@article{SchilbachAlkhaledWelkeretal.2015, author = {Schilbach, Karin and Alkhaled, Mohammed and Welker, Christian and Eckert, Franziska and Blank, Gregor and Ziegler, Hendrik and Sterk, Marco and M{\"u}ller, Friederike and Sonntag, Katja and Wieder, Thomas and Braum{\"u}ller, Heidi and Schmitt, Julia and Eyrich, Matthias and Schleicher, Sabine and Seitz, Christian and Erbacher, Annika and Pichler, Bernd J. and M{\"u}ller, Hartmut and Tighe, Robert and Lim, Annick and Gillies, Stephen D. and Strittmatter, Wolfgang and R{\"o}cken, Martin and Handgretinger, Rupert}, title = {Cancer-targeted IL-12 controls human rhabdomyosarcoma by senescence induction and myogenic differentiation}, series = {OncoImmunology}, volume = {4}, journal = {OncoImmunology}, number = {7}, doi = {10.1080/2162402X.2015.1014760}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-154579}, pages = {e1014760}, year = {2015}, abstract = {Stimulating the immune system to attack cancer is a promising approach, even for the control of advanced cancers. Several cytokines that promote interferon-γ-dominated immune responses show antitumor activity, with interleukin 12 (IL-12) being of major importance. Here, we used an antibody-IL-12 fusion protein (NHS-IL12) that binds histones of necrotic cells to treat human sarcoma in humanized mice. Following sarcoma engraftment, NHS-IL12 therapy was combined with either engineered IL-7 (FcIL-7) or IL-2 (IL-2MAB602) for continuous cytokine bioavailability. NHS-IL12 strongly induced innate and adaptive antitumor immunity when combined with IL-7 or IL-2. NHS-IL12 therapy significantly improved survival of sarcoma-bearing mice and caused long-term remissions when combined with IL-2. NHS-IL12 induced pronounced cancer cell senescence, as documented by strong expression of senescence-associated p16\(^{INK4a}\) and nuclear translocation of p-HP1γ, and permanent arrest of cancer cell proliferation. In addition, this cancer immunotherapy initiated the induction of myogenic differentiation, further promoting the hypothesis that efficient antitumor immunity includes mechanisms different from cytotoxicity for efficient cancer control in vivo.}, language = {en} } @article{ChopraBiehlSteinfattetal.2016, author = {Chopra, Martin and Biehl, Marlene and Steinfatt, Tim and Brandl, Andreas and Kums, Juliane and Amich, Jorge and Vaeth, Martin and Kuen, Janina and Holtappels, Rafaela and Podlech, J{\"u}rgen and Mottok, Anja and Kraus, Sabrina and Jord{\´a}n-Garotte, Ana-Laura and B{\"a}uerlein, Carina A. and Brede, Christian and Ribechini, Eliana and Fick, Andrea and Seher, Axel and Polz, Johannes and Ottmueller, Katja J. and Baker, Jeannette and Nishikii, Hidekazu and Ritz, Miriam and Mattenheimer, Katharina and Schwinn, Stefanie and Winter, Thorsten and Sch{\"a}fer, Viktoria and Krappmann, Sven and Einsele, Hermann and M{\"u}ller, Thomas D. and Reddehase, Matthias J. and Lutz, Manfred B. and M{\"a}nnel, Daniela N. and Berberich-Siebelt, Friederike and Wajant, Harald and Beilhack, Andreas}, title = {Exogenous TNFR2 activation protects from acute GvHD via host T reg cell expansion}, series = {Journal of Experimental Medicine}, volume = {213}, journal = {Journal of Experimental Medicine}, number = {9}, doi = {10.1084/jem.20151563}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-187640}, pages = {1881-1900}, year = {2016}, abstract = {Donor CD4\(^+\)Foxp3\(^+\) regulatory T cells (T reg cells) suppress graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HCT allo-HCT]). Current clinical study protocols rely on the ex vivo expansion of donor T reg cells and their infusion in high numbers. In this study, we present a novel strategy for inhibiting GvHD that is based on the in vivo expansion of recipient T reg cells before allo-HCT, exploiting the crucial role of tumor necrosis factor receptor 2 (TNFR2) in T reg cell biology. Expanding radiation-resistant host T reg cells in recipient mice using a mouse TNFR2-selective agonist before allo-HCT significantly prolonged survival and reduced GvHD severity in a TNFR2-and T reg cell-dependent manner. The beneficial effects of transplanted T cells against leukemia cells and infectious pathogens remained unaffected. A corresponding human TNFR2-specific agonist expanded human T reg cells in vitro. These observations indicate the potential of our strategy to protect allo-HCT patients from acute GvHD by expanding T reg cells via selective TNFR2 activation in vivo.}, language = {en} } @unpublished{MuellerDraegerMaetal.2018, author = {M{\"u}ller, Stefan and Draeger, Simon and Ma, Kiaonan and Hensen, Matthias and Kenneweg, Tristan and Pfeiffer, Walter and Brixner, Tobias}, title = {Fluorescence-Detected Two-Quantum and One-Quantum-Two-Quantum 2D Electronic Spectroscopy}, series = {Journal of Physical Chemistry Letters}, journal = {Journal of Physical Chemistry Letters}, doi = {10.1021/acs.jpclett.8b00541}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173468}, year = {2018}, abstract = {We demonstrate two-quantum (2Q) coherent two-dimensional (2D)electronic spectroscopy using a shot-to-shot-modulated pulse shaper and fluorescence detection. Broadband collinear excitation is realized with the supercontinuum output of an argon-filled hollow-core fiber, enabling us to excite multiple transitions simultaneously in the visible range. The 2Q contribution is extracted via a three-pulse sequence with 16-fold phase cycling and simulated employing cresyl violet as a model system. Furthermore, we report the first experimental realization of one-quantum-two-quantum (1Q-2Q) 2D spectroscopy, offering less congested spectra as compared with the 2Q implementation. We avoid scattering artifacts and nonresonant solvent contributions by using fluorescence as the observable. This allows us to extract quantitative information about doubly excited states that agree with literature expectations. The high sensitivity and background-free nature of fluorescence detection allow for a general applicability of this method to many other systems.}, subject = {Fluoreszenz}, language = {en} } @inproceedings{SchwaneckGlosBofingeretal.2008, author = {Schwaneck, Stefan and Glos, Michael and Bofinger, Peter and Straubhaar, Thomas and Haase, Axel and Pinkwart, Andreas and Kunze, Mario and {\"O}sterle, Irene and Seubert, Marc and Nowak, Matthias and Rosen, Holga and Steinle, Andreas and Schorr, Leander and Fichtner, Caroline and Fischl, Bernd and Wittrock, Max and G{\"u}nther, Niclas and Roth, Isabelle and Verburg, Erik and Sextl, Gerhard and Heitm{\"u}ller, Lars and M{\"u}ller, Norman and Frashek, Andr{\´e} and Stetter, Ulrich}, title = {Innovationen - Performancetreiber und nachhaltiger Wirtschaftsmotor in Deutschland? Festschrift zum 5. W{\"u}rzburger Wirtschaftssymposium}, organization = {5. W{\"u}rzburger Wirtschaftssymposium 2008}, isbn = {978-3-923959-58-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-53559}, year = {2008}, abstract = {5. W{\"u}rzburger Wirtschaftssymposium, 20.11.2008 Deutsche Erfindungen ver{\"a}ndern die Welt - heute wie vor 500 Jahren. Von Buchdruck, {\"u}ber Dieselmotor, Gl{\"u}hbirne bis hin zu Airbag, Aspirin, D{\"u}bel, Fernseher und mp3-Format. Alleine dieser bescheidene {\"U}berblick des Ph{\"a}nomens "Made in Germany" l{\"a}sst den Betrachter die Bedeutung und das Potenzial von Innovationen am Standort Deutschland schnell erkennen. Experten aus Wirtschaft, Politik und Gesellschaft setzten sich am 20.11.2008 unter der Leitfrage: "Innovationen - Performancetreiber und nachhaltiger Wirtschaftsmotor in Deutschland?" mit der Bedeutung von Innovationen f{\"u}r den Standort Deutschland auseinander. Die Festschrift rundet - neben Interviews mit und Gastbeitr{\"a}gen von Referenten der Veranstaltung - das 5. W{\"u}rzburger Wirtschaftssymposium mit Stellungnahmen und Beitr{\"a}gen renommierter Experten ab. Zu Wort kommen dabei Jungunternehmer ebenso wie Wissenschaftler der Universit{\"a}t W{\"u}rzburg und Vertreter externer Organisationen.