TY - JOUR A1 - Müller, Sara A1 - Windhof, Indra M. A1 - Maximov, Vladimir A1 - Jurkowski, Tomasz A1 - Jeltsch, Albert A1 - Förstner, Konrad U. A1 - Sharma, Cynthia M. A1 - Gräf, Ralph A1 - Nellen, Wolfgang T1 - Target recognition, RNA methylation activity and transcriptional regulation of the Dictyostelium discoideum Dnmt2-homologue (DnmA) JF - Nucleic Acids Research N2 - Although the DNA methyltransferase 2 family is highly conserved during evolution and recent reports suggested a dual specificity with stronger activity on transfer RNA (tRNA) than DNA substrates, the biological function is still obscure. We show that the Dictyostelium discoideum Dnmt2-homologue DnmA is an active tRNA methyltransferase that modifies C38 in \(tRNA^{Asp(GUC)}\) in vitro and in vivo. By an ultraviolet-crosslinking and immunoprecipitation approach, we identified further DnmA targets. This revealed specific tRNA fragments bound by the enzyme and identified \(tRNA^{Glu(CUC/UUC)}\) and \(tRNA^{Gly(GCC)}\) as new but weaker substrates for both human Dnmt2 and DnmA in vitro but apparently not in vivo. Dnmt2 enzymes form transient covalent complexes with their substrates. The dynamics of complex formation and complex resolution reflect methylation efficiency in vitro. Quantitative PCR analyses revealed alterations in dnmA expression during development, cell cycle and in response to temperature stress. However, dnmA expression only partially correlated with tRNA methylation in vivo. Strikingly, dnmA expression in the laboratory strain AX2 was significantly lower than in the NC4 parent strain. As expression levels and binding of DnmA to a target in vivo are apparently not necessarily accompanied by methylation, we propose an additional biological function of DnmA apart from methylation. KW - DNA methylferase homolog KW - drospophila KW - TRNA(ASP) KW - mechanism KW - binding Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-123149 SN - 1362-4962 VL - 41 IS - 18 ER - TY - JOUR A1 - Guhn, Anne A1 - Dresler, Thomas A1 - Andreatta, Marta A1 - Müller, Laura D. A1 - Hahn, Tim A1 - Tupak, Sara V. A1 - Polak, Thomas A1 - Deckert, Jürgen A1 - Herrmann, Martin J. T1 - Medial prefrontal cortex stimulation modulates the processing of conditioned fear N2 - The extinction of conditioned fear depends on an efficient interplay between the amygdala and the medial prefrontal cortex (mPFC). In rats, high-frequency electrical mPFC stimulation has been shown to improve extinction by means of a reduction of amygdala activity. However, so far it is unclear whether stimulation of homologues regions in humans might have similar beneficial effects. Healthy volunteers received one session of either active or sham repetitive transcranial magnetic stimulation (rTMS) covering the mPFC while undergoing a 2-day fear conditioning and extinction paradigm. Repetitive TMS was applied offline after fear acquisition in which one of two faces (CS+ but not CS−) was associated with an aversive scream (UCS). Immediate extinction learning (day 1) and extinction recall (day 2) were conducted without UCS delivery. Conditioned responses (CR) were assessed in a multimodal approach using fear-potentiated startle (FPS), skin conductance responses (SCR), functional near-infrared spectroscopy (fNIRS), and self-report scales. Consistent with the hypothesis of a modulated processing of conditioned fear after high-frequency rTMS, the active group showed a reduced CS+/CS− discrimination during extinction learning as evident in FPS as well as in SCR and arousal ratings. FPS responses to CS+ further showed a linear decrement throughout both extinction sessions. This study describes the first experimental approach of influencing conditioned fear by using rTMS and can thus be a basis for future studies investigating a complementation of mPFC stimulation to cognitive behavioral therapy (CBT). KW - fear conditioning KW - memory consolidation and extinction KW - learning KW - transcranial magnetic stimulation (TMS) KW - medial prefrontal cortex (mPFC) Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-111309 ER - TY - JOUR A1 - Müller, Stefanie H. A1 - Girard, Simon L. A1 - Hopfner, Franziska A1 - Merner, Nancy D. A1 - Bourassa, Cynthia V. A1 - Lorenz, Delia A1 - Clark, Lorraine N. A1 - Tittmann, Lukas A1 - Soto-Ortolaza, Alexandra I. A1 - Klebe, Stephan A1 - Hallett, Mark A1 - Schneider, Susanne A. A1 - Hodgkinson, Colin A. A1 - Lieb, Wolfgang A1 - Wszolek, Zbigniew K. A1 - Pendziwiat, Manuela A1 - Lorenzo-Betancor, Oswaldo A1 - Poewe, Werner A1 - Ortega-Cubero, Sara A1 - Seppi, Klaus A1 - Rajput, Alex A1 - Hussl, Anna A1 - Rajput, Ali H. A1 - Berg, Daniela A1 - Dion, Patrick A. A1 - Wurster, Isabel A1 - Shulman, Joshua M. A1 - Srulijes, Karin A1 - Haubenberger, Dietrich A1 - Pastor, Pau A1 - Vilariño-Güell, Carles A1 - Postuma, Ronald B. A1 - Bernard, Geneviève A1 - Ladwig, Karl-Heinz A1 - Dupré, Nicolas A1 - Jankovic, Joseph A1 - Strauch, Konstantin A1 - Panisset, Michel A1 - Winkelmann, Juliane A1 - Testa, Claudia M. A1 - Reischl, Eva A1 - Zeuner, Kirsten E. A1 - Ross, Owen A. A1 - Arzberger, Thomas A1 - Chouinard, Sylvain A1 - Deuschl, Günther A1 - Louis, Elan D. A1 - Kuhlenbäumer, Gregor A1 - Rouleau, Guy A. T1 - Genome-wide association study in essential tremor identifies three new loci JF - Brain N2 - We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discovery stage were genotyped in the replication stage. After Bonferroni correction two markers, one (rs10937625) located in the serine/threonine kinase STK32B and one (rs17590046) in the transcriptional coactivator PPARGC1A were associated with essential tremor. Three markers (rs12764057, rs10822974, rs7903491) in the cell-adhesion molecule CTNNA3 were significant in the combined analysis of both stages. The expression of STK32B was increased in the cerebellar cortex of patients and expression quantitative trait loci database mining showed association between the protective minor allele of rs10937625 and reduced expression in cerebellar cortex. We found no expression differences related to disease status or marker genotype for the other two genes. Replication of two lead single nucleotide polymorphisms of previous small genome-wide association studies (rs3794087 in SLC1A2, rs9652490 in LINGO1) did not confirm the association with essential tremor. KW - quality-control KW - disease KW - tool KW - movement disorders KW - genome-wide association study KW - tremor KW - genetics KW - essential tremor Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186541 VL - 139 ER - TY - JOUR A1 - Lorini, Luigi A1 - Bescós Atín, Coro A1 - Thavaraj, Selvam A1 - Müller-Richter, Urs A1 - Alberola Ferranti, Margarita A1 - Pamias Romero, Jorge A1 - Sáez Barba, Manel A1 - de Pablo García-Cuenca, Alba A1 - Braña García, Irene A1 - Bossi, Paolo A1 - Nuciforo, Paolo A1 - Simonetti, Sara T1 - Overview of oral potentially malignant disorders: from risk factors to specific therapies JF - Cancers N2 - Oral squamous cell carcinoma (OSCC) is a very aggressive cancer, representing one of the most common malignancies worldwide. Oral potentially malignant disorders (OPMDs) regroup a variegate set of different histological lesions, characterized by the potential capacity to transform in OSCC. Most of the risk factors associated with OSCC are present also in OPMDs' development; however, the molecular mechanisms and steps of malignant transformation are still unknown. Treatment of OSCC, including surgery, systemic therapy and radiotherapy (alone or in combination), has suffered a dramatic change in last years, especially with the introduction of immunotherapy. However, most cases are diagnosed during the advanced stage of the disease, decreasing drastically the survival rate of the patients. Hence, early diagnosis of premalignant conditions (OPMDs) is a priority in oral cancer, as well as a massive education about risk factors, the understanding of mechanisms involved in malignant progression and the development of specific and more efficient therapies. The aim of this article is to review epidemiological, clinical, morphological and molecular features of OPMDs, with the purpose to lay the foundation for an exhaustive comprehension of these lesions and their ability of malignant transformation and for the development of more effective and personalized treatments. KW - oral potentially malignant disorders KW - risk factors and etiology KW - morphological features KW - molecular alterations KW - treatment Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-242779 SN - 2072-6694 VL - 13 IS - 15 ER -