: 3.52–15.87) or HER2 overexpressing BC (p = 0.007; HR = 3.04 (95 % CI: 1.36–6.80) have the worst outcome compared to patients with luminal A or luminal B tumours and bone-only metastases. Conclusion The bottom line of different mathematical models is the prior importance of subcategories of breast cancer and the age at primary diagnosis for the appearance of osseous metastases. The primary tumour stage, histological subtype, tumour size, the number of affected lymph nodes, grading and NPI seem to have only a minor influence on the development of bone-only metastases. KW - BRENDA KW - breast cancer KW - bone metastases KW - skeleton KW - breast cancer subtypes Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-161173 VL - 16 IS - 307 ER - TY - JOUR A1 - Estrecho, E. A1 - Gao, T. A1 - Brodbeck, S. A1 - Kamp, M. A1 - Schneider, C. A1 - Höfling, S. A1 - Truscott, A. G. A1 - Ostrovskaya, E. A. T1 - Visualising Berry phase and diabolical points in a quantum exciton-polariton billiard JF - Scientific Reports N2 - Diabolical points (spectral degeneracies) can naturally occur in spectra of two-dimensional quantum systems and classical wave resonators due to simple symmetries. Geometric Berry phase is associated with these spectral degeneracies. Here, we demonstrate a diabolical point and the corresponding Berry phase in the spectrum of hybrid light-matter quasiparticles—exciton-polaritons in semiconductor microcavities. It is well known that sufficiently strong optical pumping can drive exciton-polaritons to quantum degeneracy, whereby they form a macroscopically populated quantum coherent state similar to a Bose-Einstein condensate. By pumping a microcavity with a spatially structured light beam, we create a two-dimensional quantum billiard for the exciton-polariton condensate and demonstrate a diabolical point in the spectrum of the billiard eigenstates. The fully reconfigurable geometry of the potential walls controlled by the optical pump enables a striking experimental visualization of the Berry phase associated with the diabolical point. The Berry phase is observed and measured by direct imaging of the macroscopic exciton-polariton probability densities. KW - Berry phase KW - diabolical points KW - quantum billiard KW - exciton-polariton Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167496 VL - 6 IS - 37653 ER - TY - JOUR A1 - Han, Yanshuo A1 - Tanios, Fadwa A1 - Reeps, Christian A1 - Zhang, Jian A1 - Schwamborn, Kristina A1 - Eckstein, Hans-Henning A1 - Zernecke, Alma A1 - Pelisek, Jaroslav T1 - Histone acetylation and histone acetyltransferases show significant alterations in human abdominal aortic aneurysm JF - Clinical Epigenetics N2 - Background Epigenetic modifications may play a relevant role in the pathogenesis of human abdominal aortic aneurysm (AAA). The aim of the study was therefore to investigate histone acetylation and expression of corresponding lysine [K] histone acetyltransferases (KATs) in AAA. Results A comparative study of AAA tissue samples (n = 37, open surgical intervention) and healthy aortae (n = 12, trauma surgery) was performed using quantitative PCR, immunohistochemistry (IHC), and Western blot. Expression of the KAT families GNAT (KAT2A, KAT2B), p300/CBP (KAT3A, KAT3B), and MYST (KAT5, KAT6A, KAT6B, KAT7, KAT8) was significantly higher in AAA than in controls (P ≤ 0.019). Highest expression was observed for KAT2B, KAT3A, KAT3B, and KAT6B (P ≤ 0.007). Expression of KAT2B significantly correlated with KAT3A, KAT3B, and KAT6B (r = 0.705, 0.564, and 0.528, respectively, P < 0.001), and KAT6B with KAT3A, KAT3B, and KAT6A (r = 0.407, 0.500, and 0.531, respectively, P < 0.05). Localization of highly expressed KAT2B, KAT3B, and KAT6B was further characterized by immunostaining. Significant correlations were observed between KAT2B with endothelial cells (ECs) (r = 0.486, P < 0.01), KAT3B with T cells and macrophages, (r = 0.421 and r = 0.351, respectively, P < 0.05), KAT6A with intramural ECs (r = 0.541, P < 0.001) and with a contractile phenotype of smooth muscle cells (SMCs) (r = 0.425, P < 0.01), and KAT6B with T cells (r = 0.553, P < 0.001). Furthermore, KAT2B was associated with AAA diameter (r = 0.382, P < 0.05), and KAT3B, KAT6A, and KAT6B correlated negatively with blood urea nitrogen (r = −0.403, −0.408, −0.478, P < 0.05). In addtion, acetylation of the histone substrates H3K9, H3K18 and H3K14 was increased in AAA compared to control aortae. Conclusions Our