@article{SchmidFalterWeberetal.2017, author = {Schmid, Tobias and Falter, Lena and Weber, Sabine and M{\"u}ller, Nils and Molitor, Konstantin and Zeller, David and Weber-Steffens, Dorothea and Hehlgans, Thomas and Wajant, Harald and Mostb{\"o}ck, Sven and M{\"a}nnel, Daniela N.}, title = {Chronic inflammation increases the sensitivity of mouse Treg for TNFR2 costimulation}, series = {Frontiers in Immunology}, volume = {8}, journal = {Frontiers in Immunology}, doi = {10.3389/fimmu.2017.01471}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173259}, year = {2017}, abstract = {TNF receptor type 2 (TNFR2) has gained attention as a costimulatory receptor for T cells and as critical factor for the development of regulatory T cells (Treg) and myeloid suppressor cells. Using the TNFR2-specific agonist TNCscTNF80, direct effects of TNFR2 activation on myeloid cells and T cells were investigated in mice. \(In\) \(vitro\), TNCscTNF80 induced T cell proliferation in a costimulatory fashion, and also supported \(in\) \(vitro\) expansion of Treg cells. In addition, activation of TNFR2 retarded differentiation of bone marrow-derived immature myeloid cells in culture and reduced their suppressor function. \(In\) \(vivo\) application of TNCscTNF80-induced mild myelopoiesis in na{\"i}ve mice without affecting the immune cell composition. Already a single application expanded Treg cells and improved suppression of CD4 T cells in mice with chronic inflammation. By contrast, multiple applications of the TNFR2 agonist were required to expand Treg cells in na{\"i}ve mice. Improved suppression of T cell proliferation depended on expression of TNFR2 by T cells in mice repeatedly treated with TNCscTNF80, without a major contribution of TNFR2 on myeloid cells. Thus, TNFR2 activation on T cells in na{\"i}ve mice can lead to immune suppression \(in\) \(vivo\). These findings support the important role of TNFR2 for Treg cells in immune regulation.}, language = {en} } @article{DrubeWeberLoschinskietal.2015, author = {Drube, Sebastian and Weber, Franziska and Loschinski, Romy and Beyer, Mandy and Rothe, Mandy and Rabenhorst, Anja and G{\"o}pfert, Christiane and Meininger, Isabel and Diamanti, Michaela A. and Stegner, David and H{\"a}fner, Norman and B{\"o}ttcher, Martin and Reinecke, Kirstin and Herdegen, Thomas and Greten, Florian R. and Nieswandt, Bernhard and Hartmann, Karin and Kr{\"a}mer, Oliver H. and Kamradt, Thomas}, title = {Subthreshold IKK activation modulates the effector functions of primary mast cells and allows specific targeting of transformed mast cells}, series = {Oncotarget}, volume = {6}, journal = {Oncotarget}, number = {7}, doi = {10.18632/oncotarget.3022}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-143681}, pages = {5354-5368}, year = {2015}, abstract = {Mast cell differentiation and proliferation depends on IL-3. IL-3 induces the activation of MAP-kinases and STATs and consequently induces proliferation and survival. Dysregulation of IL-3 signaling pathways also contribute to inflammation and tumorigenesis. We show here that IL-3 induces a SFK- and Ca2\(^{+}\)-dependent activation of the inhibitor of κB kinases 2 (IKK2) which results in mast cell proliferation and survival but does not induce IκBα-degradation and NFκB activation. Therefore we propose the term "subthreshold IKK activation". This subthreshold IKK activation also primes mast cells for enhanced responsiveness to IL-33R signaling. Consequently, co-stimulation with IL-3 and IL-33 increases IKK activation and massively enhances cytokine production induced by IL-33. We further reveal that in neoplastic mast cells expressing constitutively active Ras, subthreshold IKK activation is associated with uncontrolled proliferation. Consequently, pharmacological IKK inhibition reduces tumor growth selectively by inducing apoptosis in vivo. Together, subthreshold IKK activation is crucial to mediate the full IL-33-induced effector functions in primary mast cells and to mediate uncontrolled proliferation of neoplastic mast cells. Thus, IKK2 is a new molecularly defined target structure.}, language = {en} } @article{RaynerColemanPurvesetal.2019, author = {Rayner, Christopher and Coleman, Jonathan R. I. and Purves, Kirstin L. and Hodsoll, John and Goldsmith, Kimberley and Alpers, Georg W. and Andersson, Evelyn and Arolt, Volker and Boberg, Julia and B{\"o}gels, Susan and Creswell, Cathy and Cooper, Peter and Curtis, Charles and Deckert, J{\"u}rgen and Domschke, Katharina and El Alaoui, Samir and Fehm, Lydia and Fydrich, Thomas and Gerlach, Alexander L. and Grocholewski, Anja and Hahlweg, Kurt and Hamm, Alfons and Hedman, Erik and Heiervang, Einar R. and Hudson, Jennifer L. and J{\"o}hren, Peter and Keers, Robert and Kircher, Tilo and Lang, Thomas and Lavebratt, Catharina and Lee, Sang-hyuck and Lester, Kathryn J. and Lindefors, Nils and Margraf, J{\"u}rgen and Nauta, Maaike and Pan{\´e}-Farr{\´e}, Christiane A. and Pauli, Paul and Rapee, Ronald M. and Reif, Andreas and Rief, Winfried and Roberts, Susanna and Schalling, Martin and Schneider, Silvia and Silverman, Wendy K. and Str{\"o}hle, Andreas and Teismann, Tobias and Thastum, Mikael and Wannem{\"u}ller, Andre and Weber, Heike and Wittchen, Hans-Ulrich and Wolf, Christiane and R{\"u}ck, Christian and Breen, Gerome and Eley, Thalia C.