TY - JOUR A1 - Mercier, Rebecca A1 - Wolmarans, Annemarie A1 - Schubert, Jonathan A1 - Neuweiler, Hannes A1 - Johnson, Jill L. A1 - LaPointe, Paul T1 - The conserved NxNNWHW motif in Aha-type co-chaperones modulates the kinetics of Hsp90 ATPase stimulation JF - Nature Communications N2 - Hsp90 is a dimeric molecular chaperone that is essential for the folding and activation of hundreds of client proteins. Co-chaperone proteins regulate the ATP-driven Hsp90 client activation cycle. Aha-type co-chaperones are the most potent stimulators of the Hsp90 ATPase activity but the relationship between ATPase regulation and in vivo activity is poorly understood. We report here that the most strongly conserved region of Aha-type co-chaperones, the N terminal NxNNWHW motif, modulates the apparent affinity of Hsp90 for nucleotide substrates. The ability of yeast Aha-type co-chaperones to act in vivo is ablated when the N terminal NxNNWHW motif is removed. This work suggests that nucleotide exchange during the Hsp90 functional cycle may be more important than rate of catalysis. KW - biophysics KW - cell growth KW - chaperones KW - enzymes Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224007 VL - 10 ER - TY - JOUR A1 - Medler, Juliane A1 - Nelke, Johannes A1 - Weisenberger, Daniela A1 - Steinfatt, Tim A1 - Rothaug, Moritz A1 - Berr, Susanne A1 - Hünig, Thomas A1 - Beilhack, Andreas A1 - Wajant, Harald T1 - TNFRSF receptor-specific antibody fusion proteins with targeting controlled FcγR-independent agonistic activity JF - Cell Death & Disease N2 - Antibodies specific for TNFRSF receptors that bind soluble ligands without getting properly activated generally act as strong agonists upon FcγR binding. Systematic analyses revealed that the FcγR dependency of such antibodies to act as potent agonists is largely independent from isotype, FcγR type, and of the epitope recognized. This suggests that the sole cellular attachment, achieved by Fc domain-FcγR interaction, dominantly determines the agonistic activity of antibodies recognizing TNFRSF receptors poorly responsive to soluble ligands. In accordance with this hypothesis, we demonstrated that antibody fusion proteins harboring domains allowing FcγR-independent cell surface anchoring also act as strong agonist provided they have access to their target. This finding defines a general possibility to generate anti-TNFRSF receptor antibodies with FcγR-independent agonism. Moreover, anti-TNFRSF receptor antibody fusion proteins with an anchoring domain promise superior applicability to conventional systemically active agonists when an anchoring target with localized disease associated expression can be addressed. KW - biologics KW - proteins Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223948 VL - 10 ER - TY - JOUR A1 - Lübcke, Paul M. A1 - Ebbers, Meinolf N. B. A1 - Volzke, Johann A1 - Bull, Jana A1 - Kneitz, Susanne A1 - Engelmann, Robby A1 - Lang, Hermann A1 - Kreikemeyer, Bernd A1 - Müller-Hilke, Brigitte T1 - Periodontal treatment prevents arthritis in mice and methotrexate ameliorates periodontal bone loss JF - Scientific Reports N2 - Recent studies indicate a causal relationship between the periodontal pathogen P. gingivalis and rheumatoid arthritis involving the production of autoantibodies against citrullinated peptides. We therefore postulated that therapeutic eradication P. gingivalis may ameliorate rheumatoid arthritis development and here turned to a mouse model in order to challenge our hypothesis. F1 (DBA/1 x B10.Q) mice were orally inoculated with P. gingivalis before collagen-induced arthritis was provoked. Chlorhexidine or metronidazole were orally administered either before or during the induction phase of arthritis and their effects on arthritis progression and alveolar bone loss were compared to intraperitoneally injected methotrexate. Arthritis incidence and severity were macroscopically scored and alveolar bone loss was evaluated via microcomputed tomography. Serum antibody titres against P. gingivalis were quantified by ELISA and microbial dysbiosis following oral inoculation was monitored in stool samples via microbiome analyses. Both, oral chlorhexidine and metronidazole reduced the incidence and ameliorated the severity of collagen-induced arthritis comparable to methotrexate. Likewise, all three therapies attenuated alveolar bone loss. Relative abundance of Porphyromonadaceae was increased after oral inoculation with P. gingivalis and decreased after treatment. This is the first study to describe beneficial effects of non-surgical periodontal treatment on