results demonstrate that aberrant epigenetic modifications such as changes in the expression of KATs and acetylation of corresponding histones are present in AAA. These findings may provide new insight in the pathomechanism of AAA. KW - acetyltransferases KW - epigenetics KW - AAA KW - histone acetylation KW - KAT/HAT Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-162557 VL - 8 IS - 3 ER - TY - JOUR A1 - Moremi, Nyambura A1 - Claus, Heike A1 - Mshana, Stephen E. T1 - Antimicrobial resistance pattern: a report of microbiological cultures at a tertiary hospital in Tanzania JF - BMC Infectious Diseases N2 - Background Antimicrobial resistance has been declared by the World Health Organization as a threat to the public health. The aim of this study was to analyze antimicrobial resistance patterns of the common pathogens occurring at the Bugando Medical Centre (BMC), Mwanza, Tanzania to provide data for antimicrobial stewardship programmes. Methods A total of 3330 microbiological culture results scripts representing non-repetitive specimens reported between June 2013 and May 2015 were retrieved and analyzed for pathogens and their susceptibility patterns using STATA-11 software. Results Out of 3330 specimens, 439 (13.2%) had positive culture. Staphylococcus aureus (n = 100; 22.8%), Klebsiella pneumoniae (n = 65; 14.8%) and Escherichia coli (n = 41; 9.3%) were the most frequently isolated bacteria. Of 78 Staphylococcus aureus tested, 27 (34.6%) were found to be methicillin resistant Staphylococcus aureus (MRSA). Rates of resistance of Klebsiella pneumoniae and Escherichia coli isolates to third generation cephalosporins were 38.5% (25/65) and 29.3% (12/41) respectively. Staphylococcus aureus and Klesbiella pneumoniae were commonly isolated from bloodstream infections while Escherichia coli and Pseudomonas aeruginosa were the predominant isolates from urinary tract and wounds infections respectively. Of 23 Salmonella species isolated, 22 (95%) were recovered from the blood. Nine of the 23 Salmonella species isolates (39%) were found to be resistant to third generation cephalosporins. The resistance rate of gram-negative bacteria to third generation cephalosporins increased from 26.5% in 2014 to 57.9% in 2015 (p = 0.004) while the rate of MRSA decreased from 41.2% in 2013 to 9.5% in 2015 (p = 0.016). Multidrug-resistant gram-negative isolates were commonly isolated from Intensive Care Units and it was noted that, the majority of invasive infections were due to gram-negative bacteria. Conclusion There is an increase in proportion of gram-negative isolates resistant to third generation cephalosporins. The diversity of potential pathogens resistant to commonly prescribed antibiotics underscores the importance of sustained and standardized antimicrobial resistance surveillance and antibiotic stewardship programmes in developing countries. KW - Tanzania KW - antimicrobial resistance KW - cephalosporin-resistant gram-negative bacteria KW - MRSA Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-161185 VL - 16 IS - 756 ER - TY - JOUR A1 - Nickerson, David A1 - Atalag, Koray A1 - de Bono, Bernard A1 - Geiger, Jörg A1 - Goble, Carole A1 - Hollmann, Susanne A1 - Lonien, Joachim A1 - Müller, Wolfgang A1 - Regierer, Babette A1 - Stanford, Natalie J. A1 - Golebiewski, Martin A1 - Hunter, Peter T1 - The Human Physiome: how standards, software and innovative service infrastructures are providing the building blocks to make it achievable JF - Interface Focus N2 - Reconstructing and understanding the Human Physiome virtually is a complex mathematical problem, and a highly demanding computational challenge. Mathematical models spanning from the molecular level through to whole populations of individuals must be integrated, then personalized. This requires interoperability with multiple disparate and geographically separated data sources, and myriad computational software tools. Extracting and producing knowledge from such sources, even when the databases and software are readily available, is a challenging task. Despite the difficulties, researchers must frequently perform these tasks so that available knowledge can be continually integrated into the common framework required to realize the Human Physiome. Software and infrastructures that support the communities that generate these, together with their underlying standards to format, describe and interlink the corresponding data and computer models, are pivotal