}, subject = {Innovationsforschung}, language = {de} } @phdthesis{Mueller2010, author = {M{\"u}ller, Matthias}, title = {Dreidimensionale Konfigurationen von NMR Phased-Array Spulen mit vielen Einzelelementen}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-52399}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2010}, abstract = {In der vorliegenden Arbeit wurden alternative Phased-Array Konfigurationen untersucht, die eine gleichm{\"a}ßige r{\"A}aumliche Verteilung der Spulensensitivit{\"a}ten f{\"u}r eine 2D parallel beschleunigte NMR-Bildgebung zur Verf{\"u}gung stellen sowie eine h{\"o}here lokale Dichte probenrauschdominierter Einzelspulen als konventionelle Arraygeometrien erm{\"o}glichen. Hierzu wurde zun{\"a}chst eine neuartige 16-Kanal Doppel-Spiral Arraygeometrie einem Birdcage-{\"a}hnlichen Spulenarray mit zwei Ringen aus je acht Spulenelementen gegen{\"u}bergestellt, welches gew{\"o}hnlich in der klinischen Routine f{\"u}r NMR-Untersuchungen am menschlichen Kopf eingesetzt wird. Unter Verwendung analytischer Biot-Savart Berechnungen in der Entwicklungsumgebung Matlab konnten die jeweiligen Kodiereigenschaften sowie das mit den unterschiedlichen Arraykonfigurationen erzielbare intrinsische Signal-Rausch-Verh{\"a}ltnis ermittelt und verglichen werden. Zudem wurde auf gleiche Weise der Einfluss geometrischer Variationen im Aufbau des Doppel-Spiral Volumenarrays auf die intrinsische Isolation zwischen dem inneren, um +pi verdrehten und dem {\"A}ußeren, um -pi verdrehten Einfach-Spiral Spulenarray untersucht und Phased-Array Designs mit 32 unabh{\"A}angigen Empfangselementen evaluiert. Im Rahmen einer experimentellen Evaluierung des Doppel-Spiral Arraykonzepts wurden zuerst einzelne Spulenelemente der unterschiedlichen 16-Kanal Volumenarrays verglichen, bevor eine Doppel-Spiral Phased-Array Prototypenspule aufgebaut wurde. Mit dieser konnten sowohl die vorausgesetzte intrinsische Entkopplung der zwei Einzel-Spiral Spulenarrays als auch die in alle drei Raumrichtungen homogene Verteilung der einzelnen Spulensensitivit{\"a}ten anhand von Experimenten im NMR-System nachgewiesen werden. So war trotz der relativ geringen Anzahl von sechs unabh{\"a}ngigen Einzelkan{\"a}len eine um den Faktor 4 beschleunigte NMR-Untersuchung des menschlichen Kopfes mittels einer 3D MP-RAGE-Bildgebungssequenz m{\"o}glich. Diese hohe Beschleunigung konnte f{\"u}r jede beliebige Orientierung der Kodierrichtungen in gleichermaßen guter Bildqualit{\"a}t erzielt werden und erwies sich somit als unabh{\"a}ngig von der gew{\"u}nschten Positionierung des dreidimensionalen Untersuchungsvolumens. Das auf diese Weise best{\"a}tigte Konzept einer Doppel-Spiral Arraygeometrie stellt allerdings nicht nur eine gleichm{\"a}ßige Sensitivit{\"a}tsvariation entlang aller Raumrichtungen zur Verf{\"u}gung, sondern erm{\"o}glicht auch eine h{\"o}here Dichte probenrauschdominierter Einzelspulen. In einem zweiten Ansatz wurde das Konzept r{\"a}umlich kompakter Quadratur-Arrayelemente untersucht, die aus einer geeigneten geometrischen Kombination zweier Einzelspulen entstehen. Die Evaluierung der Leistungsf{\"a}higkeit einer derartigen Arrayelementkonfiguration erfolgte in diesem Fall durch den Vergleich einer aus vier Quadratur-Arrayelementen aufgebauten 8-Kanal Phased-Array Spule mit einem konventionellen 4-Kanal Spulenarray, welches sich aus vier waagrechten, in Reihen angeordneten Einzelspulen zusammensetzt. Die Kodiereigenschaften der jeweiligen Phased-Array Spulen sowie das zur Verf{\"u}gung stehende intrinsische SNR wurden erneut mit Hilfe von Biot-Savart Simulationen in Matlab ermittelt. Diese zeigten, dass durch eine solche neuartige Elementkonfiguration eine Steigerung des erzielbaren Signal-Rausch-Verh{\"a}ltnisses von nahezu 30\% erreicht werden kann. Zudem konnte eine deutliche Verbesserung der Kodiereigenschaften in Folge einer, bei gleicher Ausdehnung der Arraystruktur, verdoppelten Anzahl an Einzelspulen beobachtet werden. Eine experimentelle Untersuchung erfolgte anhand einer einfachen aus vier Quadratur-Arrayelementen aufgebauten 8-Kanal Phased-Array Spule. Mit dieser wurden im Kernspintomographen NMR-Untersuchungen an Phantomen durchgef{\"u}hrt, die den SNR-Gewinn sowie die signifikante Verbesserung der Kodiereigenschaften durch die Verwendung von Quadratur-Elementen in guter {\"U}bereinstimmung mit den Simulationsergebnissen best{\"a}tigen konnten. Eine derartige Steigerung der Leistungsf{\"a}higkeit eines gew{\"o}hnlichen, flachen Spulenarrays durch das Hinzuf{\"u}gen senkrechter, intrinsisch entkoppelter Spulenelemente zeigt sich auch in den Resultaten coronal und sagittal orientierter NMR-Bildgebungsuntersuchungen der Wirbels{\"a}ule eines gesunden Probanden. Hierbei sind selbst bei Beschleunigungen von einem Faktor 4 keine Artefakte aufgrund einer schlecht konditionierten parallelen Bildrekonstruktion zu beobachten.}, subject = {NMR-Bildgebung}, language = {de} } @article{MergetKoetschanHackletal.2012, author = {Merget, Benjamin and Koetschan, Christian and Hackl, Thomas and F{\"o}rster, Frank and Dandekar, Thomas and M{\"u}ller, Tobias and Schultz, J{\"o}rg and Wolf, Matthias}, title = {The ITS2 Database}, series = {Journal of Visual Expression}, volume = {61}, journal = {Journal of Visual Expression}, number = {e3806}, doi = {10.3791/3806}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124600}, year = {2012}, abstract = {The internal transcribed spacer 2 (ITS2) has been used as a phylogenetic marker for more than two decades. As ITS2 research mainly focused on the very variable ITS2 sequence, it confined this marker to low-level phylogenetics only. However, the combination of the ITS2 sequence and its highly conserved secondary structure improves the phylogenetic resolution1 and allows phylogenetic inference at multiple taxonomic ranks, including species delimitation. The ITS2 Database presents an exhaustive dataset of internal transcribed spacer 2 sequences from NCBI GenBank accurately reannotated. Following an annotation by profile Hidden Markov Models (HMMs), the secondary structure of each sequence is predicted. First, it is tested whether a minimum energy based fold (direct fold) results in a correct, four helix conformation. If this is not the case, the structure is predicted by homology modeling. In homology modeling, an already known secondary structure is transferred to another ITS2 sequence, whose secondary structure was not able to fold correctly in a direct fold. The ITS2 Database is not only a database for storage and retrieval of ITS2 sequence-structures. It also provides several tools to process your own ITS2 sequences, including annotation, structural prediction, motif detection and BLAST search on the combined sequence-structure information. Moreover, it integrates trimmed versions of 4SALE and ProfDistS for multiple sequence-structure alignment calculation and Neighbor Joining tree reconstruction. Together they form a coherent analysis pipeline from an initial set of sequences to a phylogeny based on sequence and secondary structure. In a nutshell, this workbench simplifies first phylogenetic analyses to only a few mouse-clicks, while additionally providing tools and data for comprehensive large-scale analyses.}, language = {en} } @article{FoersterBeisserGrohmeetal.2012, author = {F{\"o}rster, Frank and Beisser, Daniela and Grohme, Markus A. and Liang, Chunguang and Mali, Brahim and Siegl, Alexander Matthias and Engelmann, Julia C. and Shkumatov, Alexander V. and Schokraie, Elham and M{\"u}ller, Tobias and Schn{\"o}lzer, Martina and Schill, Ralph O. and Frohme, Marcus and Dandekar, Thomas}, title = {Transcriptome analysis in tardigrade species reveals specific molecular pathways for stress adaptations}, series = {Bioinformatics and biology insights}, volume = {6}, journal = {Bioinformatics and biology insights}, doi = {10.4137/BBI.S9150}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123089}, pages = {69-96}, year = {2012}, abstract = {Tardigrades have unique stress-adaptations that allow them to survive extremes of cold, heat, radiation and vacuum. To study this, encoded protein clusters and pathways from an ongoing transcriptome study on the tardigrade \(Milnesium\) \(tardigradum\) were analyzed using bioinformatics tools and compared to expressed sequence tags (ESTs) from \(Hypsibius\) \(dujardini\), revealing major pathways involved in resistance against extreme environmental conditions. ESTs are available on the Tardigrade Workbench along with software and databank updates. Our analysis reveals that RNA stability motifs for \(M.\) \(tardigradum\) are different from typical motifs known from higher animals. \(M.\) \(tardigradum\) and \(H.\) \(dujardini\) protein clusters and conserved domains imply metabolic storage pathways for glycogen, glycolipids and specific secondary metabolism as well as stress response pathways (including heat shock proteins, bmh2, and specific repair pathways). Redox-, DNA-, stress- and protein protection pathways complement specific repair capabilities to achieve the strong robustness of \(M.\) \(tardigradum\). These pathways are partly conserved in other animals and their manipulation could boost stress adaptation even in human cells. However, the unique combination of resistance and repair pathways make tardigrades and \(M.\) \(tardigradum\) in particular so highly stress resistant.