}, title = {A genome-wide association meta-analysis of prognostic outcomes following cognitive behavioural therapy in individuals with anxiety and depressive disorders}, series = {Translational Psychiatry}, volume = {9}, journal = {Translational Psychiatry}, number = {150}, doi = {10.1038/s41398-019-0481-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225048}, pages = {1-13}, year = {2019}, abstract = {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.}, language = {en} } @article{GottschalkRichterZiegleretal.2019, author = {Gottschalk, Michael G. and Richter, Jan and Ziegler, Christiane and Schiele, Miriam A. and Mann, Julia and Geiger, Maximilian J. and Schartner, Christoph and Homola, Gy{\"o}rgy A. and Alpers, Georg W. and B{\"u}chel, Christian and Fehm, Lydia and Fydrich, Thomas and Gerlach, Alexander L. and Gloster, Andrew T. and Helbig-Lang, Sylvia and Kalisch, Raffael and Kircher, Tilo and Lang, Thomas and Lonsdorf, Tina B. and Pan{\´e}-Farr{\´e}, Christiane A. and Str{\"o}hle, Andreas and Weber, Heike and Zwanzger, Peter and Arolt, Volker and Romanos, Marcel and Wittchen, Hans-Ulrich and Hamm, Alfons and Pauli, Paul and Reif, Andreas and Deckert, J{\"u}rgen and Neufang, Susanne and H{\"o}fler, Michael and Domschke, Katharina}, title = {Orexin in the anxiety spectrum: association of a HCRTR1 polymorphism with panic disorder/agoraphobia, CBT treatment response and fear-related intermediate phenotypes}, series = {Translational Psychiatry}, volume = {9}, journal = {Translational Psychiatry}, doi = {10.1038/s41398-019-0415-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227479}, year = {2019}, abstract = {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.}, language = {en} } @article{ChubanovFerioliWisnowskyetal.2016, author = {Chubanov, Vladimir and Ferioli, Silvia and Wisnowsky, Annika and Simmons, David G. and Leitzinger, Christin and Einer, Claudia and Jonas, Wenke and Shymkiv, Yuriy and Gudermann, Thomas and Bartsch, Harald and Braun, Attila and Akdogan, Banu and Mittermeier, Lorenz and Sytik, Ludmila and Torben, Friedrich and Jurinovic, Vindi and van der Vorst, Emiel P. C. and Weber, Christian and Yildirim, {\"O}nder A. and Sotlar, Karl and Sch{\"u}rmann, Annette and Zierler, Susanna and Zischka, Hans and Ryazanov, Alexey G.}, title = {Epithelial magnesium transport by TRPM6 is essential for prenatal development and adult survival}, series = {eLife}, volume = {5}, journal = {eLife}, doi = {10.7554/eLife.20914}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-164987}, pages = {e19686}, year = {2016}, abstract = {Mg2+ regulates many physiological processes and signalling pathways. However, little is known about the mechanisms underlying the organismal balance of Mg2+. Capitalizing on a set of newly generated mouse models, we provide an integrated mechanistic model of the regulation of organismal Mg2+ balance during prenatal development and in adult mice by the ion channel TRPM6. We show that TRPM6 activity in the placenta and yolk sac is essential for embryonic development. In adult mice, TRPM6 is required in the intestine to maintain organismal Mg2+ balance, but is dispensable in the kidney. Trpm6 inactivation in adult mice leads to a shortened lifespan, growth deficit and metabolic alterations indicative of impaired energy balance. Dietary Mg2+ supplementation not only rescues all phenotypes displayed by Trpm6-deficient adult mice, but also may extend the lifespan of wildtype mice. Hence, maintenance of organismal Mg2+ balance by TRPM6 is crucial for prenatal development and survival to adulthood.