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 - Hofmann, Lukas A1 - Karl, Franziska A1 - Sommer, Claudia A1 - Üçeyler, Nurcan T1 - Affective and cognitive behavior in the alpha-galactosidase A deficient mouse model of Fabry disease JF - PLoS ONE N2 - Fabry disease is an X-linked inherited lysosomal storage disorder with intracellular accumulation of globotriaosylceramide (Gb3) due to α-galactosidase A (α-Gal A) deficiency. Fabry patients frequently report of anxiety, depression, and impaired cognitive function. We characterized affective and cognitive phenotype of male mice with α-Gal A deficiency (Fabry KO) and compared results with those of age-matched male wildtype (WT) littermates. Young (3 months) and old (≥ 18 months) mice were tested in the naïve state and after i.pl. injection of complete Freund`s adjuvant (CFA) as an inflammatory pain model. We used the elevated plus maze (EPM), the light-dark box (LDB) and the open field test (OF) to investigate anxiety-like behavior. The forced swim test (FST) and Morris water maze (MWM) were applied to assess depressive-like and learning behavior. The EPM test revealed no intergroup difference for anxiety-like behavior in naïve young and old Fabry KO mice compared to WT littermates, except for longer time spent in open arms of the EPM for young WT mice compared to young Fabry KO mice (p<0.05). After CFA injection, young Fabry KO mice showed increased anxiety-like behavior compared to young WT littermates (p<0.05) and naïve young Fabry KO mice (p<0.05) in the EPM as reflected by shorter time spent in EPM open arms. There were no relevant differences in the LDB and the OF test, except for longer time spent in the center zone of the OF by young WT mice compared to young Fabry KO mice (p<0.05). Complementary to this, depression-like and learning behavior were not different between genotypes and age-groups, except for the expectedly lower memory performance in older age-groups compared to young mice. Our results indicate that genetic influences on affective and cognitive symptoms in FD may be of subordinate relevance, drawing attention to potential influences of environmental and epigenetic factors. KW - cognitive impairment KW - mouse models KW - depression KW - swimming KW - learning KW - Fabry disease KW - genetics Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170745 VL - 12 IS - 6 ER - TY - JOUR A1 - Sadovnick, A. Dessa A1 - Traboulsee, Anthony L. A1 - Bernales, Cecily Q. A1 - Ross, Jay P. A1 - Forwell, Amanda L. A1 - Yee, Irene M. A1 - Guillot-Noel, Lena A1 - Fontaine, Bertrand A1 - Cournu-Rebeix, Isabelle A1 - Alcina, Antonio A1 - Fedetz, Maria A1 - Izquierdo, Guillermo A1 - Matesanz, Fuencisla A1 - Hilven, Kelly A1 - Dubois, Bénédicte A1 - Goris, An A1 - Astobiza, Ianire A1 - Alloza, Iraide A1 - Antigüedad, Alfredo A1 - Vandenbroeck, Koen A1 - Akkad, Denis A. A1 - Aktas, Orhan A1 - Blaschke, Paul A1 - Buttmann, Mathias A1 - Chan, Andrew A1 - Epplen, Joerg T. A1 - Gerdes, Lisa-Ann A1 - Kroner, Antje A1 - Kubisch, Christian A1 - Kümpfel, Tania A1 - Lohse, Peter A1 - Rieckmann, Peter A1 - Zettl, Uwe K. A1 - Zipp, Frauke A1 - Bertram, Lars A1 - Lill, Christina M. A1 - Fernandez, Oscar A1 - Urbaneja, Patricia A1 - Leyva, Laura A1 - Alvarez-Cermeño, Jose Carlos A1 - Arroyo, Rafael A1 - Garagorri, Aroa M. A1 - García-Martínez, Angel A1 - Villar, Luisa M. A1 - Urcelay, Elena A1 - Malhotra, Sunny A1 - Montalban, Xavier A1 - Comabella, Manuel A1 - Berger, Thomas A1 - Fazekas, Franz A1 - Reindl, Markus A1 - Schmied, Mascha C. A1 - Zimprich, Alexander A1 - Vilariño-Güell, Carles T1 - Analysis of Plasminogen Genetic Variants in Multiple Sclerosis Patients JF - G3: Genes Genomes Genetics N2 - Multiple sclerosis (MS) is a prevalent neurological disease of complex etiology. Here, we describe the characterization of a multi-incident MS family that nominated a rare missense