collagen-induced arthritis in mice and suggests that mouthwash with chlorhexidine or metronidazole may also be beneficial for patients with rheumatoid arthritis and a coexisting periodontitis. Methotrexate ameliorated periodontitis in mice, further raising the possibility that methotrexate may also positively impact on the tooth supporting tissues of patients with rheumatoid arthritis. KW - rheumatic diseases KW - rheumatology Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-237355 VL - 9 ER - TY - JOUR A1 - Lu, Yuan A1 - Boswell, Wiliam A1 - Boswell, Mikki A1 - Klotz, Barbara A1 - Kneitz, Susanne A1 - Regneri, Janine A1 - Savage, Markita A1 - Mendoza, Cristina A1 - Postlethwait, John A1 - Warren, Wesley C. A1 - Schartl, Manfred A1 - Walter, Ronald B. T1 - Application of the Transcriptional Disease Signature (TDSs) to Screen Melanoma-Effective Compounds in a Small Fish Model JF - Scientific Reports N2 - Cell culture and protein target-based compound screening strategies, though broadly utilized in selecting candidate compounds, often fail to eliminate candidate compounds with non-target effects and/or safety concerns until late in the drug developmental process. Phenotype screening using intact research animals is attractive because it can help identify small molecule candidate compounds that have a high probability of proceeding to clinical use. Most FDA approved, first-in-class small molecules were identified from phenotypic screening. However, phenotypic screening using rodent models is labor intensive, low-throughput, and very expensive. As a novel alternative for small molecule screening, we have been developing gene expression disease profiles, termed the Transcriptional Disease Signature (TDS), as readout of small molecule screens for therapeutic molecules. In this concept, compounds that can reverse, or otherwise affect known disease-associated gene expression patterns in whole animals may be rapidly identified for more detailed downstream direct testing of their efficacy and mode of action. To establish proof of concept for this screening strategy, we employed a transgenic strain of a small aquarium fish, medaka (Oryzias latipes), that overexpresses the malignant melanoma driver gene xmrk, a mutant egfr gene, that is driven by a pigment cell-specific mitf promoter. In this model, melanoma develops with 100% penetrance. Using the transgenic medaka malignant melanoma model, we established a screening system that employs the NanoString nCounter platform to quantify gene expression within custom sets of TDS gene targets that we had previously shown to exhibit differential transcription among xmrk-transgenic and wild-type medaka. Compound-modulated gene expression was identified using an internet-accessible custom-built data processing pipeline. The effect of a given drug on the entire TDS profile was estimated by comparing compound-modulated genes in the TDS using an activation Z-score and Kolmogorov-Smirnov statistics. TDS gene probes were designed that target common signaling pathways that include proliferation, development, toxicity, immune function, metabolism and detoxification. These pathways may be utilized to evaluate candidate compounds for potential favorable, or unfavorable, effects on melanoma-associated gene expression. Here we present the logistics of using medaka to screen compounds, as well as, the development of a user-friendly NanoString data analysis pipeline to support feasibility of this novel TDS drug-screening strategy. KW - bioinformatics KW - phenotypic screening Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-237322 VL - 9 ER - TY - JOUR A1 - López, Cristina A1 - Kleinheinz, Kortine A1 - Aukema, Sietse M. A1 - Rohde, Marius A1 - Bernhart, Stephan H. A1 - Hübschmann, Daniel A1 - Wagener, Rabea A1 - Toprak, Umut H. A1 - Raimondi, Francesco A1 - Kreuz, Markus A1 - Waszak, Sebastian M. A1 - Huang, Zhiqin A1 - Sieverling, Lina A1 - Paramasivam, Nagarajan A1 - Seufert, Julian A1 - Sungalee, Stephanie A1 - Russell, Robert B. A1 - Bausinger, Julia A1 - Kretzmer, Helene A1 - Ammerpohl, Ole A1 - Bergmann, Anke K. A1 - Binder, Hans A1 - Borkhardt, Arndt A1 - Brors, Benedikt A1 - Claviez, Alexander A1 - Doose, Gero A1 - Feuerbach, Lars A1 - Haake, Andrea A1 - Hansmann, Martin-Leo A1 - Hoell, Jessica A1 - Hummel, Michael A1 - Korbel, Jan O. A1 - Lawerenz, Chris A1 - Lenze, Dido A1 - Radlwimmer, Bernhard A1 - Richter, Julia A1 - Rosenstiel, Philip A1 - Rosenwald, Andreas A1 - Schilhabel, Markus B. A1 - Stein, Harald A1 - Stilgenbauer, Stephan A1 - Stadler, Peter F. A1 - Szczepanowski, Monika