TY - JOUR A1 - Aad, G. A1 - Abbott, B. A1 - Abdallah, J. A1 - Abdel Khalek, S. A1 - Abdelalim, A. A. T1 - Search for the Standard Model Higgs boson in the H→WW(⋆)→ℓνℓνH→WW(⋆)→ℓνℓν decay mode with 4.7 fb\(^{−1}\) of ATLAS data at \(\sqrt{s}\)=7 TeV JF - Physics Letters B N2 - A search for the Standard Model Higgs boson in the H→WW(⋆)→ℓνℓνH→WW(⋆)→ℓνℓν (ℓ=e,μℓ=e,μ) decay mode is presented. The search is performed using proton–proton collision data corresponding to an integrated luminosity of 4.7 fb\(^{−1}\) at a centre-of-mass energy of 7 TeV collected during 2011 with the ATLAS detector at the Large Hadron Collider. No significant excess of events over the expected background is observed. An upper bound is placed on the Higgs boson production cross section as a function of its mass. A Standard Model Higgs boson with mass in the range between 133 GeV and 261 GeV is excluded at 95% confidence level, while the expected exclusion range is from 127 GeV to 233 GeV. KW - ATLAS KW - LHC KW - Higgs KW - WW Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-127307 VL - 761 IS - 1 ER - TY - JOUR A1 - Aad, G. A1 - Abbott, B. A1 - Abdallah, J. A1 - Abdelalim, A. A. A1 - Abdesselam, A. T1 - Electron performance measurements with the ATLAS detector using the 2010 LHC proton-proton collision data JF - The European Physical Journal C N2 - Detailed measurements of the electron performance of the ATLAS detector at the LHC are reported, using decays of the Z, W and J/ψ particles. Data collected in 2010 at s√=7 TeV are used, corresponding to an integrated luminosity of almost 40 pb\(^{−1}\). The inter-alignment of the inner detector and the electromagnetic calorimeter, the determination of the electron energy scale and resolution, and the performance in terms of response uniformity and linearity are discussed. The electron identification, reconstruction and trigger efficiencies, as well as the charge misidentification probability, are also presented. KW - electromagnetic calorimeter KW - Atlas detector KW - calorimeter Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-127313 VL - 72 IS - 1909 ER - TY - JOUR A1 - Aad, G. A1 - Abbott, B. A1 - Abdallah, J. A1 - Abdelalim, A. A. A1 - Abdesselam, A. T1 - Performance of the ATLAS Trigger System in 2010 JF - The European Physical Journal C N2 - Proton–proton collisions at √s=7 TeV and heavy ion collisions at \(\sqrt{sNN}\)=2.76 TeV were produced by the LHC and recorded using the ATLAS experiment’s trigger system in 2010. The LHC is designed with a maximum bunch crossing rate of 40 MHz and the ATLAS trigger system is designed to record approximately 200 of these per second. The trigger system selects events by rapidly identifying signatures of muon, electron, photon, tau lepton, jet, and B meson candidates, as well as using global event signatures, such as missing transverse energy. An overview of the ATLAS trigger system, the evolution of the system during 2010 and the performance of the trigger system components and selections based on the 2010 collision data are shown. A brief outline of plans for the trigger system in 2011 is presented. KW - ATLAS KW - Trigger System Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-127321 VL - 72 IS - 1849 ER - TY - JOUR A1 - Aad, G. A1 - Abbott, B. A1 - Abdallah, J. A1 - Abdelalim, A. A. A1 - Abdesselam, A. T1 - Forward-backward correlations and charged-particle azimuthal distributions in pp interactions using the ATLAS detector JF - Journal of High Energy Physics N2 - Using inelastic proton-proton interactions at s√=900 GeV and 7 TeV, recorded by the ATLAS detector at the LHC, measurements have been made of the correlations between forward and backward charged-particle multiplicities and, for the first time, between forward and backward charged-particle summed transverse momentum. In addition, jet-like structure in the events is studied by means of azimuthal distributions of charged particles relative to the charged particle with highest transverse momentum in a selected kinematic region of the event. The results are compared with predictions from tunes of the pythia and herwig++ Monte Carlo generators, which in most cases are found to provide a reasonable description of the data. KW - Hadron-Hadron Scattering Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-127336 VL - 7 IS - 19 ER - TY - JOUR A1 - Abdelmohsen, Usama Ramadan A1 - Szesny, Matthias A1 - Othman, Eman Maher A1 - Schirmeister, Tanja A1 - Grond, Stepanie A1 - Stopper, Helga A1 - Hentschel, Ute T1 - Antioxidant and Anti-Protease Activities of Diazepinomicin from the Sponge-Associated Micromonospora Strain RV115 N2 - Diazepinomicin is a dibenzodiazepine alkaloid with an unusual structure among the known microbial metabolites discovered so far. Diazepinomicin was isolated from the marine sponge-associated strain Micromonospora sp. RV115 and was identified by spectroscopic analysis and by comparison to literature data. In addition to its interesting preclinical broad-spectrum antitumor potential, we report here new antioxidant and anti-protease activities for this compound. Using the ferric reducing antioxidant power (FRAP) assay, a strong antioxidant potential of diazepinomicin was demonstrated. Moreover, diazepinomicin showed a significant antioxidant and protective capacity from genomic damage induced by the reactive oxygen species hydrogen peroxide in human kidney (HK-2) and human promyelocytic (HL-60) cell lines. Additionally, diazepinomicin inhibited the proteases rhodesain and cathepsin L at an IC50 of 70–90 μM. It also showed antiparasitic activity against trypomastigote forms of Trypanosoma brucei with an IC50 of 13.5 μM. These results showed unprecedented antioxidant and anti-protease activities of diazepinomicin, thus further highlighting its potential as a future drug candidate. KW - Biologie KW - diazepinomicin KW - anti-protease KW - antioxidant KW - actinomycetes KW - Micromonospora Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-76279 ER - TY - JOUR A1 - Aeschlimann, Martin A1 - Bauer, Michael A1 - Bayer, Daniela A1 - Brixner, Tobias A1 - Cunovic, Stefan A1 - Fischer, Alexander A1 - Melchior, Pascal A1 - Pfeiffer, Walter A1 - Rohmer, Martin A1 - Schneider, Christian A1 - Strüber, Christian A1 - Tuchscherer, Philip A1 - Voronine, Dimitri V. T1 - Optimal open-loop near-field control of plasmonic nanostructures N2 - Optimal open-loop control, i.e. the application of an analytically derived control rule, is demonstrated for nanooptical excitations using polarization-shaped laser pulses. Optimal spatial near-field localization in gold nanoprisms and excitation switching is realized by applying a shift to the relative phase of the two polarization components. The achieved near-field switching confirms theoretical predictions, proves the applicability of predefined control rules in nanooptical light–matter interaction and reveals local mode interference to be an important control mechanism. KW - Chemie Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75256 ER - TY - JOUR A1 - Agoston, Zsuzsa A1 - Li, Naixin A1 - Haslinger, Anja A1 - Wizenmann, Andrea A1 - Schulte, Dorothea T1 - Genetic and physical interaction of Meis2, Pax3 and Pax7 during dorsal midbrain development JF - BMC Developmental Biology N2 - Background: During early stages of brain development, secreted molecules, components of intracellular signaling pathways and transcriptional regulators act in positive and negative feed-back or feed-forward loops at the mid-hindbrain boundary. These genetic interactions are of central importance for the specification and subsequent development of the adjacent mid-and hindbrain. Much less, however, is known about the regulatory relationship and functional interaction of molecules that are expressed in the tectal anlage after tectal fate specification has taken place and tectal development has commenced. Results: Here, we provide experimental evidence for reciprocal regulation and subsequent cooperation of the paired-type transcription factors Pax3, Pax7 and the TALE-homeodomain protein Meis2 in the tectal anlage. Using in ovo electroporation of the mesencephalic vesicle of chick embryos we show that (i) Pax3 and Pax7 mutually regulate each other's expression in the mesencephalic vesicle, (ii) Meis2 acts downstream of Pax3/7 and requires balanced expression levels of both proteins, and (iii) Meis2 physically interacts with Pax3 and Pax7. These results extend our previous observation that Meis2 cooperates with Otx2 in tectal development to include Pax3 and Pax7 as Meis2 interacting proteins in the tectal anlage. Conclusion: The results described here suggest a model in which interdependent regulatory loops involving Pax3 and Pax7 in the dorsal mesencephalic vesicle modulate Meis2 expression. Physical interaction with Meis2 may then confer tectal specificity to a wide range of otherwise broadly expressed transcriptional regulators, including Otx2, Pax3 and Pax7. KW - dosage KW - quali-chick chimeras KW - drosophila embryo KW - neural crest KW - transcription activation KW - hindbrain boundary KW - isthmic oragnizer KW - sonic hedghog KW - expression KW - induction Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132626 VL - 12 IS - 10 ER - TY - JOUR A1 - Ahmad, Ruhel A1 - Wolber, Wanja A1 - Eckardt, Sigrid A1 - Koch, Philipp A1 - Schmitt, Jessica A1 - Semechkin, Ruslan A1 - Geis, Christian A1 - Heckmann, Manfred A1 - Brüstle, Oliver A1 - McLaughlin, John K. A1 - Sirén, Anna-Leena A1 - Müller, Albrecht M. T1 - Functional Neuronal Cells Generated by Human Parthenogenetic Stem Cells JF - PLoS One N2 - Parent of origin imprints on the genome have been implicated in the regulation of neural cell type differentiation. The ability of human parthenogenetic (PG) embryonic stem cells (hpESCs) to undergo neural lineage and cell type-specific differentiation is undefined. We determined the potential of hpESCs to differentiate into various neural subtypes. Concurrently, we examined DNA methylation and expression status of imprinted genes. Under culture conditions promoting neural differentiation, hpESC-derived neural stem cells (hpNSCs) gave rise to glia and neuron-like cells that expressed subtype-specific markers and generated action potentials. Analysis of imprinting in hpESCs and in hpNSCs revealed that maternal-specific gene expression patterns and imprinting marks were generally maintained in PG cells upon differentiation. Our results demonstrate that despite the lack of a paternal genome, hpESCs generate proliferating NSCs that are capable of differentiation into physiologically functional neuron-like cells and maintain allele-specific expression of imprinted genes. Thus, hpESCs can serve as a model to study the role of maternal and paternal genomes in neural development and to better understand imprinting-associated brain diseases. KW - methylation KW - derivation KW - blastocysts KW - pluripotent KW - differentiation KW - lines KW - brain development KW - in-vitro KW - mice KW - specification Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130268 VL - 7 IS - 8 ER - TY - JOUR A1 - Alb, Miriam A1 - Sie, Christopher A1 - Adam, Christian A1 - Chen, Suzie A1 - Becker, Jürgen C. A1 - Schrama, David T1 - Cellular and cytokine-dependent immunosuppressive mechanisms of grm1-transgenic murine melanoma JF - Cancer Immunology, Immunotherapy N2 - Grm1-transgenic mice spontaneously develop cutaneous melanoma. This model allowed us to scrutinize the generic immune responses over the course of melanoma development. To this end, lymphocytes obtained from spleens, unrelated lymph nodes and tumor-draining lymph nodes of mice with no evidence of disease, and low or high tumor burden were analyzed ex vivo and in vitro. Thereby, we could demonstrate an increase in the number of activated CD4\(^+\) and CD8+ lymphocytes in the respective organs with increasing tumor burden. However, mainly CD4\(^+\) T cells, which could constitute both T helper as well as immunosuppressive regulatory T cells, but not CD8\(^+\) T cells, expressed activation markers upon in vitro stimulation when obtained from tumor-bearing mice. Interestingly, these cells from tumor-burdened animals were also functionally hampered in their proliferative response even when subjected to strong in vitro stimulation. Further analyses revealed that the increased frequency of regulatory T cells in tumor-bearing mice is an early event present in all lymphoid organs. Additionally, expression of the immunosuppressive cytokines TGF-β1 and IL-10 became more evident with increased tumor burden. Notably, TGF-β1 is strongly expressed in both the tumor and the tumor-draining lymph node, whereas IL-10 expression is more pronounced in the lymph node, suggesting a more complex regulation of IL-10. Thus, similar to the situation in melanoma patients, both cytokines as well as cellular immune escape mechanisms seem to contribute to the observed immunosuppressed state of tumor-bearing grm1-transgenic mice, suggesting that this model is suitable for preclinical testing of immunomodulatory therapeutics. KW - regulatory T cell KW - melanoma KW - immune suppression KW - tumor-draining lymph node Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125096 VL - 61 IS - 12 ER - TY - JOUR A1 - Albert-Weissenberger, Christiane A1 - Stetter, Christian A1 - Meuth, Sven G. A1 - Göbel, Kerstin A1 - Bader, Michael A1 - Sirén, Anna-Leena A1 - Kleinschnitz, Christoph T1 - Blocking of Bradykinin Receptor B1 Protects from Focal Closed Head Injury in Mice by Reducing Axonal Damage and Astroglia Activation JF - Journal of Cerebral Blood Flow and Metabolism N2 - The two bradykinin receptors B1R and B2R are central components of the kallikrein–kinin system with different expression kinetics and binding characteristics. Activation of these receptors by kinins triggers inflammatory responses in the target organ and in most situations enhances tissue damage. We could recently show that blocking of B1R, but not B2R, protects from cortical cryolesion by reducing inflammation and edema formation. In the present study, we investigated the role of B1R and B2R in a closed head model of focal traumatic brain injury (TBI; weight drop). Increased expression of B1R in the injured hemispheres of wild-type mice was restricted to the later stages after brain trauma, i.e. day 7 (P<0.05), whereas no significant induction could be observed for the B2R (P>0.05). Mice lacking the B1R, but not the B2R, showed less functional deficits on day 3 (P<0.001) and day 7 (P<0.001) compared with controls. Pharmacological blocking of B1R in wild-type mice had similar effects. Reduced axonal injury and astroglia activation could be identified as underlying mechanisms, while inhibition of B1R had only little influence on the local inflammatory response in this model. Inhibition of B1R may become a novel strategy to counteract trauma-induced neurodegeneration. KW - R-715 KW - kinin receptors KW - closed head injury KW - β-APP KW - astrocytes KW - TNF-α Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125903 VL - 32 IS - 9 ER - TY - JOUR A1 - Albert-Weißenberger, Christiane A1 - Várrallyay, Csanád A1 - Raslan, Furat A1 - Kleinschnitz, Christoph A1 - Sirén, Anna-Leena T1 - An experimental protocol for mimicking pathomechanisms of traumatic brain injury in mice N2 - Traumatic brain injury (TBI) is a result of an outside force causing immediate mechanical disruption of brain tissue and delayed pathogenic events. In order to examine injury processes associated with TBI, a number of rodent models to induce brain trauma have been described. However, none of these models covers the entire spectrum of events that might occur in TBI. Here we provide a thorough methodological description of a straightforward closed head weight drop mouse model to assess brain injuries close to the clinical conditions of human TBI. KW - Medizin KW - closed head injury KW - traumatic brain injury KW - neurobehavioural deficits KW - astrocyte KW - microglia KW - neurons Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75368 ER - TY - JOUR A1 - Amich, Jorge A1 - Krappmann, Sven T1 - Deciphering metabolic traits of the fungal pathogen Aspergillus fumigatus: redundancy vs. essentiality JF - Frontiers in Microbiology N2 - Incidence rates of infections caused by environmental opportunistic fungi have risen over recent decades. Aspergillus species have emerged as serious threat for the immunecompromised, and detailed knowledge about virulence-determining traits is crucial for drug target identification. As a prime saprobe, A. fumigatus has evolved to efficiently adapt to various stresses and to sustain nutritional supply by osmotrophy, which is characterized by extracellular substrate digestion followed by efficient uptake of breakdown products that are then fed into the fungal primary metabolism. These intrinsic metabolic features are believed to be related with its virulence ability. The plethora of genes that encode underlying effectors has hampered their in-depth analysis with respect to pathogenesis. Recent developments in Aspergillus molecular biology allow conditional gene expression or comprehensive targeting of gene families to cope with redundancy. Furthermore, identification of essential genes that are intrinsically connected to virulence opens accurate perspectives for novel targets in antifungal therapy. KW - Aspergillus fumigatus KW - aspergillosis KW - virulence KW - conditional promoter replacement KW - nutrients KW - gene family targeting Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-123669 VL - 3 ER - TY - JOUR A1 - Angheloiu, George O. A1 - Hänscheid, Heribert A1 - Wen, Xiaoyan A1 - Capponi, Vincent A1 - Anderson, William D. A1 - Kellum, John A. T1 - Experimental first-pass method for testing and comparing sorbent polymers used in the clearance of iodine contrast materials JF - Blood Purification N2 - Background: Sorbents have been shown to adsorb iodinated radiocontrast media. Objective: In this study we describe a simple method to compare various sorbents in terms of capacity to adsorb radiocontrast media. Methods: Iodixanol solution was injected into columns filled with three types of sorbent at filtration velocities of increasing magnitude. Two variables of interest – contrast removal rate and matched iodine retention (MIR) – were calculated to measure the adsorption efficiency and the mass of contrast iodine adsorbed versus sorbent used, respectively. Results: The highest contrast removal and MIR for Porapak Q, CST 401 and Amberlite XAD4 were 41, 38 and 16% (p = 0.22 and 0.0005 for comparisons between Porapak Q-CST 401 and CST 401-Amberlite XAD4) and 0.060, 0.055 and 0.024, respectively (p = 0.18 and 0.0008). Extrapolation to a clinical scenario may suggest that removal of 8 ml iodixanol could be achieved by masses of sorbents of 43, 47 and 107 g, respectively. Conclusion: In this study we set a benchmark for comparing the radiocontrast-adsorbing efficiency of polymer sorbents during first-pass experiments, using a readily available methodology. KW - adsorption KW - acute renal failure KW - sorbents KW - iodine contrast Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-199118 SN - 0253-5068 SN - 1421-9735 N1 - Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich. VL - 34 IS - 1 ER - TY - JOUR A1 - Antoniou, Antonis C. A1 - Kuchenbaecker, Karoline B. A1 - Soucy, Penny A1 - Beesley, Jonathan A1 - Chen, Xiaoqing A1 - McGuffog, Lesley A1 - Lee, Andrew A1 - Barrowdale, Daniel A1 - Healey, Sue A1 - Sinilnikova, Olga M. A1 - Caligo, Maria A. A1 - Loman, Niklas A1 - Harbst, Katja A1 - Lindblom, Annika A1 - Arver, Brita A1 - Rosenquist, Richard A1 - Karlsson, Per A1 - Nathanson, Kate A1 - Domchek, Susan A1 - Rebbeck, Tim A1 - Jakubowska, Anna A1 - Lubinski, Jan A1 - Jaworska, Katarzyna A1 - Durda, Katarzyna A1 - Zlowowcka-Perłowska, Elżbieta A1 - Osorio, Ana A1 - Durán, Mercedes A1 - Andrés, Raquel A1 - Benítez, Javier A1 - Hamann, Ute A1 - Hogervorst, Frans B. A1 - van Os, Theo A. A1 - Verhoef, Senno A1 - Meijers-Heijboer, Hanne E. J. A1 - Wijnen, Juul A1 - Garcia, Encarna B. Gómez A1 - Ligtenberg, Marjolijn J. A1 - Kriege, Mieke A1 - Collée, Margriet A1 - Ausems, Margreet G. E. M. A1 - Oosterwijk, Jan C. A1 - Peock, Susan A1 - Frost, Debra A1 - Ellis, Steve D. A1 - Platte, Radka A1 - Fineberg, Elena A1 - Evans, D. Gareth A1 - Lalloo, Fiona A1 - Jacobs, Chris A1 - Eeles, Ros A1 - Adlard, Julian A1 - Davidson, Rosemarie A1 - Cole, Trevor A1 - Cook, Jackie A1 - Paterson, Joan A1 - Douglas, Fiona A1 - Brewer, Carole A1 - Hodgson, Shirley A1 - Morrison, Patrick J. A1 - Walker, Lisa A1 - Rogers, Mark T. A1 - Donaldson, Alan A1 - Dorkins, Huw A1 - Godwin, Andrew K. A1 - Bove, Betsy A1 - Stoppa-Lyonnet, Dominique A1 - Houdayer, Claude A1 - Buecher, Bruno A1 - de Pauw, Antoine A1 - Mazoyer, Sylvie A1 - Calender, Alain A1 - Léoné, Mélanie A1 - Bressac-de Paillerets, Brigitte A1 - Caron, Olivier A1 - Sobol, Hagay A1 - Frenay, Marc A1 - Prieur, Fabienne A1 - Ferrer, Sandra Fert A1 - Mortemousque, Isabelle A1 - Buys, Saundra A1 - Daly, Mary A1 - Miron, Alexander A1 - Terry, Mary Beth A1 - Hopper, John L. A1 - John, Esther M. A1 - Southey, Melissa A1 - Goldgar, David A1 - Singer, Christian F. A1 - Fink-Retter, Anneliese A1 - Muy-Kheng, Tea A1 - Geschwantler Kaulich, Daphne A1 - Hansen, Thomas V. O. A1 - Nielsen, Finn C. A1 - Barkardottir, Rosa B. A1 - Gaudet, Mia A1 - Kirchhoff, Tomas A1 - Joseph, Vijai A1 - Dutra-Clarke, Ana A1 - Offit, Kenneth A1 - Piedmonte, Marion A1 - Kirk, Judy A1 - Cohn, David A1 - Hurteau, Jean A1 - Byron, John A1 - Fiorica, James A1 - Toland, Amanda E. A1 - Montagna, Marco A1 - Oliani, Cristina A1 - Imyanitov, Evgeny A1 - Isaacs, Claudine A1 - Tihomirova, Laima A1 - Blanco, Ignacio A1 - Lazaro, Conxi A1 - Teulé, Alex A1 - Del Valle, J. A1 - Gayther, Simon A. A1 - Odunsi, Kunle A1 - Gross, Jenny A1 - Karlan, Beth Y. A1 - Olah, Edith A1 - Teo, Soo-Hwang A1 - Ganz, Patricia A. A1 - Beattie, Mary S. A1 - Dorfling, Cecelia M. A1 - Jansen van Rensburg, Elizabeth A1 - Diez, Orland A1 - Kwong, Ava A1 - Schmutzler, Rita K. A1 - Wappenschmidt, Barbara A1 - Engel, Christoph A1 - Meindl, Alfons A1 - Ditsch, Nina A1 - Arnold, Norbert A1 - Heidemann, Simone A1 - Niederacher, Dieter A1 - Preisler-Adams, Sabine A1 - Gadzicki, Dorothea A1 - Varon-Mateeva, Raymonda A1 - Deissler, Helmut A1 - Gehrig, Andrea A1 - Sutter, Christian A1 - Kast, Karin A1 - Fiebig, Britta A1 - Schäfer, Dieter A1 - Caldes, Trinidad A1 - de la Hoya, Miguel A1 - Nevanlinna, Heli A1 - Muranen, Taru A. A1 - Lespérance, Bernard A1 - Spurdle, Amanda B. A1 - Neuhausen, Susan L. A1 - Ding, Yuan C. A1 - Wang, Xianshu A1 - Fredericksen, Zachary A1 - Pankratz, Vernon S. A1 - Lindor, Noralane M. A1 - Peterlongo, Paulo A1 - Manoukian, Siranoush A1 - Peissel, Bernard A1 - Zaffaroni, Daniela A1 - Bonanni, Bernardo A1 - Bernard, Loris A1 - Dolcetti, Riccardo A1 - Papi, Laura A1 - Ottini, Laura A1 - Radice, Paolo A1 - Greene, Mark H. A1 - Loud, Jennifer T. A1 - Andrulis, Irene L. A1 - Ozcelik, Hilmi A1 - Mulligan, Anna Marie A1 - Glendon, Gord A1 - Thomassen, Mads A1 - Gerdes, Anne-Marie A1 - Jensen, Uffe B. A1 - Skytte, Anne-Bine A1 - Kruse, Torben A. A1 - Chenevix-Trench, Georgia A1 - Couch, Fergus J. A1 - Simard, Jacques A1 - Easton, Douglas F. T1 - Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers JF - Breast Cancer Research N2 - Introduction: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2). Methods: To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework. Results: Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 x 10\(^{-4}\)). