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  - 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  - Nejad, B. Chokoufe
A1  - Lang, J.-N. Lang
A1  - Hahn, T.
A1  - Mirabella, E.
T1  - FormCalc 8: Better Algebra and Vectorization
JF  - Acta Physica Polonica B
N2  - We present Version 8 of the Feynman-diagram calculator FormCalc. New features include, in particular, significantly improved algebraic simplification as well as vectorization of the generated code. The Cuba Library, used in FormCalc, features checkpointing to disk for all integration algorithms.
KW  - FormCalc8
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128618
VL  - 44
IS  - 11
ER  - 
TY  - JOUR
A1  - Gottschalk, Michael G.
A1  - Richter, Jan
A1  - Ziegler, Christiane
A1  - Schiele, Miriam A.
A1  - Mann, Julia
A1  - Geiger, Maximilian J.
A1  - Schartner, Christoph
A1  - Homola, György A.
A1  - Alpers, Georg W.
A1  - Büchel, Christian
A1  - Fehm, Lydia
A1  - Fydrich, Thomas
A1  - Gerlach, Alexander L.
A1  - Gloster, Andrew T.
A1  - Helbig-Lang, Sylvia
A1  - Kalisch, Raffael
A1  - Kircher, Tilo
A1  - Lang, Thomas
A1  - Lonsdorf, Tina B.
A1  - Pané-Farré, Christiane A.
A1  - Ströhle, Andreas
A1  - Weber, Heike
A1  - Zwanzger, Peter
A1  - Arolt, Volker
A1  - Romanos, Marcel
A1  - Wittchen, Hans-Ulrich
A1  - Hamm, Alfons
A1  - Pauli, Paul
A1  - Reif, Andreas
A1  - Deckert, Jürgen
A1  - Neufang, Susanne
A1  - Höfler, Michael
A1  - Domschke, Katharina
T1  - Orexin in the anxiety spectrum: association of a HCRTR1 polymorphism with panic disorder/agoraphobia, CBT treatment response and fear-related intermediate phenotypes
JF  - Translational Psychiatry
N2  - Preclinical studies point to a pivotal role of the orexin 1 (OX1) receptor in arousal and fear learning and therefore suggest the HCRTR1 gene as a prime candidate in panic disorder (PD) with/without agoraphobia (AG), PD/AG treatment response, and PD/AG-related intermediate phenotypes. Here, a multilevel approach was applied to test the non-synonymous HCRTR1 C/T Ile408Val gene variant (rs2271933) for association with PD/AG in two independent case-control samples (total n = 613 cases, 1839 healthy subjects), as an outcome predictor of a six-weeks exposure-based cognitive behavioral therapy (CBT) in PD/AG patients (n = 189), as well as with respect to agoraphobic cognitions (ACQ) (n = 483 patients, n = 2382 healthy subjects), fMRI alerting network activation in healthy subjects (n = 94), and a behavioral avoidance task in PD/AG pre- and post-CBT (n = 271). The HCRTR1 rs2271933 T allele was associated with PD/AG in both samples independently, and in their meta-analysis (p = 4.2 × 10−7), particularly in the female subsample (p = 9.8 × 10−9). T allele carriers displayed a significantly poorer CBT outcome (e.g., Hamilton anxiety rating scale: p = 7.5 × 10−4). The T allele count was linked to higher ACQ sores in PD/AG and healthy subjects, decreased inferior frontal gyrus and increased locus coeruleus activation in the alerting network. Finally, the T allele count was associated with increased pre-CBT exposure avoidance and autonomic arousal as well as decreased post-CBT improvement. In sum, the present results provide converging evidence for an involvement of HCRTR1 gene variation in the etiology of PD/AG and PD/AG-related traits as well as treatment response to CBT, supporting future therapeutic approaches targeting the orexin-related arousal system.
KW  - human behaviour
KW  - molecular neuroscience
KW  - personalized medicine
KW  - predictive markers
KW  - psychiatric disorders
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227479
VL  - 9
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  - Salker, Madhuri S.
A1  - Singh, Yogesh
A1  - Zeng, Ni
A1  - Chen, Hong
A1  - Zhang, Shaqiu
A1  - Umbach, Anja T.
A1  - Fakhri, Hajar
A1  - Kohlhofer, Ursula
A1  - Quintanilla-Martinez, Leticia
A1  - Durairaj, Ruban R. Peter
A1  - Barros, Flavio S. V.