A1 - Weniger, Marc A. A1 - Zapatka, Marc A1 - Eils, Roland A1 - Lichter, Peter A1 - Loeffler, Markus A1 - Möller, Peter A1 - Trümper, Lorenz A1 - Klapper, Wolfram A1 - Hoffmann, Steve A1 - Küppers, Ralf A1 - Burkhardt, Birgit A1 - Schlesner, Matthias A1 - Siebert, Reiner T1 - Genomic and transcriptomic changes complement each other in the pathogenesis of sporadic Burkitt lymphoma JF - Nature Communications N2 - Burkitt lymphoma (BL) is the most common B-cell lymphoma in children. Within the International Cancer Genome Consortium (ICGC), we performed whole genome and transcriptome sequencing of 39 sporadic BL. Here, we unravel interaction of structural, mutational, and transcriptional changes, which contribute to MYC oncogene dysregulation together with the pathognomonic IG-MYC translocation. Moreover, by mapping IGH translocation breakpoints, we provide evidence that the precursor of at least a subset of BL is a B-cell poised to express IGHA. We describe the landscape of mutations, structural variants, and mutational processes, and identified a series of driver genes in the pathogenesis of BL, which can be targeted by various mechanisms, including IG-non MYC translocations, germline and somatic mutations, fusion transcripts, and alternative splicing. KW - cancer genomics KW - lymphocytes KW - lymphoid tissues KW - oncology Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-237281 VL - 10 ER - TY - JOUR A1 - Liu, Yuhai A1 - Wang, Zhenjiu A1 - Sato, Toshihiro A1 - Hohenadler, Martin A1 - Wang, Chong A1 - Guo, Wenan A1 - Assaad, Fakher F. T1 - Superconductivity from the condensation of topological defects in a quantum spin-Hall insulator JF - Nature Communications N2 - The discovery of quantum spin-Hall (QSH) insulators has brought topology to the forefront of condensed matter physics. While a QSH state from spin-orbit coupling can be fully understood in terms of band theory, fascinating many-body effects are expected if it instead results from spontaneous symmetry breaking. Here, we introduce a model of interacting Dirac fermions where a QSH state is dynamically generated. Our tuning parameter further allows us to destabilize the QSH state in favour of a superconducting state through proliferation of charge-2e topological defects. This route to superconductivity put forward by Grover and Senthil is an instance of a deconfined quantum critical point (DQCP). Our model offers the possibility to study DQCPs without a second length scale associated with the reduced symmetry between field theory and lattice realization and, by construction, is amenable to large-scale fermion quantum Monte Carlo simulations. KW - computational science KW - phase transitions and critical phenomena KW - topological insulators Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-237024 VL - 10 ER - TY - JOUR A1 - Liao, Chunyu A1 - Ttofali, Fani A1 - Slotkowski, Rebecca A. A1 - Denny, Steven R. A1 - Cecil, Taylor D. A1 - Leenay, Ryan T. A1 - Keung, Albert J. A1 - Beisel, Chase L. T1 - Modular one-pot assembly of CRISPR arrays enables library generation and reveals factors influencing crRNA biogenesis JF - Nature Communications N2 - CRISPR-Cas systems inherently multiplex through CRISPR arrays—whether to defend against different invaders or mediate multi-target editing, regulation, imaging, or sensing. However, arrays remain difficult to generate due to their reoccurring repeat sequences. Here, we report a modular, one-pot scheme called CRATES to construct CRISPR arrays and array libraries. CRATES allows assembly of repeat-spacer subunits using defined assembly junctions within the trimmed portion of spacers. Using CRATES, we construct arrays for the single-effector nucleases Cas9, Cas12a, and Cas13a that mediated multiplexed DNA/RNA cleavage and gene regulation in cell-free systems, bacteria, and yeast. CRATES further allows the one-pot construction of array libraries and composite arrays utilized by multiple Cas nucleases. Finally, array characterization reveals processing of extraneous CRISPR RNAs from Cas12a terminal repeats and sequence- and context-dependent loss of RNA-directed nuclease activity via global RNA structure formation. CRATES thus can facilitate diverse multiplexing applications and help identify factors impacting crRNA biogenesis. KW - biotechnology KW - CRISPR-Cas systems KW - microbiology KW - small RNAs Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236843 VL - 10 ER - TY - JOUR A1 - Levy, Marion J. F. A1 - Boulle, Fabien A1 - Emerit, Michel Boris A1 - Poilbout, Corinne A1 - Steinbusch, Harry W. M. A1 - Van den Hove, Daniel