}, language = {en} } @article{SzaboPapinZornetal.2013, author = {Szab{\´o}, {\´A}ron and Papin, Christian and Zorn, Daniela and Ponien, Prishila and Weber, Frank and Raabe, Thomas and Rouyer, Fran{\c{c}}ois}, title = {The CK2 Kinase Stabilizes CLOCK and Represses Its Activity in the Drosophila Circadian Oscillator}, series = {PLoS Biology}, volume = {11}, journal = {PLoS Biology}, number = {8}, issn = {1545-7885}, doi = {10.1371/journal.pbio.1001645}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127234}, pages = {e1001645}, year = {2013}, abstract = {Phosphorylation is a pivotal regulatory mechanism for protein stability and activity in circadian clocks regardless of their evolutionary origin. It determines the speed and strength of molecular oscillations by acting on transcriptional activators and their repressors, which form negative feedback loops. In Drosophila, the CK2 kinase phosphorylates and destabilizes the PERIOD (PER) and TIMELESS (TIM) proteins, which inhibit CLOCK (CLK) transcriptional activity. Here we show that CK2 also targets the CLK activator directly. Downregulating the activity of the catalytic alpha subunit of CK2 induces CLK degradation, even in the absence of PER and TIM. Unexpectedly, the regulatory beta subunit of the CK2 holoenzyme is not required for the regulation of CLK stability. In addition, downregulation of \(CK2\alpha\) activity decreases CLK phosphorylation and increases per and tim transcription. These results indicate that CK2 inhibits CLK degradation while reducing its activity. Since the CK1 kinase promotes CLK degradation, we suggest that CLK stability and transcriptional activity result from counteracting effects of CK1 and CK2.}, language = {en} } @article{CouchWangMcGuffogetal.2013, author = {Couch, Fergus J. and Wang, Xianshu and McGuffog, Lesley and Lee, Andrew and Olswold, Curtis and Kuchenbaecker, Karoline B. and Soucy, Penny and Fredericksen, Zachary and Barrowdale, Daniel and Dennis, Joe and Gaudet, Mia M. and Dicks, Ed and Kosel, Matthew and Healey, Sue and Sinilnikova, Olga M. and Lee, Adam and Bacot, Fran{\c{c}}ios and Vincent, Daniel and Hogervorst, Frans B. L. and Peock, Susan and Stoppa-Lyonnet, Dominique and Jakubowska, Anna and Radice, Paolo and Schmutzler, Rita Katharina and Domchek, Susan M. and Piedmonte, Marion and Singer, Christian F. and Friedman, Eitan and Thomassen, Mads and Hansen, Thomas V. O. and Neuhausen, Susan L. and Szabo, Csilla I. and Blanco, Ingnacio and Greene, Mark H. and Karlan, Beth Y. and Garber, Judy and Phelan, Catherine M. and Weitzel, Jeffrey N. and Montagna, Marco and Olah, Edith and Andrulis, Irene L. and Godwin, Andrew K. and Yannoukakos, Drakoulis and Goldgar, David E. and Caldes, Trinidad and Nevanlinna, Heli and Osorio, Ana and Terry, Mary Beth and Daly, Mary B. and van Rensburg, Elisabeth J. and Hamann, Ute and Ramus, Susan J. and Toland, Amanda Ewart and Caligo, Maria A. and Olopade, Olufunmilayo I. and Tung, Nadine and Claes, Kathleen and Beattie, Mary S. and Southey, Melissa C. and Imyanitov, Evgeny N. and Tischkowitz, Marc and Janavicius, Ramunas and John, Esther M. and Kwong, Ava and Diez, Orland and Kwong, Ava and Balma{\~n}a, Judith and Barkardottir, Rosa B. and Arun, Banu K. and Rennert, Gad and Teo, Soo-Hwang and Ganz, Patricia A. and Campbell, Ian and van der Hout, Annemarie H. and van Deurzen, Carolien H. M. and Seynaeve, Caroline and Garcia, Encarna B. G{\´o}mez and van Leeuwen, Flora E. and Meijers-Heijboer, Hanne E. J. and Gille, Johannes J. P. and Ausems, Magreet G. E. M. and Blok, Marinus J. and Ligtenberg, Marjolinjin J. L. and Rookus, Matti A. and Devilee, Peter and Verhoef, Senno and van Os, Theo A. M. and Wijnen, Juul T. and Frost, Debra and Ellis, Steve and Fineberg, Elena and Platte, Radke and Evans, D. Gareth and Izatt, Luise and Eeles, Rosalind A. and Adlard, Julian and Eccles, Diana M. and Cook, Jackie and Brewer, Carole and Douglas, Fiona and Hodgson, Shirley and Morrison, Patrick J. and Side, Lucy E. and Donaldson, Alan and Houghton, Catherine and Rogers, Mark T. and Dorkins, Huw and Eason, Jacqueline and Gregory, Helen and McCann, Emma and Murray, Alex and Calender, Alain and Hardouin, Agn{\`e}s and Berthet, Pascaline and Delnatte, Capucine and Nogues, Catherine and Lasset, Christine and Houdayer, Claude and Leroux,, Dominique and Rouleau, Etienne and Prieur, Fabienne and Damiola, Francesca and Sobol, Hagay and Coupier, Isabelle and Venat-Bouvet, Laurence and Castera, Laurent and Gauthier-Villars, Marion and L{\´e}on{\´e}, M{\´e}lanie and Pujol, Pascal and Mazoyer, Sylvie and Bignon, Yves-Jean and Zlowocka-Perlowska, Elzbieta and Gronwald, Jacek and Lubinski,, Jan and Durda, Katarzyna and Jaworska, Katarzyna and Huzarski, Tomasz and Spurdle, Amanda B. and Viel, Alessandra and Peissel, Bernhard and Bonanni, Bernardo and Melloni, Guilia and Ottini, Laura and Papi, Laura and Varesco, Liliana and Tibiletti, Maria Grazia and Peterlongo, Paolo and Volorio, Sara and Manoukian, Siranoush and Pensotti, Valeria and Arnold, Norbert and Engel, Christoph and Deissler, Helmut and Gadzicki, Dorothea and Gehrig, Andrea and Kast, Karin and Rhiem, Kerstin and Meindl, Alfons and Niederacher, Dieter and Ditsch, Nina and Plendl, Hansjoerg and Preisler-Adams, Sabine and Engert, Stefanie and Sutter, Christian and Varon-Mateeva, Raymenda and Wappenschmidt, Barbara and Weber, Bernhard H. F. and Arver, Brita and