A1  - Vrljicak, Pavle
A1  - Ott, Sascha
A1  - Brucker, Sara Y.
A1  - Wallwiener, Diethelm
A1  - Madunić, Ivana Vrhovac
A1  - Breljak, Davorka
A1  - Sabolić, Ivan
A1  - Koepsell, Hermann
A1  - Brosens, Jan J.
A1  - Lang, Florian
T1  - Loss of endometrial sodium glucose cotransporter SGLT1 is detrimental to embryo survival and fetal growth in pregnancy
JF  - Scientific Reports
N2  - Embryo implantation requires a hospitable uterine environment. A key metabolic change that occurs during the peri-implantation period, and throughout early pregnancy, is the rise in endometrial glycogen content. Glycogen accumulation requires prior cellular uptake of glucose. Here we show that both human and murine endometrial epithelial cells express the high affinity Na\(^+\)-coupled glucose carrier SGLT1. Ussing chamber experiments revealed electrogenic glucose transport across the endometrium in wild type (\(Slc5a1^{+/+}\)) but not in SGLT1 defcient (\(Slc5a1^{−/−}\)) mice. Endometrial glycogen content, litter size and weight of offspring at birth were signifcantly lower in \(Slc5a1^{−/−}\) mice. In humans, \(SLC5A1\) expression was upregulated upon decidualization of primary endometrial stromal cells. Endometrial \(SLC5A1\) expression during the implantation window was attenuated in patients with recurrent pregnancy loss when compared with control subjects. Our fndings reveal a novel mechanism establishing adequate endometrial glycogen stores for pregnancy. Disruption of this histiotrophic pathway leads to adverse pregnancy outcome.
KW  - biology
KW  - embryology
KW  - intrauterine growth
KW  - paediatric research
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173814
VL  - 7
ER  - 
TY  - JOUR
A1  - Chifu, Irina
A1  - Heinze, Britta
A1  - Fuss, Carmina T.
A1  - Lang, Katharina
A1  - Kroiss, Matthias
A1  - Kircher, Stefan
A1  - Ronchi, Cristina L.
A1  - Altieri, Barbara
A1  - Schirbel, Andreas
A1  - Fassnacht, Martin
A1  - Hahner, Stefanie
T1  - Impact of the Chemokine Receptors CXCR4 and CXCR7 on Clinical Outcome in Adrenocortical Carcinoma
JF  - Frontiers in Endocrinology
N2  - Chemokine receptors have a negative impact on tumor progression in several human cancers and have therefore been of interest for molecular imaging and targeted therapy. However, their clinical and prognostic significance in adrenocortical carcinoma (ACC) is unknown. The aim of this study was to evaluate the chemokine receptor profile in ACC and to analyse its association with clinicopathological characteristics and clinical outcome. A chemokine receptor profile was initially evaluated by quantitative PCR in 4 normal adrenals, 18 ACC samples and human ACC cell line NCI-H295. High expression of CXCR4 and CXCR7 in both healthy and malignant adrenal tissue and ACC cells was confirmed. In the next step, we analyzed the expression and cellular localization of CXCR4 and CXCR7 in ACC by immunohistochemistry in 187 and 84 samples, respectively. These results were correlated with clinicopathological parameters and survival outcome. We detected strong membrane expression of CXCR4 and CXCR7 in 50% of ACC samples. Strong cytoplasmic CXCR4 staining was more frequent among samples derived from metastases compared to primaries (p=0.01) and local recurrences (p=0.04). CXCR4 membrane staining positively correlated with proliferation index Ki67 (r=0.17, p=0.028). CXCR7 membrane staining negatively correlated with Ki67 (r=−0.254, p=0.03) but positively with tumor size (r=0.3, p=0.02). No differences in progression-free or overall survival were observed between patients with strong and weak staining intensities for CXCR4 or CXCR7. Taken together, high expression of CXCR4 and CXCR7 in both local tumors and metastases suggests that some ACC patients might benefit from CXCR4/CXCR7-targeted therapy.
KW  - chemokine receptor
KW  - prognosis
KW  - adrenocortical carcinoma
KW  - CXCR4
KW  - CXCR7
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-216494
SN  - 1664-2392
VL  - 11
ER  -