L. A. A1 - Kenis, Gunter A1 - Lanfumey, Laurence T1 - 5-HTT independent effects of fluoxetine on neuroplasticity JF - Scientific Reports N2 - Selective serotonin reuptake inhibitors are among the most prescribed antidepressants. Fluoxetine is the lead molecule which exerts its therapeutic effects, at least in part, by promoting neuroplasticity through increased brain-derived neurotrophic factor (BDNF)/tropomyosin-related receptor kinase B (TrkB) signalling. It is unclear however, to which extent the neuroplastic effects of fluoxetine are solely mediated by the inhibition of the serotonin transporter (5-HTT). To answer this question, the effects of fluoxetine on neuroplasticity were analysed in both wild type (WT) and 5-Htt knock-out (KO) mice. Using Western blotting and RT-qPCR approaches, we showed that fluoxetine 10 µM activated BDNF/TrkB signalling pathways in both CD1 and C57BL/6J mouse primary cortical neurons. Interestingly, effects on BDNF signalling were observed in primary cortical neurons from both 5-Htt WT and KO mice. In addition, a 3-week in vivo fluoxetine treatment (15 mg/kg/d; i.p.) increased the expression of plasticity genes in brains of both 5-Htt WT and KO mice, and tended to equally enhance hippocampal cell proliferation in both genotypes, without reaching significance. Our results further suggest that fluoxetine-induced neuroplasticity does not solely depend on 5-HTT blockade, but might rely, at least in part, on 5-HTT-independent direct activation of TrkB. KW - depression KW - neurotrophic factors Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236759 VL - 9 ER - TY - JOUR A1 - Lee, Hong-Jen A1 - Li, Chien-Feng A1 - Ruan, Diane A1 - He, Jiabei A1 - Montal, Emily D. A1 - Lorenz, Sonja A1 - Girnun, Geoffrey D. A1 - Chan, Chia-Hsin T1 - Non-proteolytic ubiquitination of Hexokinase 2 by HectH9 controls tumor metabolism and cancer stem cell expansion JF - Nature Communications N2 - Enormous efforts have been made to target metabolic dependencies of cancer cells for developing new therapies. However, the therapeutic efficacy of glycolysis inhibitors is limited due to their inability to elicit cell death. Hexokinase 2 (HK2), via its mitochondrial localization, functions as a central nexus integrating glycolysis activation and apoptosis resilience. Here we identify that K63-linked ubiquitination by HectH9 regulates the mitochondrial localization and function of HK2. Through stable isotope tracer approach and functional metabolic analyses, we show that HectH9 deficiency impedes tumor glucose metabolism and growth by HK2 inhibition. The HectH9/HK2 pathway regulates cancer stem cell (CSC) expansion and CSC-associated chemoresistance. Histological analyses show that HectH9 expression is upregulated and correlated with disease progression in prostate cancer. This work uncovers that HectH9 is a novel regulator of HK2 and cancer metabolism. Targeting HectH9 represents an effective strategy to achieve long-term tumor remission by concomitantly disrupting glycolysis and inducing apoptosis. KW - cancer KW - cancer metabolism KW - molecular biology Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236445 VL - 10 ER - TY - JOUR A1 - Kremer, Mark A1 - Biesenthal, Tobias A1 - Maczewsky, Lukas J. A1 - Heinrich, Matthias A1 - Thomale, Ronny A1 - Szameit, Alexander T1 - Demonstration of a two-dimensional PT-symmetric crystal JF - Nature Communications N2 - With the discovery of PT-symmetric quantum mechanics, it was shown that even non-Hermitian systems may exhibit entirely real eigenvalue spectra. This finding did not only change the perception of quantum mechanics itself, it also significantly influenced the field of photonics. By appropriately designing one-dimensional distributions of gain and loss, it was possible to experimentally verify some of the hallmark features of PT-symmetry using electromagnetic waves. Nevertheless, an experimental platform to study the impact of PT-symmetry in two spatial dimensions has so far remained elusive. We break new grounds by devising a two-dimensional PT-symmetric system based on photonic waveguide lattices with judiciously designed refractive index landscape and alternating loss. With this system at hand, we demonstrate a non-Hermitian two-dimensional topological phase transition that is closely linked to the emergence of topological mid-gap edge states. KW - micro-optics KW - optical materials and structures KW - topological matter Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230132 VL - 10 ER - TY - JOUR A1 - Kreinberg, Sören A1 - Porte, Xavier A1 - Schicke, David