Stenmark-Askmalm, Marie and Loman, Niklas and Rosenquist, Richard and Einbeigi, Zakaria and Nathanson, Katherine L. and Rebbeck, Timothy R. and Blank, Stephanie V. and Cohn, David E. and Rodriguez, Gustavo C. and Small, Laurie and Friedlander, Michael and Bae-Jump, Victoria L. and Fink-Retter, Anneliese and Rappaport, Christine and Gschwantler-Kaulich, Daphne and Pfeiler, Georg and Tea, Muy-Kheng and Lindor, Noralane M. and Kaufman, Bella and Paluch, Shani Shimon and Laitman, Yael and Skytte, Anne-Bine and Gerdes, Anne-Marie and Pedersen, Inge Sokilde and Moeller, Sanne Traasdahl and Kruse, Torben A. and Jensen, Uffe Birk and Vijai, Joseph and Sarrel, Kara and Robson, Mark and Kauff, Noah and Mulligan, Anna Marie and Glendon, Gord and Ozcelik, Hilmi and Ejlertsen, Bent and Nielsen, Finn C. and J{\o}nson, Lars and Andersen, Mette K. and Ding, Yuan Chun and Steele, Linda and Foretova, Lenka and Teul{\´e}, Alex and Lazaro, Conxi and Brunet, Joan and Pujana, Miquel Angel and Mai, Phuong L. and Loud, Jennifer T. and Walsh, Christine and Lester, Jenny and Orsulic, Sandra and Narod, Steven A. and Herzog, Josef and Sand, Sharon R. and Tognazzo, Silvia and Agata, Simona and Vaszko, Tibor and Weaver, Joellen and Stravropoulou, Alexandra V. and Buys, Saundra S. and Romero, Atocha and de la Hoya, Miguel and Aittom{\"a}ki, Kristiina and Muranen, Taru A. and Duran, Mercedes and Chung, Wendy K. and Lasa, Adriana and Dorfling, Cecilia M. and Miron, Alexander and Benitez, Javier and Senter, Leigha and Huo, Dezheng and Chan, Salina B. and Sokolenko, Anna P. and Chiquette, Jocelyne and Tihomirova, Laima and Friebel, Tara M. and Agnarsson, Bjarne A. and Lu, Karen H. and Lejbkowicz, Flavio and James, Paul A. and Hall, Per and Dunning, Alison M. and Tessier, Daniel and Cunningham, Julie and Slager, Susan L. and Chen, Wang and Hart, Steven and Stevens, Kristen and Simard, Jacques and Pastinen, Tomi and Pankratz, Vernon S. and Offit, Kenneth and Easton, Douglas F. and Chenevix-Trench, Georgia and Antoniou, Antonis C.}, title = {Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk}, series = {PLOS Genetics}, volume = {9}, journal = {PLOS Genetics}, number = {3}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1003212}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127947}, pages = {e1003212}, year = {2013}, abstract = {BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 x 10(-8), HR = 1.14, 95\% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 x 10(-8), HR = 1.27, 95\% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 x 10(-8), HR = 1.20, 95\% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2 x 10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5\% of BRCA1 carriers at lowest risk are 28\%-50\% compared to 81\%-100\% for the 5\% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5\% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28\% or lower, whereas the 5\% at highest risk will have a risk of 63\% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.}, language = {en} } @article{WeberSchmidtScheer1989, author = {Weber, Thomas and Schmidt, Erwin and Scheer, Ulrich}, title = {Mapping of transcription units on Xenopus laevis lampbrush chromosomes by in situ hybridization with biotin-labeled cDNA probes}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-40763}, year = {1989}, abstract = {A non-radioactive in situ hybridization method is described for the localization of transcription units of defined genes to lateral loops of Xenopus laevis lampbrush chromosomes. Two Xenopus cONA probes were used encoding the nucleolar protein N038/ B23 and cytokeratin 1(8). Both proteins are known to be synthesized in Xenopus oocytes, and Northern blot analysis revealed the presence of the corresponding mRNAs in different oogenic stages. The probes were enzymatically labeled with biotin-dCTP and hybridized to lampbrush chromosomes. The sites of hybridization were detected either by indirect immunofluorescence microscopy using rabbit antibodies against biotin and fluorescein-conjugated antirabbit IgG or enzymatically using peroxidase-conjugated streptavi din. The probe encoding the nucleolar protein hybridized to two sets of lateral loops on different bivalents, the cytokeratin probe to at least four. Our finding that each probe hybridized to more than one chromosomal locus may reflect the tetraploid nature of the Xenopus laevis genome or results from cross-hybridization to other transcriptionally active members of the N038/ B23-nucleoplasmin or the cytokeratin-Iamin gene families. The method described should facilitate further in situ hybridization studies with appropriate genomic clones in order to map specific DNA sequences to defined loop regions and to come to a better understanding of the relationship between loop organization and gene transcription unit.