TY - JOUR A1 - Isles, Anthony R. A1 - Ingason, Andrés A1 - Lowther, Chelsea A1 - Walters, James A1 - Gawlick, Micha A1 - Stöber, Gerald A1 - Rees, Elliott A1 - Martin, Joanna A1 - Little, Rosie B. A1 - Potter, Harry A1 - Georgieva, Lyudmila A1 - Pizzo, Lucilla A1 - Ozaki, Norio A1 - Aleksic, Branko A1 - Kushima, Itaru A1 - Ikeda, Masashi A1 - Iwata, Nakao A1 - Levinson, Douglas F. A1 - Gejman, Pablo V. A1 - Shi, Jianxin A1 - Sanders, Alan R. A1 - Duan, Jubao A1 - Willis, Joseph A1 - Sisodiya, Sanjay A1 - Costain, Gregory A1 - Werge, Thomas M. A1 - Degenhardt, Franziska A1 - Giegling, Ina A1 - Rujescu, Dan A1 - Hreidarsson, Stefan J. A1 - Saemundsen, Evald A1 - Ahn, Joo Wook A1 - Ogilvie, Caroline A1 - Girirajan, Santhosh D. A1 - Stefansson, Hreinn A1 - Stefansson, Kari A1 - O'Donovan, Michael C. A1 - Owen, Michael J. A1 - Bassett, Anne A1 - Kirov, George T1 - Parental Origin of Interstitial Duplications at 15q11.2-q13.3 in Schizophrenia and Neurodevelopmental Disorders JF - PLoS Genetics N2 - Duplications at 15q11.2-q13.3 overlapping the Prader-Willi/Angelman syndrome (PWS/AS) region have been associated with developmental delay (DD), autism spectrum disorder (ASD) and schizophrenia (SZ). Due to presence of imprinted genes within the region, the parental origin of these duplications may be key to the pathogenicity. Duplications of maternal origin are associated with disease, whereas the pathogenicity of paternal ones is unclear. To clarify the role of maternal and paternal duplications, we conducted the largest and most detailed study to date of parental origin of 15q11.2-q13.3 interstitial duplications in DD, ASD and SZ cohorts. We show, for the first time, that paternal duplications lead to an increased risk of developing DD/ASD/multiple congenital anomalies (MCA), but do not appear to increase risk for SZ. The importance of the epigenetic status of 15q11.2-q13.3 duplications was further underlined by analysis of a number of families, in which the duplication was paternally derived in the mother, who was unaffected, whereas her offspring, who inherited a maternally derived duplication, suffered from psychotic illness. Interestingly, the most consistent clinical characteristics of SZ patients with 15q11.2-q13.3 duplications were learning or developmental problems, found in 76% of carriers. Despite their lower pathogenicity, paternal duplications are less frequent in the general population with a general population prevalence of 0.0033% compared to 0.0069% for maternal duplications. This may be due to lower fecundity of male carriers and differential survival of embryos, something echoed in the findings that both types of duplications are de novo in just over 50% of cases. Isodicentric chromosome 15 (idic15) or interstitial triplications were not observed in SZ patients or in controls. Overall, this study refines the distinct roles of maternal and paternal interstitial duplications at 15q11.2-q13.3, underlining the critical importance of maternally expressed imprinted genes in the contribution of Copy Number Variants (CNVs) at this interval to the incidence of psychotic illness. This work will have tangible benefits for patients with 15q11.2-q13.3 duplications by aiding genetic counseling. KW - interstitial duplications KW - schizophrenia KW - developmental delay KW - autism spectrum disorder KW - parental origin KW - genetics Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166706 VL - 12 IS - 5 ER - TY - JOUR A1 - Vendelova, Emilia A1 - de Lima, Jeferson Camargo A1 - Lorenzatto, Karina Rodrigues A1 - Monteiro, Karina Mariante A1 - Mueller, Thomas A1 - Veepaschit, Jyotishman A1 - Grimm, Clemens A1 - Brehm, Klaus A1 - Hrčková, Gabriela A1 - Lutz, Manfred B. A1 - Ferreira, Henrique B. A1 - Nono, Justin Komguep T1 - Proteomic Analysis of Excretory-Secretory Products of Mesocestoides corti Metacestodes Reveals Potential Suppressors of Dendritic Cell Functions JF - PLoS Neglected Tropical Diseases N2 - Accumulating evidences have assigned a central role to parasite-derived proteins in immunomodulation. Here, we report on the proteomic identification and characterization of immunomodulatory excretory-secretory (ES) products from the metacestode larva (tetrathyridium) of the tapeworm Mesocestoides corti (syn. M. vogae). We demonstrate that ES products but not larval homogenates inhibit the stimuli-driven release of the pro-inflammatory, Th1-inducing cytokine IL-12p70 by murine bone marrow-derived dendritic cells (BMDCs). Within the ES fraction, we biochemically narrowed down the immunosuppressive activity to glycoproteins since active components were lipid-free, but sensitive to heat- and carbohydrate-treatment. Finally, using bioassay-guided chromatographic analyses assisted by comparative proteomics of active and inactive fractions of the ES products, we defined a comprehensive list of candidate proteins released by M. corti tetrathyridia as potential suppressors of DC functions. Our study provides a comprehensive library of somatic and ES products and highlight some candidate parasite factors that might drive the subversion of DC functions to facilitate the persistence of M. corti tetrathyridia in their hosts. KW - proteomic analysis KW - excretory-secretory KW - Mesocestoides corti Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166742 VL - 10 IS - 10 ER - TY - JOUR A1 - Shi, Yaoyao A1 - Kuai, Yue A1 - Lei, Lizhen A1 - Weng, Yuanyuan A1 - Berberich-Siebelt, Friederike A1 - Zhang, Xinxia A1 - Wang, Jinjie A1 - Zhou, Yuan A1 - Jiang, Xin A1 - Ren, Guoping A1 - Pan, Hongyang A1 - Mao, Zhengrong A1 - Zhou, Ren T1 - The feedback loop of LITAF and BCL6 is involved in regulating apoptosis in B cell non-Hodgkin's-lymphoma JF - Oncotarget N2 - Dysregulation of the apoptotic pathway is widely recognized as a key step in lymphomagenesis. Notably, LITAF was initially identified as a p53-inducible gene, subsequently implicated as a tumor suppressor. Our previous study also showed LITAF to be methylated in 89.5% B-NHL samples. Conversely, deregulated expression of BCL6 is a pathogenic event in many lymphomas. Interestingly, our study found an oppositional expression of LITAF and BCL6 in B-NHL. In addition, LITAF was recently identified as a novel target gene of BCL6. Therefore, we sought to explore the feedback loop between LITAF and BCL6 in B-NHL. Here, our data for the first time show that LITAF can repress expression of BCL6 by binding to Region A (−87 to +65) containing a putative LITAF-binding motif (CTCCC) within the BCL6 promoter. Furthermore, the regulation of BCL6 targets (PRDM1 or c-Myc) by LITAF may be associated with B-cell differentiation. Results also demonstrate that ectopic expression of LITAF induces cell apoptosis, activated by releasing cytochrome c, cleaving PARP and caspase 3 in B-NHL cells whereas knockdown of LITAF robustly protected cells from apoptosis. Interestingly, BCL6, in turn, could reverse cell apoptosis mediated by LITAF. Collectively, our findings provide a novel apoptotic regulatory pathway in which LITAF, as a transcription factor, inhibits the expression of BCL6, which leads to activation of the intrinsic mitochondrial pathway and tumor apoptosis. Our study is expected to provide a possible biomarker as well as a target for clinical therapies to promote tumor cell apoptosis. KW - LITAF KW - BCL6 KW - apoptosis KW - lymphoma KW - B-cells Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166500 VL - 7 IS - 47 ER - TY - JOUR A1 - Vučićević, Dubravka A1 - Gehre, Maja A1 - Dhamija, Sonam A1 - Friis-Hansen, Lennart A1 - Meierhofer, David A1 - Sauer, Sascha A1 - Ørom, Ulf Andersson T1 - The long non-coding RNA PARROT is an upstream regulator of c-Myc and affects proliferation and translation JF - Oncotarget N2 - Long non-coding RNAs are important regulators of gene expression and signaling pathways. The expression of long ncRNAs is dysregulated in cancer and other diseases. The identification and characterization of long ncRNAs is often challenging due to their low expression level and localization to chromatin. Here, we identify a functional long ncRNA, PARROT (Proliferation Associated RNA and Regulator Of Translation) transcribed by RNA polymerase II and expressed at a relatively high level in a number of cell lines. The PARROT long ncRNA is associated with proliferation in both transformed and normal cell lines. We characterize the long ncRNA PARROT as an upstream regulator of c-Myc affecting cellular proliferation and translation using RNA sequencing and mass spectrometry following depletion