}, language = {en} } @article{WalterReilichThieleetal.2013, author = {Walter, Maggie C. and Reilich, Peter and Thiele, Simone and Schessl, Joachim and Schreiber, Herbert and Reiners, Karlheinz and Kress, Wolfram and M{\"u}ller-Reible, Clemens and Vorgerd, Matthias and Urban, Peter and Schrank, Bertold and Deschauer, Marcus and Schlotter-Weigel, Beate and Kohnen, Ralf and Lochm{\"u}ller, Hans}, title = {Treatment of dysferlinopathy with deflazacort: a double-blind, placebo-controlled clinical trial}, series = {Orphanet Journal of Rare Diseases}, volume = {8}, journal = {Orphanet Journal of Rare Diseases}, number = {26}, issn = {1750-1172}, doi = {10.1186/1750-1172-8-26}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125663}, year = {2013}, abstract = {Background: Dysferlinopathies are autosomal recessive disorders caused by mutations in the dysferlin (DYSF) gene encoding the dysferlin protein. DYSF mutations lead to a wide range of muscular phenotypes, with the most prominent being Miyoshi myopathy (MM) and limb girdle muscular dystrophy type 2B (LGMD2B). Methods: We assessed the one-year-natural course of dysferlinopathy, and the safety and efficacy of deflazacort treatment in a double-blind, placebo-controlled cross-over trial. After one year of natural course without intervention, 25 patients with genetically defined dysferlinopathy were randomized to receive deflazacort and placebo for six months each (1 mg/kg/day in month one, 1 mg/kg every 2nd day during months two to six) in one of two treatment sequences. Results: During one year of natural course, muscle strength declined about 2\% as measured by CIDD (Clinical Investigation of Duchenne Dystrophy) score, and 76 Newton as measured by hand-held dynamometry. Deflazacort did not improve muscle strength. In contrast, there is a trend of worsening muscle strength under deflazacort treatment, which recovers after discontinuation of the study drug. During deflazacort treatment, patients showed a broad spectrum of steroid side effects. Conclusion: Deflazacort is not an effective therapy for dysferlinopathies, and off-label use is not warranted. This is an important finding, since steroid treatment should not be administered in patients with dysferlinopathy, who may be often misdiagnosed as polymyositis.}, language = {en} } @techreport{MuellerBrandeckBocquetGiegLowingeretal.2015, type = {Working Paper}, author = {M{\"u}ller-Brandeck-Bocquet, Gisela and Gieg, Philipp and Lowinger, Timo and Gs{\"a}nger, Matthias and Becker, Michael and Kundu, Amitabh and Valerian, Rodrigues and S, Shaji and Sch{\"o}mbucher-Kusterer, Elisabeth and Biswas, Aparajita}, title = {Exploring Emerging India - Eight Essays}, editor = {M{\"u}ller-Brandeck-Bocquet, Gisela and Gieg, Philipp and Lowinger, Timo}, doi = {10.25972/OPUS-11997}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-119973}, pages = {58}, year = {2015}, abstract = {India's economic rise since the 1990s has been followed by a more prominent global role for the country. Despite economic setbacks in recent years and huge domestic challenges like poverty, caste issues, and gender inequality, India today is almost universally characterised as an "emerging power". At the same time, the country continues to show an enormous diversity. Thus, exploring emerging India can surely not be confined to economic analysis only. Instead, it is vital to take current developments in domestic and international politics, society, culture, religion, and political thinking into consideration as well. Following an interdisciplinary approach, contributions from Political Science, International Relations, Indology, Political Theory, and Economics are fundamental in order to grasp the country's diversity. This collection assembles eight essays which, individually, serve as working papers reflecting the authors' various research focuses, while collectively composing a multifaceted and multidis-ciplinary picture of emerging India. It thereby reflects the approach the University of W{\"u}rz-burg's Centre for Modern India and the Institute for Political Science and Sociology's India Forum are committed to: bringing together different academic disciplines in order to generate nuanced insights into India's manifold diversity.}, subject = {Indien / Government}, language = {en} } @article{BijuSchwarzLinkeetal.2011, author = {Biju, Joseph and Schwarz, Roland and Linke, Burkhard and Blom, Jochen and Becker, Anke and Claus, Heike and Goesmann, Alexander and Frosch, Matthias and M{\"u}ller, Tobias and Vogel, Ulrich and Schoen, Christoph}, title = {Virulence Evolution of the Human Pathogen Neisseria meningitidis by Recombination in the Core and Accessory Genome}, series = {PLoS One}, volume = {6}, journal = {PLoS One}, number = {4}, doi = {10.1371/journal.pone.0018441}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-137960}, pages = {e18441}, year = {2011}, abstract = {Background Neisseria meningitidis is a naturally transformable, facultative pathogen colonizing the human nasopharynx. Here, we analyze on a genome-wide level the impact of recombination on gene-complement diversity and virulence evolution in N. meningitidis. We combined comparative genome hybridization using microarrays (mCGH) and multilocus sequence typing (MLST) of 29 meningococcal isolates with computational comparison of a subset of seven meningococcal genome sequences. Principal Findings We found that lateral gene transfer of minimal mobile elements as well as prophages are major forces shaping meningococcal population structure. Extensive gene content comparison revealed novel associations of virulence with genetic elements besides the recently discovered meningococcal disease associated (MDA) island. In particular, we identified an association of virulence with a recently described canonical genomic island termed IHT-E and a differential distribution of genes encoding RTX toxin- and two-partner secretion systems among hyperinvasive and non-hyperinvasive lineages. By computationally screening also the core genome for signs of recombination, we provided evidence that about 40\% of the meningococcal core genes are affected by recombination primarily within metabolic genes as well as genes involved in DNA replication and repair. By comparison with the results of previous mCGH studies, our data indicated that genetic structuring as revealed by mCGH is stable over time and highly similar for isolates from different geographic origins. Conclusions Recombination comprising lateral transfer of entire genes as well as homologous intragenic recombination has a profound impact on meningococcal population structure and genome composition. Our data support the hypothesis that meningococcal virulence is polygenic in nature and that differences in metabolism might contribute to virulence.}, language = {en} } @article{SteinmannPaeleckeHabermannGeinitzetal.2012, author = {Steinmann, Diana and Paelecke-Habermann, Yvonne and Geinitz, Hans and Aschoff, Raimund and Bayerl, Anja and B{\"o}lling, Tobias and Bosch, Elisabeth and Bruns, Frank and Eichenseder-Seiss, Ute and Gerstein, Johanna and Gharbi, Nadine and Hagg, Juliane and Hipp, Matthias and Kleff, Irmgard and M{\"u}ller, Axel and Sch{\"a}fer, Christof and Schleicher, Ursula and Sehlen, Susanne and Theodorou, Marilena and Wypior, Hans-Joachim and Zehentmayr, Franz and van Oorschot, Birgitt and Vordermark, Dirk}, title = {Prospective evaluation of quality of life effects in patients undergoing palliative radiotherapy for brain metastases}, series = {BMC Cancer}, volume = {12}, journal = {BMC Cancer}, number = {283}, doi = {10.1186/1471-2407-12-283}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-135254}, year = {2012}, abstract = {Background: Recently published results of quality of life (QoL) studies indicated different outcomes of palliative radiotherapy for brain metastases. This prospective multi-center QoL study of patients with brain metastases was designed to investigate which QoL domains improve or worsen after palliative radiotherapy and which might provide prognostic information. Methods: From 01/2007-01/2009, n=151 patients with previously untreated brain metastases were recruited at 14 centers in Germany and Austria. Most patients (82 \%) received whole-brain radiotherapy. QoL was measured with the EORTC-QLQ-C15-PAL and brain module BN20 before the start of radiotherapy and after 3 months. Results: At 3 months, 88/142 (62 \%) survived. Nine patients were not able to be followed up. 62 patients (70.5 \% of 3-month survivors) completed the second set of questionnaires. Three months after the start of radiotherapy QoL deteriorated significantly in the areas of global QoL, physical function, fatigue, nausea, pain, appetite loss, hair loss, drowsiness, motor dysfunction, communication deficit and weakness of legs. Although the use of corticosteroid at 3 months could be reduced compared to pre-treatment (63 \% vs. 37 \%), the score for headaches remained stable. Initial QoL at the start of treatment was better in those alive than in those deceased at 3 months, significantly for physical function, motor dysfunction and the symptom scales fatigue, pain, appetite loss and weakness of legs. In a multivariate model, lower Karnofsky performance score, higher age and higher pain ratings before radiotherapy were prognostic of 3-month survival. Conclusions: Moderate deterioration in several QoL domains was predominantly observed three months after start of palliative radiotherapy for brain metastases. Future studies will need to address the individual subjective benefit or burden from such treatment. Baseline QoL scores before palliative radiotherapy for brain metastases may contain prognostic information.}, language = {en} } @article{SemmlerSacconiBachetal.2014, author = {Semmler, Anna-Lena and Sacconi, Sabrina and Bach, J. Elisa and Liebe, Claus and B{\"u}rmann, Jan and Kley, Rudolf A. and Ferbert, Andreas and Anderheiden, Roland and Van den Bergh, Peter and Martin, Jean-Jacques and De Jonghe, Peter and Neuen-Jacob, Eva and M{\"u}ller, Oliver and Deschauer, Marcus and Bergmann, Markus and Schr{\"o}der, J. Michael and Vorgerd, Matthias and Schulz, J{\"o}rg B. and Weis, Joachim and Kress, Wolfram and Claeys, Kristl G.