TY - JOUR A1 - Gottschalk, Michael G. A1 - Richter, Jan A1 - Ziegler, Christiane A1 - Schiele, Miriam A. A1 - Mann, Julia A1 - Geiger, Maximilian J. A1 - Schartner, Christoph A1 - Homola, György A. A1 - Alpers, Georg W. A1 - Büchel, Christian A1 - Fehm, Lydia A1 - Fydrich, Thomas A1 - Gerlach, Alexander L. A1 - Gloster, Andrew T. A1 - Helbig-Lang, Sylvia A1 - Kalisch, Raffael A1 - Kircher, Tilo A1 - Lang, Thomas A1 - Lonsdorf, Tina B. A1 - Pané-Farré, Christiane A. A1 - Ströhle, Andreas A1 - Weber, Heike A1 - Zwanzger, Peter A1 - Arolt, Volker A1 - Romanos, Marcel A1 - Wittchen, Hans-Ulrich A1 - Hamm, Alfons A1 - Pauli, Paul A1 - Reif, Andreas A1 - Deckert, Jürgen A1 - Neufang, Susanne A1 - Höfler, Michael A1 - Domschke, Katharina T1 - Orexin in the anxiety spectrum: association of a HCRTR1 polymorphism with panic disorder/agoraphobia, CBT treatment response and fear-related intermediate phenotypes JF - Translational Psychiatry N2 - Preclinical studies point to a pivotal role of the orexin 1 (OX1) receptor in arousal and fear learning and therefore suggest the HCRTR1 gene as a prime candidate in panic disorder (PD) with/without agoraphobia (AG), PD/AG treatment response, and PD/AG-related intermediate phenotypes. Here, a multilevel approach was applied to test the non-synonymous HCRTR1 C/T Ile408Val gene variant (rs2271933) for association with PD/AG in two independent case-control samples (total n = 613 cases, 1839 healthy subjects), as an outcome predictor of a six-weeks exposure-based cognitive behavioral therapy (CBT) in PD/AG patients (n = 189), as well as with respect to agoraphobic cognitions (ACQ) (n = 483 patients, n = 2382 healthy subjects), fMRI alerting network activation in healthy subjects (n = 94), and a behavioral avoidance task in PD/AG pre- and post-CBT (n = 271). The HCRTR1 rs2271933 T allele was associated with PD/AG in both samples independently, and in their meta-analysis (p = 4.2 × 10−7), particularly in the female subsample (p = 9.8 × 10−9). T allele carriers displayed a significantly poorer CBT outcome (e.g., Hamilton anxiety rating scale: p = 7.5 × 10−4). The T allele count was linked to higher ACQ sores in PD/AG and healthy subjects, decreased inferior frontal gyrus and increased locus coeruleus activation in the alerting network. Finally, the T allele count was associated with increased pre-CBT exposure avoidance and autonomic arousal as well as decreased post-CBT improvement. In sum, the present results provide converging evidence for an involvement of HCRTR1 gene variation in the etiology of PD/AG and PD/AG-related traits as well as treatment response to CBT, supporting future therapeutic approaches targeting the orexin-related arousal system. KW - human behaviour KW - molecular neuroscience KW - personalized medicine KW - predictive markers KW - psychiatric disorders Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227479 VL - 9 ER - TY - JOUR A1 - Gotru, Sanjeev Kiran A1 - van Geffen, Johanna P. A1 - Nagy, Magdolna A1 - Mammadova-Bach, Elmina A1 - Eilenberger, Julia A1 - Volz, Julia A1 - Manukjan, Georgi A1 - Schulze, Harald A1 - Wagner, Leonard A1 - Eber, Stefan A1 - Schambeck, Christian A1 - Deppermann, Carsten A1 - Brouns, Sanne A1 - Nurden, Paquita A1 - Greinacher, Andreas A1 - Sachs, Ulrich A1 - Nieswandt, Bernhard A1 - Hermanns, Heike M. A1 - Heemskerk, Johan W. M. A1 - Braun, Attila T1 - Defective Zn2+ homeostasis in mouse and human platelets with α- and δ-storage pool diseases JF - Scientific Reports N2 - Zinc (Zn2+) can modulate platelet and coagulation activation pathways, including fibrin formation. Here, we studied the (patho)physiological consequences of abnormal platelet Zn2+ storage and release. To visualize Zn2+ storage in human and mouse platelets, the Zn2+ specific fluorescent dye FluoZin3 was used. In resting platelets, the dye transiently accumulated into distinct cytosolic puncta, which were lost upon platelet activation. Platelets isolated from Unc13d−/− mice, characterized by combined defects of α/δ granular release, showed a markedly impaired Zn2+ release upon activation. Platelets from Nbeal2−/− mice mimicking Gray platelet syndrome (GPS), characterized by primarily loss of the α-granule content, had strongly reduced Zn2+ levels, which was also confirmed in primary megakaryocytes. In human platelets isolated from patients with GPS, Hermansky-Pudlak Syndrome (HPS) and Storage Pool Disease (SPD) altered Zn2+ homeostasis was detected. In turbidity and flow based assays, platelet-dependent fibrin formation was impaired in both Nbeal2−/− and Unc13d−/− mice, and the impairment could be partially restored by extracellular Zn2+. Altogether, we conclude that the release of ionic Zn2+ store from secretory granules upon platelet activation contributes to the procoagulant role of Zn2+ in platelet-dependent fibrin formation. KW - coagulation system KW - metals Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227455 VL - 9 ER - TY - CHAP A1 - Gorenstein, Dan T1 - Ants and Battlefields, Beetles and Landscapes: Rudiments for a Naturalistic Reading of Ernst Jünger’s Interwar Essays through the Lens of His Later Entomological Hermeneutics T2 - Texts, Animals, Environments: Zoopoetics and Ecopoetics N2 - No abstract available. KW - Animal Studies KW - Cultural Animal Studies KW - Cultural Studies KW - Ecocriticism KW - Environmental Humanities KW - Human-Animal Studies KW - Literary Studies Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-178043 UR - https://www.rombach-verlag.de/buecher/suchergebnis/rombach/buch/details/texts-animals-environments.html PB - Rombach Druck- und Verlagshaus CY - Freiburg i. Br. ER - TY - THES A1 - Gorelashvili, Maximilian Georg T1 - Investigation of megakaryopoiesis and the acute phase of ischemic stroke by advanced fluorescence microscopy T1 - Untersuchungen der Megakaryopoese und der akuten Phase des ischämischen Schlaganfalls mit Hilfe von hochentwickelter Fluoreszenzmikroskopie N2 - In mammals, anucleate platelets circulate in the blood flow and are primarily responsible for maintaining functional hemostasis. Platelets are generated in the bone marrow (BM) by megakaryocytes (MKs), which mainly reside directly next to the BM sinusoids to release proplatelets into the blood. MKs originate from hematopoietic stem cells and are thought to migrate from the endosteal to the vascular niche during their maturation, a process, which is, despite being intensively investigated, still not fully understood. Long-term intravital two photon microscopy (2PM) of MKs and vasculature in murine bone marrow was performed and mean squared displacement analysis of cell migration was performed. The MKs exhibited no migration, but wobbling-like movement on time scales of 3 h. Directed cell migration always results in non-random spatial distribution. Thus, a computational modelling algorithm simulating random MK distribution using real 3D light-sheet fluorescence microscopy data sets was developed. Direct comparison of real and simulated random MK distributions showed, that MKs exhibit a strong bias to vessel-contact. However, this bias is not caused by cell migration, as non-vessel-associated MKs were randomly distributed in the intervascular space. Furthermore, simulation studies revealed that MKs strongly impair migration of other cells in the bone marrow by acting as large-sized obstacles. MKs are thought to migrate from the regions close to the endosteum towards the vasculature during their maturation process. MK distribution as a function of their localization relative to the endosteal regions of the bones was investigated by light sheet fluorescence microscopy (LSFM). The results show no bone-region dependent distribution of MKs. Taken together, the newly established methods and obtained results refute the model of MK migration during their maturation. Ischemia reperfusion (I/R) injury is a frequent complication of cerebral ischemic stroke, where brain tissue damage occurs despite successful recanalization. Platelets, endothelial cells and immune cells have been demonstrated to affect the progression of I/R injury in experimental mouse models 24 h after recanalization. However, the underlying Pathomechanisms, especially in the first hours after recanalization, are poorly