of the long ncRNA. PARROT is repressed during senescence of human mammary epithelial cells and overexpressed in some cancers, suggesting an important association with proliferation through regulation of c-Myc. With this study, we add to the knowledge of cytoplasmic functional long ncRNAs and extent the long ncRNA-Myc regulatory network in transformed and normal cells. KW - PARROT KW - c-Myc KW - long ncRNA KW - upstream regulator Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166519 VL - 7 IS - 23 ER - TY - JOUR A1 - Eisenhardt, Anja E. A1 - Sprenger, Adrian A1 - Röring, Michael A1 - Herr, Ricarda A1 - Weinberg, Florian A1 - Köhler, Martin A1 - Braun, Sandra A1 - Orth, Joachim A1 - Diedrich, Britta A1 - Lanner, Ulrike A1 - Tscherwinski, Natalja A1 - Schuster, Simon A1 - Dumaz, Nicolas A1 - Schmidt, Enrico A1 - Baumeister, Ralf A1 - Schlosser, Andreas A1 - Dengjel, Jörn A1 - Brummer, Tilman T1 - Phospho-proteomic analyses of B-Raf protein complexes reveal new regulatory principles JF - Oncotarget N2 - B-Raf represents a critical physiological regulator of the Ras/RAF/MEK/ERK-pathway and a pharmacological target of growing clinical relevance, in particular in oncology. To understand how B-Raf itself is regulated, we combined mass spectrometry with genetic approaches to map its interactome in MCF-10A cells as well as in B-Raf deficient murine embryonic fibroblasts (MEFs) and B-Raf/Raf-1 double deficient DT40 lymphoma cells complemented with wildtype or mutant B-Raf expression vectors. Using a multi-protease digestion approach, we identified a novel ubiquitination site and provide a detailed B-Raf phospho-map. Importantly, we identify two evolutionary conserved phosphorylation clusters around T401 and S419 in the B-Raf hinge region. SILAC labelling and genetic/biochemical follow-up revealed that these clusters are phosphorylated in the contexts of oncogenic Ras, sorafenib induced Raf dimerization and in the background of the V600E mutation. We further show that the vemurafenib sensitive phosphorylation of the T401 cluster occurs in trans within a Raf dimer. Substitution of the Ser/Thr-residues of this cluster by alanine residues enhances the transforming potential of B-Raf, indicating that these phosphorylation sites suppress its signaling output. Moreover, several B-Raf phosphorylation sites, including T401 and S419, are somatically mutated in tumors, further illustrating the importance of phosphorylation for the regulation of this kinase. KW - BRAF KW - proteomics KW - phosphorylation KW - sorafenib KW - protein-protein interaction Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166529 VL - 7 IS - 18 ER - TY - JOUR A1 - Chenari, Hossein Mahmoudi A1 - Seibel, Christoph A1 - Hauschild, Dirk A1 - Reinert, Friedrich A1 - Abdollahian, Hossein T1 - Titanium Dioxide Nanoparticles: Synthesis, X-Ray Line Analysis and Chemical Composition Study JF - Materials Research N2 - TiO2 nanoparticleshave been synthesized by the sol-gel method using titanium alkoxide and isopropanolas a precursor. The structural properties and chemical composition of the TiO2 nanoparticles were studied usingX-ray diffraction, scanning electron microscopy, and X-ray photoelectron spectroscopy.The X-ray powder diffraction pattern confirms that the particles are mainly composed of the anatase phase with the preferential orientation along [101] direction. The physical parameters such as strain, stress and energy density were investigated from the Williamson- Hall (W-H) plot assuming a uniform deformation model (UDM), and uniform deformation energy density model (UDEDM). The W-H analysis shows an anisotropic nature of the strain in nanopowders. The scanning electron microscopy image shows clear TiO2 nanoparticles with particle sizes varying from 60 to 80nm. The results of mean particle size of TiO2 nanoparticles show an inter correlation with the W-H analysis and SEM results. Our X-ray photoelectron spectroscopy spectra show that nearly a complete amount of titanium has reacted to TiO2 KW - TiO\(_2\) KW - Nanoparticles KW - X-ray analysis KW - SEM KW - XPS Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165807 VL - 19 IS - 6 ER - TY - JOUR A1 - Dingemans, Josef A1 - Monsieurs, Pieter A1 - Yu, Sung-Huan A1 - Crabbé, Aurélie A1 - Förstner, Konrad