A1 - Lingnau, Benjamin A1 - Schneider, Christian A1 - Höfling, Sven A1 - Kanter, Ido A1 - Lüdge, Kathy A1 - Reitzenstein, Stephan T1 - Mutual coupling and synchronization of optically coupled quantum-dot micropillar lasers at ultra-low light levels JF - Nature Communications N2 - Synchronization of coupled oscillators at the transition between classical physics and quantum physics has become an emerging research topic at the crossroads of nonlinear dynamics and nanophotonics. We study this unexplored field by using quantum dot microlasers as optical oscillators. Operating in the regime of cavity quantum electrodynamics (cQED) with an intracavity photon number on the order of 10 and output powers in the 100 nW range, these devices have high β-factors associated with enhanced spontaneous emission noise. We identify synchronization of mutually coupled microlasers via frequency locking associated with a sub-gigahertz locking range. A theoretical analysis of the coupling behavior reveals striking differences from optical synchronization in the classical domain with negligible spontaneous emission noise. Beyond that, additional self-feedback leads to zero-lag synchronization of coupled microlasers at ultra-low light levels. Our work has high potential to pave the way for future experiments in the quantum regime of synchronization. KW - nanoscale devices KW - quantum optics KW - semiconductor lasers Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229811 VL - 10 ER - 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 - Doppler, Christopher E. J. A1 - Meyer, Linda A1 - Dovern, Anna A1 - Stühmer-Beckh, Jaro A1 - Weiss, Peter H. A1 - Fink, Gereon R. T1 - Differential impact of social and monetary reward on procedural learning and consolidation in aging and its structural correlates JF - Frontiers in Aging Neuroscience N2 - In young (n = 36, mean +/- SD: 24.8 +/- 4.5 years) and older (n = 34, mean +/- SD: 65.1 +/- 6.5 years) healthy participants, we employed a modified version of the Serial Reaction Time task to measure procedural learning (PL) and consolidation while providing monetary and social reward. Using voxel-based morphometry (VBM), we additionally determined the structural correlates of reward-related motor performance (RMP) and PL. Monetary reward had a beneficial effect on PL in the older subjects only. In contrast, social reward significantly enhanced PL in the older and consolidation in the young participants. VBM analyses revealed that motor performance related to monetary reward was associated with larger grey matter volume (GMV) of the left striatum in the young, and motor performance related to social reward with larger GMV of the medial orbitofrontal cortex in the older group. The differential effects of social reward in young (improved consolidation) and both social and monetary rewards in older (enhanced PL) healthy subjects point to the potential of rewards for interventions targeting aging-associated motor decline or stroke-induced motor deficits. KW - serial reaction time task KW - procedural learning KW - reinforcement learning KW - voxel-based morphometry KW - motor aging Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-222394 VL - 11 ER - TY - JOUR A1 - Cook, Nigel A1 - Geier, Andreas A1 - Schmid, Andreas A1 - Hirschfeld, Gideon A1 - Kautz, Achim A1 - Schattenberg, Jörn M. A1 - Balp, Maria-Magdalena T1 - The patient perspectives on future therapeutic options in NASH and patient needs JF - Frontiers in Medicine N2 - Background: Non-alcoholic steatohepatitis (NASH) is a chronic liver disease with severe complications and without approved therapies. Currently, there is limited data on the overall burden of the disease for patients or on patient needs and preferences. This study investigates patient preferences in relation to potential future therapies for NASH. In addition, the factors that are relevant to patients and their importance in relation to future treatment options are explored. Method: Telephone in-depth interviews (TDIs) preceded an online 30-min quantitative survey. The online survey included (1) multiple choice questions (MCQs) on NASH diagnosis and disease background. (2) An exercise to determine patients' satisfaction levels with information provided at diagnosis, and to explore symptomatology in detail. (3) Exercises to evaluate potential new products and product attributes, including a "drag and drop" ranking exercise, and an adaptive choice-based conjoint exercise (ACBC). (4) The EQ-5D-5L questionnaire and the Visual Analog Scale (VAS), which measures patients' health