understood. Here, LSFM, 2PM and complemental advanced image analysis workflows were established for investigation of platelets, the vasculature and neutrophils in ischemic brains. Quantitative analysis of thrombus formation in the ipsilateral and contralateral hemispheres at different time points revealed that platelet aggregate formation is minimal during the first 8 h after recanalization and occurs in both hemispheres. Considering that maximal tissue damage already is present at this time point, it can be concluded that infarct progression and neurological damage do not result from platelet aggregated formation. Furthermore, LSFM allowed to confirm neutrophil infiltration into the infarcted hemisphere and, here, the levels of endothelial cell marker PECAM1 were strongly reduced. However, further investigations must be carried out to clearly identify the role of neutrophils and the endothelial cells in I/R injury. N2 - In Säugetieren zirkulieren kernlose Thrombozyten im Blutstrom und sind primär für die Aufrechterhaltung der funktionellen Hämostase verantwortlich. Thrombozyten werden im Knochenmark durch Megakaryozyten gebildet, die sich hauptsächlich in direkter Nähe zu Knochenmarkssinusoiden befinden, um Proplättchen in das Blut freizusetzen. Megakaryo-zyten stammen von hämatopoetischen Stammzellen ab und man glaubt, dass sie während ihres Reifungspro¬zesses von der endostalen in die vaskuläre Nische wandern – ein Prozess, der trotz intensiver Forschung noch nicht vollständig verstanden ist. Langzeit-Zwei-Photonen-Mikroskopie von Megakaryozyten und des Gefäßbaums wurde in murinem Knochenmark von lebenden Tieren in Kombination mit der Analyse der mittleren quadratischen Verschiebung der Zellmigration durchgeführt. Die Megakaryozyten zeigten keine Migration, sondern eine wackelartige Bewegung auf Zeitskalen von 3 Stunden. Die gerichtete Zellmigration führt stets zu einer nicht zufälligen räumlichen Verteilung der Zellen. Daher wurde ein Computermodellierungsalgorithmus entwickelt, der eine zufällige Megakaryo¬zytenverteilung unter Verwendung von realen 3D-Lichtblatt-Fluoreszenzmikroskopie-Datensätzen simuliert. Der direkte Vergleich realer und simuliert zufälliger Megakaryozyten¬verteilungen zeigte, dass MKs stark mit Knochenmarksgefäßen assoziiert sind. Dieses wird jedoch nicht durch Zellmigration verursacht, da nicht-Gefäß-assoziierte MKs zufällig im intervaskulären Raum verteilt waren. Darüber hinaus zeigten Simulationsstudien, dass Megakaryozyten die Migration anderer Zellen im Knochenmark stark beeinträchtigen, da sie als sterische Hindernisse wirken. Es wird angenommen, dass MKs während ihres Reife¬prozesses von den Regionen in der Nähe des Endosteums in Richtung des Gefäßsystems wandern. Die Megakaryozytenverteilung als Funktion ihrer Lokalisierung relativ zu den endo¬stalen Regionen des Knochens wurde durch Lichtblattmikroskopie untersucht. Die Ergebnisse zeigen keine knochenregionabhängige Verteilung von Megakaryozyten. Zusammenge¬nommen widerlegen die neu etablierten Methoden und erzielten Ergebnisse das Modell der Megakaryozyten¬migration während ihrer Reifung. Ischämie-Reperfusionsschaden (I/R) ist eine häufige Komplikation des zerebralen ischämischen Schlaganfalls, bei dem trotz erfolgreicher Rekanalisierung eine Schädigung des Hirngewebes auftritt. Es wurde gezeigt, dass Thrombozyten, Endothelzellen und Immunzellen das Fortschreiten der I/R-Verletzung in experimentellen Mausmodellen 24 Stunden nach der Rekanalisierung beeinflussen. Die zugrundeliegenden Pathomechanismen, insbesondere in den ersten Stunden nach der Rekanalisierung, sind jedoch kaum verstanden. Hier wurden Lichtblattmikroskopie, Zwei-Photonen-Mikroskopie und ergänzende hochkom-plexe Bildanalyse-Workflows zur Untersuchung von Thrombozyten, der Gefäße und Neutro-philen in ischämischen Gehirnen etabliert. Die quantitative Analyse der Thrombusbildung in der ipsilateralen und kontralateralen Hemisphäre zu verschiedenen Zeitpunkten zeigte, dass die Thrombozytenaggregationsbildung während der ersten 8 Stunden nach der Rekanalisierung minimal ist und in beiden Hemisphären auftritt. In Anbetracht dessen, dass zu diesem Zeitpunkt bereits eine maximale Gewebeschädigung vorliegt, kann geschlossen werden, dass die Infarkt¬progression und der neurologische Schaden nicht aus der Bildung von Thrombozytenaggre¬gaten resultieren. Darüber hinaus erlaubte Lichtblattmikroskopie die Neutrophileninfiltration in die infarzierte Hemisphäre zu bestätigen und hier waren die Spiegel des Endothelzellmarkers PECAM1 stark reduziert. Es müssen jedoch weitere Untersuchungen durchgeführt werden, um die Rolle von Neutrophilen und Endothelzellen bei I/R-Verletzungen klar zu identifizieren. KW - Fluoreszenzmikroskopie KW - Schlaganfall KW - Megakaryozyt KW - Computersimulation KW - Light sheet microscopy KW - ischemic stroke KW - megakaryopoiesis KW - multi-photon microscopy Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186002 ER - TY - JOUR A1 - Goos, Carina A1 - Dejung, Mario A1 - Wehman, Ann M. A1 - M-Natus, Elisabeth A1 - Schmidt, Johannes A1 - Sunter, Jack A1 - Engstler, Markus A1 - Butter, Falk A1 - Kramer, Susanne T1 - Trypanosomes can initiate nuclear export co-transcriptionally JF - Nucleic Acids Research N2 - The nuclear envelope serves as important messenger RNA (mRNA) surveillance system. In yeast and human, several control systems act in parallel to prevent nuclear export of unprocessed mRNAs. Trypanosomes lack homologues to most of the involved proteins and their nuclear mRNA metabolism is non-conventional exemplified by polycistronic transcription and mRNA processing by trans-splicing. We here visualized nuclear export in trypanosomes by intra- and intermolecular multi-colour single molecule FISH. We found that, in striking contrast to other eukaryotes, the initiation of nuclear export requires neither the completion of transcription nor splicing. Nevertheless, we show that unspliced mRNAs are mostly prevented from reaching the nucleus-distant cytoplasm and instead accumulate at the nuclear periphery in cytoplasmic nuclear periphery granules (NPGs). Further characterization of NPGs by electron microscopy and proteomics revealed that the granules are located at the cytoplasmic site of the nuclear pores and contain most cytoplasmic RNA-binding proteins but none of the major translation initiation factors, consistent with a function in preventing faulty mRNAs from reaching translation. Our data indicate that trypanosomes regulate the completion of nuclear export, rather than the initiation. Nuclear export control remains poorly understood, in any organism, and the described way of control may not be restricted to trypanosomes. KW - molecular biology KW - nuclear export KW - trypanosomes KW - mRNA KW - nuclear envelope Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-177709 VL - 47 IS - 1 ER - TY - CHAP A1 - Goodbody, Axel T1 - Wolves and Wolf Men as Literary Tropes and Figures of Thought: Eco- and Zoopoetic Perspectives on Jiang Rong’s Wolf Totem and Other Wolf Narratives T2 - Texts, Animals, Environments: Zoopoetics and Ecopoetics N2 - No abstract available. KW - Animal Studies KW - Cultural Animal Studies KW - Cultural Studies KW - Ecocriticism KW - Environmental Humanities KW - Human-Animal Studies KW - Literary Studies Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-178122 UR - https://www.rombach-verlag.de/buecher/suchergebnis/rombach/buch/details/texts-animals-environments.html PB - Rombach Druck- und Verlagshaus CY - Freiburg i. Br. ER - TY - JOUR A1 - González, María Magdalena A1 - Dorner, Daniela A1 - Bretz, Thomas A1 - García-González, José Andrés T1 - Unbiased long-term monitoring at TeV energies JF - Galaxies N2 - For the understanding of the variable, transient and non-thermal universe, unbiased long-term monitoring is crucial. To constrain the emission mechanisms at the highest energies, it is important to characterize the very high energy emission and its correlation with observations at other wavelengths. At very high energies, only a limited number of instruments is available. This article reviews the current status of monitoring of the extra-galactic sky at TeV energies. KW - monitoring KW - very high energies (VHE) KW - TeV