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 x 10\(^{-5}\), P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df P = 0.007; rs1292011 2df P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 x 10\(^{-5}\)) and there was marginal evidence of association with ER- negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049). Conclusions: The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers. KW - investigators KW - genetic modifiers KW - mammographic density KW - susceptibility loci KW - ovarian cancer KW - hormone-related protein KW - genome-wide association KW - tumor subtypes KW - alleles KW - consortium Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130449 VL - 14 IS - R33 ER - TY - JOUR A1 - Arnold, Nicole A1 - Braunschweig, Holger A1 - Damme, Alexander T1 - Bis(μ-diisopropyl-phosphanido-\(κ^2\)P:P)bis-[hydrido(triisopropyl-phosphane-κP)platinum(II)] JF - Acta crystallographica. Section E, Structure reports online N2 - In the centrosymmetric molecular structure of the title compound \([Pt_2(C_6H_{14}P)_2H_2)(C_9H_{21}P)_2]\), each \(Pt^{II}\) atom is bound on one side to a phosphane ligand \((PiPr_3)\) and a hydrido ligand. On the other side, it is bound to two phosphanide ligands \((μ-PiPr_2)\), which engage a bridging position between the two \(Pt^{II}\) atoms, forming a distorted square-planar structure motif. The PtPt distance is 3.6755(2)Å. A comparable molecular structure was observed for bis-(μ-di-tert-butyl-phosphanido)bis-[hydrido(triethyl-phosphane)platinum(II)] [Itazaki et al. (2004 ). Organometallics, 23, 1610-1621]. KW - data-to-parameter ratio = 22.3 KW - mean σ(C–C) = 0.004 Å KW - single-crystal X-ray study KW - T = 100 K KW - R factor = 0.018 KW - wR factor = 0.038 Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-123723 VL - E68 ER - TY - JOUR A1 - Aso, Yoshinori A1 - Herb, Andrea A1 - Ogueta, Maite A1 - Siwanowicz, Igor A1 - Templier, Thomas A1 - Friedrich, Anja B. A1 - Ito, Kei A1 - Scholz, Henrike A1 - Tanimoto, Hiromu T1 - Three Dopamine Pathways Induce Aversive Odor Memories with Different Stability JF - PLoS Genetics N2 - Animals acquire predictive values of sensory stimuli through reinforcement. In the brain of Drosophila melanogaster, activation of two types of dopamine neurons in the PAM and PPL1 clusters has been shown to induce aversive odor memory. Here, we identified the third cell type and characterized aversive memories induced by these dopamine neurons. These three dopamine pathways all project to the mushroom body but terminate in the spatially segregated subdomains. To understand the functional difference of these dopamine pathways in electric shock reinforcement, we blocked each one of them during memory acquisition. We found that all three pathways partially contribute to electric shock memory. Notably, the memories mediated by these neurons differed in temporal stability. Furthermore, combinatorial activation of two of these pathways revealed significant interaction of individual memory components rather than their simple summation. These results cast light on a cellular mechanism by which a noxious event induces different dopamine signals to a single brain structure to synthesize an aversive memory. KW - dynamics KW - serotonin KW - expression KW - melanogaster KW - neurons form KW - olfactory memory KW - long-term-memory KW - drosophila mushroom body KW - sensitization KW - localization Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130631 VL - 8 IS - 7 ER - TY - JOUR A1 - Atienza, Nieves A1 - de Castro, Natalia A1 - Cortés, Carmen A1 - Garrido, M. Ángeles A1 - Grima, Clara I. A1 - Hernández, Gregorio A1 - Márquez, Alberto A1 - Moreno-González, Auxiliadora A1 - Nöllenburg, Martin A1 - Portillo, José Ramón A1 - Reyes, Pedro A1 - Valenzuela, Jesús A1 - Trinidad Villar, Maria A1 - Wolff, Alexander T1 - Cover contact graphs N2 - We study problems that arise in the context of covering certain geometric objects called seeds (e.g., points or disks) by a set of other geometric objects called cover (e.g., a set of disks or homothetic triangles). We insist that the interiors of the seeds and the cover elements are pairwise disjoint, respectively, but they can touch. We call the contact graph of a cover a cover contact graph (CCG). We are interested in three types of tasks, both in the general case and in the special case of seeds on a line: (a) deciding whether a given seed set has a connected CCG, (b) deciding whether a given graph has a realization as a CCG on a given seed set, and (c) bounding the sizes of certain classes of CCG’s. Concerning (a) we give efficient algorithms for the case that seeds are points and show that the problem becomes hard if seeds and covers are disks. Concerning (b) we show that this problem is hard even for point seeds and disk covers (given a fixed correspondence between graph vertices and seeds). Concerning (c) we obtain upper and lower bounds on the number of CCG’s for point seeds. KW - Informatik Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-78845 ER - TY - JOUR A1 - Azzami, Klara A1 - Ritter, Wolfgang A1 - Tautz, Jürgen A1 - Beier, Hildburg T1 - Infection of honey bees with acute bee paralysis virus does not trigger humoral or cellular immune responses JF - Archives of Virology N2 - We have studied the responses of honey bees at different life stages (Apis mellifera) to controlled infection with acute bee paralysis virus and have identified the haemolymph of infected larvae and adult worker bees as the compartment where massive propagation of ABPV occurs. Insects respond with a broad spectrum of induced innate immune reactions to bacterial infections, whereas defence mechanisms based on RNA interference play a major role in antiviral immunity. In this study, we have determined that honey bee larvae and adult workers do not produce a humoral immune reaction upon artificial infection with ABPV, in contrast to control individuals challenged with Escherichia coli. ABPV-infected bees produced neither elevated levels of specific antimicrobial peptides (AMPs), such as hymenoptaecin and defensin, nor any general antimicrobial activity, as revealed by inhibition-zone assays. Additionally, adult bees did not generate melanised nodules upon ABPV infection, an important cellular immune function activated by bacteria and viruses in some insects. Challenge of bees with both ABPV and E. coli showed that innate humoral and cellular immune reactions are induced in mixed infections, albeit at a reduced level. KW - chemosensory protein KW - bee larva KW - adult bee KW - honey bee KW - larva KW - work bee KW - infected bee KW - immune response KW - young work bee KW - capsid protein KW - abdominal KW - tergite KW - haemolymph KW - sample KW - Imd pathway KW - worker bee larva KW - antimicrobial KW - peptide Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126863 VL - 157 IS - 4 ER - TY - JOUR A1 - Bandyra, Katarzyna J. A1 - Said, Nelly A1 - Pfeiffer, Verena A1 - Górna, Maria W. A1 - Vogel, Jörg A1 - Luisi, Ben F. T1 - The Seed Region of a Small RNA Drives the Controlled Destruction of the Target mRNA by the Endoribonuclease RNase E JF - Molecular Cell N2 - Numerous small non-coding RNAs (sRNAs) in bacteria modulate rates of translation initiation and degradation of target mRNAs, which they recognize through base-pairing facilitated by the RNA chaperone Hfq. Recent evidence indicates that the ternary complex of Hfq, sRNA and mRNA guides endoribonuclease RNase E to initiate turnover of both the RNAs. We show that a sRNA not only guides RNase E to a defined site in a target RNA, but also allosterically activates the enzyme by presenting a monophosphate group at the 5′-end of the cognate-pairing “seed.” Moreover, in the absence of the target the 5′-monophosphate makes the sRNA seed region vulnerable to an attack by RNase E against which Hfq confers no protection. These results suggest that the chemical signature and pairing status of the sRNA seed region may help to both ‘proofread’ recognition and activate mRNA cleavage, as part of a dynamic process involving cooperation of RNA, Hfq and RNase E. KW - medicine Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126202 VL - 47 IS - 6 ER - TY - JOUR A1 - Barth, Thomas F. E. A1 - Herrmann, Tobias S. A1 - Tappe, Dennis A1 - Stark, Lorenz A1 - Grüner, Beate A1 - Buttenschoen, Klaus A1 - Hillenbrand, Andreas A1 - Juchems, Markus A1 - Henne-Bruns, Doris A1 - Kern, Petra A1 - Seitz, Hanns M. A1 - Möller, Peter A1 - Rausch, Robert L. A1 - Kern, Peter A1 - Deplazes, Peter T1 - Sensitive and Specific Immunohistochemical Diagnosis of Human Alveolar Echinococcosis with the Monoclonal Antibody Em2G11 JF - PLoS Neglected Tropical Diseases N2 - Background: Alveolar echinococcosis (AE) is caused by the metacestode stage of Echinococcus multilocularis. Differential diagnosis with cystic echinococcosis (CE) caused by E. granulosus and AE is challenging. We aimed at improving diagnosis of AE on paraffin sections of infected human tissue by immunohistochemical testing of a specific antibody. Methodology/Principal Findings: We have analysed 96 paraffin archived specimens, including 6 cutting needle biopsies and 3 fine needle aspirates, from patients with suspected AE or CE with the monoclonal antibody (mAb) Em2G11 specific for the Em2 antigen of E. multilocularis metacestodes. In human tissue, staining with mAb Em2G11 is highly specific for E. multilocularis metacestodes while no staining is detected in CE lesions. In addition, the antibody detects small particles of E. multilocularis (spems) of less than 1 mm outside the main lesion in necrotic tissue, liver sinusoids and lymphatic tissue most probably caused by shedding of parasitic material. The conventional histological diagnosis based on haematoxylin and eosin and PAS stainings were in accordance with the immunohistological diagnosis using mAb Em2G11 in 90 of 96 samples. In 6 samples conventional subtype diagnosis of echinococcosis had to be adjusted when revised by immunohistology with mAb Em2G11. Conclusions/Significance: Immunohistochemistry with the mAb Em2G11 is a new, highly specific and sensitive diagnostic tool for AE. The staining of small particles of E. multilocularis (spems) outside the main lesion including immunocompetent tissue, such as lymph nodes, suggests a systemic effect on the host. KW - cells KW - multilocularis KW - antigen Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135371 VL - 6 IS - 10 ER - TY - JOUR A1 - Baune, Bernhard T. A1 - Konrad, Carsten A1 - Grotegerd, Dominik A1 - Suslow, Thomas A1 - Birosova, Eva A1 - Ohrmann, Patricia A1 - Bauer, Jochen A1 - Arolt, Volker A1 - Heindel, Walter A1 - Domschke, Katharina A1 - Schöning, Sonja A1 - Rauch, Astrid V. A1 - Uhlmann, Christina A1 - Kugel, Harald A1 - Dannlowski, Udo T1 - Interleukin-6 gene (IL-6): a possible role in brain morphology in the healthy adult brain JF - Journal of Neuroinflammation N2 - Background: Cytokines such as interleukin 6 (IL-6) have been implicated in dual functions in neuropsychiatric disorders. Little is known about the genetic predisposition to neurodegenerative and neuroproliferative properties of cytokine genes. In this study the potential dual role of several IL-6 polymorphisms in brain morphology is investigated. Methodology: In a large sample of healthy individuals (N = 303), associations between genetic variants of IL-6 (rs1800795; rs1800796, rs2069833, rs2069840) and brain volume (gray matter volume) were analyzed using voxel-based morphometry (VBM). Selection of single nucleotide polymorphisms (SNPs) followed a tagging SNP approach (e. g., Stampa algorigthm), yielding a capture 97.08% of the variation in the IL-6 gene using four tagging SNPs. Principal findings/results In a whole-brain analysis, the polymorphism rs1800795 (-174 C/G) showed a strong main effect of genotype (43 CC vs. 150 CG vs. 100 GG; x = 24, y = -10, z = -15; F(2,286) = 8.54, p(uncorrected) = 0.0002; p(AlphaSim-corrected) = 0.002; cluster size k = 577) within the right hippocampus head. Homozygous carriers of the G-allele had significantly larger hippocampus gray matter volumes compared to heterozygous subjects. None of the other investigated SNPs showed a significant association with grey matter volume in whole-brain analyses. Conclusions/significance: These findings suggest a possible neuroprotective role of the G-allele of the SNP rs1800795 on hippocampal volumes. Studies on the role of this SNP in psychiatric populations and especially in those with an affected hippocampus (e.g., by maltreatment, stress) are warranted. KW - aging brain KW - hippocampal neurogenesis KW - cholinergic neurons KW - neurothrophic factor KW - Alzheimers disease KW - neurite outgrowth KW - inflammatory cytokines KW - major depression KW - nervour system KW - dentate gyrus KW - genetics KW - inflammation KW - interleukin 6 KW - neuroprotection KW - voxel-based morphometry Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130804 VL - 9 IS - 125 ER - TY - JOUR A1 - Bechtle, Philip A1 - Bringmann, Torsten A1 - Desch, Klaus A1 - Dreiner, Herbi A1 - Hamer, Matthias A1 - Hensel, Carsten A1 - Krämer, Michael A1 - Nguyen, Nelly A1 - Porod, Werner A1 - Prudent, Xavier A1 - Sarrazin, Björn A1 - Uhlenbrock, Mathias A1 - Wienemann, Peter T1 - Constrained supersymmetry after two years of LHC data: a global view with Fittino JF - Journal of High Energy Physics N2 - We perform global fits to the parameters of the Constrained Minimal Super-symmetric Standard Model (CMSSM) and to a variant with non-universal Higgs masses (NUHM1). In addition to constraints from low-energy precision observables and the cosmological dark matter density, we take into account the LHC exclusions from searches in jets plus missing transverse energy signatures with about 5 fb\(^{−1}\) of integrated luminosity. We also include the most recent upper bound on the branching ratio B\(_s\)  → μμ from LHCb. Furthermore, constraints from and implications for direct and indirect dark matter searches are discussed. The best fit of the CMSSM prefers a light Higgs boson just above the experimentally excluded mass. We find that the description of the low-energy observables, (g − 2)\(_μ\) in particular, and the non-observation of SUSY at the LHC become more and more incompatible within the CMSSM. A potential SM-like Higgs boson with mass around 126 GeV can barely be accommodated. Values for B(B\(_s\)→μμ) just around the Standard Model prediction are naturally expected in the best fit region. The most-preferred region is not yet affected by limits on direct WIMP searches, but the next generation of experiments will probe this region. Finally, we discuss implications from fine-tuning for the best fit regions. KW - supersymmetry phenomenology Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129573 VL - 06 IS - 098 ER - TY - JOUR A1 - Becker, Jürgen C. A1 - Andersen, Mads H. A1 - Hofmeister-Müller, Valeska A1 - Wobser, Marion A1 - Frey, Lidia A1 - Sandig, Christiane A1 - Walter, Steffen A1 - Singh-Jasuja, Harpreet A1 - Kämpgen, Eckhart A1 - Opitz, Andreas A1 - Zapatka, Marc A1 - Bröcker, Eva-B. A1 - thor Straten, Per A1 - Schrama, David A1 - Ugurel, Selma T1 - Survivin-specific T-cell reactivity correlates with tumor response and patient survival: a phase-II peptide vaccination trial in metastatic melanoma JF - Cancer Immunology, Immunotherapy N2 - Background Therapeutic vaccination directed to induce an anti-tumoral T-cell response is a field of extensive investigation in the treatment of melanoma. However, many vaccination trials in melanoma failed to demonstrate a correlation between the vaccine-specific immune response and therapy outcome. This has been mainly attributed to immune escape by antigen loss, rendering us in the need of new vaccination targets. Patients and methods This phase-II trial investigated a peptide vaccination against survivin, an oncogenic inhibitor-of-apoptosis protein crucial for the survival of tumor cells, in HLA-A1/-A2/-B35-positive patients with treatment-refractory stage-IV metastatic melanoma. The study endpoints were survivin-specific T-cell reactivity (SSTR), safety, response, and survival (OS). Results Sixty-one patients (ITT) received vaccination therapy using three different regimens. 55 patients (PP) were evaluable for response and survival, and 41/55 for SSTR. Patients achieving progression arrest (CR + PR + SD) more often showed SSTRs than patients with disease progression (p = 0.0008). Patients presenting SSTRs revealed a prolonged OS (median 19.6 vs. 8.6 months; p = 0.0077); multivariate analysis demonstrated SSTR as an independent predictor of survival (p = 0.013). The induction of SSTRs was associated with gender (female vs. male; p = 0.014) and disease stage (M1a/b vs. M1c; p = 0.010), but not with patient age, HLA type, performance status, or vaccination regimen. Conclusion Survivin-specific T-cell reactivities strongly correlate with tumor response and patient survival, indicating that vaccination with survivin-derived peptides is a promising treatment strategy in melanoma. KW - peptide vaccination KW - therapy KW - survivin T-cell reactivity KW - melanoma Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126215 VL - 61 IS - 11 ER - TY - JOUR A1 - Becker, Jürgen C. A1 - Andersen, Mads H. A1 - Hofmeister-Müller, Valeska A1 - Wobser, Marion A1 - Frey, Lidia A1 - Sandig, Christiane A1 - Walter, Steffen A1 - Singh-Jasuja, Harpreet A1 - Kämpgen, Eckhart A1 - Opitz, Andreas A1 - Zapatka, Marc A1 - Bröcker, Eva-B. A1 - thor Straten, Per A1 - Schrama, David A1 - Ugurel, Selma T1 - Survivin-specific T-cell reactivity correlates with tumor response and patient survival: a phase-II peptide vaccination trial in metastatic melanoma JF - Cancer Immunology, Immunotherapy N2 - Background Therapeutic vaccination directed to induce an anti-tumoral T-cell response is a field of extensive investigation in the treatment of melanoma. However, many vaccination trials in melanoma failed to demonstrate a correlation between the vaccine-specific immune response and therapy outcome. This has been mainly attributed to immune escape by antigen loss, rendering us in the need of new vaccination targets. Patients and methods This phase-II trial investigated a peptide vaccination against survivin, an oncogenic inhibitor-of-apoptosis protein crucial for the survival of tumor cells, in HLA-A1/-A2/-B35-positive patients with treatment-refractory stage-IV metastatic melanoma. The study endpoints were survivin-specific T-cell reactivity (SSTR), safety, response, and survival (OS). Results Sixty-one patients (ITT) received vaccination therapy using three different regimens. 55 patients (PP) were evaluable for response and survival, and 41/55 for SSTR. Patients achieving progression arrest (CR + PR + SD) more often showed SSTRs than patients with disease progression (p = 0.0008). Patients presenting SSTRs revealed a prolonged OS (median 19.6 vs. 8.6 months; p = 0.0077); multivariate analysis demonstrated SSTR as an independent predictor of survival (p = 0.013). The induction of SSTRs was associated with gender (female vs. male; p = 0.014) and disease stage (M1a/b vs. M1c; p = 0.010), but not with patient age, HLA type, performance status, or vaccination regimen. Conclusion Survivin-specific T-cell reactivities strongly correlate with tumor response and patient survival, indicating that vaccination with survivin-derived peptides is a promising treatment strategy in melanoma. KW - peptide vaccination KW - melanoma KW - survivin KW - T-cell reactivity KW - therapy Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124830 VL - 61 IS - 11 ER - TY - JOUR A1 - Beisser, Daniela A1 - Grohme, Markus A. A1 - Kopka, Joachim A1 - Frohme, Marcus A1 - Schill, Ralph O. A1 - Hengherr, Steffen A1 - Dandekar, Thomas A1 - Klau, Gunnar W. A1 - Dittrich, Marcus A1 - Müller, Tobias T1 - Integrated pathway modules using time-course metabolic profiles and EST data from Milnesium tardigradum N2 - Background: Tardigrades are multicellular organisms, resistant to extreme environmental changes such as heat, drought, radiation and freezing. They outlast these conditions in an inactive form (tun) to escape damage to cellular structures and cell death. Tardigrades are apparently able to prevent or repair such damage and are therefore a crucial model organism for stress tolerance. Cultures of the tardigrade Milnesium tardigradum were dehydrated by removing the surrounding water to induce tun formation. During this process and the subsequent rehydration, metabolites were measured in a time series by GC-MS. Additionally expressed sequence tags are available, especially libraries generated from the active and inactive state. The aim of this integrated analysis is to trace changes in tardigrade metabolism and identify pathways responsible for their extreme resistance against physical stress. Results: In this study we propose a novel integrative approach for the analysis of metabolic networks to identify modules of joint shifts on the transcriptomic and metabolic levels. We derive a tardigrade-specific metabolic network represented as an undirected graph with 3,658 nodes (metabolites) and 4,378 edges (reactions). Time course metabolite profiles are used to score the network nodes showing a significant change over time. The edges are scored according to information on enzymes from the EST data. Using this combined information, we identify a key subnetwork (functional module) of concerted changes in metabolic pathways, specific for de- and rehydration. The module is enriched in reactions showing significant changes in metabolite levels and enzyme abundance during the transition. It resembles the cessation of a measurablemetabolism (e.g. glycolysis and amino acid anabolism) during the tun formation, the production of storage metabolites and bioprotectants, such as DNA stabilizers, and the generation of amino acids and cellular components from monosaccharides as carbon and energy source during rehydration. Conclusions: The functional module identifies relationships among changed metabolites (e.g. spermidine) and reactions and provides first insights into important altered metabolic pathways. With sparse and diverse data available, the presented integrated metabolite network approach is suitable to integrate all existing data and analyse it in a combined manner. KW - Milnesium tardigradum KW - Integrated network analysis KW - Functional modules KW - Metabolic profiles KW - Metabolic pathways KW - Trend test Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75241 ER - TY - JOUR A1 - Beitzinger, Christoph A1 - Stefani, Caroline A1 - Kronhardt, Angelika A1 - Rolando, Monica A1 - Flatau, Gilles A1 - Lemichez, Emanuel A1 - Benz, Roland T1 - Role of N-Terminal His6-Tags in Binding and Efficient Translocation of Polypeptides into Cells Using Anthrax Protective Antigen (PA) N2 - It is of interest to define bacterial toxin biochemical properties to use them as molecular-syringe devices in order to deliver enzymatic activities into host cells. Binary toxins of the AB7/8-type are among the most potent and specialized bacterial protein toxins. The B subunits oligomerize to form a pore that binds with high affinity host cell receptors and the enzymatic A subunit. This allows the endocytosis of the complex and subsequent injection of the A subunit into the cytosol of the host cells. Here we report that the addition of an N-terminal His6-tag to different proteins increased their binding affinity to the protective antigen (PA) PA63-channels, irrespective if they are related (C2I) or unrelated (gpJ, EDIN) to the AB7/8-family of toxins. His6-EDIN exhibited voltage-dependent increase of the stability constant for binding by a factor of about 25 when the trans-side corresponding to the cell interior was set to 270 mV. Surprisingly, the C. botulinum toxin C2II-channel did not share this feature of PA63. Cell-based experiments demonstrated that addition of an N-terminal His6-tag promoted also intoxication of endothelial cells by C2I or EDIN via PA63. Our results revealed that addition of His6-tags to several factors increase their binding properties to PA63 and enhance the property to intoxicate cells. KW - Biologie Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-76325 ER - TY - JOUR A1 - Bender, Stephan A1 - Resch, Franz A1 - Klein, Christoph A1 - Renner, Tobias A1 - Fallgatter, Andreas J. A1 - Weisbrod, Matthias A1 - Romanos, Marcel T1 - Influence of Stimulant Medication and Response Speed on Lateralization of Movement-Related Potentials in Attention-Deficit/Hyperactivity Disorder JF - PLoS One N2 - Background: Hyperactivity is one of the core symptoms in attention deficit hyperactivity disorder (ADHD). However, it remains unclear in which way the motor system itself and its development are affected by the disorder. Movement-related potentials (MRP) can separate different stages of movement execution, from the programming of a movement to motor post-processing and memory traces. Pre-movement MRP are absent or positive during early childhood and display a developmental increase of negativity. Methods: We examined the influences of response-speed, an indicator of the level of attention, and stimulant medication on lateralized MRP in 16 children with combined type ADHD compared to 20 matched healthy controls. Results: We detected a significantly diminished lateralisation of MRP over the pre-motor and primary motor cortex during movement execution (initial motor potential peak, iMP) in patients