status. (5) Collection of socio-demographic data, and (6) Questions to measure patient satisfaction with the survey. Results: There were 166 patients included in this study from Canada [n = 36], Germany [n = 50], the UK [n = 30], and USA [n = 50]. Fifty seven percent of patients [n = 94] had had a liver biopsy for confirmation of NASH. Patients were often unable to link their symptoms to NASH or other conditions. ACBC results showed that efficacy, defined as "impact on liver status" was the single most important attribute of a potential future NASH therapy. Other attributes considered to have secondary importance included impact on weight, symptom control and the presence of side effects. The EQ-5D utility score was 0.81 and VAS = 67.2. Conclusion: "Impact on liver status" is the primary outcome sought. Patients demonstrate a general lack of understanding of their disease and appeared to be unfamiliar with longer-term consequences of NASH. It is necessary to improve patient understanding of NASH and its progressive nature, and there is a need for improving confirmatory diagnosis and monitoring. KW - patient preference KW - non-alcoholic fatty liver disease (NAFLD) KW - non-alcoholic steatohepatitis (NASH) KW - adaptive choice-based conjoint KW - liver disease KW - EQ5D-5L KW - patient-based evidence KW - patient-reported outcomes Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223268 VL - 6 ER - TY - JOUR A1 - Altieri, Barbara A1 - Di Dato, Carla A1 - Martini, Chiara A1 - Sciammarella, Concetta A1 - Di Sarno, Antonella A1 - Colao, Annamaria A1 - Faggiano, Antongiulio T1 - Bone Metastases in Neuroendocrine Neoplasms: From Pathogenesis to Clinical Management JF - Cancers N2 - Bone represents a common site of metastases for several solid tumors. However, the ability of neuroendocrine neoplasms (NENs) to localize to bone has always been considered a rare and late event. Thanks to the improvement of therapeutic options, which results in longer survival, and of imaging techniques, particularly after the introduction of positron emission tomography (PET) with gallium peptides, the diagnosis of bone metastases (BMs) in NENs is increasing. The onset of BMs can be associated with severe skeletal complications that impair the patient's quality of life. Moreover, BMs negatively affect the prognosis of NEN patients, bringing out the lack of curative treatment options for advanced NENs. The current knowledge on BMs in gastro-entero-pancreatic (GEP) and bronchopulmonary (BP) NENs is still scant and is derived from a few retrospective studies and case reports. This review aims to perform a critical analysis of the evidence regarding the role of BMs in GEP- and BP-NENs, focusing on the molecular mechanisms underlining the development of BMs, as well as clinical presentation, diagnosis, and treatment of BMs, in an attempt to provide suggestions that can be used in clinical practice. KW - neuroendocrine neoplasms KW - bone metastases KW - bone microenvironment KW - skeletal-related events KW - epithelial-to-mesenchymal transition KW - microRNA KW - prognosis KW - treatment KW - denosumab Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-221079 VL - 11 ER - TY - JOUR A1 - Bohmann, Ferdinand O. A1 - Kurka, Natalia A1 - du Mesnil de Rochemont, Richard A1 - Gruber, Katharina A1 - Guenther, Joachim A1 - Rostek, Peter A1 - Rai, Heike A1 - Zickler, Philipp A1 - Ertl, Michael A1 - Berlis, Ansgar A1 - Poli, Sven A1 - Mengel, Annerose A1 - Ringleb, Peter A1 - Nagel, Simon A1 - Pfaff, Johannes A1 - Wollenweber, Frank A. A1 - Kellert, Lars A1 - Herzberg, Moriz A1 - Koehler, Luzie A1 - Haeusler, Karl Georg A1 - Alegiani, Anna A1 - Schubert, Charlotte A1 - Brekenfeld, Caspar A1 - Doppler, Christopher E. J. A1 - Onur, Oezguer A. A1 - Kabbasch, Christoph A1 - Manser, Tanja A1 - Pfeilschifter, Waltraud T1 - Simulation-based training of the rapid evaluation and management of acute stroke (STREAM) — a prospective single-arm multicenter trial JF - Frontiers in Neurology N2 - Introduction: Acute stroke care delivered by interdisciplinary teams is time-sensitive. Simulation-based team training is a promising tool to improve team performance in medical operations. It has the potential to improve process times, team communication, patient safety, and staff satisfaction. We aim to assess whether a multi-level approach consisting of a stringent workflow revision based on peer-to-peer review and 2–3 one-day in situ simulation trainings can improve acute stroke care processing times in high volume neurocenters within a 6 months period. Methods and Analysis: The