to the Human Physiome being realized. They provide the foundations for integrating, exchanging and re-using data and models efficiently, and correctly, while also supporting the dissemination of growing knowledge in these forms. In this paper, we explore the standards, software tooling, repositories and infrastructures that support this work, and detail what makes them vital to realizing the Human Physiome. KW - Human Physiome KW - standards KW - repositories KW - service infrastructure KW - reproducible science KW - managing big data Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-189584 VL - 6 IS - 2 ER - TY - JOUR A1 - Kümmel, Reiner T1 - The Impact of Entropy Production and Emission Mitigation on Economic Growth JF - Entropy N2 - Entropy production in industrial economies involves heat currents, driven by gradients of temperature, and particle currents, driven by specific external forces and gradients of temperature and chemical potentials. Pollution functions are constructed for the associated emissions. They reduce the output elasticities of the production factors capital, labor, and energy in the growth equation of the capital-labor-energy-creativity model, when the emissions approach their critical limits. These are drawn by, e.g., health hazards or threats to ecological and climate stability. By definition, the limits oblige the economic actors to dedicate shares of the available production factors to emission mitigation, or to adjustments to the emission-induced changes in the biosphere. Since these shares are missing for the production of the quantity of goods and services that would be available to consumers and investors without emission mitigation, the “conventional” output of the economy shrinks. The resulting losses of conventional output are estimated for two classes of scenarios: (1) energy conservation; and (2) nuclear exit and subsidies to photovoltaics. The data of the scenarios refer to Germany in the 1980s and after 11 March 2011. For the energy-conservation scenarios, a method of computing the reduction of output elasticities by emission abatement is proposed. KW - economic growth KW - entropy production KW - emissions KW - critical limits KW - pollution functions KW - output elasticities Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-163185 VL - 18 IS - 3 ER - TY - JOUR A1 - Kurabi, Arwa A1 - Pak, Kwang K. A1 - Bernhardt, Marlen A1 - Baird, Andrew A1 - Ryan, Allen F. T1 - Discovery of a Biological Mechanism of Active Transport through the Tympanic Membrane to the Middle Ear JF - Scientific Reports N2 - Otitis media (OM) is a common pediatric disease for which systemic antibiotics are often prescribed. While local treatment would avoid the systemic treatment side-effects, the tympanic membrane (TM) represents an impenetrable barrier unless surgically breached. We hypothesized that the TM might harbor innate biological mechanisms that could mediate trans-TM transport. We used two M13-bacteriophage display biopanning strategies to search for mediators of trans-TM transport. First, aliquots of linear phage library displaying 10\(^{10th}\) 12mer peptides were applied on the TM of rats with active bacterial OM. The middle ear (ME) contents were then harvested, amplified and the preparation re-applied for additional rounds. Second, the same naïve library was sequentially screened for phage exhibiting TM binding, internalization and then transit. Results revealed a novel set of peptides that transit across the TM to the ME in a time and temperature dependent manner. The peptides with highest transport capacities shared sequence similarities. Historically, the TM was viewed as an impermeable barrier. However, our studies reveal that it is possible to translocate peptide-linked small particles across the TM. This is the first comprehensive biopanning for the isolation of TM transiting peptidic ligands. The identified mechanism offers a new drug delivery platform into the ME. KW - biological mechanism KW - otitis media KW - tympanic membrane KW - active transport KW - middle ear Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167741 VL - 6 IS - 22663 ER - TY - JOUR A1 - Kuntzen, Thomas A1 - Kuhn, Sereina A1 - Kuntzen, Daniela A1 - Seifert, Burkhardt A1 - Müllhaupt, Beat A1 - Geier, Andreas T1 - Influence of Ribavirin Serum Levels on Outcome of Antiviral Treatment and Anemia in Hepatitis C Virus Infection JF - PLoS ONE N2 - Background Ribavirin blood levels vary