}, title = {Unusual multisystemic involvement and a novel BAG3 mutation revealed by NGS screening in a large cohort of myofibrillar myopathies}, series = {Orphanet Journal of Rare Diseases}, volume = {9}, journal = {Orphanet Journal of Rare Diseases}, number = {121}, issn = {1750-1172}, doi = {10.1186/s13023-014-0121-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-115623}, year = {2014}, abstract = {Background: Myofibrillar myopathies (MFM) are a group of phenotypically and genetically heterogeneous neuromuscular disorders, which are characterized by protein aggregations in muscle fibres and can be associated with multisystemic involvement. Methods: We screened a large cohort of 38 index patients with MFM for mutations in the nine thus far known causative genes using Sanger and next generation sequencing (NGS). We studied the clinical and histopathological characteristics in 38 index patients and five additional relatives (n = 43) and particularly focused on the associated multisystemic symptoms. Results: We identified 14 heterozygous mutations (diagnostic yield of 37\%), among them the novel p. Pro209Gln mutation in the BAG3 gene, which was associated with onset in adulthood, a mild phenotype and an axonal sensorimotor polyneuropathy, in the absence of giant axons at the nerve biopsy. We revealed several novel clinical phenotypes and unusual multisystemic presentations with previously described mutations: hearing impairment with a FLNC mutation, dysphonia with a mutation in DES and the first patient with a FLNC mutation presenting respiratory insufficiency as the initial symptom. Moreover, we described for the first time respiratory insufficiency occurring in a patient with the p. Gly154Ser mutation in CRYAB. Interestingly, we detected a polyneuropathy in 28\% of the MFM patients, including a BAG3 and a MYOT case, and hearing impairment in 13\%, including one patient with a FLNC mutation and two with mutations in the DES gene. In four index patients with a mutation in one of the MFM genes, typical histological findings were only identified at the ultrastructural level (29\%). Conclusions: We conclude that extraskeletal symptoms frequently occur in MFM, particularly cardiac and respiratory involvement, polyneuropathy and/or deafness. BAG3 mutations should be considered even in cases with a mild phenotype or an adult onset. We identified a genetic defect in one of the known genes in less than half of the MFM patients, indicating that more causative genes are still to be found. Next generation sequencing techniques should be helpful in achieving this aim.}, language = {en} } @article{MorrisCarusoBuscotetal.2014, author = {Morris, E. Kathryn and Caruso, Tancredi and Buscot, Francois and Fischer, Markus and Hancock, Christine and Maier, Tanja S. and Meiners, Torsten and M{\"u}ller, Caroline and Obermaier, Elisabeth and Prati, Daniel and Socher, Stephanie A. and Sonnemann, Ilja and W{\"a}schke, Nicola and Wubet, Tesfaye and Wurst, Susanne and Rillig, Matthias C.}, title = {Choosing and using diversity indices: insights for ecological applications from the German Biodiversity Exploratories}, series = {Ecology and Evolution}, volume = {4}, journal = {Ecology and Evolution}, number = {18}, issn = {2045-7758}, doi = {10.1002/ece3.1155}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-115462}, pages = {3514-3524}, year = {2014}, abstract = {Biodiversity, a multidimensional property of natural systems, is difficult to quantify partly because of the multitude of indices proposed for this purpose. Indices aim to describe general properties of communities that allow us to compare different regions, taxa, and trophic levels. Therefore, they are of fundamental importance for environmental monitoring and conservation, although there is no consensus about which indices are more appropriate and informative. We tested several common diversity indices in a range of simple to complex statistical analyses in order to determine whether some were better suited for certain analyses than others. We used data collected around the focal plant Plantago lanceolata on 60 temperate grassland plots embedded in an agricultural landscape to explore relationships between the common diversity indices of species richness (S), Shannon's diversity (H'), Simpson's diversity (D-1), Simpson's dominance (D-2), Simpson's evenness (E), and Berger-Parker dominance (BP). We calculated each of these indices for herbaceous plants, arbuscular mycorrhizal fungi, aboveground arthropods, belowground insect larvae, and P.lanceolata molecular and chemical diversity. Including these trait-based measures of diversity allowed us to test whether or not they behaved similarly to the better studied species diversity. We used path analysis to determine whether compound indices detected more relationships between diversities of different organisms and traits than more basic indices. In the path models, more paths were significant when using H', even though all models except that with E were equally reliable. This demonstrates that while common diversity indices may appear interchangeable in simple analyses, when considering complex interactions, the choice of index can profoundly alter the interpretation of results. Data mining in order to identify the index producing the most significant results should be avoided, but simultaneously considering analyses using multiple indices can provide greater insight into the interactions in a system.}, language = {en} } @article{KoetschanKittelmannLuetal.2014, author = {Koetschan, Christian and Kittelmann, Sandra and Lu, Jingli and Al-Halbouni, Djamila and Jarvis, Graeme N. and M{\"u}ller, Tobias and Wolf, Matthias and Janssen, Peter H.}, title = {Internal Transcribed Spacer 1 Secondary Structure Analysis Reveals a Common Core throughout the Anaerobic Fungi (Neocallimastigomycota)}, series = {PLOS ONE}, volume = {9}, journal = {PLOS ONE}, number = {3}, doi = {10.1371/journal.pone.0091928}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-117058}, pages = {e91928}, year = {2014}, abstract = {The internal transcribed spacer (ITS) is a popular barcode marker for fungi and in particular the ITS1 has been widely used for the anaerobic fungi (phylum Neocallimastigomycota). A good number of validated reference sequences of isolates as well as a large number of environmental sequences are available in public databases. Its highly variable nature predisposes the ITS1 for low level phylogenetics; however, it complicates the establishment of reproducible alignments and the reconstruction of stable phylogenetic trees at higher taxonomic levels (genus and above). Here, we overcame these problems by proposing a common core secondary structure of the ITS1 of the anaerobic fungi employing a Hidden Markov Model-based ITS1 sequence annotation and a helix-wise folding approach. We integrated the additional structural information into phylogenetic analyses and present for the first time an automated sequence-structure-based taxonomy of the ITS1 of the anaerobic fungi. The methodology developed is transferable to the ITS1 of other fungal groups, and the robust taxonomy will facilitate and improve high-throughput anaerobic fungal community structure analysis of samples from various environments.}, language = {en} } @article{PeterBultinckMyantetal.2014, author = {Peter, Stefanie and Bultinck, Jennyfer and Myant, Kevin and Jaenicke, Laura A. and Walz, Susanne and M{\"u}ller, Judith and Gmachl, Michael and Treu, Matthias and Boehmelt, Guido and Ade, Casten P. and Schmitz, Werner and Wiegering, Armin and Otto, Christoph and Popov, Nikita and Sansom, Owen and Kraut, Norbert and Eilers, Martin}, title = {H Tumor cell-specific inhibition of MYC function using small molecule inhibitors of the HUWE1 ubiquitin ligase}, series = {EMBO Molecular Medicine}, volume = {6}, journal = {EMBO Molecular Medicine}, number = {12}, issn = {1757-4684}, doi = {10.15252/emmm.201403927}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-118132}, pages = {1525-41}, year = {2014}, abstract = {Deregulated expression of MYC is a driver of colorectal carcinogenesis, necessitating novel strategies to inhibit MYC function. The ubiquitin ligase HUWE1 (HECTH9, ARF-BP1, MULE) associates with both MYC and the MYC-associated protein MIZ1. We show here that HUWE1 is required for growth of colorectal cancer cells in culture and in orthotopic xenograft models. Using high-throughput screening, we identify small molecule inhibitors of HUWE1, which inhibit MYC-dependent transactivation in colorectal cancer cells, but not in stem and normal colon epithelial cells. Inhibition of HUWE1 stabilizes MIZ1. MIZ1 globally accumulates on MYC target genes and contributes to repression of MYC-activated target genes upon HUWE1 inhibition. Our data show that transcriptional activation by MYC in colon cancer cells requires the continuous degradation of MIZ1 and identify a novel principle that allows for inhibition of MYC function in tumor cells.