TY - JOUR A1 - Kohl, S. A1 - Gruendler, T. O. J. A1 - Huys, D. A1 - Sildatke, E. A1 - Dembek, T. A. A1 - Hellmich, M. A1 - Vorderwulbecke, M. A1 - Timmermann, L. A1 - Ahmari, S. E. A1 - Klosterkoetter, J. A1 - Jessen, F. A1 - Sturm, V. A1 - Visser-Vandewalle, V. A1 - Kuhn, J. T1 - Effects of deep brain stimulation on prepulse inhibition in obsessive-compulsive disorder JF - Translational Psychiatry N2 - Owing to a high response rate, deep brain stimulation (DBS) of the ventral striatal area has been approved for treatment-refractory obsessive-compulsive disorder (tr-OCD). Many basic issues regarding DBS for tr-OCD are still not understood, in particular, the mechanisms of action and the origin of side effects. We measured prepulse inhibition (PPI) in treatment-refractory OCD patients undergoing DBS of the nucleus accumbens (NAcc) and matched controls. As PPI has been used in animal DBS studies, it is highly suitable for translational research. Eight patients receiving DBS, eight patients with pharmacological treatment and eight age-matched healthy controls participated in our study. PPI was measured twice in the DBS group: one session with the stimulator switched on and one session with the stimulator switched off. OCD patients in the pharmacologic group took part in a single session. Controls were tested twice, to ensure stability of data. Statistical analysis revealed significant differences between controls and (1) patients with pharmacological treatment and (2) OCD DBS patients when the stimulation was switched off. Switching the stimulator on led to an increase in PPI at a stimulus-onset asynchrony of 200 ms. There was no significant difference in PPI between OCD patients being stimulated and the control group. This study shows that NAcc-DBS leads to an increase in PPI in tr-OCD patients towards a level seen in healthy controls. Assuming that PPI impairments partially reflect the neurobiological substrates of OCD, our results show that DBS of the NAcc may improve sensorimotor gating via correction of dysfunctional neural substrates. Bearing in mind that PPI is based on a complex and multilayered network, our data confirm that DBS most likely takes effect via network modulation. KW - nucleus KW - serotonin KW - schizophrenia KW - dopamine KW - double-blind KW - psychiatric disorders KW - in vivo KW - acoustic startle KW - reflex KW - modulation Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-138300 VL - 5 IS - e675 ER - TY - JOUR A1 - Gao, Shiqiang A1 - Nagpal, Jatin A1 - Schneider, Martin W. A1 - Kozjak-Pavlovic, Vera A1 - Nagel, Georg A1 - Gottschalk, Alexander T1 - Optogenetic manipulation of cGMP in cells and animals by the tightly light-regulated guanylyl-cyclase opsin CyclOp JF - Nature Communications N2 - Cyclic GMP (cGMP) signalling regulates multiple biological functions through activation of protein kinase G and cyclic nucleotide-gated (CNG) channels. In sensory neurons, cGMP permits signal modulation, amplification and encoding, before depolarization. Here we implement a guanylyl cyclase rhodopsin from Blastocladiella emersonii as a new optogenetic tool (BeCyclOp), enabling rapid light-triggered cGMP increase in heterologous cells (Xenopus oocytes, HEK293T cells) and in Caenorhabditis elegans. Among five different fungal CyclOps, exhibiting unusual eight transmembrane topologies and cytosolic N-termini, BeCyclOp is the superior optogenetic tool (light/dark activity ratio: 5,000; no cAMP production; turnover (20 °C) ~17 cGMPs\(^{-1}\)). Via co-expressed CNG channels (OLF in oocytes, TAX-2/4 in C. elegans muscle), BeCyclOp photoactivation induces a rapid conductance increase and depolarization at very low light intensities. In O\(_2\)/CO\(_2\) sensory neurons of C. elegans, BeCyclOp activation evokes behavioural responses consistent with their normal sensory function. BeCyclOp therefore enables precise and rapid optogenetic manipulation of cGMP levels in cells and animals. KW - carbon dioxide avoidance KW - III adenylyl cyclases KW - rhodopsin KW - in vivo KW - optical control KW - Halobacterium halobium KW - C. elegans KW - cellular camp KW - Caenorhabditis elegans KW - nucleotide-gated channel Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148197 