considerably between patients with standard weight-based dosing. Their impact on sustained virological response (SVR) with pegylated interferon and ribavirin is controversial, but has mostly been studied before the IL28b gene polymorphism as a possible confounder was discovered. Methods The impact of serum ribavirin trough levels at week 4, at the end of treatment and of mean levels across the entire antiviral treatment with pegylated interferon and ribavirin on relapse, SVR rates and anemia was retrospectively studied by univariate and multivariable logistic regression analyses in 214 patients with HCV genotype 1–4 infection, including 88 patients with available IL28b genotyping. Results Mean ribavirin levels varied between 0.68–5.65 mg/l and significantly differed between patients with or without SVR. By multivariable regression including age, sex, HCV viral load, HCV genotype, liver fibrosis stage, prior treatments, immunosuppression and IL28b genotype, ribavirin levels consistently displayed significant influence on SVR and relapse without indication for a specific importance of higher concentrations early or late in the treatment course. Although hemoglobin decline was on average more pronounced in patients with higher ribavirin levels, hemoglobin remained relatively stable in a significant proportion of these, indicating that ribavirin levels alone are insufficient to predict anemia. Conclusion While data are scarce to draw conclusions applicable for modern DAA therapies, these results support ribavirin treatment based on serum levels instead of purely weight-based dosing in combination with pegylated interferon. KW - ribavirin serum levels KW - antiviral treatment KW - anemia KW - Hepatitis C Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166888 VL - 11 IS - 7 ER - TY - JOUR A1 - Lousada, Cláudio M. A1 - Soroka, Inna L. A1 - Yagodzinskyy, Yuriy A1 - Tarakina, Nadezda V. A1 - Todoshchenko, Olga A1 - Hänninen, Hannu A1 - Korzhavyi, Pavel A. A1 - Jonsson, Mats T1 - Gamma radiation induces hydrogen absorption by copper in water JF - Scientific Reports N2 - One of the most intricate issues of nuclear power is the long-term safety of repositories for radioactive waste. These repositories can have an impact on future generations for a period of time orders of magnitude longer than any known civilization. Several countries have considered copper as an outer corrosion barrier for canisters containing spent nuclear fuel. Among the many processes that must be considered in the safety assessments, radiation induced processes constitute a key-component. Here we show that copper metal immersed in water uptakes considerable amounts of hydrogen when exposed to γ-radiation. Additionally we show that the amount of hydrogen absorbed by copper depends on the total dose of radiation. At a dose of 69 kGy the uptake of hydrogen by metallic copper is 7 orders of magnitude higher than when the absorption is driven by H\(_{2}\)(g) at a pressure of 1 atm in a non-irradiated dry system. Moreover, irradiation of copper in water causes corrosion of the metal and the formation of a variety of surface cavities, nanoparticle deposits, and islands of needle-shaped crystals. Hence, radiation enhanced uptake of hydrogen by spent nuclear fuel encapsulating materials should be taken into account in the safety assessments of nuclear waste repositories. KW - gamma radiation KW - radioactive waste KW - nuclear power KW - repositories KW - safety KW - copper KW - water Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167730 VL - 6 IS - 24234 ER - TY - JOUR A1 - Maarouf, Mohammad A1 - Neudorfer, Clemens A1 - El Majdoub, Faycal A1 - Lenartz, Doris A1 - Kuhn, Jens A1 - Sturm, Volker T1 - Deep Brain Stimulation of Medial Dorsal and Ventral Anterior Nucleus of the Thalamus in OCD: A Retrospective Case Series JF - PLoS ONE N2 - Background The current notion that cortico-striato-thalamo-cortical circuits are involved in the pathophysiology of obsessive-compulsive disorder (OCD) has instigated the search for the most suitable target for deep brain stimulation (DBS). However, despite extensive research, uncertainty about the ideal target remains with many structures being underexplored. The aim of this report is to address a new target for DBS, the medial dorsal (MD) and the ventral anterior (VA) nucleus of the thalamus, which has thus far received little attention in the treatment of OCD. Methods In this retrospective trial, four