variant (p.G420D) in plasminogen (PLG) as a putative genetic risk factor for MS. Genotyping of PLG p.G420D (rs139071351) in 2160 MS patients, and 886 controls from Canada, identified 10 additional probands, two sporadic patients and one control with the variant. Segregation in families harboring the rs139071351 variant, identified p.G420D in 26 out of 30 family members diagnosed with MS, 14 unaffected parents, and 12 out of 30 family members not diagnosed with disease. Despite considerably reduced penetrance, linkage analysis supports cosegregation of PLG p.G420D and disease. Genotyping of PLG p.G420D in 14446 patients, and 8797 controls from Canada, France, Spain, Germany, Belgium, and Austria failed to identify significant association with disease (P = 0.117), despite an overall higher prevalence in patients (OR = 1.32; 95% CI = 0.93–1.87). To assess whether additional rare variants have an effect on MS risk, we sequenced PLG in 293 probands, and genotyped all rare variants in cases and controls. This analysis identified nine rare missense variants, and although three of them were exclusively observed in MS patients, segregation does not support pathogenicity. PLG is a plausible biological candidate for MS owing to its involvement in immune system response, blood-brain barrier permeability, and myelin degradation. Moreover, components of its activation cascade have been shown to present increased activity or expression in MS patients compared to controls; further studies are needed to clarify whether PLG is involved in MS susceptibility. KW - multiple sclerosis KW - genetics KW - linkage KW - association KW - plasminogen Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165405 VL - 6 IS - 7 ER - TY - THES A1 - Schmelter, Christopher Michael T1 - Charakterisierung genetischer Aberrationen in Follikulären Lymphomen Grad 3B durch Fluoreszenz in situ Hybridisierung T1 - Characterization of Genetic Aberrations in Follicular Lymphoma Grade 3B by Fluorescence in situ Hybridization N2 - Das Follikuläre Lymphom (FL) ist nach dem Diffusen großzelligen B-Zell-Lymphom (DLBCL) das häufigste Non-Hodgkin-Lymphom in der westlichen Welt. Die aktuelle WHO-Klassifikation für Tumoren der Hämatopoetischen und Lymphoiden Gewebe aus dem Jahr 2008 unterteilt dieses maligne Lymphom nach Histologie und Wachstumsmuster in vier Gruppen, FL 1 bis FL 3A und FL 3B. Obwohl die FL 1 und FL 2 zu den indolenten Tumoren gezählt werden, und FL 3A und FL 3B tendenziell eher als aggressiv gelten, so wurde in einigen Studienarbeiten gezeigt, dass das FL 3A aufgrund seiner immunhistologischen und genetischen Charakteristika, insbesondere dem Vorhandensein der BCL2/IGH t(14;18)(q32;q21) Translokation, eher den low-grade-Lymphomen (FL 1 und FL 2) nahe steht, während das FL 3B durchaus Eigenschaften des DLBCL, wie das Fehlen einer BCL2/IGH-Translokation und das vermehrte Auftreten von Aberrationen des BCL6-Gens, zeigt. In verschiedenen Arbeiten wurde des Weiteren eine Einteilung in reine FL 3B und FL 3B mit Anteilen eines DLBCL (+ DLBCL) vorgenommen, da sich auch diese beiden Subgruppen durch unterschiedliche Proteinexpression und genetische Eigenschaften auszeichnen würden. Laut den bislang in der Literatur vorliegenden (spärlichen) Daten zeigen FL 3A und FL 3B unterschiedliche Antigen-Profile und offenbar auch unterschiedliche (primäre) genetische Veränderungen, wobei gerade für das FL 3B nur wenige Daten vorliegen. Während Grad 3A-Tumoren einige Ähnlichkeiten zu den FL 1 und 2 zeigen, scheint das FL 3B im Immunphänotyp wie in der Genetik eher dem DLBCL zu ähneln. Allerdings lässt sich bei kritischer Durchsicht der Literatur erkennen, dass die meisten Fälle eines FL Grad 3 entweder gar nicht den Graden 3A oder 3B zugeordnet, beziehungsweise in diese unterschieden wurden, oder häufig bereits einen zusätzlichen diffusen Wachstumstyp aufweisen, nach den Regeln der