with ADHD. Fast reactions (indicating increased visuo-motor attention) led to increased lateralized negativity during movement execution only in healthy controls, while in children with ADHD faster reaction times were associated with more positive amplitudes. Even though stimulant medication had some effect on attenuating group differences in lateralized MRP, this effect was insufficient to normalize lateralized iMP amplitudes. Conclusions: A reduced focal (lateralized) motor cortex activation during the command to muscle contraction points towards an immature motor system and a maturation delay of the (pre-) motor cortex in children with ADHD. A delayed maturation of the neuronal circuitry, which involves primary motor cortex, may contribute to ADHD pathophysiology. KW - deficit-hyperactivity disorder KW - anticipatory mechanisms KW - motor preparation KW - TIC disorder KW - children KW - ADHD KW - methylphenidate KW - contingent negative-variation KW - continuous performance-test KW - slow cortical potentials Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135262 VL - 7 IS - 6 ER - TY - JOUR A1 - Benisch, Peggy A1 - Schilling, Tatjana A1 - Klein-Hitpass, Ludger A1 - Frey, Sönke P. A1 - Seefried, Lothar A1 - Raaijmakers, Nadja A1 - Krug, Melanie A1 - Regensburger, Martina A1 - Zeck, Sabine A1 - Schinke, Thorsten A1 - Amling, Michael A1 - Ebert, Amling A1 - Jakob, Franz T1 - The Transcriptional Profile of Mesenchymal Stem Cell Populations in Primary Osteoporosis Is Distinct and Shows Overexpression of Osteogenic Inhibitors JF - PLoS One N2 - Primary osteoporosis is an age-related disease characterized by an imbalance in bone homeostasis. While the resorptive aspect of the disease has been studied intensely, less is known about the anabolic part of the syndrome or presumptive deficiencies in bone regeneration. Multipotent mesenchymal stem cells (MSC) are the primary source of osteogenic regeneration. In the present study we aimed to unravel whether MSC biology is directly involved in the pathophysiology of the disease and therefore performed microarray analyses of hMSC of elderly patients (79-94 years old) suffering from osteoporosis (hMSC-OP). In comparison to age-matched controls we detected profound changes in the transcriptome in hMSC-OP, e.g. enhanced mRNA expression of known osteoporosis-associated genes (LRP5, RUNX2, COL1A1) and of genes involved in osteoclastogenesis (CSF1, PTH1R), but most notably of genes coding for inhibitors of WNT and BMP signaling, such as Sclerostin and MAB21L2. These candidate genes indicate intrinsic deficiencies in self-renewal and differentiation potential in osteoporotic stem cells. We also compared both hMSC-OP and non-osteoporotic hMSC-old of elderly donors to hMSC of similar to 30 years younger donors and found that the transcriptional changes acquired between the sixth and the ninth decade of life differed widely between osteoporotic and non-osteoporotic stem cells. In addition, we compared the osteoporotic transcriptome to long term-cultivated, senescent hMSC and detected some signs for pre-senescence in hMSC-OP. Our results suggest that in primary osteoporosis the transcriptomes of hMSC populations show distinct signatures and little overlap with non-osteoporotic aging, although we detected some hints for senescence-associated changes. While there are remarkable inter-individual variations as expected for polygenetic diseases, we could identify many susceptibility genes for osteoporosis known from genetic studies. We also found new candidates, e.g. MAB21L2, a novel repressor of BMP-induced transcription. Such transcriptional changes may reflect epigenetic changes, which are part of a specific osteoporosis-associated aging process. KW - alkaline-phosphatase KW - in vitro KW - bone-mineral density KW - age-related osteoporosis KW - WNT signaling pathway KW - replicative senescence KW - morphogenetic protein KW - parathyroid-hormone KW - growth factor KW - skeletal overexpression Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133379 VL - 7 IS - 9 ER - TY - JOUR A1 - Benkert, Thomas F. A1 - Dietz, Lena A1 - Hartmann, Elena M. A1 - Leich, Ellen A1 - Rosenwald, Andreas A1 - Serfling, Edgar A1 - Buttmann, Mathias A1 - Berberich-Siebelt, Friederike T1 - Natalizumab Exerts Direct Signaling Capacity and Supports a Pro-Inflammatory Phenotype in Some Patients with Multiple Sclerosis N2 - Natalizumab is a recombinant monoclonal antibody raised against integrin alpha-4 (CD49d). It is approved for the treatment of patients with multiple sclerosis (MS), a chronic inflammatory autoimmune disease of the CNS. While having shown high therapeutic efficacy, treatment by natalizumab has been linked to progressive multifocal leukoencephalopathy (PML) as a serious adverse effect. Furthermore, drug cessation sometimes induces rebound disease activity of unknown etiology. Here we investigated whether binding of this adhesion-blocking antibody to T lymphocytes could modulate their phenotype by direct induction of intracellular signaling events. Primary CD4+ T lymphocytes either from healthy donors and treated with natalizumab in vitro or from MS patients receiving their very first dose of natalizumab were analyzed. Natalizumab induced a mild upregulation of IL-2, IFN-c and IL-17 expression in activated primary human CD4+ T cells propagated ex vivo from healthy donors, consistent with a pro-inflammatory costimulatory effect on lymphokine expression. Along with this, natalizumab binding triggered rapid MAPK/ERK phosphorylation. Furthermore, it decreased CD49d surface expression on effector cells within a few hours. Sustained CD49d downregulation could be attributed to integrin internalization and degradation. Importantly, also CD4+ T cells from some MS patients receiving their very first dose of natalizumab produced more IL-2, IFN-c and IL-17 already 24 h after infusion. Together these data indicate that in addition to its adhesion-blocking mode of action natalizumab possesses mild direct signaling capacities, which can support a pro-inflammatory phenotype of peripheral blood T lymphocytes. This might explain why a rebound of disease activity or IRIS is observed in some MS patients after natalizumab cessation. KW - Medizin Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-77905 ER - TY - JOUR A1 - Berendzen, Kenneth W. A1 - Weiste, Christoph A1 - Wanke, Dierk A1 - Kilian, Joachim A1 - Harter, Klaus A1 - Dröge-Laser, Wolfgang T1 - Bioinformatic cis-element analyses performed in Arabidopsis and rice disclose bZIP- and MYB-related binding sites as potential AuxRE-coupling elements in auxin-mediated transcription N2 - Background: In higher plants, a diverse array of developmental and growth-related processes is regulated by the plant hormone auxin. Recent publications have proposed that besides the well-characterized Auxin Response Factors (ARFs) that bind Auxin Response Elements (AuxREs), also members of the bZIP- and MYB-transcription factor (TF) families participate in transcriptional control of auxin-regulated genes via bZIP Response Elements (ZREs) or Myb Response Elements (MREs), respectively. Results: Applying a novel bioinformatic algorithm, we demonstrate on a genome-wide scale that singular motifs or composite modules of AuxREs, ZREs, MREs but also of MYC2 related elements are significantly enriched in promoters of auxin-inducible genes. Despite considerable, species-specific differences in the genome structure in terms of the GC content, this enrichment is generally conserved in dicot (Arabidopsis thaliana) and monocot (Oryza sativa) model plants. Moreover, an enrichment of defined composite modules has been observed in selected auxin-related gene families. Consistently, a bipartite module, which encompasses a bZIP-associated G-box Related Element (GRE) and an AuxRE motif, has been found to be highly enriched. Making use of transient reporter studies in protoplasts, these findings were experimentally confirmed, demonstrating that GREs functionally interact with AuxREs in regulating auxin-mediated transcription. Conclusions: Using genome-wide bioinformatic analyses, evolutionary conserved motifs have been defined which potentially function as AuxRE-dependent coupling elements to establish auxin-specific expression patterns. Based on these findings, experimental approaches can be designed to broaden our understanding of combinatorial, auxin-controlled gene regulation. KW - Arabidopsis KW - Cis-elements KW - cis-element modules KW - Auxin-regulated transcription KW - AuxRE KW - bZIP KW - MYB KW - MYC Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75138 ER - TY - JOUR A1 - Berthold, Norbert A1 - Brunner, Alexander T1 - Wie ungleich ist die Welt? Eine empirische Analyse JF - Perspektiven der Wirtschaftspolitik N2 - Kein Abstract verfügbar. KW - Ungleichheit KW - empirische Analyse Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-194171 SN - 1468-2516 SN - 1465-6493 N1 - Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich. VL - 12 IS - 4 ER - TY - JOUR A1 - Betz, Boris A1 - Schneider, Reinhard A1 - Kress, Tobias A1 - Schick, Martin Alexander A1 - Wanner, Christoph A1 - Sauvant, Christoph T1 - Rosiglitazone Affects Nitric Oxide Synthases and Improves Renal Outcome in a Rat Model of Severe Ischemia/Reperfusion Injury JF - PPAR Research N2 - Background. Nitric oxide (NO)-signal transduction plays an important role in renal ischemia/reperfusion (I/R) injury. NO produced by endothelial NO-synthase (eNOS) has protective functions whereas NO from inducible NO-synthase (iNOS) induces impairment. Rosiglitazone (RGZ), a peroxisome proliferator-activated receptor (PPAR)-gamma agonist exerted beneficial effects after renal I/R injury, so we investigated whether this might be causally linked with NOS imbalance. Methods. RGZ (5 mg/kg) was administered i.p. to SD-rats (f) subjected to bilateral renal ischemia (60 min). Following 24 h of reperfusion, inulin-and PAH-clearance as well as PAH-net secretion were determined. Morphological alterations were graded by histopathological scoring. Plasma NOx-production was measured. eNOS and iNOS expression was analyzed by qPCR. Cleaved caspase 3 (CC3) was determined as an apoptosis indicator and ED1 as a marker of macrophage infiltration in renal tissue. Results. RGZ improves renal function after renal I/R injury (PAH-/inulin-clearance, PAH-net secretion) and reduces histomorphological injury. Additionally, RGZ reduces NOx plasma levels, ED-1 positive cell infiltration and CC3 expression. iNOS-mRNA is reduced whereas eNOS-mRNA is increased by RGZ. Conclusion. RGZ has protective properties after severe renal I/R injury. Alterations of the NO pathway regarding eNOS and iNOS could be an explanation of the underlying mechanism of RGZ protection in renal I/R injury. KW - dysfunction KW - activated-receptor gamma KW - ischemia-reperfusion injury KW - failure KW - kidney KW - agnoists KW - mices KW - inos KW - pathophysiology KW - pioglitazone Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130872 VL - 2012 IS - Article ID 219319 ER - TY - JOUR A1 - Biederer, J. A1 - Beer, M. A1 - Hirsch, W. A1 - Wild, J. A1 - Fabel, M. A1 - Puderbach, M. A1 - Van Beek, E. J. R. T1 - MRI of the lung (2/3). Why … when … how? JF - Insights into Imaging N2 - Background Among the modalities for lung imaging, proton magnetic resonance imaging (MRI) has been the latest to be introduced into clinical practice. Its value to replace X-ray and computed tomography (CT) when radiation exposure or iodinated contrast material is contra-indicated is well acknowledged: i.e. for paediatric patients and pregnant women or for scientific use. One of the reasons why MRI of the lung is still rarely used, except in a few centres, is the lack of consistent protocols customised to clinical needs. Methods This article makes non-vendor-specific protocol suggestions for general use with state-of-the-art MRI scanners, based on the available literature and a consensus discussion within a panel of experts experienced in lung MRI. Results Various sequences have been successfully tested within scientific or clinical environments. MRI of the lung with appropriate combinations of these sequences comprises morphological and functional imaging aspects in a single examination. It serves in difficult clinical problems encountered in daily routine, such as assessment of the mediastinum and chest wall, and even might challenge molecular imaging techniques in the near future. Conclusion This article helps new users to implement appropriate protocols on their own MRI platforms. Main Messages • MRI of the lung can be readily performed on state-of-the-art 1.5-T MRI scanners. • Protocol suggestions based on the available literature facilitate its use for routine • MRI offers solutions for complicated thoracic masses with atelectasis and chest wall invasion. • MRI is an option for paediatrics and science when CT is contra-indicated KW - magnetic resonance imaging KW - lung KW - sequence imaging protocol Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124268 VL - 3 IS - 4 ER - TY - JOUR A1 - Biederer, Jürgen A1 - Mirsadraee, S. A1 - Beer, M. A1 - Molinari, F. A1 - Hintze, C. A1 - Bauman, G. A1 - Both, M. A1 - Van Beek, E. J. R. A1 - Wild, J. A1 - Puderbach, M. T1 - MRI of the lung (3/3)—current applications and future perspectives JF - Insights into Imaging N2 - Background MRI of the lung is recommended in a number of clinical indications. Having a non-radiation alternative is particularly attractive in children and young subjects, or pregnant women. Methods Provided there is sufficient expertise, magnetic resonance imaging (MRI) may be considered as the preferential modality in specific clinical conditions such as cystic fibrosis and acute pulmonary embolism, since additional functional information on respiratory mechanics and regional lung perfusion is provided. In other cases, such as tumours and pneumonia in children, lung MRI may be considered an alternative or adjunct to other modalities with at least similar diagnostic value. Results In interstitial lung disease, the clinical utility of MRI remains to be proven, but it could provide additional information that will be beneficial in research, or at some stage in clinical practice. Customised protocols for chest imaging combine fast breath-hold acquisitions from a “buffet” of sequences. Having introduced details of imaging protocols in previous articles, the aim of this manuscript is to discuss the advantages and limitations of lung MRI in current clinical practice. Conclusion New developments and future perspectives such as motion-compensated imaging with self-navigated sequences or fast Fourier decomposition MRI for non-contrast enhanced ventilation- and perfusion-weighted imaging of the lung are discussed. Main Messages • MRI evolves as a third lung imaging modality, combining morphological and functional information. • It may be considered first choice in cystic fibrosis and pulmonary embolism of young and pregnant patients. • In other cases (tumours, pneumonia in children), it is an alternative or adjunct to X-ray and CT. • In interstitial lung disease, it serves for research, but the clinical value remains to be proven. • New users are advised to make themselves familiar with the particular advantages and limitations. KW - functional imaging KW - magnetic resonance imaging KW - cystic fibrosis KW - pulmonary embolism KW - tumor KW - infiltrate Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124348 VL - 3 IS - 4 ER - TY - JOUR A1 - Biermann, Daniel A1 - Heilmann, Andreas A1 - Didié, Michael A1 - Schlossarek, Saskia A1 - Wahab, Azadeh A1 - Grimm, Michael A1 - Römer, Maria A1 - Reichenspurner, Hermann A1 - Sultan, Karim R. A1 - Steenpass, Anna A1 - Ergün, Süleyman A1 - Donzelli, Sonia A1 - Carrier, Lucie A1 - Ehmke, Heimo A1 - Zimmermann, Wolfram H. A1 - Hein, Lutz A1 - Böger, Rainer H. A1 - Benndorf, Ralf A. T1 - Impact of AT2 Receptor Deficiency on Postnatal Cardiovascular Development JF - PLoS One N2 - Background: The angiotensin II receptor subtype 2 (AT2 receptor) is ubiquitously and highly expressed in early postnatal life. However, its role in postnatal cardiac development remained unclear. Methodology/Principal Findings: Hearts from 1, 7, 14 and 56 days old wild-type (WT) and AT2 receptor-deficient (KO) mice were extracted for histomorphometrical analysis as well as analysis of cardiac signaling and gene expression. Furthermore, heart and body weights of examined animals were recorded and echocardiographic analysis of cardiac function as well as telemetric blood pressure measurements were performed. Moreover, gene expression, sarcomere shortening and calcium transients were examined in ventricular cardiomyocytes isolated from both genotypes. KO mice exhibited an accelerated body weight gain and a reduced heart to body weight ratio as compared to WT mice in the postnatal period. However, in adult KO mice the heart to body weight ratio was significantly increased most likely due to elevated systemic blood pressure. At postnatal day 7 ventricular capillarization index and the density of \(\alpha\)-smooth muscle cell actin-positive blood vessels were higher in KO mice as compared to WT mice but normalized during adolescence. Echocardiographic assessment of cardiac systolic function at postnatal day 7 revealed decreased contractility of KO hearts in response to beta-adrenergic stimulation. Moreover, cardiomyocytes from KO mice showed a decreased sarcomere shortening and an increased peak Ca\(^{2+}\) transient in response to isoprenaline when stimulated concomitantly with angiotensin II. Conclusion: The AT2 receptor affects postnatal cardiac growth possibly via reducing body weight gain and systemic blood pressure. Moreover, it moderately attenuates postnatal vascularization of the heart and modulates the beta adrenergic response of the neonatal heart. These AT2 receptor-mediated effects may be implicated in the physiological maturation process of the heart. KW - mice KW - II type-2 receptor KW - human endothelial cells KW - chronic kidney disease KW - angiotensin II KW - blood pressure KW - in vitro KW - cardiac hyperthrophy KW - tube formation KW - rat heart Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134902 VL - 7 IS - 10 ER - TY - JOUR A1 - Blachutzik, Jörg O. A1 - Demir, Faith A1 - Kreuzer, Ines A1 - Hedrich, Rainer A1 - Harms, Gregory S. T1 - Methods of staining and visualization of sphingolipid enriched and non-enriched plasma membrane regions of Arabidopsis thaliana with fluorescent dyes and lipid analogues N2 - Background: Sterols and Sphingolipids form lipid clusters in the plasma membranes of cell types throughout the animal and plant kingdoms. These lipid domains provide a medium for protein signaling complexes at the plasma membrane and are also observed to be principal regions of membrane contact at the inception of infection. We visualized different specific fluorescent lipophilic stains of the both sphingolipid enriched and non-sphingolipid enriched regions in the plasma membranes of live protoplasts of Arabidopsis thaliana. Results: Lipid staining protocols for several fluorescent lipid analogues in plants are presented. The most emphasis was placed on successful protocols for the single and dual staining of sphingolipid enriched regions and exclusion of sphingolipid enriched regions on the plasma membrane of Arabidopsis thaliana protoplasts. A secondary focus was placed to ensure that these staining protocols presented still maintain cell viability. Furthermore, the protocols were successfully tested with the spectrally sensitive dye Laurdan. Conclusion: Almost all existing staining procedures of the plasma membrane with fluorescent lipid analogues are specified for animal cells and tissues. In order to develop lipid staining protocols for plants, procedures were established with critical steps for the plasma membrane staining of Arabidopsis leaf tissue and protoplasts. The success of the plasma membrane staining protocols was additionally verified by measurements of lipid dynamics by the fluorescence recovery after photobleaching technique and by the observation of new phenomena such as time dependent lipid polarization events in living protoplasts, for which a putative physiological relevance is suggested. KW - Arabidopsis thaliana KW - Protoplasts KW - Lipid polarization KW - Lipophilic fluorescent dyes KW - Laurdan KW - Sphingolipid KW - Liquid (dis-) ordered phase KW - Plasma membrane KW - Fluorescence mi Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75433 ER - TY - JOUR A1 - Bohnenkamp, Anne A1 - Brüning, Gerrit A1 - Henke, Silke A1 - Henzel, Katrin A1 - Jannidis, Fotis A1 - Middel, Gregor A1 - Pravida, Dietmar A1 - Wissenbach, Moritz T1 - Perspektiven auf Goethes ›Faust‹ Werkstattbericht der historisch-kritischen Hybridedition N2 - Werkstattbericht Hybridedition zu Goethes Faust. Es handelt sich dabei um ein Gemeinschaftsprojekt des Freien deutsche Hochstifts, des Goethe- und Schiller Archivs Weimar und der Universität Würzburg. Der Aufsatz befasst sich mit dem derzeitigen Entwicklungsstand der Edition, deren Konzeption als Hybridedition und verschiedenen Aspekten der Datenmodellierung. KW - Historische Kritik KW - Goethe KW - Johann Wolfgang von KW - Entstehung KW - Digitale Edition KW - Faust KW - Archiv KW - Werkstattbericht Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-76823 ER - TY - JOUR A1 - Boll, Katharina A1 - Maibach, Christiane T1 - Ein Imagefilm für die UB. Praxisbericht über die Entstehung eines Bibliotheksfilms an der Universitätsbibliothek Würzburg N2 - Ein Imagefilm ist die Visitenkarte eines Unternehmens. Er macht Werbung in eigener Sache und fasst die Philosophie eines Unternehmens in bewegte Bilder. Daher entschied sich die UB Würzburg für die Produktion eines Imagefilms. Der Artikel bietet einen praxisorientierten Überblick über die verschiedenen Arbeitsschritte, die bei der Erstellung eines Imagefilms notwendig sind und gibt Tipps für die erfolgreiche Produktion. KW - Universitätsbibliothek Würzburg KW - Film KW - Filmproduktion Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-71451 ER - TY - JOUR A1 - Boltze, Johannes A1 - Kleinschnitz, Christoph A1 - Reymann, Klaus G. A1 - Reiser, Georg A1 - Wagner, Daniel-Christoph A1 - Kranz, Alexander A1 - Michalski, Dominik T1 - Neurovascular pathophysiology in cerebral ischemia, dementia and the ageing brain – current trends in basic, translational and clinical research JF - Experimental & Translational Stroke Medicine N2 - The 7th International Symposium on Neuroprotection and Neurorepair was held from May 2nd to May 5th, 2012 in Potsdam, Germany. The symposium, which directly continues the successful Magdeburg meeting series, attracted over 330 colleagues from 29 countries to discuss recent findings and advances in the field. The focus of the 2012 symposium was widened from stroke and traumatic brain injury to neurodegenerative diseases, notably dementia, and more generally the ageing brain. Thereby, emphasis was given on neurovascular aspects of neurodegeneration and stroke including the blood–brain barrier, recent findings regarding the pathomechanism of Alzheimer’s disease, and brain imaging approaches. In addition, neurobiochemical aspects of neuroprotection, the role of astrogliosis, the clinical progress of cell-based approaches as well as translational hurdles and opportunities were discussed in-depth. This review summarizes some of the most stimulating discussions and reports from the meeting. KW - translational research KW - small vessel disease KW - Alzheimer’s disease KW - cerebral ischemia KW - neurorepair KW - neuroprotection KW - vascular dementia KW - mitochondria KW - astrogliosis KW - in vivo imaging Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126679 VL - 4 IS - 14 ER - TY - JOUR A1 - Bonn, Maria A1 - Schmitt, Angelika A1 - Asan, Esther T1 - Double and triple in situ hybridization for coexpression studies: combined fluorescent and chromogenic detection of neuropeptide Y (NPY) and serotonin receptor subtype mRNAs expressed at different abundance levels JF - Histochemistry and Cell Biology N2 - Multiple fluorescence in situ hybridization is the method of choice for studies aimed at determining simultaneous production of signal transduction molecules and neuromodulators in neurons. In our analyses of the monoamine receptor mRNA expression of peptidergic neurons in the rat telencephalon, double tyramide-signal-amplified fluorescence in situ hybridization delivered satisfactory