patients (three female, one male) aged 31–48 years, suffering from therapy-refractory OCD underwent high-frequency DBS of the MD and VA. In two patients (de novo group) the thalamus was chosen as a primary target for DBS, whereas in two patients (rescue DBS group) lead implantation was performed in a rescue DBS attempt following unsuccessful primary stimulation. Results Continuous thalamic stimulation yielded no significant improvement in OCD symptom severity. Over the course of thalamic DBS symptoms improved in only one patient who showed “partial response” on the Yale-Brown Obsessive Compulsive (Y-BOCS) Scale. Beck Depression Inventory scores dropped by around 46% in the de novo group; anxiety symptoms improved by up to 34%. In the de novo DBS group no effect of DBS on anxiety and mood was observable. Conclusion MD/VA-DBS yielded no adequate alleviation of therapy-refractory OCD, the overall strategy in targeting MD/VA as described in this paper can thus not be recommended in DBS for OCD. The magnocellular portion of MD (MDMC), however, might prove a promising target in the treatment of mood related and anxiety disorders. KW - deep brain stimulation KW - obsessive-compulsive disorder Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166830 VL - 11 IS - 8 ER - TY - JOUR A1 - Hellenbrand, Wiebke A1 - Claus, Heike A1 - Schink, Susanne A1 - Marcus, Ulrich A1 - Wichmann, Ole A1 - Vogel, Ulrich T1 - Risk of Invasive Meningococcal Disease in Men Who Have Sex with Men: Lessons Learned from an Outbreak in Germany, 2012-2013 JF - PLoS ONE N2 - Background We undertook investigations in response to an invasive meningococcal disease (IMD) outbreak in men who have sex with men (MSM) in Berlin 2012–2013 to better understand meningococcal transmission and IMD risk in MSM. Methods We retrospectively searched for further IMD cases in MSM in Germany through local health departments and undertook exploratory interviews. We performed antigen sequence typing, characterized fHbp and aniA genes of strains with the outbreak finetype and reviewed epidemiologically or spatiotemporally linked cases from 2002–2014. Results Among the 148 IMD-cases notified from 01.01.2012–30.09.2013 in 18–59 year-old men we identified 13 MSM in 6 federal states: 11 serogroup C (MenC, all finetype C:P1.5–1,10–8:F3-6), 2 MenB. Interviews with 7 MSM revealed frequent meeting of multiple partners online or via mobile apps and illicit drug use as potential risk factors. MenC incidence was 13-fold higher in MSM than non-MSM. MenC isolates from 9/11 MSM had a novel fHbp allele 766. All C:P1.5–1,10–8:F3-6 strains from MSM versus 16/23 from non-MSM had intact aniA genes (p = 0.04). Although definitive evidence for transmission among MSM in epidemiological or spatiotemporal clusters in 2002–2014 was lacking, clusters were more frequent in men aged 20–49 years. Molecular analysis of C:P1.5–1,10–8:F3-6 strains revealed cases with intact aniA since 2007, mainly associated with fHbp361, fHbp766 and fHbp813, all involving one or more MSM. Conclusions MenC incidence was elevated in MSM during the study period. Multiple casual sexual contacts and illicit drug use were common in affected MSM. In all strains from MSM we detected an intact aniA gene coding for a nitrite reductase, which permits survival in microanaerobic environments and could play a role in meningococcal transmission in MSM through urogenital colonization. Furthermore, meningococcal transmission among MSM may be sustained over large areas and thus require modified spatiotemporal scanning algorithms for timely detection and control. KW - invasive meningococcal disease KW - men who have sex with men KW - Germany Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166842 VL - 11 IS - 8 ER - TY - JOUR A1 - Meier, Doreen A1 - Kruse, Janis A1 - Buttlar, Jann A1 - Friedrich, Michael A1 - Zenk, Fides A1 - Boesler, Benjamin A1 - Forstner, Konrad U. A1 - Hammann, Christian A1 - Nellen, Wolfgang T1 - Analysis of the Microprocessor in Dictyostelium: The Role of RbdB, a dsRNA Binding Protein JF - PLoS Genetics N2 - We identified the dsRNA binding protein RbdB as an essential component in miRNA processing in Dictyostelium discoideum. RbdB is a nuclear protein that accumulates, together with Dicer B, in nucleolar foci reminiscent of plant dicing bodies. Disruption of rbdB results in loss of miRNAs and accumulation of primary miRNAs. The phenotype can be rescued by ectopic expression of RbdB thus