WHO-Klassifikation für Tumoren der Hämatopoetischen und Lymphatischen Gewebe (2008) also als DLBCL mit einem zusätzlichen follikulären Wachstumsanteil klassifiziert würden. Somit sind die Daten insbesondere über die rein follikulär wachsenden FL 3B äußerst spärlich. Die vorliegende Arbeit beschäftigt sich mit der immunhistochemischen und genetischen Charakterisierung der FL 3B. Von besonderem Interesse war die Bestimmung der Häufigkeit der BCL2/IGH t(14;18)(q32;q21), BCL6/IGH t(3;14)(q27;q32) und MYC/IGH t(8;14)(q24;q32) Translokationen in den verschiedenen Typen der FL. Weiterhin sollte der Frage nachgegangen werden, ob die Anwendung der Tissue Microarray (TMA)-Technik und der Fluoreszenz in situ Hybridisierung (FISH) an TMAs robuste Daten zu dieser Fragestellung liefern kann. In einem ersten Schritt wurden vorhandene TMAs von FL, DLBCL und MALT-Lymphomen mit break-apart-Sonden für BCL2, BCL6, MYC und IGH hybridisiert, und die gewonnenen Ergebnisse mit Daten der konventionellen Zytogenetik abgeglichen. Hierdurch sollte nachgewiesen werden, dass die FISH in Kombination mit der TMA-Technik eine valide Testmethode zur Aufdeckung der gesuchten chromosomalen Aberrationen darstellt, die in Sensitivität und Spezifität der klassischen Zytogenetik nicht nachsteht. In einem zweiten Schritt wurden FL aus dem Archiv des Pathologischen Instituts der Universität Würzburg anhand der aktuellen WHO-Kriterien in die Grade 1, 2, 3A und 3B eingeteilt (und reklassifiziert). Diese Tumoren wurden im TMA und im Vollschnitt durch immunhistochemische Färbungen auf ihre Protein-Expression und mittels FISH auf ihre genetischen Eigenschaften untersucht und charakterisiert. N2 - Follicular lymphoma (FL) and Diffuse Large B-cell lymphoma (DLBCL) each account for approximately 30 % to 40 % of all Non-Hodgkin-lymphomas (NHL) in the Western world, thus representing the most frequent subtypes of NHL. FL are homogenously characterized by their follicular growth pattern, and the current WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues recommends their subclassification into 3 grades (FL grade 1, 2 and 3) according to the number of centroblasts. FL grade 3 have gained considerable interest because of their unresolved status as indolent or aggressive neoplasms, and their varying immunophenotypic, cytogenetic and possibly clinical features. FL grade 3 can be further distinguished into two subtypes, FL grade 3A (FL 3A, with centrocytes) and FL grade 3B (FL 3B, without centrocytes). FL 3A shows overlapping morphological and genetic features to FL 1 and FL 2, whereas FL 3B is poorly characterized on the genetic level. Almost all available data have been generated from FL 3B with an additional DLBCL component. Purely follicular FL 3B, on the other hand, is a rare neoplasm. The cytogenetic constitution of purely follicular FL3B is largely unknown. In the present work, therefore, we set out to define immunophenotypic and cytogenetic data of FL 3B, especially also paying attention to their sometimes difficult delineation from FL 3A and related variants. We performed a detailed immunohistochemical and molecular investigation of purely follicular FL 3B. In this study, we also included FL with large centrocytes (FL LCC) and FL, in which a straightforward and reproducible distinction between grades 3A or 3B was not possible (FL 3U). Moreover, we analyzed FL 1, FL 2, FL 3A and FL 3B + DLBCL, with regard to their delineation from purely follicular FL 3B. The study focussed on the expression of immunohistochemical markers and the examination of translocations involving the BCL2, BCL6, and MYC gene loci via FISH. To ensure homogenous and rapid sample processing, we constructed tissue microarrays (TMAs). To obtain insights in the reliability of FISH analysis performed on TMAs, we initially investigated B-NHL samples, whose genetic aberrations previously have been