TY - JOUR A1 - Milanese, Alessio A1 - Mende, Daniel R A1 - Paoli, Lucas A1 - Salazar, Guillem A1 - Ruscheweyh, Hans-Joachim A1 - Cuenca, Miguelangel A1 - Hingamp, Pascal A1 - Alves, Renato A1 - Costea, Paul I A1 - Coelho, Luis Pedro A1 - Schmidt, Thomas S. B. A1 - Almeida, Alexandre A1 - Mitchell, Alex L A1 - Finn, Robert D. A1 - Huerta-Cepas, Jaime A1 - Bork, Peer A1 - Zeller, Georg A1 - Sunagawa, Shinichi T1 - Microbial abundance, activity and population genomic profiling with mOTUs2 JF - Nature Communications N2 - Metagenomic sequencing has greatly improved our ability to profile the composition of environmental and host-associated microbial communities. However, the dependency of most methods on reference genomes, which are currently unavailable for a substantial fraction of microbial species, introduces estimation biases. We present an updated and functionally extended tool based on universal (i.e., reference-independent), phylogenetic marker gene (MG)-based operational taxonomic units (mOTUs) enabling the profiling of >7700 microbial species. As more than 30% of them could not previously be quantified at this taxonomic resolution, relative abundance estimates based on mOTUs are more accurate compared to other methods. As a new feature, we show that mOTUs, which are based on essential housekeeping genes, are demonstrably well-suited for quantification of basal transcriptional activity of community members. Furthermore, single nucleotide variation profiles estimated using mOTUs reflect those from whole genomes, which allows for comparing microbial strain populations (e.g., across different human body sites). KW - microbiome KW - software Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224089 VL - 10 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 - Langhauser, Friederike A1 - Casas, Ana I. A1 - Dao, Vu-Thao-Vi A1 - Guney, Emre A1 - Menche, Jörg A1 - Geuss, Eva A1 - Kleikers, Pamela W. M. A1 - López, Manuela G. A1 - Barabási, Albert-L. A1 - Kleinschnitz, Christoph A1 - Schmidt, Harald H. H. W. T1 - A diseasome cluster-based drug repurposing of soluble guanylate cyclase activators from smooth muscle relaxation to direct neuroprotection JF - npj Systems Biology and Applications N2 - Network medicine utilizes common genetic origins, markers and co-morbidities to uncover mechanistic links between diseases. These links can be summarized in the diseasome, a comprehensive network of disease–disease relationships and clusters. The diseasome has been influential during the past decade, although most of its links are not followed up experimentally. Here, we investigate a high prevalence unmet medical need cluster of disease phenotypes linked to cyclic GMP. Hitherto, the central cGMP-forming enzyme, soluble guanylate cyclase (sGC), has been targeted pharmacologically exclusively for smooth muscle modulation in cardiology and pulmonology. Here, we examine the disease associations of sGC in a non-hypothesis based manner in order to identify possibly previously unrecognized clinical indications. Surprisingly, we find that sGC, is closest linked to neurological disorders, an application that has so far not been explored clinically. Indeed, when investigating the neurological indication of this cluster with the highest unmet medical need, ischemic stroke, pre-clinically we find that sGC activity is virtually absent post-stroke. Conversely, a heme-free form of sGC, apo-sGC, was now the predominant isoform suggesting it may be a mechanism-based target in stroke. Indeed, this repurposing hypothesis could be validated experimentally in vivo as specific activators of apo-sGC were directly neuroprotective, reduced infarct size and increased survival. Thus, common mechanism clusters of the diseasome allow direct drug repurposing across previously unrelated disease phenotypes redefining them in a mechanism-based manner. Specifically, our example of repurposing apo-sGC activators for ischemic stroke should be urgently validated clinically as a possible first-in-class neuroprotective therapy. KW - neurology KW - pharmacology KW - systems biology Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236381 VL - 4 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, Ching Hua A1 - Imhof, Stefan A1 - Berger, Christian A1 - Bayer, Florian A1 - Brehm, Johannes A1 - Molenkamp, Laurens W. A1 - Kiessling, Tobias A1 - Thomale, Ronny T1 - Topolectrical Circuits JF - Communications Physics N2 - Invented by Alessandro Volta and Félix Savary in the early 19th century, circuits consisting of resistor, inductor and capacitor (RLC) components are omnipresent in modern technology. The behavior of an RLC circuit is governed by its circuit Laplacian, which is analogous to the Hamiltonian describing the energetics of a physical system. Here we show that topological insulating and semimetallic states can be realized in a periodic RLC circuit. Topological boundary resonances (TBRs) appear in the impedance read-out of a topolectrical circuit, providing a robust signal for the presence of topological admittance bands. For experimental illustration, we build the Su-Schrieffer–Heeger circuit, where our impedance measurement detects the TBR midgap state. Topolectrical circuits establish a bridge between electrical engineering and topological states of matter, where the accessibility, scalability, and operability of electronics synergizes with the intricate boundary properties of topological phases. KW - electronics, photonics and device physics KW - topological insulators Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236422 VL - 1 ER - TY - JOUR A1 - Kügel, Jens A1 - Karolak, Michael A1 - Krönlein, Andreas A1 - Serrate, David A1 - Bode, Matthias A1 - Sangiovanni, Giorgio T1 - Reversible magnetic switching of high-spin molecules on a giant Rashba surface JF - npj Quantum Materials N2 - The quantum mechanical screening of a spin via conduction electrons depends sensitively on the environment seen by the magnetic impurity. A high degree of responsiveness can be obtained with metal complexes, as the embedding of a metal ion into an organic molecule prevents intercalation or alloying and allows for a good control by an appropriate choice of the ligands. There are therefore hopes to reach an “on demand” control of the spin state of single molecules adsorbed on substrates. Hitherto one route was to rely on “switchable” molecules with intrinsic bistabilities triggered by external stimuli, such as temperature or light, or on the controlled dosing of chemicals to form reversible bonds. However, these methods constrain the functionality to switchable molecules or depend on access to atoms or molecules. Here, we present a way to induce bistability also in a planar molecule by making use of the environment. We found that the particular “habitat” offered by an antiphase boundary of the Rashba system BiAg2 stabilizes a second structure for manganese phthalocyanine molecules, in which the central Mn ion moves out of the molecular plane. This corresponds to the formation of a large magnetic moment and a concomitant change of the ground state with respect to the conventional adsorption site. The reversible spin switch found here shows how we can not only rearrange electronic levels or lift orbital degeneracies via the substrate, but even sway the effects of many-body interactions in single molecules by acting on their surrounding. KW - electronic structure of atoms and molecules KW - magnetic properties and materials KW - surfaces, interfaces and thin films Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230866 VL - 3 ER - TY - JOUR A1 - Kurabi, Arwa A1 - Schaerer, Daniel A1 - Noack, Volker A1 - Bernhardt, Marlen A1 - Pak, Kwang A1 - Alexander, Thomas A1 - Husseman, Jacob A1 - Nguyen, Quyen A1 - Harris, Jeffrey P. A1 - Ryan, Allen F. T1 - Active Transport of Peptides Across the Intact Human Tympanic Membrane JF - Scientific Reports N2 - We previously identified peptides that are actively transported across the intact tympanic membrane (TM) of rats with infected middle ears. To assess the possibility that this transport would also occur across the human TM, we first developed and validated an assay to evaluate transport in vitro using fragments of the TM. Using this assay, we demonstrated the ability of phage bearing a TM-transiting peptide to cross freshly dissected TM fragments from infected rats or from uninfected rats, guinea pigs and rabbits. We then evaluated transport across fragments of the human TM that were discarded during otologic surgery. Human trans-TM transport was similar to that seen in the animal species. Finally, we found that free peptide, unconnected to phage, was transported across the TM at a rate comparable to that seen for peptide-bearing phage. These studies provide evidence supporting the concept of peptide-mediated drug delivery across the intact TM and into the middle ears of patients. KW - assay systems KW - biological models Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230929 VL - 8 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 - THES A1 - Starz, Katharina Theresa T1 - Das Sharenting in der Zivilrechtsdogmatik : zu den Grenzen elterlicher Dispositionsbefugnis über das Persönlichkeitsrecht des Kindes T1 - Sharenting in Civil Law Dogmatics : On the Limits of Parental Power of Disposition over the Personal Rights of the Child N2 - Im Zeitalter der sozialen Medien ist es für viele Eltern zur Gewohnheit geworden, nicht nur sich selbst, sondern auch das eigene Kind der Internetgemeinschaft zu präsentieren. Diese Praxis wird als "Sharenting" ("to share" + "parenting“) bezeichnet. So kommt es, dass mittlerweile ein Großteil der Kinder bereits in sehr jungen Jahren einen - unfreiwilligen - digitalen Fußabdruck hinterlässt. Der freizügige Umgang mit den Daten des Kindes bringt zahlreiche rechtliche Probleme mit sich, welche an den Schnittstellen des Rechts zum Schutz der Persönlichkeit, des Datenschutzrechts und des Familienrechts zu verorten sind. Am Beispiel der Plattformen Facebook, Instagram und WhatsApp lotet Katharina Theresa Starz die Grenzen des rechtlich Zulässigen aus und zeigt auf, welche Konsequenzen sich ergeben können, wenn ebendiese Grenzen von den Eltern überschritten werden. Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369667 PB - Mohr Siebeck CY - Tübingen ER - TY - THES A1 - Dietz, Maximilian T1 - Synthese und Reaktivität neutraler Diboraarene T1 - Synthesis and Reactivity of Neutral Diboraarenes N2 - Die vorliegende Arbeit befasst sich mit der Darstellung und Reaktivität neutraler Diboraarene, wobei im ersten Teil die Synthese neuer Metallkomplexe eines cAAC-stabilisierten (cAAC = cyclisches Alkyl(amino)carben) 1,4-Diborabenzols sowie deren Folgereaktivität im Fokus steht. Im zweiten Abschnitt wird die Reaktivität des Diborabenzols und eines cAAC-stabilisierten 9,10-Diboraanthracens gegenüber Hauptgruppenelementverbindungen untersucht und vergleichend gegenübergestellt. Darauffolgend werden neben der Synthese neuer Metallkomplexe des Diboraanthracens auch weitere Reaktivitätsuntersuchungen der Verbindung behandelt. Der letzte Teil der Arbeit befasst sich mit der Darstellung neuartiger neutraler und cAAC-stabilisierter Diboraacene über eine Modulation des π-Systems. Dabei wird der synthetische Zugang zu einem 1,4-Diboranaphthalin und einem 6,13-Diborapentacen ermöglicht und ausgewählte Reaktivitäten beider Verbindungen demonstriert. N2 - The work presented herein deals with the preparation and reactivity of neutral diboraarenes, focusing in the first part on the synthesis of new metal complexes of a cAAC-stabilized (cAAC = cyclic alkyl(amino)carbene) 1,4-diborabenzene and their subsequent reactivity. In the second section, the reactivity of diborabenzene and a cAAC-stabilized 9,10-diboraanthracene towards main group element compounds is investigated in a comparative study. Subsequently, in addition to the synthesis of new metal complexes of diboraanthracene, further reactivity studies of the compound are also discussed. The last part of the work covers the preparation of novel neutral and cAAC-stabilized diboraacenes via modulation of the π system. Synthetic access to a 1,4-diboranaphthalene and a 6,13-diborapentacene is provided and selected reactivity patterns of both compounds are demonstrated. KW - Bor KW - Aromaten KW - Metallkomplexe KW - Diborabenzol KW - Diboraarene KW - Diboraacene KW - Arenkomplexe KW - Biradikale Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-321098 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 - 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 - 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 - Meral, Derya A1 - Provasi, Davide A1 - Prada-Gracia, Diego A1 - Möller, Jan A1 - Marino, Kristen A1 - Lohse, Martin J. A1 - Filizola, Marta T1 - Molecular details of dimerization kinetics reveal negligible populations of transient µ-opioid receptor homodimers at physiological concentrations JF - Scientific Reports N2 - Various experimental and computational techniques have been employed over the past decade to provide structural and thermodynamic insights into G Protein-Coupled Receptor (GPCR) dimerization. Here, we use multiple microsecond-long, coarse-grained, biased and unbiased molecular dynamics simulations (a total of ~4 milliseconds) combined with multi-ensemble Markov state models to elucidate the kinetics of homodimerization of a prototypic GPCR, the µ-opioid receptor (MOR), embedded in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)/cholesterol lipid bilayer. Analysis of these computations identifies kinetically distinct macrostates comprising several different short-lived dimeric configurations of either inactive or activated MOR. Calculated kinetic rates and fractions of dimers at different MOR concentrations suggest a negligible population of MOR homodimers at physiological concentrations, which is supported by acceptor photobleaching fluorescence resonance energy transfer (FRET) experiments. This study provides a rigorous, quantitative explanation for some conflicting experimental data on GPCR oligomerization. KW - computational biophysics KW - fluorescence resonance energy transfer Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223995 VL - 8 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 - THES A1 - Hahn, Sarah T1 - Investigating non-canonical, 5' UTR-dependent translation of MYC and its impact on colorectal cancer development T1 - Untersuchung der nicht-kanonischen, 5' UTR-abhängigen Translation von MYC und ihres Einflusses auf die Entwicklung von Darmkrebs N2 - Colorectal cancer (CRC) is the second most common tumour disease in Germany, with the sequential accumulation of certain mutations playing a decisive role in the transition from adenoma to carcinoma. In particular, deregulation of the Wnt signalling pathway and the associated deregulated expression of the MYC oncoprotein play a crucial role. Targeting MYC thus represents an important therapeutic approach in the treatment of tumours. Since direct inhibition of MYC is challenging, various approaches have been pursued to date to target MYC indirectly. The MYC 5' UTR contains an internal ribosomal entry site (IRES), which has a particular role in the initiation of MYC translation, especially in multiple myeloma. As basis for this work, it was hypothesised on the basis of previous data that translation of MYC potentially occurs via its IRES in CRC as well. Based on this, two IRES inhibitors were tested for their potential to regulate MYC expression in CRC cells. In addition, alternative, 5’ UTR-dependent translation of MYC and interacting factors were investigated. EIF3D was identified as a MYC 5' UTR binding protein which has the potential to regulate MYC expression in CRC. The results of this work suggest that there is a link between eIF3D and MYC expression/translation, rendering eIF3D a potential therapeutic target for MYC-driven CRCs. N2 - Das kolorektale Karzinom (KRK) ist die zweithäufigste Tumorerkrankung in Deutschland, wobei die sequenzielle Akkumulation bestimmter Mutationen eine entscheidende Rolle beim Übergang vom Adenom zum Karzinom spielt. Insbesondere die Deregulation des Wnt-Signalweges und die damit verbundene deregulierte Expression des MYC-Onkoproteins spielen eine entscheidende Rolle. MYC ist ein zentraler Vermittler von Zellfunktionen und reguliert als Transkriptionsfaktor die Expression fast aller Gene sowie verschiedener RNA-Spezies. Selbst kleine Veränderungen der zellulären MYC-Konzentration können das Proliferationsverhalten beeinflussen und die Entstehung und das Fortschreiten von Tumoren fördern. Die gezielte Beeinflussung von MYC stellt daher einen wichtigen therapeutischen Ansatz für die Behandlung von Tumoren dar. Da eine direkte Hemmung von MYC aufgrund seiner Struktur herausfordernd ist, wurden bisher verschiedene Ansätze verfolgt, um MYC indirekt zu beeinflussen, etwa über seinen Interaktionspartner MAX oder auf Ebene der Stabilität, Transkription oder Translation. In unserer eigenen Forschungsgruppe lag der Schwerpunkt in den letzten Jahren speziell auf der Translation von MYC im KRK. Es konnte gezeigt werden, dass die Hemmung der kanonischen cap-abhängigen Translation nicht wie erwartet zu einer Verringerung der zellulären MYC-Level führt, was auf einen alternativen Mechanismus der MYC-Translation hindeutet, der unabhängig vom eIF4F-Komplex abläuft. Die 5'-UTR von MYC enthält eine interne ribosomale Eintrittsstelle (IRES), die eine besondere Rolle bei der Initiierung der MYC-Translation spielt, insbesondere im Multiplen Myelom. Als Grundlage für diese Arbeit wurde daher die Hypothese aufgestellt, dass die Translation von MYC im KRK möglicherweise ebenfalls über die IRES erfolgt. Auf dieser Grundlage wurden zunächst zwei publizierte IRES-Inhibitoren auf ihr Potenzial zur Regulierung der MYC-Expression in KRK-Zellen getestet. J007-IRES hatte keine Auswirkungen auf die MYC-Proteinmenge, und Cymarin scheint weitaus globalere Auswirkungen zu haben, die nicht ausschließlich auf die Verringerung der MYC-Proteinmenge zurückzuführen sind. Daher wurde weiter untersucht, inwieweit die alternative Translation von MYC generell von der 5'-UTR und damit interagierenden Faktoren abhängig ist. EIF3D wurde als MYC-5'-UTR-Bindungsprotein identifiziert, dessen Knockdown zu reduzierten MYC-Leveln, einem Proliferationsdefizit sowie einer Verringerung der globalen Proteinsynthese in KRK-Zellen führte. Darüber hinaus führte die Depletion von EIF3D zu ähnlichen Veränderungen im zellulären Genexpressionsmuster wie die Depletion von MYC, wobei viele tumorassoziierte Signalwege betroffen waren. Mittels eCLIP-seq wurde die Bindung von eIF3D an die MYC mRNA nachgewiesen, der genaue Mechanismus einer möglicherweise durch eIF3D vermittelten Translation von MYC muss jedoch weiter untersucht werden. Die Ergebnisse dieser Arbeit deuten darauf hin, dass eine Verbindung zwischen eIF3D und der MYC-Expression/Translation besteht, wodurch eIF3D zu einem potenziellen therapeutischen Ziel für MYC-getriebene KRKs wird. KW - Myc KW - Translation KW - Colorectal cancer KW - 5' UTR Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-364202 ER - TY - THES A1 - Diehl, Janina Marie Christin T1 - Ecology and evolution of symbiont management in ambrosia beetles T1 - Ökologie und Evolution des Symbiontenmanagements bei Ambrosiakäfern N2 - The relationship between a farmer and their cultivated crops in agriculture is multifaceted, with pathogens affecting both the farmer and crop, and weeds that take advantage of resources provided by farmers. For my doctoral thesis, I aimed to gain a comprehensive understanding of the ecology and symbiosis of fungus farming ambrosia beetles. Through my research, I discovered that the microbial composition of fungus gardens, particularly the mutualists, is significantly influenced by the presence of both adults and larvae. The recognition of both beneficial and harmful symbionts is crucial for the success of ambrosia beetles, who respond differently depending on their life stage and the microbial species they encounter, which can contribute to the division of labour among family groups. The presence of antagonists and pathogens in the fungus garden depends on habitat and substrate quality, and beetle response to their introduction results in behavioural and developmental changes. Individual and social immunity measures, as well as changes in bacterial and fungal communities, were detected as a result of pathogen introduction. Additionally, the ability of ambrosia beetles to establish two nutritional fungal species depends on several factors. These insects must strike a balance between their essential functions and adapt to the constantly changing ecological and social conditions, which demonstrates their adaptive flexibility. However, interpreting data from laboratory studies should be approached with caution, as the natural environment allows for more flexibility and the potential for other beneficial symbionts to become more prominent if required. To aid in my research, I designed primers that use the ‘fungal large subunit’ (LSU) as genetic marker to identify and differentiate mutualistic and antagonistic fungi in X. saxesenii. The primers were able to distinguish closely related species of the Ophiostomataceae and other fungal symbionts. This allowed me to associate the abundance of key fungal taxa with factors such as the presence of beetles, the nest's age and condition, and the various developmental stages present. My primers are a valuable tool for understanding fungal communities, including their composition and the identification of previously unknown functional symbionts. However, some aspects should be approached with caution due to the exclusion of non-amplified taxa in the relative fungal community compositions. N2 - Die Beziehung zwischen einem Landwirt und der von ihm angebauten Nahrung in der Landwirtschaft ist vielschichtig: Pathogene, die sowohl den Landwirt als auch die Pflanzen befallen, und Unkräuter, die sich die von Landwirten bereitgestellten Ressourcen zunutzen machen. In meiner Doktorarbeit wollte ich ein umfassendes Verständnis der Ökologie und der Symbiose von pilzzüchtenden Ambrosiakäfern erlangen. Im Rahmen meiner Forschung fand ich heraus, dass die mikrobielle Zusammensetzung von Pilzgärten, insbesondere der Mutualisten, durch die Anwesenheit sowohl der erwachsenen Tiere als auch der Larven erheblich beeinflusst wird. Die Erkennung sowohl nützlicher als auch schädlicher Symbionten ist entscheidend für den Erfolg der Ambrosiakäfer, die je nach Lebensstadium und den angetroffenen Mikrobenarten unterschiedlich reagieren, was zur Arbeitsteilung zwischen Familiengruppen beitragen kann. Das Vorhandensein von Antagonisten und Krankheitserregern im Pilzgarten hängt von der Qualität des Lebensraums und des Substrats ab, und die Reaktion der Käfer auf ihre Einschleppung führt zu Veränderungen im Verhalten und in der Entwicklung. Individuelle und soziale Immunitätsmaßnahmen sowie Veränderungen der Bakterien- und Pilzgemeinschaften wurden als Folge der Einführung von Krankheitserregern festgestellt. Darüber hinaus hängt die Fähigkeit von Ambrosiakäfern, zwei Nährpilzarten zu etablieren, von mehreren Faktoren ab. Diese Insekten müssen ein Gleichgewicht zwischen ihren lebenswichtigen Funktionen herstellen und sich an die ständig ändernden ökologischen und sozialen Bedingungen anpassen, was ihre Anpassungsfähigkeit zeigt. Bei der Interpretation von Daten aus Laborstudien ist jedoch Vorsicht geboten, da die natürliche Umgebung mehr Flexibilität zulässt und die Möglichkeit bietet, dass andere nützliche Symbionten bei Bedarf stärker in Erscheinung treten. Um meine Forschung zu unterstützen, habe ich Primer entwickelt, die die ‘fungal large subunit‘ (LSU) als genetischen Marker verwenden, um mutualistische und antagonistische Pilze in X. saxesenii zu identifizieren und zu unterscheiden. Die Primer waren in der Lage, eng verwandte Arten der Ophiostomataceae und andere Pilzsymbionten zu unterscheiden. Auf diese Weise konnte ich die Häufigkeit der wichtigsten Pilztaxa mit Faktoren wie dem Vorhandensein von Käfern, dem Alter und Zustand des Nests und den verschiedenen Entwicklungsstadien in Verbindung bringen. Meine Primer sind ein wertvolles Instrument für das Verständnis von Pilzgemeinschaften, einschließlich ihrer Zusammensetzung und der Identifizierung von bisher unbekannten funktionellen Symbionten. Einige Aspekte sind jedoch mit Vorsicht zu genießen, da nicht amplifizierte Taxa in den relativen Zusammensetzungen der Pilzgemeinschaften nicht berücksichtigt werden. KW - ambrosia beetles KW - symbiont management KW - amplicon sequencing KW - fungus farming KW - microbial communities KW - social behaviour KW - Ökologie KW - Evolution Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-321213 ER - TY - THES A1 - Bönninger, Solveig Eva T1 - Förderliche und hinderliche Faktoren im Trauerprozess von Nahestehenden eines*r Verstorbenen T1 - Supporting and Hindering Factors in the Grieving Process of Close Relatives of a Deceased Person N2 - Laut Statistischem Bundesamt (Destatis) starben allein im Jahr 2020 zirka 985.500 Menschen. Die häufigsten Todesursachen waren Herz-Kreislauf- und Krebs-Erkrankungen (vgl. Destatis 2020). Die meisten Menschen haben den Wunsch zuhause zu sterben, doch die Mehrheit