energies Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-197389 SN - 2075-4434 VL - 7 IS - 2 ER - TY - JOUR A1 - Gonzalez‐Escamilla, Gabriel A1 - Muthuraman, Muthuraman A1 - Reich, Martin M. A1 - Koirala, Nabin A1 - Riedel, Christian A1 - Glaser, Martin A1 - Lange, Florian A1 - Deuschl, Günther A1 - Volkmann, Jens A1 - Groppa, Sergiu T1 - Cortical network fingerprints predict deep brain stimulation outcome in dystonia JF - Movement Disorders N2 - Background Deep brain stimulation (DBS) is an effective evidence‐based therapy for dystonia. However, no unequivocal predictors of therapy responses exist. We investigated whether patients optimally responding to DBS present distinct brain network organization and structural patterns. Methods From a German multicenter cohort of 82 dystonia patients with segmental and generalized dystonia who received DBS implantation in the globus pallidus internus, we classified patients based on the clinical response 3 years after DBS. Patients were assigned to the superior‐outcome group or moderate‐outcome group, depending on whether they had above or below 70% motor improvement, respectively. Fifty‐one patients met MRI‐quality and treatment response requirements (mean age, 51.3 ± 13.2 years; 25 female) and were included in further analysis. From preoperative MRI we assessed cortical thickness and structural covariance, which were then fed into network analysis using graph theory. We designed a support vector machine to classify subjects for the clinical response based on individual gray‐matter fingerprints. Results The moderate‐outcome group showed cortical atrophy mainly in the sensorimotor and visuomotor areas and disturbed network topology in these regions. The structural integrity of the cortical mantle explained about 45% of the DBS stimulation amplitude for optimal response in individual subjects. Classification analyses achieved up to 88% of accuracy using individual gray‐matter atrophy patterns to predict DBS outcomes. Conclusions The analysis of cortical integrity, informed by group‐level network properties, could be developed into independent predictors to identify dystonia patients who benefit from DBS. KW - brain networks KW - clinical outcome KW - deep brain stimulation KW - dystonia Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-213532 VL - 34 IS - 10 SP - 1536 EP - 1545 ER - TY - THES A1 - Gomes, Sara Ferreira Martins T1 - Induced Pluripotent Stem Cell-derived Brain Endothelial Cells as a Cellular Model to Study Neisseria meningitidis Infection T1 - Induziert pluripotente Stammzellen-basierte Hirnendothelzellen als zelluläres Modell zur Untersuchung der Infektion mit Neisseria meningitidis N2 - Bacterial meningitis occurs when blood-borne bacteria are able to penetrate highly specialized brain endothelial cells (BECs) and gain access to the meninges. Neisseria meningitidis (Nm) is a human-exclusive pathogen for which suitable in vitro models are severely lacking. Until recently, modeling BEC-Nm interactions has been almost exclusively limited to immortalized human cells that lack proper BEC phenotypes. Specifically, these in vitro models lack barrier properties, and continuous tight junctions. Alternatively, humanized mice have been used, but these must rely on known interactions and have limited translatability. This motivates the need to establish novel human-based in vitro BEC models that have barrier phenotypes to research Nm-BEC interactions. Recently, a human induced pluripotent stem cell (iPSC) model of BECs has been developed that possesses superior BEC phenotypes and closely mimics the in vivo blood vessels present at the blood-meningeal barrier. Here, iPSC-BECs were tested as a novel cellular model to study Nm-host pathogen interactions, with focus on host responses to Nm infection. Two wild type strains and three mutant strains of Nm were used to confirm that these followed similar phenotypes to previously described models. Importantly, the recruitment of the recently published pilus adhesin receptor CD147 underneath meningococcal microcolonies could be verified in iPSC-BECs. Nm was also observed to significantly increase the expression of pro-inflammatory and neutrophil-specific chemokines IL6, CXCL1, CXCL2, CXCL8, and CCL20, at distinct time points of infection, and the secretion of IFN γ and RANTES by iPSC-BECs. Nm was directly observed to disrupt tight junction proteins ZO-1, Occludin, and Claudin-5 at late time points of infection, which became frayed and/or discontinuous upon infection. This destruction is preceded by, and might be dependent on, SNAI1 activation (a transcriptional repressor of tight junction proteins). In accordance with tight junction loss, a sharp loss in trans-endothelial electrical resistance, and an increase in sodium fluorescein permeability was observed at late infection time points. Notably, bacterial transmigration correlated with junctional disruption, indicating that the paracellular route contributes for bacterial crossing of BECs. Finally, RNA-Sequencing (RNA-Seq) of sorted, infected iPSC-BECs was established through the use of fluorescence-activated cell sorting (FACS) techniques following infection. This allowed the detection of expression data of Nm-responsive host genes not previously described thus far to play a role during meningitidis. In conclusion, here the utility of iPSC-BECs in vitro to study Nm infection could be demonstrated. This is the first BEC in vitro model to express all major BEC tight junctions and to display high barrier potential. Altogether, here this model provides novel insights into Nm pathogenesis, including an impact of Nm on barrier properties and tight junction complexes and suggests that the paracellular route contributes to Nm traversal of BECs. N2 - Eine bakterielle Meningitis tritt auf, wenn durch Blut übertragene Bakterien hochspezialisierte Hirnendothelzellen (BEC) durchdringen und Zugang zu den Meningen erhalten. Neisseria meningitidis (Nm) ist ein human-exklusiver Erreger, für dessen Untersuchung es an geeigneten In-vitro-Modellen mangelt. Bis vor kurzem war die Modellierung von BEC-Nm-Wechselwirkungen fast ausschließlich auf immortalisierte humane Zellen beschränkt, denen wichtige BEC-Phänotypen fehlen. Besonders hervorzuheben sind das Fehlen physiologischer Barriereeigenschaften durch unkontinuierliche dichte Zell-Zell-Verbindungen. Als alternative Modellorganismen können humanisierte Mäuse verwendet werden, die sich jedoch auf bekannte Wirt-Erreger-Wechselwirkungen stützen und durch Speziesunterschiede eine eingeschränkte Übersetzbarkeit aufweisen. Dies begründet die Notwendigkeit, neuartige humane In-vitro-BEC-Modelle zu etablieren, die physiologische Barrierephänotypen aufweisen, um Nm-BEC-Wechselwirkungen zu untersuchen. Kürzlich wurde ein humanes Modell entwickelt, welches auf aus induziert pluripotenten Stammzellen (iPSCs) abgeleiteten humanen BECs basiert und sich durch einen physiologischen Blut-Hirn-Schranken-Phänotyp auszeichnet. Die iPSC-BECs wurden in dieser Arbeit als neuartiges zelluläres Modell getestet, um Nm-Wirt-Pathogen-Wechselwirkungen zu untersuchen, wobei der Schwerpunkt auf Wirtsreaktionen auf Nm-Infektionen lag. Zwei Wildtypstämme und drei Mutantenstämme von Nm wurden verwendet, um zu bestätigen, dass diese ähnlichen Phänotypen wie in zuvor beschriebenen Modellen folgten. Hervorzuheben ist, dass die Rekrutierung des kürzlich veröffentlichten Pilus-Adhäsin-Rezeptors CD147 unter Meningokokken-Mikrokolonien in iPSC-BECs verifiziert werden konnte. Es wurde auch beobachtet, dass Nm die Expression der entzündungsfördernden und neutrophilen spezifischen Chemokine IL6, CXCL1, CXCL2, CXCL8 und CCL20 zu bestimmten Zeitpunkten der Infektion sowie die Sekretion von IFN-γ und RANTES durch iPSC-BECs signifikant erhöht. Es wurde zudem beobachtet, dass Nm die Tight Junction-Proteine ZO-1, Occludin und Claudin-5 zu späten Zeitpunkten der Infektion zerstört, verursacht durch die Infektion wurde ein ausgefranster und/oder diskontinuierlicher Tight Junction-Phänotyp beobachtet. Dieser Zerstörung geht die SNAI1-Aktivierung (ein Transkriptionsrepressor für Tight Junction-Proteine) voraus und könnte von ihr abhängig sein. In Übereinstimmung mit dem Verlust der Tight Junctions wurde zu späten Infektionszeitpunkten ein starker