results for coexpression analysis of neuropeptide Y (NPY) and serotonin receptor 2C (5-HT2C) mRNA, a receptor subtype expressed at high-to-moderate abundance in the regions analyzed. However, expression of 5-HT1A mRNA, which is expressed at comparatively low abundance in many telencephalic areas, could not be unequivocally identified in NPY mRNA-reactive neurons due to high background and poor signal-to-noise ratio in fluorescent receptor mRNA detections. Parallel chromogenic in situ hybridization provided clear labeling for 5-HT1A mRNA and additionally offered the possibility to monitor the chromogen deposition at regular time intervals to determine the optimal signal-to-noise ratio. We first developed a double labeling protocol combining fluorescence and chromogenic in situ hybridization and subsequently expanded this variation to combine double fluorescence and chromogenic in situ hybridization for triple labelings. With this method, we documented expression of 5-HT2C and/or 5-HT1A in subpopulations of telencephalic NPY-producing neurons. The method developed in the present study appears suitable for conventional light and fluorescence microscopy, combines advantages of fluorescence and chromogenic in situ hybridization protocols and thus provides a reliable non-radioactive alternative to previously published multiple labeling methods for coexpression analyses in which one mRNA species requires highly sensitive detection. KW - triple in situ hybridization KW - Coexpression KW - NPY KW - 5-HT1A KW - 5-HT2C Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126720 VL - 137 IS - 1 ER - TY - JOUR A1 - Bonn, Maria A1 - Schmitt, Angelika A1 - Asan, Esther T1 - Double and triple in situ hybridization for coexpression studies: combined fluorescent and chromogenic detection of neuropeptide Y (NPY) and serotonin receptor subtype mRNAs expressed at different abundance levels JF - Histochemistry and Cell Biology N2 - Multiple fluorescence in situ hybridization is the method of choice for studies aimed at determining simultaneous production of signal transduction molecules and neuromodulators in neurons. In our analyses of the monoamine receptor mRNA expression of peptidergic neurons in the rat telencephalon, double tyramide-signal-amplified fluorescence in situ hybridization delivered satisfactory results for coexpression analysis of neuropeptide Y (NPY) and serotonin receptor 2C (5-HT2C) mRNA, a receptor subtype expressed at high-to-moderate abundance in the regions analyzed. However, expression of 5-HT1A mRNA, which is expressed at comparatively low abundance in many telencephalic areas, could not be unequivocally identified in NPY mRNA-reactive neurons due to high background and poor signal-to-noise ratio in fluorescent receptor mRNA detections. Parallel chromogenic in situ hybridization provided clear labeling for 5-HT1A mRNA and additionally offered the possibility to monitor the chromogen deposition at regular time intervals to determine the optimal signal-to-noise ratio. We first developed a double labeling protocol combining fluorescence and chromogenic in situ hybridization and subsequently expanded this variation to combine double fluorescence and chromogenic in situ hybridization for triple labelings. With this method, we documented expression of 5-HT2C and/or 5-HT1A in subpopulations of telencephalic NPY-producing neurons. The method developed in the present study appears suitable for conventional light and fluorescence microscopy, combines advantages of fluorescence and chromogenic in situ hybridization protocols and thus provides a reliable non-radioactive alternative to previously published multiple labeling methods for coexpression analyses in which one mRNA species requires highly sensitive detection. KW - 5-HT1A KW - NPY KW - coexpression KW - triple in situ hybridization KW - 5-HT2C Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-127080 VL - 137 IS - 1 ER - TY - JOUR A1 - Brandt, Alexander U. A1 - Zimmermann, Hanna A1 - Kaufhold, Falko A1 - Promesberger, Julia A1 - Schippling, Sven A1 - Finis, David A1 - Aktas, Orhan A1 - Geis, Christian A1 - Ringelstein, Marius A1 - Ringelstein, E. Bernd A1 - Hartung, Hans-Peter A1 - Paul, Friedemann A1 - Kleffner, Ilka A1 - Dörr, Jan T1 - Patterns of Retinal Damage Facilitate Differential Diagnosis between Susac Syndrome and MS JF - PLoS One N2 - Susac syndrome, a rare but probably underdiagnosed combination of encephalopathy, hearing loss, and visual deficits due to branch retinal artery occlusion of unknown aetiology has to be considered as differential diagnosis in various conditions. Particularly, differentiation from multiple sclerosis is often challenging since both clinical presentation and diagnostic findings may overlap. Optical coherence tomography is a powerful and easy to perform diagnostic tool to analyse the morphological integrity of retinal structures and is increasingly established to depict characteristic patterns of retinal pathology in multiple sclerosis. Against this background we hypothesised that differential patterns of retinal pathology facilitate a reliable differentiation between Susac syndrome and multiple sclerosis. In this multicenter cross-sectional observational study optical coherence tomography was performed in nine patients with a definite diagnosis of Susac syndrome. Data were compared with age-, sex-, and disease duration-matched relapsing remitting multiple sclerosis patients with and without a history of optic neuritis, and with healthy controls. Using generalised estimating equation models, Susac patients showed a significant reduction in either or both retinal nerve fibre layer thickness and total macular volume in comparison to both healthy controls and relapsing remitting multiple sclerosis patients. However, in contrast to the multiple sclerosis patients this reduction was not distributed over the entire scanning area but showed a distinct sectorial loss especially in the macular measurements. We therefore conclude that patients with Susac syndrome show distinct abnormalities in optical coherence tomography in comparison to multiple sclerosis patients. These findings recommend optical coherence tomography as a promising tool for differentiating Susac syndrome from MS. KW - optical coherence tomography KW - vasculopathy KW - artery occlusion KW - hearing loss KW - microangiopathy KW - brain KW - endotheliopathy KW - antibodies KW - multiple-sclerosis KW - retinocochleocerebral Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134013 VL - 7 IS - 6 ER - TY - JOUR A1 - Brecht, Isabel A1 - Weissbrich, Benedikt A1 - Braun, Julia A1 - Toyka, Klaus Viktor A1 - Weishaupt, Andreas A1 - Buttmann, Mathias T1 - Intrathecal, Polyspecific Antiviral Immune Response in Oligoclonal Band Negative Multiple Sclerosis JF - PLoS One N2 - Background: Oligoclonal bands (OCB) are detected in the cerebrospinal fluid (CSF) in more than 95% of patients with multiple sclerosis (MS) in the Western hemisphere. Here we evaluated the intrathecal, polyspecific antiviral immune response as a potential diagnostic CSF marker for OCB-negative MS patients. Methodology/Principal Findings: We tested 46 OCB-negative German patients with paraclinically well defined, definite MS. Sixteen OCB-negative patients with a clear diagnosis of other autoimmune CNS disorders and 37 neurological patients without evidence for autoimmune CNS inflammation served as control groups. Antibodies against measles, rubella, varicella zoster and herpes simplex virus in paired serum and CSF samples were determined by ELISA, and virus-specific immunoglobulin G antibody indices were calculated. An intrathecal antibody synthesis against at least one neurotropic virus was detected in 8 of 26 (31%) patients with relapsing-remitting MS, 8 of 12 (67%) with secondary progressive MS and 5 of 8 (63%) with primary progressive MS, in 3 of 16 (19%) CNS autoimmune and 3 of 37 (8%) non-autoimmune control patients. Antibody synthesis against two or more viruses was found in 11 of 46 (24%) MS patients but in neither of the two control groups. On average, MS patients with a positive antiviral immune response were older and had a longer disease duration than those without. Conclusion: Determination of the intrathecal, polyspecific antiviral immune response may allow to establish a CSF-supported diagnosis of MS in OCB-negative patients when two or more of the four virus antibody indices are elevated. KW - MS KW - cerebrospinal fluid KW - differential diagnosis KW - nervous-system KW - criteria KW - serum Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134426 VL - 7 IS - 7 ER - TY - JOUR A1 - Brevoord, Daniel A1 - Kranke, Peter A1 - Kuijpers, Marijn A1 - Weber, Nina A1 - Hollmann, Markus A1 - Preckel, Benedikt T1 - Remote Ischemic Conditioning to Protect against Ischemia-Reperfusion Injury: A Systematic Review and Meta-Analysis JF - PLoS One N2 - Background: Remote ischemic conditioning is gaining interest as potential method to induce resistance against ischemia reperfusion injury in a variety of clinical settings. We performed a systematic review and meta-analysis to investigate whether remote ischemic conditioning reduces mortality, major adverse cardiovascular events, length of stay in hospital and in the intensive care unit and biomarker release in patients who suffer from or are at risk for ischemia reperfusion injury. Methods and Results: Medline, EMBASE and Cochrane databases were searched for randomized clinical trials comparing remote ischemic conditioning, regardless of timing, with no conditioning. Two investigators independently selected suitable trials, assessed trial quality and extracted data. 23 studies in patients undergoing cardiac surgery (15 studies), percutaneous coronary intervention (four studies) and vascular surgery (four studies), comprising in total 1878 patients, were included in this review. Compared to no conditioning, remote ischemic conditioning did not reduce mortality (odds ratio 1.22 [95% confidence interval 0.48, 3.07]) or major adverse cardiovascular events (0.65 [0.38, 1.14]). However, the incidence of myocardial infarction was reduced with remote ischemic conditioning (0.50 [0.31, 0.82]), as was peak troponin release (standardized mean difference -0.28 [-0.47, -0.09]). Conclusion: There is no evidence that remote ischemic conditioning reduces mortality associated with ischemic events; nor does it reduce major adverse cardiovascular events. However, remote ischemic conditioning did reduce the incidence of peri-procedural myocardial infarctions, as well as the release of troponin. KW - cardiac protection KW - stent KW - acute kidney injury KW - coronary artery bypass KW - randomized controlled trial KW - myocardial-infarction KW - aneurysm repair KW - graft surgery KW - humans KW - angioplasty Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134471 VL - 7 IS - 7 ER - TY - JOUR A1 - Buchin, Kevin A1 - Buchin, Maike A1 - Byrka, Jaroslaw A1 - Nöllenburg, Martin A1 - Okamoto, Yoshio A1 - Silveira, Rodrigo I. A1 - Wolff, Alexander T1 - Drawing (Complete) Binary Tanglegrams JF - Algorithmica N2 - A binary tanglegram is a drawing of a pair of rooted binary trees whose leaf sets are in one-to-one correspondence; matching leaves are connected by inter-tree edges. For applications, for example, in phylogenetics, it is essential that both trees are drawn without edge crossings and that the inter-tree edges have as few crossings as possible. It is known that finding a tanglegram with the minimum number of crossings is NP-hard and that the problem is fixed-parameter tractable with respect to that number. We prove that under the Unique Games Conjecture there is no constant-factor approximation for binary trees. We show that the problem is NP-hard even if both trees are complete binary trees. For this case we give an O(n 3)-time 2-approximation and a new, simple fixed-parameter algorithm. We show that the maximization version of the dual problem for binary trees can be reduced to a version of MaxCut for which the algorithm of Goemans and Williamson yields a 0.878-approximation. KW - NP-hardness KW - crossing minimization KW - binary tanglegram KW - approximation algorithm KW - fixed-parameter tractability Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124622 VL - 62 ER - TY - JOUR A1 - Buga, Ana-Maria A1 - Scholz, Claus Jürgen A1 - Kumar, Senthil A1 - Herndon, James G. A1 - Alexandru, Dragos A1 - Cojocaru, Gabriel Radu A1 - Dandekar, Thomas A1 - Popa-Wagner, Aurel T1 - Identification of New Therapeutic Targets by Genome-Wide Analysis of Gene Expression in the Ipsilateral Cortex of Aged Rats after Stroke JF - PLoS One N2 - Background: Because most human stroke victims are elderly, studies of experimental stroke in the aged rather than the young rat model may be optimal for identifying clinically relevant cellular responses, as well for pinpointing beneficial interventions. Methodology/Principal Findings: We employed the Affymetrix platform to analyze the whole-gene transcriptome following temporary ligation of the middle cerebral artery in aged and young rats. The correspondence, heat map, and dendrogram analyses independently suggest a differential, age-group-specific behaviour of major gene clusters after stroke. Overall, the pattern of gene expression strongly suggests that the response of the aged rat brain is qualitatively rather than quantitatively different from the young, i.e. the total number of regulated genes is comparable in the two age groups, but the aged rats had great difficulty in mounting a timely response to stroke. Our study indicates that four genes related to neuropathic syndrome, stress, anxiety disorders and depression (Acvr1c, Cort, Htr2b and Pnoc) may have impaired response to stroke in aged rats. New therapeutic options in aged rats may also include Calcrl, Cyp11b1, Prcp, Cebpa, Cfd, Gpnmb, Fcgr2b, Fcgr3a, Tnfrsf26, Adam 17 and Mmp14. An unexpected target is the enzyme 3-hydroxy-3-methylglutaryl-Coenzyme A synthase 1 in aged rats, a key enzyme in the cholesterol synthesis pathway. Post-stroke axonal growth was compromised in both age groups. Conclusion/Significance: We suggest that a multi-stage, multimodal treatment in aged animals may be more likely to produce positive results. Such a therapeutic approach should be focused on tissue restoration but should also address other aspects of patient post-stroke therapy such as neuropathic syndrome, stress, anxiety disorders, depression, neurotransmission and blood pressure. KW - gamma KW - corticotropin-releasing hormone KW - colony-stimulating factor KW - cerebral ischemia KW - receptor KW - brain KW - protein KW - inhibitor KW - mouse KW - differentiation Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130657 VL - 7 IS - 12 ER - TY - JOUR A1 - Burek, Malgorzata A1 - Salvador, Ellaine A1 - Förster, Carola Y. T1 - Generation of an Immortalized Murine Brain Microvascular Endothelial Cell Line as an In Vitro Blood Brain Barrier Model JF - Journal of Visualized Experiments N2 - Epithelial and endothelial cells (EC) are building paracellular barriers which protect the tissue from the external and internal environment. The blood-brain barrier (BBB) consisting of EC, astrocyte end-feet, pericytes and the basal membrane is responsible for the protection and homeostasis of the brain parenchyma. In vitro BBB models are common tools to study the structure and function of the BBB at the cellular level. A considerable number of different in vitro BBB models have been established for research in different laboratories to date. Usually, the cells are obtained from bovine, porcine, rat or mouse brain tissue (discussed in detail in the review by Wilhelm et al. 1). Human tissue samples are available only in a restricted number of laboratories or companies 2,3. While primary cell preparations are time consuming and the EC cultures can differ from batch to batch, the establishment of immortalized EC lines is the focus of scientific interest. Here, we present a method for establishing an immortalized brain microvascular EC line from neonatal mouse brain. We describe the procedure step-by-step listing the reagents and solutions used. The method established by our lab allows the isolation of a homogenous immortalized endothelial cell line within four to five weeks. The brain microvascular endothelial cell lines termed cEND 4 (from cerebral cortex) and cerebEND 5 (from cerebellar cortex), were isolated according to this procedure in the Förster laboratory and have been effectively used for explanation of different physiological and pathological processes at the BBB. Using cEND and cerebEND we have demonstrated that these cells respond to glucocorticoid- 4,6-9 and estrogen-treatment 10 as well as to pro-infammatory mediators, such as TNFalpha 5,8. Moreover, we have studied the pathology of multiple sclerosis 11 and hypoxia 12,13 on the EC-level. The cEND and cerebEND lines can be considered as a good tool for studying the structure and function of the BBB, cellular responses of ECs to different stimuli or interaction of the EC with lymphocytes or cancer cells. KW - in vitro cell culture models KW - blood-brain barrier KW - neuroscience KW - immunology KW - brain KW - microvascular endothelial cells KW - immortalization KW - cEND Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126702 VL - 66 IS - e4022 ER - TY - JOUR A1 - Böhler, Elmar A1 - Creignou, Nadia A1 - Galota, Matthias A1 - Reith, Steffen A1 - Schnoor, Henning A1 - Vollmer, Heribert T1 - Complexity Classifications for Different Equivalence and Audit Problems for Boolean Circuits JF - Logical Methods in Computer Science N2 - We study Boolean circuits as a representation of Boolean functions and conskier different equivalence, audit, and enumeration problems. For a number of restricted sets of gate types (bases) we obtain efficient algorithms, while for all other gate types we show these problems are at least NP-hard. KW - hierarchy KW - satisfiability problems Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131121 VL - 8 IS - 3:27 SP - 1 EP - 25 ER - TY - JOUR A1 - Ceteci, Fatih A1 - Ceteci, Semra A1 - Zanucco, Emanuele A1 - Thakur, Chitra A1 - Becker, Matthias A1 - El-Nikhely, Nefertiti A1 - Fink, Ludger A1 - Seeger, Werner A1 - Savai, Rajkumar A1 - Rapp, Ulf R. T1 - E-Cadherin Controls Bronchiolar Progenitor Cells and Onset of Preneoplastic Lesions in Mice JF - Neoplasia N2 - Although progenitor cells of the conducting airway have been spatially localized and some insights have been gained regarding their molecular phenotype, relatively little is known about the mechanisms regulating their maintenance, activation, and differentiation. This study investigates the potential roles of E-cadherin in mouse Clara cells, as these cells were shown to represent the progenitor/stem cells of the conducting airways and have been implicated as the cell of origin of human non-small cell lung cancer. Postnatal inactivation of E-cadherin affected Clara cell differentiation and compromised airway regeneration under injury conditions. In steady-state adult lung, overexpression of the dominant negative E-cadherin led to an expansion of the bronchiolar stem cells and decreased differentiation concomitant with canonical Wnt signaling activation. Expansion of the bronchiolar stem cell pool was associated with an incessant proliferation of neuroepithelial body-associated Clara cells that ultimately gave rise to bronchiolar hyperplasia. Despite progressive hyperplasia, only a minority of the mice developed pulmonary solid tumors, suggesting that the loss of E-cadherin function leads to tumor formation when additional mutations are sustained. The present study reveals that E-cadherin plays a critical role in the regulation of proliferation and homeostasis of the epithelial cells lining the conducting airways. KW - injury KW - lung cancer KW - stem cells KW - clara cell KW - gene expression KW - basal cell KW - in vivo KW - epithelium KW - airway KW - renewal Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135407 VL - 14 IS - 12 ER - TY - JOUR A1 - Chen, Wen A1 - Gaßner, Birgit A1 - Börner, Sebastian A1 - Nikolaev, Viacheslav O. A1 - Schlegel, Nicolas A1 - Waschke, Jens A1 - Steinbronn, Nadine A1 - Strasser, Ruth A1 - Kuhn, Michaela T1 - Atrial natriuretic peptide enhances microvascular albumin permeability by the caveolae-mediated transcellular pathway JF - Cardiovascular Research N2 - Aims Cardiac atrial natriuretic peptide (ANP) participates in the maintenance of arterial blood pressure and intravascular volume homeostasis. The hypovolaemic effects of ANP result from coordinated actions in the kidney and systemic microcirculation. Hence, ANP, via its guanylyl cyclase-A (GC-A) receptor and intracellular cyclic GMP as second messenger, stimulates endothelial albumin permeability. Ultimately, this leads to a shift of plasma fluid into interstitial pools. Here we studied the role of caveolae-mediated transendothelial albumin transport in the hyperpermeability effects of ANP. Methods and results Intravital microscopy studies of the mouse cremaster microcirculation showed that ANP stimulates the extravasation of fluorescent albumin from post-capillary venules and causes arteriolar vasodilatation. The hyperpermeability effect was prevented in mice with conditional, endothelial deletion of GC-A (EC GC-A KO) or with deleted caveolin-1 (cav-1), the caveolae scaffold protein. In contrast, the vasodilating effect was preserved. Concomitantly, the acute hypovolaemic action of ANP was abolished in EC GC-A KO and Cav-1−/− mice. In cultured microvascular rat fat pad and mouse lung endothelial cells, ANP stimulated uptake and transendothelial transport of fluorescent albumin without altering endothelial electrical resistance. The stimulatory effect on albumin uptake was prevented in GC-A- or cav-1-deficient pulmonary endothelia. Finally, preparation of caveolin-enriched lipid rafts from mouse lung and western blotting showed that GC-A and cGMP-dependent protein kinase I partly co-localize with Cav-1 in caveolae microdomains. Conclusion ANP enhances transendothelial caveolae-mediated albumin transport via its GC-A receptor. This ANP-mediated cross-talk between the heart and the microcirculation is critically involved in the regulation of intravascular volume. KW - caveolin-1 KW - microvessel permeability KW - atrial natriuretic peptide Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126562 N1 - Lizenzhinweis: The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for noncommercial purposes provided that the original authorship is properly and fully attributed; the Journal, Learned Society and Oxford University Press are attributed as the original place of publication with correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. VL - 93 IS - 1 ER - TY - JOUR A1 - Chenchiah, Isaac A1 - Schlömerkemper, Anja T1 - Non-laminate microstructures in monoclinic-I martensite N2 - We study the symmetrised rank-one convex hull of monoclinic-I martensite (a twelve-variant material) in the context of geometrically-linear elasticity. We construct sets of T3s, which are (non-trivial) symmetrised rank-one convex hulls of 3-tuples of pairwise incompatible strains. Moreover we construct a five-dimensional continuum of T3s and show that its intersection with the boundary of the symmetrised rank-one convex hull is four-dimensional. We also show that there is another kind of monoclinic-I martensite with qualitatively different semi-convex hulls which, so far as we know, has not been experimentally observed. Our strategy is to combine understanding of the algebraic structure of symmetrised rank-one convex cones with knowledge of the faceting structure of the convex polytope formed by the strains. KW - Martensit KW - Mehrskalenmodell KW - Phasenumwandlung KW - Variationsrechnung KW - kubisch-monokliner Phasenübergang KW - semi-konvexe Hüllen KW - geometrisch lineare Elastizitätstheorie KW - T3s KW - cubic-monoclinic martensites KW - semi-convex hulls KW - geometrically linear elasticity KW - T3s Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-72134 ER - TY - JOUR A1 - Conzelmann, Annette A1 - Reif, Andreas A1 - Jacob, Christian A1 - Weyers, Peter A1 - Lesch, Klaus-Peter A1 - Lutz, Beat A1 - Pauli, Paul T1 - A polymorphism in the gene of the endocannabinoid-degrading enzyme FAAH (FAAH C385A) is associated with emotional-motivational reactivity JF - Psychopharmacology N2 - RATIONALE: The endocannabinoid (eCB) system is implicated in several psychiatric