TY - JOUR A1 - El-Helou, Sabine M. A1 - Biegner, Anika-Kerstin A1 - Bode, Sebastian A1 - Ehl, Stephan R. A1 - Heeg, Maximilian A1 - Maccari, Maria E. A1 - Ritterbusch, Henrike A1 - Speckmann, Carsten A1 - Rusch, Stephan A1 - Scheible, Raphael A1 - Warnatz, Klaus A1 - Atschekzei, Faranaz A1 - Beider, Renata A1 - Ernst, Diana A1 - Gerschmann, Stev A1 - Jablonka, Alexandra A1 - Mielke, Gudrun A1 - Schmidt, Reinhold E. A1 - Schürmann, Gesine A1 - Sogkas, Georgios A1 - Baumann, Ulrich H. A1 - Klemann, Christian A1 - Viemann, Dorothee A1 - Bernuth, Horst von A1 - Krüger, Renate A1 - Hanitsch, Leif G. A1 - Scheibenbogen, Carmen M. A1 - Wittke, Kirsten A1 - Albert, Michael H. A1 - Eichinger, Anna A1 - Hauck, Fabian A1 - Klein, Christoph A1 - Rack-Hoch, Anita A1 - Sollinger, Franz M. A1 - Avila, Anne A1 - Borte, Michael A1 - Borte, Stephan A1 - Fasshauer, Maria A1 - Hauenherm, Anja A1 - Kellner, Nils A1 - Müller, Anna H. A1 - Ülzen, Anett A1 - Bader, Peter A1 - Bakhtiar, Shahrzad A1 - Lee, Jae-Yun A1 - Heß, Ursula A1 - Schubert, Ralf A1 - Wölke, Sandra A1 - Zielen, Stefan A1 - Ghosh, Sujal A1 - Laws, Hans-Juergen A1 - Neubert, Jennifer A1 - Oommen, Prasad T. A1 - Hönig, Manfred A1 - Schulz, Ansgar A1 - Steinmann, Sandra A1 - Klaus, Schwarz A1 - Dückers, Gregor A1 - Lamers, Beate A1 - Langemeyer, Vanessa A1 - Niehues, Tim A1 - Shai, Sonu A1 - Graf, Dagmar A1 - Müglich, Carmen A1 - Schmalzing, Marc T. A1 - Schwaneck, Eva C. A1 - Tony, Hans-Peter A1 - Dirks, Johannes A1 - Haase, Gabriele A1 - Liese, Johannes G. A1 - Morbach, Henner A1 - Foell, Dirk A1 - Hellige, Antje A1 - Wittkowski, Helmut A1 - Masjosthusmann, Katja A1 - Mohr, Michael A1 - Geberzahn, Linda A1 - Hedrich, Christian M. A1 - Müller, Christiane A1 - Rösen-Wolff, Angela A1 - Roesler, Joachim A1 - Zimmermann, Antje A1 - Behrends, Uta A1 - Rieber, Nikolaus A1 - Schauer, Uwe A1 - Handgretinger, Rupert A1 - Holzer, Ursula A1 - Henes, Jörg A1 - Kanz, Lothar A1 - Boesecke, Christoph A1 - Rockstroh, Jürgen K. A1 - Schwarze-Zander, Carolynne A1 - Wasmuth, Jan-Christian A1 - Dilloo, Dagmar A1 - Hülsmann, Brigitte A1 - Schönberger, Stefan A1 - Schreiber, Stefan A1 - Zeuner, Rainald A1 - Ankermann, Tobias A1 - Bismarck, Philipp von A1 - Huppertz, Hans-Iko A1 - Kaiser-Labusch, Petra A1 - Greil, Johann A1 - Jakoby, Donate A1 - Kulozik, Andreas E. A1 - Metzler, Markus A1 - Naumann-Bartsch, Nora A1 - Sobik, Bettina A1 - Graf, Norbert A1 - Heine, Sabine A1 - Kobbe, Robin A1 - Lehmberg, Kai A1 - Müller, Ingo A1 - Herrmann, Friedrich A1 - Horneff, Gerd A1 - Klein, Ariane A1 - Peitz, Joachim A1 - Schmidt, Nadine A1 - Bielack, Stefan A1 - Groß-Wieltsch, Ute A1 - Classen, Carl F. A1 - Klasen, Jessica A1 - Deutz, Peter A1 - Kamitz, Dirk A1 - Lassy, Lisa A1 - Tenbrock, Klaus A1 - Wagner, Norbert A1 - Bernbeck, Benedikt A1 - Brummel, Bastian A1 - Lara-Villacanas, Eusebia A1 - Münstermann, Esther A1 - Schneider, Dominik T. A1 - Tietsch, Nadine A1 - Westkemper, Marco A1 - Weiß, Michael A1 - Kramm, Christof A1 - Kühnle, Ingrid A1 - Kullmann, Silke A1 - Girschick, Hermann A1 - Specker, Christof A1 - Vinnemeier-Laubenthal, Elisabeth A1 - Haenicke, Henriette A1 - Schulz, Claudia A1 - Schweigerer, Lothar A1 - Müller, Thomas G. A1 - Stiefel, Martina A1 - Belohradsky, Bernd H. A1 - Soetedjo, Veronika A1 - Kindle, Gerhard A1 - Grimbacher, Bodo T1 - The German national registry of primary immunodeficiencies (2012-2017) JF - Frontiers in Immunology N2 - Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs. Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel. Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1-25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0-88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE-syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%-subcutaneous; 29%-intravenous; 1%-unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy. Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment. KW - registry for primary immunodeficiency KW - primary immunodeficiency (PID) KW - German PID-NET registry KW - PID prevalence KW - European Society for Immunodeficiencies (ESID) KW - IgG substitution therapy KW - CVID Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226629 VL - 10 ER - TY - JOUR A1 - Redlich, Sarah A1 - Zhang, Jie A1 - Benjamin, Caryl A1 - Dhillon, Maninder Singh A1 - Englmeier, Jana A1 - Ewald, Jörg A1 - Fricke, Ute A1 - Ganuza, Cristina A1 - Haensel, Maria A1 - Hovestadt, Thomas A1 - Kollmann, Johannes A1 - Koellner, Thomas A1 - Kübert‐Flock, Carina A1 - Kunstmann, Harald A1 - Menzel, Annette A1 - Moning, Christoph A1 - Peters, Wibke A1 - Riebl, Rebekka A1 - Rummler, Thomas A1 - Rojas‐Botero, Sandra A1 - Tobisch, Cynthia A1 - Uhler, Johannes A1 - Uphus, Lars A1 - Müller, Jörg A1 - Steffan‐Dewenter, Ingolf T1 - Disentangling effects of climate and land use on biodiversity and ecosystem services—A multi‐scale experimental design JF - Methods in Ecology and Evolution N2 - Climate and land-use change are key drivers of environmental degradation in the Anthropocene, but too little is known about their interactive effects on biodiversity and ecosystem services. Long-term data on biodiversity trends are currently lacking. Furthermore, previous ecological studies have rarely considered climate and land use in a joint design, did not achieve variable independence or lost statistical power by not covering the full range of environmental gradients. Here, we introduce a multi-scale space-for-time study design to disentangle effects of climate and land use on biodiversity and ecosystem services. The site selection approach coupled extensive GIS-based exploration (i.e. using a Geographic information system) and correlation heatmaps with a crossed and nested design covering regional, landscape and local scales. Its implementation in Bavaria (Germany) resulted in a set of study plots that maximise the potential range and independence of environmental variables at different spatial scales. Stratifying the state of Bavaria into five climate zones (reference period 1981–2010) and three prevailing land-use types, that is, near-natural, agriculture and urban, resulted in 60 study regions (5.8 × 5.8 km quadrants) covering a mean annual temperature gradient of 5.6–9.8°C and a spatial extent of ~310 × 310 km. Within these regions, we nested 180 study plots located in contrasting local land-use types, that is, forests, grasslands, arable land or settlement (local climate gradient 4.5–10°C). This approach achieved low correlations between climate and land use (proportional cover) at the regional and landscape scale with |r ≤ 0.33| and |r ≤ 0.29| respectively. Furthermore, using correlation heatmaps for local plot selection reduced potentially confounding relationships between landscape composition and configuration for plots located in forests, arable land and settlements. The suggested design expands upon previous research in covering a significant range of environmental gradients and including a diversity of dominant land-use types at different scales within different climatic contexts. It allows independent assessment of the relative contribution of multi-scale climate and land use on biodiversity and ecosystem services. Understanding potential interdependencies among global change drivers is essential to develop effective restoration and mitigation strategies against biodiversity decline, especially in expectation of future climatic changes. Importantly, this study also provides a baseline for long-term ecological monitoring programs. KW - study design KW - biodiversity KW - climate change KW - ecosystem functioning KW - insect monitoring KW - land use KW - space-for-time approach KW - spatial scales Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-258270 VL - 13 IS - 2 ER - TY - JOUR A1 - Schilbach, Karin A1 - Alkhaled, Mohammed A1 - Welker, Christian A1 - Eckert, Franziska A1 - Blank, Gregor A1 - Ziegler, Hendrik A1 - Sterk, Marco A1 - Müller, Friederike A1 - Sonntag, Katja A1 - Wieder, Thomas A1 - Braumüller, Heidi A1 - Schmitt, Julia A1 - Eyrich, Matthias A1 - Schleicher, Sabine A1 - Seitz, Christian A1 - Erbacher, Annika A1 - Pichler, Bernd J. A1 - Müller, Hartmut A1 - Tighe, Robert A1 - Lim, Annick A1 - Gillies, Stephen D. A1 - Strittmatter, Wolfgang A1 - Röcken, Martin A1 - Handgretinger, Rupert T1 - Cancer-targeted IL-12 controls human rhabdomyosarcoma by senescence induction and myogenic differentiation JF - OncoImmunology N2 - Stimulating the immune system to attack cancer is a promising approach, even for the control of advanced cancers. Several cytokines that promote interferon-γ-dominated immune responses show antitumor activity, with interleukin 12 (IL-12) being of major importance. Here, we used an antibody-IL-12 fusion protein (NHS-IL12) that binds histones of necrotic cells to treat human sarcoma in humanized mice. Following sarcoma engraftment, NHS-IL12 therapy was combined with either engineered IL-7 (FcIL-7) or IL-2 (IL-2MAB602) for continuous cytokine bioavailability. NHS-IL12 strongly induced innate and adaptive antitumor immunity when combined with IL-7 or IL-2. NHS-IL12 therapy significantly improved survival of sarcoma-bearing mice and caused long-term remissions when combined with IL-2. NHS-IL12 induced pronounced cancer cell senescence, as documented by strong expression of senescence-associated p16\(^{INK4a}\) and nuclear translocation of p-HP1γ, and permanent arrest of cancer cell proliferation. In addition, this cancer immunotherapy initiated the induction of myogenic differentiation, further promoting the hypothesis that efficient antitumor immunity includes mechanisms different from cytotoxicity for efficient cancer control in vivo. KW - TH17 cells KW - cancer-targeted IL-12 KW - differentiation KW - humanized mice KW - immunocytokine KW - immunotherapy KW - M1/M2 macrophages KW - rhabdomyosarcoma KW - TH1-induced senescence KW - tumor-infiltrating lymphocytes Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-154579 VL - 4 IS - 7 ER - TY - JOUR A1 - Müller, J. G. A1 - Stahl-Hennig, Christiane A1 - Rethwilm, Axel A1 - Kneitz, C. A1 - Kerkau, Thomas A1 - Schmauser, B. A1 - Schindler, C A1 - Krenn, V. A1 - terMeulen, V. A1 - Müller-Hermelink, H.K. T1 - Morphologische Untersuchungen von Lymphknoten und Thymusin der Frühphase der SIV-Infektion bei Rhesus-Affen T1 - Morpholoical alterations of lymph nodes and thymus during the early course of SIV infection of rhesus monkeys N2 - Rhesus monkeys (M. mulatta) were i. v. infected with SIV mac251. Three phases of lymph node changes were observed. 1: physiological follicular hyperplasia (3 and 6 weeks p.i.). 2: Alterations of germinal centers: loss of follicular mantle zone, fragmentation or sclerosis (12 and 24 weeks p.i.). 3: Partial depletion of T-lymphocytes, accumulation of plasma cells, increased numbers of syncytial giant cells, hemophgocytosis in the sinuses (about 1 year p.i.). The thymus of the juvenile animals showed first changes 12 and 24 weeks after infection with focalloss of immature (and Ki-67 positive) cortical thymocytes, leading to severe accidental involution of the thymuses one year after infection and reduced numbers of Hassalls corpuscles. These investigations show the value of this animal model for the study of morphology and pathogenesis of AIDS. KW - Affenimmundefizienzvirus Y1 - 1991 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-47183 ER - TY - JOUR A1 - Lagler, Charlotte A1 - El-Mesery, Mohamed A1 - Kübler, Alexander Christian A1 - Müller-Richter, Urs Dietmar Achim A1 - Stühmer, Thorsten A1 - Nickel, Joachim A1 - Müller, Thomas Dieter A1 - Wajant, Harald A1 - Seher, Axel T1 - The anti-myeloma activity of bone morphogenetic protein 2 predominantly relies on the induction of growth arrest and is apoptosis-independent JF - PLoS ONE N2 - Multiple myeloma (MM), a malignancy of the bone marrow, is characterized by a pathological increase in antibody-producing plasma cells and an increase in immunoglobulins (plasmacytosis). In recent years, bone morphogenetic proteins (BMPs) have been reported to be activators of apoptotic cell death in neoplastic B cells in MM. Here, we use bone morphogenetic protein 2 (BMP2) to show that the "apoptotic" effect of BMPs on human neoplastic B cells is dominated by anti-proliferative activities and cell cycle arrest and is apoptosis-independent. The anti-proliferative effect of BMP2 was analysed in the human cell lines KMS12-BM and L363 using WST-1 and a Coulter counter and was confirmed using CytoTox assays with established inhibitors of programmed cell death (zVAD-fmk and necrostatin-1). Furthermore, apoptotic activity was compared in both cell lines employing western blot analysis for caspase 3 and 8 in cells treated with BMP2 and FasL. Additionally, expression profiles of marker genes of different cell death pathways were analysed in both cell lines after stimulation with BMP2 for 48h using an RT-PCR-based array. In our experiments we observed that there was rather no reduction in absolute cell number, but cells stopped proliferating following treatment with BMP2 instead. The time frame (48–72 h) after BMP2 treatment at which a reduction in cell number is detectable is too long to indicate a directly BMP2-triggered apoptosis. Moreover, in comparison to robust apoptosis induced by the approved apoptotic factor FasL, BMP2 only marginally induced cell death. Consistently, neither the known inhibitor of apoptotic cell death zVAD-fmk nor the necroptosis inhibitor necrostatin-1 was able to rescue myeloma cell growth in the presence of BMP2. KW - apoptosis KW - gene expression KW - necrotic cell death KW - multiple myeloma KW - cell metabolism KW - cell cycle and cell division KW - B cells Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158993 VL - 12 IS - 10 ER - TY - JOUR A1 - Seher, Axel A1 - Lagler, Charlotte A1 - Stühmer, Thorsten A1 - Müller-Richter, Urs Dietmar Achim A1 - Kübler, Alexander Christian A1 - Sebald, Walter A1 - Müller, Thomas Dieter A1 - Nickel, Joachim T1 - Utilizing BMP-2 muteins for treatment of multiple myeloma JF - PLoS ONE N2 - Multiple myeloma (MM) represents a haematological cancer characterized by the pathological hyper proliferation of antibody-producing B-lymphocytes. Patients typically suffer from kidney malfunction and skeletal disorders. In the context of MM, the transforming growth factor β (TGFβ) member Activin A was recently identified as a promoter of both accompanying symptoms. Because studies have shown that bone morphogenetic protein (BMP)-2-mediated activities are counteracted by Activin A, we analysed whether BMP2, which also binds to the Activin A receptors ActRII and ActRIIB but activates the alternative SMAD-1/5/8 pathway, can be used to antagonize Activin A activities, such as in the context of MM. Therefore three BMP2 derivatives were generated with modified binding activities for the type II (ActRIIB) and/or type I receptor (BMPRIA) showing either increased or decreased BMP2 activity. In the context of MM these BMP2 muteins show two functionalities since they act as a) an anti-proliferative/apoptotic agent against neoplastic B-cells, b) as a bone-formation promoting growth factor. The molecular basis of both activities was shown in two different cellular models to clearly rely on the properties of the investigated BMP2 muteins to compete for the binding of Activin A to the Activin type II receptors. The experimental outcome suggests new therapeutic strategies using BMP2 variants in the treatment of MM-related pathologies. KW - multiple myeloma KW - signaling KW - cell proliferation KW - cell binding KW - membrane receptor signaling KW - BMP KW - gene expression KW - B cell receptors KW - B cells Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158144 VL - 12 IS - 5 ER - TY - JOUR A1 - Schümann, Franziska Lea A1 - Groß, Elisabeth A1 - Bauer, Marcus A1 - Rohde, Christian A1 - Sandmann, Sarah A1 - Terziev, Denis A1 - Müller, Lutz P. A1 - Posern, Guido A1 - Wienke, Andreas A1 - Fend, Falko A1 - Hansmann, Martin-Leo A1 - Klapper, Wolfram A1 - Rosenwald, Andreas A1 - Stein, Harald A1 - Dugas, Martin A1 - Müller-Tidow, Carsten A1 - Wickenhauser, Claudia A1 - Binder, Mascha A1 - Weber, Thomas T1 - Divergent effects of EZH1 and EZH2 protein expression on the prognosis of patients with T-cell lymphomas JF - Biomedicines N2 - 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. KW - T-cell non-Hodgkin's lymphomas KW - PTCL KW - epigenetics KW - EZH1 KW - EZH2 KW - H3K27me3 KW - immunohistochemistry KW - next generation sequencing Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-252155 SN - 2227-9059 VL - 9 IS - 12 ER - TY - JOUR A1 - Herrmann, Andreas B. A1 - Müller, Martha‐Lena A1 - Orth, Martin F. A1 - Müller, Jörg P. A1 - Zernecke, Alma A1 - Hochhaus, Andreas A1 - Ernst, Thomas A1 - Butt, Elke A1 - Frietsch, Jochen J. T1 - Knockout of LASP1 in CXCR4 expressing CML cells promotes cell persistence, proliferation and TKI resistance JF - Journal of Cellular and Molecular Medicine N2 - Chronic myeloid leukaemia (CML) is a clonal myeloproliferative stem cell disorder characterized by the constitutively active BCR‐ABL tyrosine kinase. The LIM and SH3 domain protein 1 (LASP1) has recently been identified as a novel BCR‐ABL substrate and is associated with proliferation, migration, tumorigenesis and chemoresistance in several cancers. Furthermore, LASP1 was shown to bind to the chemokine receptor 4 (CXCR4), thought to be involved in mechanisms of relapse. In order to identify potential LASP1‐mediated pathways and related factors that may help to further eradicate minimal residual disease (MRD), the effect of LASP1 on processes involved in progression and maintenance of CML was investigated. The present data indicate that not only overexpression of CXCR4, but also knockout of LASP1 contributes to proliferation, reduced apoptosis and migration as well as increased adhesive potential of K562 CML cells. Furthermore, LASP1 depletion in K562 CML cells leads to decreased cytokine release and reduced NK cell‐mediated cytotoxicity towards CML cells. Taken together, these results indicate that in CML, reduced levels of LASP1 alone and in combination with high CXCR4 expression may contribute to TKI resistance. KW - BCR‐ABL KW - CML KW - CXCR4 KW - LASP1 KW - nilotinib KW - precursor cells Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-214122 VL - 24 IS - 5 SP - 2942 EP - 2955 ER - TY - JOUR A1 - Müller, Joachim A1 - Brill, Stefan A1 - Hagen, Rudolf A1 - Moeltner, Alexander A1 - Brockmeier, Steffi-Johanna A1 - Stark, Thomas A1 - Helbig, Silke A1 - Maurer, Jan A1 - Zahnert, Thomas A1 - Zierhofer, Clemens A1 - Nopp, Peter A1 - Anderson, Ilona T1 - Clinical Trial Results with the MED-EL Fine Structure Processing Coding Strategy in Experienced Cochlear Implant Users JF - ORL N2 - Objectives: To assess the subjective and objective performance of the new fine structure processing strategy (FSP) compared to the previous generation coding strategies CIS+ and HDCIS. Methods: Forty-six adults with a minimum of 6 months of cochlear implant experience were included. CIS+, HDCIS and FSP were compared in speech perception tests in noise, pitch scaling and questionnaires. The randomized tests were performed acutely (interval 1) and again after 3 months of FSP experience (interval 3). The subjective evaluation included questionnaire 1 at intervals 1 and 3, and questionnaire 2 at interval 2, 1 month after interval 1. Results: Comparison between FSP and CIS+ showed that FSP performed at least as well as CIS+ in all speech perception tests, and outperformed CIS+ in vowel and monosyllabic word discrimination. Comparison between FSP and HDCIS showed that both performed equally well in all speech perception tests. Pitch scaling showed that FSP performed at least as well as HDCIS. With FSP, sound quality was at least as good and often better than with HDCIS. Conclusions: Results indicate that FSP performs better than CIS+ in vowel and monosyllabic word understanding. Subjective evaluation demonstrates strong user preferences for FSP when listening to speech and music. KW - pitch KW - CIS+ KW - OPUS KW - fine structure processing KW - cochlear implant KW - coding strategy KW - speech perception KW - music Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196396 SN - 0301-1569 SN - 1423-0275 N1 - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively. VL - 74 IS - 4 ER - TY - JOUR A1 - Davis, Lea K. A1 - Yu, Dongmei A1 - Keenan, Clare L. A1 - Gamazon, Eric R. A1 - Konkashbaev, Anuar I. A1 - Derks, Eske M. A1 - Neale, Benjamin M. A1 - Yang, Jian A1 - Lee, S. Hong A1 - Evans, Patrick A1 - Barr, Cathy L. A1 - Bellodi, Laura A1 - Benarroch, Fortu A1 - Berrio, Gabriel Bedoya A1 - Bienvenu, Oscar J. A1 - Bloch, Michael H. A1 - Blom, Rianne M. A1 - Bruun, Ruth D. A1 - Budman, Cathy L. A1 - Camarena, Beatriz A1 - Campbell, Desmond A1 - Cappi, Carolina A1 - Cardona Silgado, Julio C. A1 - Cath, Danielle C. A1 - Cavallini, Maria C. A1 - Chavira, Denise A. A1 - Chouinard, Sylvian A1 - Conti, David V. A1 - Cook, Edwin H. A1 - Coric, Vladimir A1 - Cullen, Bernadette A. A1 - Deforce, Dieter A1 - Delorme, Richard A1 - Dion, Yves A1 - Edlund, Christopher K. A1 - Egberts, Karin A1 - Falkai, Peter A1 - Fernandez, Thomas V. A1 - Gallagher, Patience J. A1 - Garrido, Helena A1 - Geller, Daniel A1 - Girard, Simon L. A1 - Grabe, Hans J. A1 - Grados, Marco A. A1 - Greenberg, Benjamin D. A1 - Gross-Tsur, Varda A1 - Haddad, Stephen A1 - Heiman, Gary A. A1 - Hemmings, Sian M. J. A1 - Hounie, Ana G. A1 - Illmann, Cornelia A1 - Jankovic, Joseph A1 - Jenike, Micheal A. A1 - Kennedy, James L. A1 - King, Robert A. A1 - Kremeyer, Barbara A1 - Kurlan, Roger A1 - Lanzagorta, Nuria A1 - Leboyer, Marion A1 - Leckman, James F. A1 - Lennertz, Leonhard A1 - Liu, Chunyu A1 - Lochner, Christine A1 - Lowe, Thomas L. A1 - Macciardi, Fabio A1 - McCracken, James T. A1 - McGrath, Lauren M. A1 - Restrepo, Sandra C. Mesa A1 - Moessner, Rainald A1 - Morgan, Jubel A1 - Muller, Heike A1 - Murphy, Dennis L. A1 - Naarden, Allan L. A1 - Ochoa, William Cornejo A1 - Ophoff, Roel A. A1 - Osiecki, Lisa A1 - Pakstis, Andrew J. A1 - Pato, Michele T. A1 - Pato, Carlos N. A1 - Piacentini, John A1 - Pittenger, Christopher A1 - Pollak, Yehunda A1 - Rauch, Scott L. A1 - Renner, Tobias J. A1 - Reus, Victor I. A1 - Richter, Margaret A. A1 - Riddle, Mark A. A1 - Robertson, Mary M. A1 - Romero, Roxana A1 - Rosàrio, Maria C. A1 - Rosenberg, David A1 - Rouleau, Guy A. A1 - Ruhrmann, Stephan A1 - Ruiz-Linares, Andreas A1 - Sampaio, Aline S. A1 - Samuels, Jack A1 - Sandor, Paul A1 - Sheppard, Broke A1 - Singer, Harvey S. A1 - Smit, Jan H. A1 - Stein, Dan J. A1 - Strengman, E. A1 - Tischfield, Jay A. A1 - Valencia Duarte, Ana V. A1 - Vallada, Homero A1 - Van Nieuwerburgh, Flip A1 - Veenstra-VanderWeele, Jeremy A1 - Walitza, Susanne A1 - Wang, Ying A1 - Wendland, Jens R. A1 - Westenberg, Herman G. M. A1 - Shugart, Yin Yao A1 - Miguel, Euripedes C. A1 - McMahon, William A1 - Wagner, Michael A1 - Nicolini, Humberto A1 - Posthuma, Danielle A1 - Hanna, Gregory L. A1 - Heutink, Peter A1 - Denys, Damiaan A1 - Arnold, Paul D. A1 - Oostra, Ben A. A1 - Nestadt, Gerald A1 - Freimer, Nelson B. A1 - Pauls, David L. A1 - Wray, Naomi R. A1 - Stewart, S. Evelyn A1 - Mathews, Carol A. A1 - Knowles, James A. A1 - Cox, Nancy J. A1 - Scharf, Jeremiah M. T1 - Partitioning the Heritability of Tourette Syndrome and Obsessive Compulsive Disorder Reveals Differences in Genetic Architecture JF - PLoS Genetics N2 - The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for 21% of the TS heritability and 0% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. The results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures. KW - TIC disorders KW - missing heritability KW - complex diseases KW - neuropsychiatric disorders KW - common SNPS KW - gilles KW - family KW - brain KW - expression KW - autism Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-127377 SN - 1553-7390 VL - 9 IS - 10 ER - TY - JOUR A1 - Boivin, Valérie A1 - Beyersdorf, Niklas A1 - Palm, Dieter A1 - Nikolaev, Viacheslav O. A1 - Schlipp, Angela A1 - Müller, Justus A1 - Schmidt, Doris A1 - Kocoski, Vladimir A1 - Kerkau, Thomas A1 - Hünig, Thomas A1 - Ertl, Georg A1 - Lohse, Martin J. A1 - Jahns, Roland T1 - Novel Receptor-Derived Cyclopeptides to Treat Heart Failure Caused by \(Anti-β_1-Adrenoceptor\) Antibodies in a Human-Analogous Rat Model JF - PLoS One N2 - Despite recent therapeutic advances the prognosis of heart failure remains poor. Recent research suggests that heart failure is a heterogeneous syndrome and that many patients have stimulating auto-antibodies directed against the second extracellular loop of the \(β_1\) adrenergic receptor \((β_1EC2)\). In a human-analogous rat model such antibodies cause myocyte damage and heart failure. Here we used this model to test a novel antibody-directed strategy aiming to prevent and/or treat antibody-induced cardiomyopathy. To generate heart failure, we immunised n = 76/114 rats with a fusion protein containing the human β1EC2 (amino-acids 195–225) every 4 weeks; n = 38/114 rats were control-injected with 0.9% NaCl. Intravenous application of a novel cyclic peptide mimicking \(β_1EC2\) (\(β_1EC2-CP\), 1.0 mg/kg every 4 weeks) or administration of the \(β_1-blocker\) bisoprolol (15 mg/kg/day orally) was initiated either 6 weeks (cardiac function still normal, prevention-study, n = 24 (16 treated vs. 8 untreated)) or 8.5 months after the 1st immunisation (onset of cardiomyopathy, therapy-study, n = 52 (40 treated vs. 12 untreated)); n = 8/52 rats from the therapy-study received \(β_1EC2-CP/bisoprolol\) co-treatment. We found that \(β_1EC2-CP\) prevented and (alone or as add-on drug) treated antibody-induced cardiac damage in the rat, and that its efficacy was superior to mono-treatment with bisoprolol, a standard drug in heart failure. While bisoprolol mono-therapy was able to stop disease-progression, \(β_1EC2-CP\) mono-therapy -or as an add-on to bisoprolol- almost fully reversed antibody-induced cardiac damage. The cyclo¬peptide acted both by scavenging free \(anti-β_1EC2-antibodies\) and by targeting \(β_1EC2\)-specific memory B-cells involved in antibody-production. Our model provides the basis for the clinical translation of a novel double-acting therapeutic strategy that scavenges harmful \(anti-β_1EC2-antibodies\) and also selectively depletes memory B-cells involved in the production of such antibodies. Treatment with immuno-modulating cyclopeptides alone or as an add-on to \(β_1\)-blockade represents a promising new therapeutic option in immune-mediated heart failure. KW - memory B cells KW - antibodies KW - T cells KW - B cells KW - heart KW - heart failure KW - kidneys KW - enzyme-linked