trial is being carried out in a pre-test-post-test design at 7 tertiary care university hospital neurocenters in Germany. The intervention is directed at the interdisciplinary multiprofessional stroke teams. Before and after the intervention, process times of all direct-to-center stroke patients receiving IV thrombolysis (IVT) and/or endovascular therapy (EVT) will be recorded. The primary outcome measure will be the “door-to-needle” time of all consecutive stroke patients directly admitted to the neurocenters who receive IVT. Secondary outcome measures will be intervention-related process times of the fraction of patients undergoing EVT and effects on team communication, perceived patient safety, and staff satisfaction via a staff questionnaire. Interventions: We are applying a multi-level intervention in cooperation with three “STREAM multipliers” from each center. First step is a central meeting of the multipliers at the sponsor's institution with the purposes of algorithm review in a peer-to-peer process that is recorded in a protocol and an introduction to the principles of simulation training and debriefing as well as crew resource management and team communication. Thereafter, the multipliers cooperate with the stroke team trainers from the sponsor's institution to plan and execute 2–3 one-day simulation courses in situ in the emergency department and CT room of the trial centers whereupon they receive teaching materials to perpetuate the trainings. Clinical Trial Registration: STREAM is a registered trial at https://clinicaltrials.gov/ct2/show/NCT03228251. KW - CRM KW - thrombolysis (tPA) KW - stroke KW - emergency care KW - simulation training Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369239 SN - 1664-2295 VL - 10 ER - TY - JOUR A1 - Kraus, Amelie J. A1 - Brink, Benedikt G. A1 - Siegel, T. Nicolai T1 - Efficient and specific oligo-based depletion of rRNA JF - Scientific Reports N2 - In most organisms, ribosomal RNA (rRNA) contributes to >85% of total RNA. Thus, to obtain useful information from RNA-sequencing (RNA-seq) analyses at reasonable sequencing depth, typically, mature polyadenylated transcripts are enriched or rRNA molecules are depleted. Targeted depletion of rRNA is particularly useful when studying transcripts lacking a poly(A) tail, such as some non-coding RNAs (ncRNAs), most bacterial RNAs and partially degraded or immature transcripts. While several commercially available kits allow effective rRNA depletion, their efficiency relies on a high degree of sequence homology between oligonucleotide probes and the target RNA. This restricts the use of such kits to a limited number of organisms with conserved rRNA sequences. In this study we describe the use of biotinylated oligos and streptavidin-coated paramagnetic beads for the efficient and specific depletion of trypanosomal rRNA. Our approach reduces the levels of the most abundant rRNA transcripts to less than 5% with minimal off-target effects. By adjusting the sequence of the oligonucleotide probes, our approach can be used to deplete rRNAs or other abundant transcripts independent of species. Thus, our protocol provides a useful alternative for rRNA removal where enrichment of polyadenylated transcripts is not an option and commercial kits for rRNA are not available. KW - parasite biology KW - RNA sequencing KW - transcriptomics Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224829 VL - 9 ER - TY - JOUR A1 - Kotz, Frederik A1 - Risch, Patrick A1 - Arnold, Karl A1 - Sevim, Semih A1 - Puigmartí-Luis, Josep A1 - Quick, Alexander A1 - Thiel, Michael A1 - Hrynevich, Andrei A1 - Dalton, Paul D. A1 - Helmer, Dorothea A1 - Rapp, Bastian E. T1 - Fabrication of arbitrary three-dimensional suspended hollow microstructures in transparent fused silica glass JF - Nature Communications N2 - Fused silica glass is the preferred material for applications which require long-term chemical and mechanical stability as well as excellent optical properties. The manufacturing of complex hollow microstructures within transparent fused silica glass is of particular interest for, among others, the miniaturization of chemical synthesis towards more versatile, configurable and environmentally friendly flow-through chemistry as well as high-quality optical waveguides or capillaries. However, microstructuring of such complex three-dimensional structures in glass has proven evasive due to its high thermal and chemical stability as well as mechanical hardness. Here we present an approach for the generation of hollow microstructures in fused silica glass with high