TY - JOUR A1 - Havik, Bjarte A1 - Degenhardt, Franziska A. A1 - Johansson, Stefan A1 - Fernandes, Carla P. D. A1 - Hinney, Anke A1 - Scherag, André A1 - Lybaek, Helle A1 - Djurovic, Srdjan A1 - Christoforou, Andrea A1 - Ersland, Kari M. A1 - Giddaluru, Sudheer A1 - O'Donovan, Michael C. A1 - Owen, Michael J. A1 - Craddock, Nick A1 - Mühleisen, Thomas W. A1 - Mattheisen, Manuel A1 - Schimmelmann, Benno G. A1 - Renner, Tobias A1 - Warnke, Andreas A1 - Herpertz-Dahlmann, Beate A1 - Sinzig, Judith A1 - Albayrak, Özgür A1 - Rietschel, Marcella A1 - Nöthen, Markus M. A1 - Bramham, Clive R. A1 - Werge, Thomas A1 - Hebebrand, Johannes A1 - Haavik, Jan A1 - Andreassen, Ole A. A1 - Cichon, Sven A1 - Steen, Vidar M. A1 - Le Hellard, Stephanie T1 - DCLK1 Variants Are Associated across Schizophrenia and Attention Deficit/Hyperactivity Disorder JF - PLoS One N2 - Doublecortin and calmodulin like kinase 1 (DCLK1) is implicated in synaptic plasticity and neurodevelopment. Genetic variants in DCLK1 are associated with cognitive traits, specifically verbal memory and general cognition. We investigated the role of DCLK1 variants in three psychiatric disorders that have neuro-cognitive dysfunctions: schizophrenia (SCZ), bipolar affective disorder (BP) and attention deficit/hyperactivity disorder (ADHD). We mined six genome wide association studies (GWASs) that were available publically or through collaboration; three for BP, two for SCZ and one for ADHD. We also genotyped the DCLK1 region in additional samples of cases with SCZ, BP or ADHD and controls that had not been whole-genome typed. In total, 9895 subjects were analysed, including 5308 normal controls and 4,587 patients (1,125 with SCZ, 2,496 with BP and 966 with ADHD). Several DCLK1 variants were associated with disease phenotypes in the different samples. The main effect was observed for rs7989807 in intron 3, which was strongly associated with SCZ alone and even more so when cases with SCZ and ADHD were combined (P-value = 4x10\(^{-5}\) and 4x10\(^{-6}\), respectively). Associations were also observed with additional markers in intron 3 (combination of SCZ, ADHD and BP), intron 19 (SCZ+BP) and the 3'UTR (SCZ+BP). Our results suggest that genetic variants in DCLK1 are associated with SCZ and, to a lesser extent, with ADHD and BP. Interestingly the association is strongest when SCZ and ADHD are considered together, suggesting common genetic susceptibility. Given that DCLK1 variants were previously found to be associated with cognitive traits, these results are consistent with the role of DCLK1 in neurodevelopment and synaptic plasticity. KW - psychosis KW - deficit hyperactivity disorder KW - genome-wide association KW - bipolar disorder KW - VAL66MET polymorphism KW - doublecortine-like KW - genes KW - kinase KW - BDNF KW - endophenotype Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135285 VL - 7 IS - 4 ER - TY - JOUR A1 - 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 - Steinmann, Diana A1 - Paelecke-Habermann, Yvonne A1 - Geinitz, Hans A1 - Aschoff, Raimund A1 - Bayerl, Anja A1 - Bölling, Tobias A1 - Bosch, Elisabeth A1 - Bruns, Frank A1 - Eichenseder-Seiss, Ute A1 - Gerstein, Johanna A1 - Gharbi, Nadine A1 - Hagg, Juliane A1 - Hipp, Matthias A1 - Kleff, Irmgard A1 - Müller, Axel A1 - Schäfer, Christof A1 - Schleicher, Ursula A1 - Sehlen, Susanne A1 - Theodorou, Marilena A1 - Wypior, Hans-Joachim A1 - Zehentmayr, Franz A1 - van Oorschot, Birgitt A1 - Vordermark, Dirk T1 - Prospective evaluation of quality of life effects in patients undergoing palliative radiotherapy for brain metastases JF - BMC Cancer N2 - Background: Recently published results of quality of life (QoL) studies indicated different outcomes of palliative radiotherapy for brain metastases. This prospective multi-center QoL study of patients with brain metastases was designed to investigate which QoL domains improve or worsen after palliative radiotherapy and which might provide prognostic information. Methods: From 01/2007-01/2009, n=151 