Verlust des transendothelialen elektrischen Widerstands und eine Zunahme der Natriumfluoreszein-Permeabilität beobachtet. Bemerkenswerterweise korrelierte die bakterielle Transmigration mit dem Verlust der Tight Junctions, was darauf hinweist, dass der parazelluläre Weg zur bakteriellen Überwindung von BECs eine entscheidende Rolle spielt. Schließlich wurde die RNA-Sequencing (RNA-Seq) von sortierten, infizierten iPSC-BECs durch die Verwendung von fluoreszenzaktivierten Zellsortiertechniken (FACS) nach der Infektion durchgeführt. Dies ermöglichte erstmalig den Nachweis von Expressionsdaten von Nm-responsiven Wirtsgenen, welche bei der Meningitidis eine Rolle zu spielen scheinen. Zusammenfassend konnte im Rahmen der vorliegenden Arbeit der Nutzen von iPSC-BECs In-Vitro-Modellen zur Untersuchung von Nm-Infektionen gezeigt werden. Dies ist das erste BEC-In-vitro-Modell, das alle wichtigen BEC-Tight Junctions exprimiert und ein hohes Barrierepotential aufweist. Insgesamt liefert das eingesetzte Modell neue Einblicke in die Nm-Pathogenese, einschließlich der Beeinflussung der Barriereeigenschaften und der Tight Junction-Komplexe durch Nm, und gibt erste Hinweise darauf, dass die parazelluläre Route zum Nm-Übertritt von BEC-Barrieren eine entscheidende Rolle spielt. KW - Neisseria meningitidis KW - endothelial cells KW - blood brain barrier KW - blood cerebrospinal fluid barrier KW - cellular model KW - Neisseria meningitidis KW - endothelial cells Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188550 ER - TY - JOUR A1 - Gomes, Sara F. Martins A1 - Westermann, Alexander J. A1 - Sauerwein, Till A1 - Hertlein, Tobias A1 - Förstner, Konrad U. A1 - Ohlsen, Knut A1 - Metzger, Marco A1 - Shusta, Eric V. A1 - Kim, Brandon J. A1 - Appelt-Menzel, Antje A1 - Schubert-Unkmeir, Alexandra T1 - Induced pluripotent stem cell-derived brain endothelial cells as a cellular model to study Neisseria meningitidis infection JF - Frontiers in Microbiology N2 - Meningococcal meningitis is a severe central nervous system infection that occurs when Neisseria meningitidis (Nm) penetrates brain endothelial cells (BECs) of the meningeal blood-cerebrospinal fluid barrier. As a human-specific pathogen, in vivo models are greatly limited and pose a significant challenge. In vitro cell models have been developed, however, most lack critical BEC phenotypes limiting their usefulness. Human BECs generated from induced pluripotent stem cells (iPSCs) retain BEC properties and offer the prospect of modeling the human-specific Nm interaction with BECs. Here, we exploit iPSC-BECs as a novel cellular model to study Nm host-pathogen interactions, and provide an overview of host responses to Nm infection. Using iPSC-BECs, we first confirmed that multiple Nm strains and mutants follow similar phenotypes to previously described models. The recruitment of the recently published pilus adhesin receptor CD147 underneath meningococcal microcolonies could be verified in iPSC-BECs. Nm was also observed to significantly increase the expression of pro-inflammatory and neutrophil-specific chemokines IL6, CXCL1, CXCL2, CXCL8, and CCL20, and the secretion of IFN-γ and RANTES. For the first time, we directly observe that Nm disrupts the three tight junction proteins ZO-1, Occludin, and Claudin-5, which become frayed and/or discontinuous in BECs upon Nm challenge. In accordance with tight junction loss, a sharp loss in trans-endothelial electrical resistance, and an increase in sodium fluorescein permeability and in bacterial transmigration, was observed. Finally, we established RNA-Seq of sorted, infected iPSC-BECs, providing expression data of Nm-responsive host genes. Altogether, this model provides novel insights into Nm pathogenesis, including an impact of Nm on barrier properties and tight junction complexes, and suggests that the paracellular route may contribute to Nm traversal of BECs. KW - Neisseria meningitidis KW - meningococcus KW - bacteria KW - stem cells KW - blood-cerebrospinal fluid barrier KW - blood-brain barrier KW - brain endothelial cells Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201562 VL - 10 IS - 1181 ER - TY - JOUR A1 - Glutsch, Valerie A1 - Grän, Franziska A1 - Weber, Judith A1 - Gesierich, Anja A1 - Goebeler, Matthias A1 - Schilling, Bastian T1 - Response to combined ipilimumab and nivolumab after development of a nephrotic syndrome related to PD-1 monotherapy JF - Journal for ImmunoTherapy of Cancer N2 - Background High response rates of metastatic melanoma have been reported upon immune checkpoint inhibition by PD-1 blockade alone or in combination with CTLA-4 inhibitors. However, the majority of patients with a primary resistance to anti-PD-1 monotherapy is also refractory to a subsequent combined checkpoint inhibition. In BRAF wildtype patients with a primary resistance to PD-1 inhibitors, therapeutic options are therefore limited and immune-related adverse events (irAE) have to be taken into consideration when discussing a subsequent immunotherapy. Case presentation We report the case of a 68-year-old male patient with metastatic melanoma who experienced an acute renal failure with nephrotic syndrome due to a minimal change disease developing after a single dose of the anti-PD-1 antibody pembrolizumab. A kidney biopsy revealed a podocytopathy without signs of interstitial nephritis. Renal function recovered to almost normal creatinine and total urine protein levels upon treatment with oral steroids and diuretics. Unfortunately, a disease progression (PD, RECIST 1.1) was observed in a CT scan after resolution of the irAE. In a grand round, re-exposure to a PD-1-containing regime was recommended. Consensually, a combined immunotherapy with ipilimumab and nivolumab was initiated. Nephrotoxicity was tolerable during combined immunotherapy and a CT scan of chest and abdomen showed a deep partial remission (RECIST 1.1) after three doses of ipilimumab (3 mg/kg) and nivolumab (1 mg/kg). Conclusion This case illustrates that a fulminant response to combined checkpoint inhibition is possible after progression after anti-PD-1 monotherapy and a severe irAE. KW - PD-1 KW - Immune-related adverse event KW - Minimal change disease KW - Ipilimumab KW - Nivolumab Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201214 VL - 7 ER - TY - JOUR A1 - Glaser, Kirsten A1 - Gradzka-Luczewska, Anna A1 - Szymankiewicz-Breborowicz, Marta A1 - Kawczynska-Leda, Natalia A1 - Henrich, Birgit A1 - Waaga-Gasser, Ana Maria A1 - Speer, Christian P. T1 - Perinatal ureaplasma exposure is associated with increased risk of late onset sepsis and imbalanced inflammation in preterm infants and may add to lung injury JF - Frontiers in Cellular and Infection Microbiology N2 - Background: Controversy remains concerning the impact of Ureaplasma on preterm neonatal morbidity. Methods: Prospective single-center study in very low birth weight infants <30 weeks' gestation. Cord blood and initial nasopharyngeal swabs were screened for Ureaplasma parvum and U. urealyticum using culture technique and polymerase chain reaction. Neonatal outcomes were followed until death or discharge. Multi-analyte immunoassay provided cord blood levels of inflammatory markers. Using multivariate regression analyses, perinatal Ureaplasma exposure was evaluated as risk factor for the development of bronchopulmonary dysplasia (BPD), other neonatal morbidities until discharge and systemic inflammation at admission. Results: 40/103 (39%) infants were positive for Ureaplasma in one or both specimens, with U. parvum being the predominant species. While exposure to Ureaplasma alone was not associated with BPD, we found an increased risk of BPD in Ureaplasma-positive infants ventilated ≥5 days (OR 1.64; 95% CI 0.12–22.98; p = 0.009). Presence of Ureaplasma was associated with a 7-fold risk of late onset sepsis (LOS) (95% CI 1.80–27.39; p = 0.014). Moreover, Ureaplasma-positive infants had higher I/T ratios (b 0.39; 95% CI 0.08–0.71; p = 0.014), increased levels of interleukin (IL)-17 (b 0.16; 95% CI 0.02–0.30; p = 0.025) and matrix metalloproteinase 8 (b 0.77; 95% CI 0.10–1.44; p = 0.020), decreased levels of IL-10 (b −0.77; 95% CI −1.58 to −0.01; p = 0.043) and increased ratios of Tumor necrosis factor-α, IL-8, and IL-17 to