disorders. Investigating emotional-motivational dysfunctions as underlying mechanisms, a study in humans revealed that in the C385A polymorphism of the fatty acid amide hydrolase (FAAH), the degrading enzyme of the eCB anandamide (AEA), A carriers, who are characterized by increased signaling of AEA as compared to C/C carriers, exhibited reduced brain reactivity towards unpleasant faces and enhanced reactivity towards reward. However, the association of eCB system with emotional-motivational reactivity is complex and bidirectional due to upcoming compensatory processes. OBJECTIVES: Therefore, we further investigated the relationship of the FAAH polymorphism and emotional-motivational reactivity in humans. METHODS: We assessed the affect-modulated startle, and ratings of valence and arousal in response to higher arousing pleasant, neutral, and unpleasant pictures in 67 FAAH C385A C/C carriers and 45 A carriers. RESULTS: Contrarily to the previous functional MRI study, A carriers compared to C/C carriers exhibited an increased startle potentiation and therefore emotional responsiveness towards unpleasant picture stimuli and reduced startle inhibition indicating reduced emotional reactivity in response to pleasant pictures, while both groups did not differ in ratings of arousal and valence. CONCLUSIONS: Our findings emphasize the bidirectionality and thorough examination of the eCB system's impact on emotional reactivity as a central endophenotype underlying various psychiatric disorders. KW - startle reflex KW - endocannabinoid KW - FAAH KW - genetics KW - emotion Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126845 VL - 224 IS - 4 ER - TY - JOUR A1 - Conzelmann, Annette A1 - Reif, Andreas A1 - Jacob, Christian A1 - Weyers, Peter A1 - Lesch, Klaus-Peter A1 - Lutz, Beat A1 - Pauli, Paul T1 - A polymorphism in the gene of the endocannabinoid-degrading enzyme FAAH (FAAH C385A) is associated with emotional–motivational reactivity JF - Psychopharmacology N2 - Rationale The endocannabinoid (eCB) system is implicated in several psychiatric disorders. Investigating emotional–motivational dysfunctions as underlying mechanisms, a study in humans revealed that in the C385A polymorphism of the fatty acid amide hydrolase (FAAH), the degrading enzyme of the eCB anandamide (AEA), A carriers, who are characterized by increased signaling of AEA as compared to C/C carriers, exhibited reduced brain reactivity towards unpleasant faces and enhanced reactivity towards reward. However, the association of eCB system with emotional–motivational reactivity is complex and bidirectional due to upcoming compensatory processes. Objectives Therefore, we further investigated the relationship of the FAAH polymorphism and emotional–motivational reactivity in humans. Methods We assessed the affect-modulated startle, and ratings of valence and arousal in response to higher arousing pleasant, neutral, and unpleasant pictures in 67 FAAH C385A C/C carriers and 45 A carriers. Results Contrarily to the previous functional MRI study, A carriers compared to C/C carriers exhibited an increased startle potentiation and therefore emotional responsiveness towards unpleasant picture stimuli and reduced startle inhibition indicating reduced emotional reactivity in response to pleasant pictures, while both groups did not differ in ratings of arousal and valence. Conclusions Our findings emphasize the bidirectionality and thorough examination of the eCB system’s impact on emotional reactivity as a central endophenotype underlying various psychiatric disorders. KW - startle reflex KW - FAAH KW - genetics KW - endocannabinoid KW - emotion Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129936 VL - 224 IS - 4 ER - TY - JOUR A1 - Cornelius, C. A1 - Leingärtner, A. A1 - Hoiss, B. A1 - Krauss, J. A1 - Steffan-Dewenter, I. A1 - Menzel, A. T1 - Phenological response of grassland species to manipulative snowmelt and drought along an altitudinal gradient N2 - Plant communities in the European Alps are assumed to be highly affected by climate change since temperature rise in this region is above the global average. It is predicted that higher temperatures will lead to advanced snowmelt dates and that the number of extreme weather events will increase. The aims of this study were to determine the impacts of extreme climatic events on flower phenology and to assess whether those impacts differed between lower and higher altitudes. In 2010 an experiment simulating advanced and delayed snowmelt as well as drought event was conducted along an altitudinal transect ca. every 250m (600-2000 m a.s.l.) in the Berchtesgaden National Park, Germany. The study showed that flower phenology is strongly affected by altitude; however there were few effects of the manipulative treatments on flowering. The effects of advanced snowmelt were significantly greater at higher than at lower sites, but no significant difference was found between both altitudinal bands for the other treatments. The response of flower phenology to temperature declined through the season and the length of flowering duration was not significantly influenced by treatments. The stronger effect of advanced snowmelt at higher altitudes might be a response to differences in treatment intensity across the gradient. Consequently, shifts in the date of snowmelt due to global warming may affect species more at higher than at lower altitudes since changes may be more pronounced at higher altitudes. Our data indicate a rather low risk of drought events on flowering phenology in the Bavarian Alps. KW - Biologie KW - Advanced snowmelt KW - Alps KW - BBCH KW - Climate change KW - Delayed snowmelt KW - Flowering Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-77969 N1 - ist zugleich: IV. Kapitel der Dissertation von Bernhard Hoiß ER - TY - JOUR A1 - d'Alquen, Daniela A1 - De Boeck, Kris A1 - Bradley, Judy A1 - Vávrová, Věra A1 - Dembski, Brigit A1 - Wagner, Thomas O.F. A1 - Pfalz, Annette A1 - Hebestreit, Helge T1 - Quality assessment of expert answers to lay questions about cystic fibrosis from various language zones in Europe: the ECORN-CF project N2 - Background: The European Centres of Reference Network for Cystic Fibrosis (ECORN-CF) established an Internet forum which provides the opportunity for CF patients and other interested people to ask experts questions about CF in their mother language. The objectives of this study were to: 1) develop a detailed quality assessment tool to analyze quality of expert answers, 2) evaluate the intra- and inter-rater agreement of this tool, and 3) explore changes in the quality of expert answers over the time frame of the project. Methods: The quality assessment tool was developed by an expert panel. Five experts within the ECORN-CF project used the quality assessment tool to analyze the quality of 108 expert answers published on ECORN-CF from six language zones. 25 expert answers were scored at two time points, one year apart. Quality of answers was also assessed at an early and later period of the project. Individual rater scores and group mean scores were analyzed for each expert answer. Results: A scoring system and training manual were developed analyzing two quality categories of answers: content and formal quality. For content quality, the grades based on group mean scores for all raters showed substantial agreement between two time points, however this was not the case for the grades based on individual rater scores. For formal quality the grades based on group mean scores showed only slight agreement between two time points and there was also poor agreement between time points for the individual grades. The inter-rater agreement for content quality was fair (mean kappa value 0.232 ± 0.036, p < 0.001) while only slight agreement was observed for the grades of the formal quality (mean kappa value 0.105 ± 0.024, p < 0.001). The quality of expert answers was rated high (four language zones) or satisfactory (two language zones) and did not change over time. Conclusions: The quality assessment tool described in this study was feasible and reliable when content quality was assessed by a group of raters. Within ECORN-CF, the tool will help ensure that CF patients all over Europe have equal possibility of access to high quality expert advice on their illness. KW - ECORN-CF Projekt Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75072 ER - TY - JOUR A1 - Dandekar, Thomas A1 - Fieselmann, Astrid A1 - Popp, Jasmin A1 - Hensel, Michael T1 - Salmonella enterica: a surprisingly well-adapted intracellular lifestyle JF - Frontiers in Microbiology N2 - The infectious intracellular lifestyle of Salmonella enterica relies on the adaptation to nutritional conditions within the Salmonella-containing vacuole (SCV) in host cells. We summarize latest results on metabolic requirements for Salmonella during infection. This includes intracellular phenotypes of mutant strains based on metabolic modeling and experimental tests, isotopolog profiling using (13)C-compounds in intracellular Salmonella, and complementation of metabolic defects for attenuated mutant strains towards a comprehensive understanding of the metabolic requirements of the intracellular lifestyle of Salmonella. Helpful for this are also genomic comparisons. We outline further recent studies and which analyses of intracellular phenotypes and improved metabolic simulations were done and comment on technical required steps as well as progress involved in the iterative refinement of metabolic flux models, analyses of mutant phenotypes, and isotopolog analyses. Salmonella lifestyle is well-adapted to the SCV and its specific metabolic requirements. Salmonella metabolism adapts rapidly to SCV conditions, the metabolic generalist Salmonella is quite successful in host infection. KW - Salmonella enterica KW - metabolism KW - Salmonella-containing vacuole KW - regulation KW - virulence Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-123135 ER - TY - JOUR A1 - Darwish, Hany W. A1 - Attia, Mohamed I. T1 - New spectrofluorimetric methods for determination of melatonin in the presence of N-{2-[1-({3-[2-(acetylamino)ethyl]-5-methoxy-1H-indol-2-yl}methyl)-5-methoxy-1H-indol-3-yl]ethyl} acetamide: a contaminant in commercial melatonin preparations JF - Chemistry Central Journal N2 - Background: Melatonin (MLT) has many health implications, therefore it is of valuable importance to develop specific analytical methods for determination of MLT in the presence of its main contaminant, N-{2-[1-({3-[2(acetylamino)ethyl]-5-methoxy-1H-indol-2-yl}methyl)-5-methoxy-1H-indol-3-yl]ethyl}acetamide (10). For development of these analytical methods, compound 10 had to be prepared in an adequate amount. Results: Compound 10 was synthesized in six steps starting from 5-methoxyindole-2-carboxylic acid (1). Analytical performance of the proposed spectrofluorimetric methods was statistically validated with respect to linearity, accuracy, precision and specificity. The proposed methods were successfully applied for the assay of MLT in laboratory prepared mixtures containing up to 60 % of compound 10 and in commercial MLT tablets with recoveries not less than 99.00 %. No interference was observed from common pharmaceutical additives and the results were favorably compared with those obtained by a reference method. Conclusions: This work describes simple, sensitive, and reliable second derivative spectrofluorimetric method in addition to two multivariate calibration methods, principal component regression (PCR) and partial least square (PLS), for the determination of MLT in the presence of compound 10. KW - melatonin KW - commercial preparations KW - spectrofluorimetry KW - synthesis KW - contaminants Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134606 VL - 6 IS - 36 ER - TY - JOUR A1 - Darwish, Hany W. A1 - Attia, Mohamed I. T1 - New spectrofluorimetric methods for determination of melatonin in the presence of N-{2-[1-({3-[2-(acetylamino)ethyl]-5-methoxy-1H-indol-2-yl}methyl)-5-methoxy-1H-indol-3-yl]- ethyl}acetamide: a contaminant in commercial melatonin preparations N2 - Background: Melatonin (MLT) has many health implications, therefore it is of valuable importance to develop specific analytical methods for determination of MLT in the presence of its main contaminant, N-{2-[1-({3-[2-(acetylamino)ethyl]-5-methoxy-1H-indol-2-yl}methyl)-5-methoxy-1H-indol-3-yl]ethyl}acetamide (10). For development of these analytical methods, compound 10 had to be prepared in an adequate amount. Results: Compound 10 was synthesized in six steps starting from 5-methoxyindole-2-carboxylic acid (1). Analytical performance of the proposed spectrofluorimetric methods was statistically validated with respect to linearity, accuracy, precision and specificity. The proposed methods were successfully applied for the assay of MLT in laboratory prepared mixtures containing up to 60 % of compound 10 and in commercial MLT tablets with recoveries not less than 99.00 %. No interference was observed from common pharmaceutical additives and the results were favorably compared with those obtained by a reference method. Conclusions: This work describes simple, sensitive, and reliable second derivative spectrofluorimetric method in addition to two multivariate calibration methods, principal component regression (PCR) and partial least square (PLS), for the determination of MLT in the presence of compound 10. KW - Chemie KW - Melatonin KW - Contaminants KW - Synthesis KW - Spectrofluorimetry KW - Commercial preparations Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-78234 ER - TY - JOUR A1 - Dietz, U. A. A1 - Wichelmann, C. A1 - Wunder, C. A1 - Kauczok, J. A1 - Spor, L. A1 - Strauß, A. A1 - Wildenauer, R. A1 - Jurowich, C. A1 - Germer, C. T. T1 - Early repair of open abdomen with a tailored two-component mesh and conditioning vacuum packing: a safe alternative to the planned giant ventral hernia JF - Hernia N2 - Purpose Once open abdomen therapy has succeeded, the problem of closing the abdominal wall must be addressed. We present a new four-stage procedure involving the application of a two-component mesh and vacuum conditioning for abdominal wall closure of even large defects. The aim is to prevent the development of a giant ventral hernia and the eventual need for the repair of the abdominal wall. Methods Nineteen of 62 patients treated by open abdomen over a two-year period could not receive primary abdominal wall closure. To achieve closure in these patients, we applied the following four-stage procedure: stage 1: abdominal damage control and conditioning of the abdominal wall; stage 2: attachment of a tailored two-component mesh of polyglycolic acid (PGA) and large pore polypropylene (PP) in intraperitoneal position (IPOM) plus placement of a vacuum bandage; stage 3: vacuum therapy for 3–4 weeks to allow granulation of the mesh and optimization of dermatotraction; stage 4: final skin suture. During stage 3, eligible patients were weaned from respirator and mobilized. Results The abdominal wall gap in the 19 patients ranged in size from 240 cm2 to more than 900 cm2. An average of 3.44 vacuum dressing changes over 19 days were required to achieve 60–100 % granulation of the surface area, so final skin suture could be made. Already in stage 3, 14 patients (73.68 %) could be weaned from respirator an average of 6.78 days after placement of the two-component mesh; 6 patients (31.57 %) could be mobilized on the edge of the bed and/or to a bedside chair after an average of 13 days. No mesh-related hematomas, seromas, or intestinal fistulas were observed. Conclusion The four-stage procedure presented here is a viable option for achieving abdominal wall closure in patients treated with open abdomen, enabling us to avoid the development of planned giant ventral hernias. It has few complications and has the special advantage of allowing mobilization of the patients before final skin closure. Long-term course in a large number of patients must still confirm this result. KW - synthetic mesh KW - giant ventral hernia KW - laparostomy KW - open abdomen KW - vacuum conditioning Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126732 VL - 16 IS - 4 ER - TY - JOUR A1 - Dietz, U. A. A1 - Wichelmann, C. A1 - Wunder, C. A1 - Kauczok, J. A1 - Spor, L. A1 - Strauß, A. A1 - Wildenauer, R. A1 - Jurowich, C. A1 - Germer, C. T. T1 - Early repair of open abdomen with a tailored two-component mesh and conditioning vacuum packing: a safe alternative to the planned giant ventral hernia JF - Hernia N2 - Purpose Once open abdomen therapy has succeeded, the problem of closing the abdominal wall must be addressed. We present a new four-stage procedure involving the application of a two-component mesh and vacuum conditioning for abdominal wall closure of even large defects. The aim is to prevent the development of a giant ventral hernia and the eventual need for the repair of the abdominal wall. Methods Nineteen of 62 patients treated by open abdomen over a two-year period could not receive primary abdominal wall closure. To achieve closure in these patients, we applied the following four-stage procedure: stage 1: abdominal damage control and conditioning of the abdominal wall; stage 2: attachment of a tailored two-component mesh of polyglycolic acid (PGA) and large pore polypropylene (PP) in intraperitoneal position (IPOM) plus placement of a vacuum bandage; stage 3: vacuum therapy for 3–4 weeks to allow granulation of the mesh and optimization of dermatotraction; stage 4: final skin suture. During stage 3, eligible patients were weaned from respirator and mobilized. Results The abdominal wall gap in the 19 patients ranged in size from 240 cm2 to more than 900 cm2. An average of 3.44 vacuum dressing changes over 19 days were required to achieve 60–100 % granulation of the surface area, so final skin suture could be made. Already in stage 3, 14 patients (73.68 %) could be weaned from respirator an average of 6.78 days after placement of the two-component mesh; 6 patients (31.57 %) could be mobilized on the edge of the bed and/or to a bedside chair after an average of 13 days. No mesh-related hematomas, seromas, or intestinal fistulas were observed. Conclusion The four-stage procedure presented here is a viable option for achieving abdominal wall closure in patients treated with open abdomen, enabling us to avoid the development of planned giant ventral hernias. It has few complications and has the special advantage of allowing mobilization of the patients before final skin closure. Long-term course in a large number of patients must still confirm this result. KW - synthetic mesh KW - open abdomen KW - laparostomy KW - giant ventral hernia KW - vacuum conditioning Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124686 VL - 16 IS - 4 ER - TY - JOUR A1 - Dorsch, Oliver A1 - Krieter, Detlef H. A1 - Lemke, Horst-Dieter A1 - Fischer, Stefan A1 - Melzer, Nima A1 - Sieder, Christian A1 - Bramlage, Peter A1 - Harenberg, Job T1 - A multi-center, prospective, open-label, 8-week study of certoparin for anticoagulation during maintenance hemodialysis – the membrane study JF - BMC Nephrology N2 - Background Adequate anticoagulation is prerequisite for effective hemodialysis to prevent clotting in the extracorporeal circuit. We aimed providing first data on the efficacy and safety of the low-molecular-weight heparin certoparin in this setting. Methods Multicenter, open-label, 8-week trial. Patients received a single dose of 3,000 IU certoparin i.v. with additional titration steps of 600 IU and/or continuous infusion if necessary. Results 120 patients were screened, 109 enrolled (median age 71; range 26–90 years) and 106 available for efficacy analyses. The percentage of unsatisfactory dialysis results at 8 weeks due to clotting or bleeding, was 1.9% (n = 2/106; 95% confidence interval [CI] 0.23–6.65%); no major bleeding. 1.9% had moderate/severe clotting in the lines/bubble catcher and 2.8% in the dialyser at week 8. 15.7 ± 14.3% of the dialysis filters’ visual surface area was showing redness. In subgroups of patients receiving median doses of 3000 ± 0, 3000 (2400–6000) and 4200 (3000–6600) IU, plasma aXa levels at baseline, 4 and 8 weeks were 0.24 [95%CI 0.21–0.27], 0.33 [0.27–0.40] and 0.38 [0.33–0.45] aXa IU/ml at 2 h. \(C_{48h}\) was 0.01 [0.01–0.02] aXa IU at all visits. At baseline and 4 weeks \(AUC_{0-48h}\) was 2.66 [2.19–3.24] and 3.66 [3.00–4.45] aXa IU*h/ml. In 3.0% of dialyses (n = 83/2724) prolonged fistula compression times were documented. Eight patients (7.34%) had at least one episode of minor bleeding. 4) 85.3% of patients had any adverse event, 9.2% were serious without suspected drug relation; and in 32 patients a drug-relation was suspected. Conclusions Certoparin appears effective and safe for anticoagulation in patients undergoing maintenance hemodialysis. KW - hemodialysis Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124052 VL - 13 IS - 50 ER - TY - JOUR A1 - Dorsch, Oliver A1 - Krieter, Detlef H. A1 - Lemke, Horst-Dieter A1 - Fischer, Stefan A1 - Melzer, Nima A1 - Sieder, Christian A1 - Bramlage, Peter A1 - Harenberg, Job T1 - A multi-center, prospective, open-label, 8-week study of certoparin for anticoagulation during maintenance hemodialysis - the membrane study JF - BMC Nephrology N2 - Background: Adequate anticoagulation is prerequisite for effective hemodialysis to prevent clotting in the extracorporeal circuit. We aimed providing first data on the efficacy and safety of the low-molecular-weight heparin certoparin in this setting. Methods: Multicenter, open-label, 8-week trial. Patients received a single dose of 3,000 IU certoparin i.v. with additional titration steps of 600 IU and/or continuous infusion if necessary. Results: 120 patients were screened, 109 enrolled (median age 71; range 26-90 years) and 106 available for efficacy analyses. The percentage of unsatisfactory dialysis results at 8 weeks due to clotting or bleeding, was 1.9% (n = 2/106; 95% confidence interval [CI] 0.23-6.65%); no major bleeding. 1.9% had moderate/severe clotting in the lines/bubble catcher and 2.8% in the dialyser at week 8.15.7 +/- 14.3% of the dialysis filters' visual surface area was showing redness. In subgroups of patients receiving median doses of 3000 +/- 0, 3000 (2400-6000) and 4200 (3000-6600) IU, plasma aXa levels at baseline, 4 and 8 weeks were 0.24 [ 95% CI 0.21-0.27], 0.33 [0.27-0.40] and 0.38 [0.33-0.45] aXa IU/ml at 2 h. C-48h was 0.01 [0.01-0.02] aXa IU at all visits. At baseline and 4 weeks AUC(0-48h) was 2.66 [2.19-3.24] and 3.66 [3.00-4.45] aXa IU*h/ml. In 3.0% of dialyses (n = 83/2724) prolonged fistula compression times were documented. Eight patients (7.34%) had at least one episode of minor bleeding. 