stirbt in Krankenhäusern, Alten- und Pflegeheimen (vgl. DHPV 2017; Dasch et al. 2015). Der Tod eines nahestehenden Menschen kann bei Hinterbliebenen zu großen Belastungen, gesundheitlichen Problemen sowie einer gesteigerten Mortalität führen (vgl. Stroebe et al. 2007). Ziel dieser Arbeit war es, mit Hilfe von halbstandardisierten Interviews mit 30 Trauernden Faktoren herauszuarbeiten, die sich förderlich oder hinderlich auf den Trauerprozess auswirken können. Die Interviews wurden mit der Transkriptionssoftware f4transkript verschriftlicht und mittels qualitativer Inhaltsanalyse nach Mayring ausgewertet. Es entstand ein Kategoriensystem mit je vier Oberkategorien innerhalb der zwei Hauptkategorien, Förderliche und Hinderliche Faktoren. Folgende Faktoren konnten identifiziert werden: Förderliche Faktoren in der Oberkategorie Betreuung der erkrankten und trauernden Person sind eine gute Symptomkontrolle sowie der verständnisvolle Umgang mit den Nahestehenden, während mangelhafte Kommunikation wiederum hinderlich für eine positive Trauerbewältigung ist. In der Oberkategorie Intrapersonale Faktoren sind die Antizipation des Todes sowie die Auseinandersetzung mit der Trauer förderlich, während negative Gefühle (z.B. Schuldgefühle, Hilfslosigkeit) sich in besagter Hinsicht hinderlich auswirken. In der Oberkategorie Beziehung zur verstorbenen Person können die optimale Nutzung der verbliebenen Zeit sowie der offene Umgang mit der Erkrankung förderliche Faktoren darstellen, während ein “schwieriger“ Abschied sowie ungeklärte Konflikte oder offene Fragen Hindernisse für den Trauerprozess sein können. In der Oberkategorie Soziales Umfeld sind die unaufgeforderte Unterstützung, die emotionale Begleitung sowie ein flexibler Arbeitgeber förderlich. Streitigkeiten innerhalb der Familie und Unverständnis der Mitmenschen dagegen sind hinderlich. Eine gute und würdevolle Sterbebegleitung, wie sie in der Palliativmedizin in der Regel gewährleistet ist, ist von großer Bedeutung für einen gelingenden Trauerprozess. Daher sollte eine palliative Haltung disziplinübergreifend vorangebracht und ausgebaut werden. In der Gesellschaft sollte Trauernden mehr Toleranz und Verständnis entgegengebracht und offen mit dem Thema Tod und Sterben umgegangen werden. N2 - According to the German Federal Statistical Office (Destatis), approximately 985,500 people died in the year 2020 in Germany. The most common causes of death were cardiovascular diseases and cancer (cf. Destatis 2020). Most people wish to die at home, but the majority die in hospitals and care facilities (cf. DHPV 2017; Dasch et al. 2015). The death of a close person can lead to significant difficulties, health problems, and increased mortality among the bereaved (cf. Stroebe et al. 2007). The aim of this study was to identify factors that can have a supporting or hindering effect on the grieving process by conducting semi-structured interviews with 30 mourners. The interviews were transcribed using the f4transkript transcription software and evaluated using qualitative content analysis according to Mayring. A category system was developed with four subcategories within the two main categories, Supporting and Hindering Factors. The following factors were identified: Supporting factors in the subcategory "Care of the sick and grieving person" include good symptom control and understanding treatment of the relatives, while poor communication, in turn, is a hindrance to positive grief coping. In the subcategory "Intrapersonal factors", the anticipation of death and dealing with grief are supportive, while negative emotions (e.g., feelings of guilt, helplessness) have a hindering effect in this regard. In the subcategory "Relationship with the deceased person", optimal use of the remaining time and open handling of the illness can be supporting factors, while a "difficult" farewell and unresolved conflicts or open questions can be obstacles to the grieving process. In the subcategory "Social environment", unsolicited support, emotional companionship, and a flexible employer are supporting. Family disputes and a lack of understanding from others, on the other hand, are hindering. Good and dignified end-of-life care, as is generally ensured in palliative medicine, is of great importance for a successful grieving process. Therefore, a palliative attitude should be promoted and expanded across disciplines. In society, more tolerance and understanding should be shown to mourners, and the topic of death and dying should be dealt with openly. KW - Trauer KW - Trauerarbeit KW - Prolonged grief disorder KW - Trauerprozess KW - Soziales Umfeld KW - Beziehung zur verstorbenen Person KW - Medizinisch-psychologische Betreuung KW - Intrapersonale Faktoren KW - Milieu Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-364319 ER - TY - THES A1 - Merscher, Alma-Sophia T1 - To Fear or not to Fear: Unraveling the (Oculo)motor and Autonomic Components of Defensive States in Humans T1 - Vor Furcht Erstarren: Charakterisierung der (Okulo)motorischen und Autonomen Komponenten Menschlicher Defensivreaktionen N2 - Defensive behaviors in response to threats are key factors in maintaining mental and physical health, but their phenomenology remains poorly understood. Prior work reported an inhibition of oculomotor activity in response to avoidable threat in humans that reminded of freezing behaviors in rodents. This notion of a homology between defensive responding in rodents and humans was seconded by concomitant heart rate decrease and skin conductance increase. However, several aspects of this presumed defense state remained ambiguous. For example, it was unclear whether the observed oculomotor inhibition would 1) robustly occur during preparation for threat-avoidance irrespective of task demands, 2) reflect a threat-specific defensive state, 3) be related to an inhibition of somatomotor activity as both motion metrics have been discussed as indicators for freezing behaviors in humans, and 4) manifest in unconstrained settings. We thus embarked on a series of experiments to unravel the robustness, threat-specificity, and validity of previously observed (oculo)motor and autonomic dynamics upon avoidable threat in humans. We provided robust evidence for reduced gaze dispersion, significantly predicting the speed of subsequent motor reactions across a wide range of stimulus contexts. Along this gaze pattern, we found reductions in body movement and showed that the temporal profiles between gaze and body activity were positively related within individuals, suggesting that both metrics reflect the same construct. A simultaneous activation of the parasympathetic (i.e., heart rate deceleration) and sympathetic (i.e., increased skin conductance and pupil dilation) nervous system was present in both defensive and appetitive contexts, suggesting that these autonomic dynamics are not only sensitive to threat but reflecting a more general action-preparatory mechanism. We further gathered evidence for two previously proposed defensive states involving a decrease of (oculo)motor activity in a naturalistic, unconstrained virtual reality environment. Specifically, we observed a state consisting of a cessation of ongoing behaviors and orienting upon relatively distal, ambiguous threat (Attentive Immobility) while an entire immobilization and presumed allocation of attention to the threat stimulus became apparent upon approaching potential threat (Immobility under Attack). Taken together, we provided evidence for specific oculomotor and autonomic dynamics upon increasing levels of threat that may inspire future translational work in rodents and humans on shared mechanisms of threat processing, ultimately supporting the development of novel therapeutic approaches. N2 - Angemessen auf Gefahren zu reagieren, ist überlebensnotwendig, wissenschaftlich jedoch wenig verstanden. Eine frühere Studie wies auf, dass ProbandInnen ihre Augen weniger bewegten, wenn sie mit einer Bedrohung konfrontiert waren, der sie mit einer schnellen Bewegung entkommen konnten. Dieses eingeschränkte Blickbewegungsmuster wurde von einer Herzraten-Dezeleration und einem Anstieg der Hautleitfähigkeit begleitet und wies damit Ähnlichkeiten mit bestimmten Erstarrungsreaktionen auf Bedrohungen (Freezing) bei Nagetieren auf. Es blieb jedoch unklar, ob die eingeschränkten Augenbewegungen 1. robust und unabhängig von spezifischen Aufgabenstellungen als Reaktion auf eine vermeidbare Bedrohung auftreten, 2. eine bedrohungsspezifische Komponente eines Defensivzustands darstellen, 3. von einer körperlichen Bewegungsreduktion begleitet und 4. im freien Raum auftreten würden. Wir haben daher untersucht, ob dieses eingeschränkte Blickbewegungsmuster sowie seine autonomen Begleiterscheinungen robust, bedrohungsspezifisch und valide sind. In unseren Studien traten verringerte Augenbewegungen robust und bedrohungsspezifisch als Reaktion auf vermeidbare Bedrohungen auf und sagten schnellere Reaktionszeiten vorher. Die eingeschränkten Augenbewegungen wurden von verringerten Körperbewegungen begleitet, deren zeitliche Verläufe miteinander korrelierten. Dies könnte auf ein zugrundeliegendes gemeinsames Konstrukt hinweisen. Wir beobachteten außerdem eine Herzraten-Dezeleration sowie erhöhte Hautleitfähigkeit und Pupillendilation in bedrohlichen und appetitiven Kontexten, was darauf hindeutet, dass diese autonomen Dynamiken nicht nur durch Bedrohungen, sondern auch allgemein handlungsvorbereitend ausgelöst werden können. Zuletzt konnten wir in einer frei explorierbaren, virtuellen Umgebung Hinweise auf zwei Defensivzustände liefern, deren Unterscheidung zuvor postuliert, jedoch noch nicht weitreichend belegt war. Bei relativ weit entfernter und ambivalenter Gefahr hielten die ProbandInnen inne und drehten sich, vermutlich zur Orientierung, zum potentiellen Ort der Bedrohung hin (Attentive Immobility). Wenn sich die Bedrohung jedoch näherte, verringerten sich sowohl Körper- als auch Augenbewegungen, als würden die ProbandInnen ihre Aufmerksamkeit auf die Bedrohung ausrichten (Immobility under Attack). Zusammenfassend lieferten unsere Erhebungen damit Belege für spezifische (okulo)motorische und autonome Dynamiken bei steigender Bedrohung, die zukünftige translationale Forschungen über Homologien von Defensivzuständen zwischen Nagetieren und Menschen inspirieren und damit womöglich die Entwicklung neuer therapeutischer Verfahren unterstützen können. KW - Furcht KW - Fear Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-327913 ER - TY - THES A1 - Kanmegne Tamga, Dan Emmanuel T1 - Modelling Carbon Sequestration of Agroforestry Systems in West Africa using Remote Sensing T1 - Modellierung der Kohlenstoffbindung von agroforstwirtschaftlichen Systemen in Westafrika mittels Fernerkundung N2 - The production of commodities such as cocoa, rubber, oil palm and cashew, is the main driver of deforestation in West Africa (WA). The practiced production systems correspond to a land managment approach referred to as agroforestry systems (AFS), which consist of managing trees and crops on the same unit of land.Because of the ubiquity of trees, AFS reported as viable solution for climate mitigation; the carbon sequestrated by the trees could be estimated with remote sensing (RS) data and methods and reported as emission reduction efforts. However, the diversity in AFS in relation to their composition, structure and spatial distribution makes it challenging for an accurate monitoring of carbon stocks using RS. Therefore, the aim of this research is to propose a RS-based approach for the estimation of carbon sequestration in AFS across the climatic regions of WA. The main objectives were to (i) provide an accurate classification map of AFS by modelling the spatial distribution of the classification error; (ii) estimate the carbon stock of AFS in the main climatic regions of WA using RS data; (iii) evaluate the dynamic of carbon stocks within AFS across WA. Three regions of interest (ROI) were defined in Cote d'Ivoire and Burkina Faso, one in each climatic region of WA namely the Guineo-Congolian, Guinean and Sudanian, and three field campaigns were carried out for data collection. The collected data consisted of reference points for image classification, biometric tree measurements (diameter, height, species) for biomass estimation. A total of 261 samples were collected in 12 AFS across WA. For the RS data, yearly composite images from Sentinel-1 and -2 (S1 and S2), ALOS-PALSAR and GEDI data were used. A supervised classification using random forest (RF) was implemented and the classification error was assessed using the Shannon entropy generated from the class