anti-inflammatory IL-10 (p = 0.003, p = 0.012, p < 0.001). Conclusions: Positive Ureaplasma screening was not associated with BPD. However, exposure contributed to BPD in infants ventilated ≥5 days and conferred an increased risk of LOS and imbalanced inflammatory cytokine responses. KW - Ureaplasma parvum KW - Ureaplasma urealyticum KW - preterm infants KW - VLBW KW - bronchopulmonary dysplasia KW - late onset sepsis KW - neonatal outcome KW - inflammation Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201270 VL - 9 IS - 68 ER - TY - JOUR A1 - Giampaolo, Sabrina A1 - Wójcik, Gabriela A1 - Klein-Hessling, Stefan A1 - Serfling, Edgar A1 - Patra, Amiya K. T1 - B cell development is critically dependent on NFATc1 activity JF - Cellular & Molecular Immunology N2 - B cell development in bone marrow is a precisely regulated complex process. Through successive stages of differentiation, which are regulated by a multitude of signaling pathways and an array of lineage-specific transcription factors, the common lymphoid progenitors ultimately give rise to mature B cells. Similar to early thymocyte development in the thymus, early B cell development in bone marrow is critically dependent on IL-7 signaling. During this IL-7-dependent stage of differentiation, several transcription factors, such as E2A, EBF1, and Pax5, among others, play indispensable roles in B lineage specification and maintenance. Although recent studies have implicated several other transcription factors in B cell development, the role of NFATc1 in early B cell developmental stages is not known. Here, using multiple gene-manipulated mouse models and applying various experimental methods, we show that NFATc1 activity is vital for early B cell differentiation. Lack of NFATc1 activity in pro-B cells suppresses EBF1 expression, impairs immunoglobulin gene rearrangement, and thereby preBCR formation, resulting in defective B cell development. Overall, deficiency in NFATc1 activity arrested the pro-B cell transition to the pre-B cell stage, leading to severe B cell lymphopenia. Our findings suggest that, along with other transcription factors, NFATc1 is a critical component of the signaling mechanism that facilitates early B cell differentiation. KW - differentiation KW - EBF1 KW - NFATc1 KW - pro-B KW - pre-B Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233006 VL - 16 ER - TY - JOUR A1 - Gernert, Michael A1 - Tony, Hans-Peter A1 - Schwaneck, Eva Christina A1 - Gadeholt, Ottar A1 - Schmalzing, Marc T1 - Autologous hematopoietic stem cell transplantation in systemic sclerosis induces long-lasting changes in B cell homeostasis toward an anti-inflammatory B cell cytokine pattern JF - Arthritis Research & Therapy N2 - Background Autologous hematopoietic stem cell transplantation (aHSCT) is performed in patients with aggressive forms of systemic sclerosis (SSc). The profile of B cell reconstitution after aHSCT is not fully understood. The aim of this study was to investigate changes of B cell subsets and cytokine production of B cells in patients with SSc after aHSCT. Methods Peripheral blood of six patients with SSc was collected at defined intervals up to 16 months after aHSCT. Immunophenotyping was performed, and B cell function was determined by measuring cytokine secretion in supernatants of stimulated B cell cultures. Results Within 1 month after aHSCT, a peak in the percentage of CD38\(^{++}\)/CD10\(^+\)/IgD\(^+\) transitional B cells and CD38\(^{++}\)/CD27\(^{++}\)/IgD\(^−\) plasmablasts was detected. Long-term changes persisted up to 14 months after aHSCT and showed an increased percentage of total B cells; the absolute B cell number did not change significantly. Within the B cell compartment, an increased CD27/IgD\(^+\) naïve B cell percentage was found whereas decreased percentages of CD27\(^+\)/IgD\(^+\) pre-switched memory, CD27\(^+\)/IgD\(^−\) post-switched memory, and CD27\(^−\) /IgD\(^−\) double-negative B cells were seen after aHSCT. Cytokine secretion in B cell cultures showed significantly increased IL-10 concentrations 13 to 16 months after aHSCT. Conclusion A changed composition of the B cell compartment is present for up to 14 months after aHSCT indicating positive persisting effects of aHSCT on B cell homeostasis. The cytokine secretion profile of B cells changes in the long term and shows an increased production of the immune regulatory cytokine IL-10 after aHSCT. These findings might promote the clinical improvements after aHSCT in SSc patients. KW - Systemic sclerosis KW - B cells KW - Memory B cells KW - naïve B cells KW - Autologous hematopoietic stem cell transplantation KW - Interleukin-10 Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201004 VL - 21 ER - TY - THES A1 - Gerner, Frank T1 - Functional analysis of polarization and podosome formation of murine and human megakaryocytes T1 - Funktionale Untersuchungen der Polarisation und Podosomenbildung muriner und humaner Megakaryozyten N2 - In mammals, blood platelets are produced by large bone marrow (BM) precursor cells, megakaryocytes (MK) that extend polarized cell protrusions (proplateles) into BM sinusoids. Proplatelet formation (PPF) requires substantial cytoskeletal rearrangements that have been shown to involve the formation of podosomes, filamentous actin (F-actin) and integrin-rich structures. However, the exact molecular mechanisms regulating MK podosome formation, polarization and migration within the BM are poorly defined. According to current knowledge obtained from studies with other cell types, these processes are regulated by Rho GTPase proteins like RhoA and Cdc42. In this thesis, polarization and podosome formation were investigated in MKs from genetically modified mice, as well as the cell lines K562 and Meg01 by pharmacological modulation of signaling pathways. The first part of this thesis describes establishment of the basic assays for investigation of MK polarization. Initial data on polarization of the MK-like erythroleukemia cell line K562 revealed first insights into actin and tubulin dynamics of wild type (WT) and RhoA knock-out (RhoA-/-) K562 cells. Phorbol 12-myristate 13-acetate (PMA)-induction of K562 cells led to the expected MK-receptor upregulation but also RhoA depletion and altered polarization patterns. The second part of this thesis focuses on podosome formation of MKs. RhoA is shown to be dispensable for podosome formation. Cdc42 is revealed as an important, but not essential regulator of MK spreading and podosome formation. Studies of signaling pathways of podosome formation reveal the importance of the tyrosine kinases Src, Syk, as well as glycoprotein (GP)VI in MK spreading and podosome formation. This thesis provides novel insights into the mechanisms underlying polarization and podosome formation of MKs and reveals new, important information about cytoskeletal dynamics of MKs and potentially also platelets. N2 - Bei Säugetieren entstehen Blutplättchen aus großen Knochenmark-vorläuferzellen, Megakaryozyten, die lange, polarisierte Zellprotrusionen (Proplättchen) in Knochenmarkssinusoide ausstülpen. Die Bildung von Proplättchen erfordert eine umfangreiche Reorganisation des Zytoskeletts, die die Bildung von Podosomen, F-Aktin- und Integrinreichen Strukturen beinhaltet. Die genauen molekularen Mechanismen, die megakaryozytäre Podosomenbildung, Polarisation und Migration im Knochenmark regulieren, sind jedoch bisher unzureichend erforscht. Rho GTPasen wie beispielsweise RhoA und Cdc42 sind nachgewiesenermaßen beteiligt an der klassischen Zytoskelettregulierung. In dieser Dissertation wurden die obengenannten Reifungsprozesse mithilfe von Megakaryozyten von genetisch modifizierten Mäusen sowie den Zelllinien K562 und Meg01 durch pharmakologische Beeinflussung zellulärer Signaltransmitter erforscht. Im ersten Teil der Dissertation wurden Experimente zur Untersuchung megakaryozytärer Polarisation etabliert. Initiale Daten über die Polarisation der megakaryozytären, erythroleukämischen Zelllinie K562 erlaubten Einblicke in Aktin- und Tubulindynamik von Wildtyp- und RhoA-defizienten K562 Zellen. Phorbol-12-myristat-13-acetat (PMA)-induzierte K562-Differenzierung verursachte die erwartete Hochregulierung megakaryozytärer Rezeptoren, aber auch eine unerwartete