}, language = {en} } @article{WolfChenSongetal.2013, author = {Wolf, Matthias and Chen, Shilin and Song, Jingyuan and Ankenbrand, Markus and M{\"u}ller, Tobias}, title = {Compensatory Base Changes in ITS2 Secondary Structures Correlate with the Biological Species Concept Despite Intragenomic Variability in ITS2 Sequences - A Proof of Concept}, series = {PLoS ONE}, journal = {PLoS ONE}, doi = {10.1371/journal.pone.0066726}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-96450}, year = {2013}, abstract = {Compensatory base changes (CBCs) in internal transcribed spacer 2 (ITS2) rDNA secondary structures correlate with Ernst Mayr's biological species concept. This hypothesis also referred to as the CBC species concept recently was subjected to large-scale testing, indicating two distinct probabilities. (1) If there is a CBC then there are two different species with a probability of ~0.93. (2) If there is no CBC then there is the same species with a probability of ~0.76. In ITS2 research, however, the main problem is the multicopy nature of ITS2 sequences. Most recently, 454 pyrosequencing data have been used to characterize more than 5000 intragenomic variations of ITS2 regions from 178 plant species, demonstrating that mutation of ITS2 is frequent, with a mean of 35 variants per species, respectively per individual organism. In this study, using those 454 data, the CBC criterion is reconsidered in the light of intragenomic variability, a proof of concept, a necessary criterion, expecting no intragenomic CBCs in variant ITS2 copies. In accordance with the CBC species concept, we could demonstrate that the probability that there is no intragenomic CBC is ~0.99.}, language = {en} } @article{SweeneySeubertStarketal.2012, author = {Sweeney, Reinhart A. and Seubert, Benedikt and Stark, Silke and Homann, Vanessa and M{\"u}ller, Gerd and Flentje, Michael and Guckenbeger, Matthias}, title = {Accuracy and inter-observer variability of 3D versus 4D cone-beam CT based image-guidance in SBRT for lung tumors}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75698}, year = {2012}, abstract = {Background: To analyze the accuracy and inter-observer variability of image-guidance (IG) using 3D or 4D cone-beam CT (CBCT) technology in stereotactic body radiotherapy (SBRT) for lung tumors. Materials and methods: Twenty-one consecutive patients treated with image-guided SBRT for primary and secondary lung tumors were basis for this study. A respiration correlated 4D-CT and planning contours served as reference for all IG techniques. Three IG techniques were performed independently by three radiation oncologists (ROs) and three radiotherapy technicians (RTTs). Image-guidance using respiration correlated 4D-CBCT (IG-4D) with automatic registration of the planning 4D-CT and the verification 4D-CBCT was considered gold-standard. Results were compared with two IG techniques using 3D-CBCT: 1) manual registration of the planning internal target volume (ITV) contour and the motion blurred tumor in the 3D-CBCT (IG-ITV); 2) automatic registration of the planning reference CT image and the verification 3D-CBCT (IG-3D). Image quality of 3D-CBCT and 4D-CBCT images was scored on a scale of 1-3, with 1 being best and 3 being worst quality for visual verification of the IGRT results. Results: Image quality was scored significantly worse for 3D-CBCT compared to 4D-CBCT: the worst score of 3 was given in 19 \% and 7.1 \% observations, respectively. Significant differences in target localization were observed between 4D-CBCT and 3D-CBCT based IG: compared to the reference of IG-4D, tumor positions differed by 1.9 mm± 0.9 mm (3D vector) on average using IG-ITV and by 3.6 mm± 3.2 mm using IG-3D; results of IG-ITV were significantly closer to the reference IG-4D compared to IG-3D. Differences between the 4D-CBCT and 3D-CBCT techniques increased significantly with larger motion amplitude of the tumor; analogously, differences increased with worse 3D-CBCT image quality scores. Inter-observer variability was largest in SI direction and was significantly larger in IG using 3D-CBCT compared to 4D-CBCT: 0.6 mm versus 1.5 mm (one standard deviation). Inter-observer variability was not different between the three ROs compared to the three RTTs. Conclusions: Respiration correlated 4D-CBCT improves the accuracy of image-guidance by more precise target localization in the presence of breathing induced target motion and by reduced inter-observer variability.}, subject = {Medizin}, language = {en} } @phdthesis{Mueller2004, author = {M{\"u}ller, Matthias}, title = {Vergleich von in-vitro-Ergebnissen im Mikrokerntest und den klinischen Beobachtungen nach Bestrahlung}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-10212}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2004}, abstract = {Hintergrund: Mikrokerne sind Chromosomenfragmente, die nicht in den Hauptkern integriert wurden und im Zytoplasma von proliferierenden Zellen nach ionisierender Strahlung oder Behandlung mit mutagensierenden Substanzen zu finden sind. In vielen F{\"a}llen konnte gezeigt werden, dass die Mikrokernfrequenz als Indikator f{\"u}r den strahleninduzierten Schaden dienen kann. Humane Lymphozyten und Fibroblasten von Patientinnen mit Brustkrebs nach Brusterhaltender Therapie wurden bestrahlt, im Mikrokerntest ausgewertet und die Ergebnisse mit den klinischen Akutreaktionen verglichen. Methode: Beide Zelltypen der 24 Patientinnen mit dem selben Bestrahlungsproceder (50 Gy + 10 Gy Boost) und ohne Chemotherapie wurden untersucht. Die Normalgewebsreaktionen wurden unter Verwendung der RTOG-Kriterien bestimmt. Die Zellen wurden in vitro mit 0-, 1-, 2-Gy-Einmaldosis-Bestrahlung (Lymphozyten) bzw. 0-, 2-, 4-Gy-Einmaldosis-Bestrahlung behandelt, {\"u}ber 72 h kultiviert, auf Objekttr{\"a}gern fixiert und bei 400 - 1000facher Vergr{\"o}ßerung (Fluoreszenzmikroskop) ausgewertet. Die Zellteilung der Lymphozyten wurde mittels Cytochalasin B (Cyt B) inhibiert. Ergebnisse: Es konnte keine signifikante Korrelation der in-vitro-Strahlenempfindlichkeit und den Normalgewebsreaktionen beobachtet werden. Des weiteren wurde kein Zusammenhang zwischen der Strahlenempfindlichkeit der lymphozyten und den Fibroblasten, die vom selben Spender gewonnen wurden, beobachtet. Zusammenfassung: Die Daten unterst{\"u}tzen nicht den Nutzen des Mikrokern-Testes in der Vorhersage von Normalgewebsreaktionen auf die Strahlentherapie bei Malignompatienten.}, language = {de} } @article{KarimiFreundWageretal.2021, author = {Karimi, Sohail M. and Freund, Matthias and Wager, Brittney M. and Knoblauch, Michael and Fromm, J{\"o}rg and M. Mueller, Heike and Ache, Peter and Krischke, Markus and Mueller, Martin J. and M{\"u}ller, Tobias and Dittrich, Marcus and Geilfus, Christoph-Martin and Alfaran, Ahmed H. and Hedrich, Rainer and Deeken, Rosalia}, title = {Under salt stress guard cells rewire ion transport and abscisic acid signaling}, series = {New Phytologist}, volume = {231}, journal = {New Phytologist}, number = {3}, doi = {10.1111/nph.17376}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259635}, pages = {1040-1055}, year = {2021}, abstract = {Soil salinity is an increasingly global problem which hampers plant growth and crop yield. Plant productivity depends on optimal water-use efficiency and photosynthetic capacity balanced by stomatal conductance. Whether and how stomatal behavior contributes to salt sensitivity or tolerance is currently unknown. This work identifies guard cell-specific signaling networks exerted by a salt-sensitive and salt-tolerant plant under ionic and osmotic stress conditions accompanied by increasing NaCl loads. We challenged soil-grown Arabidopsis thaliana and Thellungiella salsuginea plants with short- and long-term salinity stress and monitored genome-wide gene expression and signals of guard cells that determine their function. Arabidopsis plants suffered from both salt regimes and showed reduced stomatal conductance while Thellungiella displayed no obvious stress symptoms. The salt-dependent gene expression changes of guard cells supported the ability of the halophyte to maintain high potassium to sodium ratios and to attenuate the abscisic acid (ABA) signaling pathway which the glycophyte kept activated despite fading ABA concentrations. Our study shows that salinity stress and even the different tolerances are manifested on a single cell level. Halophytic guard cells are less sensitive than glycophytic guard cells, providing opportunities to manipulate stomatal behavior and improve plant productivity.