}, subject = {Cytologie}, language = {en} } @article{WeberScholzDomschkeetal.2012, author = {Weber, Heike and Scholz, Claus J{\"u}rgen and Domschke, Katharina and Baumann, Christian and Klauke, Benedikt and Jacob, Christian P. and Maier, Wolfgang and Fritze, J{\"u}rgen and Bandelow, Borwin and Zwanzger, Peter Michael and Lang, Thomas and Fehm, Lydia and Str{\"o}hle, Andreas and Hamm, Alfons and Gerlach, Alexander L. and Alpers, Georg W. and Kircher, Tilo and Wittchen, Hans-Ulrich and Arolt, Volker and Pauli, Paul and Deckert, J{\"u}rgen and Reif, Andreas}, title = {Gender Differences in Associations of Glutamate Decarboxylase 1 Gene (GAD1) Variants with Panic Disorder}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75830}, year = {2012}, abstract = {Background: Panic disorder is common (5\% prevalence) and females are twice as likely to be affected as males. The heritable component of panic disorder is estimated at 48\%. Glutamic acid dehydrogenase GAD1, the key enzyme for the synthesis of the inhibitory and anxiolytic neurotransmitter GABA, is supposed to influence various mental disorders, including mood and anxiety disorders. In a recent association study in depression, which is highly comorbid with panic disorder, GAD1 risk allele associations were restricted to females. Methodology/Principal Findings: Nineteen single nucleotide polymorphisms (SNPs) tagging the common variation in GAD1 were genotyped in two independent gender and age matched case-control samples (discovery sample n = 478; replication sample n = 584). Thirteen SNPs passed quality control and were examined for gender-specific enrichment of risk alleles associated with panic disorder by using logistic regression including a genotype6gender interaction term. The latter was found to be nominally significant for four SNPs (rs1978340, rs3762555, rs3749034, rs2241165) in the discovery sample; of note, the respective minor/risk alleles were associated with panic disorder only in females. These findings were not confirmed in the replication sample; however, the genotype6gender interaction of rs3749034 remained significant in the combined sample. Furthermore, this polymorphism showed a nominally significant association with the Agoraphobic Cognitions Questionnaire sum score. Conclusions/Significance: The present study represents the first systematic evaluation of gender-specific enrichment of risk alleles of the common SNP variation in the panic disorder candidate gene GAD1. Our tentative results provide a possible explanation for the higher susceptibility of females to panic disorder.}, subject = {Medizin}, language = {en} } @article{SimsekyilmazLiehnWeinandyetal.2016, author = {Simsekyilmaz, Sakine and Liehn, Elisa A. and Weinandy, Stefan and Schreiber, Fabian and Megens, Remco T. A. and Theelen, Wendy and Smeets, Ralf and Jockenh{\"o}vel, Stefan and Gries, Thomas and M{\"o}ller, Martin and Klee, Doris and Weber, Christian and Zernecke, Alma}, title = {Targeting In-Stent-Stenosis with RGD- and CXCL1-Coated Mini-Stents in Mice}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {5}, doi = {10.1371/journal.pone.0155829}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-179745}, year = {2016}, abstract = {Atherosclerotic lesions that critically narrow the artery can necessitate an angioplasty and stent implantation. Long-term therapeutic effects, however, are limited by excessive arterial remodeling. We here employed a miniaturized nitinol-stent coated with star-shaped polyethylenglycole (star-PEG), and evaluated its bio-functionalization with RGD and CXCL1 for improving in-stent stenosis after implantation into carotid arteries of mice. Nitinol foils or stents (bare metal) were coated with star-PEG, and bio-functionalized with RGD, or RGD/CXCL1. Cell adhesion to star-PEG-coated nitinol foils was unaltered or reduced, whereas bio-functionalization with RGD but foremost RGD/CXCL1 increased adhesion of early angiogenic outgrowth cells (EOCs) and endothelial cells but not smooth muscle cells when compared with bare metal foils. Stimulation of cells with RGD/CXCL1 furthermore increased the proliferation of EOCs. In vivo, bio-functionalization with RGD/CXCL1 significantly reduced neointima formation and thrombus formation, and increased re-endothelialization in apoE\(^{-/-}\) carotid arteries compared with bare-metal nitinol stents, star-PEG-coated stents, and stents bio-functionalized with RGD only. Bio-functionalization of star-PEG-coated nitinol-stents with RGD/CXCL1 reduced in-stent neointima formation. By supporting the adhesion and proliferation of endothelial progenitor cells, RGD/CXCL1 coating of stents may help to accelerate endothelial repair after stent implantation, and thus may harbor the potential to limit the complication of in-stent restenosis in clinical approaches.