4) 85.3% of patients had any adverse event, 9.2% were serious without suspected drug relation; and in 32 patients a drug-relation was suspected. Conclusions: Certoparin appears effective and safe for anticoagulation in patients undergoing maintenance hemodialysis. KW - XA KW - low molecular weight KW - severe renal insufficiency KW - unfractionated heparin KW - standard heparin KW - enoxaparin KW - metaanalysis KW - coagulation KW - fragmin KW - sodium Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134845 VL - 13 IS - 50 ER - TY - JOUR A1 - Dosso, Kanvaly A1 - Yeo, Kolo A1 - Konate, Souleymane A1 - Linsenmair, Karl Eduard T1 - Importance of protected areas for biodiversity conservation in central Cote d'Ivoire: Comparison of termite assemblages between two neighboring areas under differing levels of disturbance JF - Journal of Insect Science N2 - To highlight human impact on biodiversity in the Lamto region, termites were studied with regard to their use as bio-indicators of habitat change in the tropics. Using a standardized method, termites were sampled in the three most common habitat types, i.e., in semi-deciduous forest, savanna woodland, and annually burned savanna, all inside Lamto Reserve and its surrounding rural domain. Termite species richness fell from 25 species in the Lamto forest to 13 species in the rural area, involving strong modification in the species composition (species turnover = 59 %). In contrast, no significant change in diversity was found between the Lamto savannas and the rural ones. In addition, the relative abundance of termites showed a significantly greater decline in the rural domain, even in the species Ancistrotermes cavithorax (Sjostedt) (Isoptera: Termitidae), which is known to be ecologically especially versatile. Overall, the findings of this study suggest further investigation around Lamto Reserve on the impact of human activities on biodiversity, focusing on forest conversion to land uses (e.g. agricultural and silvicultural systems). KW - species richness KW - Savanna KW - trinervitermes KW - rural domain KW - ant communities KW - gradient KW - Amazonia KW - forest disturbance KW - diversity KW - soil macrofauna KW - West Africa KW - land use KW - burned savanna KW - forest KW - Lamto Reserve KW - relative abundance KW - savanna woodland KW - species composition Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133218 VL - 12 IS - 131 ER - TY - JOUR A1 - Drechsler, Johannes A1 - Groetzinger, Joachim A1 - Hermanns, Heike M. T1 - Characterization of the Rat Oncostatin M Receptor Complex Which Resembles the Human, but Differs from the Murine Cytokine Receptor JF - PLoS One N2 - Evaluation of a pathophysiological role of the interleukin-6-type cytokine oncostatin M (OSM) for human diseases has been complicated by the fact that mouse models of diseases targeting either OSM or the OSM receptor (OSMR) complex cannot fully reflect the human situation. This is due to earlier findings that human OSM utilizes two receptor complexes, glycoprotein 130 (gp130)/leukemia inhibitory factor receptor (LIFR) (type I) and gp130/OSMR (type II), both with wide expression profiles. Murine OSM on the other hand only binds to the gp130/OSMR (type II) receptor complex with high affinity. Here, we characterize the receptor usage for rat OSM. Using different experimental approaches (knock-down of the OSMR expression by RNA interference, blocking of the LIFR by LIF-05, an antagonistic LIF variant and stably transfected Ba/F3 cells) we can clearly show that rat OSM surprisingly utilizes both, the type I and type II receptor complex, therefore mimicking the human situation. Furthermore, it displays cross-species activities and stimulates cells of human as well as murine origin. Its signaling capacities closely mimic those of human OSM in cell types of different origin in the way that strong activation of the Jak/STAT, the MAP kinase as well as the PI3K/Akt pathways can be observed. Therefore, rat disease models would allow evaluation of the relevance of OSM for human biology. KW - in vitro KW - leukemia-inhibitory factor KW - ciliary neurotrophic factor KW - T cell development KW - swiss model KW - fetal liver KW - interleukin-6-type cytokines KW - rheumatoid arthritis KW - signal transduction KW - growth regulator Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133879 VL - 7 IS - 8 ER - TY - JOUR A1 - Drechsler, Johannes A1 - Grötzinger, Joachim A1 - Hermanns, Heike M. T1 - Characterization of the Rat Oncostatin M Receptor Complex Which Resembles the Human, but Differs from the Murine Cytokine Receptor N2 - Evaluation of a pathophysiological role of the interleukin-6-type cytokine oncostatin M (OSM) for human diseases has been complicated by the fact that mouse models of diseases targeting either OSM or the OSM receptor (OSMR) complex cannot fully reflect the human situation. This is due to earlier findings that human OSM utilizes two receptor complexes, glycoprotein 130 (gp130)/leukemia inhibitory factor receptor (LIFR) (type I) and gp130/OSMR (type II), both with wide expression profiles. Murine OSM on the other hand only binds to the gp130/OSMR (type II) receptor complex with high affinity. Here, we characterize the receptor usage for rat OSM. Using different experimental approaches (knock-down of the OSMR expression by RNA interference, blocking of the LIFR by LIF-05, an antagonistic LIF variant and stably transfected Ba/F3 cells) we can clearly show that rat OSM surprisingly utilizes both, the type I and type II receptor complex, therefore mimicking the human situation. Furthermore, it displays cross-species activities and stimulates cells of human as well as murine origin. Its signaling capacities closely mimic those of human OSM in cell types of different origin in the way that strong activation of the Jak/STAT, the MAP kinase as well as the PI3K/Akt pathways can be observed. Therefore, rat disease models would allow evaluation of the relevance of OSM for human biology. KW - Biologie Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-78856 ER - TY - JOUR A1 - Dreyer, Ingo A1 - Gomez-Porras, Judith Lucia A1 - Riaño-Pachón, Diego Mauricio A1 - Hedrich, Rainer A1 - Geiger, Dietmar T1 - Molecular Evolution of Slow and Quick Anion Channels (SLACs and QUACs/ALMTs) JF - Frontiers in Plant Science N2 - Electrophysiological analyses conducted about 25 years ago detected two types of anion channels in the plasma membrane of guard cells. One type of channel responds slowly to changes in membrane voltage while the other responds quickly. Consequently, they were named SLAC, for SLow Anion Channel, and QUAC, for QUick Anion Channel. Recently, genes SLAC1 and QUAC1/ALMT12, underlying the two different anion current components, could be identified in the model plant Arabidopsis thaliana. Expression of the gene products in Xenopus oocytes confirmed the quick and slow current kinetics. In this study we provide an overview on our current knowledge on slow and quick anion channels in plants and analyze the molecular evolution of ALMT/QUAC-like and SLAC-like channels. We discovered fingerprints that allow screening databases for these channel types and were able to identify 192 (177 non-redundant) SLAC-like and 422 (402 non-redundant) ALMT/QUAC-like proteins in the fully sequenced genomes of 32 plant species. Phylogenetic analyses provided new insights into the molecular evolution of these channel types. We also combined sequence alignment and clustering with predictions of protein features, leading to the identification of known conserved phosphorylation sites in SLAC1-like channels along with potential sites that have not been yet experimentally confirmed. Using a similar strategy to analyze the hydropathicity of ALMT/QUAC-like channels, we propose a modified topology with additional transmembrane regions that integrates structure and function of these membrane proteins. Our results suggest that cross-referencing phylogenetic analyses with position-specific protein properties and functional data could be a very powerful tool for genome research approaches in general. KW - anion channel KW - evolution KW - SLAC/SLAH KW - ALMT KW - QUAC KW - voltage dependent KW - topology KW - phosphorylation Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-189345 SN - 1664-462X VL - 3 ER - TY - JOUR A1 - Dubovyk, Olena A1 - Menz, Gunter A1 - Conrad, Christopher A1 - Kann, Elena A1 - Machwitz, Miriam A1 - Khamzina, Asia T1 - Spatio-temporal analyses of cropland degradation in the irrigated lowlands of Uzbekistan using remote-sensing and logistic regression modeling JF - Environmental Monitoring and Assessment N2 - Advancing land degradation in the irrigated areas of Central Asia hinders sustainable development of this predominantly agricultural region. To support decisions on mitigating cropland degradation, this study combines linear trend analysis and spatial logistic regression modeling to expose a land degradation trend in the Khorezm region, Uzbekistan, and to analyze the causes. Time series of the 250-m MODIS NDVI, summed over the growing seasons of 2000–2010, were used to derive areas with an apparent negative vegetation trend; this was interpreted as an indicator of land degradation. About one third (161,000 ha) of the region’s area experienced negative trends of different magnitude. The vegetation decline was particularly evident on the low-fertility lands bordering on the natural sandy desert, suggesting that these areas should be prioritized in mitigation planning. The results of logistic modeling indicate that the spatial pattern of the observed trend is mainly associated with the level of the groundwater table (odds = 330 %), land-use intensity (odds = 103 %), low soil quality (odds = 49 %), slope (odds = 29 %), and salinity of the groundwater (odds = 26 %). Areas, threatened by land degradation, were mapped by fitting the estimated model parameters to available data. The elaborated approach, combining remote-sensing and GIS, can form the basis for developing a common tool for monitoring land degradation trends in irrigated croplands of Central Asia. KW - lower reaches of Amu Darya River KW - cropland abandonment KW - linear trend analysis KW - logistic regression modeling KW - MODIS KW - NDVI Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129912 VL - 185 IS - 6 ER - TY - JOUR A1 - Dupuis, Luc A1 - Dengler, Reinhard A1 - Heneka, Michael T. A1 - Meyer, Thomas A1 - Zierz, Stephan A1 - Kassubek, Jan A1 - Fischer, Wilhelm A1 - Steiner, Franziska A1 - Lindauer, Eva A1 - Otto, Markus A1 - Dreyhaupt, Jens A1 - Grehl, Torsten A1 - Hermann, Andreas A1 - Winkler, Andrea S. A1 - Bogdahn, Ulrich A1 - Benecke, Reiner A1 - Schrank, Bertold A1 - Wessig, Carsten A1 - Grosskreutz, Julian A1 - Ludolph, Albert C. T1 - A Randomized, Double Blind, Placebo-Controlled Trial of Pioglitazone in Combination with Riluzole in Amyotrophic Lateral Sclerosis JF - PLoS One N2 - Background: Pioglitazone, an oral anti-diabetic that stimulates the PPAR-gamma transcription factor, increased survival of mice with amyotrophic lateral sclerosis (ALS). Methods/Principal Findings: We performed a phase II, double blind, multicentre, placebo controlled trial of pioglitazone in ALS patients under riluzole. 219 patients were randomly assigned to receive 45 mg/day of pioglitazone or placebo (one: one allocation ratio). The primary endpoint was survival. Secondary endpoints included incidence of non-invasive ventilation and tracheotomy, and slopes of ALS-FRS, slow vital capacity, and quality of life as assessed using EUROQoL EQ-5D. The study was conducted under a two-stage group sequential test, allowing to stop for futility or superiority after interim analysis. Shortly after interim analysis, 30 patients under pioglitazone and 24 patients under placebo had died. The trial was stopped for futility; the hazard ratio for primary endpoint was 1.21 (95% CI: 0.71-2.07, p = 0.48). Secondary endpoints were not modified by pioglitazone treatment. Pioglitazone was well tolerated. Conclusion/Significance: Pioglitazone has no beneficial effects on the survival of ALS patients as add-on therapy to riluzole. KW - ALS KW - transgenic mouse model KW - central nervous system KW - nonalcoholic steatohepatitis KW - PPAR-gamme KW - hexanucleotide repeat KW - disease progression KW - delays progression KW - SOD1 mutations KW - monocycline Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130255 VL - 7 IS - 6 ER - TY - JOUR A1 - Durrenberger, Pascal F. A1 - Grünblatt, Edna A1 - Fernando, Francesca S. A1 - Monoranu, Camelia Maria A1 - Evans, Jordan A1 - Riederer, Peter A1 - Reynolds, Richard A1 - Dexter, David T. T1 - Inflammatory Pathways in Parkinson’s Disease; A BNE Microarray Study JF - Parkinson's Disease N2 - The aetiology of Parkinson's disease (PD) is yet to be fully understood but it is becoming more and more evident that neuronal cell death may be multifactorial in essence. The main focus of PD research is to better understand substantia nigra homeostasis disruption, particularly in relation to the wide-spread deposition of the aberrant protein α-synuclein. Microarray technology contributed towards PD research with several studies to date and one gene, ALDH1A1 (Aldehyde dehydrogenase 1 family, member A1), consistently reappeared across studies including the present study, highlighting dopamine (DA) metabolism dysfunction resulting in oxidative stress and most probably leading to neuronal cell death. Neuronal cell death leads to increased inflammation through the activation of astrocytes and microglia. Using our dataset, we aimed to isolate some of these pathways so to offer potential novel neuroprotective therapeutic avenues. To that effect our study has focused on the upregulation of P2X7 (purinergic receptor P2X, ligand-gated ion channel, 7) receptor pathway (microglial activation) and on the NOS3 (nitric oxide synthase 3) pathway (angiogenesis). In summary, although the exact initiator of striatal DA neuronal cell death remains to be determined, based on our analysis, this event does not remain without consequence. Extracellular ATP and reactive astrocytes appear to be responsible for the activation of microglia which in turn release proinflammatory cytokines contributing further to the parkinsonian condition. In addition to tackling oxidative stress pathways we also suggest to reduce microglial and endothelial activation to support neuronal outgrowth. Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124380 VL - 2012 IS - 214714 ER - TY - JOUR A1 - El-Keredy, Amira A1 - Schleyer, Michael A1 - König, Christian A1 - Ekim, Aslihan A1 - Gerber, Bertram T1 - Behavioural Analyses of Quinine Processing in Choice, Feeding and Learning of Larval Drosophila JF - PLoS One N2 - Gustatory stimuli can support both immediate reflexive behaviour, such as choice and feeding, and can drive internal reinforcement in associative learning. For larval Drosophila, we here provide a first systematic behavioural analysis of these functions with respect to quinine as a study case of a substance which humans report as "tasting bitter". We describe the dose-effect functions for these different kinds of behaviour and find that a half-maximal effect of quinine to suppress feeding needs substantially higher quinine concentrations (2.0 mM) than is the case for internal reinforcement (0.6 mM). Interestingly, in previous studies (Niewalda et al. 2008, Schipanski et al 2008) we had found the reverse for sodium chloride and fructose/sucrose, such that dose-effect functions for those tastants were shifted towards lower concentrations for feeding as compared to reinforcement, arguing that the differences in dose-effect function between these behaviours do not reflect artefacts of the types of assay used. The current results regarding quinine thus provide a starting point to investigate how the gustatory system is organized on the cellular and/or molecular level to result in different behavioural tuning curves towards a bitter tastant. KW - honeybees KW - chemosensory system KW - bitter taste KW - melanogaster KW - receptor KW - reward KW - brain KW - organization KW - architecture KW - perception Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130811 VL - 7 IS - 7 ER - TY - JOUR A1 - Erhardt, A. A1 - Akula, N. A1 - Schumacher, J. A1 - Czamara, D. A1 - Karbalai, N. A1 - Müller-Myhsok, B. A1 - Mors, O. A1 - Borglum, A. A1 - Kristensen, A. S. A1 - Woldbye, D. P. D. A1 - Koefoed, P. A1 - Eriksson, E. A1 - Maron, E. A1 - Metspalu, A. A1 - Nurnberger, J. A1 - Philibert, R. A. A1 - Kennedy, J. A1 - Domschke, K. A1 - Reif, A. A1 - Deckert, J. A1 - Otowa, T. A1 - Kawamura, Y. A1 - Kaiya, H. A1 - Okazaki, Y. A1 - Tanii, H. A1 - Tokunaga, K. A1 - Sasaki, T. A1 - Ioannidis, J. P. A. A1 - McMahon, F. J. A1 - Binder, E. B. T1 - Replication and meta-analysis of TMEM132D gene variants in panic disorder JF - Translational Psychiatry N2 - A recent genome-wide association study in patients with panic disorder (PD) identified a risk haplotype consisting of two single-nucleotide polymorphisms (SNPs) (rs7309727 and rs11060369) located in intron 3 of TMEM132D to be associated with PD in three independent samples. Now we report a subsequent confirmation study using five additional PD case-control samples (n = 1670 cases and n 2266 controls) assembled as part of the Panic Disorder International Consortium (PanIC) study for a total of 2678 cases and 3262 controls in the analysis. In the new independent samples of European ancestry (EA), the association of rs7309727 and the risk haplotype rs7309727-rs11060369 was, indeed, replicated, with the strongest signal coming from patients with primary PD, that is, patients without major psychiatric comorbidities (n 1038 cases and n 2411 controls). This finding was paralleled by the results of the meta-analysis across all samples, in which the risk haplotype and rs7309727 reached P-levels of P = 1.4e-8 and P = 1.1e-8, respectively, when restricting the samples to individuals of EA with primary PD. In the Japanese sample no associations with PD could be found. The present results support the initial finding that TMEM132D gene contributes to genetic susceptibility for PD in individuals of EA. Our results also indicate that patient ascertainment and genetic background could be important sources of heterogeneity modifying this association signal in different populations. KW - candidate gene KW - genome-wide association KW - Japanese population Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133324 VL - 2 IS - e156 ER - TY - JOUR A1 - Ermert, Volker A1 - Fink, Andreas H. A1 - Morse, Andrew P. A1 - Paeth, Heiko T1 - The Impact of Regional Climate Change on Malaria Risk due to Greenhouse Forcing and Land-Use Changes in Tropical Africa JF - Environmental Health Perspectives N2 - BACKGROUND: Climate change will probably alter the spread and transmission intensity of malaria in Africa. OBJECTIVES: In this study, we assessed potential changes in the malaria transmission via an integrated weather disease model. METHODS: We simulated mosquito biting rates using the Liverpool Malaria Model (LMM). The input data for the LMM were bias-corrected temperature and precipitation data from the regional model (REMO) on a 0.5 degrees latitude longitude grid. A Plasmodium falciparum infection model expands the LMM simulations to incorporate information on the infection rate among children. Malaria projections were carried out with this integrated weather disease model for 2001 to 2050 according to two climate scenarios that include the effect of anthropogenic land-use and land-cover changes on climate. RESULTS: Model-based estimates for the present climate (1960 to 2000) are consistent with observed data for the spread of malaria in Africa. In the model domain, the regions where malaria is epidemic are located in the Sahel as well as in various highland territories. A decreased spread of malaria over most parts of tropical Africa is projected because of simulated increased surface temperatures and a significant reduction in annual rainfall. However, the likelihood of malaria epidemics is projected to increase in the southern part of the Sahel. In most of East Africa, the intensity of malaria transmission is expected to increase. Projections indicate that highland areas that were formerly unsuitable for malaria will become epidemic, whereas in the lower-altitude regions of the East African highlands, epidemic risk will decrease. CONCLUSIONS: We project that climate changes driven by greenhouse-gas and land-use changes will significantly affect the spread of malaria in tropical Africa well before 2050. The geographic distribution of areas where malaria is epidemic might have to be significantly altered in the coming decades. KW - climate change KW - West Africa KW - highland malaria KW - malaria KW - malaria model KW - malaria projection KW - Sahel KW - transmission KW - model KW - highlands KW - temperatures KW - validation KW - resurgence KW - scenarios KW - epidemic KW - deseases Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135562 VL - 120 IS - 1 ER - TY - JOUR A1 - Fehrholz, Markus A1 - Bersani, Iliana A1 - Kramer, Boris W. A1 - Speer, Christian P. A1 - Kunzmann, Steffen T1 - Synergistic Effect of Caffeine and Glucocorticoids on Expression of Surfactant Protein B (SP-B) mRNA N2 - Administration of glucocorticoids and caffeine is a common therapeutic intervention in the neonatal period, but possible interactions between these substances are still unclear. The present study investigated the effect of caffeine and different glucocorticoids on expression of surfactant protein (SP)-B, crucial for the physiological function of pulmonary surfactant. We measured expression levels of SP-B, various SP-B transcription factors including erythroblastic leukemia viral oncogene homolog 4 (ErbB4) and thyroid transcription factor-1 (TTF-1), as well as the glucocorticoid receptor (GR) after administering different doses of glucocorticoids, caffeine, cAMP, or the phosphodiesterase-4 inhibitor rolipram in the human airway epithelial cell line NCI-H441. Administration of dexamethasone (1 mM) or caffeine (5 mM) stimulated SP-B mRNA expression with a maximal of 38.8611.1-fold and 5.261.4-fold increase, respectively. Synergistic induction was achieved after coadministration of dexamethasone (1 mM) in combination with caffeine (10 mM) (206659.7-fold increase, p,0.0001) or cAMP (1 mM) (2136111-fold increase, p = 0.0108). SP-B mRNA was synergistically induced also by administration of caffeine with hydrocortisone (87.9639.0), prednisolone (154666.8), and betamethasone (12366.4). Rolipram also induced SP-B mRNA (64.9621.0-fold increase). We detected a higher expression of ErbB4 and GR mRNA (7.0- and 1.7-fold increase, respectively), whereas TTF-1, Jun B, c-Jun, SP1, SP3, and HNF-3a mRNA expression was predominantly unchanged. In accordance with mRNA data, mature SP-B was induced significantly by dexamethasone with caffeine (13.869.0-fold increase, p = 0.0134). We found a synergistic upregulation of SP-B mRNA expression induced by co-administration of various glucocorticoids and caffeine, achieved by accumulation of intracellular cAMP. This effect was mediated by a caffeinedependent phosphodiesterase inhibition and by upregulation of both ErbB4 and the GR. These results suggested that caffeine is able to induce the expression of SP-transcription factors and affects the signaling pathways of glucocorticoids, amplifying their effects. Co-administration of caffeine and corticosteroids may therefore be of benefit in surfactant homeostasis. KW - Medizin Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-77927 ER - TY - JOUR A1 - Fernández-Rodríguez, Juana A1 - Quiles, Francisco A1 - Blanco, Ignacio A1 - Teulé, Alex A1 - Feliubadaló, Lídia A1 - del Valle, Jesús A1 - Salinas, Mónica A1 - Izquierdo, Ángel A1 - Darder, Esther A1 - Schindler, Detlev A1 - Capellá, Gabriel A1 - Brunet, Joan A1 - Lázaro, Conxi A1 - Angel Pujana, Miguel T1 - Analysis of SLX4/FANCP in non-BRCA1/2-mutated breast cancer families JF - BMC Cancer N2 - Background: Genes that, when mutated, cause Fanconi anemia or greatly increase breast cancer risk encode for proteins that converge on a homology-directed DNA damage repair process. Mutations in the SLX4 gene, which encodes for a scaffold protein involved in the repair of interstrand cross-links, have recently been identified in unclassified Fanconi anemia patients. A mutation analysis of SLX4 in German or Byelorussian familial cases of breast cancer without detected mutations in BRCA1 or BRCA2 has been completed, with globally negative results. Methods: The genomic region of SLX4, comprising all exons and exon-intron boundaries, was sequenced in 94 Spanish familial breast cancer cases that match a criterion indicating the potential presence of a highly-penetrant germline mutation, following exclusion of BRCA1 or BRCA2 mutations. Results: This mutational analysis revealed extensive genetic variation of SLX4, with 21 novel single nucleotide variants; however, none could be linked to a clear alteration of the protein function. Nonetheless, genotyping 10 variants (nine novel, all missense amino acid changes) in a set of controls (138 women and 146 men) did not detect seven of them. Conclusions: Overall, while the results of this study do not identify clearly pathogenic mutations of SLX4 contributing to breast cancer risk, further genetic analysis, combined with functional assays of the identified rare variants, may be warranted to conclusively assess the potential link with the disease. KW - SLX4 KW - Holliday junction reolvass KW - Fanconi-anemia subtype KW - susceptibility gene KW - helicase BRIP1 KW - ovarian cancer KW - DNA repair KW - mutations KW - protein KW - RAD51C Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131772 VL - 12 IS - 84 ER - TY - JOUR A1 - Finze, Maik A1 - Reiss, Guido J. T1 - Trimethyl­sulfonium 1-amino-6-fluoro-2,3,4,5,7,8,9,10,11,12-decaiodo-1-carba-closo-dodeca­borate N2 - no abstract available KW - Chemie KW - single-crystal X-ray study KW - T = 100 K KW - wR factor = 0.052 KW - data-to-parameter ratio = 20.8 Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75397 ER - TY - JOUR A1 - Finze, Maik A1 - Reiss, Guido J. A1 - Frohn, Hermann-Josef T1 - 2,3,5,6-Tetrafluoro-1,4-bis(trimethylsilyl)benzene N2 - no abstract available KW - Chemie KW - single-crystal X-ray study KW - T = 199 K KW - R factor = 0.027 KW - wR factor = 0.068 KW - data-to-parameter ratio = 14.0. Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75401 ER - TY - JOUR A1 - Franke, B. A1 - Faraone, S. V. A1 - Asherson, P. A1 - Buitelaar, J. A1 - Bau, C. H. D. A1 - Ramos-Quiroga, J. A. A1 - Mick, E. A1 - Grevet, E. H. A1 - Johansson, S. A1 - Haavik, J. A1 - Lesch, K.-P. A1 - Cormand, B. A1 - Reif, A. T1 - The genetics of attention deficit/hyperactivity disorder in adults, a review JF - Molecular Psychiatry N2 - The adult form of attention deficit/hyperactivity disorder (aADHD) has a prevalence of up to 5% and is the most severe long-term outcome of this common neurodevelopmental disorder. Family studies in clinical samples suggest an increased familial liability for aADHD compared with childhood ADHD (cADHD), whereas twin studies based on self-rated symptoms in adult population samples show moderate heritability estimates of 30–40%. However, using multiple sources of information, the heritability of clinically diagnosed aADHD and cADHD is very similar. Results of candidate gene as well as genome-wide molecular genetic studies in aADHD samples implicate some of the same genes involved in ADHD in children, although in some cases different alleles and different genes may be responsible for adult versus childhood ADHD. Linkage studies have been successful in identifying loci for aADHD and led to the identification of LPHN3 and CDH13 as novel genes associated with ADHD across the lifespan. In addition, studies of rare genetic variants have identified probable causative mutations for aADHD. Use of endophenotypes based on neuropsychology and neuroimaging, as well as next-generation genome analysis and improved statistical and bioinformatic analysis methods hold the promise of identifying additional genetic variants involved in disease etiology. Large, international collaborations have paved the way for well-powered studies. Progress in identifying aADHD risk genes may provide us with tools for the prediction of disease progression in the clinic and better treatment, and ultimately may help to prevent persistence of ADHD into adulthood. KW - IMpACT KW - persistent ADHD KW - molecular genetics KW - heritability KW - endophenotype Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124677 VL - 17 ER - TY - JOUR A1 - Fraunholz, Martin A1 - Sinha, Bhanu T1 - Intracellular staphylococcus aureus: Live-in and let die JF - Frontiers in Cellular and Infection Microbiology N2 - Staphylococcus aureus uses a plethora of virulence factors to accommodate a diversity of niches in its human host. Aside from the classical manifestations of S. aureus-induced diseases, the pathogen also invades and survives within mammalian host cells. The survival strategies of the pathogen are as diverse as strains or host cell types used. S. aureus is able to replicate in the phagosome or freely in the cytoplasm of its host cells. It escapes the phagosome of professional and non-professional phagocytes, subverts autophagy, induces cell death mechanisms such as apoptosis and pyronecrosis, and even can induce anti-apoptotic programs in phagocytes. The focus of this review is to present a guide to recent research outlining the variety of intracellular fates of S. aureus. KW - staphylococcus aureus KW - bacterial persistence KW - host cell death KW - autophagy KW - phagocytosis KW - phagosomalescape Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-123374 VL - 2 IS - 43 ER - TY - JOUR A1 - Fröhlich, Kathrin S. A1 - Papenfort, Kai A1 - Berger, Allison A. A1 - Vogel, Jörg T1 - A conserved RpoS-dependent small RNA controls the synthesis of major porin OmpD JF - Nucleic Acids Research N2 - A remarkable feature of many small non-coding RNAs (sRNAs) of Escherichia coli and Salmonella is their accumulation in the stationary phase of bacterial growth. Several stress response regulators and sigma factors have been reported to direct the transcription of stationary phase-specific sRNAs, but a widely conserved sRNA gene that is controlled by the major stationary phase and stress sigma factor, Sigma(S) (RpoS), has remained elusive. We have studied in Salmonella the conserved SdsR sRNA, previously known as RyeB, one of the most abundant stationary phase-specific sRNAs in E. coli. Alignments of the sdsR promoter region and genetic analysis strongly suggest that this sRNA gene is selectively transcribed by Sigma(S). We show that SdsR down-regulates the synthesis of the major Salmonella porin OmpD by Hfq-dependent base pairing; SdsR thus represents the fourth sRNA to regulate this major outer membrane porin. Similar to the InvR, MicC and RybB sRNAs, SdsR recognizes the ompD mRNA in the coding sequence, suggesting that this mRNA may be primarily targeted downstream of the start codon. The SdsR-binding site in ompD was localized by 3'-RACE, an experimental approach that promises to be of use in predicting other sRNA-target interactions in bacteria. KW - shock sigma factor KW - general stress response KW - down regulation KW - stationary phase KW - salmonella enterica KW - messenger RNA KW - escherichia coli KW - enterica serovar typhimurium KW - outer-membrane proteins KW - small noncoding RNAs Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134230 VL - 40 IS - 8 ER - TY - JOUR A1 - Förster, Frank A1 - Beisser, Daniela A1 - Grohme, Markus A. A1 - Liang, Chunguang A1 - Mali, Brahim A1 - Siegl, Alexander Matthias A1 - Engelmann, Julia C. A1 - Shkumatov, Alexander V. A1 - Schokraie, Elham A1 - Müller, Tobias A1 - Schnölzer, Martina A1 - Schill, Ralph O. A1 - Frohme, Marcus A1 - Dandekar, Thomas T1 - Transcriptome analysis in tardigrade species reveals specific molecular pathways for stress adaptations JF - Bioinformatics and biology insights N2 - Tardigrades have unique stress-adaptations that allow them to survive extremes of cold, heat, radiation and vacuum. To study this, encoded protein clusters and pathways from an ongoing transcriptome study on the tardigrade \(Milnesium\) \(tardigradum\) were analyzed using bioinformatics tools and compared to expressed sequence tags (ESTs) from \(Hypsibius\) \(dujardini\), revealing major pathways involved in resistance against extreme environmental conditions. ESTs are available on the Tardigrade Workbench along with software and databank updates. Our analysis reveals that RNA stability motifs for \(M.\) \(tardigradum\) are different from typical motifs known from higher animals. \(M.\) \(tardigradum\) and \(H.\) \(dujardini\) protein clusters and conserved domains imply metabolic storage pathways for glycogen, glycolipids and specific secondary metabolism as well as stress response pathways (including heat shock proteins, bmh2, and specific repair pathways). Redox-, DNA-, stress- and protein protection pathways complement specific repair capabilities to achieve the strong robustness of \(M.\) \(tardigradum\). These pathways are partly conserved in other animals and their manipulation could boost stress adaptation even in human cells. However, the unique combination of resistance and repair pathways make tardigrades and \(M.\) \(tardigradum\) in particular so highly stress resistant. KW - RNA KW - expressed sequence tag KW - cluster KW - protein familiy KW - adaption KW - tardigrada KW - transcriptome Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-123089 N1 - This is an open access article. Unrestricted non-commercial use is permitted provided the original work is properly cited. VL - 6 ER - TY - JOUR A1 - Gaiser, Timo A1 - Geissinger, Eva A1 - Schattenberg, Torsten A1 - Scharf, Hanns-Peter A1 - Dürken, Matthias A1 - Dinter, Dietmar A1 - Rosenwald, Andreas A1 - Marx, Alexander T1 - Case report: a unique pediatric case of a primary CD8 expressing ALK-1 positive anaplastic large cell lymphoma of skeletal muscle JF - Diagnostic Pathology N2 - Primary involvement of skeletal muscle is a very rare event in ALK-1 positive anaplastic large cell lymphoma (ALCL). We describe a case of a 10-year old boy presenting with a three week history of pain and a palpable firm swelling at the dorsal aspect of the left thigh. Histological examination of the lesion revealed a tumoral and diffuse polymorphic infiltration of the muscle by large lymphoid cells. Tumor cells displayed eccentric, lobulated "horse shoe" or "kidney-shape" nuclei. The cells showed immunohistochemical positivity for CD30, ALK-1, CD2, CD3, CD7, CD8, and Perforin. Fluorescence in situ hybridization analysis revealed a characteristic rearrangement of the ALK-1 gene in 2p23 leading to the diagnosis of ALK-1 positive ALCL. Chemotherapy according to the ALCL-99-NHL-BFM protocol was initiated and resulted in a complete remission after two cycles. This case illustrates the unusual presentation of a pediatric ALCL in soft tissue with a good response to chemotherapy. KW - pediatric lymphoma KW - psoas muscle KW - classification KW - translocation KW - features KW - gene KW - ALK-1 KW - anaplastic large cell lymphoma KW - CD30 Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135381 VL - 7 IS - 38 ER - TY - JOUR A1 - Galetzka, Danuta A1 - Hansmann, Tamara A1 - El Hajj, Nady A1 - Weis, Eva A1 - Irmscher, Benjamin A1 - Ludwig, Marco A1 - Schneider-Rätzke, Brigitte A1 - Kohlschmidt, Nicolai A1 - Beyer, Vera A1 - Bartsch, Oliver A1 - Zechner, Ulrich A1 - Spix, Claudia A1 - Haaf, Thomas T1 - Monozygotic twins discordant for constitutive BRCA1 promoter methylation, childhood cancer and secondary cancer JF - Epigenetics N2 - We describe monozygotic twins discordant for childhood leukemia and secondary thyroid carcinoma. We used bisulfite pyrosequencing to compare the constitutive promoter methylation of BRCA1 and several other tumor suppressor genes in primary fibroblasts. The affected twin displayed an increased BRCA1 methylation (12%), compared with her sister (3%). Subsequent bisulfite plasmid sequencing demonstrated that 13% (6 of 47) BRCA1 alleles were fully methylated in the affected twin, whereas her sister displayed only single CpG errors without functional implications. This between-twin methylation difference was also found in irradiated fibroblasts and untreated saliva cells. The BRCA1 epimutation may have originated by an early somatic event in the affected twin: approximately 25% of her body cells derived from different embryonic cell lineages carry one epigenetically inactivated BRCA1 allele. This epimutation was associated with reduced basal protein levels and a higher induction of BRCA1 after DNA damage. In addition, we performed a genome-wide microarray analysis of both sisters and found several copy number variations, i.e., heterozygous deletion and reduced expression of the RSPO3 gene in the affected twin. This monozygotic twin pair represents an impressive example of epigenetic somatic mosaicism, suggesting a role for constitutive epimutations, maybe along with de novo genetic alterations in recurrent tumor development. KW - BRCA1 KW - childhood cancer KW - DNA Methylation KW - epimutation KW - monozygotic twins KW - secondary cancer KW - somatic mosaicism Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125386 VL - 7 IS - 1 ER - TY - JOUR A1 - Galimberti, Daniela A1 - Dell'Osso, Bernardo A1 - Fenoglio, Chiara A1 - Villa, Chiara A1 - Cortini, Francesca A1 - Serpente, Maria A1 - Kittel-Schneider, Sarah A1 - Weigl, Johannes A1 - Neuner, Maria A1 - Volkert, Juliane A1 - Leonhard, C. A1 - Olmes, David G. A1 - Kopf, Juliane A1 - Cantoni, Claudia A1 - Ridolfi, Elisa A1 - Palazzo, Carlotta A1 - Ghezzi, Laura A1 - Bresolin, Nereo A1 - Altamura, A.C. A1 - Scarpini, Elio A1 - Reif, Andreas T1 - Progranulin Gene Variability and Plasma Levels in Bipolar Disorder and Schizophrenia JF - PLoS One N2 - Basing on the assumption that frontotemporal lobar degeneration (FTLD), schizophrenia and bipolar disorder (BPD) might share common aetiological mechanisms, we analyzed genetic variation in the FTLD risk gene progranulin (GRN) in a German population of patients with schizophrenia (n=271) or BPD (n=237) as compared with 574 age-, gender-and ethnicity-matched controls. Furthermore, we measured plasma progranulin levels in 26 German BPD patients as well as in 61 Italian BPD patients and 29 matched controls. A significantly decreased allelic frequency of the minor versus the wild-type allele was observed for rs2879096 (23.2 versus 34.2%, P<0.001, OR: 0.63, 95% CI: 0.49-0.80), rs4792938 (30.7 versus 39.7%, P=0.005, OR: 0.70, 95% CI: 0.55-0.89) and rs5848 (30.3 versus 36.8, P=0.007, OR: 0.71, 95% CI: 0.56-0.91). Mean +/- SEM progranulin plasma levels were significantly decreased in BPD patients, either Germans or Italians, as compared with controls (89.69 +/- 3.97 and 116.14 +/- 5.80 ng/ml, respectively, versus 180.81 +/- 18.39 ng/ml P<0.001) and were not correlated with age. In conclusion, GRN variability decreases the risk to develop BPD and schizophrenia, and progranulin plasma levels are significantly lower in BPD patients than in controls. Nevertheless, a larger replication analysis would be needed to confirm these preliminary results. KW - people KW - frontotemporal lobar degeneration KW - genome-wide association KW - Alzheimers disease KW - risk genes KW - dementia KW - GRN KW - mutation KW - families KW - linkage Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131910 VL - 7 IS - 4 ER - TY - JOUR A1 - Gallo, Lorenzo T1 - Natural hybrids in Sedum series Rupestria Berger (Crassulaceae): a review of taxonomy and nomenclature N2 - The nothotaxa of the genus Sedum series Rupestria Berger (Crassulaceae) are reviewed, three new hybrids (S. ×affomarcoi, S. ×henkii and S. ×pascalianum) are described and Sedum brevierei Chass. is typified. The identity of the western (French) populations of S. rupestre L. subsp. erectum ‘t Hart is also clarified, and a table with all known combinations is given. KW - Botanik KW - Dickblattgewächse KW - Nothotaxa KW - typification KW - Sedum rupestre L. subsp. erectum ‘t Hart Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-71945 ER - TY - JOUR A1 - Gassen, Alwine A1 - Brechtefeld, Doris A1 - Schandry, Niklas A1 - Arteaga-Salas, J. Manuel A1 - Israel, Lars A1 - Imhof, Axel A1 - Janzen, Christian J. T1 - DOT1A-dependent H3K76 methylation is required for replication regulation in Trypanosoma brucei JF - Nucleic Acids Research N2 - Cell-cycle progression requires careful regulation to ensure accurate propagation of genetic material to the daughter cells. Although many cell-cycle regulators are evolutionarily conserved in the protozoan parasite Trypanosoma brucei, novel regulatory mechanisms seem to have evolved. Here, we analyse the function of the histone methyltransferase DOT1A during cell-cycle progression. Over-expression of DOT1A generates a population of cells with aneuploid nuclei as well as enucleated cells. Detailed analysis shows that DOT1A over-expression causes continuous replication of the nuclear DNA. In contrast, depletion of DOT1A by RNAi abolishes replication but does not prevent karyokinesis. As histone H3K76 methylation has never been associated with replication control in eukaryotes before, we have discovered a novel function of DOT1 enzymes, which might not be unique to trypanosomes. KW - variants KW - cell-cycle regulation KW - blood-stream forms KW - african trypanosomes KW - mammalian cells KW - DNA replication KW - DOT1 KW - protein KW - transcription KW - cultivation Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131449 VL - 40 IS - 20 ER - TY - JOUR A1 - Gavvovidis, Ioannis A1 - Rost, Isabell A1 - Trimborn, Marc A1 - Kaiser, Frank J. A1 - Purps, Josephine A1 - Wiek, Konstanze A1 - Haneberg, Helmut A1 - Neitzel, Heidemarie A1 - Schindler, Detlev T1 - A Novel MCPH1 Isoform Complements the Defective Chromosome Condensation of Human MCPH1-Deficient Cells N2 - Biallelic mutations in MCPH1 cause primary microcephaly (MCPH) with the cellular phenotype of defective chromosome condensation. MCPH1 encodes a multifunctional protein that notably is involved in brain development, regulation of chromosome condensation, and DNA damage response. In the present studies, we detected that MCPH1 encodes several distinct transcripts, including two major forms: full-length MCPH1 (MCPH1-FL) and a second transcript lacking the six 39 exons (MCPH1De9–14). Both variants show comparable tissue-specific expression patterns, demonstrate nuclear localization that is mediated independently via separate NLS motifs, and are more abundant in certain fetal than adult organs. In addition, the expression of either isoform complements the chromosome condensation defect found in genetically MCPH1-deficient or MCPH1 siRNA-depleted cells, demonstrating a redundancy of both MCPH1 isoforms for the regulation of chromosome condensation. Strikingly however, both transcripts are regulated antagonistically during cell-cycle progression and there are functional differences between the isoforms with regard to the DNA damage response; MCPH1-FL localizes to phosphorylated H2AX repair foci following ionizing irradiation, while MCPH1De9–14 was evenly distributed in the nucleus. In summary, our results demonstrate here that MCPH1 encodes different isoforms that are differentially regulated at the transcript level and have different functions at the protein level. KW - MCPH1 Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75050 ER - TY - JOUR A1 - Gentschev, Ivaylo A1 - Adelfinger, Marion A1 - Josupeit, Rafael A1 - Rudolph, Stephan A1 - Ehrig, Klaas A1 - Donat, Ulrike A1 - Weibel, Stephanie A1 - Chen, Nanhai G. A1 - Yu, Yong A. A1 - Zhang, Qian A1 - Heisig, Martin A1 - Thamm, Douglas A1 - Stritzker, Jochen A1 - MacNeill, Amy A1 - Szalay, Aladar A. T1 - Preclinical Evaluation of Oncolytic Vaccinia Virus for Therapy of Canine Soft Tissue Sarcoma JF - PLoS One N2 - Virotherapy using oncolytic vaccinia virus (VACV) strains is one promising new strategy for canine cancer therapy. In this study we describe the establishment of an in vivo model of canine soft tissue sarcoma (CSTS) using the new isolated cell line STSA-1 and the analysis of the virus-mediated oncolytic and immunological effects of two different Lister VACV LIVP1.1.1 and GLV-1h68 strains against CSTS. Cell culture data demonstrated that both tested VACV strains efficiently infected and destroyed cells of the canine soft tissue sarcoma line STSA-1. In addition, in our new canine sarcoma tumor xenograft mouse model, systemic administration of LIVP1.1.1 or GLV-1h68 viruses led to significant inhibition of tumor growth compared to control mice. Furthermore, LIVP1.1.1 mediated therapy resulted in almost complete tumor regression and resulted in long-term survival of sarcoma-bearing mice. The replication of the tested VACV strains in tumor tissues led to strong oncolytic effects accompanied by an intense intratumoral infiltration of host immune cells, mainly neutrophils. These findings suggest that the direct viral oncolysis of tumor cells and the virus-dependent activation of tumor-associated host immune cells could be crucial parts of anti-tumor mechanism in STSA-1 xenografts. In summary, the data showed that both tested vaccinia virus strains and especially LIVP1.1.1 have great potential for effective treatment of CSTS. KW - breast-tumors KW - animal-model KW - nude-mice KW - cell-line KW - in-vitro KW - glv-1h68 KW - cancer KW - virotherapy KW - dogs KW - neutrophils Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129998 VL - 7 IS - 5 ER - TY - JOUR A1 - Gerlach, Manfred A1 - Maetzler, Walter A1 - Broich, Karl A1 - Hampel, Harald A1 - Rems, Lucas A1 - Reum, Torsten A1 - Riederer, Peter A1 - Stäffler, Albrecht A1 - Streffer, Johannes A1 - Berg, Daniela T1 - Biomarker candidates of neurodegeneration in Parkinson's disease for the evaluation of disease-modifying therapeutics JF - Journal of Neural Transmission N2 - Reliable biomarkers that can be used for early diagnosis and tracking disease progression are the cornerstone of the development of disease-modifying treatments for Parkinson’s disease (PD). The German Society of Experimental and Clinical Neurotherapeutics (GESENT) has convened a Working Group to review the current status of proposed biomarkers of neurodegeneration according to the following criteria and to develop a consensus statement on biomarker candidates for evaluation of disease-modifying therapeutics in PD. The criteria proposed are that the biomarker should be linked to fundamental features of PD neuropathology and mechanisms underlying neurodegeneration in PD, should be correlated to disease progression assessed by clinical rating scales, should monitor the actual disease status, should be pre-clinically validated, and confirmed by at least two independent studies conducted by qualified investigators with the results published in peer-reviewed journals. To date, available data have not yet revealed one reliable biomarker to detect early neurodegeneration in PD and to detect and monitor effects of drug candidates on the disease process, but some promising biomarker candidates, such as antibodies against neuromelanin, pathological forms of α-synuclein, DJ-1, and patterns of gene expression, metabolomic and protein profiling exist. Almost all of the biomarker candidates were not investigated in relation to effects of treatment, validated in experimental models of PD and confirmed in independent studies. KW - disease progression KW - biomarkers KW - neuroprotection KW - disease-modifying therapies KW - Parkinson’s disease KW - surrogate endpoints KW - drug development Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125375 VL - 119 IS - 1 ER - TY - JOUR A1 - Gessner, Viktoria H. T1 - Diphenyl[2-(phenyl-sulfon-yl)propan-2-yl]-\(\lambda^5\)-phosphanethione JF - Acta crystallographica. Section E, Structure reports online N2 - The title compound, \(C_{21}H_{21}O_2PS_2\), was obtained from the corresponding dilithio methandiide by treatment with iodo-methane. The bond lengths and angles deviate considerably from those in the dimetallated compound. These differences are most pronounced in the PCS backbone. While the title compound features C-P and C-S distances of 1.9082(17) and 1.8348(17)Å, respectively, the dianion showed \(C-P_{av}\) distances shortened by 11% [1.710(4)Å] and C-S distances shortened by 12% [1.614(3)Å]. Additionally, the P-C-S angle experiences a contraction by methyl-ation of the dianion from 121.4(2) to 111.96(9)° in the title compound. KW - wR factor = 0.068 KW - mean σ(C–C) = 0.003 Å KW - T = 173 K KW - single-crystal X-ray study KW - R factor = 0.025 KW - data-to-parameter ratio = 14.6 Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-123635 VL - E68 IS - o1045 ER - TY - JOUR A1 - Grafe, T. Ulmar A1 - Preininger, Doris A1 - Sztatecsny, Marc A1 - Kasah, Rosli A1 - Dehling, J. Maximilian A1 - Proksch, Sebastian A1 - Hödl, Walter T1 - Multimodal Communication in a Noisy Environment: A Case Study of the Bornean Rock Frog Staurois parvus JF - PLoS One N2 - High background noise is an impediment to signal detection and perception. We report the use of multiple solutions to improve signal perception in the acoustic and visual modality by the Bornean rock frog, Staurois parvus. We discovered that vocal communication was not impaired by continuous abiotic background noise characterised by fast-flowing water. Males modified amplitude, pitch, repetition rate and duration of notes within their advertisement call. The difference in sound pressure between advertisement calls and background noise at the call dominant frequency of 5578 Hz was 8 dB, a difference sufficient for receiver detection. In addition, males used several visual signals to communicate with conspecifics with foot flagging and foot flashing being the most common and conspicuous visual displays, followed by arm waving, upright posture, crouching, and an open-mouth display. We used acoustic playback experiments to test the efficacy-based alerting signal hypothesis of multimodal communication. In support of the alerting hypothesis, we found that acoustic signals and foot flagging are functionally linked with advertisement calling preceding foot flagging. We conclude that S. parvus has solved the problem of continuous broadband low-frequency noise by both modifying its advertisement call in multiple ways and by using numerous visual signals. This is the first example of a frog using multiple acoustic and visual solutions to communicate in an environment characterised