}, language = {en} } @article{TemmeAdamAhnenetal.2017, author = {Temme, Fabian and Adam, Jan and Ahnen, Max L. and Baack, Dominik and Balbo, Matteo and Bergmann, Matthias and Biland, Adrian and Blank, Michael and Bretz, Thomas and Br{\"u}gge, Kai A. and Buss, Jens and Dmytriiev, Anton and Dorner, Daniela and Einecke, Sabrina and Hempfling, Christina and Hildebrand, Dorothee and Hughes, Gareth and Linhoff, Lena and Mannheim, Karl and M{\"u}ller, Sebastian and Neise, Dominik and Neronov, Andrii and N{\"o}the, Max and Paravac, Aleksander and Pauss, Felicitas and Rhode, Wolfgang and Shukla, Amit and Thaele, Julia and Walter, Roland}, title = {Long-Term monitoring of bright blazars in the multi-GeV to TeV range with FACT}, series = {Galaxies}, volume = {5}, journal = {Galaxies}, number = {1}, publisher = {MDPI}, issn = {2075-4434}, doi = {10.3390/galaxies5010018}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-198088}, pages = {18}, year = {2017}, abstract = {Blazars like Markarian 421 or Markarian 501 are active galactic nuclei (AGN), with their jets orientated towards the observer. They are among the brightest objects in the very high energy (VHE) gamma ray regime (>100 GeV). Their emitted gamma-ray fluxes are extremely variable, with changing activity levels on timescales between minutes, months, and even years. Several questions are part of the current research, such as the question of the emission regions or the engine of the AGN and the particle acceleration. A dedicated longterm monitoring program is necessary to investigate the properties of blazars in detail. A densely sampled and unbiased light curve allows for observation of both high and low states of the sources, and the combination with multi-wavelength observation could contribute to the answer of several questions mentioned above. FACT (First G-APD Cherenkov Telescope) is the first operational telescope using silicon photomultiplier (SiPM, also known as Geigermode—Avalanche Photo Diode, G-APD) as photon detectors. SiPM have a very homogenous and stable longterm performance, and allow operation even during full moon without any filter, leading to a maximal duty cycle for an Imaging Air Cherenkov Telescope (IACT). Hence, FACT is an ideal device for such a longterm monitoring of bright blazars. A small set of sources (e.g., Markarian 421, Markarian 501, 1ES 1959+650, and 1ES 2344+51.4) is currently being monitored. In this contribution, the FACT telescope and the concept of longterm monitoring of bright blazars will be introduced. The results of the monitoring program will be shown, and the advantages of densely sampled and unbiased light curves will be discussed.}, language = {en} } @article{MuellerSpenstKagereretal.2022, author = {M{\"u}ller, Ulrich and Spenst, Peter and Kagerer, Philipp and Stolte, Matthias and W{\"u}rthner, Frank and Pflaum, Jens}, title = {Photon-Correlation Studies on Multichromophore Macrocycles of Perylene Dyes}, series = {Advanced Optical Materials}, volume = {10}, journal = {Advanced Optical Materials}, number = {14}, doi = {10.1002/adom.202200234}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-287219}, year = {2022}, abstract = {Organic dyes offer unique properties for their application as room temperature single photon emitters. By means of photon-correlation, the emission characteristics of macrocyclic para-xylylene linked perylene bisimide (PBI) trimers and tetramers dispersed in polymethyl methacrylate matrices are analyzed. The optical data indicate that, despite of the strong emission enhancement of PBI trimers and tetramers according to their larger number of chromophores, the photon-correlation statistics still obeys that of single photon emitters. Moreover, driving PBI trimers and tetramers at higher excitation powers, saturated emission behavior for monomers is found while macrocycle emission is still far-off saturation but shows enhanced fluctuations. This observation is attributed to fast singlet-singlet annihilation, i.e., faster than the radiative lifetime of the excited S1 state, and the enlarged number of conformational arrangements of multichromophores in the polymeric host. Finally, embedding trimeric PBI macrocycles in active organic light-emitting diode matrices, electrically driven bright fluorescence together with an indication for antibunching at room temperature can be detected. This, so far, has only been observed for phosphorescent emitters that feature much longer lifetimes of the excited states and, thus, smaller radiative recombination rates. The results are discussed in the context of possible effects on the g(2) behavior of molecular emitters.}, language = {en} } @article{KleinHesslingMuhammadKleinetal.2017, author = {Klein-Hessling, Stefan and Muhammad, Khalid and Klein, Matthias and Pusch, Tobias and Rudolf, Ronald and Fl{\"o}ter, Jessica and Qureischi, Musga and Beilhack, Andreas and Vaeth, Martin and Kummerow, Carsten and Backes, Christian and Schoppmeyer, Rouven and Hahn, Ulrike and Hoth, Markus and Bopp, Tobias and Berberich-Siebelt, Friederike and Patra, Amiya and Avots, Andris and M{\"u}ller, Nora and Schulze, Almut and Serfling, Edgar}, title = {NFATc1 controls the cytotoxicity of CD8\(^{+}\) T cells}, series = {Nature Communications}, volume = {8}, journal = {Nature Communications}, number = {511}, doi = {10.1038/s41467-017-00612-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170353}, year = {2017}, abstract = {Cytotoxic T lymphocytes are effector CD8\(^{+}\) T cells that eradicate infected and malignant cells. Here we show that the transcription factor NFATc1 controls the cytotoxicity of mouse cytotoxic T lymphocytes. Activation of Nfatc1\(^{-/-}\) cytotoxic T lymphocytes showed a defective cytoskeleton organization and recruitment of cytosolic organelles to immunological synapses. These cells have reduced cytotoxicity against tumor cells, and mice with NFATc1-deficient T cells are defective in controlling Listeria infection. Transcriptome analysis shows diminished RNA levels of numerous genes in Nfatc1\(^{-/-}\) CD8\(^{+}\) T cells, including Tbx21, Gzmb and genes encoding cytokines and chemokines, and genes controlling glycolysis. Nfatc1\(^{-/-}\), but not Nfatc2\(^{-/-}\) CD8\(^{+}\) T cells have an impaired metabolic switch to glycolysis, which can be restored by IL-2. Genome-wide ChIP-seq shows that NFATc1 binds many genes that control cytotoxic T lymphocyte activity. Together these data indicate that NFATc1 is an important regulator of cytotoxic T lymphocyte effector functions.}, language = {en} } @article{KoleKošćakAmaretal.2022, author = {Kole, Goutam Kumar and Košćak, Marta and Amar, Anissa and Majhen, Dragomira and Božinović, Ksenija and Brkljaca, Zlatko and Ferger, Matthias and Michail, Evripidis and Lorenzen, Sabine and Friedrich, Alexandra and Krummenacher, Ivo and Moos, Michael and Braunschweig, Holger and Boucekkine, Abdou and Lambert, Christoph and Halet, Jean-Fran{\c{c}}ois and Piantanida, Ivo and M{\"u}ller-Buschbaum, Klaus and Marder, Todd B.}, title = {Methyl Viologens of Bis-(4'-Pyridylethynyl)Arenes - Structures, Photophysical and Electrochemical Studies, and their Potential Application in Biology}, series = {Chemistry - A European Journal}, volume = {28}, journal = {Chemistry - A European Journal}, number = {40}, doi = {10.1002/chem.202200753}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-287126}, year = {2022}, abstract = {A series of bis-(4'-pyridylethynyl)arenes (arene=benzene, tetrafluorobenzene, and anthracene) were synthesized and their bis-N-methylpyridinium compounds were investigated as a class of π-extended methyl viologens. Their structures were determined by single crystal X-ray diffraction, and their photophysical and electrochemical properties (cyclic voltammetry), as well as their interactions with DNA/RNA were investigated. The dications showed bathochromic shifts in emission compared to the neutral compounds. The neutral compounds showed very small Stokes shifts, which are a little larger for the dications. All of the compounds showed very short fluorescence lifetimes (<4 ns). The neutral compound with an anthracene core has a quantum yield of almost unity. With stronger acceptors, the analogous bis-N-methylpyridinium compound showed a larger two-photon absorption cross-section than its neutral precursor. All of the dicationic compounds interact with DNA/RNA; while the compounds with benzene and tetrafluorobenzene cores bind in the grooves, the one with an anthracene core intercalates as a consequence of its large, condensed aromatic linker moiety, and it aggregates within the polynucleotide when in excess over DNA/RNA. Moreover, all cationic compounds showed highly specific CD spectra upon binding to ds-DNA/RNA, attributed to the rare case of forcing the planar, achiral molecule into a chiral rotamer, and negligible toxicity toward human cell lines at ≤10 μM concentrations. The anthracene-analogue exhibited intracellular accumulation within lysosomes, preventing its interaction with cellular DNA/RNA. However, cytotoxicity was evident at 1 μM concentration upon exposure to light, due to singlet oxygen generation within cells. These multi-faceted features, in combination with its two-photon absorption properties, suggest it to be a promising lead compound for development of novel light-activated theranostic agents.