}, language = {en} } @article{SchuemannGrossBaueretal.2021, author = {Sch{\"u}mann, Franziska Lea and Groß, Elisabeth and Bauer, Marcus and Rohde, Christian and Sandmann, Sarah and Terziev, Denis and M{\"u}ller, Lutz P. and Posern, Guido and Wienke, Andreas and Fend, Falko and Hansmann, Martin-Leo and Klapper, Wolfram and Rosenwald, Andreas and Stein, Harald and Dugas, Martin and M{\"u}ller-Tidow, Carsten and Wickenhauser, Claudia and Binder, Mascha and Weber, Thomas}, title = {Divergent effects of EZH1 and EZH2 protein expression on the prognosis of patients with T-cell lymphomas}, series = {Biomedicines}, volume = {9}, journal = {Biomedicines}, number = {12}, issn = {2227-9059}, doi = {10.3390/biomedicines9121842}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-252155}, year = {2021}, abstract = {T-cell lymphomas are highly heterogeneous and their prognosis is poor under the currently available therapies. Enhancers of zeste homologue 1 and 2 (EZH1/2) are histone H3 lysine-27 trimethyltransferases (H3K27me3). Despite the rapid development of new drugs inhibiting EZH2 and/or EZH1, the molecular interplay of these proteins and the impact on disease progression and prognosis of patients with T-cell lymphomas remains insufficiently understood. In this study, EZH1/2 mutation status was evaluated in 33 monomorphic epitheliotropic intestinal T-cell lymphomas by next generation sequencing and EZH1/2 and H3K27me3 protein expression levels were detected by immunohistochemistry in 46 T-cell lymphomas. Correlations with clinicopathologic features were analyzed and survival curves generated. No EZH1 mutations and one (3\%) EZH2 missense mutation were identified. In univariable analysis, high EZH1 expression was associated with an improved overall survival (OS) and progression-free survival (PFS) whereas high EZH2 and H3K27me3 expression were associated with poorer OS and PFS. Multivariable analysis revealed EZH1 (hazard ratio (HR) = 0.183; 95\% confidence interval (CI): 0.044-0.767; p = 0.020;) and EZH2 (HR = 8.245; 95\% CI: 1.898-35.826; p = 0.005) to be independent, divergent prognostic markers for OS. In conclusion, EZH1/2 protein expression had opposing effects on the prognosis of T-cell lymphoma patients.}, language = {en} } @article{ButtStempfleListeretal.2020, author = {Butt, Elke and Stempfle, Katrin and Lister, Lorenz and Wolf, Felix and Kraft, Marcella and Herrmann, Andreas B. and Viciano, Cristina Perpina and Weber, Christian and Hochhaus, Andreas and Ernst, Thomas and Hoffmann, Carsten and Zernecke, Alma and Frietsch, Jochen J.}, title = {Phosphorylation-dependent differences in CXCR4-LASP1-AKT1 interaction between breast cancer and chronic myeloid leukemia}, series = {Cells}, volume = {9}, journal = {Cells}, number = {2}, issn = {2073-4409}, doi = {10.3390/cells9020444}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200638}, year = {2020}, abstract = {The serine/threonine protein kinase AKT1 is a downstream target of the chemokine receptor 4 (CXCR4), and both proteins play a central role in the modulation of diverse cellular processes, including proliferation and cell survival. While in chronic myeloid leukemia (CML) the CXCR4 is downregulated, thereby promoting the mobilization of progenitor cells into blood, the receptor is highly expressed in breast cancer cells, favoring the migratory capacity of these cells. Recently, the LIM and SH3 domain protein 1 (LASP1) has been described as a novel CXCR4 binding partner and as a promoter of the PI3K/AKT pathway. In this study, we uncovered a direct binding of LASP1, phosphorylated at S146, to both CXCR4 and AKT1, as shown by immunoprecipitation assays, pull-down experiments, and immunohistochemistry data. In contrast, phosphorylation of LASP1 at Y171 abrogated these interactions, suggesting that both LASP1 phospho-forms interact. Finally, findings demonstrating different phosphorylation patterns of LASP1 in breast cancer and chronic myeloid leukemia may have implications for CXCR4 function and tyrosine kinase inhibitor treatment.