well-defined and characterized by chromosome banding approaches. KW - B-Zell-Lymphom KW - Lymphom KW - Non-Hodgkin-Lymphom KW - Zentroblastisches Lymphom KW - Fluoreszenz-in-situ-Hybridisierung KW - Immuncytochemie KW - Genetik KW - Follikuläres Lymphom KW - Grad 3B KW - FISH KW - Immunhistochemie KW - Genetik KW - follicular lymphoma KW - grade 3B KW - FISH KW - immunohistochemistry KW - genetics Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-57649 ER - TY - THES A1 - Glotzbach-Schoon, Evelyn T1 - Contextual fear conditioning in humans: The return of contextual anxiety and the influence of genetic polymorphisms T1 - Kontextuelle Furchtkonditionierung beim Menschen: die Wiederkehr von Kontextangst und der Einfluss von genetischen Polymorphismen N2 - Als Angst bezeichnet man einen nicht auf spezifische Objekte gerichteten länger anhaltenden zukunfts-orientierten Zustand der Besorgnis. Diese ist kennzeichnend für Angststörungen wie Panikstörung, generalisierte Angststörung und Posttraumatische Belastungsstörung (PTBS). Experimentell kann Angst durch kontextuelle Furchtkonditionierung ausgelöst werden. Bei dieser Art der Konditionierung werden aversive Ereignisse als unvorhersehbar erlebt, wodurch der gesamte Kontext mit der Gefahr assoziiert wird. Diese Arbeit hat zum Ziel, Mechanismen der Entstehung und Aufrechterhaltung von Kontextangst zu untersuchen. Dies sind zum einem erleichterte Akquisition von Kontextkonditionierungen und deren fehlerhafte Extinktion. Hier ist vor allem die Fragestellung relevant, wie dies durch genetische Varianten moduliert wird (Studie 1). Zum anderen soll die Wiederkehr der Angst nach der Extinktion mit einem neuen Reinstatement-Paradigma untersucht werden (Studie 2). Zur Untersuchung dieser Forschungsfragen wurden zwei kontextuelle Furchtkonditionierungsstudien in virtueller Realität (VR) durchgeführt. Während der Akquisition wurden leicht schmerzhafte elektrische Reize (unkonditionierter Stimulus, US) unvorhersehbar präsentiert, während die Probanden in einem virtuellen Büroraum waren. Dadurch wurde dieser Raum zum Angstkontext (CXT+). Ein zweiter Büroraum wurde nie mit dem US gepaart, deshalb wurde dieser Raum zum Sicherheitskontext (CXT-). Die Extinktion, in der die Kontexte ohne US präsentiert wurden, fand 24 h später statt, und ein Test zum Abruf der Extinktion bzw. zur Wiederkehr der Angst nochmals 24 h später. In beiden Studien wurde die Angst auf drei verschiedenen Ebenen gemessen: Verhalten (angstpotenzierter Schreckreflex), Physiologie (tonische Hautleitfähigkeit), und verbale Ebene (explizite Ratings). Die Probanden für Studie 1 wurden anhand der 5-HTTLPR (S+ Risikoallel vs. LL nicht-Risikoallel) und NPSR1 rs324981 (T+ Risikoallel vs. AA nicht-Risikoallel) Polymorphismen stratifiziert, sodass vier kombinierte Genotyp Gruppen (S+/T+, S+/LL, LL/T+ und LL/AA) mit je 20 Probanden vorlagen. Es zeigte sich, dass der angstpotenzierte Schreckreflex durch die Interaktion zwischen beiden genetischen Polymorphismen moduliert wurde. Nur Träger beider Risikoallele (S+ Träger des 5-HTTLPR und T+ Träger des NPSR1 Polymorphismus) zeigten einen höheren Schreckreflex im CXT+ als im CXT- während der Akquisition. Der Abruf der Extinktion an Tag 3, gemessen anhand des Schreckreflexes, wurde allerdings nicht durch die Genotypen moduliert. Interessanterweise zeigte sich auf dem expliziten Angstlevel (Valenz- und Angstratings) nur ein Einfluss des NPSR1 Polymorphismus, und zwar bewerteten die nicht-Risikoallel Träger (AA) den CXT+ mit negativerer Valenz und höherer Angst im Vergleich zum CXT-; die Risikoallel Träger (T+) taten dies nicht. In der zweiten Studie wurde fast das gleiche Paradigma benutzt wie in der ersten Studie mit der Ausnahme, dass eine Versuchsgruppe (Reinstatementgruppe) den US noch einmal am Anfang des dritten Untersuchungstages vor der Präsentation von CXT+ und CXT- appliziert bekam. Die