}, language = {en} } @article{BerntRangrezEdenetal.2016, author = {Bernt, Alexander and Rangrez, Ashraf Y. and Eden, Matthias and Jungmann, Andreas and Katz, Sylvia and Rohr, Claudia and M{\"u}ller, Oliver J. and Katus, Hugo A. and Sossalla, Samuel T. and Williams, Tatjana and Ritter, Oliver and Frank, Derk and Frey, Norbert}, title = {Sumoylation-independent activation of Calcineurin-NFAT-signaling via SUMO2 mediates cardiomyocyte hypertrophy}, series = {Scientific Reports}, volume = {6}, journal = {Scientific Reports}, number = {35758}, doi = {10.1038/srep35758}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-167525}, year = {2016}, abstract = {The objective of this study was to identify unknown modulators of Calcineurin (Cn)-NFAT signaling. Measurement of NFAT reporter driven luciferase activity was therefore utilized to screen a human cardiac cDNA-library (~10\(^{7}\) primary clones) in C2C12 cells through serial dilutions until single clones could be identified. This extensive screening strategy culminated in the identification of SUMO2 as a most efficient Cn-NFAT activator. SUMO2-mediated activation of Cn-NFAT signaling in cardiomyocytes translated into a hypertrophic phenotype. Prohypertrophic effects were also observed in mice expressing SUMO2 in the heart using AAV9 (Adeno-associated virus), complementing the in vitro findings. In addition, increased SUMO2-mediated sumoylation in human cardiomyopathy patients and in mouse models of cardiomyopathy were observed. To decipher the underlying mechanism, we generated a sumoylation-deficient SUMO2 mutant (ΔGG). Surprisingly, ΔGG replicated Cn-NFAT-activation and the prohypertrophic effects of native SUMO2, both in vitro and in vivo, suggesting a sumoylation-independent mechanism. Finally, we discerned a direct interaction between SUMO2 and CnA, which promotes CnA nuclear localization. In conclusion, we identified SUMO2 as a novel activator of Cn-NFAT signaling in cardiomyocytes. In broader terms, these findings reveal an unexpected role for SUMO2 in cardiac hypertrophy and cardiomyopathy, which may open the possibility for therapeutic manipulation of this pathway.}, language = {en} } @article{KlughammerDittrichBlometal.2017, author = {Klughammer, Johanna and Dittrich, Marcus and Blom, Jochen and Mitesser, Vera and Vogel, Ulrich and Frosch, Matthias and Goesmann, Alexander and M{\"u}ller, Tobias and Schoen, Christoph}, title = {Comparative genome sequencing reveals within-host genetic changes in Neisseria meningitidis during invasive disease}, series = {PLoS ONE}, volume = {12}, journal = {PLoS ONE}, number = {1}, doi = {10.1371/journal.pone.0169892}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-159547}, pages = {e0169892}, year = {2017}, abstract = {Some members of the physiological human microbiome occasionally cause life-threatening disease even in immunocompetent individuals. A prime example of such a commensal pathogen is Neisseria meningitidis, which normally resides in the human nasopharynx but is also a leading cause of sepsis and epidemic meningitis. Using N. meningitidis as model organism, we tested the hypothesis that virulence of commensal pathogens is a consequence of within host evolution and selection of invasive variants due to mutations at contingency genes, a mechanism called phase variation. In line with the hypothesis that phase variation evolved as an adaptation to colonize diverse hosts, computational comparisons of all 27 to date completely sequenced and annotated meningococcal genomes retrieved from public databases showed that contingency genes are indeed enriched for genes involved in host interactions. To assess within-host genetic changes in meningococci, we further used ultra-deep whole-genome sequencing of throat-blood strain pairs isolated from four patients suffering from invasive meningococcal disease. We detected up to three mutations per strain pair, affecting predominantly contingency genes involved in type IV pilus biogenesis. However, there was not a single (set) of mutation(s) that could invariably be found in all four pairs of strains. Phenotypic assays further showed that these genetic changes were generally not associated with increased serum resistance, higher fitness in human blood ex vivo or differences in the interaction with human epithelial and endothelial cells in vitro. In conclusion, we hypothesize that virulence of meningococci results from accidental emergence of invasive variants during carriage and without within host evolution of invasive phenotypes during disease progression in vivo.}, language = {en} } @article{WenNowakKrolNagleretal.2019, author = {Wen, Xinbo and Nowak-Kr{\´o}l, Agnieszka and Nagler, Oliver and Kraus, Felix and Zhu, Na and Zheng, Nan and M{\"u}ller, Matthias and Schmidt, David and Xie, Zengqi and W{\"u}rthner, Frank}, title = {Tetrahydroxy-perylene bisimide embedded in zinc oxide thin film as electron transporting layer for high performance non-fullerene organic solar cells}, series = {Angewandte Chemie International Edition}, volume = {58}, journal = {Angewandte Chemie International Edition}, number = {37}, doi = {10.1002/anie.201907467}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-204723}, pages = {13051-13055}, year = {2019}, abstract = {By introduction of four hydroxy (HO) groups into the two perylene bisimide (PBI) bay areas, new HO-PBI ligands were obtained which upon deprotonation can complex ZnII ions and photosensitize semiconductive zinc oxide thin films. Such coordination is beneficial for dispersing PBI photosensitizer molecules evenly into metal oxide films to fabricate organic-inorganic hybrid interlayers for organic solar cells. Supported by the photoconductive effect of the ZnO:HO-PBI hybrid interlayers, improved electron collection and transportation is achieved in fullerene and non-fullerene polymer solar cell devices, leading to remarkable power conversion efficiencies of up to 15.95 \% for a non-fullerene based organic solar cell.}, language = {en} } @article{WischnewskySchwentnerDiessneretal.2021, author = {Wischnewsky, Manfred and Schwentner, Lukas and Diessner, Joachim and De Gregorio, Amelie and Joukhadar, Ralf and Davut, Dayan and Salmen, Jessica and Bekes, Inga and Kiesel, Matthias and M{\"u}ller-Reiter, Max and Blettner, Maria and Wolters, Regine and Janni, Wolfgang and Kreienberg, Rolf and W{\"o}ckel, Achim and Ebner, Florian}, title = {BRENDA-Score, a hghly significant, internally and externally validated prognostic marker for metastatic recurrence: analysis of 10,449 primary breast cancer patients}, series = {Cancers}, volume = {13}, journal = {Cancers}, number = {13}, issn = {2072-6694}, doi = {10.3390/cancers13133121}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-241064}, year = {2021}, abstract = {Background Current research in breast cancer focuses on individualization of local and systemic therapies with adequate escalation or de-escalation strategies. As a result, about two-thirds of breast cancer patients can be cured, but up to one-third eventually develop metastatic disease, which is considered incurable with currently available treatment options. This underscores the importance to develop a metastatic recurrence score to escalate or de-escalate treatment strategies. Patients and methods Data from 10,499 patients were available from 17 clinical cancer registries (BRENDA-project. In total, 8566 were used to develop the BRENDA-Index. This index was calculated from the regression coefficients of a Cox regression model for metastasis-free survival (MFS). Based on this index, patients were categorized into very high, high, intermediate, low, and very low risk groups forming the BRENDA-Score. Bootstrapping was used for internal validation and an independent dataset of 1883 patients for external validation. The predictive accuracy was checked by Harrell's c-index. In addition, the BRENDA-Score was analyzed as a marker for overall survival (OS) and compared to the Nottingham prognostic score (NPS). Results: Intrinsic subtypes, tumour size, grading, and nodal status were identified as statistically significant prognostic factors in the multivariate analysis. The five prognostic groups of the BRENDA-Score showed highly significant (p < 0.001) differences regarding MFS:low risk: hazard ratio (HR) = 2.4, 95\%CI (1.7-3.3); intermediate risk: HR = 5.0, 95\%CI.(3.6-6.9); high risk: HR = 10.3, 95\%CI (7.4-14.3) and very high risk: HR = 18.1, 95\%CI (13.2-24.9). The external validation showed congruent results. A multivariate Cox regression model for OS with BRENDA-Score and NPS as covariates showed that of these two scores only the BRENDA-Score is significant (BRENDA-Score p < 0.001; NPS p = 0.447). Therefore, the BRENDA-Score is also a good prognostic marker for OS. Conclusion: The BRENDA-Score is an internally and externally validated robust predictive tool for metastatic recurrence in breast cancer patients. It is based on routine parameters easily accessible in daily clinical care. In addition, the BRENDA-Score is a good prognostic marker for overall survival. Highlights: The BRENDA-Score is a highly significant predictive tool for metastatic recurrence of breast cancer patients. The BRENDA-Score is stable for at least the first five years after primary diagnosis, i.e., the sensitivities and specificities of this predicting system is rather similar to the NPI with AUCs between 0.76 and 0.81 the BRENDA-Score is a good prognostic marker for overall survival.