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Reifarth, René ; Altstadt, Sebastian ; Göbel, Kathrin ; Heftrich, Tanja ; Heil, Michael ; Koloczek, Alexander ; Langer, Christoph ; Plag, Ralf ; Pohl, M. ; Sonnabend, Kerstin ; Weigand, Mario ; Adachi, T. ; Aksouh, Farouk ; Al-Khalili, J. ; AlGarawi, M. ; AlGhamdi, S. ; Alkhazov, G. ; Alkhomashi, N. ; Alvarez-Pol, Héctor ; Alvarez-Rodriguez, R. ; Andreev, V. ; Andrei, B. ; Atar, Leyla ; Aumann, Thomas ; Avdeichikov, Vladimir ; Bacri, C. ; Bagchi, S. ; Barbieri, Carlo ; Beceiro, Saul ; Beck, C. ; Beinrucker, Clemens ; Belier, Gilbert ; Bemmerer, Daniel ; Bendel, M. ; Benlliure Anaya, Jose Fernando ; Benzoni, G. ; Berjillos, R. ; Bertini, D. ; Bertulani, Carlos A. ; Bishop, S. ; Blasi, N. ; Bloch, T. ; Blumenfeld, Y. ; Bonaccorso, A. ; Boretzky, Konstanze ; Botvina, Alexander ; Boudard, A. ; Boutachkov, P. ; Boztosun, I. ; Bracco, A. ; Brambilla, S. ; Monago, J.Briz ; Caamano, Manuel ; Caesar, Christoph ; Camera, F. ; Casarejos Ruiz, Enrique ; Catford, Wilton N. ; Cederkäll, Joakim ; Cederwall, B. ; Chartier, Marielle ; Chatillon, Audrey ; Cherciu, M. ; Chulkov, Leonid V. ; Coleman-Smith, P. ; Cortina Gil, Dolores ; Crespi, F. ; Crespo, Raquel ; Cresswell, J. ; Csatlós, Margit ; Déchery, F. ; Davids, B. ; Davinson, Thomas ; Derya, Vera ; Detistov, P. ; Díaz Fernández, Paloma ; DiJulio, D. ; Dmitry, S. ; Doré, D. ; Dueñas, J. ; Dupont, Emmeric ; Egelhof, Peter ; Egorova, I. ; Elekes, Zoltán ; Enders, Joachim ; Endres, Janis ; Ershov, S. ; Ershova, Olga ; Fernández Domínguez, Beatriz ; Fetisov, A. ; Fiori, Enrico ; Fomichev, A. ; Fonseca, M. ; Fraile, L. ; Freer, Martin ; Friese, Jürgen ; Garcia Borge, Maria José ; Galaviz Redondo, Daniel ; Gannon, S. ; Garg, U. ; Gašparić, Igor ; Gasques, L. ; Gastineau, B. ; Geissel, Hans ; Gernhäuser, Roman ; Ghosh, T. ; Gilbert, M. ; Glorius, Jan ; Golubev, Pavel ; Gorshkov, Alexander ; Gourishetty, A. ; Grigorenko, Leonid V. ; Gulyas, J. ; Haiduc, Maria ; Hammache, F. ; Harakeh, Muhsin N. ; Hass, M. ; Heine, Marcel ; Hennig, Andreas ; Henriques, Ana ; Herzberg, Rolf-Dietmar ; Holl, Matthias ; Ignatov, Alexander ; Ignatyuk, A. ; Ilieva, Stoyanka ; Ivanov, Marian ; Iwasa, N. ; Jakobsson, B. ; Johansson, Håkan T. ; Jonson, Björn ; Joshi, P. ; Junghans, Arnd Rudolf ; Jurado Apruzzese, Beatriz ; Körner, G. ; Kalantar, N. ; Kanungo, Rituparna ; Kelic-Heil, Aleksandra ; Kezzar, K. ; Khan, E. ; Khanzadeev, Alexei ; Kiselev, Oleg A. ; Kogimtzis, M. ; Körper, D. ; Kräckmann, S. ; Kröll, Thorsten ; Krücken, Reiner ; Krasznahorkay, Attila ; Kratz, Jens-Volker ; Kresan, Dmytro ; Krings, Thomas ; Krumbholz, A. ; Krupko, S. ; Kulessa, Reinhard ; Kumar, Shyam ; Kurz, Nikolaus ; Kuzmin, E. ; Labiche, Marc ; Langanke, Karlheinz ; Lazarus, I. ; Bleis, T.Le ; Lederer, Claudia ; Lemasson, A. ; Lemmon, Roy Crawford ; Liberati, V. ; Litvinov, Yuri A. ; Löher, Bastian ; Herraiz, J.Lopez ; Münzenberg, G. ; Machado, Jorge ; Maev, E. ; Mahata, Kripamay ; Mancusi, D. ; Marganiec, Justyna ; Perez, M.Martinez ; Marusov, V. ; Mengoni, D. ; Million, B. ; Morcelle, V. ; Moreno, O. ; Movsesyan, Alina ; Nácher González, Enrique ; Najafi, Mohammad Ali ; Nakamura, T. ; Naqvi, F. ; Nikolski, E. ; Nilsson, Thomas ; Nociforo, Chiara ; Nolan, P. ; Novatsky, B. ; Nyman, Göran Hugo ; Ornelas, A. ; Palit, R. ; Pandit, S. ; Panin, Valerii ; Paradela Dobarro, Carlos ; Parkar, V. ; Paschalis, Stefanos ; Pawłowski, P. ; Perea Martinez, Angel ; Pereira, J. ; Petrache, C. ; Petri, Marina ; Pickstone, Simon Glynn ; Pietralla, Norbert ; Pietri, Stephane ; Pivovarov, Y. ; Potlog, P. ; Prokofiev, Andrey ; Rastrepina, G. ; Rauscher, Thomas ; Ribeiro Jimenez, Guillermo ; Ricciardi, Maria Valentina ; Richter, Achim ; Rigollet, Catherine ; Riisager, Karsten ; Rios, A. ; Ritter, C. ; Rodríguez Frutos, Tomás Raúl ; Rodríguez Vignote, Javier ; Röder, Marko ; Romig, Christopher ; Rossi, Dominic M. ; Roussel-Chomaz, P. ; Rout, Prakash Chandra ; Roy, S. ; Söderström, P. ; Saha Sarkar, Maitreyee ; Sakuta, S. ; Salsac, M. ; Sampson, J. ; Sanchez, J. ; Saez, del Rio ; Rosado, J.Sanchez ; Sanjari, Mohammad Shahab ; Sarriguren, P. ; Sauerwein, Anne ; Savran, Deniz ; Scheidenberger, Christoph ; Scheit, Heiko ; Schmidt, Stefan ; Schmitt, C. ; Schnorrenberger, Linda ; Schrock, P. ; Schwengner, R. ; Seddon, D. ; Sherrill, B. ; Shrivastava, A. ; Sidorchuk, S. ; Silva, Joel ; Simon, Haik ; Simpson, E. ; Singh, P. ; Slobodan, D. ; Sohler, D. ; Spieker, Mark-Christoph ; Stach, D. ; Stan, E. ; Stanoiu, M. ; Stepantsov, S. ; Stevenson, P. ; Strieder, F. ; Stuhl, László ; Suda, T. ; Sümmerer, Klaus ; Streicher, Branislav ; Taieb, Julien ; Takechi, M. ; Tanihata, I. ; Taylor, J. ; Tengblad, Olof ; Ter-Akopian, G. ; Terashima, S. ; Teubig, P. ; Thies, Ronja ; Thoennessen, M. ; Thomas, T. ; Thornhill, J. ; Thungstrom, G. ; Timar, J. ; Togano, Yasuhiro ; Tomohiro, U. ; Tornyi, T. ; Tostevin, J. ; Townsley, C. ; Trautmann, Wolfgang ; Trivedi, T. ; Typel, Stefan ; Uberseder, E. ; Udias, J. ; Uesaka, T. ; Uvarov, L. ; Vajta, Z. ; Velho, Paulo ; Vikhrov, V. ; Volknandt, Meiko ; Volkov, Vasily ; Neumann-Cosel, Peter von ; Schmid, Mirko von ; Wagner, A. ; Wamers, Felix ; Weick, Helmut ; Wells, D. ; Westerberg, L. ; Wieland, Oliver ; Wiescher, Michael ; Wimmer, Christine ; Wimmer, K. ; Winfield, John S. ; Winkel, M. ; Woods, Philip John ; Wyss, R. ; Yakorev, Dmitry ; Yavor, M. ; Zamora Cardona, Juan Carlos ; Zartova, I. ; Zerguerras, T. ; Zgura, M. ; Zhdanov, A. ; Zhukov, Mikhail V. ; Zieblinski, M. ; Zilges, Andreas ; Zuber, Kai