allowing for a detailed analysis of domain function. The lack of cytoplasmic dsRBD proteins involved in miRNA processing, suggests that both processing steps take place in the nucleus thus resembling the plant pathway. However, we also find features e.g. in the domain structure of Dicer which suggest similarities to animals. Reduction of miRNAs in the rbdB- strain and their increase in the Argonaute A knock out allowed the definition of new miRNAs one of which appears to belong to a new non-canonical class. KW - microprocessor KW - Dictyostelium discoideum KW - dsRNA binding protein KW - RbdB Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166687 VL - 12 IS - 6 ER - TY - JOUR A1 - Gökbuget, N. A1 - Kelsh, M. A1 - Chia, V. A1 - Advani, A. A1 - Bassan, R. A1 - Dombret, H. A1 - Doubek, M. A1 - Fielding, A. K. A1 - Giebel, S. A1 - Haddad, V. A1 - Hoelzer, D. A1 - Holland, C. A1 - Ifrah, N. A1 - Katz, A. A1 - Maniar, T. A1 - Martinelli, G. A1 - Morgades, M. A1 - O'Brien, S. A1 - Ribera, J.-M. A1 - Rowe, J. M. A1 - Stein, A. A1 - Topp, M. A1 - Wadleigh, M. A1 - Kantarjian, H. T1 - Blinatumomab vs historical standard therapy of adult relapsed/refractory acute lymphoblastic leukemia JF - Blood Cancer Journal N2 - We compared outcomes from a single-arm study of blinatumomab in adult patients with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia (R/R ALL) with a historical data set from Europe and the United States. Estimates of complete remission (CR) and overall survival (OS) were weighted by the frequency distribution of prognostic factors in the blinatumomab trial. Outcomes were also compared between the trial and historical data using propensity score methods. The historical cohort included 694 patients with CR data and 1112 patients with OS data compared with 189 patients with CR and survival data in the blinatumomab trial. The weighted analysis revealed a CR rate of 24% (95% CI: 20–27%) and a median OS of 3.3 months (95% CI: 2.8–3.6) in the historical cohort compared with a CR/CRh rate of 43% (95% CI: 36–50%) and a median OS of 6.1 months (95% CI: 4.2–7.5) in the blinatumomab trial. Propensity score analysis estimated increased odds of CR/CRh (OR=2.68, 95% CI: 1.67–4.31) and improved OS (HR=0.536, 95% CI: 0.394–0.730) with blinatumomab. The analysis demonstrates the application of different study designs and statistical methods to compare novel therapies for R/R ALL with historical data. KW - Acute lymphocytic leukaemia KW - Drug development Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164495 VL - 6 ER - TY - JOUR A1 - Kleber, Jörg A1 - Chen, Yi-Chun A1 - Michels, Birgit A1 - Saumweber, Timo A1 - Schleyer, Michael A1 - Kähne, Thilo A1 - Buchner, Erich A1 - Gerber, Bertram T1 - Synapsin is required to "boost" memory strength for highly salient events JF - Learning and Memory N2 - Synapsin is an evolutionarily conserved presynaptic phosphoprotein. It is encoded by only one gene in the Drosophila genome and is expressed throughout the nervous system. It regulates the balance between reserve and releasable vesicles, is required to maintain transmission upon heavy demand, and is essential for proper memory function at the behavioral level. Task-relevant sensorimotor functions, however, remain intact in the absence of Synapsin. Using an odor-sugar reward associative learning paradigm in larval Drosophila, we show that memory scores in mutants lacking Synapsin (syn\(^{97}\)) are lower than in wild-type animals only when more salient, higher concentrations of odor or of the sugar reward are used. Furthermore, we show that Synapsin is selectively required for larval short-term memory. Thus, without Synapsin Drosophila larvae can learn and remember, but Synapsin is required to form memories that match in strength to event salience-in particular to a high saliency of odors, of rewards, or the salient recency of an event. We further show that the residual memory scores upon a lack of Synapsin are not further decreased by an additional lack of the Sap47 protein. In combination with mass spectrometry data showing an up-regulated phosphorylation of Synapsin in the larval nervous system upon a lack of Sap47, this is suggestive of a functional interdependence of Synapsin and Sap47. KW - mushroom body KW - Kenyon cells KW - larval drosophila KW - Sap47 KW - phosphorylation KW - synaptic vesicles KW - short-term memory Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-191440 VL - 23 IS - 1 ER -