zweite Versuchsgruppe (Kontrollgruppe) erhielt keinen US, sondern wurde direkt durch CXT+ und CXT- geführt. Es zeigte sich, dass nur in der Reinstatementgruppe die Angst auf impliziter und expliziter Ebene wiederkehrte, d.h. die Probanden zeigten einen höheren Schreckreflex und höhere Angstratings auf den CXT+ im Vergleich zum CXT-. Wichtig war vor allem, dass die Wiederkehr der Angst in der Reinstatementgruppe mit der Veränderung der Zustandsangst und der Stimmung (von der Extinktion zum Test) korrelierte. D.h. je größer die Angst und je negativer die Stimmung wurden, desto höher war die Wiederkehr der Angst. Zusammengefasst belegt Studie 1, dass erleichterte kontextuelle Furchtkonditionierung auf impliziter Ebene (Schreckreflex) ein Endophänotyp für Angststörungen sein könnte, was zu unserem Verständnis der Ätiologie von Angststörungen beitragen könnte. Die Ergebnisse der zweiten Studie legen nahe, dass eine ängstliche und negative Stimmung nach der Extinktion die Rückkehr von Angst begünstigen könnte. Darüber hinaus scheint das VR-basierte kontextuelle Furchtkonditionierungsparadigma ein geeignetes Mittel zu sein, um Mechanismen der Angstentstehung und Angstwiederkehr experimentell zu erforschen. Weiterführende Studien könnten nun auch Angstpatienten untersuchen und das Paradigma auf evolutionär-relevante Kontexte (z.B. Höhe, Dunkelheit, weite Plätze) ausweiten. N2 - Sustained anxiety is considered as a chronic and future-oriented state of apprehension that does not belong to a specific object. It is discussed as an important characteristic of anxiety disorders including panic disorder, generalized anxiety disorder (GAD) and posttraumatic stress disorder (PTSD). Experimentally, sustained anxiety can be induced by contextual fear conditioning in which aversive events are unpredictably presented and therefore the whole context becomes associated with the threat. This thesis aimed at investigating important mechanisms in the development and maintenance of sustained anxiety: (1) facilitated acquisition and resistant extinction of contextual anxiety due to genetic risk factors (Study 1), and (2) the return of contextual anxiety after successful extinction using a new reinstatement paradigm (Study 2). To this end, two contextual fear conditioning studies were conducted in virtual reality (VR). During acquisition one virtual office was paired with unpredictable mildly painful electric stimuli (unconditioned stimulus, US), thus becoming the anxiety context (CXT+). Another virtual office was never paired with any US, thus becoming the safety context (CXT-). Extinction was conducted 24 h later, i.e. no US was presented, and extinction recall was tested another 24 h later on Day 3. In both studies context-evoked anxiety was measured on three different response levels: behavioral (anxiety-potentiated startle reflex), physiological (skin conductance level), and verbal (explicit ratings). In Study 1, participants were stratified for 5-HTTLPR (S+ risk allele vs. LL no risk allele) and NPSR1 rs324981 (T+ risk allele vs. AA no risk allele) polymorphisms, resulting in four combined genotype groups with 20 participants each: S+/T+, S+/LL, LL/T+, and LL/AA. Results showed that acquisition of anxiety-potentiated startle was influenced by a gene × gene interaction: only carriers of both risk alleles (S+ carriers of the 5-HTTLPR and T+ carriers of the NPSR1 polymorphism) exhibited significantly higher startle magnitudes in CXT+ compared to CXT-. However, extinction recall as measured with anxiety-potentiated startle was not affected by any genotype. Interestingly, the explicit anxiety level, i.e. valence and anxiety ratings, was only influenced by the NPSR1 genotype, in a way that no risk allele carriers (AA) reported higher anxiety and more negative valence in response to CXT+ compared to CXT-, whereas risk allele carriers (T+) did