immunoassays Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126028 VL - 10 IS - 2 ER - TY - JOUR A1 - Merget, Benjamin A1 - Koetschan, Christian A1 - Hackl, Thomas A1 - Förster, Frank A1 - Dandekar, Thomas A1 - Müller, Tobias A1 - Schultz, Jörg A1 - Wolf, Matthias T1 - The ITS2 Database JF - Journal of Visual Expression N2 - The internal transcribed spacer 2 (ITS2) has been used as a phylogenetic marker for more than two decades. As ITS2 research mainly focused on the very variable ITS2 sequence, it confined this marker to low-level phylogenetics only. However, the combination of the ITS2 sequence and its highly conserved secondary structure improves the phylogenetic resolution1 and allows phylogenetic inference at multiple taxonomic ranks, including species delimitation. The ITS2 Database presents an exhaustive dataset of internal transcribed spacer 2 sequences from NCBI GenBank accurately reannotated. Following an annotation by profile Hidden Markov Models (HMMs), the secondary structure of each sequence is predicted. First, it is tested whether a minimum energy based fold (direct fold) results in a correct, four helix conformation. If this is not the case, the structure is predicted by homology modeling. In homology modeling, an already known secondary structure is transferred to another ITS2 sequence, whose secondary structure was not able to fold correctly in a direct fold. The ITS2 Database is not only a database for storage and retrieval of ITS2 sequence-structures. It also provides several tools to process your own ITS2 sequences, including annotation, structural prediction, motif detection and BLAST search on the combined sequence-structure information. Moreover, it integrates trimmed versions of 4SALE and ProfDistS for multiple sequence-structure alignment calculation and Neighbor Joining tree reconstruction. Together they form a coherent analysis pipeline from an initial set of sequences to a phylogeny based on sequence and secondary structure. In a nutshell, this workbench simplifies first phylogenetic analyses to only a few mouse-clicks, while additionally providing tools and data for comprehensive large-scale analyses. KW - homology modeling KW - molecular systematics KW - internal transcribed spacer 2 KW - alignment KW - genetics KW - secondary structure KW - ribosomal RNA KW - phylogenetic tree KW - phylogeny Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124600 VL - 61 IS - e3806 ER - TY - JOUR A1 - Kneitz, Christian A1 - Kerkau, Thomas A1 - Müller, Justus A1 - Coulibaly, Cheick A1 - Stahl-Henning, Christiane A1 - Hunsmann, Gerhard A1 - Hünig, Thomas A1 - Schimpl, Anneliese T1 - Early phenotypic and functional alterations in lymphocytes from simian immunodeficiency virus infected macaques N2 - Phenotypic and functional changes in lymphocytes from rhesus monkeys (Macaca mulatta) were investigated during the first 6 months after infection with SIVmac 32H. Animals preimmunized with keyhole limpet hemocyanin (KLH) were sacrificed l, 3, 6, 12, and 24 weeks post infection. Subset composition and function of lymphocytes from blood, spleen, lymph node and thymus were analysed. In addition to a rapid decline in CD4/CD8 ratios, a massive reduction in CD29+CD4+ cells was seen in the periphery. Although depletion of this subset was observed throughout the course of this experiment, the loss of proliferative T cell responses was most pronounced very early after infection and partially recovered after Month 3. Polyclonal cytotoxic responses were only slightly affected. In the thymus, a gradual, but moderate loss of CD4 + CD8 + immature thymocytes, and a relative increase in both CD4 + and CD8 + mature subsets was observed. Infectious virus was readily recovered from homogenates of lymph node and spleen, but not of thymus tissue. Interestingly, however, virus was detected in thymocytes from all infected animals by cocultivation with a simian immunodeficiency virus (SIV) susceptible cell line. Y1 - 1993 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-32593 ER - TY - JOUR A1 - Guhn, Anne A1 - Dresler, Thomas A1 - Andreatta, Marta A1 - Müller, Laura D. A1 - Hahn, Tim A1 - Tupak, Sara V. A1 - Polak, Thomas A1 - Deckert, Jürgen A1 - Herrmann, Martin J. T1 - Medial prefrontal cortex stimulation modulates the processing of conditioned fear N2 - The extinction of conditioned fear depends on an efficient interplay between the amygdala and the medial prefrontal cortex (mPFC). In rats, high-frequency electrical mPFC stimulation has been shown to improve extinction by means of a reduction of amygdala activity. However, so far it is unclear whether stimulation of homologues regions in humans might have similar beneficial effects. Healthy volunteers received one session of either active or sham repetitive transcranial magnetic stimulation (rTMS) covering the mPFC while undergoing a 2-day fear conditioning and extinction paradigm. Repetitive TMS was applied offline after fear acquisition in which one of two faces (CS+ but not CS−) was associated with an aversive scream (UCS). Immediate extinction learning (day 1) and extinction recall (day 2) were conducted without UCS delivery. Conditioned responses (CR) were assessed in a multimodal approach using fear-potentiated startle (FPS), skin conductance responses (SCR), functional near-infrared spectroscopy (fNIRS), and self-report scales. Consistent with the hypothesis of a modulated processing of conditioned fear after high-frequency rTMS, the active group showed a reduced CS+/CS− discrimination during extinction learning as evident in FPS as well as in SCR and arousal ratings. FPS responses to CS+ further showed a linear decrement throughout both extinction sessions. This study describes the first experimental approach of influencing conditioned fear by using rTMS and can thus be a basis for future studies investigating a complementation of mPFC stimulation to cognitive behavioral therapy (CBT). KW - fear conditioning KW - memory consolidation and extinction KW - learning KW - transcranial magnetic stimulation (TMS) KW - medial prefrontal cortex (mPFC) Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-111309 ER - TY - JOUR A1 - Hebestreit, Helge A1 - Zeidler, Cornelia A1 - Schippers, Christopher A1 - de Zwaan, Martina A1 - Deckert, Jürgen A1 - Heuschmann, Peter A1 - Krauth, Christian A1 - Bullinger, Monika A1 - Berger, Alexandra A1 - Berneburg, Mark A1 - Brandstetter, Lilly A1 - Deibele, Anna A1 - Dieris-Hirche, Jan A1 - Graessner, Holm A1 - Gündel, Harald A1 - Herpertz, Stephan A1 - Heuft, Gereon A1 - Lapstich, Anne-Marie A1 - Lücke, Thomas A1 - Maisch, Tim A1 - Mundlos, Christine A1 - Petermann-Meyer, Andrea A1 - Müller, Susanne A1 - Ott, Stephan A1 - Pfister, Lisa A1 - Quitmann, Julia A1 - Romanos, Marcel A1 - Rutsch, Frank A1 - Schaubert, Kristina A1 - Schubert, Katharina A1 - Schulz, Jörg B. A1 - Schweiger, Susann A1 - Tüscher, Oliver A1 - Ungethüm, Kathrin A1 - Wagner, Thomas O. F. A1 - Haas, Kirsten T1 - Dual guidance structure for evaluation of patients with unclear diagnosis in centers for rare diseases (ZSE-DUO): study protocol for a controlled multi-center cohort study JF - Orphanet Journal of Rare Diseases N2 - Background In individuals suffering from a rare disease the diagnostic process and the confirmation of a final diagnosis often extends over many years. Factors contributing to delayed diagnosis include health care professionals' limited knowledge of rare diseases and frequent (co-)occurrence of mental disorders that may complicate and delay the diagnostic process. The ZSE-DUO study aims to assess the benefits of a combination of a physician focusing on somatic aspects with a mental health expert working side by side as a tandem in the diagnostic process. Study design This multi-center, prospective controlled study has a two-phase cohort design. Methods Two cohorts of 682 patients each are sequentially recruited from 11 university-based German Centers for Rare Diseases (CRD): the standard care cohort (control, somatic expertise only) and the innovative care cohort (experimental, combined somatic and mental health expertise). Individuals aged 12 years and older presenting with symptoms and signs which are not explained by current diagnoses will be included. Data will be collected prior to the first visit to the CRD’s outpatient clinic (T0), at the first visit (T1) and 12 months thereafter (T2). Outcomes Primary outcome is the percentage of patients with one or more confirmed diagnoses covering the symptomatic spectrum presented. Sample size is calculated to detect a 10 percent increase from 30% in standard care to 40% in the innovative dual expert cohort. Secondary outcomes are (a) time to diagnosis/diagnoses explaining the symptomatology; (b) proportion of patients successfully referred from CRD to standard care; (c) costs of diagnosis including incremental cost effectiveness ratios; (d) predictive value of screening instruments administered at T0 to identify patients with mental disorders; (e) patients’ quality of life and evaluation of care; and f) physicians’ satisfaction with the innovative care approach. Conclusions This is the first multi-center study to investigate the effects of a mental health specialist working in tandem with a somatic expert physician in CRDs. If this innovative approach proves successful, it will be made available on a larger scale nationally and promoted internationally. In the best case, ZSE-DUO can significantly shorten the time to diagnosis for a suspected rare disease. KW - rare diseases KW - multi‑center cohort study KW - dual guidance Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300440 VL - 17 IS - 1 ER - TY - JOUR A1 - Steiner, Thomas A1 - Zachary, Marie A1 - Bauer, Susanne A1 - Müller, Martin J. A1 - Krischke, Markus A1 - Radziej, Sandra A1 - Klepsch, Maximilian A1 - Huettel, Bruno A1 - Eisenreich, Wolfgang A1 - Rudel, Thomas A1 - Beier, Dagmar T1 - Central Role of Sibling Small RNAs NgncR_162 and NgncR_163 in Main Metabolic Pathways of Neisseria gonorrhoeae JF - mBio N2 - Small bacterial regulatory RNAs (sRNAs) have been implicated in the regulation of numerous metabolic pathways. In most of these studies, sRNA-dependent regulation of mRNAs or proteins of enzymes in metabolic pathways has been predicted to affect the metabolism of these bacteria. However, only in a very few cases has the role in metabolism been demonstrated. Here, we performed a combined transcriptome and metabolome analysis to define the regulon of the sibling sRNAs NgncR_162 and NgncR_163 (NgncR_162/163) and their impact on the metabolism of Neisseria gonorrhoeae. These sRNAs have been reported to control genes of the citric acid and methylcitric acid cycles by posttranscriptional negative regulation. By transcriptome analysis, we now expand the NgncR_162/163 regulon by several new members and provide evidence that the sibling sRNAs act as both negative and positive regulators of target gene expression. Newly identified NgncR_162/163 targets are mostly involved in transport processes, especially in the uptake of glycine, phenylalanine, and branched-chain amino acids. NgncR_162/163 also play key roles in the control of serine-glycine metabolism and, hence, probably affect biosyntheses of nucleotides, vitamins, and other amino acids via the supply of one-carbon (C\(_1\)) units. Indeed, these roles were confirmed by metabolomics and metabolic flux analysis, which revealed a bipartite metabolic network with glucose degradation for the supply of anabolic pathways and the usage of amino acids via the citric acid cycle for energy metabolism. Thus, by combined deep RNA sequencing (RNA-seq) and metabolomics, we significantly extended the regulon of NgncR_162/163 and demonstrated the role of NgncR_162/163 in the regulation of central metabolic pathways of the gonococcus. KW - sRNA KW - Neisseria gonorrhoeae KW - posttranscriptional regulation KW - amino acid transporter KW - bipartite metabolism Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-313323 VL - 14 ER - TY - JOUR A1 - Sommerfeld, Andreas A1 - Senf, Cornelius A1 - Buma, Brian A1 - D'Amato, Anthony W. A1 - Després, Tiphaine A1 - Díaz-Hormazábal, Ignacio A1 - Fraver, Shawn A1 - Frelich, Lee E. A1 - Gutiérrez, Álvaro G. A1 - Hart, Sarah J. A1 - Harvey, Brian J. A1 - He, Hong S. A1 - Hlásny, Tomáš A1 - Holz, Andrés A1 - Kitzberger, Thomas A1 - Kulakowski, Dominik A1 - Lindenmayer, David A1 - Mori, Akira S. A1 - Müller, Jörg A1 - Paritsis, Juan A1 - Perry, George L. W. A1 - Stephens, Scott L. A1 - Svoboda, Miroslav A1 - Turner, Monica G. A1 - Veblen, Thomas T. A1 - Seidl, Rupert T1 - Patterns and drivers of recent disturbances across the temperate forest biome JF - Nature Communications N2 - Increasing evidence indicates that forest disturbances are changing in response to global change, yet local variability in disturbance remains high. We quantified this considerable variability and analyzed whether recent disturbance episodes around the globe were consistently driven by climate, and if human influence modulates patterns of forest disturbance. We combined remote sensing data on recent (2001–2014) disturbances with in-depth local information for 50 protected landscapes and their surroundings across the temperate biome. Disturbance patterns are highly variable, and shaped by variation in disturbance agents and traits of prevailing tree species. However, high disturbance activity is consistently linked to warmer and drier than average conditions across the globe. Disturbances in protected areas are smaller and more complex in shape compared to their surroundings affected by human land use. This signal disappears in areas with high recent natural disturbance activity, underlining the potential of climate-mediated disturbance to transform forest landscapes. KW - forest ecology KW - forestry Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239157 VL - 9 ER - TY - JOUR A1 - Dornelas, Maria A1 - Antão, Laura H. A1 - Moyes, Faye A1 - Bates, Amanda E. A1 - Magurran, Anne E. A1 - Adam, Dušan A1 - Akhmetzhanova, Asem A. A1 - Appeltans, Ward A1 - Arcos, José Manuel A1 - Arnold, Haley A1 - Ayyappan, Narayanan A1 - Badihi, Gal A1 - Baird, Andrew H. A1 - Barbosa, Miguel A1 - Barreto, Tiago Egydio A1 - Bässler, Claus A1 - Bellgrove, Alecia A1 - Belmaker, Jonathan A1 - Benedetti-Cecchi, Lisandro A1 - Bett, Brian J. A1 - Bjorkman, Anne D. A1 - Błażewicz, Magdalena A1 - Blowes, Shane A. A1 - Bloch, Christopher P. Bloch A1 - Bonebrake, Timothy C. A1 - Boyd, Susan A1 - Bradford, Matt A1 - Brooks, Andrew J. A1 - Brown, James H. A1 - Bruelheide, Helge A1 - Budy, Phaedra A1 - Carvalho, Fernando A1 - Castañeda-Moya, Edward A1 - Chen, Chaolun Allen A1 - Chamblee, John F. A1 - Chase, Tory J. A1 - Siegwart Collier, Laura A1 - Collinge, Sharon K. A1 - Condit, Richard A1 - Cooper, Elisabeth J. A1 - Cornelissen, J. Hans C. A1 - Cotano, Unai A1 - Crow, Shannan Kyle A1 - Damasceno, Gabriella A1 - Davies, Claire H. A1 - Davis, Robert A. A1 - Day, Frank P. A1 - Degraer, Steven A1 - Doherty, Tim S. A1 - Dunn, Timothy E. A1 - Durigan, Giselda A1 - Duffy, J. Emmett A1 - Edelist, Dor A1 - Edgar, Graham J. A1 - Elahi, Robin A1 - Elmendorf, Sarah C. A1 - Enemar, Anders A1 - Ernest, S. K. Morgan A1 - Escribano, Rubén A1 - Estiarte, Marc A1 - Evans, Brian S. A1 - Fan, Tung-Yung A1 - Turini Farah, Fabiano A1 - Loureiro Fernandes, Luiz A1 - Farneda, Fábio Z. A1 - Fidelis, Alessandra A1 - Fitt, Robert A1 - Fosaa, Anna Maria A1 - Franco, Geraldo Antonio Daher Correa A1 - Frank, Grace E. A1 - Fraser, William R. A1 - García, Hernando A1 - Cazzolla Gatti, Roberto A1 - Givan, Or A1 - Gorgone-Barbosa, Elizabeth A1 - Gould, William A. A1 - Gries, Corinna A1 - Grossman, Gary D. A1 - Gutierréz, Julio R. A1 - Hale, Stephen A1 - Harmon, Mark E. A1 - Harte, John A1 - Haskins, Gary A1 - Henshaw, Donald L. A1 - Hermanutz, Luise A1 - Hidalgo, Pamela A1 - Higuchi, Pedro A1 - Hoey, Andrew A1 - Van Hoey, Gert A1 - Hofgaard, Annika A1 - Holeck, Kristen A1 - Hollister, Robert D. A1 - Holmes, Richard A1 - Hoogenboom, Mia A1 - Hsieh, Chih-hao A1 - Hubbell, Stephen P. A1 - Huettmann, Falk A1 - Huffard, Christine L. A1 - Hurlbert, Allen H. A1 - Ivanauskas, Natália Macedo A1 - Janík, David A1 - Jandt, Ute A1 - Jażdżewska, Anna A1 - Johannessen, Tore A1 - Johnstone, Jill A1 - Jones, Julia A1 - Jones, Faith A. M. A1 - Kang, Jungwon A1 - Kartawijaya, Tasrif A1 - Keeley, Erin C. A1 - Kelt, Douglas A. A1 - Kinnear, Rebecca A1 - Klanderud, Kari A1 - Knutsen, Halvor A1 - Koenig, Christopher C. A1 - Kortz, Alessandra R. A1 - Král, Kamil A1 - Kuhnz, Linda A. A1 - Kuo, Chao-Yang A1 - Kushner, David J. A1 - Laguionie-Marchais, Claire A1 - Lancaster, Lesley T. A1 - Lee, Cheol Min A1 - Lefcheck, Jonathan S. A1 - Lévesque, Esther A1 - Lightfoot, David A1 - Lloret, Francisco A1 - Lloyd, John D. A1 - López-Baucells, Adrià A1 - Louzao, Maite A1 - Madin, Joshua S. A1 - Magnússon, Borgþór A1 - Malamud, Shahar A1 - Matthews, Iain A1 - McFarland, Kent P. A1 - McGill, Brian A1 - McKnight, Diane A1 - McLarney, William O. A1 - Meador, Jason A1 - Meserve, Peter L. A1 - Metcalfe, Daniel J. A1 - Meyer, Christoph F. J. A1 - Michelsen, Anders A1 - Milchakova, Nataliya A1 - Moens, Tom A1 - Moland, Even A1 - Moore, Jon A1 - Moreira, Carolina Mathias A1 - Müller, Jörg A1 - Murphy, Grace A1 - Myers-Smith, Isla H. A1 - Myster, Randall W. A1 - Naumov, Andrew A1 - Neat, Francis A1 - Nelson, James A. A1 - Nelson, Michael Paul A1 - Newton, Stephen F. A1 - Norden, Natalia A1 - Oliver, Jeffrey C. A1 - Olsen, Esben M. A1 - Onipchenko, Vladimir G. A1 - Pabis, Krzysztof A1 - Pabst, Robert J. A1 - Paquette, Alain A1 - Pardede, Sinta A1 - Paterson, David M. A1 - Pélissier, Raphaël A1 - Peñuelas, Josep A1 - Pérez-Matus, Alejandro A1 - Pizarro, Oscar A1 - Pomati, Francesco A1 - Post, Eric A1 - Prins, Herbert H. T. A1 - Priscu, John C. A1 - Provoost, Pieter A1 - Prudic, Kathleen L. A1 - Pulliainen, Erkki A1 - Ramesh, B. R. A1 - Ramos, Olivia Mendivil A1 - Rassweiler, Andrew A1 - Rebelo, Jose Eduardo A1 - Reed, Daniel C. A1 - Reich, Peter B. A1 - Remillard, Suzanne M. A1 - Richardson, Anthony J. A1 - Richardson, J. Paul A1 - van Rijn, Itai A1 - Rocha, Ricardo A1 - Rivera-Monroy, Victor H. A1 - Rixen, Christian A1 - Robinson, Kevin P. A1 - Rodrigues, Ricardo Ribeiro A1 - de Cerqueira Rossa-Feres, Denise A1 - Rudstam, Lars A1 - Ruhl, Henry A1 - Ruz, Catalina S. A1 - Sampaio, Erica M. A1 - Rybicki, Nancy A1 - Rypel, Andrew A1 - Sal, Sofia A1 - Salgado, Beatriz A1 - Santos, Flavio A. M. A1 - Savassi-Coutinho, Ana Paula A1 - Scanga, Sara A1 - Schmidt, Jochen A1 - Schooley, Robert A1 - Setiawan, Fakhrizal A1 - Shao, Kwang-Tsao A1 - Shaver, Gaius R. A1 - Sherman, Sally A1 - Sherry, Thomas W. A1 - Siciński, Jacek A1 - Sievers, Caya A1 - da Silva, Ana Carolina A1 - da Silva, Fernando Rodrigues A1 - Silveira, Fabio L. A1 - Slingsby, Jasper A1 - Smart, Tracey A1 - Snell, Sara J. A1 - Soudzilovskaia, Nadejda A. A1 - Souza, Gabriel B. G. A1 - Souza, Flaviana Maluf A1 - Souza, Vinícius Castro A1 - Stallings, Christopher D. A1 - Stanforth, Rowan A1 - Stanley, Emily H. A1 - Sterza, José Mauro A1 - Stevens, Maarten A1 - Stuart-Smith, Rick A1 - Suarez, Yzel Rondon A1 - Supp, Sarah A1 - Tamashiro, Jorge Yoshio A1 - Tarigan, Sukmaraharja A1 - Thiede, Gary P. A1 - Thorn, Simon A1 - Tolvanen, Anne A1 - Toniato, Maria Teresa Zugliani A1 - Totland, Ørjan A1 - Twilley, Robert R. A1 - Vaitkus, Gediminas A1 - Valdivia, Nelson A1 - Vallejo, Martha Isabel A1 - Valone, Thomas J. A1 - Van Colen, Carl A1 - Vanaverbeke, Jan A1 - Venturoli, Fabio A1 - Verheye, Hans M. A1 - Vianna, Marcelo A1 - Vieira, Rui P. A1 - Vrška, Tomáš A1 - Vu, Con Quang A1 - Vu, Lien Van A1 - Waide, Robert B. A1 - Waldock, Conor A1 - Watts, Dave A1 - Webb, Sara A1 - Wesołowski, Tomasz A1 - White, Ethan P. A1 - Widdicombe, Claire E. A1 - Wilgers, Dustin A1 - Williams, Richard A1 - Williams, Stefan B. A1 - Williamson, Mark A1 - Willig, Michael R. A1 - Willis, Trevor J. A1 - Wipf, Sonja A1 - Woods, Kerry D. A1 - Woehler, Eric J. A1 - Zawada, Kyle A1 - Zettler, Michael L. T1 - BioTIME: A database of biodiversity time series for the Anthropocene JF - Global Ecology and Biogeography N2 - Motivation The BioTIME database contains raw data on species identities and abundances in ecological assemblages through time. These data enable users to calculate temporal trends in biodiversity within and amongst assemblages using a broad range of metrics. BioTIME is being developed as a community-led open-source database of biodiversity time series. Our goal is to accelerate and facilitate quantitative analysis of temporal patterns of biodiversity in the Anthropocene. Main types of variables included The database contains 8,777,413 species abundance records, from assemblages consistently sampled for a minimum of 2 years, which need not necessarily be consecutive. In addition, the database contains metadata relating to sampling methodology and contextual information about each record. Spatial location and grain BioTIME is a global database of 547,161 unique sampling locations spanning the marine, freshwater and terrestrial realms. Grain size varies across datasets from 0.0000000158 km2 (158 cm2) to 100 km2 (1,000,000,000,000 cm2). Time period and grain BioTIME records span from 1874 to 2016. The minimal temporal grain across all datasets in BioTIME is a year. Major taxa and level of measurement BioTIME includes data from 44,440 species across the plant and animal kingdoms, ranging from plants, plankton and terrestrial invertebrates to small and large vertebrates. Software format .csv and .SQL. KW - biodiversity KW - global KW - spatial KW - species richness KW - temporal KW - turnover Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-222846 VL - 27 ER - TY - JOUR A1 - Blättner, Sebastian A1 - Das, Sudip A1 - Paprotka, Kerstin A1 - Eilers, Ursula A1 - Krischke, Markus A1 - Kretschmer, Dorothee A1 - Remmele, Christian W. A1 - Dittrich, Marcus A1 - Müller, Tobias A1 - Schuelein-Voelk, Christina A1 - Hertlein, Tobias A1 - Mueller, Martin J. A1 - Huettel, Bruno A1 - Reinhardt, Richard A1 - Ohlsen, Knut A1 - Rudel, Thomas A1 - Fraunholz, Martin J. T1 - Staphylococcus aureus Exploits a Non-ribosomal Cyclic Dipeptide to Modulate Survival within Epithelial Cells and Phagocytes JF - PLoS Pathogens N2 - Community-acquired (CA) Staphylococcus aureus cause various diseases even in healthy individuals. Enhanced virulence of CA-strains is partly attributed to increased production of toxins such as phenol-soluble modulins (PSM). The pathogen is internalized efficiently by mammalian host cells and intracellular S. aureus has recently been shown to contribute to disease. Upon internalization, cytotoxic S. aureus strains can disrupt phagosomal membranes and kill host cells in a PSM-dependent manner. However, PSM are not sufficient for these processes. Here we screened for factors required for intracellular S. aureus virulence. We infected escape reporter host cells with strains from an established transposon mutant library and detected phagosomal escape rates using automated microscopy. We thereby, among other factors, identified a non-ribosomal peptide synthetase (NRPS) to be required for efficient phagosomal escape and intracellular survival of S. aureus as well as induction of host cell death. By genetic complementation as well as supplementation with the synthetic NRPS product, the cyclic dipeptide phevalin, wild-type phenotypes were restored. We further demonstrate that the NRPS is contributing to virulence in a mouse pneumonia model. Together, our data illustrate a hitherto unrecognized function of the S. aureus NRPS and its dipeptide product during S. aureus infection. KW - cell death KW - cytotoxicity KW - Staphylococcus aureus KW - host cells KW - neutrophils KW - macrophages KW - transposable elements KW - epithelial cells Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-180380 VL - 12 IS - 9 ER - TY - JOUR A1 - Schneider, Eberhard A1 - El Hajj, Nady A1 - Müller, Fabian A1 - Navarro, Bianca A1 - Haaf, Thomas T1 - Epigenetic Dysregulation in the Prefrontal Cortex of Suicide Completers JF - Cytogenetic and Genome Research N2 - The epigenome is thought to mediate between genes and the environment, particularly in response to adverse life experiences. Similar to other psychiatric diseases, the suicide liability of an individual appears to be influenced by many genetic factors of small effect size as well as by environmental stressors. To identify epigenetic marks associated with suicide, which is considered the endpoint of complex gene-environment interactions, we compared the cortex DNA methylation patterns of 6 suicide completers versus 6 non-psychiatric sudden-death controls, using Illumina 450K methylation arrays. Consistent with a multifactorial disease model, we found DNA methylation changes in a large number of genes, but no changes with large effects reaching genome-wide significance. Global methylation of all analyzed CpG sites was significantly (0.25 percentage point) lower in suicide than in control brains, whereas the vast majority (97%) of the top 1,000 differentially methylated regions (DMRs) were higher methylated (0.6 percentage point) in suicide brains. Annotation analysis of the top 1,000 DMRs revealed an enrichment of differentially methylated promoters in functional categories associated with transcription and expression in the brain. In addition, we performed a comprehensive literature research to identify suicide genes that have been replicated in independent genetic association, brain methylation and/or expression studies. Although, in general, there was no significant overlap between different published data sets or between our top 1,000 DMRs and published data sets, our methylation screen strengthens a number of candidate genes (APLP2, BDNF, HTR1A, NUAK1, PHACTR3, MSMP, SLC6A4, SYN2, and SYNE2) and supports a role for epigenetics in the pathophysiology of suicide. KW - Cortex KW - DNA methylation KW - Suicidal behavior KW - Transcription regulation Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-199032 SN - 1424-8581 SN - 1424-859X VL - 146 IS - 1 ER - TY - JOUR A1 - Maierhofer, Anna A1 - Flunkert, Julia A1 - Oshima, Junko A1 - Martin, George M. A1 - Poot, Martin A1 - Nanda, Indrajit A1 - Dittrich, Marcus A1 - Müller, Tobias A1 - Haaf, Thomas T1 - Epigenetic signatures of Werner syndrome occur early in life and are distinct from normal epigenetic aging processes JF - Aging Cell N2 - Werner Syndrome (WS) is an adult‐onset segmental progeroid syndrome. Bisulfite pyrosequencing of repetitive DNA families revealed comparable blood DNA methylation levels between classical (18 WRN‐mutant) or atypical WS (3 LMNA‐mutant and 3 POLD1‐mutant) patients and age‐ and sex‐matched controls. WS was not associated with either age‐related accelerated global losses of ALU, LINE1, and α‐satellite DNA methylations or gains of rDNA methylation. Single CpG methylation was analyzed with Infinium MethylationEPIC arrays. In a correspondence analysis, atypical WS samples clustered together with the controls and were clearly separated from classical WS, consistent with distinct epigenetic pathologies. In classical WS, we identified 659 differentially methylated regions (DMRs) comprising 3,656 CpG sites and 613 RefSeq genes. The top DMR was located in the HOXA4 promoter. Additional DMR genes included LMNA, POLD1, and 132 genes which have been reported to be differentially expressed in WRN‐mutant/depleted cells. DMRs were enriched in genes with molecular functions linked to transcription factor activity and sequence‐specific DNA binding to promoters transcribed by RNA polymerase II. We propose that transcriptional misregulation of downstream genes by the absence of WRN protein contributes to the variable premature aging phenotypes of WS. There were no CpG sites showing significant differences in DNA methylation changes with age between WS patients and controls. Genes with both WS‐ and age‐related methylation changes exhibited a constant offset of methylation between WRN‐mutant patients and controls across the entire analyzed age range. WS‐specific epigenetic signatures occur early in life and do not simply reflect an acceleration of normal epigenetic aging processes. KW - (classical and atypical) Werner syndrome KW - bisulfite pyrosequencing KW - methylation array KW - premature aging KW - segmental progeria KW - transcription deficiency Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202733 VL - 18 ER - TY - JOUR A1 - El Hajj, Nady A1 - Dittrich, Marcus A1 - Böck, Julia A1 - Kraus, Theo F. J. A1 - Nanda, Indrajit A1 - Müller, Tobias A1 - Seidmann, Larissa A1 - Tralau, Tim A1 - Galetzka, Danuta A1 - Schneider, Eberhard A1 - Haaf, Thomas T1 - Epigenetic dysregulation in the developing Down syndrome cortex JF - Epigenetics N2 - Using Illumina 450K arrays, 1.85% of all analyzed CpG sites were significantly hypermethylated and 0.31% hypomethylated in fetal Down syndrome (DS) cortex throughout the genome. The methylation changes on chromosome 21 appeared to be balanced between hypo- and hyper-methylation, whereas, consistent with prior reports, all other chromosomes showed 3-11times more hyper- than hypo-methylated sites. Reduced NRSF/REST expression due to upregulation of DYRK1A (on chromosome 21q22.13) and methylation of REST binding sites during early developmental stages may contribute to this genome-wide excess of hypermethylated sites. Upregulation of DNMT3L (on chromosome 21q22.4) could lead to de novo methylation in neuroprogenitors, which then persists in the fetal DS brain where DNMT3A and DNMT3B become downregulated. The vast majority of differentially methylated promoters and genes was hypermethylated in DS and located outside chromosome 21, including the protocadherin gamma (PCDHG) cluster on chromosome 5q31, which is crucial for neural circuit formation in the developing brain. Bisulfite pyrosequencing and targeted RNA sequencing showed that several genes of PCDHG subfamilies A and B are hypermethylated and transcriptionally downregulated in fetal DS cortex. Decreased PCDHG expression is expected to reduce dendrite arborization and growth in cortical neurons. Since constitutive hypermethylation of PCDHG and other genes affects multiple tissues, including blood, it may provide useful biomarkers for DS brain development and pharmacologic targets for therapeutic interventions. KW - trisomy 21 KW - DNA methylation KW - Down syndrome KW - fetal brain development KW - frontal cortex KW - protocadherin gamma cluster Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-191239 VL - 11 IS - 8 ER - TY - JOUR A1 - Tony, Hans-Peter A1 - Burmester, Gerd A1 - Schulze-Koops, Hendrik A1 - Grunke, Mathias A1 - Henes, Joerg A1 - Kötter, Ina A1 - Haas, Judith A1 - Unger, Leonore A1 - Lovric, Svjetlana A1 - Haubitz, Marion A1 - Fischer-Betz, Rebecca A1 - Chehab, Gamal A1 - Rubbert-Roth, Andrea A1 - Specker, Christof A1 - Weinerth, Jutta A1 - Holle, Julia A1 - Müller-Ladner, Ulf A1 - König, Ramona A1 - Fiehn, Christoph A1 - Burgwinkel, Philip A1 - Budde, Klemens A1 - Sörensen, Helmut A1 - Meurer, Michael A1 - Aringer, Martin A1 - Kieseier, Bernd A1 - Erfurt-Berge, Cornelia A1 - Sticherling, Michael A1 - Veelken, Roland A1 - Ziemann, Ulf A1 - Strutz, Frank A1 - von Wussow, Praxis A1 - Meier, Florian MP A1 - Hunzelmann, Nico A1 - Schmidt, Enno A1 - Bergner, Raoul A1 - Schwarting, Andreas A1 - Eming, Rüdiger A1 - Schwarz-Eywill, Michael A1 - Wassenberg, Siegfried A1 - Fleck, Martin A1 - Metzler, Claudia A1 - Zettl, Uwe A1 - Westphal, Jens A1 - Heitmann, Stefan A1 - Herzog, Anna L. A1 - Wiendl, Heinz A1 - Jakob, Waltraud A1 - Schmidt, Elvira A1 - Freivogel, Klaus A1 - Dörner, Thomas A1 - Hertl, Michael A1 - Stadler, Rudolf T1 - Safety and clinical outcomes of rituximab therapy in patients with different autoimmune diseases: experience from a national registry (GRAID) JF - Arthritis Research & Therapy N2 - Introduction: Evidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard-of-care. The objective of this study was to evaluate the safety and clinical outcomes of rituximab in several standard-of-care-refractory autoimmune diseases (within rheumatology, nephrology, dermatology and neurology) other than rheumatoid arthritis or non-Hodgkin’s lymphoma in a real-life clinical setting. Methods: Patients who received rituximab having shown an inadequate response to standard-of-care had their safety and clinical outcomes data retrospectively analysed as part of the German Registry of Autoimmune Diseases. The main outcome measures were safety and clinical response, as judged at the discretion of the investigators. Results: A total of 370 patients (299 patient-years) with various autoimmune diseases (23.0% with systemic lupus erythematosus, 15.7% antineutrophil cytoplasmic antibody-associated granulomatous vasculitides, 15.1% multiple sclerosis and 10.0% pemphigus) from 42 centres received a mean dose of 2,440 mg of rituximab over a median (range) of 194 (180 to 1,407) days. The overall rate of serious infections was 5.3 per 100 patient-years during rituximab therapy. Opportunistic infections were infrequent across the whole study population, and mostly occurred in patients with systemic lupus erythematosus. There were 11 deaths (3.0% of patients) after rituximab treatment (mean 11.6 months after first infusion, range 0.8 to 31.3 months), with most of the deaths caused by infections. Overall (n = 293), 13.3% of patients showed no response, 45.1% showed a partial response and 41.6% showed a complete response. Responses were also reflected by reduced use of glucocorticoids and various immunosuppressives during rituximab therapy and follow-up compared with before rituximab. Rituximab generally had a positive effect on patient well-being (physician’s visual analogue scale; mean improvement from baseline of 12.1 mm) KW - GRAID Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-142856 VL - 13 IS - R75 ER - TY - JOUR A1 - Schneider, Eberhard A1 - Dittrich, Marcus A1 - Böck, Julia A1 - Nanda, Indrajit A1 - Müller, Tobias A1 - Seidmann, Larissa A1 - Tralau, Tim A1 - Galetzka, Danuta A1 - El Hajj, Nady A1 - Haaf, Thomas T1 - CpG sites with continuously increasing or decreasing methylation from early to late human fetal brain development JF - Gene N2 - Normal human brain development is dependent on highly dynamic epigenetic processes for spatial and temporal gene regulation. Recent work identified wide-spread changes in DNA methylation during fetal brain development. We profiled CpG methylation in frontal cortex of 27 fetuses from gestational weeks 12-42, using Illumina 450K methylation arrays. Sites showing genome-wide significant correlation with gestational age were compared to a publicly available data set from gestational weeks 3-26. Altogether, we identified 2016 matching developmentally regulated differentially methylated positions (m-dDMPs): 1767 m-dDMPs were hypermethylated and 1149 hypomethylated during fetal development. M-dDMPs are underrepresented in CpG islands and gene promoters, and enriched in gene bodies. They appear to cluster in certain chromosome regions. M-dDMPs are significantly enriched in autism-associated genes and CpGs. Our results promote the idea that reduced methylation dynamics during fetal brain development may predispose to autism. In addition, m-dDMPs are enriched in genes with human-specific brain expression patterns and/or histone modifications. Collectively, we defined a subset of dDMPs exhibiting constant methylation changes from early to late pregnancy. The same epigenetic mechanisms involving methylation changes in cis-regulatory regions may have been adopted for human brain evolution and ontogeny. KW - Autism spectrum disorders KW - DNA methylation KW - Genome KW - Autism KW - Frontal cortex KW - Human prefrontal cortex KW - Gene-expression KW - Schizophrenia KW - Patterns KW - Transcription KW - Epigenetics KW - Environment KW - Fetal brain development KW - DNA methylation dynamics KW - Methylome Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186936 VL - 592 IS - 1 ER - TY - JOUR A1 - Chopra, Martin A1 - Biehl, Marlene A1 - Steinfatt, Tim A1 - Brandl, Andreas A1 - Kums, Juliane A1 - Amich, Jorge A1 - Vaeth, Martin A1 - Kuen, Janina A1 - Holtappels, Rafaela A1 - Podlech, Jürgen A1 - Mottok, Anja A1 - Kraus, Sabrina A1 - Jordán-Garotte, Ana-Laura A1 - Bäuerlein, Carina A. A1 - Brede, Christian A1 - Ribechini, Eliana A1 - Fick, Andrea A1 - Seher, Axel A1 - Polz, Johannes A1 - Ottmueller, Katja J. A1 - Baker, Jeannette A1 - Nishikii, Hidekazu A1 - Ritz, Miriam A1 - Mattenheimer, Katharina A1 - Schwinn, Stefanie A1 - Winter, Thorsten A1 - Schäfer, Viktoria A1 - Krappmann, Sven A1 - Einsele, Hermann A1 - Müller, Thomas D. A1 - Reddehase, Matthias J. A1 - Lutz, Manfred B. A1 - Männel, Daniela N. A1 - Berberich-Siebelt, Friederike A1 - Wajant, Harald A1 - Beilhack, Andreas T1 - Exogenous TNFR2 activation protects from acute GvHD via host T reg cell expansion JF - Journal of Experimental Medicine N2 - Donor CD4\(^+\)Foxp3\(^+\) regulatory T cells (T reg cells) suppress graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HCT allo-HCT]). Current clinical study protocols rely on the ex vivo expansion of donor T reg cells and their infusion in high numbers. In this study, we present a novel strategy for inhibiting GvHD that is based on the in vivo expansion of recipient T reg cells before allo-HCT, exploiting the crucial role of tumor necrosis factor receptor 2 (TNFR2) in T reg cell biology. Expanding radiation-resistant host T reg cells in recipient mice using a mouse TNFR2-selective agonist before allo-HCT significantly prolonged survival and reduced GvHD severity in a TNFR2-and T reg cell-dependent manner. The beneficial effects of transplanted T cells against leukemia cells and infectious pathogens remained unaffected. A corresponding human TNFR2-specific agonist expanded human T reg cells in vitro. These observations indicate the potential of our strategy to protect allo-HCT patients from acute GvHD by expanding T reg cells via selective TNFR2 activation in vivo. KW - Tumor-necrosis-factor KW - Regulatory-cells KW - Bone marrow transplantantation KW - Graft-versus-leukemia KW - Rheumatoid arthritis KW - Autoimmune diseases KW - Factor receptor KW - Alpha therapy KW - Expression KW - Suppression Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187640 VL - 213 IS - 9 ER - TY - JOUR A1 - Paschke, Ralf A1 - Lincke, Thomas A1 - Müller, Stefan P. A1 - Kreissl, Michael C. A1 - Dralle, Henning A1 - Fassnacht, Martin T1 - The Treatment of Well-Differentiated Thyroid Carcinoma JF - Deutsches Ärzteblatt International N2 - Background: Recent decades have seen a rise in the incidence of well-differentiated (mainly papillary) thyroid carcinoma around the world. In Germany, the age-adjusted incidence of well-differentiated thyroid carcinoma in 2010 was 3.5 per 100 000 men and 8.7 per 100 000 women per year. Method: This review is based on randomized, controlled trials and multicenter trials on the treatment of well-differentiated thyroid carcinoma that were retrieved by a selective literature search, as well as on three updated guidelines issued in the past two years. Results: The recommended extent of surgical resection depends on whether the tumor is classified as low-risk or high-risk, so that papillary microcar cinomas, which carry a highly favorable prognosis, will not be overtreated. More than 90% of localized, well-differentiated thyroid carcinomas can be cured with a combination of surgery and radioactive iodine therapy. Radio active iodine therapy is also effective in the treatment of well-differentiated thyroid carcinomas with distant metastases, yielding a 10-year survival rate of 90%, as long as there is good iodine uptake and the tumor goes into remission after treatment; otherwise, the 10-year survival rate is only 10%. In the past two years, better treatment options have become available for radioactive-iodine-resistant thyroid carcinoma. Phase 3 studies of two different tyrosine kinase inhibitors have shown that either one can markedly prolong progression-free survival, but not overall survival. Their more common clinically significant side effects are hand-foot syndrome, hypertension, diarrhea, proteinuria, and weight loss. Conclusion: Slow tumor growth, good resectability, and susceptibility to radioactive iodine therapy lend a favorable prognosis to most cases of well-differentiated thyroid carcinoma. The treatment should be risk-adjusted and interdisciplinary, in accordance with the current treatment guidelines. Even metastatic thyroid carcinoma has a favorable prognosis as long as there is good iodine uptake. The newly available medical treatment options for radioactive-iodine-resistant disease need to be further studied. KW - BRAF(V600E) mutation KW - distant metastases KW - papillary KW - guidelines KW - surgery KW - dissection KW - management KW - association KW - cancer KW - radioiodine therapy Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151636 VL - 112 SP - 452 EP - 458 ER - TY - JOUR A1 - Oberländer, Uwe A1 - Pletinckx, Katrien A1 - Dähler, Anja A1 - Müller, Nora A1 - Lutz, Manfred A1 - Arzberger, Thomas A1 - Riederer, Peter A1 - Gerlach, Manfred A1 - Koutsilieri, Eleni A1 - Scheller, Carsten T1 - Neuromelanin is an Immune Stimulator for Dendritic Cells in vitro N2 - Background: Parkinson’s disease (PD) is characterized at the cellular level by a destruction of neuromelanin (NM)-containing dopaminergic cells and a profound reduction in striatal dopamine. It has been shown recently that antimelanin antibodies are increased in sera of Parkinson patients, suggesting that NM may act as an autoantigen. In this study we tested whether NM is being recognized by dendritic cells (DCs), the major cell type for inducing Tand B-cell responses in vivo. This recognition of NM by DCs is a prerequisite to trigger an adaptive autoimmune response directed against NM-associated structures. Results: Murine DCs were treated with NM of substantia nigra (SN) from human subjects or with synthetic dopamine melanin (DAM). DCs effectively phagocytized NM and subsequently developed a mature phenotype (CD86high/MHCIIhigh). NM-activated DCs secreted the proinflammatory cytokines IL-6 and TNF-a. In addition, they potently triggered T cell proliferation in a mixed lymphocyte reaction, showing that DC activation was functional to induce a primary T cell response. In contrast, DAM, which lacks the protein and lipid components of NM but mimics the dopamine-melanin backbone of NM, had only very little effect on DC phenotype and function. Conclusions: NM is recognized by DCs in vitro and triggers their maturation. If operative in vivo, this would allow the DC-mediated transport and presentation of SN antigens to the adaptive immune system, leading to autoimmmunity in susceptible individuals. Our data provide a rationale for an autoimmune-based pathomechanism of PD with NM as the initial trigger. KW - Immunstimulation KW - Dendritische Zelle Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-69210 ER - TY - JOUR A1 - Beisser, Daniela A1 - Grohme, Markus A. A1 - Kopka, Joachim A1 - Frohme, Marcus A1 - Schill, Ralph O. A1 - Hengherr, Steffen A1 - Dandekar, Thomas A1 - Klau, Gunnar W. A1 - Dittrich, Marcus A1 - Müller, Tobias T1 - Integrated pathway modules using time-course metabolic profiles and EST data from Milnesium tardigradum N2 - Background: Tardigrades are multicellular organisms, resistant to extreme environmental changes such as heat, drought, radiation and freezing. They outlast these conditions in an inactive form (tun) to escape damage to cellular structures and cell death. Tardigrades are apparently able to prevent or repair such damage and are therefore a crucial model organism for stress tolerance. Cultures of the tardigrade Milnesium tardigradum were dehydrated by removing the surrounding water to induce tun formation. During this process and the subsequent rehydration, metabolites were measured in a time series by GC-MS. Additionally expressed sequence tags are available, especially libraries generated from the active and inactive state. The aim of this integrated analysis is to trace changes in tardigrade metabolism and identify pathways responsible for their extreme resistance against physical stress. Results: In this study we propose a novel integrative approach for the analysis of metabolic networks to identify modules of joint shifts on the transcriptomic and metabolic levels. We derive a tardigrade-specific metabolic network represented as an undirected graph with 3,658 nodes (metabolites) and 4,378 edges (reactions). Time course metabolite profiles are used to score the network nodes showing a significant change over time. The edges are scored according to information on enzymes from the EST data. Using this combined information, we identify a key subnetwork (functional module) of concerted changes in metabolic pathways, specific for de- and rehydration. The module is enriched in reactions showing significant changes in metabolite levels and enzyme abundance during the transition. It resembles the cessation of a measurablemetabolism (e.g. glycolysis and amino acid anabolism) during the tun formation, the production of storage metabolites and bioprotectants, such as DNA stabilizers, and the generation of amino acids and cellular components from monosaccharides as carbon and energy source during rehydration. Conclusions: The functional module identifies relationships among changed metabolites (e.g. spermidine) and reactions and provides first insights into important altered metabolic pathways. With sparse and diverse data available, the presented integrated metabolite network approach is suitable to integrate all existing data and analyse it in a combined manner. KW - Milnesium tardigradum KW - Integrated network analysis KW - Functional modules KW - Metabolic profiles KW - Metabolic pathways KW - Trend test Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75241 ER - TY - JOUR A1 - Krzymanski, Maciej A1 - Waaga, Ana M. A1 - Ulrichs, Karin A1 - Deja, Aadam A1 - Oko, Andrzej A1 - Rommel, Thomas A1 - Müller-Ruchholtz, Wolfgang T1 - The influence of MHC class II antigen blockade by perfusion with a monoclonal antibody on rat renal graft survival N2 - To decrease immunogenicity of the rat kidney, grafts were perfused with an anti-MHC class li monoclonal antibody (mAb ). How effectively this procedure blocked dass li-positive cells, which were mainly dendritic in appearance, was checked by immunostaining renal sections after perfusion and comparing them with in vitro stained sections. Optimum conditions were applied for graft pretreatment before transplantation. This procedure prolonged graft survival, though not satisfactorily from the biological point ofview (9.6 ± 0.8 versus 7.7 ± 0.5 days in the control group; P < 0.02). The dendritic cells were not killed but blocked. Several hours after transplantation, the mAb dissociated from these dass li-positive cells. It was also shown that donor cells migrate into the recipient's spieen early after transplantation. The number of these cells was smaller when the transplanted organ was perfused with the mAb. Further studies are suggested to deplete the graft of donor dendritic cells more adequately. They should also combine graft perfusion with antidass II mAb and recipient immunosuppression at reduced doses. KW - Chirurgie KW - Class II antigen blockade KW - rat KW - renal transplantation KW - Monoclonal antibody KW - dass II antigen blockade Y1 - 1991 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-64431 ER - TY - JOUR A1 - Albrecht, Marco A1 - Sharma, Cynthia M. A1 - Dittrich, Marcus T. A1 - Müller, Tobias A1 - Reinhardt, Richard A1 - Vogel, Jörg A1 - Rudel, Thomas T1 - The Transcriptional Landscape of Chlamydia pneumoniae N2 - Background: Gene function analysis of the obligate intracellular bacterium Chlamydia pneumoniae is hampered by the facts that this organism is inaccessible to genetic manipulations and not cultivable outside the host. The genomes of several strains have been sequenced; however, very little information is available on the gene structure and transcriptome of C. pneumoniae. Results: Using a differential RNA-sequencing approach with specific enrichment of primary transcripts, we defined the transcriptome of purified elementary bodies and reticulate bodies of C. pneumoniae strain CWL-029; 565 transcriptional start sites of annotated genes and novel transcripts were mapped. Analysis of adjacent genes for cotranscription revealed 246 polycistronic transcripts. In total, a distinct transcription start site or an affiliation to an operon could be assigned to 862 out of 1,074 annotated protein coding genes. Semi-quantitative analysis of mapped cDNA reads revealed significant differences for 288 genes in the RNA levels of genes isolated from elementary bodies and reticulate bodies. We have identified and in part confirmed 75 novel putative non-coding RNAs. The detailed map of transcription start sites at single nucleotide resolution allowed for the first time a comprehensive and saturating analysis of promoter consensus sequences in Chlamydia. Conclusions: The precise transcriptional landscape as a complement to the genome sequence will provide new insights into the organization, control and function of genes. Novel non-coding RNAs and identified common promoter motifs will help to understand gene regulation of this important human pathogen. KW - Chlamydia pneumoniae Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-69116 ER - TY - CHAP A1 - Schwaneck, Stefan A1 - Glos, Michael A1 - Bofinger, Peter A1 - Straubhaar, Thomas A1 - Haase, Axel A1 - Pinkwart, Andreas A1 - Kunze, Mario A1 - Österle, Irene A1 - Seubert, Marc A1 - Nowak, Matthias A1 - Rosen, Holga A1 - Steinle, Andreas A1 - Schorr, Leander A1 - Fichtner, Caroline A1 - Fischl, Bernd A1 - Wittrock, Max A1 - Günther, Niclas A1 - Roth, Isabelle A1 - Verburg, Erik A1 - Sextl, Gerhard A1 - Heitmüller, Lars A1 - Müller, Norman A1 - Frashek, André A1 - Stetter, Ulrich T1 - Innovationen – Performancetreiber und nachhaltiger Wirtschaftsmotor in Deutschland? Festschrift zum 5. Würzburger Wirtschaftssymposium N2 - 5. Würzburger Wirtschaftssymposium, 20.11.2008 Deutsche Erfindungen verändern die Welt - heute wie vor 500 Jahren. Von Buchdruck, über Dieselmotor, Glühbirne bis hin zu Airbag, Aspirin, Dübel, Fernseher und mp3-Format. Alleine dieser bescheidene Überblick des Phänomens “Made in Germany” lässt den Betrachter die Bedeutung und das Potenzial von Innovationen am Standort Deutschland schnell erkennen. Experten aus Wirtschaft, Politik und Gesellschaft setzten sich am 20.11.2008 unter der Leitfrage: “Innovationen – Performancetreiber und nachhaltiger Wirtschaftsmotor in Deutschland?” mit der Bedeutung von Innovationen für den Standort Deutschland auseinander. Die Festschrift rundet - neben Interviews mit und Gastbeiträgen von Referenten der Veranstaltung - das 5. Würzburger Wirtschaftssymposium mit Stellungnahmen und Beiträgen renommierter Experten ab. Zu Wort kommen dabei Jungunternehmer ebenso wie Wissenschaftler der Universität Würzburg und Vertreter externer Organisationen. KW - Innovationsforschung KW - Innovationsmanagement KW - Innovationspotenzial KW - Sozialinnovation KW - Produktinnovation KW - Technische Innovation KW - Würzburg KW - Wirtschaft KW - Partner für Innovation KW - Entrepreneurship KW - Universität KW - economics KW - innovation KW - entrepreneurship Y1 - 2008 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-53559 SN - 978-3-923959-58-7 ER - TY - JOUR A1 - Förster, Frank A1 - Beisser, Daniela A1 - Grohme, Markus A. A1 - Liang, Chunguang A1 - Mali, Brahim A1 - Siegl, Alexander Matthias A1 - Engelmann, Julia C. A1 - Shkumatov, Alexander V. A1 - Schokraie, Elham A1 - Müller, Tobias A1 - Schnölzer, Martina A1 - Schill, Ralph O. A1 - Frohme, Marcus A1 - Dandekar, Thomas T1 - Transcriptome analysis in tardigrade species reveals specific molecular pathways for stress adaptations JF - Bioinformatics and biology insights N2 - Tardigrades have unique stress-adaptations that allow them to survive extremes of cold, heat, radiation and vacuum. To study this, encoded protein clusters and pathways from an ongoing transcriptome study on the tardigrade \(Milnesium\) \(tardigradum\) were analyzed using bioinformatics tools and compared to expressed sequence tags (ESTs) from \(Hypsibius\) \(dujardini\), revealing major pathways involved in resistance against extreme environmental conditions. ESTs are available on the Tardigrade Workbench along with software and databank updates. Our analysis reveals that RNA stability motifs for \(M.\) \(tardigradum\) are different from typical motifs known from higher animals. \(M.\) \(tardigradum\) and \(H.\) \(dujardini\) protein clusters and conserved domains imply metabolic storage pathways for glycogen, glycolipids and specific secondary metabolism as well as stress response pathways (including heat shock proteins, bmh2, and specific repair pathways). Redox-, DNA-, stress- and protein protection pathways complement specific repair capabilities to achieve the strong robustness of \(M.\) \(tardigradum\). These pathways are partly conserved in other animals and their manipulation could boost stress adaptation even in human cells. However, the unique combination of resistance and repair pathways make tardigrades and \(M.