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 - 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, 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 -