The nucleosynthesis of elements beyond iron is dominated by neutron captures in the s and r processes. However, 32 stable, proton-rich isotopes cannot be formed during those processes, because they are shielded from the s-process flow and r-process β-decay chains. These nuclei are attributed to the p and rp process.
For all those processes, current research in nuclear astrophysics addresses the need for more precise reaction data involving radioactive isotopes. Depending on the particular reaction, direct or inverse kinematics, forward or time-reversed direction are investigated to determine or at least to constrain the desired reaction cross sections.
The Facility for Antiproton and Ion Research (FAIR) will offer unique, unprecedented opportunities to investigate many of the important reactions. The high yield of radioactive isotopes, even far away from the valley of stability, allows the investigation of isotopes involved in processes as exotic as the r or rp processes.
The antibacterial properties of nanosilver have led to a versatile application spectrum including medical purposes and personal care products. However, the increasing use of nanosilver has raised concerns about its environmental impacts. Long-term exposure studies with aquatic invertebrates are essential to assess possible adverse effects on aquatic ecosystems. In the present study, acute (48 h), chronic (21 d) and long-term effects of nanosilver (primary size 15 nm) on five successive generations of three Daphnia species (D. magna, D. pulex, and D. galeata) were investigated. Acute EC50 values of nanosilver were 121 µg Ag L−1 for D. magna being the least sensitive species and 8.95 and 13.9 µg Ag L−1 for D. pulex and D. galeata, respectively. Chronic exposure provided EC10 values of 0.92 µg Ag L−1 for D. magna showing the most sensitive chronic reaction and 2.25 and 3.45 µg Ag L−1 for D. pulex and D. galeata, respectively. Comparative exposure to AgNO3 revealed a generally higher toxicity of the soluble form of silver. The multi-generation experiments resulted in effects on the population level for all tested species. Exposure of D. magna indicated an increased toxicity of nanosilver in the fifth generation of animals exposed to 10 µg Ag L−1. Neonates from pre-exposed parental daphnids did not completely recover when transferred into clean water. Exposure of D. pulex and D. galeata revealed not only increasing toxicity in some generations, but also greater tolerance to nanosilver. This study contributes to the assessment of the risk potential of nanosilver on aquatic ecosystems. It shows that effects of nanosilver vary within one genus and change with exposure duration. Therefore, long-term studies considering different aquatic species are needed to better understand the possible effects of nanosilver on aquatic ecosystems.
