TY - JOUR A1 - Hommers, L. G. A1 - Richter, J. A1 - Yang, Y. A1 - Raab, A. A1 - Baumann, C. A1 - Lang, K. A1 - Schiele, M. A. A1 - Weber, H. A1 - Wittmann, A. A1 - Wolf, C. A1 - Alpers, G. W. A1 - Arolt, V. A1 - Domschke, K. A1 - Fehm, L. A1 - Fydrich, T. A1 - Gerlach, A. A1 - Gloster, A. T. A1 - Hamm, A. O. A1 - Helbig-Lang, S. A1 - Kircher, T. A1 - Lang, T. A1 - Pané-Farré, C. A. A1 - Pauli, P. A1 - Pfleiderer, B. A1 - Reif, A. A1 - Romanos, M. A1 - Straube, B. A1 - Ströhle, A. A1 - Wittchen, H.-U. A1 - Frantz, S. A1 - Ertl, G. A1 - Lohse, M. J. A1 - Lueken, U. A1 - Deckert, J. T1 - A functional genetic variation of SLC6A2 repressor hsa-miR-579-3p upregulates sympathetic noradrenergic processes of fear and anxiety JF - Translational Psychiatry N2 - Increased sympathetic noradrenergic signaling is crucially involved in fear and anxiety as defensive states. MicroRNAs regulate dynamic gene expression during synaptic plasticity and genetic variation of microRNAs modulating noradrenaline transporter gene (SLC6A2) expression may thus lead to altered central and peripheral processing of fear and anxiety. In silico prediction of microRNA regulation of SLC6A2 was confirmed by luciferase reporter assays and identified hsa-miR-579-3p as a regulating microRNA. The minor (T)-allele of rs2910931 (MAFcases = 0.431, MAFcontrols = 0.368) upstream of MIR579 was associated with panic disorder in patients (pallelic = 0.004, ncases = 506, ncontrols = 506) and with higher trait anxiety in healthy individuals (pASI = 0.029, pACQ = 0.047, n = 3112). Compared to the major (A)-allele, increased promoter activity was observed in luciferase reporter assays in vitro suggesting more effective MIR579 expression and SLC6A2 repression in vivo (p = 0.041). Healthy individuals carrying at least one (T)-allele showed a brain activation pattern suggesting increased defensive responding and sympathetic noradrenergic activation in midbrain and limbic areas during the extinction of conditioned fear. Panic disorder patients carrying two (T)-alleles showed elevated heart rates in an anxiety-provoking behavioral avoidance test (F(2, 270) = 5.47, p = 0.005). Fine-tuning of noradrenaline homeostasis by a MIR579 genetic variation modulated central and peripheral sympathetic noradrenergic activation during fear processing and anxiety. This study opens new perspectives on the role of microRNAs in the etiopathogenesis of anxiety disorders, particularly their cardiovascular symptoms and comorbidities. KW - clinical genetics KW - psychiatric disorders Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-322497 VL - 8 ER - TY - JOUR A1 - Bhavsar, Shefalee K. A1 - Singh, Yogesh A1 - Sharma, Piyush A1 - Khairnar, Vishal A1 - Hosseinzadeh, Zohreh A1 - Zhang, Shaqiu A1 - Palmada, Monica A1 - Sabolic, Ivan A1 - Koepsell, Hermann A1 - Lang, Karl S. A1 - Lang, Philipp A. A1 - Lang, Florian T1 - Expression of JAK3 Sensitive Na\(^+\) Coupled Glucose Carrier SGLT1 in Activated Cytotoxic T Lymphocytes JF - Cellular Physiology and Biochemistry N2 - Background: Similar to tumor cells, activated T-lymphocytes generate ATP mainly by glycolytic degradation of glucose. Lymphocyte glucose uptake involves non-concentrative glucose carriers of the GLUT family. In contrast to GLUT isoforms, Na+-coupled glucose-carrier SGLT1 accumulates glucose against glucose gradients and is effective at low extracellular glucose concentrations. The present study explored expression and regulation of SGLT1 in activated murine splenic cytotoxic T cells (CTLs) and human Jurkat T cells. Methods: FACS analysis, immunofluorescence, confocal microscopy, chemiluminescence and Western blotting were employed to estimate SGLT1 expression, function and regulation in lymphocytes, as well as dual electrode voltage clamp in SGLT1 ± JAK3 expressing Xenopus oocytes to quantify the effect of janus kinase3 (JAK3) on SGLT1 function. Results: SGLT1 is expressed in murine CTLs and also in human Jurkat T cells. 