not. Study 2 adopted nearly the same paradigm with the modification that one group (reinstatement group) received one unsignaled US at the beginning of the experimental session on Day 3 before seeing CXT+ and CXT-. The second group served as a control group and received no US, but was immediately exposed to CXT+ and CXT-. Results showed a return of anxiety on the implicit and explicit level (higher startle responses and anxiety ratings in response to CXT+ compared to CXT-) in the reinstatement group only. Most important, the return of contextual anxiety in the reinstatement group was associated with a change of state anxiety and mood from extinction to test, that is the more anxiety and negative mood participants experienced before the reinstatement procedure, the higher their return of anxiety was. In sum, results of Study 1 showed that facilitated contextual fear conditioning on an implicit behavioral level (startle response) could be regarded as an endophenotype for anxiety disorders, which can contribute to our understanding of the etiology of anxiety disorders. Results of Study 2 imply that anxiety and negative mood after extinction could be an important facilitator for the return of anxiety. Furthermore, the present VR-based contextual fear conditioning paradigm seems to be an ideal tool to experimentally study mechanisms underlying the acquisition and the return of anxiety. Future studies could investigate clinical samples and extend the VR paradigm to evolutionary-relevant contexts (e.g., heights, darkness, open spaces). KW - Angst KW - Genetik KW - Kontextkonditionierung KW - context conditioning KW - anxiety KW - genetics KW - virtual reality KW - Virtuelle Realität Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-87955 ER - TY - JOUR A1 - Lodha, Manivel A1 - Muchsin, Ihsan A1 - Jürges, Christopher A1 - Juranic Lisnic, Vanda A1 - L’Hernault, Anne A1 - Rutkowski, Andrzej J. A1 - Prusty, Bhupesh K. A1 - Grothey, Arnhild A1 - Milic, Andrea A1 - Hennig, Thomas A1 - Jonjic, Stipan A1 - Friedel, Caroline C. A1 - Erhard, Florian A1 - Dölken, Lars T1 - Decoding murine cytomegalovirus JF - PLOS Pathogens N2 - The genomes of both human cytomegalovirus (HCMV) and murine cytomegalovirus (MCMV) were first sequenced over 20 years ago. Similar to HCMV, the MCMV genome had initially been proposed to harbor ≈170 open reading frames (ORFs). More recently, omics approaches revealed HCMV gene expression to be substantially more complex comprising several hundred viral ORFs. Here, we provide a state-of-the art reannotation of lytic MCMV gene expression based on integrative analysis of a large set of omics data. Our data reveal 365 viral transcription start sites (TiSS) that give rise to 380 and 454 viral transcripts and ORFs, respectively. The latter include 200 small ORFs, some of which represented the most highly expressed viral gene products. By combining TiSS profiling with metabolic RNA labelling and chemical nucleotide conversion sequencing (dSLAM-seq), we provide a detailed picture of the expression kinetics of viral transcription. This not only resulted in the identification of a novel MCMV immediate early transcript encoding the m166.5 ORF, which we termed ie4, but also revealed a group of well-expressed viral transcripts that are induced later than canonical true late genes and contain an initiator element (Inr) but no TATA- or TATT-box in their core promoters. We show that viral upstream ORFs (uORFs) tune gene expression of longer viral ORFs expressed in cis at translational level. Finally, we identify a truncated isoform of the viral NK-cell immune evasin m145 arising from a viral TiSS downstream of the canonical m145 mRNA. Despite being ≈5-fold more abundantly expressed than the canonical m145 protein it was not required for downregulating the NK cell ligand, MULT-I. In summary, our work will pave the way for future