probabilities. For carbon estimation, different RS data, machine learning algorithms and carbon reference sources were compared for the prediction of the aboveground biomass in AFS. The assessment of the carbon dynamic was carried between 2017 and 2021. An average carbon map was genrated and use as reference for the comparison of annual carbon estimations, using the standard deviation as threshold. As far as the results are concerned, the classification accuracy was higher than 0.9 in all the ROIs, and AFS were mainly represented by rubber (38.9%), cocoa (36.4%), palm (10.8%) in the ROI-1, mango (15.2%) and cashew (13.4%) in ROI-2, shea tree (55.7%) and African locust bean (28.1%) in ROI-3. However, evidence of misclassification was found in cocoa, mango, and shea butter. The assessment of the classification error suggested that the error level was higher in the ROI-3 and ROI-1. The error generated from the entropy was able to reduced the level of misclassification by 63% with 11% of loss of information. Moreover, the approach was able to accuretely detect encroachement in protected areas. On carbon estimation, the highest prediction accuracy (R²>0.8) was obtained for a RF model using the combination of S1 and S2 and AGB derived from field measurements. Predictions from GEDI could only be used as reference in the ROI-1 but resulted in a prediction error was higher in cashew, mango, rubber and cocoa plantations, and the carbon stock level was higher in African locust bean (43.9 t/ha), shea butter (15 t/ha), cashew (13.8 t/ha), mango (12.8 t/ha), cocoa (7.51 t/ha) and rubber (7.33 t/ha). The analysis showed that carbon stock is determined mainly by the diameter (R²=0.45) and height (R²=0.13) of trees. It was found that crop plantations had the lowest biodiversity level, and no significant relationship was found between the considered biodiversity indices and carbon stock levels. The assessment of the spatial distribution of carbon sources and sinks showed that cashew plantations are carbon emitters due to firewood collection, while cocoa plantations showed the highest potential for carbon sequestration. The study revealed that Sentinel data could be used to support a RS-based approach for modelling carbon sequestration in AFS. Entropy could be used to map crop plantations and to monitor encroachment in protected areas. Moreover, field measurements with appropriate allometric models could ensure an accurate estimation of carbon stocks in AFS. Even though AFS in the Sudanian region had the highest carbon stocks level, there is a high potential to increase the carbon level in cocoa plantations by integrating and/or maintaining forest trees. N2 - Die Produktion von Rohstoffen wie Kakao, Kautschuk, Ölpalmen und Cashew ist die Hauptursache fur die Entwaldung in Westafrika (WA). Die verwendeten Produktionssyteme entsprechen einem Landbewirtschaftungskonzept, welches als Agroforstsysteme (AFS) bezeichnet wird und darin besteht, Baume und Nutzpflanzen auf der gleichen Landeinheit zu bewirtschaften. Aufgrund der kohlenstoffbindung durch Baumen sind AFS als praktikable Losung fur den Klimaschutz anerkannt, die Vielfalt der AFS in Bezug auf ihre Zusammensetzung, Struktur un raumliche Verteilung erschwert jedoch eine genaue Schatzung der Kohlenstoffvorrate. Hier konnen Daten und Methoden der satellitenbasierten Erdbeobachtung ansetzten. Ziel dieser Forschungsarbeit ist es daher, einen fernerkundungs-basierten Ansatz fur die Schatzung der Kohlenstoffbindung in AFS in den Klimaregionen von WA vorzuschlagen. Die Hauptziele waren (i) die Erstellung einer genauen Klassifizierungskarte von AFS durch Modellierung der raumlichen verteilung des Klassifizierungsfehlers; (ii) die Shatzung des Kohlenstoffbestands von AFS in den wichtigsten Klimaregionen von WA unter Verwendung von Fernerkundungs-daten (RS); (iii) die Bewertung der raumlichen Verteilung von Kohlenstoffquellen und -senken innerhalb von AFS in ganz WA. Fur jede Klimaregion in West Afrika wurden drei Regionen von Interesse (ROI) festgelegt, namlich die guineisch-kongolesische (ROI 1), die guineische (ROI 2) und die sudanesische Region (ROI 3) in Côte d'Ivoire und Burkina Faso, und es wurden drei Feldkampagnen zur Datenerhebung durchgefuhrt. Die gesammelten Daten bestanden aus Referenzpunkten fur die Bildklassifizierung und biometrischen Messungen (Durchmesser, Hohe, Artname) zur Schatzung der Biomasse. Insgesamt wurden 261 Proben in 12 AFS in ganz WA gesammelt. Fur die RS-Daten wurden jahrliche Komposite von Sentinel-1 und -2 (s1 und S3), ALOS-PALSAR und GEDI-Daten verwendet. Es wurde eine uberwachte Klassifizierung mit Random Forest (RF) algorithmus durch gefuhrt, und der Klassifizierungsfehler wurde anhand der aus den Klassenwahrscheinlichkeiten generierten Shannon-Entropie bewertet. Fur die Kohlenstoffschatzung wurden verschiedene RS-Daten, Algorithmen fur maschinelles Lernen und Kohlenstoff-Referenzquellen fur die Vorhesage des Kohlenstoffs in AFS verglichen. Die Bewertung der raumlichen Verteilung von Kohlenstoffsenken und -quellen basierte auf der Bewertung von Anomalien in der Kohlenstoffdynamik zwischen 2017 und 2021. Es wurde eine Karte zum durchschnittliche gebundenen Kohkenstoff erstellt, und die jahrliche Differenz wurde verwendet, um Kohlenstoffsenken und -quellen zu identifizieren. Die Klassifizierungsgenauigkeit war in allen ROI hoher als 0.9, in der Region dominierten Kautschuk (38.9%), Kakao (36.4%), Palme (10.8%) in ROI-1, Mango (15.2%) und Cashew (13.4%) in ROI-2, Sheabaum (55.7%) und Johannisbrot (28.1%) in ROI-3. Hinweise auf eine Fehlklassifizierung wurden vor allem bei Kakao, Mango un Sheabutter gefunden. Die Bewertung des Klassifizierungsfehlers ergab, dass das Fehlerniveau in ROI-3 und ROI-1 hoher war. Der aus der Entropie generiete Fehler konnte das Ausmass der Fehlklassifizierung reduzieren, ohne die gut klassifizierten Pixel zu beeintrachtigen. Ausserdem war der Ansatz in der Lage, Eingriffe in Schutzgebiete zuverlassig un akkurat zu erkennen. Was die Kohlenstoffschatzung betrifft, so wrude die hochste Vorhersagegenauigkeit (R²> 0.8)bei der Kombination von S1 und S2 mit Random Forest und AGB aus Feldmessungen erzielt. Vorhersagen von GEDI konnten nur als Referenz in der ROI verwendet werden, fuhrten aber zu einem Vorhersagefehler bei Cashew-, Mango-, Kautschuk- und Kakaoplantagen hoher war und der Kohlenstoffbestand bei Johannisbrot (43.9t/ha), Sheabutter (15 t/ha), Cashew (13.8 t/ha), Mango (12.8t/ha), Kakao (7.51 t/ha) und Kautschuk (7.33 t/ha) hoher war. Die Analyse zeigte, dass der Kohlenstoffbestand hauptsachlich durch den Durchmesser (R²=0.45) und die Hohe (R²=0.13) der Baume beeinflusst wird. Zudem wurde festgestellt, dass Plantagenkulturen die geringste Biodiversitat aufweisen, und es wurde kein signifikanter Zusammenhang zwischen Biodiversitatsindizes und Kohlenstoffvorraten festgestellt. Die Bewertung der raumlichen Verteilung von Kohlenstoffquellen und -senken zeigte, dass Cashew ein Kohlenstoffemittent ist, da in dieser Region Brennholz gesammelt wird, wahrend Kakaoplantagen wichtige Kohlenstoffsenken sind. Die Studie ergab zudem, dass Sentinel-Daten zur Unterstutzung eines RS-basierten Ansatzes fur die Modellierung der Kohlenstoffbindung in AFS verwendet werden konnten. Die Entropie konnte zur Kartierung von Anbauplantagen und zur uberwachen von Schutzgebiete verwendet werden. Daruber hinaus gewahrleisten feldmessungen mit geeigneten allometrischen Modellen eine genaue Schatzung der Kohlenstoffvorrate in AFS. Die AFS in der sudanesischen Region weisen die hochsten Kohlenstoffvorrate auf, aber es besteht die Moglichkeit, den Kohlenstoffgehalt in Kakaoplantagen durch die Integration und/oder Erhaltung von Waldbaumen zu erhoehen. KW - Sequestrierung KW - Fernerkundung KW - Westafrika KW - carbon sequestration KW - agroforestry systems KW - remote sensing KW - West Africa Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369269 ER - TY - THES A1 - Morabbian, Jasamin T1 - Etablierung von Stammzell-Sphäroiden mit inkorporierten Biokeramik-Partikeln zur Förderung der osteogenen Differenzierung T1 - Establishment of stem cell spheroids with incorporated bioceramic particles for the promotion of osteogenic differentiation N2 - In der vorliegenden Dissertationsarbeit wurden Sphäroide aus mesenchymalen Stammzellen aus dem Fettgewebe oder dem Knochenmark mittels der Micromold-Methode hergestellt. Den Sphäroiden wurden entweder Calciumphosphat- oder Calcium-Magnesium-Phosphat-Partikel hinzugefügt. Zum einen sollte überprüft werden, ob die Zugabe von Partikeln die osteogene Differenzierung der Sphäroide fördert und somit zur weiteren Entwicklung von körpereigenem Knochenersatzmaterial in der regenerativen Medizin beiträgt. Zum anderen sollte festgestellt werden, ob eine der beiden Biokeramiken hinsichtlich der osteogenen Differenzierung überlegen ist. N2 - In this dissertation, spheroids were produced from mesenchymal stem cells from adipose tissue or bone marrow using the micromold method. Either calcium phosphate or calcium magnesium phosphate particles were added to the spheroids. On the one hand, it was to be examined whether the addition of particles promotes the osteogenic differentiation of the spheroids and thus contributes to the further development of endogenous bone replacement material in regenerative medicine. Secondly, to determine whether one of the two bioceramics is superior in terms of osteogenic differentiation. KW - Stammzelle KW - Calciumphosphat KW - Spheroid KW - Knochenzement KW - Knochenersatzmaterial KW - Calcium-Magnesium-Phosphat Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369256 ER - TY - THES A1 - Yabe, Marie T1 - Untersuchung des Mental Rotation-Paradigmas bei Patienten mit fokaler Dystonie T1 - Mental Rotation performance in patients with focal dystonia N2 - Das mR-Paradigma beschreibt die Fähigkeit Objekte gedanklich zu drehen und erfordert dabei komplexe neuronale Prozesse. Bisherige Studien konnten nicht klären, ob es ein spezifisches Muster der Beeinträchtigung im mR-Test bei fokalen Dystonien gibt. Die übergeordnete Fragestellung der vorliegenden Arbeit war, ob eine verlangsamte Reaktion bei der mR von körperlichen Abbildungen einen stabilen Endophänotyp fokaler Dystonien darstellt. Die Zielsetzung war die Überprüfung der Hypothesen, 1) dass bisherige Ergebnisse, die eine verlängerte Reaktionszeit von CD-Patienten bei der mR von körperlichen Abbildungen aufzeigten, reproduzierbar sind und 2) dass eine erhöhte Reaktionszeit bei der mR von körperlichen Abbildungen auch bei Patienten mit BSP vorliegt. Um dabei die mR möglichst spezifisch zu untersuchen, wurden folgende sekundäre Hypothesen formuliert: a) die kognitive Leistungsfähigkeit und b) das allgemeine Reaktionsvermögen der Teilnehmer stellen potenzielle Störfaktoren für die Reaktionszeit bei der mR-Aufgabe dar. Diese wurden neben der Händigkeit und der allgemeinen Geschicklichkeit systematisch erhoben. 