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose uptake was significantly decreased by SGLT1-blocker phloridzin (0.2 mM) and by pharmacological inhibition of JAK3 with WHI-P131 (156 µM), WHI-P154 (11.2 µM) and JAK3 inhibitor VI (0.5 µM). Electrogenic glucose transport (Iglucose) in Xenopus oocytes expressing human SGLT1 was increased by additional expression of human wild type JAK3, active A568VJAK3 but not inactive K851AJAK3. Coexpression of JAK3 enhanced the maximal transport rate without significantly modifying affinity of the carrier. Iglucose in SGLT1+JAK3 expressing oocytes was significantly decreased by WHI-P154 (11.2 µM). JAK3 increased the SGLT1 protein abundance in the cell membrane. Inhibition of carrier insertion by brefeldin A (5 µM) in SGLT1+JAK3 expressing oocytes resulted in a decline of Iglucose, which was similar in presence and absence of JAK3. Conclusions: SGLT1 is expressed in murine cytotoxic T cells and human Jurkat T cells and significantly contributes to glucose uptake in those cells post activation. JAK3 up-regulates SGLT1 activity by increasing the carrier protein abundance in the cell membrane, an effect enforcing cellular glucose uptake into activated lymphocytes and thus contributing to the immune response. KW - tumor cell KW - Cytotoxic T lymphocytes KW - Glucose uptake KW - Jurkat T cells KW - Energy depletion KW - Janus kinase Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164900 VL - 39 IS - 3 ER - TY - JOUR A1 - Ziegler, C. A1 - Richter, J. A1 - Mahr, M. A1 - Gajewska, A. A1 - Schiele, M.A. A1 - Gehrmann, A. A1 - Schmidt, B. A1 - Lesch, K.-P. A1 - Lang, T. A1 - Helbig-Lang, S. A1 - Pauli, P. A1 - Kircher, T. A1 - Reif, A. A1 - Rief, W. A1 - Vossbeck-Elsebusch, A.N. A1 - Arolt, V. A1 - Wittchen, H.-U. A1 - Hamm, A.O. A1 - Deckert, J. A1 - Domschke, K. T1 - MAOA gene hypomethylation in panic disorder-reversibility of an epigenetic risk pattern by psychotherapy JF - Translational Psychiatry N2 - Epigenetic signatures such as methylation of the monoamine oxidase A (MAOA) gene have been found to be altered in panic disorder (PD). Hypothesizing temporal plasticity of epigenetic processes as a mechanism of successful fear extinction, the present psychotherapy-epigenetic study for we believe the first time investigated MAOA methylation changes during the course of exposure-based cognitive behavioral therapy (CBT) in PD. MAOA methylation was compared between N=28 female Caucasian PD patients (discovery sample) and N=28 age- and sex-matched healthy controls via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells. MAOA methylation was furthermore analyzed at baseline (T0) and after a 6-week CBT (T1) in the discovery sample parallelized by a waiting time in healthy controls, as well as in an independent sample of female PD patients (N=20). Patients exhibited lower MAOA methylation than healthy controls (P<0.001), and baseline PD severity correlated negatively with MAOA methylation (P=0.01). In the discovery sample, MAOA methylation increased up to the level of healthy controls along with CBT response (number of panic attacks; T0-T1: +3.37±2.17%), while non-responders further decreased in methylation (-2.00±1.28%; P=0.001). In the replication sample, increases in MAOA methylation correlated with agoraphobic symptom reduction after CBT (P=0.02-0.03). The