}, language = {en} } @article{WurmbFrankeSchorscheretal.2020, author = {Wurmb, Thomas and Franke, Axel and Schorscher, Nora and Kowalzik, Barbara and Helm, Matthias and Bohnen, Renate and Helmerichs, Jutta and Grueneisen, Ulrich and Cwojdzinski, Detlef and Jung, Georg and L{\"u}cking, Gesa and Weber, Martin}, title = {Emergency response to terrorist attacks: results of the federal-conducted evaluation process in Germany}, series = {European Journal of Trauma and Emergency Surgery}, volume = {46}, journal = {European Journal of Trauma and Emergency Surgery}, issn = {1863-9933}, doi = {10.1007/s00068-020-01347-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-231777}, pages = {725-730}, year = {2020}, abstract = {Purpose Rescue missions during terrorist attacks are extremely challenging for all rescue forces (police as well as non-police forces) involved. To improve the quality and safety of the rescue missions during an active killing event, it is obligatory to adapt common rescue mission goals and strategies. Methods After the recent attacks in Europe, the Federal Office of Civil Protection and Disaster Assistance started an evaluation process on behalf of the Federal Ministry of the Interior and the Federal Ministry of Health. This was done to identify weaknesses, lessons learned and to formulate new adapted guidelines. Results The presented bullet point recommendations summarise the basic and most important results of the ongoing evaluation process for the Federal Republic of Germany. The safety of all the rescue forces and survival of the greatest possible number of casualties are the priority goals. Furthermore, the preservation and re-establishment of the socio-political integrity are the overarching goals of the management of active killing events. Strategic incident priorities are to stop the killing and to save as much lives as possible. The early identification and prioritised transportation of casualties with life-threatening non-controllable bleeding are major tasks and the shortest possible on-scene time is an important requirement with respect to safety issues. Conclusion With respect to hazard prevention tactics within Germany, we attributed the highest priority impact to the bullet points. The focus of the process has now shifted to intense work about possible solutions for the identified deficits and implementation strategies of such solutions during mass killing incidents.}, language = {en} } @article{TanoeyBaechleBrenneretal.2022, author = {Tanoey, Justine and Baechle, Christina and Brenner, Hermann and Deckert, Andreas and Fricke, Julia and G{\"u}nther, Kathrin and Karch, Andr{\´e} and Keil, Thomas and Kluttig, Alexander and Leitzmann, Michael and Mikolajczyk, Rafael and Obi, Nadia and Pischon, Tobias and Schikowski, Tamara and Schipf, Sabine M. and Schulze, Matthias B. and Sedlmeier, Anja and Moreno Vel{\´a}squez, Ilais and Weber, Katharina S. and V{\"o}lzke, Henry and Ahrens, Wolfgang and Gastell, Sylvia and Holleczek, Bernd and J{\"o}ckel, Karl-Heinz and Katzke, Verena and Lieb, Wolfgang and Michels, Karin B. and Schmidt, B{\"o}rge and Teismann, Henning and Becher, Heiko}, title = {Birth order, Caesarean section, or daycare attendance in relation to child- and adult-onset type 1 diabetes: results from the German National Cohort}, series = {International Journal of Environmental Research and Public Health}, volume = {19}, journal = {International Journal of Environmental Research and Public Health}, number = {17}, issn = {1660-4601}, doi = {10.3390/ijerph191710880}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-286216}, year = {2022}, abstract = {(1) Background: Global incidence of type 1 diabetes (T1D) is rising and nearly half occurred in adults. However, it is unclear if certain early-life childhood T1D risk factors were also associated with adult-onset T1D. This study aimed to assess associations between birth order, delivery mode or daycare attendance and type 1 diabetes (T1D) risk in a population-based cohort and whether these were similar for childhood- and adult-onset T1D (cut-off age 15); (2) Methods: Data were obtained from the German National Cohort (NAKO Gesundheitsstudie) baseline assessment. Self-reported diabetes was classified as T1D if: diagnosis age ≤ 40 years and has been receiving insulin treatment since less than one year after diagnosis. Cox regression was applied for T1D risk analysis; (3) Results: Analyses included 101,411 participants (100 childhood- and 271 adult-onset T1D cases). Compared to "only-children", HRs for second- or later-born individuals were 0.70 (95\% CI = 0.50-0.96) and 0.65 (95\% CI = 0.45-0.94), respectively, regardless of parental diabetes, migration background, birth year and perinatal factors. In further analyses, higher birth order reduced T1D risk in children and adults born in recent decades. Caesarean section and daycare attendance showed no clear associations with T1D risk; (4) Conclusions: Birth order should be considered in both children and adults' T1D risk assessment for early detection.