VL - 6 IS - 8046 ER - TY - JOUR A1 - Kroeber, Jana A1 - Wenger, Barbara A1 - Schwegler, Manuela A1 - Daniel, Christoph A1 - Schmidt, Manfred A1 - Djuzenova, Cholpon S A1 - Polat, Bülent A1 - Flentje, Michael A1 - Fietkau, Rainer A1 - Distel, Luitpold V. T1 - Distinct increased outliers among 136 rectal cancer patients assessed by \(\gamma\)H2AX JF - Radiation Oncology N2 - Background: In recent years attention has focused on \(\gamma\)H2AX as a very sensitive double strand break indicator. It has been suggested that \(\gamma\)H2AX might be able to predict individual radiosensitivity. Our aim was to study the induction and repair of DNA double strand breaks labelled by \(\gamma\)H2AX in a large cohort. Methods: In a prospective study lymphocytes of 136 rectal cancer (RC) patients and 59 healthy individuals were ex vivo irradiated (IR) and initial DNA damage was compared to remaining DNA damage after 2 Gy and 24 hours repair time and preexisting DNA damage in unirradiated lymphocytes. Lymphocytes were immunostained with anti-\(\gamma\)H2AX antibodies and microscopic images with an extended depth of field were acquired. \(\gamma\)H2AX foci counting was performed using a semi-automatic image analysis software. Results: Distinct increased values of preexisting and remaining \(\gamma\)H2AX foci in the group of RC patients were found compared to the healthy individuals. Additionally there are clear differences within the groups and there are outliers in about 12% of the RC patients after ex vivo IR. Conclusions: The \(\gamma\)H2AX assay has the capability to identify a group of outliers which are most probably patients with increased radiosensitivity having the highest risk of suffering radiotherapy-related late sequelae. KW - histone H2AX KW - blood lymphocytes KW - in vivo KW - foci KW - individual radiosensitivity KW - rectal cancer KW - radiotherapy KW - DNA double strand breaks KW - phosphorylation KW - neck cancer KW - oral mucositis KW - DNA damage KW - radiosensitivity KW - repair KW - \(\gamma\)h2ax Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-144085 VL - 10 IS - 36 ER - TY - JOUR A1 - Schatton, Tobias A1 - Yang, Jun A1 - Kleffel, Sonja A1 - Uehara, Mayuko A1 - Barthel, Steven R. A1 - Schlapbach, Christoph A1 - Zhan, Qian A1 - Dudeney, Stephen A1 - Mueller, Hansgeorg A1 - Lee, Nayoung A1 - de Vries, Juliane C. A1 - Meier, Barbara A1 - Beken, Seppe Vander A1 - Kluth, Mark A. A1 - Ganss, Christoph A1 - Sharpe, Arlene H. A1 - Waaga-Gasser, Ana Maria A1 - Sayegh, Mohamed H. A1 - Abdi, Reza A1 - Scharffetter-Kochanek, Karin A1 - Murphy, George F. A1 - Kupper, Thomas S. A1 - Frank, Natasha Y. A1 - Frank, Markus H. T1 - ABCB5 Identifies Immunoregulatory Dermal Cells JF - Cell Reports N2 - Cell-based strategies represent a new frontier in the treatment of immune-mediated disorders. However, the paucity of markers for isolation of molecularly defined immunomodulatory cell populations poses a barrier to this field. Here, we show that ATP-binding cassette member B5 (ABCB5) identifies dermal immunoregulatory cells (DIRCs) capable of exerting therapeutic immunoregulatory functions through engagement of programmed cell death 1 (PD-1). Purified Abcb5\(^+\) DIRCs suppressed T cell proliferation, evaded immune rejection, homed to recipient immune tissues, and induced Tregs in vivo. In fully major-histocompatibility-complex-mismatched cardiac allotransplantation models, allogeneic DIRCs significantly prolonged allograft survival. Blockade of DIRC-expressed PD-1 reversed the inhibitory effects of DIRCs on T cell activation, inhibited DIRC-dependent Treg induction, and attenuated DIRC-induced prolongation of cardiac allograft survival, indicating that DIRC immunoregulatory function is mediated, at least in part, through PD-1. Our results identify ABCB5\(^+\) DIRCs as a distinct immunoregulatory cell population and suggest promising roles of this expandable cell subset in cellular immunotherapy. KW - mesenchymal stem cells KW - P-glycoprotein KW - regulatory T cells KW - maintain immune homeostasis KW - malignant melanoma KW - in vivo KW - skin KW - generation KW - transplant KW - tolerance Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-149989 VL - 12 SP - 1564 EP - 1574 ER -