present results support previous evidence for MAOA hypomethylation as a PD risk marker and suggest reversibility of MAOA hypomethylation as a potential epigenetic correlate of response to CBT. The emerging notion of epigenetic signatures as a mechanism of action of psychotherapeutic interventions may promote epigenetic patterns as biomarkers of lasting extinction effects. KW - Adult KW - Case-Control Studies KW - Cognitive Therapy KW - DNA Methylation KW - Epigenesis KW - Genetic KW - Female KW - Humans KW - Monoamine Oxidase/genetics KW - Panic Disorder/genetics KW - Panic Disorder/therapy KW - Sequence Analysis KW - DNA Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164422 IS - 6 ER - TY - JOUR A1 - Lang, R. A1 - Herzog, C. A1 - Stangl, R. A1 - Brunn, E. A1 - Braun, M. A1 - Christl, Manfred A1 - Peters, K. A1 - Peters, E.-M. A1 - Schnering, H. G. von T1 - Reaktionen von Homobenzvalenen mit 4-Phenyl-3H-1,2,4-triazol-3,5(4H)-dion, Tetracyanethylen, Chlorsulfonylisocyanat und Schwefeldioxid. Einige konzertierte 1,4-Additionen an eine Vinylcyclopropan-Einheit T1 - Reactions of Homobenzvalenes wlth 4-Phenyl-3H-1,2,4-trlazole-3,5(4H)-dione, Tetracyanoethylene, Chlorosulfonyl Isocyanate, and Sulfur Dioxide. Several Concerted 1,4-Additions to a Vinylcyclopropane Subunit N2 - No abstract available KW - Organische Chemie KW - 6-Thiatricyclo[3.2.1.o 2.7 ]oct-3-ene 6 KW - 6-dioxide KW - Homo Diels-Alder reactions KW - Cyclopropanetetracarbonitrile derivatives KW - Barbaralane derivatives KW - Urazoles KW - polycyclic Y1 - 1990 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-58527 ER - TY - JOUR A1 - Straube, B. A1 - Reif, A. A1 - Richter, J. A1 - Lueken, U. A1 - Weber, H. A1 - Arolt, V. A1 - Jansen, A. A1 - Zwanzger, P. A1 - Domschke, K. A1 - Pauli, P. A1 - Konrad, C. A1 - Gerlach, A. L. A1 - Lang, T. A1 - Fydrich, T. A1 - Alpers, G. W. A1 - Stroehle, A. A1 - Wittmann, A. A1 - Pfleiderer, B. A1 - Wittchen, H.-U. A1 - Hamm, A. A1 - Deckert, J. A1 - Kircher, T. T1 - The functional - 1019C/G HTR1A polymorphism and mechanisms of fear JF - Translational Psychiatry N2 - Serotonin receptor 1A gene (HTR1A) knockout mice show pronounced defensive behaviour and increased fear conditioning to ambiguous conditioned stimuli. Such behaviour is a hallmark of pathological human anxiety, as observed in panic disorder with agoraphobia (PD/AG). Thus, variations in HTR1A might contribute to neurophysiological differences within subgroups of PD/AG patients. Here, we tested this hypothesis by combining genetic with behavioural techniques and neuroimaging. In a clinical multicentre trial, patients with PD/AG received 12 sessions of manualized cognitive-behavioural therapy (CBT) and were genotyped for HTR1A rs6295. In four subsamples of this multicentre trial, exposure behaviour (n = 185), defensive reactivity measured using a behavioural avoidance test (BAT; before CBT: n = 245; after CBT: n = 171) and functional magnetic resonance imaging (fMRI) data during fear conditioning were acquired before and after CBT (n = 39). HTR1A risk genotype (GG) carriers more often escaped during the BAT before treatment. Exploratory fMRI results suggest increased activation of the amygdala in response to threat as well as safety cues before and after treatment in GG carriers. Furthermore, GG carriers demonstrated reduced effects of CBT on differential conditioning in regions including the bilateral insulae and the anterior cingulate cortex. Finally, risk genotype carriers demonstrated reduced self-initiated exposure behaviour to aversive situations. This study demonstrates the effect of HTR1A variation on defensive behaviour, amygdala