\) \(tardigradum\) in particular so highly stress resistant. KW - RNA KW - expressed sequence tag KW - cluster KW - protein familiy KW - adaption KW - tardigrada KW - transcriptome Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-123089 N1 - This is an open access article. Unrestricted non-commercial use is permitted provided the original work is properly cited. VL - 6 ER - TY - JOUR A1 - Klammert, Uwe A1 - Müller, Thomas D. A1 - Hellmann, Tina V. A1 - Wuerzler, Kristian K. A1 - Kotzsch, Alexander A1 - Schliermann, Anna A1 - Schmitz, Werner A1 - Kuebler, Alexander C. A1 - Sebald, Walter A1 - Nickel, Joachim T1 - GDF-5 can act as a context-dependent BMP-2 antagonist JF - BMC Biology N2 - Background Bone morphogenetic protein (BMP)-2 and growth and differentiation factor (GDF)-5 are two related transforming growth factor (TGF)-β family members with important functions in embryonic development and tissue homeostasis. BMP-2 is best known for its osteoinductive properties whereas GDF-5—as evident from its alternative name, cartilage derived morphogenetic protein 1—plays an important role in the formation of cartilage. In spite of these differences both factors signal by binding to the same subset of BMP receptors, raising the question how these different functionalities are generated. The largest difference in receptor binding is observed in the interaction with the type I receptor BMPR-IA. GDF-5, in contrast to BMP-2, shows preferential binding to the isoform BMPR-IB, which is abrogated by a single amino acid (A57R) substitution. The resulting variant, GDF-5 R57A, represents a “BMP-2 mimic” with respect to BMP receptor binding. In this study we thus wanted to analyze whether the two growth factors can induce distinct signals via an identically composed receptor. Results Unexpectedly and dependent on the cellular context, GDF-5 R57A showed clear differences in its activity compared to BMP-2. In ATDC-5 cells, both ligands induced alkaline phosphatase (ALP) expression with similar potency. But in C2C12 cells, the BMP-2 mimic GDF-5 R57A (and also wild-type GDF-5) clearly antagonized BMP-2-mediated ALP expression, despite signaling in both cell lines occurring solely via BMPR-IA. The BMP-2- antagonizing properties of GDF-5 and GDF-5 R57A could also be observed in vivo when implanting BMP-2 and either one of the two GDF-5 ligands simultaneously at heterotopic sites. Conclusions Although comparison of the crystal structures of the GDF-5 R57A:BMPR-IAEC- and BMP-2:BMPR-IAEC complex revealed small ligand-specific differences, these cannot account for the different signaling characteristics because the complexes seem identical in both differently reacting cell lines. We thus predict an additional component, most likely a not yet identified GDF-5-specific co-receptor, which alters the output of the signaling complexes. Hence the presence or absence of this component then switches GDF-5′s signaling capabilities to act either similar to BMP-2 or as a BMP-2 antagonist. These findings might shed new light on the role of GDF-5, e.g., in cartilage maintenance and/or limb development in that it might act as an inhibitor of signaling events initiated by other BMPs. KW - growth and differentiation factor 5 KW - ligand-receptor complex KW - crystal structure KW - antagonist Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125550 VL - 13 IS - 77 ER - TY - JOUR A1 - Eberhardt, Christiane S. A1 - Haas, Johannes-Peter A1 - Girschick, Hermann A1 - Schwarz, Tobias A1 - Morbach, Henner A1 - Rösen-Wolff, Angela A1 - Foell, Dirk A1 - Dannecker, Guenther A1 - Schepp, Carsten A1 - Ganser, Gerd A1 - Honke, Nora A1 - Eggermann, Thomas A1 - Müller-Berghaus, Jan A1 - Wagner, Norbert A1 - Ohl, Kim A1 - Tenbrock, Klaus T1 - No association of IL-12p40 pro1.1 polymorphism with juvenile idiopathic arthritis JF - Pediatric Rheumatology N2 - Background: IL-12p40 plays an important role in the activation of the T-cell lines like Th17 and Th1-cells. Theses cells are crucial in the pathogenesis of juvenile idiopathic arthritis. A polymorphism in its promoter region and the genotype IL12p40 pro1.1 leads to a higher production of IL-12p40. We studied whether there is a difference in the distribution of the genotype in patients with JIA and the healthy population. Methods: In 883 patients and 321 healthy controls the IL-12p40 promoter genotype was identified by ARMS-PCR. Results: There is no association of IL-12p40 pro polymorphism neither in patients with JIA compared to controls nor in subtypes of JIA compared to oligoarthritis. We found a non-significant tendency of a higher prevalence of the genotype pro1.1 in systemic arthritis (32.4 %) and in rheumatoid factor negative polyarthritis (30.5 %) and a lower pro1.1 genotype in persistent oligoarthritis (20.7 %) and in enthesitis-related arthritis (17 %). Likelihood of the occurrence of genotype IL12-p40 pro1.1 in patients with systemic arthritis (OR 1.722, CI 95 % 1.344-2.615, p 0.0129) and RF-negative polyarthritis (OR 1.576, CI 95 % 1.046-2.376, p 0.0367) compared to persistent oligoarthritis was significantly higher. This was also true for comparison of their homozygous genotypes IL-12p40 pro 1.1 and 2.2 in systemic arthritis (OR 1.779, CI 95 % 1.045-3.029, p 0.0338). However, in Bonferroni correction for multiple hypothesis this was not significant. Conclusion: A tendency of a higher prevalence of the genotype IL-12p40 pro1.1 in systemic arthritis and in rheumatoid factor negative polyarthritis was observed but not significant. Further investigations should be done to clarify the role IL-12p40 in the different subtypes of JIA. KW - polymorphism KW - cytokine KW - children KW - serum KW - IL12B KW - gene KW - cells KW - juvenile idiopathic arthritis KW - IL-12p40 KW - IL-12B KW - promoter Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-136281 VL - 13 IS - 61 ER - TY - JOUR A1 - Diestel, Uschi A1 - Resch, Marcus A1 - Meinhardt, Kathrin A1 - Weiler, Sigrid A1 - Hellmann, Tina V. A1 - Mueller, Thomas D. A1 - Nickel, Joachim A1 - Eichler, Jutta A1 - Muller, Yves A. T1 - Identification of a Novel TGF-beta-Binding Site in the Zona Pellucida C-terminal (ZP-C) Domain of TGF-\(\beta\)-Receptor-3 (TGFR-3) JF - PLoS ONE N2 - The zona pellucida (ZP) domain is present in extracellular proteins such as the zona pellucida proteins and tectorins and participates in the formation of polymeric protein networks. However, the ZP domain also occurs in the cytokine signaling co-receptor transforming growth factor beta (TGF-\(\beta\)) receptor type 3 (TGFR-3, also known as betaglycan) where it contributes to cytokine ligand recognition. Currently it is unclear how the ZP domain architecture enables this dual functionality. Here, we identify a novel major TGF-beta-binding site in the FG loop of the C-terminal subdomain of the murine TGFR-3 ZP domain (ZP-C) using protein crystallography, limited proteolysis experiments, surface plasmon resonance measurements and synthetic peptides. In the murine 2.7 angstrom crystal structure that we are presenting here, the FG-loop is disordered, however, well-ordered in a recently reported homologous rat ZP-C structure. Surprisingly, the adjacent external hydrophobic patch (EHP) segment is registered differently in the rat and murine structures suggesting that this segment only loosely associates with the remaining ZP-C fold. Such a flexible and temporarily-modulated association of the EHP segment with the ZP domain has been proposed to control the polymerization of ZP domain-containing proteins. Our findings suggest that this flexibility also extends to the ZP domain of TGFR-3 and might facilitate co-receptor ligand interaction and presentation via the adjacent FG-loop. This hints that a similar C-terminal region of the ZP domain architecture possibly regulates both the polymerization of extracellular matrix proteins and cytokine ligand recognition of TGFR-3. KW - coreceptor KW - receptor type III KW - growth factor beta KW - ligand binding KW - betaglycan KW - proteins KW - mutagenesis KW - polymerization KW - glycoprotein KW - superfamily Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130904 VL - 8 IS - 6 ER - TY - JOUR A1 - van Dinther, Maarten A1 - Zhang, Juan A1 - Weidauer, Stella E. A1 - Boschert, Verena A1 - Muth, Eva-Maria A1 - Knappik, Achim A1 - de Gorter, David J. J. A1 - van Kasteren, Puck B. A1 - Frisch, Christian A1 - Müller, Thomas D. A1 - ten Dijke, Peter T1 - Anti-Sclerostin Antibody Inhibits Internalization of Sclerostin and Sclerostin-Mediated Antagonism of Wnt/LRP6 Signaling JF - PLoS ONE N2 - Sclerosteosis is a rare high bone mass disease that is caused by inactivating mutations in the SOST gene. Its gene product, Sclerostin, is a key negative regulator of bone formation and might therefore serve as a target for the anabolic treatment of osteoporosis. The exact molecular mechanism by which Sclerostin exerts its antagonistic effects on Wnt signaling in bone forming osteoblasts remains unclear. Here we show that Wnt3a-induced transcriptional responses and induction of alkaline phosphatase activity, an early marker of osteoblast differentiation, require the Wnt co-receptors LRP5 and LRP6. Unlike Dickkopf1 (DKK1), Sclerostin does not inhibit Wnt-3a-induced phosphorylation of LRP5 at serine 1503 or LRP6 at serine 1490. Affinity labeling of cell surface proteins with \([^{125} I]\) Sclerostin identified LRP6 as the main specific Sclerostin receptor in multiple mesenchymal cell lines. When cells were challenged with Sclerostin fused to recombinant green fluorescent protein (GFP) this was internalized, likely via a Clathrin-dependent process, and subsequently degraded in a temperature and proteasome-dependent manner. Ectopic expression of LRP6 greatly enhanced binding and cellular uptake of Sclerostin-GFP, which was reduced by the addition of an excess of non-GFP-fused Sclerostin. Finally, an anti-Sclerostin antibody inhibited the internalization of Sclerostin-GFP and binding of Sclerostin to LRP6. Moreover, this antibody attenuated the antagonistic activity of Sclerostin on canonical Wnt-induced responses. KW - gene KW - rat model KW - Dickkopf proteins KW - postmenopausal osteoporosis KW - increases bone-formation KW - WNT KW - LRP6 KW - density KW - receptor KW - ligand Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130981 VL - 8 IS - 4 ER - TY - JOUR A1 - Müller, J. G. A1 - Krenn, V. A1 - Schindler, C. A1 - Czub, S. A1 - Stahl-Henning, C. A1 - Coulibaly, C. A1 - Hunsmann, G. A1 - Kneitz, C. A1 - Kerkau, Thomas A1 - Rethwilm, Axel A1 - terMeulen, Volker T1 - Alterations of thymus cortical epithelium and interdigitating dendritic cells but no increase of thymocyte cell death in the early course of simian immunodeficiency virus infection N2 - No abstract available Y1 - 1993 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-32583 ER - TY - JOUR A1 - Müller-Thomas, Catharina A1 - Rudelius, Martina A1 - Rondak, Ina-Christine A1 - Haferlach, Torsten A1 - Schanz, Julie A1 - Huberle, Christina A1 - Schmidt, Burkard A1 - Blaser, Rainer A1 - Kremer, Marcus A1 - Peschel, Christian A1 - Germing, Ulrich A1 - Platzbecker, Uwe A1 - Goetze, Katharina T1 - Response to azacitidine is independent of p53 expression in higher-risk myelodysplastic syndromes and secondary acute myeloid leukemia JF - HAEMATOLOGICA N2 - No abstract available. KW - TP53 mutations KW - DEL(5Q) KW - MDS KW - p53 expression KW - azacitidine KW - scoring system KW - prognosis KW - karyotype Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-115313 SN - 1592-8721 VL - 99 IS - 10 ER - TY - JOUR A1 - Remmele, Christian W. A1 - Xian, Yibo A1 - Albrecht, Marco A1 - Faulstich, Michaela A1 - Fraunholz, Martin A1 - Heinrichs, Elisabeth A1 - Dittrich, Marcus T. A1 - Müller, Tobias A1 - Reinhardt, Richard A1 - Rudel, Thomas T1 - Transcriptional landscape and essential genes of Neisseria gonorrhoeae N2 - The WHO has recently classified Neisseria gonorrhoeae as a super-bacterium due to the rapid spread of antibiotic resistant derivatives and an overall dramatic increase in infection incidences. Genome sequencing has identified potential genes, however, little is known about the transcriptional organization and the presence of non-coding RNAs in gonococci. We performed RNA sequencing to define the transcriptome and the transcriptional start sites of all gonococcal genes and operons. Numerous new transcripts including 253 potentially non-coding RNAs transcribed from intergenic regions or antisense to coding genes were identified. Strikingly, strong antisense transcription was detected for the phase-variable opa genes coding for a family of adhesins and invasins in pathogenic Neisseria, that may have regulatory functions. Based on the defined transcriptional start sites, promoter motifs were identified. We further generated and sequenced a high density Tn5 transposon library to predict a core of 827 gonococcal essential genes, 133 of which have no known function. Our combined RNA-Seq and Tn-Seq approach establishes a detailed map of gonococcal genes and defines the first core set of essential gonococcal genes. KW - Neisseria gonorrhoeae Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-113676 ER - TY - JOUR A1 - Morton, Charles Oliver A1 - Fliesser, Mirjam A1 - Dittrich, Marcus A1 - Müller, Tobias A1 - Bauer, Ruth A1 - Kneitz, Susanne A1 - Hope, William A1 - Rogers, Thomas Richard A1 - Einsele, Hermann A1 - Löffler, Jürgen T1 - Gene Expression Profiles of Human Dendritic Cells Interacting with Aspergillus fumigatus in a Bilayer Model of the Alveolar Epithelium/Endothelium Interface N2 - The initial stages of the interaction between the host and Aspergillus fumigatus at the alveolar surface of the human lung are critical in the establishment of aspergillosis. Using an in vitro bilayer model of the alveolus, including both the epithelium (human lung adenocarcinoma epithelial cell line, A549) and endothelium (human pulmonary artery epithelial cells, HPAEC) on transwell membranes, it was possible to closely replicate the in vivo conditions. Two distinct sub-groups of dendritic cells (DC), monocyte-derived DC (moDC) and myeloid DC (mDC), were included in the model to examine immune responses to fungal infection at the alveolar surface. RNA in high quantity and quality was extracted from the cell layers on the transwell membrane to allow gene expression analysis using tailored custom-made microarrays, containing probes for 117 immune-relevant genes. This microarray data indicated minimal induction of immune gene expression in A549 alveolar epithelial cells in response to germ tubes of A. fumigatus. In contrast, the addition of DC to the system greatly increased the number of differentially expressed immune genes. moDC exhibited increased expression of genes including CLEC7A, CD209 and CCL18 in the absence of A. fumigatus compared to mDC. In the presence of A. fumigatus, both DC subgroups exhibited up-regulation of genes identified in previous studies as being associated with the exposure of DC to A. fumigatus and exhibiting chemotactic properties for neutrophils, including CXCL2, CXCL5, CCL20, and IL1B. This model closely approximated the human alveolus allowing for an analysis of the host pathogen interface that complements existing animal models of IA. KW - aspergillus fumigatus KW - gene expression KW - immune receptors KW - immune response KW - denritic cells KW - B cell receptors KW - gene regulation KW - RNA extraction Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-112893 ER - TY - THES A1 - Müller, Thomas M. T1 - Computergestütztes Materialdesign: Mikrostruktur und elektrische Eigenschaften von Zirkoniumdioxid–Aluminiumoxid Keramiken T1 - Computer-Aided Material Design: Microstructure and Electrical Properties of Zirconia-Alumina-Ceramics N2 - Die Mikrostruktur von Zirkonoxid–Aluminiumoxid Keramiken wurde im Rasterelektronenmikroskop (REM) untersucht und mittels quantitativer Bildanalyse weiter charakterisiert. Die so erhaltenen spezifischen morphologischen Kennwerte wurden mit denen, die an dreidimensionalen Modellstrukturen äquivalent gewonnen wurden, verglichen. Es wurden modifizierte Voronoistrukturen benutzt, um die beteiligten Phasen in repräsentativen Volumenelementen (RVE) auf Voxelbasis zu erzeugen. Poren wurden an den Ecken und Kanten dieser Strukturen nachträglich hinzugefüg. Nachdem alle relevanten Kennwerte der Modellstrukturen an die realen keramischen Mikrostrukturen angepasst wurden, musste das RVE für die Finite Element Simulationen (FES) geeignet vernetzt werden. Eine einfache Übernahme der Voxelstrukturen in hexaedrische Elemente führt zu sehr langen Rechenzeiten, und die erforderliche Genauigkeit der FES konnte nicht erreicht werden. Deshalb wurde zunächst eine adaptive Oberflächenvernetzung ausgehend von einem generally classed marching tetrahedra Algorithmus erzeugt. Dabei wurde besonderer Wert auf die Beibehaltung der zuvor angepassten Kennwerte gelegt. Um die Rechenzeiten zu verkürzen ohne die Genauigkeit der FES zu beeinträchtigen, wurden die Oberflächenvernetzungen dergestalt vereinfacht, dass eine hohe Auflösung an den Ecken und Kanten der Strukturen erhalten blieb, während sie an flachen Korngrenzen stark verringert wurde. Auf Basis dieser Oberflächenvernetzung wurden Volumenvernetzungen, inklusive der Abbildung der Korngrenzen durch Volumenelemente, erzeugt und für die FES benutzt. Dazu wurde ein FE-Modell zur Simulation der Impedanzspektren aufgestellt und validiert. Um das makroskopische elektrische Verhalten der polykristallinen Keramiken zu simulieren, mussten zunächst die elektrischen Eigenschaften der beteiligten Einzelphasen gemessen werden. Dazu wurde eine Anlage zur Impedanzspektroskopie bis 1000 °C aufgebaut und verwendet. Durch weitere Auswertung der experimentellen Daten unter besonderer Berücksichtigung der Korngrenzeffekte wurden die individuellen Phaseneigenschaften erhalten. Die Zusammensetzung der Mischkeramiken reichte von purem Zirkonoxid (3YSZ) bis zu purem Aluminiumoxid. Es wurde eine sehr gute Übereinstimmung zwischen den experimentellen und simulierten Werten bezüglich der betrachteten elektrischen, mechanischen und thermischen Eigenschaften erreicht. Die FES wurden verwendet, um die Einflüsse verschiedener mikrostruktureller Parameter, wie Porosität, Korngröße und Komposition, auf das makroskopische Materialverhalten näher zu untersuchen. N2 - The microstructures of zirconia–alumina ceramics are investigated by scanning electron microscopy (SEM) and further characterised by quantitative image analysis. This leads to specific morphological parameters which are compared with the same parameters derived from three-dimensional model structures generated in voxel-based representative volume elements (RVE). Modified Voronoi clusters are employed to represent alumina and zirconia phases. Pores are added at the grain corners and edges respectively. After adjusting all the relevant morphological parameters of the model to the real ceramics’ microstructure, the RVE has to be meshed for finite element simulations (FES). Hexahedral elements which simply use the voxel structure did not lead to sufficient accuracy of the FES. As a first step, an adapted surface tessellation is generated, using a generally classed marching tetrahedra method. Special care is taken to preserve the topology as well as the individual volumes and interfaces of the model. In terms of processing time and accuracy of the FES it is very important to simplify the initially generated surface mesh in a manner that preserves detailed resolution at corners and along edges, while decimating the number of surface elements in flat regions, i.e. at the grain boundaries. From the surface mesh an adequate tetrahedral volume tessellation, including solid elements representing the grain boundaries, is created, which is used for the FES. Therefore, a FE-model for the simulation of impedance spectra has been established and validated. To simulate the macroscopic electrical behaviour of polycrystalline ceramics, the electrical properties of the individual constituting phases need to be measured. This is done by impedance spectroscopy up to 1000 °C. Further analysis of the experimental data with special respect to the effect of the grain boundaries is carried out to obtain the individual phases’ properties. The sample composition was varied from pure zirconia to pure alumina. A very good agreement between experimental and simulated data was achieved in terms of electrical, thermal and mechanical properties. The FES were employed to scrutinize the effects of systematically varying microstructural properties, such as porosity, grain size and composition, on the macroscopic material behaviour. KW - Keramischer Werkstoff KW - Mikrostruktur–Eigenschafts–Korrelationen KW - Mikrostrukturmodellierung KW - Impedanzspektroskopie KW - Finite Element Simulationen KW - Microstructure–Property–Relationship KW - Microstructure Modelling KW - Impedance Spectroscopy KW - Finite Element Simulations KW - Mikrostruktur KW - Computersimulation KW - Finite-Elemente-Methode KW - Simulation KW - Dreidimensionales Modell KW - Gefügekunde Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-110942 ER - TY - JOUR A1 - Zeller, Mario A1 - Müller, Alexander A1 - Gutberlet, Marcel A1 - Nichols, Thomas A1 - Hahn, Dietbert A1 - Köstler, Herbert A1 - Bartsch, Andreas J. T1 - Boosting BOLD fMRI by K-Space Density Weighted Echo Planar Imaging JF - PLoS ONE N2 - Functional magnetic resonance imaging (fMRI) has become a powerful and influential method to non-invasively study neuronal brain activity. For this purpose, the blood oxygenation level-dependent (BOLD) effect is most widely used. T2* weighted echo planar imaging (EPI) is BOLD sensitive and the prevailing fMRI acquisition technique. Here, we present an alternative to its standard Cartesian recordings, i.e. k-space density weighted EPI, which is expected to increase the signal-to-noise ratio in fMRI data. Based on in vitro and in vivo pilot measurements, we show that fMRI by k-space density weighted EPI is feasible and that this new acquisition technique in fact boosted spatial and temporal SNR as well as the detection of local fMRI activations. Spatial resolution, spatial response function and echo time were identical for density weighted and conventional Cartesian EPI. The signal-to-noise ratio gain of density weighting can improve activation detection and has the potential to further increase the sensitivity of fMRI investigations. KW - data acquisition KW - density KW - echo planar imaging KW - functional magnetic resonance imaging KW - imaging techniques KW - matched filters KW - signal filtering KW - statistical data Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-97233 ER - TY - JOUR A1 - Hartmann, Stefan A1 - Lessner, Grit A1 - Mentzel, Thomas A1 - Kübler, Alexander C. A1 - Müller-Richter, Urs T1 - An adult spindle cell rhabdomyosarcoma in the head and neck region with long-term survival: a case report N2 - Introduction Spindle cell rhabdomyosarcoma of the head and neck is a very rare tumor in adults. We report on one case with long-term survival. Case presentation A 41-year-old nonsmoking Caucasian man presented in June 2007 with a painless swelling under his tongue. A diagnosis of a soft tissue sarcoma, and a myofibrosarcoma in particular, was made via biopsy. After multimodal treatment, including local and systemic therapy, our patient remained disease-free until September 2010. The local recurrence was treated unsuccessfully with various chemotherapy regimens. In September 2011, our patient underwent surgical resection again, and a spindle cell rhabdomyosarcoma was diagnosed. To analyze the mismatch between the original diagnosis of a myofibrosarcoma and the second diagnosis, the two specimens were reassessed, and a final diagnosis of a spindle cell rhabdomyosarcoma was made. In 2012 and 2013, our patient suffered further recurrences that were surgically treated, and he is still alive with disease six years and 10 months after the initial diagnosis in June 2007. Conclusions In adults, the spindle cell rhabdomyosarcoma tumor is very rare in the head and neck region. In contrast to childhood tumors, spindle cell rhabdomyosarcoma in adulthood is often associated with a poor prognosis. In the present case, the radical surgical treatment might have helped to prolong the patient’s overall survival, which has lasted more than six years. To our knowledge, this is the longest overall survival reported so far for this tumor entity in the head and neck region. KW - Rhabdomyosarcoma KW - Spindle cell KW - Adult KW - Surgery KW - Head Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-110362 ER - TY - JOUR A1 - Hendricks, Anne A1 - Müller, Sophie A1 - Fassnacht, Martin A1 - Germer, Christoph-Thomas A1 - Wiegering, Verena A. A1 - Wiegering, Armin A1 - Reibetanz, Joachim T1 - Impact of lymphadenectomy on the oncologic outcome of patients with adrenocortical carcinoma — a systematic review and meta-analysis JF - Cancers N2 - (1) Background: Locoregional lymphadenectomy (LND) in adrenocortical carcinoma (ACC) may impact oncological outcome, but the findings from individual studies are conflicting. The aim of this systematic review and meta-analysis was to determine the oncological value of LND in ACC by summarizing the available literature. (2) Methods: A systematic search on studies published until December 2020 was performed according to the PRISMA statement. The primary outcome was the impact of lymphadenectomy on overall survival (OS). Two separate meta-analyses were performed for studies including patients with localized ACC (stage I–III) and those including all tumor stages (I–IV). Secondary endpoints included postoperative mortality and length of hospital stay (LOS). (3) Results: 11 publications were identified for inclusion. All studies were retrospective studies, published between 2001–2020, and 5 were included in the meta-analysis. Three studies (N = 807 patients) reported the impact of LND on disease-specific survival in patients with stage I–III ACC and revealed a survival benefit of LND (hazard ratio (HR) = 0.42, 95% confidence interval (95% CI): 0.26–0.68). Based on results of studies including patients with ACC stage I–IV (2 studies, N = 3934 patients), LND was not associated with a survival benefit (HR = 1.00, 95% CI: 0.70–1.42). None of the included studies showed an association between LND and postoperative mortality or LOS. (4) Conclusion: Locoregional lymphadenectomy seems to offer an oncologic benefit in patients undergoing curative-intended surgery for localized ACC (stage I–III). KW - adrenocortical carcinoma KW - adrenal cancer KW - lymphadenectomy KW - lymph