patients with previously untreated brain metastases were recruited at 14 centers in Germany and Austria. Most patients (82 %) received whole-brain radiotherapy. QoL was measured with the EORTC-QLQ-C15-PAL and brain module BN20 before the start of radiotherapy and after 3 months. Results: At 3 months, 88/142 (62 %) survived. Nine patients were not able to be followed up. 62 patients (70.5 % of 3-month survivors) completed the second set of questionnaires. Three months after the start of radiotherapy QoL deteriorated significantly in the areas of global QoL, physical function, fatigue, nausea, pain, appetite loss, hair loss, drowsiness, motor dysfunction, communication deficit and weakness of legs. Although the use of corticosteroid at 3 months could be reduced compared to pre-treatment (63 % vs. 37 %), the score for headaches remained stable. Initial QoL at the start of treatment was better in those alive than in those deceased at 3 months, significantly for physical function, motor dysfunction and the symptom scales fatigue, pain, appetite loss and weakness of legs. In a multivariate model, lower Karnofsky performance score, higher age and higher pain ratings before radiotherapy were prognostic of 3-month survival. Conclusions: Moderate deterioration in several QoL domains was predominantly observed three months after start of palliative radiotherapy for brain metastases. Future studies will need to address the individual subjective benefit or burden from such treatment. Baseline QoL scores before palliative radiotherapy for brain metastases may contain prognostic information. KW - breast cancer KW - brain tumours KW - survival KW - validation KW - symptoms KW - EORTC-QLQ-C15-PAL KW - EORTC-BN20 KW - whole-brain radiotherapy KW - partitioning analysis RPA KW - cancer patients KW - lung cancer KW - prognostic index KW - radiation oncology KW - clinical trials Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135254 VL - 12 IS - 283 ER - TY - JOUR A1 - Leistner, Stefanie A1 - Benik, Steffen A1 - Laumeier, Inga A1 - Ziegler, Annerose A1 - Nieweler, Gabriele A1 - Nolte, Christian H. A1 - Heuschmann, Peter U. A1 - Audebert, Heinrich J. T1 - Secondary Prevention after Minor Stroke and TIA - Usual Care and Development of a Support Program JF - PLoS One N2 - Background: Effective methods of secondary prevention after stroke or TIA are available but adherence to recommended evidence-based treatments is often poor. The study aimed to determine the quality of secondary prevention in usual care and to develop a stepwise modeled support program. Methods: Two consecutive cohorts of patients with acute minor stroke or TIA undergoing usual outpatient care versus a secondary prevention program were compared. Risk factor control and medication adherence were assessed in 6-month follow-ups (6M-FU). Usual care consisted of detailed information concerning vascular risk factor targets given at discharge and regular outpatient care by primary care physicians. The stepwise modeled support program additionally employed up to four outpatient appointments. A combination of educational and behavioral strategies was employed. Results: 168 patients in the observational cohort who stated their openness to participate in a prevention program (mean age 64.7 y, admission blood pressure (BP): 155/84 mmHg) and 173 patients participating in the support program (mean age 67.6 y, BP: 161/84 mmHg) were assessed at 6 months. Proportions of patients with BP according to guidelines were 50% in usual-care and 77% in the support program (p<0.01). LDL<100 mg/dl was measured in 62 versus 71% (p = 0.12). Proportions of patients who stopped smoking were 50 versus 79% (p<0.01). 