precision and freedom of three-dimensional designs. The process combines the concept of sacrificial template replication with a room-temperature molding process for fused silica glass. The fabricated glass chips are versatile tools for, among other, the advance of miniaturization in chemical synthesis on chip. KW - chemical engineering KW - fluidics KW - materials for optics Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224787 VL - 10 ER - TY - JOUR A1 - Knop, Janin A1 - Spilgies, Lisanne M. A1 - Rufli, Stefanie A1 - Reinhart, Ramona A1 - Vasilikos, Lazaros A1 - Yabal, Monica A1 - Owsley, Erika A1 - Jost, Philipp J. A1 - Marsh, Rebecca A. A1 - Wajant, Harald A1 - Robinson, Mark D. A1 - Kaufmann, Thomas A1 - W. Wei-Lynn, Wong T1 - TNFR2 induced priming of the inflammasome leads to a RIPK1-dependent cell death in the absence of XIAP JF - Cell Death & Disease N2 - The pediatric immune deficiency X-linked proliferative disease-2 (XLP-2) is a unique disease, with patients presenting with either hemophagocytic lymphohistiocytosis (HLH) or intestinal bowel disease (IBD). Interestingly, XLP-2 patients display high levels of IL-18 in the serum even while in stable condition, presumably through spontaneous inflammasome activation. Recent data suggests that LPS stimulation can trigger inflammasome activation through a TNFR2/TNF/TNFR1 mediated loop in xiap−/− macrophages. Yet, the direct role TNFR2-specific activation plays in the absence of XIAP is unknown. We found TNFR2-specific activation leads to cell death in xiap−/− myeloid cells, particularly in the absence of the RING domain. RIPK1 kinase activity downstream of TNFR2 resulted in a TNF/TNFR1 cell death, independent of necroptosis. TNFR2-specific activation leads to a similar inflammatory NF-kB driven transcriptional profile as TNFR1 activation with the exception of upregulation of NLRP3 and caspase-11. Activation and upregulation of the canonical inflammasome upon loss of XIAP was mediated by RIPK1 kinase activity and ROS production. While both the inhibition of RIPK1 kinase activity and ROS production reduced cell death, as well as release of IL-1β, the release of IL-18 was not reduced to basal levels. This study supports targeting TNFR2 specifically to reduce IL-18 release in XLP-2 patients and to reduce priming of the inflammasome components. KW - cell death and immune response KW - inflammation Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-325946 VL - 10 ER - TY - JOUR A1 - Kim, Bo-Mi A1 - Amores, Angel A1 - Kang, Seunghyun A1 - Ahn, Do-Hwan A1 - Kim, Jin-Hyoung A1 - Kim, Il-Chan A1 - Lee, Jun Hyuck A1 - Lee, Sung Gu A1 - Lee, Hyoungseok A1 - Lee, Jungeun A1 - Kim, Han-Woo A1 - Desvignes, Thomas A1 - Batzel, Peter A1 - Sydes, Jason A1 - Titus, Tom A1 - Wilson, Catherine A. A1 - Catchen, Julian M. A1 - Warren, Wesley C. A1 - Schartl, Manfred A1 - Detrich, H. William III A1 - Postlethwait, John H. A1 - Park, Hyun T1 - Antarctic blackfin icefish genome reveals adaptations to extreme environments JF - Nature Ecology & Evolution N2 - Icefishes (suborder Notothenioidei; family Channichthyidae) are the only vertebrates that lack functional haemoglobin genes and red blood cells. Here, we report a high-quality genome assembly and linkage map for the Antarctic blackfin icefish Chaenocephalus aceratus, highlighting evolved genomic features for its unique physiology. Phylogenomic analysis revealed that Antarctic fish of the teleost suborder Notothenioidei, including icefishes, diverged from the stickleback lineage about 77 million years ago and subsequently evolved cold-adapted phenotypes as the Southern Ocean cooled to sub-zero temperatures. Our results show that genes involved in protection from ice damage, including genes encoding antifreeze glycoprotein and zona pellucida proteins, are highly expanded in the icefish genome. Furthermore, genes that encode enzymes that help to control cellular redox state, including members of the sod3 and nqo1 gene families, are expanded, probably as evolutionary adaptations to the relatively high concentration of oxygen dissolved in cold Antarctic waters. In contrast, some crucial regulators of circadian homeostasis (cry and per genes) are absent from the icefish genome, suggesting compromised control of biological rhythms in the polar light environment. The availability of the icefish genome sequence will accelerate our understanding of adaptation to extreme Antarctic environments. KW - animal physiology KW - evolutionary genetics KW - genomics KW - ichthyology Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-325811 VL - 3 ER -