23 CD-Patienten und 23 gesunde Kontrollpersonen sowie 21 BSP- und 19 HFS-Patienten wurden hinsichtlich Geschlechterverteilung, Alter und Bildungsstand verglichen. Zudem wurden Händigkeit, Fingergeschicklichkeit, allgemeine Reaktionszeit und kognitiver Status jedes Teilnehmers erhoben. Im mR-Test wurden Fotos von Körperteilen (Hand, Fuß oder Kopf) und einem nicht-körperlichen Objekt (Auto) gezeigt, die in sechs verschiedene Winkelgrade um die eigene Achse in der Bildebene rotiert waren. Die Teilnehmer wurden gebeten, die Lateralität des dargestellten Bildes per Tastendruck anzugeben. Bewertet wurden sowohl Geschwindigkeit als auch Richtigkeit der Antworten. Im Vergleich zu gesunden Kontrollpersonen schnitten CD- und HFS-Patienten bei der mR der Hände schlechter ab, während die BSP-Patienten vergleichbare Leistungen zeigten. Es bestand ein signifikanter Zusammenhang zwischen einer verlängerten mR-Reaktionszeit und reduzierten MoCA-Scores sowie einer erhöhten mR-Reaktionszeit und verlängerter allgemeiner Reaktionszeit. Nach Ausschluss der Patienten mit MCI zeigten CD-Patienten, nicht jedoch HFS-Patienten, im Vergleich zur gesunden Kontrollgruppe weiterhin verlangsamte Reaktionszeiten der Hände. Die vorliegende Studie konnte die Frage, ob eine verlangsamte Reaktion bei der mR von körperlichen Abbildungen einen stabilen Endophänotyp fokaler Dystonien darstellt, nicht sicher beantworten. Es stellte sich jedoch heraus, dass Kognition und allgemeine Reaktionszeit starke Einflussfaktoren bei der mR-Aufgabe sind. Dies wurde in den früheren Arbeiten nicht berücksichtigt und stellt daher ein neues und wichtiges Ergebnis dar. Die verlangsamte Reaktion bei der mR der Hände bei CD-Patienten auch nach Ausschluss von Patienten mit MCI lässt ein spezifisches Defizit der Fähigkeit der mR vermuten. Das Vorliegen einer tiefergreifenden zugrundeliegenden Netzwerkstörung, die sich auf die Leistung im mR-Test auswirkt, wäre dabei denkbar. N2 - Mental rotation (mR) describes the ability to rotate objects in mind. Previous studies could not clarify whether there is a specific pattern of mR impairment in focal dystonia. This study aimed to investigate whether patients with cervical dystonia (CD) and blepharospasm (BSP) show an increased reaction time (RT) in mR of body parts. Besides the study aimed to assess potential confounders such as cognitive performance and general reaction time. 23 CD patients and 23 healthy controls (K) as well as 21 BSP and 19 hemifacial spasm (HFS) patients were matched for sex, age, and education level. Disease severity was evaluated by clinical scales. Besides handedness, finger dexterity, general reaction time, and cognitive status were assessed. The mR-task included photographs of body parts (hand, foot or head) and a non-corporal object (car) displayed at different angles rotated within their plane. Subjects were asked to judge laterality of the presented image by keystroke. Both speed and correctness were evaluated. CD and HFS patients showed increased RT in mR of hands compared to K, whereas BSP group showed comparable performance. There was a significant association of prolonged mR-RT with reduced MoCA scores and with increased general reaction time. After exclusion of patients with mild cognitive impairment, increased RT in the mR of hands was confined to CD group, but not HFS. The present study could not clarify whether a prolonged RT in mR of body parts defines a dystonic endophenotype. However, it showed that cognition and general reaction time have strong influence on mR. The increased RT in the mR of the hands in CD patients, even after exclusion of patients with mild cognitive impairment, implicate a specific deficit in mR ability. Thereby an underlying network disorder that affects mR performance is conceivable. KW - mental rotation KW - fokale Dystonie Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-363927 ER - TY - THES A1 - Laqua, Caroline T1 - Association of myocardial tissue characteristics and functional outcome in biopsy-verified myocarditis assessed by cardiac magnetic resonance imaging T1 - Zusammenhänge zwischen geweblichen Eigenschaften des Myokards und funktionellem Outcome bei biopsie-verifizierter Myokarditis im Kardio-MRT N2 - The relation between LV function and cardiac MRI tissue characteristics in separate myocardial segments and their change over time has yet to be explored in myocarditis. Thus, our research aimed to investigate possible associations between global and regional myocardial T1 and T2 times and peak strain in patients with suspected myocarditis. From 2012 to 2015, 129 patients with clinically suspected myocarditis of the prospective, observational MyoRacer-Trial underwent systematic biventricular EMB at baseline and cardiac MRI at baseline and after three months as a follow-up. We divided the LV myocardium into 17 segments and estimated the segmental myocardial strain using FT. We registered T1 and T2 maps to the cine sequences and transferred the segmentations used for FT to ensure conformity of the myocardial segments. Multi-level multivariable linear mixed effects regression was applied to investigate the relation of segmental myocardial strain to relaxation times and their respective change from baseline to follow-up. We found a significant improvement in myocardial peak strain from baseline to follow-up (p < 0.001; all p-values given for likelihood ratio tests) and significant associations between higher T1 and T2 times and lower segmental myocardial peak strain (p ranging from < 0.001 to 0.049). E.g., regression coefficient (Reg. coef.) for segmental radial peak strain in short axis view (SRPS_SAX) and T1 time: -1.9, 95% CI (-2.6;-1.2) %/100 ms, p < 0.001. A decrease in T1 and T2 times from baseline to follow-up was also significantly related to a recovery of segmental peak strains (p ranging from < 0.001 to 0.050). E.g., Reg. coef. for SRPS_SAX per ΔT1: -1.8, 95% CI (-2.5;-1.0) %/100 ms, p < 0.001. Moreover, the higher the baseline T1 time, the more substantial the functional recovery from baseline to follow-up (p ranging from 0.004 to 0.042, e.g., for SRPS_SAX: Reg. coef. 1.3, 95% CI (0.4;2.1) %/100 ms, p 0.004). We did not find an effect modification by the presence of myocarditis in the EMB (p > 0.1). Our cross-sectional and longitudinal analyses provide evidence of dose-dependent correlations between T1 and T2 relaxation times and myocardial peak strain in patients with clinical presentation of myocarditis, regardless of the EMB result. Thus, assessing strain values and mapping relaxation times helps estimate the functional prognosis in patients with clinically suspected myocarditis. N2 - Die Zusammenhänge zwischen der kardialen linksventrikulären (LV) Funktion und magnetresonanztomographisch erhebbaren Parametern des Myokards sowie deren jeweiligen Entwicklungen im zeitlichen Verlauf einer Myokarditis sind bisher nicht umfassend untersucht. Daher beschäftigt sich die vorliegende Arbeit mit der Erforschung des Verhältnisses von globalen und regionalen peak strain-Werten und T1 und T2 Zeiten des LV Myokards in der Magnetresonanztomographie (MRT) bei Patienten mit Verdacht auf Myokarditis. Die MyoRacer-Studie ist eine prospektive Beobachtungsstudie, die von 2012 bis 2015 am Herzzentrum des Universitätsklinikums Leipzig durchgeführt wurde. Dabei wurden 129 Patienten mit klinischem Verdacht auf Myokarditis mittels biventrikulärer Myokardbiopsie sowie kardialer MRT untersucht. Drei Monate nach der Erstuntersuchung (EU) erfolgte eine MRT-Folgeuntersuchung (FU). Für unsere Analysen unterteilten wir das LV Myokard standardmäßig in 17 Segmente, um mithilfe der Technik des feature trackings den segmentalen peak strain zu evaluieren. Weiterhin registrierten wir T1 und T2 maps gegen cine-Sequenzen der MRT und übertrugen die Segmentierungen aus den cine-Sequenzen zwecks Übereinstimmung in die MRT maps. Anschließend analysierten wir die Zusammenhänge zwischen segmentalem strain und T1 und T2 Zeiten und deren jeweiligen Veränderungen im zeitlichen Verlauf mithilfe eines hierarchischen, multivariablen, gemischten linearen Regressionsmodells. Unsere Ergebnisse zeigen eine signifikante Verbesserung der peak strain-Werte von der EU zur FU (p < 0.001; alle p-Werte für likelihood ratio tests angegeben) sowie eine signifikante Assoziation von erhöhten T1 und T2 Zeiten mit verminderten segmentalen peak strain-Werten (p zwischen < 0.001 und 0.049). Weiterhin war ein Abfall der T1 und T2 Zeiten von der EU zur FU signifikant mit einer Erholung der segmentalen peak strain-Werte verknüpft (p zwischen < 0.001 und 0.050). Je höher die T1 Zeiten bei der EU ausfielen, desto stärker erholte bzw. verbesserte sich der peak strain von der EU zur FU (p zwischen 0.004 und 0.042). Eine Effektmodifikation durch den bioptischen Nachweis einer Myokarditis war nicht zu beobachten (p > 0.1). Unsere Quer- und Längsschnittanalysen belegen dosisabhängige Zusammenhänge zwischen T1 und T2 Zeiten und myokardialen peak strain-Werten bei Patienten mit dem klinischen Bild einer Myokarditis, unabhängig vom Ergebnis der Myokardbiopsie. Daher ist die Bestimmung von T1 und T2 Zeiten und myokardialem strain mittels kardialer MRT zur Abschätzung der funktionellen Prognose bei Patienten mit klinischem Verdacht auf Myokarditis hilfreich. KW - Myokarditis KW - Kernspintomografie KW - T1-Zeit KW - T2-Zeit KW - strain KW - t1 time KW - t2 time KW - myocarditis KW - MRI Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-363903 ER - TY - RPRT A1 - Männel, Jonathan A1 - Borschinsky, Erik A1 - Kayal, Hakan A1 - Neumann, Tobias A1 - Riegler, Clemens T1 - SATEX: Extraterrestrik mit Kleinsatelliten - Kurzbericht N2 - Dieser Kurzbericht beleuchtet die Einsatzmöglichkeiten von Kleinsatelliten in der extraterrestrischen Forschung und zeigt auf welche technologischen Herausforderungen sich bei ihrem Einsatz ergeben. Die präsentierten Ergebnisse sind Teil der SATEX Untersuchung (FKZ 50OO2222). In diesem Dokument werden zunächst die allgemeinen Einsatzmöglichkeiten von Kleinsatelliten in der Extraterrestrik anhand ausgewählter Beispielmissionen beleuchtet. Daraufhin erfolgt die Erörterung spezifischer technischer Herausforderungen und Umweltbedingungen bei cislunaren und interplanetaren Kleinsatellitenmissionen, gefolgt von einer kurzen Präsentation von Nutzerwünsche aus Deutschland für Missionen zur Erforschung des Weltraums. Zum Abschluss werden zehn konkrete, im Rahmen der Untersuchung ermittelte, Missionsideen vorgestellt und bewertet. Schließlich erfolgt die Zusammenfassung der wichtigsten Erkenntnisse und Empfehlungen. KW - Extraterrestrische Forschung KW - Kleinsatellit KW - Stand von Wissenschaft und Technik KW - Satellitentechnik KW - cislunar KW - technische Herausforderungen KW - Kleinsatellitenmissionen Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-363256 N1 - In der Datei ist es zu einem Fehler bei der Darstellung einer Abbildung gekommen. Eine korrigierte Version finden Sie unter https://doi.org/10.25972/OPUS-36979 ER - TY - RPRT A1 - Männel, Jonathan A1 - Borschinsky, Erik A1 - Kayal, Hakan A1 - Neumann, Tobias A1 - Riegler, Clemens T1 - SATEX: Extraterrestrik mit Kleinsatelliten - Kurzbericht N2 - Dieser Kurzbericht beleuchtet die Einsatzmöglichkeiten von Kleinsatelliten in der extraterrestrischen Forschung und zeigt auf welche technologischen Herausforderungen sich bei ihrem Einsatz ergeben. Die präsentierten Ergebnisse sind Teil der SATEX Untersuchung (FKZ 50OO2222). In diesem Dokument werden zunächst die allgemeinen Einsatzmöglichkeiten von Kleinsatelliten in der Extraterrestrik anhand ausgewählter Beispielmissionen beleuchtet. Daraufhin erfolgt die Erörterung spezifischer technischer Herausforderungen und Umweltbedingungen bei cislunaren und interplanetaren Kleinsatellitenmissionen, gefolgt von einer kurzen Präsentation von Nutzerwünsche aus Deutschland für Missionen zur Erforschung des Weltraums. Zum Abschluss werden zehn konkrete, im Rahmen der Untersuchung ermittelte, Missionsideen vorgestellt und bewertet. Schließlich erfolgt die Zusammenfassung der wichtigsten Erkenntnisse und Empfehlungen. T3 - Raumfahrttechnik und Extraterrestrik - 5 KW - Extraterrestrische Forschung KW - Kleinsatellit KW - Stand von Wissenschaft und Technik KW - Satellitentechnik KW - cislunar KW - technische Herausforderungen KW - Kleinsatellitenmissionen Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369793 N1 - Ursprüngliche Version unter https://doi.org/10.25972/OPUS-36325 ET - korrigierte Version ER - TY - JOUR A1 - Snaebjornsson, Marteinn T A1 - Schulze, Almut T1 - Non-canonical functions of enzymes facilitate cross-talk between cell metabolic and regulatory pathways JF - Experimental & Molecular Medicine N2 - The metabolic rewiring that occurs during cell transformation is a hallmark of cancer. It is diverse in different cancers as it reflects different combinations of oncogenic drivers, tumor suppressors, and the microenvironment. Metabolic rewiring is essential to cancer as it enables uncontrolled proliferation and adaptation to the fluctuating availability of nutrients and oxygen caused by poor access to the vasculature due to tumor growth and a foreign microenvironment encountered during metastasis. Increasing evidence now indicates that the metabolic state in cancer cells also plays a causal role in tumor growth and metastasis, for example through the action of oncometabolites, which modulate cell signaling and epigenetic pathways to promote malignancy. In addition to altering the metabolic state in cancer cells, some multifunctional enzymes possess non-metabolic functions that also contribute to cell transformation. Some multifunctional enzymes that are highly expressed in cancer, such as pyruvate kinase M2 (PKM2), have non-canonical functions that are co-opted by oncogenic signaling to drive proliferation and inhibit apoptosis. Other multifunctional enzymes that are frequently downregulated in cancer, such as fructose-bisphosphatase 1 (FBP1), are tumor suppressors, directly opposing mitogenic signaling via their non-canonical functions. In some cases, the enzymatic and non-canonical roles of these enzymes are functionally linked, making the modulation of non-metabolic cellular processes dependent on the metabolic state of the cell. KW - cancer metabolism Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-238763 VL - 50 ER - TY - JOUR A1 - Sirtl, Simon A1 - Knoll, Gertrud A1 - Dieu Thuy, Trinh A1 - Lang, Isabell A1 - Siegmund, Daniela A1 - Gross, Stefanie A1 - Schuler-Thurner, Beatrice A1 - Neubert, Patrick A1 - Jantsch, Jonathan A1 - Wajant, Harald A1 - Ehrenschwender, Martin T1 - Hypertonicity-enforced BCL-2 addiction unleashes the cytotoxic potential of death receptors JF - Oncogene N2 - Attempts to exploit the cytotoxic activity of death receptors (DR) for treating cancer have thus far been disappointing. DR activation in most malignant cells fails to trigger cell death and may even promote tumor growth by activating cell death-independent DR-associated signaling pathways. Overcoming apoptosis resistance is consequently a prerequisite for successful clinical exploitation of DR stimulation. Here we show that hyperosmotic stress in the tumor microenvironment unleashes the deadly potential of DRs by enforcing BCL-2 addiction of cancer cells. Hypertonicity robustly enhanced cytotoxicity of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and other DR ligands in various cancer entities. Initial events in TRAIL DR signaling remained unaffected, but hypertonic conditions unlocked activation of the mitochondrial death pathway and thus amplified the apoptotic signal. Mechanistically, we demonstrate that hyperosmotic stress imposed a BCL-2-addiction on cancer cells to safeguard the integrity of the outer mitochondrial membrane (OMM), essentially exhausting the protective capacity of BCL-2-like pro-survival proteins. Deprivation of these mitochondrial safeguards licensed DR-generated truncated BH3-interacting domain death agonist (tBID) to activate BCL-2-associated X protein (BAX) and initiated mitochondrial outer membrane permeabilization (MOMP). Our work highlights that hyperosmotic stress in the tumor environment primes mitochondria for death and lowers the threshold for DR-induced apoptosis. Beyond TRAIL-based therapies, our findings could help to strengthen the efficacy of other apoptosis-inducing cancer treatment regimens. KW - apoptosis KW - cancer microenvironment KW - cytokines Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-238327 VL - 37 ER - TY - JOUR A1 - Stegmann, Yannik A1 - Reicherts, Philipp A1 - Andreatta, Marta A1 - Pauli, Paul A1 - Wieser, Matthias J. T1 - The effect of trait anxiety on attentional mechanisms in combined context and cue conditioning and extinction learning JF - Scientific Reports N2 - Sensory processing and attention allocation are shaped by threat, but the role of trait-anxiety in sensory processing as a function of threat predictability remains incompletely understood. Therefore, we measured steady-state visual evoked potentials (ssVEPs) as an index of sensory processing of predictable and unpredictable threat cues in 29 low (LA) and 29 high (HA) trait-anxious participants during a modified NPU-paradigm followed by an extinction phase. Three different contextual cues indicated safety (N), predictable (P) or unpredictable threat (U), while foreground cues signalled shocks in the P-condition only. All participants allocated increased attentional resources to the central P-threat cue, replicating previous findings. Importantly, LA individuals exhibited larger ssVEP amplitudes to contextual threat (U and P) than to contextual safety cues, while HA individuals did not differentiate among contextual cues in general. Further, HA exhibited higher aversive ratings of all contexts compared to LA. These results suggest that high trait-anxious individuals might be worse at discriminating contextual threat stimuli and accordingly overestimate the probability and aversiveness of unpredictable threat. These findings support the notion of aberrant sensory processing of unpredictable threat in anxiety disorders, as this processing pattern is already evident in individuals at risk of these disorders. KW - attention KW - fear conditioning Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239394 VL - 9 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 - Shumilova, T. G. A1 - Lutoev, V. P. A1 - Isaenko, S. I. A1 - Kovalchuk, N. S. A1 - Makeev, B. A. A1 - Lysiuk, A. Yu. A1 - Zubov, A. A. A1 - Ernstson, K. T1 - Spectroscopic features of ultrahigh-pressure impact glasses of the Kara astrobleme JF - Scientific Reports N2 - The state of substances under ultrahigh pressures and temperatures (UHPHT) now raises a special interest as a matter existing under extreme conditions and as potential new material. Under laboratory conditions only small amounts of micrometer-sized matter are produced at a pressure up to 100 GPa and at room temperature. Simultaneous combination of ultrahigh pressures and temperatures in a lab still requires serious technological effort. Here we describe the composition and structure of the UHPHT vein-like impact glass discovered by us in 2015 on the territory of the Kara astrobleme (Russia) and compare its properties with impact glass from the Ries crater (Germany). A complex of structural and spectroscopic methods presents unusual high pressure marks of structural elements in 8-fold co-ordination that had been described earlier neither in synthetic nor natural glasses. The Kara natural UHPHT glasses being about 70 Ma old have well preserved initial structure, presenting some heterogeneity as a result of partial liquation and crystallization differentiation where an amorphous component is proposed to originate from low level polymerization. Homogeneous parts of the UHPHT glasses can be used to deepened fundamental investigation of a substance under extreme PT conditions and to technological studies for novel material creations. KW - glasses KW - mineralogy KW - phase transitions and critical phenomena Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-237983 VL - 8 ER - TY - JOUR A1 - Solimando, A G A1 - Brandl, A A1 - Mattenheimer, K A1 - Graf, C A1 - Ritz, M A1 - Ruckdeschel, A A1 - Stühmer, T A1 - Mokhtari, Z A1 - Rudelius, M A1 - Dotterweich, J A1 - Bittrich, M A1 - Desantis, V A1 - Ebert, R A1 - Trerotoli, P A1 - Frassanito, M A A1 - Rosenwald, A A1 - Vacca, A A1 - Einsele, H A1 - Jakob, F A1 - Beilhack, A T1 - JAM-A as a prognostic factor and new therapeutic target in multiple myeloma JF - Leukemia N2 - Cell adhesion in the multiple myeloma (MM) microenvironment has been recognized as a major mechanism of MM cell survival and the development of drug resistance. Here we addressed the hypothesis that the protein junctional adhesion molecule-A (JAM-A) may represent a novel target and a clinical biomarker in MM. We evaluated JAM-A expression in MM cell lines and in 147 MM patient bone marrow aspirates and biopsies at different disease stages. Elevated JAM-A levels in patient-derived plasma cells were correlated with poor prognosis. Moreover, circulating soluble JAM-A (sJAM-A) levels were significantly increased in MM patients as compared with controls. Notably, in vitro JAM-A inhibition impaired MM migration, colony formation, chemotaxis, proliferation and viability. In vivo treatment with an anti-JAM-A monoclonal antibody (αJAM-A moAb) impaired tumor progression in a murine xenograft MM model. These results demonstrate that therapeutic targeting of JAM-A has the potential to prevent MM progression, and lead us to propose JAM-A as a biomarker in MM, and sJAM-A as a serum-based marker for clinical stratification. KW - haematological cancer KW - myeloma Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239069 VL - 32 ER - TY - JOUR A1 - Soltamov, V. A. A1 - Kasper, C. A1 - Poshakinskiy, A. V. A1 - Anisimov, A. N. A1 - Mokhov, E. N. A1 - Sperlich, A. A1 - Tarasenko, S. A. A1 - Baranov, P. G. A1 - Astakhov, G. V. A1 - Dyakonov, V. T1 - Excitation and coherent control of spin qudit modes in silicon carbide at room temperature JF - Nature Communications N2 - One of the challenges in the field of quantum sensing and information processing is to selectively address and coherently manipulate highly homogeneous qubits subject to external perturbations. Here, we present room-temperature coherent control of high-dimensional quantum bits, the so-called qudits, associated with vacancy-related spins in silicon carbide enriched with nuclear spin-free isotopes. In addition to the excitation of a spectrally narrow qudit mode at the pump frequency, several other modes are excited in the electron spin resonance spectra whose relative positions depend on the external magnetic field. We develop a theory of multipole spin dynamics and demonstrate selective quantum control of homogeneous spin packets with sub-MHz spectral resolution. Furthermore, we perform two-frequency Ramsey interferometry to demonstrate absolute dc magnetometry, which is immune to thermal noise and strain inhomogeneity. KW - quantum information KW - qubits Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239149 VL - 10 ER - TY - JOUR A1 - Siegmund, Daniela A1 - Ehrenschwender, Martin A1 - Wajant, Harald T1 - TNFR2 unlocks a RIPK1 kinase activity-dependent mode of proinflammatory TNFR1 signaling JF - Cell Death & Disease N2 - TNF is not only a major effector molecule of PAMP/DAMP-activated macrophages, but also regulates macrophage function and viability. We recently demonstrated that TNFR2 triggers necroptosis in macrophages with compromised caspase activity by two cooperating mechanisms: induction of endogenous TNF with subsequent stimulation of TNFR1 and depletion of cytosolic TRAF2-cIAP complexes. Here we show that TNFR2 activation in caspase-inhibited macrophages results in the production of endogenous TNF and TNFR1 stimulation followed by upregulation of A20, TRAF1, IL-6, and IL-1β. Surprisingly, TNFR1-mediated induction of IL-6 and IL-1β was clearly evident in response to TNFR2 stimulation but occurred not or only weakly in macrophages selectively and directly stimulated via TNFR1. Moreover, TNFR2-induced TNFR1-mediated gene induction was largely inhibited by necrostatin-1, whereas upregulation of A20 and TRAF1 by direct and exclusive stimulation of TNFR1 remained unaffected by this compound. Thus, treatment with TNFR2/ZVAD enables TNFR1 in macrophages to stimulate gene induction via a pathway requiring RIPK1 kinase activity. TNFR2/ZVAD-induced production of IL-6 and IL-1β was largely blocked in necroptosis-resistant MLKL- and RIPK3-deficient macrophages, whereas induction of A20 and TRAF1 remained unaffected. In sum, our results show that in caspase-inhibited macrophages TNFR2 not only triggers TNF/TNFR1-mediated necroptosis but also TNF/TNFR1-mediated RIPK3/MLKL-dependent and -independent gene induction. Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-238034 VL - 9 ER - TY - JOUR A1 - Vaeth, Martin A1 - Wang, Yin-Hu A1 - Eckstein, Miriam A1 - Yang, Jun A1 - Silverman, Gregg J. A1 - Lacruz, Rodrigo S. A1 - Kannan, Kasthuri A1 - Feske, Stefan T1 - Tissue resident and follicular Treg cell differentiation is regulated by CRAC channels JF - Nature Communications N2 - T regulatory (Treg) cells maintain immunological tolerance and organ homeostasis. Activated Treg cells differentiate into effector Treg subsets that acquire tissue-specific functions. Ca2+ influx via Ca2+ release-activated Ca2+ (CRAC) channels formed by STIM and ORAI proteins is required for the thymic development of Treg cells, but its function in mature Treg cells remains unclear. Here we show that deletion of Stim1 and Stim2 genes in mature Treg cells abolishes Ca2+ signaling and prevents their differentiation into follicular Treg and tissue-resident Treg cells. Transcriptional profiling of STIM1/STIM2-deficient Treg cells reveals that Ca2+ signaling regulates transcription factors and signaling pathways that control the identity and effector differentiation of Treg cells. In the absence of STIM1/STIM2 in Treg cells, mice develop a broad spectrum of autoantibodies and fatal multiorgan inflammation. Our findings establish a critical role of CRAC channels in controlling lineage identity and effector functions of Treg cells. KW - gene regulation in immune cells KW - lymphocytes KW - regulatory T cells KW - signal transduction Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232148 VL - 10 ER - TY - JOUR A1 - Sulzer, David A1 - Cassidy, Clifford A1 - Horga, Guillermo A1 - Kang, Un Jung A1 - Fahn, Stanley A1 - Casella, Luigi A1 - Pezzoli, Gianni A1 - Langley, Jason A1 - Hu, Xiaoping P. A1 - Zucca, Fabio A. A1 - Isaias, Ioannis U. A1 - Zecca, Luigi T1 - Neuromelanin detection by magnetic resonance imaging (MRI) and its promise as a biomarker for Parkinson’s disease JF - npj Parkinson's Disease N2 - The diagnosis of Parkinson’s disease (PD) occurs after pathogenesis is advanced and many substantia nigra (SN) dopamine neurons have already died. Now that therapies to block this neuronal loss are under development, it is imperative that the disease be diagnosed at earlier stages and that the response to therapies is monitored. Recent studies suggest this can be accomplished by magnetic resonance imaging (MRI) detection of neuromelanin (NM), the characteristic pigment of SN dopaminergic, and locus coeruleus (LC) noradrenergic neurons. NM is an autophagic product synthesized via oxidation of catecholamines and subsequent reactions, and in the SN and LC it increases linearly during normal aging. In PD, however, the pigment is lost when SN and LC neurons die. As shown nearly 25 years ago by Zecca and colleagues, NM’s avid binding of iron provides a paramagnetic source to enable electron and nuclear magnetic resonance detection, and thus a means for safe and noninvasive measure in living human brain. Recent technical improvements now provide a means for MRI to differentiate between PD patients and age-matched healthy controls, and should be able to identify changes in SN NM with age in individuals. We discuss how MRI detects NM and how this approach might be improved. We suggest that MRI of NM can be used to confirm PD diagnosis and monitor disease progression. We recommend that for subjects at risk for PD, and perhaps generally for older people, that MRI sequences performed at regular intervals can provide a pre-clinical means to detect presymptomatic PD. Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-240207 VL - 4 ER - TY - JOUR A1 - Ullrich, M A1 - Weber, M A1 - Post, A M A1 - Popp, S A1 - Grein, J A1 - Zechner, M A1 - González, H Guerrero A1 - Kreis, A A1 - Schmitt, A G A1 - Üҫeyler, N A1 - Lesch, K-P A1 - Schuh, K T1 - OCD-like behavior is caused by dysfunction of thalamo-amygdala circuits and upregulated TrkB/ERK-MAPK signaling as a result of SPRED2 deficiency JF - Molecular Psychiatry N2 - Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disease affecting about 2% of the general population. It is characterized by persistent intrusive thoughts and repetitive ritualized behaviors. While gene variations, malfunction of cortico-striato-thalamo-cortical (CSTC) circuits, and dysregulated synaptic transmission have been implicated in the pathogenesis of OCD, the underlying mechanisms remain largely unknown. Here we show that OCD-like behavior in mice is caused by deficiency of SPRED2, a protein expressed in various brain regions and a potent inhibitor of Ras/ERK-MAPK signaling. Excessive self-grooming, reflecting OCD-like behavior in rodents, resulted in facial skin lesions in SPRED2 knockout (KO) mice. This was alleviated by treatment with the selective serotonin reuptake inhibitor fluoxetine. In addition to the previously suggested involvement of cortico-striatal circuits, electrophysiological measurements revealed altered transmission at thalamo-amygdala synapses and morphological differences in lateral amygdala neurons of SPRED2 KO mice. Changes in synaptic function were accompanied by dysregulated expression of various pre- and postsynaptic proteins in the amygdala. This was a result of altered gene transcription and triggered upstream by upregulated tropomyosin receptor kinase B (TrkB)/ERK-MAPK signaling in the amygdala of SPRED2 KO mice. Pathway overactivation was mediated by increased activity of TrkB, Ras, and ERK as a specific result of SPRED2 deficiency and not elicited by elevated brain-derived neurotrophic factor levels. Using the MEK inhibitor selumetinib, we suppressed TrkB/ERK-MAPK pathway activity in vivo and reduced OCD-like grooming in SPRED2 KO mice. Altogether, this study identifies SPRED2 as a promising new regulator, TrkB/ERK-MAPK signaling as a novel mediating mechanism, and thalamo-amygdala synapses as critical circuitry involved in the pathogenesis of OCD. KW - molecular biology KW - neuroscience KW - physiology KW - psychiatric disorders Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232096 VL - 23 ER - TY - JOUR A1 - Trautz, Florian A1 - Franke, Heike A1 - Bohnert, Simone A1 - Hammer, Niels A1 - Müller, Wolf A1 - Stassart, Ruth A1 - Tse, Rexson A1 - Zwirner, Johann A1 - Dreßler, Jan A1 - Ondruschka, Benjamin T1 - Survival-time dependent increase in neuronal IL-6 and astroglial GFAP expression in fatally injured human brain tissue JF - Scientific Reports N2 - Knowledge on trauma survival time prior to death following a lethal traumatic brain injury (TBI) may be essential for legal purposes. Immunohistochemistry studies might allow to narrow down this survival interval. The biomarkers interleukin-6 (IL-6) and glial fibrillary acidic protein (GFAP) are well known in the clinical setting for their usability in TBI prediction. Here, both proteins were chosen in forensics to determine whether neuronal or glial expression in various brain regions may be associated with the cause of death and the survival time prior to death following TBI. IL-6 positive neurons, glial cells and GFAP positive astrocytes all concordantly increase with longer trauma survival time, with statistically significant changes being evident from three days post-TBI (p < 0.05) in the pericontusional zone, irrespective of its definite cortical localization. IL-6 staining in neurons increases significantly in the cerebellum after trauma, whereas increasing GFAP positivity is also detected in the cortex contralateral to the focal lesion. These systematic chronological changes in biomarkers of pericontusional neurons and glial cells allow for an estimation of trauma survival time. Higher numbers of IL-6 and GFAP-stained cells above threshold values in the pericontusional zone substantiate the existence of fatal traumatic changes in the brain with reasonable certainty. KW - cell death in the nervous system KW - diagnostic markers KW - outcomes research Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229037 VL - 9 ER - TY - JOUR A1 - Tylek, Tina A1 - Schilling, Tatjana A1 - Schlegelmilch, Katrin A1 - Ries, Maximilian A1 - Rudert, Maximilian A1 - Jakob, Franz A1 - Groll, Jürgen T1 - Platelet lysate outperforms FCS and human serum for co-culture of primary human macrophages and hMSCs JF - Scientific Reports N2 - In vitro co-cultures of different primary human cell types are pivotal for the testing and evaluation of biomaterials under conditions that are closer to the human in vivo situation. Especially co-cultures of macrophages and mesenchymal stem cells (MSCs) are of interest, as they are both present and involved in tissue regeneration and inflammatory reactions and play crucial roles in the immediate inflammatory reactions and the onset of regenerative processes, thus reflecting the decisive early phase of biomaterial contact with the host. A co-culture system of these cell types might thus allow for the assessment of the biocompatibility of biomaterials. The establishment of such a co-culture is challenging due to the different in vitro cell culture conditions. For human macrophages, medium is usually supplemented with human serum (hS), whereas hMSC culture is mostly performed using fetal calf serum (FCS), and these conditions are disadvantageous for the respective other cell type. We demonstrate that human platelet lysate (hPL) can replace hS in macrophage cultivation and appears to be the best option for co-cultivation of human macrophages with hMSCs. In contrast to FCS and hS, hPL maintained the phenotype of both cell types, comparable to that of their respective standard culture serum, as well as the percentage of each cell population. Moreover, the expression profile and phagocytosis activity of macrophages was similar to hS. KW - biomaterials – cells KW - tissue engineering Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229174 VL - 9 ER - TY - JOUR A1 - Straub, Tobias A1 - Freudenberg, Marina A. A1 - Schleicher, Ulrike A1 - Bogdan, Christian A1 - Gasteiger, Georg A1 - Pircher, Hanspeter T1 - Bacterial coinfection restrains antiviral CD8 T-cell response via LPS-induced inhibitory NK cells JF - Nature Communications N2 - Infection of specific pathogen-free mice with lymphocytic choriomeningitis virus (LCMV) is a widely used model to study antiviral T-cell immunity. Infections in the real world, however, are often accompanied by coinfections with unrelated pathogens. Here we show that in mice, systemic coinfection with E. coli suppresses the LCMV-specific cytotoxic T-lymphocyte (CTL) response and virus elimination in a NK cell- and TLR2/4-dependent manner. Soluble TLR4 ligand LPS also induces NK cell-mediated negative CTL regulation during LCMV infection. NK cells in LPS-treated mice suppress clonal expansion of LCMV-specific CTLs by a NKG2D- or NCR1-independent but perforin-dependent mechanism. These results suggest a TLR4-mediated immunoregulatory role of NK cells during viral-bacterial coinfections. KW - Bacterial infection KW - infection KW - lymphocyte activation KW - viral infection Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-240075 VL - 9 ER - TY - JOUR A1 - Vujanić, Gordan M. A1 - Gessler, Manfred A1 - Ooms, Ariadne H. A. G. A1 - Collini, Paola A1 - Coulomb-l'Hermine, Aurore A1 - D'Hooghe, Ellen A1 - de Krijger, Ronald R. A1 - Perotti, Daniela A1 - Pritchard-Jones, Kathy A1 - Vokuhl, Christian A1 - van den Heuvel-Eibrink, Marry M. A1 - Graf, Norbert T1 - The UMBRELLA SIOP–RTSG 2016 Wilms tumour pathology and molecular biology protocol JF - Nature Reviews Urology N2 - On the basis of the results of previous national and international trials and studies, the Renal Tumour Study Group of the International Society of Paediatric Oncology (SIOP–RTSG) has developed a new study protocol for paediatric renal tumours: the UMBRELLA SIOP–RTSG 2016 protocol (the UMBRELLA protocol). Currently, the overall outcomes of patients with Wilms tumour are excellent, but subgroups with poor prognosis and increased relapse rates still exist. The identification of these subgroups is of utmost importance to improve treatment stratification, which might lead to reduction of the direct and late effects of chemotherapy. The UMBRELLA protocol aims to validate new prognostic factors, such as blastemal tumour volume and molecular markers, to further improve outcome. To achieve this aim, large, international, high-quality databases are needed, which dictate optimization and international harmonization of specimen handling and comprehensive sampling of biological material, refine definitions and improve logistics for expert review. To promote broad implementation of the UMBRELLA protocol, the updated SIOP–RTSG pathology and molecular biology protocol for Wilms tumours has been outlined, which is a consensus from the SIOP–RTSG pathology panel. KW - molecular biology KW - paediatric cancer KW - pathology KW - renal cancer Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233265 VL - 15 ER - TY - JOUR A1 - Tan, Z. B. A1 - Elo, T. A1 - Puska, A. A1 - Sarkar, J. A1 - Lähteenmäki, P. A1 - Duerr, F. A1 - Gould, C. A1 - Molenkamp, L. W. A1 - Nagaev, K. E. A1 - Hakonen, P. J. T1 - Hanbury-Brown and Twiss exchange and non-equilibrium-induced correlations in disordered, four-terminal graphene-ribbon conductor JF - Scientific Reports N2 - We have investigated current-current correlations in a cross-shaped conductor made of graphene. The mean free path of charge carriers is on the order of the ribbon width which leads to a hybrid conductor where there is diffusive transport in the device arms while the central connection region displays near ballistic transport. Our data on auto and cross correlations deviate from the predictions of Landauer-Büttiker theory, and agreement can be obtained only by taking into account contributions from non-thermal electron distributions at the inlets to the semiballistic center, in which the partition noise becomes strongly modified. The experimental results display distinct Hanbury – Brown and Twiss (HBT) exchange correlations, the strength of which is boosted by the non-equilibrium occupation-number fluctuations internal to this hybrid conductor. Our work demonstrates that variation in electron coherence along atomically-thin, two-dimensional conductors has significant implications on their noise and cross correlation properties. KW - conductive hybrid KW - partition noise KW - occupation number fluctuations KW - current-current correlation KW - device arm Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-240348 VL - 8 ER - TY - JOUR A1 - Woodcock, B. A. A1 - Garratt, M. P. D. A1 - Powney, G. D. A1 - Shaw, R. F. A1 - Osborne, J. L. A1 - Soroka, J. A1 - Lindström, S. A. M. A1 - Stanley, D. A1 - Ouvrard, P. A1 - Edwards, M. E. A1 - Jauker, F. A1 - McCracken, M. E. A1 - Zou, Y. A1 - Potts, S. G. A1 - Rundlöf, M. A1 - Noriega, J. A. A1 - Greenop, A. A1 - Smith, H. G. A1 - Bommarco, R. A1 - van der Werf, W. A1 - Stout, J. C. A1 - Steffan-Dewenter, I. A1 - Morandin, L. A1 - Bullock, J. M. A1 - Pywell, R. F. T1 - Meta-analysis reveals that pollinator functional diversity and abundance enhance crop pollination and yield JF - Nature Communications N2 - How insects promote crop pollination remains poorly understood in terms of the contribution of functional trait differences between species. We used meta-analyses to test for correlations between community abundance, species richness and functional trait metrics with oilseed rape yield, a globally important crop. While overall abundance is consistently important in predicting yield, functional divergence between species traits also showed a positive correlation. This result supports the complementarity hypothesis that pollination function is maintained by non-overlapping trait distributions. In artificially constructed communities (mesocosms), species richness is positively correlated with yield, although this effect is not seen under field conditions. As traits of the dominant species do not predict yield above that attributed to the effect of abundance alone, we find no evidence in support of the mass ratio hypothesis. Management practices increasing not just pollinator abundance, but also functional divergence, could benefit oilseed rape agriculture. KW - agroecology KW - agriculture KW - ecosystem services KW - environmental sciences Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233787 VL - 10 ER - TY - JOUR A1 - Went, Molly A1 - Sud, Amit A1 - Speedy, Helen A1 - Sunter, Nicola J. A1 - Försti, Asta A1 - Law, Philip J. A1 - Johnson, David C. A1 - Mirabella, Fabio A1 - Holroyd, Amy A1 - Li, Ni A1 - Orlando, Giulia A1 - Weinhold, Niels A1 - van Duin, Mark A1 - Chen, Bowang A1 - Mitchell, Jonathan S. A1 - Mansouri, Larry A1 - Juliusson, Gunnar A1 - Smedby, Karin E A1 - Jayne, Sandrine A1 - Majid, Aneela A1 - Dearden, Claire A1 - Allsup, David J. A1 - Bailey, James R. A1 - Pratt, Guy A1 - Pepper, Chris A1 - Fegan, Chris A1 - Rosenquist, Richard A1 - Kuiper, Rowan A1 - Stephens, Owen W. A1 - Bertsch, Uta A1 - Broderick, Peter A1 - Einsele, Hermann A1 - Gregory, Walter M. A1 - Hillengass, Jens A1 - Hoffmann, Per A1 - Jackson, Graham H. A1 - Jöckel, Karl-Heinz A1 - Nickel, Jolanta A1 - Nöthen, Markus M. A1 - da Silva Filho, Miguel Inacio A1 - Thomsen, Hauke A1 - Walker, Brian A. A1 - Broyl, Annemiek A1 - Davies, Faith E. A1 - Hansson, Markus A1 - Goldschmidt, Hartmut A1 - Dyer, Martin J. S. A1 - Kaiser, Martin A1 - Sonneveld, Pieter A1 - Morgan, Gareth J. A1 - Hemminki, Kari A1 - Nilsson, Björn A1 - Catovsky, Daniel A1 - Allan, James M. A1 - Houlston, Richard S. T1 - Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology JF - Blood Cancer Journal N2 - The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 controls. A significant genetic correlation between these two B-cell malignancies was shown (Rg = 0.4, P = 0.0046). Furthermore, four of the 45 known CLL risk loci were shown to associate with MM risk and five of the 23 known MM risk loci associate with CLL risk. By integrating eQTL, Hi-C and ChIP-seq data, we show that these pleiotropic risk loci are enriched for B-cell regulatory elements and implicate B-cell developmental genes. These data identify shared biological pathways influencing the development of CLL and, MM and further our understanding of the aetiological basis of these B-cell malignancies. KW - cancer genetics KW - myeloma Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233627 VL - 9 ER - TY - JOUR A1 - Wen, Lai A1 - Feil, Susanne A1 - Wolters, Markus A1 - Thunemann, Martin A1 - Regler, Frank A1 - Schmidt, Kjestine A1 - Friebe, Andreas A1 - Olbrich, Marcus A1 - Langer, Harald A1 - Gawaz, Meinrad A1 - de Wit, Cor A1 - Feil, Robert T1 - A shear-dependent NO-cGMP-cGKI cascade in platelets acts as an auto-regulatory brake of thrombosis JF - Nature Communications N2 - Mechanisms that limit thrombosis are poorly defined. One of the few known endogenous platelet inhibitors is nitric oxide (NO). NO activates NO sensitive guanylyl cyclase (NO-GC) in platelets, resulting in an increase of cyclic guanosine monophosphate (cGMP). Here we show, using cGMP sensor mice to study spatiotemporal dynamics of platelet cGMP, that NO-induced cGMP production in pre-activated platelets is strongly shear-dependent. We delineate a new mode of platelet-inhibitory mechanotransduction via shear-activated NO-GC followed by cGMP synthesis, activation of cGMP-dependent protein kinase I (cGKI), and suppression of Ca2+ signaling. Correlative profiling of cGMP dynamics and thrombus formation in vivo indicates that high cGMP concentrations in shear-exposed platelets at the thrombus periphery limit thrombosis, primarily through facilitation of thrombus dissolution. We propose that an increase in shear stress during thrombus growth activates the NO-cGMP-cGKI pathway, which acts as an auto-regulatory brake to prevent vessel occlusion, while preserving wound closure under low shear. KW - calcium signalling KW - fluorescence imaging KW - platelets KW - thrombosis Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233616 VL - 9 ER - TY - JOUR A1 - Welz, M. A1 - Eickhoff, S. A1 - Abdullah, Z. A1 - Trebicka, J. A1 - Gartlan, K. H. A1 - Spicer, J. A. A1 - Demetris, A. J. A1 - Akhlaghi, H. A1 - Anton, M. A1 - Manske, K. A1 - Zehn, D. A1 - Nieswandt, B. A1 - Kurts, C. A1 - Trapani, J. A. A1 - Knolle, P. A1 - Wohlleber, D. A1 - Kastenmüller, W. T1 - Perforin inhibition protects from lethal endothelial damage during fulminant viral hepatitis JF - Nature Communications N2 - CD8 T cells protect the liver against viral infection, but can also cause severe liver damage that may even lead to organ failure. Given the lack of mechanistic insights and specific treatment options in patients with acute fulminant hepatitis, we develop a mouse model reflecting a severe acute virus-induced CD8 T cell-mediated hepatitis. Here we show that antigen-specific CD8 T cells induce liver damage in a perforin-dependent manner, yet liver failure is not caused by effector responses targeting virus-infected hepatocytes alone. Additionally, CD8 T cell mediated elimination of cross-presenting liver sinusoidal endothelial cells causes endothelial damage that leads to a dramatically impaired sinusoidal perfusion and indirectly to hepatocyte death. With the identification of perforin-mediated killing as a critical pathophysiologic mechanism of liver failure and the protective function of a new class of perforin inhibitor, our study opens new potential therapeutic angles for fulminant viral hepatitis. KW - cytotoxic T cells KW - hepatology KW - imaging the immune system KW - viral infection Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233593 VL - 9 ER - TY - JOUR A1 - Walker, Brian A. A1 - Mavrommatis, Konstantinos A1 - Wardell, Christopher P. A1 - Ashby, T. Cody A1 - Bauer, Michael A1 - Davies, Faith A1 - Rosenthal, Adam A1 - Wang, Hongwei A1 - Qu, Pingping A1 - Hoering, Antje A1 - Samur, Mehmet A1 - Towfic, Fadi A1 - Ortiz, Maria A1 - Flynt, Erin A1 - Yu, Zhinuan A1 - Yang, Zhihong A1 - Rozelle, Dan A1 - Obenauer, John A1 - Trotter, Matthew A1 - Auclair, Daniel A1 - Keats, Jonathan A1 - Bolli, Niccolo A1 - Fulciniti, Mariateresa A1 - Szalat, Raphael A1 - Moreau, Phillipe A1 - Durie, Brian A1 - Stewart, A. Keith A1 - Goldschmidt, Hartmut A1 - Raab, Marc S. A1 - Einsele, Hermann A1 - Sonneveld, Pieter A1 - San Miguel, Jesus A1 - Lonial, Sagar A1 - Jackson, Graham H. A1 - Anderson, Kenneth C. A1 - Avet-Loiseau, Herve A1 - Munshi, Nikhil A1 - Thakurta, Anjan A1 - Morgan, Gareth T1 - A high-risk, Double-Hit, group of newly diagnosed myeloma identified by genomic analysis JF - Leukemia N2 - Patients with newly diagnosed multiple myeloma (NDMM) with high-risk disease are in need of new treatment strategies to improve the outcomes. Multiple clinical, cytogenetic, or gene expression features have been used to identify high-risk patients, each of which has significant weaknesses. Inclusion of molecular features into risk stratification could resolve the current challenges. In a genome-wide analysis of the largest set of molecular and clinical data established to date from NDMM, as part of the Myeloma Genome Project, we have defined DNA drivers of aggressive clinical behavior. Whole-genome and exome data from 1273 NDMM patients identified genetic factors that contribute significantly to progression free survival (PFS) and overall survival (OS) (cumulative R2 = 18.4% and 25.2%, respectively). Integrating DNA drivers and clinical data into a Cox model using 784 patients with ISS, age, PFS, OS, and genomic data, the model has a cumlative R2 of 34.3% for PFS and 46.5% for OS. A high-risk subgroup was defined by recursive partitioning using either a) bi-allelic TP53 inactivation or b) amplification (≥4 copies) of CKS1B (1q21) on the background of International Staging System III, comprising 6.1% of the population (median PFS = 15.4 months; OS = 20.7 months) that was validated in an independent dataset. Double-Hit patients have a dire prognosis despite modern therapies and should be considered for novel therapeutic approaches. KW - cancer genomics KW - risk factors Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233299 VL - 33 ER - TY - JOUR A1 - Wegert, Jenny A1 - Vokuhl, Christian A1 - Collord, Grace A1 - Del Castillo Velasco-Herrera, Martin A1 - Farndon, Sarah J. A1 - Guzzo, Charlotte A1 - Jorgensen, Mette A1 - Anderson, John A1 - Slater, Olga A1 - Duncan, Catriona A1 - Bausenwein, Sabrina A1 - Streitenberger, Heike A1 - Ziegler, Barbara A1 - Furtwängler, Rhoikos A1 - Graf, Norbert A1 - Stratton, Michael R. A1 - Campbell, Peter J. A1 - Jones, David TW A1 - Koelsche, Christian A1 - Pfister, Stefan M. A1 - Mifsud, William A1 - Sebire, Neil A1 - Sparber-Sauer, Monika A1 - Koscielniak, Ewa A1 - Rosenwald, Andreas A1 - Gessler, Manfred A1 - Behjati, Sam T1 - Recurrent intragenic rearrangements of EGFR and BRAF in soft tissue tumors of infants JF - Nature Communications N2 - Soft tissue tumors of infancy encompass an overlapping spectrum of diseases that pose unique diagnostic and clinical challenges. We studied genomes and transcriptomes of cryptogenic congenital mesoblastic nephroma (CMN), and extended our findings to five anatomically or histologically related soft tissue tumors: infantile fibrosarcoma (IFS), nephroblastomatosis, Wilms tumor, malignant rhabdoid tumor, and clear cell sarcoma of the kidney. A key finding is recurrent mutation of EGFR in CMN by internal tandem duplication of the kinase domain, thus delineating CMN from other childhood renal tumors. Furthermore, we identify BRAF intragenic rearrangements in CMN and IFS. Collectively these findings reveal novel diagnostic markers and therapeutic strategies and highlight a prominent role of isolated intragenic rearrangements as drivers of infant tumors. KW - cancer KW - genetics Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233446 VL - 9 ER - TY - JOUR A1 - Waldherr, Max A1 - Lundt, Nils A1 - Klaas, Martin A1 - Betzold, Simon A1 - Wurdack, Matthias A1 - Baumann, Vasilij A1 - Estrecho, Eliezer A1 - Nalitov, Anton A1 - Cherotchenko, Evgenia A1 - Cai, Hui A1 - Ostrovskaya, Elena A. A1 - Kavokin, Alexey V. A1 - Tongay, Sefaattin A1 - Klembt, Sebastian A1 - Höfling, Sven A1 - Schneider, Christian T1 - Observation of bosonic condensation in a hybrid monolayer MoSe2-GaAs microcavity JF - Nature Communications N2 - Bosonic condensation belongs to the most intriguing phenomena in physics, and was mostly reserved for experiments with ultra-cold quantum gases. More recently, it became accessible in exciton-based solid-state systems at elevated temperatures. Here, we demonstrate bosonic condensation driven by excitons hosted in an atomically thin layer of MoSe2, strongly coupled to light in a solid-state resonator. The structure is operated in the regime of collective strong coupling between a Tamm-plasmon resonance, GaAs quantum well excitons, and two-dimensional excitons confined in the monolayer crystal. Polariton condensation in a monolayer crystal manifests by a superlinear increase of emission intensity from the hybrid polariton mode, its density-dependent blueshift, and a dramatic collapse of the emission linewidth, a hallmark of temporal coherence. Importantly, we observe a significant spin-polarization in the injected polariton condensate, a fingerprint for spin-valley locking in monolayer excitons. Our results pave the way towards highly nonlinear, coherent valleytronic devices and light sources. KW - polaritons KW - two-dimensional materials Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233280 VL - 9 ER -