by continuous noise. KW - call KW - dart-poison frog KW - animal communication KW - auditory masking KW - acoustic communication KW - anthropogenic noise KW - courtship displays KW - traffic noise KW - higher pitch KW - signals Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133718 VL - 7 IS - 5 ER - TY - JOUR A1 - Grassmann, Felix A1 - Fritsche, Lars G. A1 - Keilhauer, Claudia N. A1 - Heid, Iris M. A1 - Weber, Bernhard H. F. T1 - Modelling the Genetic Risk in Age-Related Macular Degeneration JF - PLoS One N2 - Late-stage age-related macular degeneration (AMD) is a common sight-threatening disease of the central retina affecting approximately 1 in 30 Caucasians. Besides age and smoking, genetic variants from several gene loci have reproducibly been associated with this condition and likely explain a large proportion of disease. Here, we developed a genetic risk score (GRS) for AMD based on 13 risk variants from eight gene loci. The model exhibited good discriminative accuracy, area-under-curve (AUC) of the receiver-operating characteristic of 0.820, which was confirmed in a cross-validation approach. Noteworthy, younger AMD patients aged below 75 had a significantly higher mean GRS (1.87, 95% CI: 1.69-2.05) than patients aged 75 and above (1.45, 95% CI: 1.36-1.54). Based on five equally sized GRS intervals, we present a risk classification with a relative AMD risk of 64.0 (95% CI: 14.11-1131.96) for individuals in the highest category (GRS 3.44-5.18, 0.5% of the general population) compared to subjects with the most common genetic background (GRS -0.05-1.70, 40.2% of general population). The highest GRS category identifies AMD patients with a sensitivity of 7.9% and a specificity of 99.9% when compared to the four lower categories. Modeling a general population around 85 years of age, 87.4% of individuals in the highest GRS category would be expected to develop AMD by that age. In contrast, only 2.2% of individuals in the two lowest GRS categories which represent almost 50% of the general population are expected to manifest AMD. Our findings underscore the large proportion of AMD cases explained by genetics particularly for younger AMD patients. The five-category risk classification could be useful for therapeutic stratification or for diagnostic testing purposes once preventive treatment is available. KW - AMD KW - complement factor-H KW - grading system KW - United States KW - vitamin C KW - prevalence KW - variants KW - susceptibility KW - association KW - maculopathy KW - variant genotypes KW - genetic loci KW - macular degeneration KW - genetics of disease KW - eyes KW - cased-control studies KW - genotyping KW - human genetics Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131315 VL - 7 IS - 5 ER - TY - JOUR A1 - Greiser, Eberhard M. A1 - Greiser, Karin Halina A1 - Ahrens, Wolfgang A1 - Hagen, Rudolf A1 - Lazszig, Roland A1 - Maier, Heinz A1 - Schick, Bernhard A1 - Zenner, Hans Peter T1 - Risk factors for nasal malignancies in German men: the South-German Nasal cancer study JF - BMC Cancer N2 - Background: There are few studies of the effects of nasal snuff and environmental factors on the risk of nasal cancer. This study aimed to investigate the impact of using nasal snuff and of other risk factors on the risk of nasal cancer in German men. Methods: A population-based case-control study was conducted in the German Federal States of Bavaria and Baden-Wurttemberg. Tumor registries and ear, nose and throat departments provided access to patients born in 1926 or later. Results: Telephone interviews were conducted with 427 cases (mean age 62.1 years) and 2.401 population-based controls (mean age 60.8 years). Ever-use of nasal snuff was associated with an odds ratio (OR) for nasal cancer of 1.45 (95% confidence interval [CI] 0.88-2.38) in the total study population, whereas OR in smokers was 2.01 (95% CI 1.00-4.02) and in never smokers was 1.10 (95% CI 0.43-2.80). The OR in ever-smokers vs. never-smokers was 1.60 (95% CI 1.24-2.07), with an OR of 1.06 (95% CI 1.05-1.07) per pack-year smoked, and the risk was significantly decreased after quitting smoking. Exposure to hardwood dust for at least 1 year resulted in an OR of 2.33 (95% CI 1.40-3.91) in the total population, which was further increased in never-smokers (OR 4.89, 95% CI 1.92-12.49) in analyses stratified by smoking status. The OR for nasal cancer after exposure to organic solvents for at least 1 year was 1.53 (1.17-2.01). Ever-use of nasal sprays/nasal lavage for at least 1 month rendered an OR of 1.59 (1.04-2.44). The OR after use of insecticides in homes was 1.48 (95% CI 1.04-2.11). Conclusions: Smoking and exposure to hardwood dust were confirmed as risk factors for nasal carcinoma. There is evidence that exposure to organic solvents, and in-house use of insecticides could represent novel risk factors. Exposure to asbestos and use of nasal snuff were risk factors in smokers only. KW - paranasal sinuses KW - case-control study KW - nasal snuff KW - nasopharyngeal carcinoma KW - sinonasal cancer KW - occupational exposures KW - cigarette smoking KW - Univted-States KW - maxillary sinus KW - wood dust KW - formaldehyde KW - cavity KW - nasal cancer KW - smoking KW - hardwood dust KW - asbestos KW - organic solvents KW - insecticides KW - nasal spray KW - nasal lavage Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133365 VL - 12 IS - 506 ER - TY - JOUR A1 - Gresle, Melissa M. A1 - Alexandrou, Estella A1 - Wu, Qizhu A1 - Egan, Gary A1 - Jokubaitis, Vilija A1 - Ayers, Margaret A1 - Jonas, Anna A1 - Doherty, William A1 - Friedhuber, Anna A1 - Shaw, Gerry A1 - Sendtner, Michael A1 - Emery, Ben A1 - Kilpatrick, Trevor A1 - Butzkueven, Helmut T1 - Leukemia Inhibitory Factor Protects Axons in Experimental Autoimmune Encephalomyelitis via an Oligodendrocyte-Independent Mechanism JF - PLoS One N2 - Leukemia inhibitory factor (LIF) and Ciliary Neurotrophic factor (CNTF) are members of the interleukin-6 family of cytokines, defined by use of the gp130 molecule as an obligate receptor. In the murine experimental autoimmune encephalomyelitis (EAE) model, antagonism of LIF and genetic deletion of CNTF worsen disease. The potential mechanism of action of these cytokines in EAE is complex, as gp130 is expressed by all neural cells, and could involve immuno-modulation, reduction of oligodendrocyte injury, neuronal protection, or a combination of these actions. In this study we aim to investigate whether the beneficial effects of CNTF/LIF signalling in EAE are associated with axonal protection; and whether this requires signalling through oligodendrocytes. We induced MOG\(_{35-55}\) EAE in CNTF, LIF and double knockout mice. On a CNTF null background, LIF knockout was associated with increased EAE severity (EAE grade 2.1\(\pm\)0.14 vs 2.6\(\pm\)0.19; P<0.05). These mice also showed increased axonal damage relative to LIF heterozygous mice, as indicated by decreased optic nerve parallel diffusivity on MRI (1540\(\pm\)207 \(\mu\)m\(^2\)-/s vs 1310\(\pm\)175 \(\mu\)m\(^2\)-/s; P<0.05), and optic nerve (-12.5%) and spinal cord (-16%) axon densities; and increased serum neurofilament-H levels (2.5 fold increase). No differences in inflammatory cell numbers or peripheral auto-immune T-cell priming were evident. Oligodendrocyte-targeted gp130 knockout mice showed that disruption of CNTF/LIF signalling in these cells has no effect on acute EAE severity. These studies demonstrate that endogenous CNTF and LIF act centrally to protect axons from acute inflammatory destruction via an oligodendrocyte-independent mechanism. KW - receptor KW - ciliary neurotrophic factor KW - mulitple-sclerosis patients KW - factor prevents KW - demyelination KW - survival KW - neurons KW - injury KW - degeneration KW - motoneurons Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134617 VL - 7 IS - 10 ER - TY - JOUR A1 - Gross, Henrik A1 - Hennard, Christine A1 - Masouris, Ilias A1 - Cassel, Christian A1 - Barth, Stephanie A1 - Stober-Grässer, Ute A1 - Mamiani, Alfredo A1 - Moritz, Bodo A1 - Ostareck, Dirk A1 - Ostareck-Lederer, Antje A1 - Neuenkirchen, Nils A1 - Fischer, Utz A1 - Deng, Wen A1 - Leonhardt, Heinrich A1 - Noessner, Elfriede A1 - Kremmer, Elisabeth A1 - Grässer, Friedrich A. T1 - Binding of the Heterogeneous Ribonucleoprotein K (hnRNP K) to the Epstein-Barr Virus Nuclear Antigen 2 (EBNA2) Enhances Viral LMP2A Expression JF - PLoS One N2 - The Epstein-Barr Virus (EBV) -encoded EBNA2 protein, which is essential for the in vitro transformation of B-lymphocytes, interferes with cellular processes by binding to proteins via conserved sequence motifs. Its Arginine-Glycine (RG) repeat element contains either symmetrically or asymmetrically di-methylated arginine residues (SDMA and ADMA, respectively). EBNA2 binds via its SDMA-modified RG-repeat to the survival motor neurons protein (SMN) and via the ADMA-RG-repeat to the NP9 protein of the human endogenous retrovirus K (HERV-K (HML-2) Type 1). The hypothesis of this work was that the methylated RG-repeat mimics an epitope shared with cellular proteins that is used for interaction with target structures. With monoclonal antibodies against the modified RG-repeat, we indeed identified cellular homologues that apparently have the same surface structure as methylated EBNA2. With the SDMA-specific antibodies, we precipitated the Sm protein D3 (SmD3) which, like EBNA2, binds via its SDMA-modified RG-repeat to SMN. With the ADMA-specific antibodies, we precipitated the heterogeneous ribonucleoprotein K (hnRNP K). Specific binding of the ADMA-antibody to hnRNP K was demonstrated using E. coli expressed/ADMA-methylated hnRNP K. In addition, we show that EBNA2 and hnRNP K form a complex in EBV-infected B-cells. Finally, hnRNP K, when co-expressed with EBNA2, strongly enhances viral latent membrane protein 2A (LMP2A) expression by an unknown mechanism as we did not detect a direct association of hnRNP K with DNA-bound EBNA2 in gel shift experiments. Our data support the notion that the methylated surface of EBNA2 mimics the surface structure of cellular proteins to interfere with or co-opt their functional properties. KW - SM proteins KW - protein argentine methyltranserase KW - motor-neuron protein KW - RNA-polymerase-II KW - messenger RNA KW - C-MYC KW - gene expression KW - splicing factor KW - down regulation KW - living cells Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133707 VL - 7 IS - 8 ER - TY - JOUR A1 - Grundmeier, Natalie A1 - Hamm, Henning A1 - Weissbrich, Benedikt A1 - Lang, Sabrina Christine A1 - Bröcker, Eva-Bettina A1 - Kerstan, Andreas T1 - High-risk human papillomavirus infection in Bowen’s disease of the nail unit: report of three cases and review of the literature JF - Dermatology N2 - Background: Bowen’s disease (BD) of the nail unit is associated with human papillomavirus (HPV) infection. Objective: This study aimed to investigate the frequency of high-risk HPV infection, gender, age and digital distribution in this condition. Methods: Biopsy specimens of 3 consecutive cases with periungual BD were investigated for the presence of HPV DNA by in situ hybridization and by polymerase chain reaction (PCR). Furthermore, 74 cases of ungual BD conducted with HPV genotyping as reported in the literature were reviewed. Results: PCR of biopsy specimens revealed in 2 cases infection with HPV-16 and in 1 case with HPV-73. Additionally, in 1 HPV-16-positive case HPV-31/33 was detected by in situ hybridization. In line, review of the literature demonstrated a clear association of HPV-positive BD with high-risk HPV types. Interestingly, age at diagnosis was significantly lower in women. Whereas in both genders the second to fourth fingers on both hands were commonly diseased, only in men the thumbs were also prominently affected. Conclusions: Infection with high-risk HPV types is common in BD of the nail unit suggesting the aetiological cause. Therefore, patients and partners should be closely followed up for digital and genital HPV-associated lesions. KW - Nail unit KW - Human papillomavirus KW - Bowen’s disease, periungual Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196638 SN - 1018-8665 SN - 1421-9832 N1 - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively. VL - 223 IS - 4 SP - 293 EP - 300 ER - TY - JOUR A1 - Gruss, L. Forest A1 - Wieser, Matthias J. A1 - Schweinberger, Stefan R. A1 - Keil, Andreas T1 - Face-evoked steady-state visual potentials: effects of presentation rate and face inversion JF - Frontiers in Human Neuroscience N2 - Face processing can be explored using electrophysiological methods. Research with event-related potentials has demonstrated the so-called face inversion effect, in which the N170 component is enhanced in amplitude and latency to inverted, compared to upright, faces. The present study explored the extent to which repetitive lower-level visual cortical engagement, reflected in flicker steady-state visual evoked potentials (ssVEPs), shows similar amplitude enhancement to face inversion. We also asked if inversion-related ssVEP modulation would be dependent on the stimulation rate at which upright and inverted faces were flickered. To this end, multiple tagging frequencies were used (5, 10, 15, and 20 Hz) across two studies (n=21, n=18). Results showed that amplitude enhancement of the ssVEP for inverted faces was found solely at higher stimulation frequencies (15 and 20 Hz). By contrast, lower frequency ssVEPs did not show this inversion effect. These findings suggest that stimulation frequency affects the sensitivity of ssVEPs to face inversion. KW - N170 KW - upside-down faces KW - selective attention KW - spatial attention KW - cortex KW - perception KW - recognition KW - brain KW - FMRI KW - area Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134399 VL - 6 IS - 316 ER - TY - JOUR A1 - Guckenberger, Matthias A1 - Alexandrow, Nikolaus A1 - Flentje, Michael T1 - Radiotherapy alone for stage I-III low grade follicular lymphoma: long-term outcome and comparison of extended field and total nodal irradiation N2 - Background: To analyze long-term results of radiotherapy alone for stage I-III low grade follicular lymphoma and to compare outcome after extended field irradiation (EFI) and total nodal irradiation (TNI). Methods and materials: Between 1982 and 2007, 107 patients were treated with radiotherapy alone for low grade follicular lymphoma at Ann Arbor stage I (n = 50), II (n = 36) and III (n = 21); 48 and 59 patients were treated with EFI and TNI, respectively. The median total dose in the first treatment series of the diaphragmatic side with larger lymphoma burden was 38 Gy (25 Gy – 50 Gy) and after an interval of median 30 days, a total dose of 28 Gy (12.6 Gy – 45 Gy) was given in the second treatment series completing TNI. Results: After a median follow-up of 14 years for living patients, 10-years and 15-years overall survival (OS) were 64% and 50%, respectively. Survival was not significantly different between stages I, II and III. TNI and EFI resulted in 15-years OS of 65% and 34% but patients treated with TNI were younger, had better performance status and higher stage of disease compared to patients treated with EFI. In multivariate analysis, only age at diagnosis (p<0.001, relative risk [RR] 1.06) and Karnofsky performance status (p = 0.04, RR = 0.96) were significantly correlated with OS. Freedom from progression (FFP) was 58% and 56% after 10-years and 15-years, respectively. Recurrences outside the irradiated volume were significantly reduced after TNI compared to EFI; however, increased rates of in-field recurrences and extra-nodal out-of-field recurrence counterbalanced this effect resulting in no significant difference in FFP between TNI and EFI. In univariate analysis, FFP was significantly improved in stage I compared to stage II but no differences were observed between stages I/II and stage III. In multivariate analysis no patient or treatment parameter was correlated with FFP. Acute toxicity was significantly increased after TNI compared to EFI with a trend to increased late toxicity as well. Conclusions: Radiotherapy alone for stage I and II follicular lymphoma resulted in long-term OS with high rates of disease control; no benefit of TNI over EFI was observed. For stage III follicular lymphoma, TNI achieved promising OS and FFP and should be considered as a potentially curative treatment option. KW - Medizin KW - Follicular lymphoma KW - Total nodal irradiation KW - Extended field irradiation Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75702 ER - TY - JOUR A1 - Guckenberger, Matthias A1 - Hawkins, Maria A1 - Flentje, Michael A1 - Sweeney, Reinhart A. T1 - Fractionated radiosurgery for painful spinal metastases: DOSIS - a phase II trial N2 - Background One third of all cancer patients will develop bone metastases and the vertebral column is involved in approximately 70 % of these patients. Conventional radiotherapy with of 1–10 fractions and total doses of 8-30 Gy is the current standard for painful vertebral metastases; however, the median pain response is short with 3–6 months and local tumor control is limited with these rather low irradiation doses. Recent advances in radiotherapy technology – intensity modulated radiotherapy for generation of highly conformal dose distributions and image-guidance for precise treatment delivery – have made dose-escalated radiosurgery of spinal metastases possible and early results of pain and local tumor control are promising. The current study will investigate efficacy and safety of radiosurgery for painful vertebral metastases and three characteristics will distinguish this study. 1) A prognostic score for overall survival will be used for selection of patients with longer life expectancy to allow for analysis of long-term efficacy and safety. 2) Fractionated radiosurgery will be performed with the number of treatment fractions adjusted to either good (10 fractions) or intermediate (5 fractions) life expectancy. Fractionation will allow inclusion of tumors immediately abutting the spinal cord due to higher biological effective doses at the tumor - spinal cord interface compared to single fraction treatment. 3) Dose intensification will be performed in the involved parts of the vertebrae only, while uninvolved parts are treated with conventional doses using the simultaneous integrated boost concept. Methods / Design It is the study hypothesis that hypo-fractionated image-guided radiosurgery significantly improves pain relief compared to historic data of conventionally fractionated radiotherapy. Primary endpoint is pain response 3 months after radiosurgery, which is defined as pain reduction of ≥2 points at the treated vertebral site on the 0 to 10 Visual Analogue Scale. 60 patients will be included into this two-centre phase II trial. Conclusions Results of this study will refine the methods of patient selection, target volume definition, treatment planning and delivery as well as quality assurance for radiosurgery. It is the intention of this study to form the basis for a future randomized controlled trial comparing conventional radiotherapy with fractionated radiosurgery for palliation of painful vertebral metastases. Trial registration ClinicalTrials.gov Identifier: NCT01594892 KW - Medizin KW - Phase II trial KW - Spinal metastasis KW - Pain KW - Radiosurgery KW - Stereotactic body radiotherapy Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75853 ER - TY - JOUR A1 - Guckenberger, Matthias A1 - Roesch, Johannes A1 - Baier, Kurt A1 - Sweeney, Reinhart A. A1 - Flentje, Michael T1 - Dosimetric consequences of translational and rotational errors in frame-less image-guided radiosurgery N2 - Background: To investigate geometric and dosimetric accuracy of frame-less image-guided radiosurgery (IG-RS) for brain metastases. Methods and materials: Single fraction IG-RS was practiced in 72 patients with 98 brain metastases. Patient positioning and immobilization used either double- (n = 71) or single-layer (n = 27) thermoplastic masks. Pre-treatment set-up errors (n = 98) were evaluated with cone-beam CT (CBCT) based image-guidance (IG) and were corrected in six degrees of freedom without an action level. CBCT imaging after treatment measured intra-fractional errors (n = 64). Pre- and posttreatment errors were simulated in the treatment planning system and target coverage and dose conformity were evaluated. Three scenarios of 0 mm, 1 mm and 2 mm GTV-to-PTV (gross tumor volume, planning target volume) safety margins (SM) were simulated. Results: Errors prior to IG were 3.9 mm± 1.7 mm (3D vector) and the maximum rotational error was 1.7° ± 0.8° on average. The post-treatment 3D error was 0.9 mm± 0.6 mm. No differences between double- and single-layer masks were observed. Intra-fractional errors were significantly correlated with the total treatment time with 0.7mm±0.5mm and 1.2mm±0.7mm for treatment times ≤23 minutes and >23 minutes (p<0.01), respectively. Simulation of RS without image-guidance reduced target coverage and conformity to 75% ± 19% and 60% ± 25% of planned values. Each 3D set-up error of 1 mm decreased target coverage and dose conformity by 6% and 10% on average, respectively, with a large inter-patient variability. Pre-treatment correction of translations only but not rotations did not affect target coverage and conformity. Post-treatment errors reduced target coverage by >5% in 14% of the patients. A 1 mm safety margin fully compensated intra-fractional patient motion. Conclusions: IG-RS with online correction of translational errors achieves high geometric and dosimetric accuracy. Intra-fractional errors decrease target coverage and conformity unless compensated with appropriate safety margins. KW - Medizin KW - Radiosurgery KW - Frame-less KW - Frame-based KW - Stereotactic KW - Image-guidance Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75669 ER - TY - JOUR A1 - Gutknecht, Lise A1 - Araragi, Naozumi A1 - Merker, Sören A1 - Waider, Jonas A1 - Sommerlandt, Frank M. J. A1 - Mlinar, Boris A1 - Baccini, Gilda A1 - Mayer, Ute A1 - Proft, Florian A1 - Hamon, Michel A1 - Schmitt, Angelika G. A1 - Corradetti, Renato A1 - Lanfumey, Laurence A1 - Lesch, Klaus-Peter T1 - Impacts of Brain Serotonin Deficiency following Tph2 Inactivation on Development and Raphe Neuron Serotonergic Specification JF - PLoS One N2 - Brain serotonin (5-HT) is implicated in a wide range of functions from basic physiological mechanisms to complex behaviors, including neuropsychiatric conditions, as well as in developmental processes. Increasing evidence links 5-HT signaling alterations during development to emotional dysregulation and psychopathology in adult age. To further analyze the importance of brain 5-HT in somatic and brain development and function, and more specifically differentiation and specification of the serotonergic system itself, we generated a mouse model with brain-specific 5-HT deficiency resulting from a genetically driven constitutive inactivation of neuronal tryptophan hydroxylase-2 (Tph2). Tph2 inactivation (Tph2-/-) resulted in brain 5-HT deficiency leading to growth retardation and persistent leanness, whereas a sex- and age-dependent increase in body weight was observed in Tph2+/- mice. The conserved expression pattern of the 5-HT neuron-specific markers (except Tph2 and 5-HT) demonstrates that brain 5-HT synthesis is not a prerequisite for the proliferation, differentiation and survival of raphe neurons subjected to the developmental program of serotonergic specification. Furthermore, although these neurons are unable to synthesize 5-HT from the precursor tryptophan, they still display electrophysiological properties characteristic of 5-HT neurons. Moreover, 5-HT deficiency induces an up-regulation of 5-HT\(_{1A}\) and 5-HT\(_{1B}\) receptors across brain regions as well as a reduction of norepinephrine concentrations accompanied by a reduced number of noradrenergic neurons. Together, our results characterize developmental, neurochemical, neurobiological and electrophysiological consequences of brain-specific 5-HT deficiency, reveal a dual dose-dependent role of 5-HT in body weight regulation and show that differentiation of serotonergic neuron phenotype is independent from endogenous 5-HT synthesis. KW - lacking KW - knock-out mice KW - energy expenditure KW - locomotor activity KW - 5-HT transporter KW - anxiety like KW - receptors KW - behavior KW - tryptophan KW - nucleus Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133728 VL - 7 IS - 8 ER -