72 versus 89% of patients with atrial fibrillation were on oral anticoagulation (p = 0.09). Conclusions: Risk factor control remains unsatisfactory in usual care. Targets of secondary prevention were met more often within the supported cohort. Effects on (cerebro-)vascular recurrence rates are going to be assessed in a multicenter randomized trial. KW - atherothrombosis KW - multifactorial KW - clinical trial KW - hypertension KW - disease KW - transient ischemic attack KW - randomized controlled trial KW - cardiovascular risk factors KW - blood pressure KW - event rates Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135247 VL - 7 IS - 12 ER - TY - JOUR A1 - Roier, Sandro A1 - Leitner, Deborah R. A1 - Iwashkiw, Jeremy A1 - Schild-Prüfert, Kristina A1 - Feldman, Mario F. A1 - Krohne, Georg A1 - Reidl, Joachim A1 - Schild, Stefan T1 - Intranasal Immunization with Nontypeable Haemophilus influenzae Outer Membrane Vesicles Induces Cross-Protective Immunity in Mice JF - PLoS One N2 - Haemophilus influenzae is a Gram-negative human-restricted bacterium that can act as a commensal and a pathogen of the respiratory tract. Especially nontypeable H. influenzae (NTHi) is a major threat to public health and is responsible for several infectious diseases in humans, such as pneumonia, sinusitis, and otitis media. Additionally, NTHi strains are highly associated with exacerbations in patients suffering from chronic obstructive pulmonary disease. Currently, there is no licensed vaccine against NTHi commercially available. Thus, this study investigated the utilization of outer membrane vesicles (OMVs) as a potential vaccine candidate against NTHi infections. We analyzed the immunogenic and protective properties of OMVs derived from various NTHi strains by means of nasopharyngeal immunization and colonization studies with BALB/c mice. The results presented herein demonstrate that an intranasal immunization with NTHi OMVs results in a robust and complex humoral and mucosal immune response. Immunoprecipitation revealed the most important immunogenic proteins, such as the heme utilization protein, protective surface antigen D15, heme binding protein A, and the outer membrane proteins P1, P2, P5 and P6. The induced immune response conferred not only protection against colonization with a homologous NTHi strain, which served as an OMV donor for the immunization mixtures, but also against a heterologous NTHi strain, whose OMVs were not part of the immunization mixtures. These findings indicate that OMVs derived from NTHi strains have a high potential to act as a vaccine against NTHi infections. KW - conjugate KW - obstructive pulmonary disease KW - vaccine KW - vibrio cholerae KW - detoxified lipooligosaccharide KW - nasopharyngeal colonization KW - functional characterization KW - growing escherichia coli KW - DNA-binding vesicles KW - otitis media KW - hemophilus influenzae Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135201 VL - 7 IS - 8 ER - TY - JOUR A1 - Wolter, Steffen A1 - Aizezers, Janis A1 - Fennel, Franziska A1 - Seidel, Marcus A1 - Würthner, Frank A1 - Kühn, Oliver A1 - Lochbrunner, Stefan T1 - Size-dependent exciton dynamics in one-dimensional perylene bisimide aggregates JF - New Journal of Physics N2 - The size-dependent exciton dynamics of one-dimensional aggregates of substituted perylene bisimides are studied by ultrafast transient absorption spectroscopy and kinetic Monte-Carlo simulations as a function of the excitation density and the temperature in the range of 25-90 degrees C. For low temperatures, the aggregates can be treated as infinite chains and the dynamics is dominated by diffusion-driven exciton-exciton annihilation. With increasing temperature the aggregates dissociate into small fragments consisting of very few monomers. This scenario is also supported by the time-dependent anisotropy deduced from polarization-dependent experiments. KW - rotational diffusion KW - spectroscopy KW - dyes KW - annihilation KW - migration KW - films Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135190 VL - 14 IS - 105027 ER - TY - JOUR A1 - Harrington, John M. A1 - Scelsi, Chris A1 - Hartel, Andreas A1 - Jones, Nicola G. A1 - Engstler, Markus A1 - Capewell, Paul A1 - MacLeod, Annette A1 - Hajduk, Stephen T1 - Novel African Trypanocidal Agents: Membrane Rigidifying Peptides JF - PLoS One