activity, CBT-induced neural plasticity and normalization of defence behaviour in PD/AG. Our results, therefore, translate evidence from animal studies to humans and suggest a central role for HTR1A in differentiating subgroups of patients with anxiety disorders. KW - randomized-controlled trial KW - panic disorder KW - 5-HT1A receptor KW - defensive reactivity KW - major depression KW - cognitive-behavioral therapy KW - receptor gene polymorphism KW - C(-1019)G polymorphism KW - anxiety disorders KW - serotonin(1A) receptor Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-114369 SN - 2158-3188 VL - 4 ER - TY - JOUR A1 - Rayner, Christopher A1 - Coleman, Jonathan R. I. A1 - Purves, Kirstin L. A1 - Hodsoll, John A1 - Goldsmith, Kimberley A1 - Alpers, Georg W. A1 - Andersson, Evelyn A1 - Arolt, Volker A1 - Boberg, Julia A1 - Bögels, Susan A1 - Creswell, Cathy A1 - Cooper, Peter A1 - Curtis, Charles A1 - Deckert, Jürgen A1 - Domschke, Katharina A1 - El Alaoui, Samir A1 - Fehm, Lydia A1 - Fydrich, Thomas A1 - Gerlach, Alexander L. A1 - Grocholewski, Anja A1 - Hahlweg, Kurt A1 - Hamm, Alfons A1 - Hedman, Erik A1 - Heiervang, Einar R. A1 - Hudson, Jennifer L. A1 - Jöhren, Peter A1 - Keers, Robert A1 - Kircher, Tilo A1 - Lang, Thomas A1 - Lavebratt, Catharina A1 - Lee, Sang-hyuck A1 - Lester, Kathryn J. A1 - Lindefors, Nils A1 - Margraf, Jürgen A1 - Nauta, Maaike A1 - Pané-Farré, Christiane A. A1 - Pauli, Paul A1 - Rapee, Ronald M. A1 - Reif, Andreas A1 - Rief, Winfried A1 - Roberts, Susanna A1 - Schalling, Martin A1 - Schneider, Silvia A1 - Silverman, Wendy K. A1 - Ströhle, Andreas A1 - Teismann, Tobias A1 - Thastum, Mikael A1 - Wannemüller, Andre A1 - Weber, Heike A1 - Wittchen, Hans-Ulrich A1 - Wolf, Christiane A1 - Rück, Christian A1 - Breen, Gerome A1 - Eley, Thalia C. T1 - A genome-wide association meta-analysis of prognostic outcomes following cognitive behavioural therapy in individuals with anxiety and depressive disorders JF - Translational Psychiatry N2 - Major depressive disorder and the anxiety disorders are highly prevalent, disabling and moderately heritable. Depression and anxiety are also highly comorbid and have a strong genetic correlation (r(g) approximate to 1). Cognitive behavioural therapy is a leading evidence-based treatment but has variable outcomes. Currently, there are no strong predictors of outcome. Therapygenetics research aims to identify genetic predictors of prognosis following therapy. We performed genome-wide association meta-analyses of symptoms following cognitive behavioural therapy in adults with anxiety disorders (n = 972), adults with major depressive disorder (n = 832) and children with anxiety disorders (n = 920; meta-analysis n = 2724). We (h(SNP)(2)) and polygenic scoring was used to examine genetic associations between therapy outcomes and psychopathology, personality and estimated the variance in therapy outcomes that could be explained by common genetic variants learning. No single nucleotide polymorphisms were strongly associated with treatment outcomes. No significant estimate of h(SNP)(2) could be obtained, suggesting the heritability of therapy outcome is smaller than our analysis was powered to detect. Polygenic scoring failed to detect genetic overlap between therapy outcome and psychopathology, personality or learning. This study is the largest therapygenetics study to date. Results are consistent with previous, similarly powered genome-wide association studies of complex traits. KW - Human behaviour KW - Personalized medicine KW - Prognostic markers KW - Psychiatric disorders Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225048 VL - 9 IS - 150 ER -