RhoA-Depletion und bisher unbeobachtete Polarisationsmuster. Der zweite Teil dieser Dissertation galt der Untersuchung der Podosomenbildung von Megakaryozyten. RhoA zeigte sich als entbehrlich für die Podosomenbildung, während Cdc42 sich als wichtiger, dennoch nicht essentieller Regulator der podosomenbildenden Zytoskelettdynamik erwies. Untersuchungen von Signalwegen in der Podosomenbildung von Megakaryozyten offenbarten die Bedeutung von Tyrosinkinasen Src, Syk sowie Glykoprotein VI bei der MK-Adhäsion und der Bildung von Podosomen. Somit liefert diese Dissertation neue Einblicke in die Signalwege der dynamischen Regulation des Zytoskeletts in Megakaryozyten. KW - Megakaryozyt KW - megakaryocyte KW - polarization KW - RhoA KW - CDC42 KW - podosome formation Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-160508 ER - TY - JOUR A1 - Geran, Rohat A1 - Uecker, Florian C. A1 - Prüss, Harald A1 - Haeusler, Karl Georg A1 - Paul, Friedemann A1 - Ruprecht, Klemens A1 - Harms, Lutz A1 - Schmidt, Felix A. T1 - Olfactory and Gustatory Dysfunction in Patients With Autoimmune Encephalitis JF - Frontiers in Neurology N2 - Objective: To test the hypothesis that olfactory (OF) and gustatory function (GF) is disturbed in patients with autoimmune encephalitides (AE). Methods: The orthonasal OF was tested in 32 patients with AE and 32 age- and sex-matched healthy controls (HC) with the standardized Threshold Discrimination Identification (TDI) score. This validated olfactory testing method yields individual scores for olfactory threshold (T), odor discrimination (D), and identification (I), along with a composite TDI score. The GF was determined by the Taste Strip Test (TST). Results: Overall, 24/32 (75%) of patients with AE, but none of 32 HC (p < 0.001) had olfactory dysfunction in TDI testing. The results of the threshold, discrimination and identification subtests were significantly reduced in patients with AE compared to HC (all p < 0.001). Assessed by TST, 5/19 (26.3%) of patients with AE, but none of 19 HC presented a significant limitation in GF (p < 0.001). The TDI score was correlated with the subjective estimation of the olfactory capacity on a visual analog scale (VAS; rs = 0.475, p = 0.008). Neither age, sex, modified Rankin Scale nor disease duration were associated with the composite TDI score. Conclusions: This is the first study investigating OF and GF in AE patients. According to unblinded assessment, patients with AE have a reduced olfactory and gustatory capacity compared to HC, suggesting that olfactory and gustatory dysfunction are hitherto unrecognized symptoms in AE. Further studies with larger number of AE patients would be of interest to verify our results. KW - autoimmune encephalitis KW - olfactory dysfunction KW - gustatory dysfunction KW - olfactory testing KW - threshold discrimination identification test Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232921 VL - 10 ER - TY - JOUR A1 - Gehrke, Thomas A1 - Scherzad, Agmal A1 - Hagen, Rudolf A1 - Hackenberg, Stephan T1 - Risk factors for children requiring adenotonsillectomy and their impact on postoperative complications: a retrospective analysis of 2000 patients JF - Anaesthesia N2 - Adenotonsillectomies are commonly performed procedures and sleep‐disordered breathing is becoming increasingly important as an indication for surgery. Because of the higher risks in patients with obstructive sleep apnoea, the required level of postoperative care for these patients is currently under discussion, and better identification of patients at risk may reduce unnecessary postoperative monitoring. To evaluate the influence of obstructive sleep apnoea, and other risk factors, on peri‐operative complications in children requiring adenotonsillectomy, we performed a retrospective case‐control study that included 1995 patients treated between January 2009 and June 2017. In our analysis, young age (OR 3.8, 95%CI 2.1–7.1), low body weight (OR 2.6, 95%CI 1.5–4.4), obstructive sleep apnoea (OR 2.4, 95%CI 1.5–3.8), pre‐existing craniofacial or syndromal disorders (OR 2.3, 95%CI 1.4–3.8) and adenotonsillectomy, compared with adenoidectomy alone, (OR 7.9, 95%CI 4.7–13.1) were identified as risk factors for complications during or after surgery, p < 0.001. All 13 patients suffering from complications more than 3 h postoperatively had obstructive sleep apnoea plus at least one more of these risk factors. Patients at risk of postoperative complications can therefore be identified by several criteria pre‐operatively, and should be monitored postoperatively using pulse oximetry overnight. For all other patients, postoperative observation on a surgical ward without extra monitoring is sufficient. Admission to paediatric intensive care should be reserved for patients suffering serious intra‐operative complications. KW - adenotonsillectromy KW - monotoring KW - obstructive sleep apnoea KW - paediatrics KW - retrospective KW - risk factors Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-204787 VL - 74 IS - 12 ER - TY - JOUR A1 - Gebert, Friederike A1 - Steffan-Dewenter, Ingolf A1 - Moretto, Philippe A1 - Peters, Marcell K. T1 - Climate rather than dung resources predict dung beetle abundance and diversity along elevational and land use gradients on Mt. Kilimanjaro JF - Journal of Biogeography N2 - Aim: While elevational gradients in species richness constitute some of the best depicted patterns in ecology, there is a large uncertainty concerning the role of food resource availability for the establishment of diversity gradients in insects. Here, we analysed the importance of climate, area, land use and food resources for determining diversity gradients of dung beetles along extensive elevation and land use gradients on Mt. Kilimanjaro, Tanzania. Location: Mt. Kilimanjaro, Tanzania. Taxon: Scarabaeidae (Coleoptera). Methods: Dung beetles were recorded with baited pitfall traps at 66 study plots along a 3.6 km elevational gradient. In order to quantify food resources for the dung beetle community in form of mammal defecation rates, we assessed mammalian diversity and biomass with camera traps. Using a multi‐model inference framework and path analysis, we tested the direct and indirect links between climate, area, land use and mammal defecation rates on the species richness and abundance of dung beetles. Results: We found that the species richness of dung beetles declined exponentially with increasing elevation. Human land use diminished the species richness of functional groups exhibiting complex behaviour but did not have a significant influence on total species richness. Path analysis suggested that climate, in particular temperature and to a lesser degree precipitation, were the most important predictors of dung beetle species richness while mammal defecation rate was not supported as a predictor variable. Main conclusions: Along broad climatic gradients, dung beetle diversity is mainly limited by climatic factors rather than by food resources. Our study points to a predominant role of temperature‐driven processes for the maintenance and origination of species diversity of ectothermic organisms, which will consequently be subject to ongoing climatic changes. KW - altitudinal gradients KW - diversity gradients KW - enercy-richness hypothesis KW - food resources KW - insect abundance KW - land use KW - Scarabaeidae KW - temperature‐richness hypothesis KW - temperature‐mediated resource exploitation hypothesis KW - species‐area hypothesis Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-204701 VL - 47 IS - 2 SP - 371 EP - 381 ER - TY - JOUR A1 - Gablonski, Thorsten-Christian A1 - Pryss, Rüdiger A1 - Probst, Thomas A1 - Vogel, Carsten A1 - Andreas, Sylke T1 - Intersession-Online: A smartphone application for systematic recording and controlling of intersession experiences in psychotherapy JF - J — Multidisciplinary Scientific Journal N2 - Mobile health technologies have become more and more important in psychotherapy research and practice. The market is being flooded by several psychotherapeutic online services for different purposes. However, mobile health technologies are particularly suitable for data collection and monitoring, as data can be recorded economically in real time. Currently, there is