N2 - The bloodstream developmental forms of pathogenic African trypanosomes are uniquely susceptible to killing by small hydrophobic peptides. Trypanocidal activity is conferred by peptide hydrophobicity and charge distribution and results from increased rigidity of the plasma membrane. Structural analysis of lipid-associated peptide suggests a mechanism of phospholipid clamping in which an internal hydrophobic bulge anchors the peptide in the membrane and positively charged moieties at the termini coordinate phosphates of the polar lipid headgroups. This mechanism reveals a necessary phenotype in bloodstream form African trypanosomes, high membrane fluidity, and we suggest that targeting the plasma membrane lipid bilayer as a whole may be a novel strategy for the development of new pharmaceutical agents. Additionally, the peptides we have described may be valuable tools for probing the biosynthetic machinery responsible for the unique composition and characteristics of African trypanosome plasma membranes. KW - depth KW - trypanosome lytic factor KW - signal peptides KW - cell surface KW - protein KW - brucei KW - environment KW - bilayers KW - binding KW - probes Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135179 VL - 7 IS - 9 ER - TY - JOUR A1 - Kneissl, Sabrina A1 - Abel, Tobias A1 - Rasbach, Anke A1 - Brynza, Julia A1 - Schneider-Schaulies, Jürgen A1 - Buchholz, Christian J. T1 - Measles Virus Glycoprotein-Based Lentiviral Targeting Vectors That Avoid Neutralizing Antibodies JF - PLoS One N2 - Lentiviral vectors (LVs) are potent gene transfer vehicles frequently applied in research and recently also in clinical trials. Retargeting LV entry to cell types of interest is a key issue to improve gene transfer safety and efficacy. Recently, we have developed a targeting method for LVs by incorporating engineered measles virus (MV) glycoproteins, the hemagglutinin (H), responsible for receptor recognition, and the fusion protein into their envelope. The H protein displays a single-chain antibody (scFv) specific for the target receptor and is ablated for recognition of the MV receptors CD46 and SLAM by point mutations in its ectodomain. A potential hindrance to systemic administration in humans is pre-existing MV-specific immunity due to vaccination or natural infection. We compared transduction of targeting vectors and non-targeting vectors pseudotyped with MV glycoproteins unmodified in their ectodomains (MV-LV) in presence of \(\alpha\)-MV antibody-positive human plasma. At plasma dilution 1: 160 MV-LV was almost completely neutralized, whereas targeting vectors showed relative transduction efficiencies from 60% to 90%. Furthermore, at plasma dilution 1: 80 an at least 4-times higher multiplicity of infection (MOI) of MV-LV had to be applied to obtain similar transduction efficiencies as with targeting vectors. Also when the vectors were normalized to their p24 values, targeting vectors showed partial protection against \(\alpha\)-MV antibodies in human plasma. Furthermore, the monoclonal neutralizing antibody K71 with a putative epitope close to the receptor binding sites of H, did not neutralize the targeting vectors, but did neutralize MV-LV. The observed escape from neutralization may be due to the point mutations in the H ectodomain that might have destroyed antibody binding sites. Furthermore, scFv mediated cell entry via the target receptor may proceed in presence of a-MV antibodies interfering with entry via the natural MV receptors. These results are promising for in vivo applications of targeting vectors in humans. KW - vivo KW - gene delivery KW - hemagglutinin KW - cells KW - neurovirulence KW - encephalitis KW - transduction KW - domain Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134993 VL - 7 IS - 10 ER - TY - JOUR A1 - Ip, Chi Wang A1 - Kroner, Antje A1 - Groh, Janos A1 - Huber, Marianne A1 - Klein, Dennis A1 - Spahn, Irene A1 - Diem, Ricarda A1 - Williams, Sarah K. A1 - Nave, Klaus-Armin A1 - Edgar, Julia M. A1 - Martini, Rudolf