U. A1 - Malfroot, Anne A1 - Cornelis, Pierre A1 - Van Houdt, Rob T1 - Effect of Shear Stress on Pseudomonas aeruginosa Isolated from the Cystic Fibrosis Lung JF - mBio N2 - Chronic colonization of the lungs by Pseudomonas aeruginosa is one of the major causes of morbidity and mortality in cystic fibrosis (CF) patients. To gain insights into the characteristic biofilm phenotype of P. aeruginosa in the CF lungs, mimicking the CF lung environment is critical. We previously showed that growth of the non-CF-adapted P. aeruginosa PAO1 strain in a rotating wall vessel, a device that simulates the low fluid shear (LS) conditions present in the CF lung, leads to the formation of in-suspension, self-aggregating biofilms. In the present study, we determined the phenotypic and transcriptomic changes associated with the growth of a highly adapted, transmissible P. aeruginosa CF strain in artificial sputum medium under LS conditions. Robust self-aggregating biofilms were observed only under LS conditions. Growth under LS conditions resulted in the upregulation of genes involved in stress response, alginate biosynthesis, denitrification, glycine betaine biosynthesis, glycerol metabolism, and cell shape maintenance, while genes involved in phenazine biosynthesis, type VI secretion, and multidrug efflux were downregulated. In addition, a number of small RNAs appeared to be involved in the response to shear stress. Finally, quorum sensing was found to be slightly but significantly affected by shear stress, resulting in higher production of autoinducer molecules during growth under high fluid shear (HS) conditions. In summary, our study revealed a way to modulate the behavior of a highly adapted P. aeruginosa CF strain by means of introducing shear stress, driving it from a biofilm lifestyle to a more planktonic lifestyle. KW - biology Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165821 VL - 7 IS - 4 ER - TY - JOUR A1 - Drgonova, Jana A1 - Walther, Donna A1 - Hartstein, G Luke A1 - Bukhari, Mohammad O A1 - Baumann, Michael H A1 - Katz, Jonathan A1 - Hall, F Scott A1 - Arnold, Elizabeth R A1 - Flax, Shaun A1 - Riley, Anthony A1 - Rivero, Olga A1 - Lesch, Klaus-Peter A1 - Troncoso, Juan A1 - Ranscht, Barbara A1 - Uhl, George R T1 - Cadherin 13: Human cis-Regulation and Selectively Altered Addiction Phenotypes and Cerebral Cortical Dopamine in Knockout Mice JF - Molecular Medicine N2 - The Cadherin 13 (CDH13) gene encodes a cell adhesion molecule likely to influence development and connections of brain circuits that modulate addiction, locomotion and cognition, including those that involve midbrain dopamine neurons. Human CDH13 mRNA expression differs by more than 80% in postmortem cerebral cortical samples from individuals with different CDH13 genotypes, supporting examination of mice with altered CDH13 expression as models for common human variation at this locus. Constitutive CDH13 knockout mice display evidence for changed cocaine reward: shifted dose response relationship in tests of cocaine-conditioned place preference using doses that do not alter cocaine-conditioned taste aversion. Reduced adult CDH13 expression in conditional knockouts also alters cocaine reward in ways that correlate with individual differences in cortical CDH13 mRNA levels. In control and comparison behavioral assessments, knockout mice display modestly quicker acquisition of rotarod and water maze tasks, with a trend toward faster acquisition of 5-choice serial reaction time tasks that otherwise displayed no genotype-related differences. They display significant differences in locomotion in some settings, with larger effects in males. In assessments of brain changes that might contribute to these behavioral differences, there are selective alterations of dopamine levels, dopamine/metabolite ratios, dopaminergic fiber densities and mRNA encoding the activity dependent transcription factor npas4 in cerebral cortex of knockout mice. These novel data and previously reported human associations of CDH13 variants with addiction, individual differences in responses to stimulant administration and attention deficit hyperactivity disorder (ADHD) phenotypes suggest that levels of CDH13 expression, through mechanisms likely to include effects on mesocortical