node dissection KW - LND KW - LNE KW - review KW - meta-analysis Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-254798 SN - 2072-6694 VL - 14 IS - 2 ER - TY - JOUR A1 - Temme, Fabian A1 - Adam, Jan A1 - Ahnen, Max L. A1 - Baack, Dominik A1 - Balbo, Matteo A1 - Bergmann, Matthias A1 - Biland, Adrian A1 - Blank, Michael A1 - Bretz, Thomas A1 - Brügge, Kai A. A1 - Buss, Jens A1 - Dmytriiev, Anton A1 - Dorner, Daniela A1 - Einecke, Sabrina A1 - Hempfling, Christina A1 - Hildebrand, Dorothee A1 - Hughes, Gareth A1 - Linhoff, Lena A1 - Mannheim, Karl A1 - Müller, Sebastian A1 - Neise, Dominik A1 - Neronov, Andrii A1 - Nöthe, Max A1 - Paravac, Aleksander A1 - Pauss, Felicitas A1 - Rhode, Wolfgang A1 - Shukla, Amit A1 - Thaele, Julia A1 - Walter, Roland T1 - Long-Term monitoring of bright blazars in the multi-GeV to TeV range with FACT JF - Galaxies N2 - Blazars like Markarian 421 or Markarian 501 are active galactic nuclei (AGN), with their jets orientated towards the observer. They are among the brightest objects in the very high energy (VHE) gamma ray regime (>100 GeV). Their emitted gamma-ray fluxes are extremely variable, with changing activity levels on timescales between minutes, months, and even years. Several questions are part of the current research, such as the question of the emission regions or the engine of the AGN and the particle acceleration. A dedicated longterm monitoring program is necessary to investigate the properties of blazars in detail. A densely sampled and unbiased light curve allows for observation of both high and low states of the sources, and the combination with multi-wavelength observation could contribute to the answer of several questions mentioned above. FACT (First G-APD Cherenkov Telescope) is the first operational telescope using silicon photomultiplier (SiPM, also known as Geigermode—Avalanche Photo Diode, G-APD) as photon detectors. SiPM have a very homogenous and stable longterm performance, and allow operation even during full moon without any filter, leading to a maximal duty cycle for an Imaging Air Cherenkov Telescope (IACT). Hence, FACT is an ideal device for such a longterm monitoring of bright blazars. A small set of sources (e.g., Markarian 421, Markarian 501, 1ES 1959+650, and 1ES 2344+51.4) is currently being monitored. In this contribution, the FACT telescope and the concept of longterm monitoring of bright blazars will be introduced. The results of the monitoring program will be shown, and the advantages of densely sampled and unbiased light curves will be discussed. KW - Imaging Air Cherenkov Telescope KW - First G-APD Cherenkov Telescope KW - very high energy gamma rays KW - long-term monitoring KW - silicon photo multiplier Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-198088 SN - 2075-4434 VL - 5 IS - 1 PB - MDPI ER - TY - JOUR A1 - Schwedhelm, Ivo A1 - Zdzieblo, Daniela A1 - Appelt-Menzel, Antje A1 - Berger, Constantin A1 - Schmitz, Tobias A1 - Schuldt, Bernhard A1 - Franke, Andre A1 - Müller, Franz-Josef A1 - Pless, Ole A1 - Schwarz, Thomas A1 - Wiedemann, Philipp A1 - Walles, Heike A1 - Hansmann, Jan T1 - Automated real-time monitoring of human pluripotent stem cell aggregation in stirred tank reactors JF - Scientific Reports N2 - The culture of human induced pluripotent stem cells (hiPSCs) at large scale becomes feasible with the aid of scalable suspension setups in continuously stirred tank reactors (CSTRs). Innovative monitoring options and emerging automated process control strategies allow for the necessary highly defined culture conditions. Next to standard process characteristics such as oxygen consumption, pH, and metabolite turnover, a reproducible and steady formation of hiPSC aggregates is vital for process scalability. In this regard, we developed a hiPSC-specific suspension culture unit consisting of a fully monitored CSTR system integrated into a custom-designed and fully automated incubator. As a step towards cost-effective hiPSC suspension culture and to pave the way for flexibility at a large scale, we constructed and utilized tailored miniature CSTRs that are largely made from three-dimensional (3D) printed polylactic acid (PLA) filament, which is a low-cost material used in fused deposition modelling. Further, the monitoring tool for hiPSC suspension cultures utilizes in situ microscopic imaging to visualize hiPSC aggregation in real-time to a statistically significant degree while omitting the need for time-intensive sampling. Suitability of our culture unit, especially concerning the developed hiPSC-specific CSTR system, was proven by demonstrating pluripotency of CSTR-cultured hiPSCs at RNA (including PluriTest) and protein level. KW - Biomedical engineering KW - Stem-cell biotechnology Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202649 VL - 9 ER - TY - JOUR A1 - Doll, Julia A1 - Kolb, Susanne A1 - Schnapp, Linda A1 - Rad, Aboulfazl A1 - Rüschendorf, Franz A1 - Khan, Imran A1 - Adli, Abolfazl A1 - Hasanzadeh, Atefeh A1 - Liedtke, Daniel A1 - Knaup, Sabine A1 - Hofrichter, Michaela AH A1 - Müller, Tobias A1 - Dittrich, Marcus A1 - Kong, Il-Keun A1 - Kim, Hyung-Goo A1 - Haaf, Thomas A1 - Vona, Barbara T1 - Novel loss-of-function variants in CDC14A are associated with recessive sensorineural hearing loss in Iranian and Pakistani patients JF - International Journal of Molecular Sciences N2 - CDC14A encodes the Cell Division Cycle 14A protein and has been associated with autosomal recessive non-syndromic hearing loss (DFNB32), as well as hearing impairment and infertile male syndrome (HIIMS) since 2016. To date, only nine variants have been associated in patients whose initial symptoms included moderate-to-profound hearing impairment. Exome analysis of Iranian and Pakistani probands who both showed bilateral, sensorineural hearing loss revealed a novel splice site variant (c.1421+2T>C, p.?) that disrupts the splice donor site and a novel frameshift variant (c.1041dup, p.Ser348Glnfs*2) in the gene CDC14A, respectively. To evaluate the pathogenicity of both loss-of-function variants, we analyzed the effects of both variants on the RNA-level. The splice variant was characterized using a minigene assay. Altered expression levels due to the c.1041dup variant were assessed using RT-qPCR. In summary, cDNA analysis confirmed that the c.1421+2T>C variant activates a cryptic splice site, resulting in a truncated transcript (c.1414_1421del, p.Val472Leufs*20) and the c.1041dup variant results in a defective transcript that is likely degraded by nonsense-mediated mRNA decay. The present study functionally characterizes two variants and provides further confirmatory evidence that CDC14A is associated with a rare form of hereditary hearing loss. KW - CDC14A KW - DFNB32 KW - autosomal recessive hearing loss KW - exome sequencing KW - splicing KW - frameshift KW - non-sense mediated mRNA decay Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285142 SN - 1422-0067 VL - 21 IS - 1 ER - TY - JOUR A1 - Remmele, Christian W. A1 - Luther, Christian H. A1 - Balkenhol, Johannes A1 - Dandekar, Thomas A1 - Müller, Tobias A1 - Dittrich, Marcus T. T1 - Integrated inference and evaluation of host-fungi interaction networks JF - Frontiers in Microbiology N2 - Fungal microorganisms frequently lead to life-threatening infections. Within this group of pathogens, the commensal Candida albicans and the filamentous fungus Aspergillus fumigatus are by far the most important causes of invasive mycoses in Europe. A key capability for host invasion and immune response evasion are specific molecular interactions between the fungal pathogen and its human host. Experimentally validated knowledge about these crucial interactions is rare in literature and even specialized host pathogen databases mainly focus on bacterial and viral interactions whereas information on fungi is still sparse. To establish large-scale host fungi interaction networks on a systems biology scale, we develop an extended inference approach based on protein orthology and data on gene functions. Using human and yeast intraspecies networks as template, we derive a large network of pathogen host interactions (PHI). Rigorous filtering and refinement steps based on cellular localization and pathogenicity information of predicted interactors yield a primary scaffold of fungi human and fungi mouse interaction networks. Specific enrichment of known pathogenicity-relevant genes indicates the biological relevance of the predicted PHI. A detailed inspection of functionally relevant subnetworks reveals novel host fungal interaction candidates such as the Candida virulence factor PLB1 and the anti-fungal host protein APP. Our results demonstrate the applicability of interolog-based prediction methods for host fungi interactions and underline the importance of filtering and refinement steps to attain biologically more relevant interactions. This integrated network framework can serve as a basis for future analyses of high-throughput host fungi transcriptome and proteome data. KW - candida genome database KW - computational prediction KW - potential role KW - network inference KW - bioinformatics and computational biology KW - protein interaction database KW - Aspergillus fumigatus KW - cell wall KW - functional modules KW - alzheimers disease KW - molecular cloning KW - Candida albicans KW - pathogen-host interaction (PHI) KW - protein-protein interaction KW - pathogenicity KW - interolog Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148278 VL - 6 IS - 764 ER - TY - RPRT A1 - Müller, Jörg A1 - Scherer-Lorenzen, Michael A1 - Ammer, Christian A1 - Eisenhauer, Nico A1 - Seidel, Dominik A1 - Schuldt, Bernhard A1 - Biedermann, Peter A1 - Schmitt, Thomas A1 - Künzer, Claudia A1 - Wegmann, Martin A1 - Cesarz, Simone A1 - Peters, Marcell A1 - Feldhaar, Heike A1 - Steffan-Dewenter, Ingolf A1 - Claßen, Alice A1 - Bässler, Claus A1 - von Oheimb, Goddert A1 - Fichtner, Andreas A1 - Thorn, Simon A1 - Weisser, Wolfgang T1 - BETA-FOR: Erhöhung der strukturellen Diversität zwischen Waldbeständen zur Erhöhung der Multidiversität und Multifunktionalität in Produktionswäldern. Antragstext für die DFG Forschungsgruppe FOR 5375 T1 - BETA-FOR: Enhancing the structural diversity between patches for improving multidiversity and multifunctionality in production forests. Proposal for DFG Research Unit FOR 5375 BT - β\(_4\) : Proposal for the 1st phase (2022-2026) of the DFG Research Unit FOR 5375/1 (DFG Forschergruppe FOR 5375/1 – BETA-FOR), Fabrikschleichach, October 2021 N2 - Der in jüngster Zeit beobachtete kontinuierliche Verlust der β-Diversität in Ökosystemen deutet auf homogene Gemeinschaften auf Landschaftsebene hin, was hauptsächlich auf die steigende Landnutzungsintensität zurückgeführt wird. Biologische Vielfalt ist mit zahlreichen Funktionen und der Stabilität von Ökosystemen verknüpft. Es ist daher zu erwarten, dass eine abnehmende β-Diversität auch die Multifunktionalität verringert. Wir kombinieren hier Fachwissen aus der Forstwissenschaft, der Ökologie, der Fernerkundung, der chemischen Ökologie und der Statistik in einem gemeinschaftlichen und experimentellen β-Diversitätsdesign, um einerseits die Auswirkungen der Homogenisierung zu bewerten und andererseits Konzepte zu entwickeln, um negative Auswirkungen durch Homogenisierung in Wäldern rückgängig zu machen. Konkret werden wir uns mit der Frage beschäftigen, ob die Verbesserung der strukturellen β-Komplexität (ESBC) in Wäldern durch Waldbau oder natürliche Störungen die Biodiversität und Multifunktionalität in ehemals homogenen Produktionswäldern erhöhen kann. Unser Ansatz wird mögliche Mechanismen hinter den beobachteten Homogenisierungs-Diversitäts-Beziehungen identifizieren und zeigen, wie sich diese auf die Multifunktionalität auswirken. An elf Standorten in ganz Deutschland haben wir dazu zwei Waldbestände als zwei kleine "Waldlandschaften" ausgewählt. In einem dieser beiden Bestände haben wir ESBC (Enhancement of Structural Beta Complexity)-Behandlungen durchgeführt. Im zweiten, dem Kontrollbestand, werden wir die gleich Anzahl 50x50m Parzellen ohne ESBC einrichten. Auf allen Parzellen werden wir 18 taxonomische Artengruppen aller trophischer Ebenen und 21 Ökosystemfunktionen, einschließlich der wichtigsten Funktionen in Wäldern der gemäßigten Zonen, messen. Der statistische Rahmen wird eine umfassende Analyse der Biodiversität ermöglichen, indem verschiedenen Aspekte (taxonomische, funktionelle und phylogenetische Vielfalt) auf verschiedenen Skalenebenen (α-, β-, γ-Diversität) quantifiziert werden. Um die Gesamtdiversität zu kombinieren, werden wir das Konzept der Multidiversität auf die 18 Taxa anwenden. Wir werden neue Ansätze zur Quantifizierung und Aufteilung der Multifunktionalität auf α- und β-Skalen verwenden und entwickeln. Durch die experimentelle Beschreibung des Zusammenhangs zwischen β-Diversität und Multifunktionalität in einer Reallandschaft wird unsere Forschung einen neuen Weg einschlagen. Darüber hinaus werden wir dazu beitragen, verbesserte Leitlinien für waldbauliche Konzepte und für das Management natürlicher Störungen zu entwickeln, um Homogenisierungseffekte der Vergangenheit umzukehren. N2 - The recently observed consistent loss of β-diversity across ecosystems indicates increasingly homogeneous communities in patches of landscapes, mainly caused by increasing land-use intensity. Biodiversity is related to numerous ecosystem functions and stability. Therefore, decreasing β-diversity is also expected to reduce multifunctionality. To assess the impact of homogenization and to develop guidelines to reverse its potentially negative effects, we combine expertise from forest science, ecology, remote sensing, chemical ecology and statistics in a collaborative and experimental β-diversity approach. Specifically, we will address the question whether the Enhancement of Structural Beta Complexity (ESBC) in forests by silviculture or natural disturbances will increase biodiversity and multifunctionality in formerly homogeneously structured production forests. Our approach will identify potential mechanisms behind observed homogenization-diversity-relationships and show how these translate into effects on multifunctionality. At eleven forest sites throughout Germany, we selected two districts as two types of small ‘forest landscapes’. In one of these two districts, we established ESBC treatments (nine differently treated 50x50 m patches with a focus on canopy cover and deadwood features). In the second, the control district, we will establish nine patches without ESBC. By a comprehensive sampling, we will monitor 18 taxonomic groups and measure 21 ecosystem functions, including key functions in temperate forests, on all patches. The statistical framework will allow a comprehensive biodiversity assessment by quantifying the different aspects of multitrophic biodiversity (taxonomical, functional and phylogenetic diversity) on different levels of biodiversity (α-, β-, γ-diversity). To combine overall diversity, we will apply the concept of multidiversity across the 18 taxa. We will use and develop new approaches for quantification and partitioning of multifunctionality at α- and β- scales. Overall, our study will herald a new research avenue, namely by experimentally describing the link between β-diversity and multifunctionality. Furthermore, we will help to develop guidelines for improved silvicultural concepts and concepts for management of natural disturbances in temperate forests reversing past homogenization effects. KW - Waldökosystem KW - Biodiversität KW - BETA-Multifunktionalität KW - beta-multifunctionality KW - BETA-Diversität KW - beta diversity KW - Forschungsstation Fabrikschleichach Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290849 ER - TY - JOUR A1 - Köhler, Franziska A1 - Reese, Lena A1 - Hendricks, Anne A1 - Kastner, Carolin A1 - Müller, Sophie A1 - Lock, Johan F. A1 - Germer, Christoph-Thomas A1 - Wiegering, Armin T1 - Low-grade mucinous neoplasms (LAMN) of the appendix in Germany between 2011 and 2018: a nationwide analysis based on data provided by the German Center for Cancer Registry Data (ZfKD) at the Robert Koch Institute (RKI) JF - Langenbeck’s Archives of Surgery N2 - Introduction Low-grade appendiceal mucinous neoplasms (LAMN) are semi-malignant tumors of the appendix which are incidentally found in up to 1% of appendectomy specimen. To this day, no valid descriptive analysis on LAMN is available for the German population. Methods Data of LAMN (ICD-10: D37.3) were collected from the population-based cancer registries in Germany, provided by the German Center for Cancer Registry Data (Zentrum für Krebsregisterdaten—ZfKD). Data was anonymized and included gender, age at diagnosis, tumor staging according to the TNM-classification, state of residence, information on the performed therapy, and survival data. Results A total of 612 cases were reported to the ZfKD between 2011 and 2018. A total of 63.07% were female and 36.93% were male. Great inhomogeneity in reporting cases was seen in the federal states of Germany including the fact that some federal states did not report any cases at all. Age distribution showed a mean age of 62.03 years (SD 16.15) at diagnosis. However, data on tumor stage was only available in 24.86% of cases (n = 152). A total of 49.34% of these patients presented with a T4-stage. Likewise, information regarding performed therapy was available in the minority of patients: 269 patients received surgery, 22 did not and for 312 cases no information was available. Twenty-four patients received chemotherapy, 188 did not, and for 400 cases, no information was available. Overall 5-year survival was estimated at 79.52%. Patients below the age of 55 years at time of diagnosis had a significantly higher 5-year survival rate compared to patients above the age of 55 years (85.77% vs. 73.27%). Discussion In this study, we observed an incidence of LAMN in 0.13% of all appendectomy specimen in 2018. It seems likely that not all cases were reported to the ZfKD; therefore, case numbers may be considered underestimated. Age and gender distribution goes in line with international studies with females being predominantly affected. Especially regarding tumor stage and therapy in depth information cannot be provided through the ZfKD-database. This data analysis emphasizes the need for further studies and the need for setting up a specialized registry for this unique tumor entity to develop guidelines for the appropriate treatment and follow-up. KW - LAMN KW - low-grade mucinous neoplasm KW - appendix KW - epidemiology KW - ZfKD KW - Germany Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-323919 VL - 407 IS - 8 ER - TY - JOUR A1 - Englmeier, Jana A1 - Mitesser, Oliver A1 - Benbow, M. Eric A1 - Hothorn, Torsten A1 - von Hoermann, Christian A1 - Benjamin, Caryl A1 - Fricke, Ute A1 - Ganuza, Cristina A1 - Haensel, Maria A1 - Redlich, Sarah A1 - Riebl, Rebekka A1 - Rojas Botero, Sandra A1 - Rummler, Thomas A1 - Steffan-Dewenter, Ingolf A1 - Stengel, Elisa A1 - Tobisch, Cynthia A1 - Uhler, Johannes A1 - Uphus, Lars A1 - Zhang, Jie A1 - Müller, Jörg T1 - Diverse effects of climate, land use, and insects on dung and carrion decomposition JF - Ecosystems N2 - Land-use intensification and climate change threaten ecosystem functions. A fundamental, yet often overlooked, function is decomposition of necromass. The direct and indirect anthropogenic effects on decomposition, however, are poorly understood. We measured decomposition of two contrasting types of necromass, rat carrion and bison dung, on 179 study sites in Central Europe across an elevational climate gradient of 168–1122 m a.s.l. and within both local and regional land uses. Local land-use types included forest, grassland, arable fields, and settlements and were embedded in three regional land-use types (near-natural, agricultural, and urban). The effects of insects on decomposition were quantified by experimental exclusion, while controlling for removal by vertebrates. We used generalized additive mixed models to evaluate dung weight loss and carrion decay rate along elevation and across regional and local land-use types. We observed a unimodal relationship of dung decomposition with elevation, where greatest weight loss occurred between 600 and 700 m, but no effects of local temperature, land use, or insects. In contrast to dung, carrion decomposition was continuously faster with both increasing elevation and local temperature. Carrion reached the final decomposition stage six days earlier when insect access was allowed, and this did not depend on land-use effect. Our experiment identified different major drivers of decomposition on each necromass form. The results show that dung and carrion decomposition are rather robust to local and regional land use, but future climate change and decline of insects could alter decomposition processes and the self-regulation of ecosystems. KW - decay KW - ecosystem function KW - global change KW - land-use intensification KW - necrobiome KW - urbanization Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-325064 SN - 1432-9840 VL - 26 IS - 2 ER - TY - JOUR A1 - Hetzer, Benjamin A1 - Orth-Höller, Dorothea A1 - Würzner, Reinhard A1 - Kreidl, Peter A1 - Lackner, Michaela A1 - Müller, Thomas A1 - Knabl, Ludwig A1 - Geisler-Moroder, Daniel Rudolf A1 - Mellmann, Alexander A1 - Sesli, Özcan A1 - Holzknecht, Jeanett A1 - Noce, Damia A1 - Akarathum, Noppadon A1 - Chotinaruemol, Somporn A1 - Prelog, Martina A1 - Oberdorfer, Peninnah T1 - “Enhanced acquisition of antibiotic-resistant intestinal E. coli during the first year of life assessed in a prospective cohort study” JF - Antimicrobial Resistance & Infection Control N2 - Background Increasing bacterial resistance to antibiotics is a serious problem worldwide. We sought to record the acquisition of antibiotic-resistant Escherichia coli (E. coli) in healthy infants in Northern Thailand and investigated potential determinants. Methods Stool samples from 142 infants after birth, at ages 2wk, 2mo, 4 to 6mo, and 1y, and parent stool samples were screened for E. coli resistance to tetracycline, ampicillin, co-trimoxazole, and cefazoline by culture, and isolates were further investigated for multiresistance by disc diffusion method. Pulsed-field gel electrophoresis was performed to identify persistent and transmitted strains. Genetic comparison of resistant and transmitted strains was done by multilocus sequence typing (MLST) and strains were further investigated for extra- and intra-intestinal virulence factors by multiplex PCR. Results Forty-seven (33%) neonatal meconium samples contained resistant E. coli. Prevalence increased continuously: After 1y, resistance proportion (tetracycline 80%, ampicillin 72%, co-trimoxazole 66%, cefazoline 35%) almost matched those in parents. In 8 infants (6%), identical E. coli strains were found in at least 3 sampling time points (suggesting persistence). Transmission of resistant E. coli from parents to child was observed in only 8 families. MLST showed high diversity. We could not identify any virulence genes or factors associated with persistence, or transmission of resistant E. coli. Full-term, vaginal birth and birth in rural hospital were identified as risk factors for early childhood colonization with resistant E. coli. Conclusion One third of healthy Thai neonates harboured antibiotic-resistant E. coli in meconium. The proportion of resistant E. coli increased during the first year of life almost reaching the value in adults. We hypothesize that enhancement of infection control measures and cautious use of antibiotics may help to control further increase of resistance. KW - Escherichia coli KW - antibiotic resistance KW - multiresistance KW - transmission KW - persistence KW - children KW - neonates Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-320284 VL - 8 ER - TY - JOUR A1 - Latifi, Hooman A1 - Holzwarth, Stefanie A1 - Skidmore, Andrew A1 - Brůna, Josef A1 - Červenka, Jaroslav A1 - Darvishzadeh, Roshanak A1 - Hais, Martin A1 - Heiden, Uta A1 - Homolová, Lucie A1 - Krzystek, Peter A1 - Schneider, Thomas A1 - Starý, Martin A1 - Wang, Tiejun A1 - Müller, Jörg A1 - Heurich, Marco T1 - A laboratory for conceiving Essential Biodiversity Variables (EBVs)—The ‘Data pool initiative for the Bohemian Forest Ecosystem’ JF - Methods in Ecology and Evolution N2 - Effects of climate change‐induced events on forest ecosystem dynamics of composition, function and structure call for increased long‐term, interdisciplinary and integrated research on biodiversity indicators, in particular within strictly protected areas with extensive non‐intervention zones. The long‐established concept of forest supersites generally relies on long‐term funds from national agencies and goes beyond the logistic and financial capabilities of state‐ or region‐wide protected area administrations, universities and research institutes. We introduce the concept of data pools as a smaller‐scale, user‐driven and reasonable alternative to co‐develop remote sensing and forest ecosystem science to validated products, biodiversity indicators and management plans. We demonstrate this concept with the Bohemian Forest Ecosystem Data Pool, which has been established as an interdisciplinary, international data pool within the strictly protected Bavarian Forest and Šumava National Parks and currently comprises 10 active partners. We demonstrate how the structure and impact of the data pool differs from comparable cases. We assessed the international influence and visibility of the data pool with the help of a systematic literature search and a brief analysis of the results. Results primarily suggest an increase in the impact and visibility of published material during the life span of the data pool, with highest visibilities achieved by research conducted on leaf traits, vegetation phenology and 3D‐based forest inventory. We conclude that the data pool results in an efficient contribution to the concept of global biodiversity observatory by evolving towards a training platform, functioning as a pool of data and algorithms, directly communicating with management for implementation and providing test fields for feasibility studies on earth observation missions. KW - bohemian forest ecosystem KW - data pool KW - forest ecosystem science KW - remote sensing KW - remote sensing‐enabled essential biodiversity variables Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262743 VL - 12 IS - 11 ER - TY - JOUR A1 - Maierhofer, Anna A1 - Flunkert, Julia A1 - Dittrich, Marcus A1 - Müller, Tobias A1 - Schindler, Detlev A1 - Nanda, Indrajit A1 - Haaf, Thomas T1 - Analysis of global DNA methylation