mechanistic studies on previously unknown cytomegalovirus gene products in an important virus animal model. KW - virology KW - genetics KW - molecular biology KW - immunology KW - microbiology KW - parasitology KW - murine cytomegalovirus (MCMV) Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-350480 SN - 1553-7374 VL - 19 IS - 5 ER - TY - JOUR A1 - Harrison, Odile B. A1 - Claus, Heike A1 - Jiang, Ying A1 - Bennett, Julia S. A1 - Bratcher, Holly B. A1 - Jolley, Keith A. A1 - Corton, Craig A1 - Care, Rory A1 - Poolman, Jan T. A1 - Zollinger, Wendell D. A1 - Frasch, Carl E. A1 - Stephens, David S. A1 - Feavers, Ian A1 - Frosch, Matthias A1 - Parkhill, Julian A1 - Vogel, Ulrich A1 - Quail, Michael A. A1 - Bentley, Stephen D. A1 - Maiden, Martin C. J. T1 - Description and Nomenclature of Neisseria meningitidis Capsule Locus JF - Emerging Infectious Diseases N2 - Pathogenic Neisseria meningitidis isolates contain a polysaccharide capsule that is the main virulence determinant for this bacterium. Thirteen capsular polysaccharides have been described, and nuclear magnetic resonance spectroscopy has enabled determination of the structure of capsular polysaccharides responsible for serogroup specificity. Molecular mechanisms involved in N. meningitidis capsule biosynthesis have also been identified, and genes involved in this process and in cell surface translocation are clustered at a single chromosomal locus termed cps. The use of multiple names for some of the genes involved in capsule synthesis, combined with the need for rapid diagnosis of serogroups commonly associated with invasive meningococcal disease, prompted a requirement for a consistent approach to the nomenclature of capsule genes. In this report, a comprehensive description of all N. meningitidis serogroups is provided, along with a proposed nomenclature, which was presented at the 2012 XVIIIth International Pathogenic Neisseria Conference. KW - genetics KW - nuclear magnetic resonance KW - structural determination KW - meningococcal polysaccharides KW - chemical properties KW - serogroup-Y KW - group-B KW - antigen KW - biosynthesis KW - elucidation Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131703 VL - 19 IS - 4 ER - TY - JOUR A1 - Cerezo-Echevarria, Argiñe A1 - Kehl, Alexandra A1 - Beitzinger, Christoph A1 - Müller, Tobias A1 - Klopfleisch, Robert A1 - Aupperle-Lellbach, Heike T1 - Evaluating the histologic grade of digital squamous cell carcinomas in dogs and copy number variation of KIT Ligand — a correlation study JF - Veterinary Sciences N2 - Dark-haired dogs are predisposed to the development of digital squamous cell carcinoma (DSCC). This may potentially suggest an underlying genetic predisposition not yet completely elucidated. Some authors have suggested a potential correlation between the number of copies KIT Ligand (KITLG) and the predisposition of dogs to DSCC, containing a higher number of copies in those affected by the neoplasm. In this study, the aim was to evaluate a potential correlation between the number of copies of the KITLG and the histological grade of malignancy in dogs with DSCC. For this, 72 paraffin-embedded DSCCs with paired whole blood samples of 70 different dogs were included and grouped according to their haircoat color as follow: Group 0/unknown haircoat color (n = 11); Group 1.a/black non-Schnauzers (n = 15); group 1.b/black Schnauzers (n = 33); group 1.c/black and tan dogs (n = 7); group 2/tan animals (n = 4). The DSCCs were histologically graded. Additionally, KITLG Copy Number Variation (CNV) was determined by ddPCR. A significant correlation was observed between KITLG copy number and the histological grade and score value. This finding may suggest a possible factor for the development of canine DSCC, thus potentially having an impact on personalized veterinary oncological strategies and breeding programs. KW - canine KW - cancer KW - toe KW - grading KW - haircoat KW - color KW - genetics KW - gene Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304824 SN - 2306-7381 VL - 10 IS - 2 ER - TY - JOUR A1 - Vigorito, Elena A1 - Kuchenbaecker, Karoline B. A1 - Beesley, Jonathan A1 - Adlard, Julian A1 - Agnarsson, Bjarni A. A1 - Andrulis, Irene L. A1 - Arun, Banu K. A1 - Barjhoux, Laure A1 - Belotti, Muriel A1 - Benitez, Javier A1 - Berger, Andreas A1 - Bojesen, Anders A1 - Bonanni, Bernardo A1 - Brewer, Carole A1 - Caldes, Trinidad A1 - Caligo, Maria A. A1 - Campbell, Ian A1 - Chan, Salina B. A1 - Claes, Kathleen B. M. A1 - Cohn, David E. A1 - Cook, Jackie A1 - Daly, Mary B. A1 - Damiola, Francesca A1 - Davidson, Rosemarie A1 - de Pauw, Antoine A1 - Delnatte, Capucine A1 - Diez, Orland A1 - Domchek, Susan M. A1 - Dumont, Martine A1 - Durda, Katarzyna A1 - Dworniczak, Bernd A1 - Easton, Douglas F. A1 - Eccles, Diana A1 - Ardnor, Christina Edwinsdotter A1 - Eeles, Ros A1 - Ejlertsen, Bent A1 - Ellis, Steve A1 - Evans, D. Gareth A1 - Feliubadalo, Lidia A1 - Fostira, Florentia A1 - Foulkes, William D. A1 - Friedman, Eitan A1 - Frost, Debra A1 - Gaddam, Pragna A1 - Ganz, Patricia A. A1 - Garber, Judy A1 - Garcia-Barberan, Vanesa A1 - Gauthier-Villars, Marion A1 - Gehrig, Andrea A1 - Gerdes, Anne-Marie A1 - Giraud, Sophie A1 - Godwin, Andrew K. A1 - Goldgar, David E. A1 - Hake, Christopher R. A1 - Hansen, Thomas V. O. A1 - Healey, Sue A1 - Hodgson, Shirley A1 - Hogervorst, Frans B. L. A1 - Houdayer, Claude A1 - Hulick, Peter J. A1 - Imyanitov, Evgeny N. A1 - Isaacs, Claudine A1 - Izatt, Louise A1 - Izquierdo, Angel A1 - Jacobs, Lauren A1 - Jakubowska, Anna A1 - Janavicius, Ramunas A1 - Jaworska-Bieniek, Katarzyna A1 - Jensen, Uffe Birk A1 - John, Esther M. A1 - Vijai, Joseph A1 - Karlan, Beth Y. A1 - Kast, Karin A1 - Khan, Sofia A1 - Kwong, Ava A1 - Laitman, Yael A1 - Lester, Jenny A1 - Lesueur, Fabienne A1 - Liljegren, Annelie A1 - Lubinski, Jan A1 - Mai, Phuong L. A1 - Manoukian, Siranoush A1 - Mazoyer, Sylvie A1 - Meindl, Alfons A1 - Mensenkamp, Arjen R. A1 - Montagna, Marco A1 - Nathanson, Katherine L. A1 - Neuhausen, Susan L. A1 - Nevanlinna, Heli A1 - Niederacher, Dieter A1 - Olah, Edith A1 - Olopade, Olufunmilayo I. A1 - Ong, Kai-ren A1 - Osorio, Ana A1 - Park, Sue Kyung A1 - Paulsson-Karlsson, Ylva A1 - Pedersen, Inge Sokilde A1 - Peissel, Bernard A1 - Peterlongo, Paolo A1 - Pfeiler, Georg A1 - Phelan, Catherine M. A1 - Piedmonte, Marion A1 - Poppe, Bruce A1 - Pujana, Miquel Angel A1 - Radice, Paolo A1 - Rennert, Gad A1 - Rodriguez, Gustavo C. A1 - Rookus, Matti A. A1 - Ross, Eric A. A1 - Schmutzler, Rita Katharina A1 - Simard, Jacques A1 - Singer, Christian F. A1 - Slavin, Thomas P. A1 - Soucy, Penny A1 - Southey, Melissa A1 - Steinemann, Doris A1 - Stoppa-Lyonnet, Dominique A1 - Sukiennicki, Grzegorz A1 - Sutter, Christian A1 - Szabo, Csilla I. A1 - Tea, Muy-Kheng A1 - Teixeira, Manuel R. A1 - Teo, Soo-Hwang A1 - Terry, Mary Beth A1 - Thomassen, Mads A1 - Tibiletti, Maria Grazia A1 - Tihomirova, Laima A1 - Tognazzo, Silvia A1 - van Rensburg, Elizabeth J. A1 - Varesco, Liliana A1 - Varon-Mateeva, Raymonda A1 - Vratimos, Athanassios A1 - Weitzel, Jeffrey N. A1 - McGuffog, Lesley A1 - Kirk, Judy A1 - Toland, Amanda Ewart A1 - Hamann, Ute A1 - Lindor, Noralane A1 - Ramus, Susan J. A1 - Greene, Mark H. A1 - Couch, Fergus J. A1 - Offit, Kenneth A1 - Pharoah, Paul D. P. A1 - Chenevix-Trench, Georgia A1 - Antoniou, Antonis C. T1 - Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers JF - PLoS ONE N2 - Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10−16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10−6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population. KW - fine-scale mapping KW - ovarian cancer KW - genetics KW - BRCA1 KW - BRCA2 Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166869 VL - 11 IS - 7 ER -