}, language = {en} } @article{MohmeSchmalzingMuelleretal.2020, author = {Mohme, Sophia and Schmalzing, Marc and M{\"u}ller, Cornelia S.L. and Vogt, Thomas and Goebeler, Matthias and Stoevesandt, Johanna}, title = {Immunizations in immunocompromised patients: a guide for dermatologists}, series = {JDDG: Journal der Deutschen Dermatologischen Gesellschaft}, volume = {18}, journal = {JDDG: Journal der Deutschen Dermatologischen Gesellschaft}, number = {7}, doi = {10.1111/ddg.14156}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-217982}, pages = {699 -- 723}, year = {2020}, abstract = {The increasingly frequent use of immunomodulatory agents in dermatology requires the observance of specific recommendations for immunization. These recommendations are developed and regularly updated by the German Standing Committee on Vaccination (STIKO), an independent advisory group at the Robert Koch Institute. Dermatological patients on immunosuppressive treatment should ideally receive all vaccinations included in the standard immunization schedule. Additionally, it is recommended that they also undergo vaccination against the seasonal flu, pneumococci, and herpes zoster (inactivated herpes zoster subunit vaccine for patients ≥ 50 years). Additional immunizations against Haemophilus influenzae type B, hepatitis B and meningococci may be indicated depending on individual comorbidities and exposure risk. Limitations of use, specific contraindications and intervals to be observed between vaccination and immunosuppression depend on the immunosuppressive agent used and its dosing. Only under certain conditions may live-attenuated vaccines be administered in patients on immunosuppressive therapy. Given its strong suppressive effect on the humoral immune response, no vaccines - except for flu shots - should be given within six months after rituximab therapy. This CME article presents current recommendations on immunization in immunocompromised individuals, with a special focus on dermatological patients. Its goal is to enable readers to provide competent counseling and to initiate necessary immunizations in this vulnerable patient group.}, language = {en} } @article{SchmittMeybohmNeefetal.2022, author = {Schmitt, Elke and Meybohm, Patrick and Neef, Vanessa and Baumgarten, Peter and Bayer, Alexandra and Choorapoikayil, Suma and Friederich, Patrick and Friedrich, Jens and Geisen, Christof and G{\"u}resir, Erdem and Gr{\"u}newald, Matthias and Gutjahr, Martin and Helmer, Philipp and Herrmann, Eva and M{\"u}ller, Markus and Narita, Diana and Raadts, Ansgar and Schwendner, Klaus and Seifried, Erhard and Stark, Patrick and Steinbicker, Andrea U. and Thoma, Josef and Velten, Markus and Weigt, Henry and Wiesenack, Christoph and Wittmann, Maria and Zacharowski, Kai and Piekarski, Florian}, title = {Preoperative anaemia and red blood cell transfusion in patients with aneurysmal subarachnoid and intracerebral haemorrhage - a multicentre subanalysis of the German PBM Network Registry}, series = {Acta Neurochirurgica}, volume = {164}, journal = {Acta Neurochirurgica}, organization = {German PBM Network Collaborators}, doi = {10.1007/s00701-022-05144-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-346754}, pages = {985-999}, year = {2022}, abstract = {Purpose Anaemia is common in patients presenting with aneurysmal subarachnoid (aSAH) and intracerebral haemorrhage (ICH). In surgical patients, anaemia was identified as an idenpendent risk factor for postoperative mortality, prolonged hospital length of stay (LOS) and increased risk of red blood cell (RBC) transfusion. This multicentre cohort observation study describes the incidence and effects of preoperative anaemia in this critical patient collective for a 10-year period. Methods This multicentre observational study included adult in-hospital surgical patients diagnosed with aSAH or ICH of 21 German hospitals (discharged from 1 January 2010 to 30 September 2020). Descriptive, univariate and multivariate analyses were performed to investigate the incidence and association of preoperative anaemia with RBC transfusion, in-hospital mortality and postoperative complications in patients with aSAH and ICH. Results A total of n = 9081 patients were analysed (aSAH n = 5008; ICH n = 4073). Preoperative anaemia was present at 28.3\% in aSAH and 40.9\% in ICH. RBC transfusion rates were 29.9\% in aSAH and 29.3\% in ICH. Multivariate analysis revealed that preoperative anaemia is associated with a higher risk for RBC transfusion (OR = 3.25 in aSAH, OR = 4.16 in ICH, p < 0.001), for in-hospital mortality (OR = 1.48 in aSAH, OR = 1.53 in ICH, p < 0.001) and for several postoperative complications. Conclusions Preoperative anaemia is associated with increased RBC transfusion rates, in-hospital mortality and postoperative complications in patients with aSAH and ICH.}, language = {en} } @article{GoeringSchumannMuelleretal.2022, author = {G{\"o}ring, Lukas and Schumann, Sarah and M{\"u}ller, Jessica and Buck, Andreas K. and Port, Matthias and Lassmann, Michael and Scherthan, Harry and Eberlein, Uta}, title = {Repair of a-particle-induced DNA damage in peripheral blood mononuclear cells after internal ex vivo irradiation with \(^{223}\)Ra}, series = {European Journal of Nuclear Medicine and Molecular Imaging}, volume = {49}, journal = {European Journal of Nuclear Medicine and Molecular Imaging}, number = {12}, doi = {10.1007/s00259-022-05860-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324557}, pages = {3981-3988}, year = {2022}, abstract = {Purpose As α-emitters for radiopharmaceutical therapies are administered systemically by intravenous injection, blood will be irradiated by α-particles that induce clustered DNA double-strand breaks (DSBs). Here, we investigated the induction and repair of DSB damage in peripheral blood mononuclear cells (PBMCs) as a function of the absorbed dose to the blood following internal ex vivo irradiation with [\(^{223}\)Ra]RaCl2. Methods Blood samples of ten volunteers were irradiated by adding [\(^{223}\)Ra]RaCl2 solution with different activity concentrations resulting in absorbed doses to the blood of 3 mGy, 25 mGy, 50 mGy and 100 mGy. PBMCs were isolated, divided in three parts and either fixed directly (d-samples) or after 4 h or 24 h culture. After immunostaining, the induced γ-H2AX α-tracks were counted. The time-dependent decrease in α-track frequency was described with a model assuming a repair rate R and a fraction of non-repairable damage Q. Results For 25 mGy, 50 mGy and 100 mGy, the numbers of α-tracks were significantly increased compared to baseline at all time points. Compared to the corresponding d-samples, the α-track frequency decreased significantly after 4 h and after 24 h. The repair rates R were (0.24 ± 0.05) h-1 for 25 mGy, (0.16 ± 0.04) h-1 for 50 mGy and (0.13 ± 0.02) h-1 for 100 mGy, suggesting faster repair at lower absorbed doses, while Q-values were similar. Conclusion The results obtained suggest that induction and repair of the DSB damage depend on the absorbed dose to the blood. Repair rates were similar to what has been observed for irradiation with low linear energy transfer.}, language = {en} } @article{HerrmannMuellerNotzetal.2023, author = {Herrmann, Johannes and M{\"u}ller, Kerstin and Notz, Quirin and H{\"u}bsch, Martha and Haas, Kirsten and Horn, Anna and Schmidt, Julia and Heuschmann, Peter and Maschmann, Jens and Frosch, Matthias and Deckert, J{\"u}rgen and Einsele, Hermann and Ertl, Georg and Frantz, Stefan and Meybohm, Patrick and Lotz, Christopher}, title = {Prospective single-center study of health-related quality of life after COVID-19 in ICU and non-ICU patients}, series = {Scientific Reports}, volume = {13}, journal = {Scientific Reports}, doi = {10.1038/s41598-023-33783-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357174}, year = {2023}, abstract = {Long-term sequelae in hospitalized Coronavirus Disease 2019 (COVID-19) patients may result in limited quality of life. The current study aimed to determine health-related quality of life (HRQoL) after COVID-19 hospitalization in non-intensive care unit (ICU) and ICU patients. This is a single-center study at the University Hospital of Wuerzburg, Germany. Patients eligible were hospitalized with COVID-19 between March 2020 and December 2020. Patients were interviewed 3 and 12 months after hospital discharge. Questionnaires included the European Quality of Life 5 Dimensions 5 Level (EQ-5D-5L), patient health questionnaire-9 (PHQ-9), the generalized anxiety disorder 7 scale (GAD-7), FACIT fatigue scale, perceived stress scale (PSS-10) and posttraumatic symptom scale 10 (PTSS-10). 85 patients were included in the study. The EQ5D-5L-Index significantly differed between non-ICU (0.78 ± 0.33 and 0.84 ± 0.23) and ICU (0.71 ± 0.27; 0.74 ± 0.2) patients after 3- and 12-months. Of non-ICU 87\% and 80\% of ICU survivors lived at home without support after 12 months. One-third of ICU and half of the non-ICU patients returned to work. A higher percentage of ICU patients was limited in their activities of daily living compared to non-ICU patients. Depression and fatigue were present in one fifth of the ICU patients. Stress levels remained high with only 24\% of non-ICU and 3\% of ICU patients (p = 0.0186) having low perceived stress. Posttraumatic symptoms were present in 5\% of non-ICU and 10\% of ICU patients. HRQoL is limited in COVID-19 ICU patients 3- and 12-months post COVID-19 hospitalization, with significantly less improvement at 12-months compared to non-ICU patients. Mental disorders were common highlighting the complexity of post-COVID-19 symptoms as well as the necessity to educate patients and primary care providers about monitoring mental well-being post COVID-19.}, language = {en} }