changes in primary human fibroblasts in the early phase following X-ray irradiation JF - PLoS ONE N2 - Epigenetic alterations may contribute to the generation of cancer cells in a multi-step process of tumorigenesis following irradiation of normal body cells. Primary human fibroblasts with intact cell cycle checkpoints were used as a model to test whether X-ray irradiation with 2 and 4 Gray induces direct epigenetic effects (within the first cell cycle) in the exposed cells. ELISA-based fluorometric assays were consistent with slightly reduced global DNA methylation and hydroxymethylation, however the observed between-group differences were usually not significant. Similarly, bisulfite pyrosequencing of interspersed LINE-1 repeats and centromeric α-satellite DNA did not detect significant methylation differences between irradiated and non-irradiated cultures. Methylation of interspersed ALU repeats appeared to be slightly increased (one percentage point; p = 0.01) at 6 h after irradiation with 4 Gy. Single-cell analysis showed comparable variations in repeat methylation among individual cells in both irradiated and control cultures. Radiation-induced changes in global repeat methylation, if any, were much smaller than methylation variation between different fibroblast strains. Interestingly, α-satellite DNA methylation positively correlated with gestational age. Finally, 450K methylation arrays mainly targeting genes and CpG islands were used for global DNA methylation analysis. There were no detectable methylation differences in genic (promoter, 5' UTR, first exon, gene body, 3' UTR) and intergenic regions between irradiated and control fibroblast cultures. Although we cannot exclude minor effects, i.e. on individual CpG sites, collectively our data suggest that global DNA methylation remains rather stable in irradiated normal body cells in the early phase of DNA damage response. KW - DNA methylation KW - fibroblasts KW - methylation KW - alu elements KW - DNA damage KW - epigenetics KW - cancer treatment Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170895 VL - 12 IS - 5 ER - TY - JOUR A1 - Thorn, Simon A1 - Seibold, Sebastian A1 - Leverkus, Alexandro B A1 - Michler, Thomas A1 - Müller, Jörg A1 - Noss, Reed F A1 - Stork, Nigel A1 - Vogel, Sebastian A1 - Lindenmayer, David B T1 - The living dead: acknowledging life after tree death to stop forest degradation JF - Frontiers in Ecology and the Environment N2 - Global sustainability agendas focus primarily on halting deforestation, yet the biodiversity crisis resulting from the degradation of remaining forests is going largely unnoticed. Forest degradation occurs through the loss of key ecological structures, such as dying trees and deadwood, even in the absence of deforestation. One of the main drivers of forest degradation is limited awareness by policy makers and the public on the importance of these structures for supporting forest biodiversity and ecosystem function. Here, we outline management strategies to protect forest health and biodiversity by maintaining and promoting deadwood, and propose environmental education initiatives to improve the general awareness of the importance of deadwood. Finally, we call for major reforms to forest management to maintain and restore deadwood; large, old trees; and other key ecological structures. KW - forest degradation KW - biodiversity KW - deadwood Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-218575 VL - 18 IS - 9 SP - 505 EP - 512 ER - TY - JOUR A1 - Müller, Thomas A1 - Mueller, Bernhard Klaus A1 - Riederer, Peter T1 - Perspective: Treatment for disease modification in chronic neurodegeneration JF - Cells N2 - Symptomatic treatments are available for Parkinson's disease and Alzheimer's disease. An unmet need is cure or disease modification. This review discusses possible reasons for negative clinical study outcomes on disease modification following promising positive findings from experimental research. It scrutinizes current research paradigms for disease modification with antibodies against pathological protein enrichment, such as α-synuclein, amyloid or tau, based on post mortem findings. Instead a more uniform regenerative and reparative therapeutic approach for chronic neurodegenerative disease entities is proposed with stimulation of an endogenously existing repair system, which acts independent of specific disease mechanisms. The repulsive guidance molecule A pathway is involved in the regulation of peripheral and central neuronal restoration. Therapeutic antagonism of repulsive guidance molecule A reverses neurodegeneration according to experimental outcomes in numerous disease models in rodents and monkeys. Antibodies against repulsive guidance molecule A exist. First clinical studies in neurological conditions with an acute onset are under way. Future clinical trials with these antibodies should initially focus on well characterized uniform cohorts of patients. The efficiency of repulsive guidance molecule A antagonism and associated stimulation of neurogenesis should be demonstrated with objective assessment tools to counteract dilution of therapeutic effects by subjectivity and heterogeneity of chronic disease entities. Such a research concept will hopefully enhance clinical test strategies and improve the future therapeutic armamentarium for chronic neurodegeneration. KW - neurodegeneration KW - repulsive guidance molecule A KW - neuroprotection KW - repair KW - oxidative stress KW - apoptosis KW - neurogenesis Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236644 SN - 2073-4409 VL - 10 IS - 4 ER - TY - JOUR A1 - Pinkawa, Michael A1 - Aebersold, Daniel M. A1 - Böhmer, Dirk A1 - Flentje, Michael A1 - Ghadjar, Pirus A1 - Schmidt-Hegemann, Nina-Sophie A1 - Höcht, Stefan A1 - Hölscher, Tobias A1 - Müller, Arndt-Christian A1 - Niehoff, Peter A1 - Sedlmayer, Felix A1 - Wolf, Frank A1 - Zamboglou, Constantinos A1 - Zips, Daniel A1 - Wiegel, Thomas T1 - Radiotherapy in nodal oligorecurrent prostate cancer JF - Strahlentherapie und Onkologie N2 - Objective The current article encompasses a literature review and recommendations for radiotherapy in nodal oligorecurrent prostate cancer. Materials and methods A literature review focused on studies comparing metastasis-directed stereotactic ablative radiotherapy (SABR) vs. external elective nodal radiotherapy (ENRT) and studies analyzing recurrence patterns after local nodal treatment was performed. The DEGRO Prostate Cancer Expert Panel discussed the results and developed treatment recommendations. Results Metastasis-directed radiotherapy results in high local control (often > 90% within a follow-up of 1–2 years) and can be used to improve progression-free survival or defer androgen deprivation therapy (ADT) according to prospective randomized phase II data. Distant progression after involved-node SABR only occurs within a few months in the majority of patients. ENRT improves metastases-free survival rates with increased toxicity in comparison to SABR according to retrospective comparative studies. The majority of nodal recurrences after initial local treatment of pelvic nodal metastasis are detected within the true pelvis and common iliac vessels. Conclusion ENRT with or without a boost should be preferred to SABR in pelvic nodal recurrences. In oligometastatic prostate cancer with distant (extrapelvic) nodal recurrences, SABR alone can be performed in selected cases. Application of additional systemic treatments should be based on current guidelines, with ADT as first-line treatment for hormone-sensitive prostate cancer. Only in carefully selected patients can radiotherapy be initially used without additional ADT outside of the current standard recommendations. Results of (randomized) prospective studies are needed for definitive recommendations. KW - prostate cancer KW - oligorecurrence KW - metastasis-directed therapy KW - radiation therapy KW - androgen deprivation therapy KW - stereotactic body radiotherapy KW - oligmometastases KW - lymph node metastases Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-307763 SN - 0179-7158 SN - 1439-099X VL - 197 IS - 7 ER - TY - JOUR A1 - Luther, Christian H. A1 - Brandt, Philipp A1 - Vylkova, Slavena A1 - Dandekar, Thomas A1 - Müller, Tobias A1 - Dittrich, Marcus T1 - Integrated analysis of SR-like protein kinases Sky1 and Sky2 links signaling networks with transcriptional regulation in Candida albicans JF - Frontiers in Cellular and Infection Microbiology N2 - Fungal infections are a major global health burden where Candida albicans is among the most common fungal pathogen in humans and is a common cause of invasive candidiasis. Fungal phenotypes, such as those related to morphology, proliferation and virulence are mainly driven by gene expression, which is primarily regulated by kinase signaling cascades. Serine-arginine (SR) protein kinases are highly conserved among eukaryotes and are involved in major transcriptional processes in human and S. cerevisiae. Candida albicans harbors two SR protein kinases, while Sky2 is important for metabolic adaptation, Sky1 has similar functions as in S. cerevisiae. To investigate the role of these SR kinases for the regulation of transcriptional responses in C. albicans, we performed RNA sequencing of sky1Δ and sky2Δ and integrated a comprehensive phosphoproteome dataset of these mutants. Using a Systems Biology approach, we study transcriptional regulation in the context of kinase signaling networks. Transcriptomic enrichment analysis indicates that pathways involved in the regulation of gene expression are downregulated and mitochondrial processes are upregulated in sky1Δ. In sky2Δ, primarily metabolic processes are affected, especially for arginine, and we observed that arginine-induced hyphae formation is impaired in sky2Δ. In addition, our analysis identifies several transcription factors as potential drivers of the transcriptional response. Among these, a core set is shared between both kinase knockouts, but it appears to regulate different subsets of target genes. To elucidate these diverse regulatory patterns, we created network modules by integrating the data of site-specific protein phosphorylation and gene expression with kinase-substrate predictions and protein-protein interactions. These integrated signaling modules reveal shared parts but also highlight specific patterns characteristic for each kinase. Interestingly, the modules contain many proteins involved in fungal morphogenesis and stress response. Accordingly, experimental phenotyping shows a higher resistance to Hygromycin B for sky1Δ. Thus, our study demonstrates that a combination of computational approaches with integration of experimental data can offer a new systems biological perspective on the complex network of signaling and transcription. With that, the investigation of the interface between signaling and transcriptional regulation in C. albicans provides a deeper insight into how cellular mechanisms can shape the phenotype. KW - sky kinases KW - kinase signaling KW - network analysis KW - transcriptome KW - transcriptional regulation KW - phosphoproteome KW - Candida albicans Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-311771 SN - 2235-2988 VL - 13 ER - TY - JOUR A1 - Mohme, Sophia A1 - Schmalzing, Marc A1 - Müller, Cornelia S.L. A1 - Vogt, Thomas A1 - Goebeler, Matthias A1 - Stoevesandt, Johanna T1 - Immunizations in immunocompromised patients: a guide for dermatologists JF - JDDG: Journal der Deutschen Dermatologischen Gesellschaft N2 - The increasingly frequent use of immunomodulatory agents in dermatology requires the observance of specific recommendations for immunization. These recommendations are developed and regularly updated by the German Standing Committee on Vaccination (STIKO), an independent advisory group at the Robert Koch Institute. Dermatological patients on immunosuppressive treatment should ideally receive all vaccinations included in the standard immunization schedule. Additionally, it is recommended that they also undergo vaccination against the seasonal flu, pneumococci, and herpes zoster (inactivated herpes zoster subunit vaccine for patients ≥ 50 years). Additional immunizations against Haemophilus influenzae type B, hepatitis B and meningococci may be indicated depending on individual comorbidities and exposure risk. Limitations of use, specific contraindications and intervals to be observed between vaccination and immunosuppression depend on the immunosuppressive agent used and its dosing. Only under certain conditions may live‐attenuated vaccines be administered in patients on immunosuppressive therapy. Given its strong suppressive effect on the humoral immune response, no vaccines – except for flu shots – should be given within six months after rituximab therapy. This CME article presents current recommendations on immunization in immunocompromised individuals, with a special focus on dermatological patients. Its goal is to enable readers to provide competent counseling and to initiate necessary immunizations in this vulnerable patient group. Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-217982 VL - 18 IS - 7 SP - 699 EP - 723 ER - TY - JOUR A1 - Fazeli, Gholamreza A1 - Beer, Katharina B. A1 - Geisenhof, Michaela A1 - Tröger, Sarah A1 - König, Julia A1 - Müller-Reichert, Thomas A1 - Wehman, Ann M. T1 - Loss of the Major Phosphatidylserine or Phosphatidylethanolamine Flippases Differentially Affect Phagocytosis JF - Frontiers in Cell and Developmental Biology N2 - The lipids phosphatidylserine (PtdSer) and phosphatidylethanolamine (PtdEth) are normally asymmetrically localized to the cytosolic face of membrane bilayers, but can both be externalized during diverse biological processes, including cell division, cell fusion, and cell death. Externalized lipids in the plasma membrane are recognized by lipid-binding proteins to regulate the clearance of cell corpses and other cell debris. However, it is unclear whether PtdSer and PtdEth contribute in similar or distinct ways to these processes. We discovered that disruption of the lipid flippases that maintain PtdSer or PtdEth asymmetry in the plasma membrane have opposite effects on phagocytosis in Caenorhabditis elegans embryos. Constitutive PtdSer externalization caused by disruption of the major PtdSer flippase TAT-1 led to increased phagocytosis of cell debris, sometimes leading to two cells engulfing the same debris. In contrast, PtdEth externalization caused by depletion of the major PtdEth flippase TAT-5 or its activator PAD-1 disrupted phagocytosis. These data suggest that PtdSer and PtdEth externalization have opposite effects on phagocytosis. Furthermore, externalizing PtdEth is associated with increased extracellular vesicle release, and we present evidence that the extent of extracellular vesicle accumulation correlates with the extent of phagocytic defects. Thus, a general loss of lipid asymmetry can have opposing impacts through different lipid subtypes simultaneously exerting disparate effects. KW - phagocytosis KW - lipid asymmetry KW - flippase KW - phosphatidylserine KW - phosphatidylethanolamine KW - extracellular vesicle Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-208771 SN - 2296-634X VL - 8 ER - TY - JOUR A1 - Müller, Sophie A1 - Köhler, Franziska A1 - Hendricks, Anne A1 - Kastner, Carolin A1 - Börner, Kevin A1 - Diers, Johannes A1 - Lock, Johan F. A1 - Petritsch, Bernhard A1 - Germer, Christoph-Thomas A1 - Wiegering, Armin T1 - Brain metastases from colorectal cancer: a systematic review of the literature and meta-analysis to establish a guideline for daily treatment JF - Cancers N2 - Colorectal cancer (CRC) is the third most common malignancy worldwide. Most patients with metastatic CRC develop liver or lung metastases, while a minority suffer from brain metastases. There is little information available regarding the presentation, treatment, and overall survival of brain metastases (BM) from CRC. This systematic review and meta-analysis includes data collected from three major databases (PubMed, Cochrane, and Embase) based on the key words “brain”, “metastas*”, “tumor”, “colorectal”, “cancer”, and “malignancy”. In total, 1318 articles were identified in the search and 86 studies matched the inclusion criteria. The incidence of BM varied between 0.1% and 11.5%. Most patients developed metastases at other sites prior to developing BM. Lung metastases and KRAS mutations were described as risk factors for additional BM. Patients with BM suffered from various symptoms, but up to 96.8% of BM patients were asymptomatic at the time of BM diagnosis. Median survival time ranged from 2 to 9.6 months, and overall survival (OS) increased up to 41.1 months in patients on a multimodal therapy regimen. Several factors including age, blood levels of carcinoembryonic antigen (CEA), multiple metastases sites, number of brain lesions, and presence of the KRAS mutation were predictors of OS. For BM diagnosis, MRI was considered to be state of the art. Treatment consisted of a combination of surgery, radiation, or systemic treatment. KW - brain metastases KW - cerebral metastases KW - BM KW - colorectal cancer KW - CRC KW - systematic review KW - meta-analysis Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228883 SN - 2072-6694 VL - 13 IS - 4 ER - TY - JOUR A1 - Uhler, Johannes A1 - Redlich, Sarah A1 - Zhang, Jie A1 - Hothorn, Torsten A1 - Tobisch, Cynthia A1 - Ewald, Jörg A1 - Thorn, Simon A1 - Seibold, Sebastian A1 - Mitesser, Oliver A1 - Morinère, Jérôme A1 - Bozicevic, Vedran A1 - Benjamin, Caryl S. A1 - Englmeier, Jana A1 - Fricke, Ute A1 - Ganuza, Cristina A1 - Haensel, Maria A1 - Riebl, Rebekka A1 - Rojas-Botero, Sandra A1 - Rummler, Thomas A1 - Uphus, Lars A1 - Schmidt, Stefan A1 - Steffan-Dewenter, Ingolf A1 - Müller, Jörg T1 - Relationships of insect biomass and richness with land use along a climate gradient JF - Nature Communications N2 - Recently reported insect declines have raised both political and social concern. Although the declines have been attributed to land use and climate change, supporting evidence suffers from low taxonomic resolution, short time series, a focus on local scales, and the collinearity of the identified drivers. In this study, we conducted a systematic assessment of insect populations in southern Germany, which showed that differences in insect biomass and richness are highly context dependent. We found the largest difference in biomass between semi-natural and urban environments (-42%), whereas differences in total richness (-29%) and the richness of threatened species (-56%) were largest from semi-natural to agricultural environments. These results point to urbanization and agriculture as major drivers of decline. We also found that richness and biomass increase monotonously with increasing temperature, independent of habitat. The contrasting patterns of insect biomass and richness question the use of these indicators as mutual surrogates. Our study provides support for the implementation of more comprehensive measures aimed at habitat restoration in order to halt insect declines. KW - biodiversity KW - ecology Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265058 VL - 12 IS - 1 ER - TY - JOUR A1 - Schulz, Herbert A1 - Ruppert, Ann-Kathrin A1 - Herms, Stefan A1 - Wolf, Christiane A1 - Mirza-Schreiber, Nazanin A1 - Stegle, Oliver A1 - Czamara, Darina A1 - Forstner, Andreas J. A1 - Sivalingam, Sugirthan A1 - Schoch, Susanne A1 - Moebus, Susanne A1 - Pütz, Benno A1 - Hillmer, Axel A1 - Fricker, Nadine A1 - Vatter, Hartmut A1 - Müller-Myhsok, Bertram A1 - Nöthen, Markus M. A1 - Becker, Albert J. A1 - Hoffmann, Per A1 - Sander, Thomas A1 - Cichon, Sven T1 - Genome-wide mapping of genetic determinants influencing DNA methylation and gene expression in human hippocampus JF - Nature Communications N2 - Emerging evidence emphasizes the strong impact of regulatory genomic elements in neurodevelopmental processes and the complex pathways of brain disorders. The present genome-wide quantitative trait loci analyses explore the \(cis\)-regulatory effects of single-nucleotide polymorphisms (SNPs) on DNA methylation (meQTL) and gene expression (eQTL) in 110 human hippocampal biopsies. We identify \(cis\)-meQTLs at 14,118 CpG methylation sites and \(cis\)-eQTLs for 302 3′-mRNA transcripts of 288 genes. Hippocampal \(cis\)-meQTL-CpGs are enriched in flanking regions of active promoters, CpG island shores, binding sites of the transcription factor CTCF and brain eQTLs. \(Cis\)-acting SNPs of hippocampal meQTLs and eQTLs significantly overlap schizophrenia-associated SNPs. Correlations of CpG methylation and RNA expression are found for 34 genes. Our comprehensive maps of \(cis\)-acting hippocampal meQTLs and eQTLs provide a link between disease-associated SNPs and the regulatory genome that will improve the functional interpretation of non-coding genetic variants in the molecular genetic dissection of brain disorders. KW - psychiatry KW - epigenetics in the nervous system KW - epigenomics KW - gene expression KW - neurological disorders Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173168 VL - 8 ER - TY - JOUR A1 - Katzorke, Andrea A1 - Zeller, Julia B. M. A1 - Müller, Laura D. A1 - Lauer, Martin A1 - Polak, Thomas A1 - Reif, Andreas A1 - Deckert, Jürgen A1 - Herrmann, Martin J. T1 - Reduced activity in the right inferior frontal gyrus in elderly APOE-E4 carriers during a verbal fluency task JF - Frontiers in Human Neuroscience N2 - Apolipoprotein-E4 (APOE-E4) is a major genetic risk factor for developing Alzheimer’s disease (AD). The verbal fluency task (VFT), especially the subtask category fluency, has shown to provide a good discrimination between cognitively normal controls and subjects with AD. Interestingly, APOE-E4 seems to have no effect on the behavioral performance during a VFT in healthy elderly. Thus, the purpose of the present study was to reveal possible compensation mechanisms by investigating the effect of APOE-E4 on the hemodynamic response in non-demented elderly during a VFT by using functional near-infrared spectroscopy (fNIRS). We compared performance and hemodynamic response of high risk APOE-E4/E4, -E3/E4 carriers with neutral APOE-E3/E3 non-demented subjects (N = 288; 70–77 years). No difference in performance was found. APOE-E4/E4, -E3/E4 carriers had a decreased hemodynamic response in the right inferior frontal junction (IFJ) with a corresponding higher response in the left middle frontal gyrus (MFG) during category fluency. Performance was correlated with the hemodynamic response in the MFG. We assume a compensation of decreased IFJ brain activation by utilizing the MFG during category fluency and thus resulting in no behavioral differences between APOE-groups during the performance of a VFT. KW - psychiatry KW - near-infrared spectroscopy KW - verbal fluency task KW - apolipoprotein-E4 KW - Alzheimer's disease KW - elderly Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-171892 VL - 11 ER - TY - JOUR A1 - Schmid, Tobias A1 - Falter, Lena A1 - Weber, Sabine A1 - Müller, Nils A1 - Molitor, Konstantin A1 - Zeller, David A1 - Weber-Steffens, Dorothea A1 - Hehlgans, Thomas A1 - Wajant, Harald A1 - Mostböck, Sven A1 - Männel, Daniela N. T1 - Chronic inflammation increases the sensitivity of mouse Treg for TNFR2 costimulation JF - Frontiers in Immunology N2 - 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 naïve 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 naïve 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 naïve mice can lead to immune suppression \(in\) \(vivo\). These findings support the important role of TNFR2 for Treg cells in immune regulation. KW - molecular medicine KW - inflammation KW - immune regulation KW - costimulation KW - MDSC KW - TNFR2 KW - regulatory T cell Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173259 VL - 8 ER - TY - JOUR A1 - Doll, Julia A1 - Vona, Barbara A1 - Schnapp, Linda A1 - Rüschendorf, Franz A1 - Khan, Imran A1 - Khan, Saadullah A1 - Muhammad, Noor A1 - Alam Khan, Sher A1 - Nawaz, Hamed A1 - Khan, Ajmal A1 - Ahmad, Naseer A1 - Kolb, Susanne M. A1 - Kühlewein, Laura A1 - Labonne, Jonathan D. J. A1 - Layman, Lawrence C. A1 - Hofrichter, Michaela A. H. A1 - Röder, Tabea A1 - Dittrich, Marcus A1 - Müller, Tobias A1 - Graves, Tyler D. A1 - Kong, Il-Keun A1 - Nanda, Indrajit A1 - Kim, Hyung-Goo A1 - Haaf, Thomas T1 - Genetic Spectrum of Syndromic and Non-Syndromic Hearing Loss in Pakistani Families JF - Genes N2 - The current molecular genetic diagnostic rates for hereditary hearing loss (HL) vary considerably according to the population background. Pakistan and other countries with high rates of consanguineous marriages have served as a unique resource for studying rare and novel forms of recessive HL. A combined exome sequencing, bioinformatics analysis, and gene mapping approach for 21 consanguineous Pakistani families revealed 13 pathogenic or likely pathogenic variants in the genes GJB2, MYO7A, FGF3, CDC14A, SLITRK6, CDH23, and MYO15A, with an overall resolve rate of 61.9%. GJB2 and MYO7A were the most frequently involved genes in this cohort. All the identified variants were either homozygous or compound heterozygous, with two of them not previously described in the literature (15.4%). Overall, seven missense variants (53.8%), three nonsense variants (23.1%), two frameshift variants (15.4%), and one splice-site variant (7.7%) were observed. Syndromic HL was identified in five (23.8%) of the 21 families studied. This study reflects the extreme genetic heterogeneity observed in HL and expands the spectrum of variants in deafness-associated genes. KW - genetic diagnosis KW - consanguinity KW - genome-wide linkage analysis KW - hearing loss KW - Pakistan KW - exome sequencing Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-219293 SN - 2073-4425 VL - 11 IS - 11 ER - TY - JOUR A1 - Wilde, Anne-Christin Beatrice A1 - Lieb, Charlotte A1 - Leicht, Elise A1 - Greverath, Lena Maria A1 - Steinhagen, Lara Marleen A1 - Wald de Chamorro, Nina A1 - Petersen, Jörg A1 - Hofmann, Wolf Peter A1 - Hinrichsen, Holger A1 - Heyne, Renate A1 - Berg, Thomas A1 - Naumann, Uwe A1 - Schwenzer, Jeannette A1 - Vermehren, Johannes A1 - Geier, Andreas A1 - Tacke, Frank A1 - Müller, Tobias T1 - Real-world clinical management of patients with primary biliary cholangitis — a retrospective multicenter study from Germany JF - Journal of Clinical Medicine N2 - Background: Clinical practice guidelines for patients with primary biliary cholangitis (PBC) have been recently revised and implemented for well-established response criteria to standard first-line ursodeoxycholic acid (UDCA) therapy at 12 months after treatment initiation for the early identification of high-risk patients with inadequate treatment responses who may require treatment modification. However, there are only very limited data concerning the real-world clinical management of patients with PBC in Germany. Objective: The aim of this retrospective multicenter study was to evaluate response rates to standard first-line UDCA therapy and subsequent Second-line treatment regimens in a large cohort of well-characterized patients with PBC from 10 independent hepatological referral centers in Germany prior to the introduction of obeticholic acid as a licensed second-line treatment option. Methods: Diagnostic confirmation of PBC, standard first-line UDCA treatment regimens and response rates at 12 months according to Paris-I, Paris-II, and Barcelona criteria, the follow-up cut-off alkaline phosphatase (ALP) ≤ 1.67 × upper limit of normal (ULN) and the normalization of bilirubin (bilirubin ≤ 1 × ULN) were retrospectively examined between June 1986 and March 2017. The management and hitherto applied second-line treatment regimens in patients with an inadequate response to UDCA and subsequent response rates at 12 months were also evaluated. Results: Overall, 480 PBC patients were included in this study. The median UDCA dosage was 13.2 mg UDCA/kg bodyweight (BW)/d. Adequate UDCA treatment response rates according to Paris-I, Paris-II, and Barcelona criteria were observed in 91, 71.3, and 61.3% of patients, respectively. In 83.8% of patients, ALP ≤ 1.67 × ULN were achieved. A total of 116 patients (24.2%) showed an inadequate response to UDCA according to at least one criterion. The diverse second-line treatment regimens applied led to significantly higher response rates according to Paris-II (35 vs. 60%, p = 0.005), Barcelona (13 vs. 34%, p = 0.0005), ALP ≤ 1.67 × ULN and bilirubin ≤ 1 × ULN (52.1 vs. 75%, p = 0.002). The addition of bezafibrates appeared to induce the strongest beneficial effect in this cohort (Paris II: 24 vs. 74%, p = 0.004; Barcelona: 50 vs. 84%, p = 0.046; ALP < 1.67 × ULN and bilirubin ≤ 1 × ULN: 33 vs. 86%, p = 0.001). Conclusion: Our large retrospective multicenter study confirms high response rates following UDCA first-line standard treatment in patients with PBC and highlights the need for close monitoring and early treatment modification in high-risk patients with an insufficient response to UDCA since early treatment modification significantly increases subsequent response rates of these patients. KW - primary biliary cholangitis KW - autoantibodies KW - ursodeoxycholic acid KW - treatment response KW - second line therapy Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234003 SN - 2077-0383 VL - 10 IS - 5 ER - TY - JOUR A1 - Barbieri, Flavia L. A1 - Gardon, Jacques A1 - Ruiz-Castell, María A1 - Paco V., Pamela A1 - Muckelbauer, Rebecca A1 - Casiot, Corinne A1 - Freydier, Rémi A1 - Duprey, Jean-Louis A1 - Chen, Chih-Mei A1 - Müller-Nordhorn, Jacqueline A1 - Keil, Thomas T1 - Toxic trace elements in maternal and cord blood and social determinants in a Bolivian mining city JF - International Journal of Environmental Health Research N2 - This study assessed lead, arsenic, and antimony in maternal and cord blood, and associations between maternal concentrations and social determinants in the Bolivian mining city of Oruro using the baseline assessment of the ToxBol/Mine-Niño birth cohort. We recruited 467 pregnant women, collecting venous blood and sociodemographic information as well as placental cord blood at birth. Metallic/semimetallic trace elements were measured using inductively coupled plasma mass spectrometry. Lead medians in maternal and cord blood were significantly correlated (Spearman coefficient = 0.59; p < 0.001; 19.35 and 13.50 μg/L, respectively). Arsenic concentrations were above detection limit (3.30 μg/L) in 17.9 % of maternal and 34.6 % of cord blood samples. They were not associated (Fischer’s p = 0.72). Antimony medians in maternal and cord blood were weakly correlated (Spearman coefficient = 0.15; p < 0.03; 9.00 and 8.62 μg/L, respectively). Higher concentrations of toxic elements in maternal blood were associated with maternal smoking, low educational level, and partner involved in mining. KW - environmental exposure KW - metallic trace elements KW - maternal exposure KW - prenatal exposure KW - risk factors Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-150385 VL - 26 IS - 2 ER - TY - JOUR A1 - Müller, Stefanie H. A1 - Girard, Simon L. A1 - Hopfner, Franziska A1 - Merner, Nancy D. A1 - Bourassa, Cynthia V. A1 - Lorenz, Delia A1 - Clark, Lorraine N. A1 - Tittmann, Lukas A1 - Soto-Ortolaza, Alexandra I. A1 - Klebe, Stephan A1 - Hallett, Mark A1 - Schneider, Susanne A. A1 - Hodgkinson, Colin A. A1 - Lieb, Wolfgang A1 - Wszolek, Zbigniew K. A1 - Pendziwiat, Manuela A1 - Lorenzo-Betancor, Oswaldo A1 - Poewe, Werner A1 - Ortega-Cubero, Sara A1 - Seppi, Klaus A1 - Rajput, Alex A1 - Hussl, Anna A1 - Rajput, Ali H. A1 - Berg, Daniela A1 - Dion, Patrick A. A1 - Wurster, Isabel A1 - Shulman, Joshua M. A1 - Srulijes, Karin A1 - Haubenberger, Dietrich A1 - Pastor, Pau A1 - Vilariño-Güell, Carles A1 - Postuma, Ronald B. A1 - Bernard, Geneviève A1 - Ladwig, Karl-Heinz A1 - Dupré, Nicolas A1 - Jankovic, Joseph A1 - Strauch, Konstantin A1 - Panisset, Michel A1 - Winkelmann, Juliane A1 - Testa, Claudia M. A1 - Reischl, Eva A1 - Zeuner, Kirsten E. A1 - Ross, Owen A. A1 - Arzberger, Thomas A1 - Chouinard, Sylvain A1 - Deuschl, Günther A1 - Louis, Elan D. A1 - Kuhlenbäumer, Gregor A1 - Rouleau, Guy A. T1 - Genome-wide association study in essential tremor identifies three new loci JF - Brain N2 - We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discovery stage were genotyped in the replication stage. After Bonferroni correction two markers, one (rs10937625) located in the serine/threonine kinase STK32B and one (rs17590046) in the transcriptional coactivator PPARGC1A were associated with essential tremor. Three markers (rs12764057, rs10822974, rs7903491) in the cell-adhesion molecule CTNNA3 were significant in the combined analysis of both stages. The expression of STK32B was increased in the cerebellar cortex of patients and expression quantitative trait loci database mining showed association between the protective minor allele of rs10937625 and reduced expression in cerebellar cortex. We found no expression differences related to disease status or marker genotype for the other two genes. Replication of two lead single nucleotide polymorphisms of previous small genome-wide association studies (rs3794087 in SLC1A2, rs9652490 in LINGO1) did not confirm the association with essential tremor. KW - quality-control KW - disease KW - tool KW - movement disorders KW - genome-wide association study KW - tremor KW - genetics KW - essential tremor Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186541 VL - 139 ER - TY - JOUR A1 - Müller, Philipp L. A1 - Meigen, Thomas T1 - M-sequences in ophthalmic electrophysiology JF - Journal of Vision N2 - The aim of this review is to use the multimedia aspects of a purely digital online publication to explain and illustrate the highly capable technique of m-sequences in multifocal ophthalmic electrophysiology. M-sequences have been successfully applied in clinical routines during the past 20 years. However, the underlying mathematical rationale is often daunting. These mathematical properties of m-sequences allow one not only to separate the responses from different fields but also to analyze adaptational effects and impacts of former events. By explaining the history, the formation, and the different aspects of application, a better comprehension of the technique is intended. With this review we aim to clarify the opportunities of m-sequences in order to motivate scientists to use m-sequences in their future research. KW - vision Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165796 VL - 16 IS - 1,15 ER - TY - JOUR A1 - vom Dahl, Christian A1 - Müller, Christoph Emanuel A1 - Berisha, Xhevat A1 - Nagel, Georg A1 - Zimmer, Thomas T1 - Coupling the cardiac voltage-gated sodium channel to channelrhodopsin-2 generates novel optical switches for action potential studies JF - Membranes N2 - Voltage-gated sodium (Na\(^+\)) channels respond to short membrane depolarization with conformational changes leading to pore opening, Na\(^+\) influx, and action potential (AP) upstroke. In the present study, we coupled channelrhodopsin-2 (ChR2), the key ion channel in optogenetics, directly to the cardiac voltage-gated Na\(^+\) channel (Na\(_v\)1.5). Fusion constructs were expressed in Xenopus laevis oocytes, and electrophysiological recordings were performed by the two-microelectrode technique. Heteromeric channels retained both typical Na\(_v\)1.5 kinetics and light-sensitive ChR2 properties. Switching to the current-clamp mode and applying short blue-light pulses resulted either in subthreshold depolarization or in a rapid change of membrane polarity typically seen in APs of excitable cells. To study the effect of individual K\(^+\) channels on the AP shape, we co-expressed either K\(_v\)1.2 or hERG with one of the Na\(_v\)1.5-ChR2 fusions. As expected, both delayed rectifier K\(^+\) channels shortened AP duration significantly. K\(_v\)1.2 currents remarkably accelerated initial repolarization, whereas hERG channel activity efficiently restored the resting membrane potential. Finally, we investigated the effect of the LQT3 deletion mutant ΔKPQ on the AP shape and noticed an extremely prolonged AP duration that was directly correlated to the size of the non-inactivating Na\(^+\) current fraction. In conclusion, coupling of ChR2 to a voltage-gated Na\(^+\) channel generates optical switches that are useful for studying the effect of individual ion channels on the AP shape. Moreover, our novel optogenetic approach provides the potential for an application in pharmacology and optogenetic tissue-engineering. KW - optogenetics KW - channelrhodopsin KW - voltage-gated Na\(^+\) channel KW - action potential KW - delayed rectifier potassium channel KW - hERG KW - long QT syndrome Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288228 SN - 2077-0375 VL - 12 IS - 10 ER - TY - JOUR A1 - Stratos, Ioannis A1 - Rinas, Ingmar A1 - Schröpfer, Konrad A1 - Hink, Katharina A1 - Herlyn, Philipp A1 - Bäumler, Mario A1 - Histing, Tina A1 - Bruhn, Sven A1 - Müller-Hilke, Brigitte A1 - Menger, Michael D. A1 - Vollmar, Brigitte A1 - Mittlmeier, Thomas T1 - Effects on bone and muscle upon treadmill interval training in hypogonadal male rats JF - Biomedicines N2 - Testosterone deficiency in males is linked to various pathological conditions, including muscle and bone loss. This study evaluated the potential of different training modalities to counteract these losses in hypogonadal male rats. A total of 54 male Wistar rats underwent either castration (ORX, n = 18) or sham castration (n = 18), with 18 castrated rats engaging in uphill, level, or downhill interval treadmill training. Analyses were conducted at 4, 8, and 12 weeks postsurgery. Muscle force of the soleus muscle, muscle tissue samples, and bone characteristics were analyzed. No significant differences were observed in cortical bone characteristics. Castrated rats experienced decreased trabecular bone mineral density compared to sham-operated rats. However, 12 weeks of training increased trabecular bone mineral density, with no significant differences among groups. Muscle force measurements revealed decreased tetanic force in castrated rats at week 12, while uphill and downhill interval training restored force to sham group levels and led to muscle hypertrophy compared to ORX animals. Linear regression analyses showed a positive correlation between bone biomechanical characteristics and muscle force. The findings suggest that running exercise can prevent bone loss in osteoporosis, with similar bone restoration effects observed across different training modalities. KW - osteoporosis KW - muscle KW - force KW - bone KW - micro-CT KW - training Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-319266 SN - 2227-9059 VL - 11 IS - 5 ER - TY - JOUR A1 - Ampattu, Biju Joseph A1 - Hagmann, Laura A1 - Liang, Chunguang A1 - Dittrich, Marcus A1 - Schlüter, Andreas A1 - Blom, Jochen A1 - Krol, Elizaveta A1 - Goesmann, Alexander A1 - Becker, Anke A1 - Dandekar, Thomas A1 - Müller, Tobias A1 - Schoen, Christoph T1 - Transcriptomic buffering of cryptic genetic variation contributes to meningococcal virulence JF - BMC Genomics N2 - Background: Commensal bacteria like Neisseria meningitidis sometimes cause serious disease. However, genomic comparison of hyperinvasive and apathogenic lineages did not reveal unambiguous hints towards indispensable virulence factors. Here, in a systems biological approach we compared gene expression of the invasive strain MC58 and the carriage strain α522 under different ex vivo conditions mimicking commensal and virulence compartments to assess the strain-specific impact of gene regulation on meningococcal virulence. Results: Despite indistinguishable ex vivo phenotypes, both strains differed in the expression of over 500 genes under infection mimicking conditions. These differences comprised in particular metabolic and information processing genes as well as genes known to be involved in host-damage such as the nitrite reductase and numerous LOS biosynthesis genes. A model based analysis of the transcriptomic differences in human blood suggested ensuing metabolic flux differences in energy, glutamine and cysteine metabolic pathways along with differences in the activation of the stringent response in both strains. In support of the computational findings, experimental analyses revealed differences in cysteine and glutamine auxotrophy in both strains as well as a strain and condition dependent essentiality of the (p)ppGpp synthetase gene relA and of a short non-coding AT-rich repeat element in its promoter region. Conclusions: Our data suggest that meningococcal virulence is linked to transcriptional buffering of cryptic genetic variation in metabolic genes including global stress responses. They further highlight the role of regulatory elements for bacterial virulence and the limitations of model strain approaches when studying such genetically diverse species as N. meningitidis. KW - neisseria meningitidis KW - MITE KW - virulenceregulatory evolution KW - systems biology KW - metabolism KW - cryptic KW - genetic variation KW - stringent response KW - relA Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-157534 VL - 18 IS - 282 ER - TY - JOUR A1 - Floren, Andreas A1 - von Rintelen, Thomas A1 - Herbert, Paul D. N. A1 - de Araujo, Bruno Cancian A1 - Schmidt, Stefan A1 - Balke, Michael A1 - Narakusumo, Raden Pramesa A1 - Peggie, Djunijanti A1 - Ubaidillah, Rosichon A1 - von Rintelen, Kristina A1 - Müller, Tobias T1 - Integrative ecological and molecular analysis indicate high diversity and strict elevational separation of canopy beetles in tropical mountain forests JF - Scientific Reports N2 - Tropical mountain forests contribute disproportionately to terrestrial biodiversity but little is known about insect diversity in the canopy and how it is distributed between tree species. We sampled tree-specific arthropod communities from 28 trees by canopy fogging and analysed beetle communities which were first morphotyped and then identified by their DNA barcodes. Our results show that communities from forests at 1100 and 1700 m a.s.l. are almost completely distinct. Diversity was much lower in the upper forest while community structure changed from many rare, less abundant species to communities with a pronounced dominance structure. We also found significantly higher beta-diversity between trees at the lower than higher elevation forest where community similarity was high. Comparisons on tree species found at both elevations reinforced these results. There was little species overlap between sites indicating limited elevational ranges. Furthermore, we exploited the advantage of DNA barcodes to patterns of haplotype diversity in some of the commoner species. Our results support the advantage of fogging and DNA barcodes for community studies and underline the need for comprehensive research aimed at the preservation of these last remaining pristine forests. KW - beta-diversity KW - community data KW - gradients KW - insects KW - hypthesis KW - evolution KW - passes KW - ants Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230565 VL - 10 ER - TY - JOUR A1 - Rinaldetti, Sébastien A1 - Pfirrmann, Markus A1 - Manz, Kirsi A1 - Guilhot, Joelle A1 - Dietz, Christian A1 - Panagiotidis, Panayiotidis A1 - Spiess, Birgit A1 - Seifarth, Wolfgang A1 - Fabarius, Alice A1 - Müller, Martin A1 - Pagoni, Maria A1 - Dimou, Maria A1 - Dengler, Jolanta A1 - Waller, Cornelius F. A1 - Brümmendorf, Tim H. A1 - Herbst, Regina A1 - Burchert, Andreas A1 - Janßen, Carsten A1 - Goebeler, Maria Elisabeth A1 - Jost, Philipp J. A1 - Hanzel, Stefan A1 - Schafhausen, Philippe A1 - Prange-Krex, Gabriele A1 - Illmer, Thomas A1 - Janzen, Viktor A1 - Klausmann, Martine A1 - Eckert, Robert A1 - Büschel, Gerd A1 - Kiani, Alexander A1 - Hofmann, Wolf-Karsten A1 - Mahon, François-Xavier A1 - Saussele, Susanne T1 - Effect of ABCG2, OCT1, and ABCB1 (MDR1) Gene Expression on Treatment-Free Remission in a EURO-SKI Subtrial JF - Clinical Lymphoma, Myeloma & Leukemia N2 - Within the EURO-SKI trial, 132 chronic phase CML patients discontinued imatinib treatment. RNA was isolated from peripheral blood in order to analyze the expression of MDR1, ABCG2 and OCT1. ABCG2 was predictive for treatment-free remission in Cox regression analysis. High transcript levels of the ABCG2 efflux transporter (>4.5 parts per thousand) were associated with a twofold higher risk of relapse. Introduction: Tyrosine kinase inhibitors (TKIs) can safely be discontinued in chronic myeloid leukemia (CML) patients with sustained deep molecular response. ABCG2 (breast cancer resistance protein), OCT1 (organic cation transporter 1), and ABCB1 (multidrug resistance protein 1) gene products are known to play a crucial role in acquired pharmacogenetic TKI resistance. Their influence on treatment-free remission (TFR) has not yet been investigated. Materials and Methods: RNA was isolated on the last day of TKI intake from peripheral blood leukocytes of 132 chronic phase CML patients who discontinued TKI treatment within the European Stop Tyrosine Kinase Inhibitor Study trial. Plasmid standards were designed including subgenic inserts of OCT1, ABCG2, and ABCB1 together with GUSB as reference gene. For expression analyses, quantitative real-time polymerase chain reaction was used. Multiple Cox regression analysis was performed. In addition, gene expression cutoffs for patient risk stratification were investigated. Results: The TFR rate of 132 patients, 12 months after TKI discontinuation, was 54% (95% confidence interval [CI], 46%-62%). ABCG2 expression (parts per thousand) was retained as the only significant variable (P=.02; hazard ratio, 1.04; 95% CI, 1.01-1.07) in multiple Cox regression analysis. Only for the ABCG2 efflux transporter, a significant cutoff was found (P=.04). Patients with an ABCG2/GUSB transcript level >4.5 parts per thousand (n=93) showed a 12-month TFR rate of 47% (95% CI, 37%-57%), whereas patients with low ABCG2 expression (<= 4.5 parts per thousand; n=39) had a 12-month TFR rate of 72% (95% CI, 55%-82%). Conclusion: In this study, we investigated the effect of pharmacogenetics in the context of a CML treatment discontinuation trial. The transcript levels of the efflux transporter ABCG2 predicted TFR after TKI discontinuation. (C) 2018 The Authors. Published by Elsevier Inc. KW - ABCG2 KW - Biomarker KW - CML KW - Imatinib KW - Prediction Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226281 VL - 18 IS - 4 ER - TY - JOUR A1 - Hennessen, Fabienne A1 - Miethke, Marcus A1 - Zaburannyi, Nestor A1 - Loose, Maria A1 - Lukežič, Tadeja A1 - Bernecker, Steffen A1 - Hüttel, Stephan A1 - Jansen, Rolf A1 - Schmiedel, Judith A1 - Fritzenwanker, Moritz A1 - Imirzalioglu, Can A1 - Vogel, Jörg A1 - Westermann, Alexander J. A1 - Hesterkamp, Thomas A1 - Stadler, Marc A1 - Wagenlehner, Florian A1 - Petković, Hrvoje A1 - Herrmann, Jennifer A1 - Müller, Rolf T1 - Amidochelocardin overcomes resistance mechanisms exerted on tetracyclines and natural chelocardin JF - Antibiotics N2 - The reassessment of known but neglected natural compounds is a vital strategy for providing novel lead structures urgently needed to overcome antimicrobial resistance. Scaffolds with resistance-breaking properties represent the most promising candidates for a successful translation into future therapeutics. Our study focuses on chelocardin, a member of the atypical tetracyclines, and its bioengineered derivative amidochelocardin, both showing broad-spectrum antibacterial activity within the ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) panel. Further lead development of chelocardins requires extensive biological and chemical profiling to achieve favorable pharmaceutical properties and efficacy. This study shows that both molecules possess resistance-breaking properties enabling the escape from most common tetracycline resistance mechanisms. Further, we show that these compounds are potent candidates for treatment of urinary tract infections due to their in vitro activity against a large panel of multidrug-resistant uropathogenic clinical isolates. In addition, the mechanism of resistance to natural chelocardin was identified as relying on efflux processes, both in the chelocardin producer Amycolatopsis sulphurea and in the pathogen Klebsiella pneumoniae. Resistance development in Klebsiella led primarily to mutations in ramR, causing increased expression of the acrAB-tolC efflux pump. Most importantly, amidochelocardin overcomes this resistance mechanism, revealing not only the improved activity profile but also superior resistance-breaking properties of this novel antibacterial compound. KW - chelocardins KW - atypical tetracyclines KW - broad-spectrum antibiotics KW - clinical isolates KW - uropathogens KW - urinary tract infection (UTI) KW - resistance-breaking properties KW - mechanism of resistance KW - AcrAB-TolC efflux pump Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-213149 SN - 2079-6382 VL - 9 IS - 9 ER - TY - JOUR A1 - Heinemann, Sascha A1 - Siegmann, Bastian A1 - Thonfeld, Frank A1 - Muro, Javier A1 - Jedmowski, Christoph A1 - Kemna, Andreas A1 - Kraska, Thorsten A1 - Muller, Onno A1 - Schultz, Johannes A1 - Udelhoven, Thomas A1 - Wilke, Norman A1 - Rascher, Uwe T1 - Land surface temperature retrieval for agricultural areas using a novel UAV platform equipped with a thermal infrared and multispectral sensor JF - Remote Sensing N2 - Land surface temperature (LST) is a fundamental parameter within the system of the Earth’s surface and atmosphere, which can be used to describe the inherent physical processes of energy and water exchange. The need for LST has been increasingly recognised in agriculture, as it affects the growth phases of crops and crop yields. However, challenges in overcoming the large discrepancies between the retrieved LST and ground truth data still exist. Precise LST measurement depends mainly on accurately deriving the surface emissivity, which is very dynamic due to changing states of land cover and plant development. In this study, we present an LST retrieval algorithm for the combined use of multispectral optical and thermal UAV images, which has been optimised for operational applications in agriculture to map the heterogeneous and diverse agricultural crop systems of a research campus in Germany (April 2018). We constrain the emissivity using certain NDVI thresholds to distinguish different land surface types. The algorithm includes atmospheric corrections and environmental thermal emissions to minimise the uncertainties. In the analysis, we emphasise that the omission of crucial meteorological parameters and inaccurately determined emissivities can lead to a considerably underestimated LST; however, if the emissivity is underestimated, the LST can be overestimated. The retrieved LST is validated by reference temperatures from nearby ponds and weather stations. The validation of the thermal measurements indicates a mean absolute error of about 0.5 K. The novelty of the dual sensor system is that it simultaneously captures highly spatially resolved optical and thermal images, in order to construct the precise LST ortho-mosaics required to monitor plant diseases and drought stress and validate airborne and satellite data. KW - UAV KW - thermal infrared KW - multispectral VNIR KW - LST KW - emissivity KW - NDVI thresholds KW - atmospheric correction KW - agricultural mapping KW - low-cost applications Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-203557 SN - 2072-4292 VL - 12 IS - 7 ER - TY - JOUR A1 - Hofrichter, Michaela A. H. A1 - Mojarad, Majid A1 - Doll, Julia A1 - Grimm, Clemens A1 - Eslahi, Atiye A1 - Hosseini, Neda Sadat A1 - Rajati, Mohsen A1 - Müller, Tobias A1 - Dittrich, Marcus A1 - Maroofian, Reza A1 - Haaf, Thomas A1 - Vona, Barbara T1 - The conserved p.Arg108 residue in S1PR2 (DFNB68) is fundamental for proper hearing: evidence from a consanguineous Iranian family JF - BMC Medical Genetics N2 - Background: Genetic heterogeneity and consanguineous marriages make recessive inherited hearing loss in Iran the second most common genetic disorder. Only two reported pathogenic variants (c.323G>C, p.Arg108Pro and c.419A>G, p.Tyr140Cys) in the S1PR2 gene have previously been linked to autosomal recessive hearing loss (DFNB68) in two Pakistani families. We describe a segregating novel homozygous c.323G>A, p.Arg108Gln pathogenic variant in S1PR2 that was identified in four affected individuals from a consanguineous five generation Iranian family. Methods: Whole exome sequencing and bioinformatics analysis of 116 hearing loss-associated genes was performed in an affected individual from a five generation Iranian family. Segregation analysis and 3D protein modeling of the p.Arg108 exchange was performed. Results: The two Pakistani families previously identified with S1PR2 pathogenic variants presented profound hearing loss that is also observed in the affected Iranian individuals described in the current study. Interestingly, we confirmed mixed hearing loss in one affected individual. 