T1 - Neuroinflammation by Cytotoxic T-Lymphocytes Impairs Retrograde Axonal Transport in an Oligodendrocyte Mutant Mouse JF - PLoS One N2 - Mice overexpressing proteolipid protein (PLP) develop a leukodystrophy-like disease involving cytotoxic, CD8+ T-lymphocytes. Here we show that these cytotoxic T-lymphocytes perturb retrograde axonal transport. Using fluorogold stereotactically injected into the colliculus superior, we found that PLP overexpression in oligodendrocytes led to significantly reduced retrograde axonal transport in retina ganglion cell axons. We also observed an accumulation of mitochondria in the juxtaparanodal axonal swellings, indicative for a disturbed axonal transport. PLP overexpression in the absence of T-lymphocytes rescued retrograde axonal transport defects and abolished axonal swellings. Bone marrow transfer from wildtype mice, but not from perforin- or granzyme B-deficient mutants, into lymphocyte-deficient PLP mutant mice led again to impaired axonal transport and the formation of axonal swellings, which are predominantly located at the juxtaparanodal region. This demonstrates that the adaptive immune system, including cytotoxic T-lymphocytes which release perforin and granzyme B, are necessary to perturb axonal integrity in the PLP-transgenic disease model. Based on our observations, so far not attended molecular and cellular players belonging to the immune system should be considered to understand pathogenesis in inherited myelin disorders with progressive axonal damage. KW - myelin KW - experimental autoimmune encephalomyelitis KW - degeneration KW - axonopathic changes KW - neural apoptosis KW - nervous system KW - motor function KW - proteolipid protein gene KW - retinal ganglion cells KW - granzyme B KW - multiple sclerosis Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134982 VL - 7 IS - 8 ER - TY - JOUR A1 - Jäger, Dominik A1 - Pernitzsch, Sandy R. A1 - Richter, Andreas S. A1 - Backofen, Rolf A1 - Sharma, Cynthia M. A1 - Schmitz, Ruth A. T1 - An archaeal sRNA targeting cis- and trans-encoded mRNAs via two distinct domains JF - Nucleic Acids Research N2 - We report on the characterization and target analysis of the small (s) RNA\(_{162}\) in the methanoarchaeon Methanosarcina mazei. Using a combination of genetic approaches, transcriptome analysis and computational predictions, the bicistronic MM2441-MM2440 mRNA encoding the transcription factor MM2441 and a protein of unknown function was identified as a potential target of this sRNA, which due to processing accumulates as three stabile 5' fragments in late exponential growth. Mobility shift assays using various mutants verified that the non-structured single-stranded linker region of sRNA\(_{162}\) (SLR) base-pairs with the MM2440-MM2441 mRNA internally, thereby masking the predicted ribosome binding site of MM2441. This most likely leads to translational repression of the second cistron resulting in dis-coordinated operon expression. Analysis of mutant RNAs in vivo confirmed that the SLR of sRNA\(_{162}\) is crucial for target interactions. Furthermore, our results indicate that sRNA\(_{162}\)-controlled MM2441 is involved in regulating the metabolic switch between the carbon sources methanol and methylamine. Moreover, biochemical studies demonstrated that the 50 end of sRNA\(_{162}\) targets the 5'-untranslated region of the cis-encoded MM2442 mRNA. Overall, this first study of archaeal sRNA/mRNA-target interactions unraveled that sRNA\(_{162}\) acts as an antisense (as) RNA on cis- and trans-encoded mRNAs via two distinct domains, indicating that cis-encoded asRNAs can have larger target regulons than previously anticipated. KW - strain KW - escherichia coli KW - methanosarcina mazei GO1 KW - methanol methyltransferase isozymes KW - small nucleolar RNAs KW - acetivorans C2A KW - antisense RNAs KW - GO1 KW - transcriptional regulator KW - translational initiation KW - pyrococcus furiosus Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134972 VL - 40 IS - 21 ER -