dopamine, influence stimulant reward and may contribute modestly to cognitive and locomotor phenotypes relevant to ADHD. KW - Cadherin (CDH13) KW - CDH13 mRNA KW - Attention Deficit Hyperactivity Disorder (ADHD) KW - CDH13 Expression KW - Human CDH13 Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165842 VL - 22 ER - TY - JOUR A1 - van de Kerkhof, Nora WA A1 - Fekkes, Durk A1 - van der Heijden, Frank MMA A1 - Hoogendijk, Witte JG A1 - Stöber, Gerald A1 - Egger, Jos IM A1 - Verhoeven, Willem MA T1 - Cycloid psychoses in the psychosis spectrum: evidence for biochemical differences with schizophrenia JF - Neuropsychiatric Disease and Treatment N2 - Cycloid psychoses (CP) differ from schizophrenia regarding symptom profile, course, and prognosis and over many decades they were thought to be a separate entity within the psychosis spectrum. As to schizophrenia, research into the pathophysiology has focused on dopamine, brain-derived neurotrophic factor, and glutamate signaling in which, concerning the latter, the N-methyl-d-aspartate receptor plays a crucial role. The present study aims to determine whether CP can biochemically be delineated from schizophrenia. Eighty patients referred for psychotic disorders were assessed with the Comprehensive Assessment of Symptoms and History, and (both at inclusion and after 6 weeks of antipsychotic treatment) with the Positive and Negative Syndrome Scale and Clinical Global Impression. From 58 completers, 33 patients were diagnosed with schizophrenia and ten with CP according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and Leonhard criteria, respectively. Fifteen patients were diagnosed with other disorders within the psychosis spectrum. At both time points, blood levels of the dopamine metabolite homovanillic acid, brain-derived neurotrophic factor, and amino acids related to glutamate neurotransmission were measured and compared with a matched control sample. Patients with CP showed a significantly better response to antipsychotic treatment as compared to patients with schizophrenia. In CP, glycine levels were elevated and tryptophan levels were lowered as compared to schizophrenia. Glutamate levels were increased in both patient groups as compared to controls. These results, showing marked differences in both treatment outcome and glutamate-related variable parameters, may point at better neuroplasticity in CP, necessitating demarcation of this subgroup within the psychosis spectrum. KW - cycloid psychoses KW - schizophrenia KW - glutamate KW - glycine KW - tryptophan KW - neuroplasticity Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166255 VL - 12 ER - TY - JOUR A1 - Hargart, F A1 - Roy-Choudhury, K A1 - John, T A1 - Portalupi, S L A1 - Schneider, C A1 - Höfling, S A1 - Kamp, M A1 - Hughes, S A1 - Michler, P T1 - Probing different regimes of strong field light-matter interaction with semiconductor quantum dots and few cavity photons JF - New Journal of Physics N2 - In this work we present an extensive experimental and theoretical investigation of different regimes of strong field light–matter interaction for cavity-driven quantum dot (QD) cavity systems. The electric field enhancement inside a high-Q micropillar cavity facilitates exceptionally strong interaction with few cavity photons, enabling the simultaneous investigation for a wide range of QD-laser detuning. In case of a resonant drive, the formation of dressed states and a Mollow triplet sideband splitting of up to 45 μeV is measured for amean cavity photon number \(\leq\) 1. In the asymptotic limit of the linear ACStark effect we systematically investigate the power and detuning dependence of more than 400 QDs. Some QD-cavity systems exhibit an unexpected anomalous Stark shift, which can be explained by an extended dressed 4-levelQDmodel.Weprovide a detailed analysis of the QD-cavity systems properties enabling this novel effect. The experimental results are successfully reproduced using a polaron master equation approach for the QD-cavity system, which includes the driving laser field, exciton-cavity and exciton-phonon interactions KW - light–matter interaction KW - quantum dots KW - AC Stark effect KW - dressed states Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166278 VL - 18 ER -