3D protein modeling suggests that the p.Arg108 position plays a key role in ligand receptor interaction, which is disturbed by the p.Arg108Gln change. Conclusion: In summary, we report the third overall mutation in S1PR2 and the first report outside the Pakistani population. Furthermore, we describe a novel variant that causes an amino acid exchange (p.Arg108Gln) in the same amino acid residue as one of the previously reported Pakistani families (p.Arg108Pro). This finding emphasizes the importance of the p.Arg108 amino acid in normal hearing and confirms and consolidates the role of S1PR2 in autosomal recessive hearing loss. KW - 3D modeling KW - autosomal recessive non-synstromic hearing loss KW - DFNB68 KW - mixed hearing loss KW - whole exome sequencing KW - S1PR2 Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-175755 VL - 19 IS - 81 ER - TY - JOUR A1 - Barbieri, Flavia L. A1 - Gardon, Jacques A1 - Ruiz-Castell, María A1 - Paco V., Pamela A1 - Muckelbauer, Rebecca A1 - Casiot, Corinne A1 - Freydier, Rémi A1 - Duprey, Jean-Louis A1 - Chen, Chih-Mei A1 - Müller-Nordhorn, Jacqueline A1 - Keil, Thomas T1 - Toxic trace elements in maternal and cord blood and social determinants in a Bolivian mining city JF - International Journal of Environmental Health Research N2 - This study assessed lead, arsenic, and antimony in maternal and cord blood, and associations between maternal concentrations and social determinants in the Bolivian mining city of Oruro using the baseline assessment of the ToxBol/Mine-Nino birth cohort. We recruited 467 pregnant women, collecting venous blood and sociodemographic information as well as placental cord blood at birth. Metallic/semimetallic trace elements were measured using inductively coupled plasma mass spectrometry. Lead medians in maternal and cord blood were significantly correlated (Spearman coefficient=0.59; p<0.001; 19.35 and 13.50 μg/L, respectively). Arsenic concentrations were above detection limit (3.30 μg/L) in 17.9% of maternal and 34.6% of cord blood samples. They were not associated (Fischer's p=0.72). Antimony medians in maternal and cord blood were weakly correlated (Spearman coefficient=0.15; p<0.03; 9.00 and 8.62 μg/L, respectively). Higher concentrations of toxic elements in maternal blood were associated with maternal smoking, low educational level, and partner involved in mining. KW - environmental exposure KW - metallic trace elements KW - maternal exposure KW - prenatal exposure KW - risk factors Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-190703 VL - 26 IS - 2 ER - TY - JOUR A1 - Englmeier, Jana A1 - von Hoermann, Christian A1 - Rieker, Daniel A1 - Benbow, Marc Eric A1 - Benjamin, Caryl A1 - Fricke, Ute A1 - Ganuza, Cristina A1 - Haensel, Maria A1 - Lackner, Tomáš A1 - Mitesser, Oliver A1 - Redlich, Sarah A1 - Riebl, Rebekka A1 - Rojas-Botero, Sandra A1 - Rummler, Thomas A1 - Salamon, Jörg-Alfred A1 - Sommer, David A1 - Steffan-Dewenter, Ingolf A1 - Tobisch, Cynthia A1 - Uhler, Johannes A1 - Uphus, Lars A1 - Zhang, Jie A1 - Müller, Jörg T1 - Dung-visiting beetle diversity is mainly affected by land use, while community specialization is driven by climate JF - Ecology and Evolution N2 - Dung beetles are important actors in the self-regulation of ecosystems by driving nutrient cycling, bioturbation, and pest suppression. Urbanization and the sprawl of agricultural areas, however, destroy natural habitats and may threaten dung beetle diversity. In addition, climate change may cause shifts in geographical distribution and community composition. We used a space-for-time approach to test the effects of land use and climate on α-diversity, local community specialization (H\(_2\)′) on dung resources, and γ-diversity of dung-visiting beetles. For this, we used pitfall traps baited with four different dung types at 115 study sites, distributed over a spatial extent of 300 km × 300 km and 1000 m in elevation. Study sites were established in four local land-use types: forests, grasslands, arable sites, and settlements, embedded in near-natural, agricultural, or urban landscapes. Our results show that abundance and species density of dung-visiting beetles were negatively affected by agricultural land use at both spatial scales, whereas γ-diversity at the local scale was negatively affected by settlements and on a landscape scale equally by agricultural and urban land use. Increasing precipitation diminished dung-visiting beetle abundance, and higher temperatures reduced community specialization on dung types and γ-diversity. These results indicate that intensive land use and high temperatures may cause a loss in dung-visiting beetle diversity and alter community networks. A decrease in dung-visiting beetle diversity may disturb decomposition processes at both local and landscape scales and alter ecosystem functioning, which may lead to drastic ecological and economic damage. KW - coleoptera KW - coprophagous beetles KW - decomposition KW - global change KW - hill numbers KW - network analysis Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-312846 SN - 2045-7758 VL - 12 IS - 10 ER - TY - JOUR A1 - Köhler, Franziska A1 - Reese, Lena A1 - Kastner, Carolin A1 - Hendricks, Anne A1 - Müller, Sophie A1 - Lock, Johan F. A1 - Germer, Christoph-Thomas A1 - Wiegering, Armin T1 - Surgical site infection following single-port appendectomy: a systematic review of the literature and meta-analysis JF - Frontiers in Surgery N2 - Introduction Surgical site infections (SSIs) are one of the most common postoperative complications after appendectomy leading to recurrent surgery, prolonged hospital stay, and the use of antibiotics. Numerous studies and meta-analyses have been published on the effect of open versus conventional laparoscopic appendectomy (CLA) reporting faster postoperative recovery and less postoperative pain for CLA. A development from CLA has been the single-port appendectomy (SPA), associated with a better cosmesis but seemingly having a higher risk of wound infections. The aim of this systematic literature review and meta-analysis is to investigate whether reduced port or SPA alters the ratio of SSIs. Methods Pubmed, Embase, and Cochrane databases were screened for suitable articles. All articles published between January 1, 2002, and March 23, 2022, were included. Articles regarding children below the age of 18 were excluded as well as manuscripts that investigated solemnly open appendectomies. Articles were screened for inclusion criteria by two independent authors. Incidence of SSI was the primary outcome. Duration of operation and length of hospital stay were defined as secondary outcomes. Results A total of 25 studies were found through a database search describing 5484 patients. A total of 2749 patients received SPA and 2735 received CLA. There was no statistical difference in the rate of SSI (P = 0.98). A total of 22 studies including 4699 patients reported the duration of operation (2223 SPA and 2476 CLA). There was a significantly shorter operation time seen in CLA. The length of hospital stay was reported in 23 studies (4735 patients: 2235 SPA and 2500 CLA). A shorter hospital stay was seen in the SPA group (P < 0.00001). Separately performed analysis of randomized controlled trials could not confirm this effect (P = 0.29). Discussion SPA is an equally safe procedure considering SSI compared to CLA and does not lead to an increased risk of SSI. A longer operation time for SPA and a minor difference in the length of stay does lead to the use of SPA in selected patients only. KW - appendicitis KW - appendectomy KW - surgical site infection KW - single-port appendectomy KW - conventional laparoscopic appendectomy KW - wound infection KW - SSI Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-276943 SN - 2296-875X VL - 9 ER - TY - JOUR A1 - Haertle, Larissa A1 - El Hajj, Nady A1 - Dittrich, Marcus A1 - Müller, Tobias A1 - Nanda, Indrajit A1 - Lehnen, Harald A1 - Haaf, Thomas T1 - Epigenetic signatures of gestational diabetes mellitus on cord blood methylation JF - Clinical Epigenetics N2 - Background: Intrauterine exposure to gestational diabetes mellitus (GDM) confers a lifelong increased risk for metabolic and other complex disorders to the offspring. GDM-induced epigenetic modifications modulating gene regulation and persisting into later life are generally assumed to mediate these elevated disease susceptibilities. To identify candidate genes for fetal programming, we compared genome-wide methylation patterns of fetal cord bloods (FCBs) from GDM and control pregnancies. Methods and results: Using Illumina’s 450K methylation arrays and following correction for multiple testing, 65 CpG sites (52 associated with genes) displayed significant methylation differences between GDM and control samples. Four candidate genes, ATP5A1, MFAP4, PRKCH, and SLC17A4, from our methylation screen and one, HIF3A, from the literature were validated by bisulfite pyrosequencing. The effects remained significant after adjustment for the confounding factors maternal BMI, gestational week, and fetal sex in a multivariate regression model. In general, GDM effects on FCB methylation were more pronounced in women with insulin-dependent GDM who had a more severe metabolic phenotype than women with dietetically treated GDM. Conclusions: Our study supports an association between maternal GDM and the epigenetic status of the exposed offspring. Consistent with a multifactorial disease model, the observed FCB methylation changes are of small effect size but affect multiple genes/loci. The identified genes are primary candidates for transmitting GDM effects to the next generation. They also may provide useful biomarkers for the diagnosis, prognosis, and treatment of adverse prenatal exposures. KW - fetal programming KW - insulin treatment KW - DNA methylation KW - fetal cord blood KW - gestational diabetes mellitus Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-159459 VL - 9 IS - 28 ER - TY - JOUR A1 - Kirchner, André A1 - Herrmann, Nico A1 - Matras, Paul A1 - Müller, Iris A1 - Meister, Julia A1 - Schattner, Thomas G. T1 - A pedo-geomorphological view on land use and its potential in the surroundings of the ancient Hispano-Roman city Munigua (Seville, SW Spain) JF - E&G Quaternary Science Journal N2 - This study investigates the surroundings of Munigua (municipium Flavium Muniguense), a small Roman town in the ancient province of Hispania Baetica (SW Spain). The city's economy was based primarily on copper and iron mining, which brought financial prosperity to its citizens. Local production of agricultural goods is thought to have been of little importance, as the regional soil conditions do not seem to be suitable for extensive agriculture. To evaluate the recent soil agro-potential and to find evidence for prehistoric and historic land use in the surroundings of Munigua, we applied a pedo-geomorphological approach based on the physico-chemical analysis of 14 representative soil and sediment exposures. Selected samples were analyzed for bulk chemistry, texture and phytoliths. The chronostratigraphy of the sequences was based on radiocarbon dating of charcoal samples. The site evaluation of the present-day soil agro-potential was carried out according to standard procedures and included evaluation of potential rootability, available water-storage capacity and nutrient budget within the uppermost 1 m. The results show that moderate to very good soil agro-potential prevails in the granitic and floodplain areas surrounding Munigua. Clearly, recent soil agro-potential in these areas allows the production of basic agricultural goods, and similar limited agricultural use should also have been possible in ancient times. In contrast, weak to very weak present-day soil agro-potential prevails in the metamorphic landscape due to the occurrence of shallow and sandy to stony soils. In addition, the study provides pedo-geomorphological evidence for prehistoric and historic land use in pre-Roman, Roman and post-Roman times. Catenary soil mapping in the vicinity of a Roman house complex reveals multi-layered colluvial deposits. They document phases of hillslope erosion mainly triggered by human land use between 4063 ± 82 and 3796 ± 76 cal BP, around 2601 ± 115 cal BP, and between 1424 ± 96 and 421 ± 88 cal BP. Moreover, geochemical and phytolith analyses of a Roman hortic Anthrosol indicate the local cultivation of agricultural products that contributed to the food supply of Munigua. Overall, the evidence of Roman agricultural use in the Munigua area indicates that the city's economy was by no means focused solely on mining. The production of basic agricultural products was also part of Munigua's economic portfolio. Our geoarcheological study thus supports the archeological concept of economically diversified Roman cities in the province of Baetica and in Hispania. KW - land use KW - Munigua KW - geomorphology Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300141 VL - 71 IS - 2 SP - 123 EP - 143 ER - TY - JOUR A1 - Baur, Johannes A1 - Otto, Christoph A1 - Steger, Ulrich A1 - Klein-Hessling, Stefan A1 - Muhammad, Khalid A1 - Pusch, Tobias A1 - Murti, Krisna A1 - Wismer, Rhoda A1 - Germer, Christoph-Thomas A1 - Klein, Ingo A1 - Müller, Nora A1 - Serfling, Edgar A1 - Avots, Andris T1 - The transcription factor NFaTc1 supports the rejection of heterotopic heart allografts JF - Frontiers in Immunology N2 - The immune suppressants cyclosporin A (CsA) and tacrolimus (FK506) are used worldwide in transplantation medicine to suppress graft rejection. Both CsA and FK506 inhibit the phosphatase calcineurin (CN) whose activity controls the immune receptor-mediated activation of lymphocytes. Downstream targets of CN in lymphocytes are the nuclear factors of activated T cells (NFATs). We show here that the activity of NFATc1, the most prominent NFAT factor in activated lymphocytes supports the acute rejection of heterotopic heart allografts. While ablation of NFATc1 in T cells prevented graft rejection, ectopic expression of inducible NFATc1/αA isoform led to rejection of heart allografts in recipient mice. Acceptance of transplanted hearts in mice bearing NFATc1-deficient T cells was accompanied by a reduction in number and cytotoxicity of graft infiltrating cells. In CD8\(^+\) T cells, NFATc1 controls numerous intracellular signaling pathways that lead to the metabolic switch to aerobic glycolysis and the expression of numerous lymphokines, chemokines, and their receptors, including Cxcr3 that supports the rejection of allogeneic heart transplants. These findings favors NFATc1 as a molecular target for the development of new strategies to control the cytotoxicity of T cells upon organ transplantation. KW - NFATc1 KW - transplantation KW - heterologous KW - CD8+ T cells KW - ChIPseq KW - metabolism Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-221530 VL - 9 ER - TY - JOUR A1 - Müller, Laura S. M. A1 - Cosentino, Raúl O. A1 - Förstner, Konrad U. A1 - Guizetti, Julien A1 - Wedel, Carolin A1 - Kaplan, Noam A1 - Janzen, Christian J. A1 - Arampatzi, Panagiota A1 - Vogel, Jörg A1 - Steinbiss, Sascha A1 - Otto, Thomas D. A1 - Saliba, Antoine-Emmanuel A1 - Sebra, Robert P. A1 - Siegel, T. Nicolai T1 - Genome organization and DNA accessibility control antigenic variation in trypanosomes JF - Nature N2 - Many evolutionarily distant pathogenic organisms have evolved similar survival strategies to evade the immune responses of their hosts. These include antigenic variation, through which an infecting organism prevents clearance by periodically altering the identity of proteins that are visible to the immune system of the host1. Antigenic variation requires large reservoirs of immunologically diverse antigen genes, which are often generated through homologous recombination, as well as mechanisms to ensure the expression of one or very few antigens at any given time. Both homologous recombination and gene expression are affected by three-dimensional genome architecture and local DNA accessibility2,3. Factors that link three-dimensional genome architecture, local chromatin conformation and antigenic variation have, to our knowledge, not yet been identified in any organism. One of the major obstacles to studying the role of genome architecture in antigenic variation has been the highly repetitive nature and heterozygosity of antigen-gene arrays, which has precluded complete genome assembly in many pathogens. Here we report the de novo haplotype-specific assembly and scaffolding of the long antigen-gene arrays of the model protozoan parasite Trypanosoma brucei, using long-read sequencing technology and conserved features of chromosome folding4. Genome-wide chromosome conformation capture (Hi-C) reveals a distinct partitioning of the genome, with antigen-encoding subtelomeric regions that are folded into distinct, highly compact compartments. In addition, we performed a range of analyses—Hi-C, fluorescence in situ hybridization, assays for transposase-accessible chromatin using sequencing and single-cell RNA sequencing—that showed that deletion of the histone variants H3.V and H4.V increases antigen-gene clustering, DNA accessibility across sites of antigen expression and switching of the expressed antigen isoform, via homologous recombination. Our analyses identify histone variants as a molecular link between global genome architecture, local chromatin conformation and antigenic variation. KW - histone variants KW - genome architecture KW - single molecule real time (SMRT) KW - brucei genome KW - distance-dependent decay Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224265 VL - 563 ER - TY - JOUR A1 - Krah, Franz-Sebastian A1 - Büntgen, Ulf A1 - Schaefer, Hanno A1 - Müller, Jörg A1 - Andrew, Carrie A1 - Boddy, Lynne A1 - Diez, Jeffrey A1 - Egli, Simon A1 - Freckleton, Robert A1 - Gange, Alan C. A1 - Halvorsen, Rune A1 - Heegaard, Einar A1 - Heideroth, Antje A1 - Heibl, Christoph A1 - Heilmann-Clausen, Jacob A1 - Høiland, Klaus A1 - Kar, Ritwika A1 - Kauserud, Håvard A1 - Kirk, Paul M. A1 - Kuyper, Thomas W. A1 - Krisai-Greilhuber, Irmgard A1 - Norden, Jenni A1 - Papastefanou, Phillip A1 - Senn-Irlet, Beatrice A1 - Bässler, Claus T1 - European mushroom assemblages are darker in cold climates JF - Nature Communications N2 - Thermal melanism theory states that dark-colored ectotherm organisms are at an advantage at low temperature due to increased warming. This theory is generally supported for ectotherm animals, however, the function of colors in the fungal kingdom is largely unknown. Here, we test whether the color lightness of mushroom assemblages is related to climate using a dataset of 3.2 million observations of 3,054 species across Europe. Consistent with the thermal melanism theory, mushroom assemblages are significantly darker in areas with cold climates. We further show differences in color phenotype between fungal lifestyles and a lifestyle differentiated response to seasonality. These results indicate a more complex ecological role of mushroom colors and suggest functions beyond thermal adaption. Because fungi play a crucial role in terrestrial carbon and nutrient cycles, understanding the links between the thermal environment, functional coloration and species’ geographical distributions will be critical in predicting ecosystem responses to global warming. KW - evolutionary ecology KW - fungal ecology KW - fungal evolution KW - macroecology Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224815 VL - 10 ER - TY - JOUR A1 - Hofrichter, Michaela A. H. A1 - Doll, Julia A1 - Habibi, Haleh A1 - Enayati, Samaneh A1 - Mehrjardi, Mohammad Yahya Vahidi A1 - Müller, Tobias A1 - Dittrich, Marcus A1 - Haaf, Thomas A1 - Vona, Barbara T1 - Exome-wide copy number variation analysis identifies a COL9A1 in frame deletion that is associated with hearing loss JF - European Journal of Medical Genetics N2 - Pathogenic variants in COL9A1 are primarily associated with autosomal recessive Stickler syndrome. Patients with COL9A1-associated Stickler syndrome (STL) present hearing loss (HL), ophthalmic manifestations and skeletal abnormalities. However, the clinical spectrum of patients with COL9A1 variants can also include multiple epiphyseal dysplasia, as well as non-syndromic HL that was observed in one previously reported proband. Exome sequencing was performed on the genomic DNA of an Iranian patient and his affected brother who both report non-syndromic HL. A 44.6 kb homozygous in-frame deletion spanning exons 6 to 33 of COL9A1 was detected via exome-based copy number variation analysis. The deleted exons were confirmed by PCR in the patient and his affected brother, who both have non-syndromic HL. Segregation analysis via qPCR confirmed the parents as heterozygous deletion carriers. Breakpoint analysis mapped the homozygous deletion spanning introns 5 to 33 (g.70,948,188_70,997,277del, NM_001851.4(COL9A1):c.697–3754_2112+769del, p.(Phe233_Ser704del), with an additional 67 bp of inserted intronic sequence that may have originated due to a fork stalling and template switching/microhomology-mediated break-induced replication (FoSTeS/MMBIR) mechanism. This mechanism has not been previously implicated in HL or STL. This is also the first reported copy number variation in COL9A1 that was identified through an exome data set in an Iranian family with apparent non-syndromic HL. The present study emphasizes the importance of exome-wide copy number variation analysis in molecular diagnosis and provides supporting evidence to associate COL9A1 with autosomal recessive non-syndromic HL. KW - COL9A1 KW - copy number variation KW - FoSTeS/MMBIR mechanism KW - non-syndromic hearing loss KW - Stickler syndrome Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-322008 VL - 62 ER - TY - JOUR A1 - Flunkert, Julia A1 - Maierhofer, Anna A1 - Dittrich, Marcus A1 - Müller, Tobias A1 - Horvath, Steve A1 - Nanda, Indrajit A1 - Haaf, Thomas T1 - Genetic and epigenetic changes in clonal descendants of irradiated human fibroblasts JF - Experimental Cell Research N2 - To study delayed genetic and epigenetic radiation effects, which may trigger radiation-induced carcinogenesis, we have established single-cell clones from irradiated and non-irradiated primary human fibroblasts. Stable clones were endowed with the same karyotype in all analyzed metaphases after 20 population doublings (PDs), whereas unstable clones displayed mosaics of normal and abnormal karyotypes. To account for variation in radiation sensitivity, all experiments were performed with two different fibroblast strains. After a single X-ray dose of 2 Gy more than half of the irradiated clones exhibited radiation-induced genome instability (RIGI). Irradiated clones displayed an increased rate of loss of chromosome Y (LOY) and copy number variations (CNVs), compared to controls. CNV breakpoints clustered in specific chromosome regions, in particular 3p14.2 and 7q11.21, coinciding with common fragile sites. CNVs affecting the FHIT gene in FRA3B were observed in independent unstable clones and may drive RIGI. Bisulfite pyrosequencing of control clones and the respective primary culture revealed global hypomethylation of ALU, LINE-1, and alpha-satellite repeats as well as rDNA hypermethylation during in vitro ageing. Irradiated clones showed further reduced ALU and alpha-satellite methylation and increased rDNA methylation, compared to controls. Methylation arrays identified several hundred differentially methylated genes and several enriched pathways associated with in vitro ageing. Methylation changes in 259 genes and the MAP kinase signaling pathway were associated with delayed radiation effects (after 20 PDs). Collectively, our results suggest that both genetic (LOY and CNVs) and epigenetic changes occur in the progeny of exposed cells that were not damaged directly by irradiation, likely contributing to radiation-induced carcinogenesis. We did not observe epigenetic differences between stable and unstable irradiated clones. The fact that the DNA methylation (DNAm) age of clones derived from the same primary culture varied greatly suggests that DNAm age of a single cell (represented by a clone) can be quite different from the DNAm age of a tissue. We propose that DNAm age reflects the emergent property of a large number of individual cells whose respective DNAm ages can be highly variable. KW - copy number variation (CNV) KW - delayed radiation effects KW - DNA methylation (DNAm) age KW - global DNA methylation KW - loss of chromosome Y (LOY); KW - methylation array analysis KW - radiation-induced genome instability (RIGI) Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228177 VL - 370 ER - TY - JOUR A1 - Lehmann, Julian A1 - Jørgensen, Morten E. A1 - Fratz, Stefanie A1 - Müller, Heike M. A1 - Kusch, Jana A1 - Scherzer, Sönke A1 - Navarro-Retamal, Carlos A1 - Mayer, Dominik A1 - Böhm, Jennifer A1 - Konrad, Kai R. A1 - Terpitz, Ulrich A1 - Dreyer, Ingo A1 - Mueller, Thomas D. A1 - Sauer, Markus A1 - Hedrich, Rainer A1 - Geiger, Dietmar A1 - Maierhofer, Tobias T1 - Acidosis-induced activation of anion channel SLAH3 in the flooding-related stress response of Arabidopsis JF - Current Biology N2 - Plants, as sessile organisms, gained the ability to sense and respond to biotic and abiotic stressors to survive severe changes in their environments. The change in our climate comes with extreme dry periods but also episodes of flooding. The latter stress condition causes anaerobiosis-triggered cytosolic acidosis and impairs plant function. The molecular mechanism that enables plant cells to sense acidity and convey this signal via membrane depolarization was previously unknown. Here, we show that acidosis-induced anion efflux from Arabidopsis (Arabidopsis thaliana) roots is dependent on the S-type anion channel AtSLAH3. Heterologous expression of SLAH3 in Xenopus oocytes revealed that the anion channel is directly activated by a small, physiological drop in cytosolic pH. Acidosis-triggered activation of SLAH3 is mediated by protonation of histidine 330 and 454. Super-resolution microscopy analysis showed that the increase in cellular proton concentration switches SLAH3 from an electrically silent channel dimer into its active monomeric form. Our results show that, upon acidification, protons directly switch SLAH3 to its open configuration, bypassing kinase-dependent activation. Moreover, under flooding conditions, the stress response of Arabidopsis wild-type (WT) plants was significantly higher compared to SLAH3 loss-of-function mutants. Our genetic evidence of SLAH3 pH sensor function may guide the development of crop varieties with improved stress tolerance. KW - SLAH3 KW - S-type anion channel KW - hypoxia KW - pH KW - cytosolic acidification KW - flooding KW - PALM KW - stoichiometry Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-363320 VL - 31 ER -