}, language = {en} } @article{HaederSchaeubleGehlenetal.2023, author = {H{\"a}der, Antje and Sch{\"a}uble, Sascha and Gehlen, Jan and Thielemann, Nadja and Buerfent, Benedikt C. and Sch{\"u}ller, Vitalia and Hess, Timo and Wolf, Thomas and Schr{\"o}der, Julia and Weber, Michael and H{\"u}nniger, Kerstin and L{\"o}ffler, J{\"u}rgen and Vylkova, Slavena and Panagiotou, Gianni and Schumacher, Johannes and Kurzai, Oliver}, title = {Pathogen-specific innate immune response patterns are distinctly affected by genetic diversity}, series = {Nature Communications}, volume = {14}, journal = {Nature Communications}, doi = {10.1038/s41467-023-38994-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357441}, year = {2023}, abstract = {Innate immune responses vary by pathogen and host genetics. We analyze quantitative trait loci (eQTLs) and transcriptomes of monocytes from 215 individuals stimulated by fungal, Gram-negative or Gram-positive bacterial pathogens. We identify conserved monocyte responses to bacterial pathogens and a distinct antifungal response. These include 745 response eQTLs (reQTLs) and corresponding genes with pathogen-specific effects, which we find first in samples of male donors and subsequently confirm for selected reQTLs in females. reQTLs affect predominantly upregulated genes that regulate immune response via e.g., NOD-like, C-type lectin, Toll-like and complement receptor-signaling pathways. Hence, reQTLs provide a functional explanation for individual differences in innate response patterns. Our identified reQTLs are also associated with cancer, autoimmunity, inflammatory and infectious diseases as shown by external genome-wide association studies. Thus, reQTLs help to explain interindividual variation in immune response to infection and provide candidate genes for variants associated with a range of diseases.}, language = {en} } @article{GroebnerWorstWeischenfeldtetal.2018, author = {Gr{\"o}bner, Susanne N. and Worst, Barbara C. and Weischenfeldt, Joachim and Buchhalter, Ivo and Kleinheinz, Kortine and Rudneva, Vasilisa A. and Johann, Pascal D. and Balasubramanian, Gnana Prakash and Segura-Wang, Maia and Brabetz, Sebastian and Bender, Sebastian and Hutter, Barbara and Sturm, Dominik and Pfaff, Elke and H{\"u}bschmann, Daniel and Zipprich, Gideon and Heinold, Michael and Eils, J{\"u}rgen and Lawerenz, Christian and Erkek, Serap and Lambo, Sander and Waszak, Sebastian and Blattmann, Claudia and Borkhardt, Arndt and Kuhlen, Michaela and Eggert, Angelika and Fulda, Simone and Gessler, Manfred and Wegert, Jenny and Kappler, Roland and Baumhoer, Daniel and Stefan, Burdach and Kirschner-Schwabe, Renate and Kontny, Udo and Kulozik, Andreas E. and Lohmann, Dietmar and Hettmer, Simone and Eckert, Cornelia and Bielack, Stefan and Nathrath, Michaela and Niemeyer, Charlotte and Richter, G{\"u}nther H. and Schulte, Johannes and Siebert, Reiner and Westermann, Frank and Molenaar, Jan J. and Vassal, Gilles and Witt, Hendrik and Burkhardt, Birgit and Kratz, Christian P. and Witt, Olaf and van Tilburg, Cornelis M. and Kramm, Christof M. and Fleischhack, Gudrun and Dirksen, Uta and Rutkowski, Stefan and Fr{\"u}hwald, Michael and Hoff, Katja von and Wolf, Stephan and Klingebeil, Thomas and Koscielniak, Ewa and Landgraf, Pablo and Koster, Jan and Resnick, Adam C. and Zhang, Jinghui and Liu, Yanling and Zhou, Xin and Waanders, Angela J. and Zwijnenburg, Danny A. and Raman, Pichai and Brors, Benedikt and Weber, Ursula D. and Northcott, Paul A. and Pajtler, Kristian W. and Kool, Marcel and Piro, Rosario M. and Korbel, Jan O. and Schlesner, Matthias and Eils, Roland and Jones, David T. W. and Lichter, Peter and Chavez, Lukas and Zapatka, Marc and Pfister, Stefan M.}, title = {The landscape of genomic alterations across childhood cancers}, series = {Nature}, volume = {555}, journal = {Nature}, organization = {ICGC PedBrain-Seq Project, ICGC MMML-Seq Project,}, doi = {10.1038/nature25480}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229579}, pages = {321-327}, year = {2018}, abstract = {Pan-cancer analyses that examine commonalities and differences among various cancer types have emerged as a powerful way to obtain novel insights into cancer biology. Here we present a comprehensive analysis of genetic alterations in a pan-cancer cohort including 961 tumours from children, adolescents, and young adults, comprising 24 distinct molecular types of cancer. Using a standardized workflow, we identified marked differences in terms of mutation frequency and significantly mutated genes in comparison to previously analysed adult cancers. Genetic alterations in 149 putative cancer driver genes separate the tumours into two classes: small mutation and structural/copy-number variant (correlating with germline variants). Structural variants, hyperdiploidy, and chromothripsis are linked to TP53 mutation status and mutational signatures. Our data suggest that 7-8\% of the children in this cohort carry an unambiguous predisposing germline variant and that nearly 50\% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials.}, language = {en} }