DNA damage in oocytes induces a switch of the quality control factor TAp63α from dimer to tetramer
(2011)
Deutsch, Gregor ; Zielonka, Elisabeth M. ; Coutandin, Daniel ; Weber, Tobias Alexander ; Schäfer, Birgit ; Hannewald, Jens ; Luh, Laura Martina ; Durst, Florian ; Ibrahim, Mohamed ; Hoffmann, Jan ; Niesen, Frank H. ; Sentürk, Aycan ; Kunkel, Hana ; Brutschy, Bernd ; Schleiff, Enrico ; Knapp, Stefan ; Acker-Palmer, Amparo ; Grez, Manuel ; McKeon, Frank ; Dötsch, Volker
TAp63a, a homolog of the p53 tumor suppressor, is a quality control factor in the female germline. Remarkably, already undamaged oocytes express high levels of the protein, suggesting that TAp63a’s activity is under tight control of an inhibitory mechanism. Biochemical studies have proposed that inhibition requires the C-terminal transactivation inhibitory domain. However, the structural mechanism of TAp63a inhibition remains unknown. Here, we show that TAp63a is kept in an inactive dimeric state. We reveal that relief of inhibition leads to tetramer formation with ~20-fold higher DNA affinity. In vivo, phosphorylation-triggered tetramerization of TAp63a is not reversible by dephosphorylation. Furthermore, we show that a helix in the oligomerization domain of p63 is crucial for tetramer stabilization and competes with the transactivation domain for the same binding site. Our results demonstrate how TAp63a is inhibited by complex domain-domain interactions that provide the basis for regulating quality control in oocytes.
Gottschalk, Michael G. ; Richter, Jan ; Ziegler, Christiane ; Schiele, Miriam A. ; Mann, Julia ; Geiger, Maximilian J. ; Schartner, Christoph ; Homola, György Ádám ; Alpers, Georg W. ; Büchel, Christian ; Fehm, Lydia ; Fydrich, Thomas ; Gerlach, Alexander ; Gloster, Andrew T. ; Helbig-Lang, Sylvia ; Kalisch, Raffael ; Kircher, Tilo ; Lang, Thomas ; Lonsdorf, Tina B. ; Pané-Farré, Christiane A. ; Ströhle, Andreas ; Weber, Heike ; Zwanzger, Peter M. ; Arolt, Volker ; Romanos, Marcel ; Wittchen, Hans-Ulrich ; Hamm, Alfons ; Pauli, Paul ; Reif, Andreas ; Deckert, Jürgen ; Neufang, Susanne ; Höfler, Michael ; Domschke, Katharina
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.
Hommers, Leif ; Richter, Jan ; Yang, Yunbo ; Raab, Annette ; Baumann, Christian ; Lang, Konstantin ; Schiele, Miriam A. ; Weber, Heike ; Wittmann, André ; Wolf, Christiane ; Alpers, Georg W. ; Arolt, Volker ; Domschke, Katharina ; Fehm, Lydia ; Fydrich, Thomas ; Gerlach, Alexander ; Gloster, Andrew T. ; Hamm, Alfons ; Helbig-Lang, Sylvia ; Kircher, Tilo ; Lang, Thomas ; Pané-Farré, Christiane A. ; Pauli, Paul ; Pfleiderer, Bettina ; Reif, Andreas ; Romanos, Marcel ; Straube, Benjamin ; Ströhle, Andreas ; Wittchen, Hans-Ulrich ; Frantz, Stefan ; Ertl, Georg ; Lohse, Martin ; Lüken, Ulrike ; Deckert, Jürgen
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.
Ziegler, Christiane ; Richter, Jan ; Mahr, Marina ; Gajewska, Agnes ; Schiele, Miriam A. ; Gehrmann, Andrea ; Schmidt, Brad ; Lesch, Klaus-Peter J. ; Lang, Thomas ; Helbig-Lang, Sylvia ; Pauli, Paul ; Kircher, Tilo ; Reif, Andreas ; Rief, Winfried ; Voßbeck-Elsebusch, Anna Nicola ; Arolt, Volker ; Wittchen, Hans-Ulrich ; Hamm, Alfons ; Deckert, Jürgen ; Domschke, Katharina
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.