no appropriate method to assess intersession experiences systematically in psychotherapeutic practice. The aim of our project was the development of a smartphone application framework for systematic recording and controlling of intersession experiences. Intersession-Online, an iOS- and Android-App, offers the possibility to collect data on intersession experiences easily, to provide the results to therapists in an evaluated form and, if necessary, to induce or interrupt intersession experiences with the primary aim to improve outcome of psychotherapy. In general, the smartphone application could be a helpful, evidence-based tool for research and practice. Overall speaking, further research to investigate the efficacy of Intersession-Online is necessary. KW - intersession experiences KW - intersession processes KW - psychotherapy KW - mobile app KW - smartphone app Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285597 SN - 2571-8800 VL - 2 IS - 4 SP - 480 EP - 495 ER - TY - THES A1 - Gabel, Judith T1 - Interface Engineering of Functional Oxides: A Photoemission Study T1 - Kontrollierte Manipulation der Grenzflächen in funktionellen oxidischen Heterostrukturen: Eine Photoemissionsstudie N2 - Due to their complex chemical structure transition metal oxides display many fascinating properties which conventional semiconductors lack. For this reason transition metal oxides hold a lot of promise for novel electronic functionalities. Just as in conventional semiconductor heterostructures, the interfaces between different materials play a key role in oxide electronics. The textbook example is the (001) interface between the band insulators LaAlO\(_3\) and SrTiO\(_3\) at which a two-dimensional electron system (2DES) forms. In order to utilize such a 2DES in prospective electronic devices, it is vital that the electronic properties of the interface can be controlled and manipulated at will. Employing photoelectron spectroscopy as well as electronic transport measurements, this thesis examines how such interface engineering can be realized in the case of the LaAlO\(_3\)/SrTiO\(_3\) heterostructure: By photoemission we manage to unambiguously distinguish the different mechanisms by which SrTiO\(_3\) can be doped with electrons. An electronic reconstruction is identified as the driving mechanism to render stoichiometric LaAlO\(_3\)/SrTiO\(_3\) interfaces metallic. The doping of the LaAlO\(_3\)/SrTiO\(_3\) heterointerface can furthermore be finely adjusted by changing the oxygen vacancy \(V_{\mathrm{O}}\) concentration in the heterostructure. Combining intense x-ray irradiation with oxygen dosing, we even achieve control over the \(V_{\mathrm{O}}\) concentration and, consequently, the doping in the photoemission experiment itself. Exploiting this method, we investigate how the band diagram of SrTiO\(_3\)-based heterostructures changes as a function of the \(V_{\mathrm{O}}\) concentration and temperature by hard x-ray photoemission spectroscopy. With the band bending in the SrTiO\(_3\) substrate changing as a function of the \(V_{\mathrm{O}}\) concentration, the interfacial band alignment is found to vary as well. The relative permittivity of the SrTiO\(_3\) substrate and, in particular, its dependence on temperature and electric field is identified as one of the essential parameters determining the electronic interface properties. That is also why the sample temperature affects the charge carrier distribution. The mobile charge carriers are shown to shift toward the SrTiO\(_3\) bulk when the sample temperature is lowered. This effect is, however, only pronounced if the total charge carrier concentration is small. At high charge carrier concentrations the charge carriers are always confined to the interface, independent of the sample temperature. The dependence of the electronic interface properties on the \(V_{\mathrm{O}}\) concentration is also investigated by a complementary method, viz. by electronic transport measurements. These experiments confirm that the mobile charge carrier concentration increases concomitantly to the \(V_{\mathrm{O}}\) concentration. The mobility of the charge carriers changes as well depending on the \(V_{\mathrm{O}}\) concentration. Comparing spectroscopy and transport results, we are able to draw conclusions about the processes limiting the mobility in electronic transport. We furthermore build a memristor device from our LaAlO\(_3\)/SrTiO\(_3\) heterostructures and demonstrate how interface engineering is used in practice in such novel electronic applications. This thesis furthermore investigates how the electronic structure of the 2DES is affected by the interface topology: We show that, akin to the (001) LaAlO\(_3\)/SrTiO\(_3\) heterointerface, an electronic reconstruction also renders the (111) interface between LaAlO\(_3\) and SrTiO\(_3\) metallic. The change in interface topology becomes evident in the Fermi surface of the buried 2DES which is probed by soft x-ray photoemission. Based on the asymmetry in the Fermi surface, we estimate the extension of the conductive layer in the (111)-oriented LaAlO\(_3\)/SrTiO\(_3\) heterostructure. The spectral function measured furthermore identifies the charge carriers at the interface as large polarons. N2 - Aufgrund ihrer komplexen chemischen Struktur weisen Übergangsmetalloxide viele faszinierende Eigenschaften auf, die konventionelle Halbleitermaterialien entbehren und die Potenzial für neuartige elektronische Funktionalitäten bergen. Genauso wie in konventionellen Halbleiterstrukturen kommt dabei den Grenzflächen zwischen den Materialien besondere Bedeutung zu. In der Oxid-Elektronik ist ein Paradebeispiel hierfür die (001)-Grenzfläche zwischen den Bandisolatoren LaAlO\(_3\) und SrTiO\(_3\), an der sich ein zweidimensionales Elektronensystem (2DES) ausbildet. Um solche Elektronensysteme zukünftig in elektronischen Anwendungen zu nutzen, ist es jedoch unabdingbar, dass die elektronischen Eigenschaften der Grenzfläche gezielt kontrolliert und manipuliert werden können. Mittels Photoelektronenspektroskopie sowie Transportmessungen untersucht diese Arbeit am Beispiel der LaAlO\(_3\)/SrTiO\(_3\)-Grenzfläche, wie eine derartige Kontrolle realisiert werden kann. Mithilfe von Photoemissionsexperimenten gelingt es, verschiedene Mechanismen zu unterscheiden, mit denen SrTiO\(_3\) dotiert werden kann. In stöchiometrischen LaAlO\(_3\)/SrTiO\(_3\)-Heterostrukturen kann so die elektronische Rekonstruktion als treibender Mechanismus identifiziert werden, der zur Ausbildung der leitfähigen Grenzschicht führt. Die Dotierung der LaAlO\(_3\)/SrTiO\(_3\)-Heterostruktur kann weiterhin auch durch die kontrollierte Erzeugung von Sauerstofffehlstellen \(V_{\mathrm{O}}\) gezielt gesteuert werden. Die \(V_{\mathrm{O}}\)-Konzentration kann sogar während der Photoemissionsexperimente zielgerichtet variiert werden, wenn die Bestrahlung mit intensivem Röntgenlicht mit einer Sauerstoffbehandlung kombiniert wird. Diese Methode nutzen wir in Folge aus, um in Photoemissionsmessungen mit harter Röntgenstrahlung systematisch zu untersuchen, wie sich das Banddiagramm von SrTiO\(_3\)-basierten Heterostrukturen als Funktion der \(V_{\mathrm{O}}\)-Konzentration und Temperatur ändert. Wir zeigen, dass sich parallel zur Bandverbiegung im SrTiO\(_3\)-Substrat auch die Bandanordnung an der Grenzfläche als Funktion der \(V_{\mathrm{O}}\)-Konzentration ändert. Dabei stellt sich heraus, dass die dielektrische Funktion des SrTiO\(_3\)-Substrats - insbesondere durch ihre starke Abhängigkeit vom elektrischen Feld und Temperatur - maßgeblich die elektronischen Eigenschaften der Grenzfläche bestimmt. Aus diesem Grund hat die Temperatur der Probe Einfluss auf die Ladungsträgerverteilung. Die mobilen Ladungsträger verschieben sich weg von der Grenzfläche tiefer in das Substrat, je niedriger die Temperatur gewählt wird. Dieser Effekt ist jedoch nur bei niedriger Dotierung zu beobachten. Bei hoher Dotierung ist das zweidimensionale Elektronensystem unabhängig von der Temperatur nahe der Grenzfläche lokalisiert. Die Abhängigkeit der elektronischen Eigenschaften von der \(V_{\mathrm{O}}\)-Konzentration wird auch komplementär im elektronischen Transport untersucht. Auch hier steigt die Ladungsträgerdichte simultan zur \(V_{\mathrm{O}}\)-Konzentration. Zugleich ändert sich auch die Mobilität der Ladungsträger. Der direkte Vergleich von Spektroskopie- und Transportmessungen erlaubt Rückschlüsse auf die Prozesse, die die Ladungsträgermobilität begrenzen. Am Beispiel eines LaAlO\(_3\)/SrTiO\(_3\)-basierten Memristors wird darüber hinaus praktisch demonstriert, wie die Kontrolle über die Grenzfläche in neuartigen elektronischen Anwendungen tatsächlich eingesetzt werden kann. Ferner untersucht diese Arbeit, wie die Topologie der Grenzfläche die elektronische Struktur des 2DES beeinflusst: Wir weisen nach, dass analog zur (001)-Grenzfläche auch die (111)-Grenzfläche zwischen LaAlO\(_3\) und SrTiO\(_3\) durch eine elektronische Rekonstruktion dotiert wird. Die Änderung in der Grenzflächentopologie zeigt sich deutlich in der Fermifläche des vergrabenen 2DES, die mittels resonanter Photoemission untersucht wird. Anhand der Asymmetrie der Fermifläche wird überdies die Ausdehnung des Elektronensystems abgeschätzt, wohingegen die Spektralfunktion Hinweise auf die Elektron-Phonon-Kopplung an der Grenzfläche liefert. KW - Übergangsmetalloxide KW - Grenzfläche KW - Strontiumtitanat KW - Heterostruktur KW - Röntgen-Photoelektronenspektroskopie KW - oxide heterostructure KW - interface conductivity KW - oxygen vacancies KW - LaAlO3/SrTiO3 KW - hard x-ray photoemission KW - soft x-ray photoemission Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-192275 ER - TY - JOUR A1 - Fux, Robert A1 - Arndt, Daniela A1 - Langenmayer, Martin C. A1 - Schwaiger, Julia A1 - Ferling, Hermann A1 - Fischer, Nicole A1 - Indenbirken, Daniela A1 - Grundhoff, Adam A1 - Dölken, Lars A1 - Adamek, Mikolaj A1 - Steinhagen, Dieter A1 - Sutter, Gerd T1 - Piscine orthoreovirus 3 is not the causative pathogen of proliferative darkening syndrome (PDS) of brown trout (Salmo trutta fario) JF - Viruses N2 - The proliferative darkening syndrome (PDS) is a lethal disease of brown trout (Salmo trutta fario) which occurs in several alpine Bavarian limestone rivers. Because mortality can reach 100%, PDS is a serious threat for affected fish populations. Recently, Kuehn and colleagues reported that a high throughput RNA sequencing approach identified a piscine orthoreovirus (PRV) as a causative agent of PDS. We investigated samples from PDS-affected fish obtained from two exposure experiments performed at the river Iller in 2008 and 2009. Using a RT-qPCR and a well-established next-generation RNA sequencing pipeline for pathogen detection, PRV-specific RNA was not detectable in PDS fish from 2009. In contrast, PRV RNA was readily detectable in several organs from diseased fish in 2008. However, similar virus loads were detectable in the control fish which were not exposed to Iller water and did not show any signs of the disease. Therefore, we conclude that PRV is not the causative agent of PDS of brown trout in the rhithral region of alpine Bavarian limestone rivers. The abovementioned study by Kuehn used only samples from the exposure experiment from 2008 and detected a subclinical PRV bystander infection. Work is ongoing to identify the causative agent of PDS. KW - proliferative darkening syndrome KW - black trout syndrome KW - piscine orthoreovirus KW - orthoreovirus KW - brown trout KW - Salmo trutta fario KW - next generation sequencing KW - RT-qPCR Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196991 SN - 1999-4915 VL - 11 IS - 2 ER - TY - JOUR A1 - Fuchs, A. A1 - Youssef, A. A1 - Seher, A. A1 - Hochleitner, G. A1 - Dalton, P. D. A1 - Hartmann, S. A1 - Brands, R. C. A1 - Müller-Richter, U. D. A. A1 - Linz, C, T1 - Medical-grade polycaprolactone scaffolds made by melt electrospinning writing for oral bone regeneration – a pilot study in vitro JF - BMC Oral Health N2 - Background The spectrum of indications for the use of membranes and scaffolds in the field of oral and maxillofacial surgery includes, amongst others, guided bone regeneration (GBR). Currently available membrane systems face certain disadvantages such as difficult clinical handling, inconsistent degradation, undirected cell growth and a lack of stability that often complicate their application. Therefore, new membranes which can overcome these issues are of great interest in this field. Methods In this pilot study, we investigated polycaprolactone (PCL) scaffolds intended to enhance oral wound healing by means of melt electrospinning writing (MEW), which allowed for three-dimensional (3D) printing of micron scale fibers and very exact fiber placement. A singular set of box-shaped scaffolds of different sizes consisting of medical-grade PCL was examined and the scaffolds’ morphology was evaluated via scanning electron microscopy (SEM). Each prototype sample with box sizes of 225 μm, 300 μm, 375 μm, 450 μm and 500 μm was assessed for cytotoxicity and cell growth by seeding each scaffold with human osteoblast-like cell line MG63. Results All scaffolds demonstrated good cytocompatibility according to cell viability, protein concentration, and cell number. SEM analysis revealed an exact fiber placement of the MEW scaffolds and the growth of viable MG63 cells on them. For the examined box-shaped scaffolds with pore sizes between 225 μm and 500 μm, a preferred box size for initial osteoblast attachment could not be found. Conclusions These well-defined 3D scaffolds consisting of medical-grade materials optimized for cell attachment and cell growth hold the key to a promising new approach in GBR in oral and maxillofacial surgery. KW - melt electrospinning writing KW - polycaprolactone KW - scaffold KW - guided bone regeneration Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200274 VL - 19 ER - TY - JOUR A1 - Franke, Maximilian A1 - Conzelmann, Annette A1 - Grünblatt, Edna A1 - Werling, Anna M. A1 - Spieles, Helen A1 - Wewetzer, Christoph A1 - Warnke, Andreas A1 - Romanos, Marcel A1 - Walitza, Susanne A1 - Renner, Tobias J. T1 - No Association of Variants of the NPY-System With Obsessive-Compulsive Disorder in Children and Adolescents JF - Frontiers in Molecular Neuroscience N2 - Obsessive-compulsive disorder (OCD) causes severe distress and is therefore counted by the World Health Organisation (WHO) as one of the 10 most impairing illnesses. There is evidence for a strong genetic underpinning especially in early onset OCD (eoOCD). Though several genes involved in neurotransmission have been reported as candidates, there is still a need to identify new pathways. In this study, we focussed on genetic variants of the Neuropeptide Y (NPY) system. NPY is one of the most abundant neuropeptides in the human brain with emerging evidence of capacity to modulate stress response, which is of high relevance in OCD. We focussed on tag-SNPs of NPY and its receptor gene NPY1R in a family-based approach. The sample comprised 86 patients (children and adolescents) with eoOCD with both their biological parents. However, this first study on genetic variants of the NPY-system could not confirm the association between the investigated SNPs and eoOCD. Based on the small sample size results have to be interpreted as preliminary and should be replicated in larger samples. However, also in an additional GWAS analysis in a large sample, we could not observe an associations between NPY and OCD. Overall, these preliminary results point to a minor role of NPY on the stress response of OCD. KW - NPY KW - obsessive-compulsive KW - children KW - anxiety KW - neuropeptide Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229051 VL - 12 ER - TY - THES A1 - Franke, Christian T1 - Advancing Single-Molecule Localization Microscopy: Quantitative Analyses and Photometric Three-Dimensional Imaging T1 - Weiterentwicklung von Einzel-Molekül Lokalisations-Mikroskopie: Quantitative Analysen und photometrische drei-dimensionale Bildgebung N2 - Since its first experimental implementation in 2005, single-molecule localization microscopy (SMLM) emerged as a versatile and powerful imaging tool for biological structures with nanometer resolution. By now, SMLM has compiled an extensive track-record of novel insights in sub- and inter- cellular organization.\\ Moreover, since all SMLM techniques rely on the analysis of emission patterns from isolated fluorophores, they inherently allocate molecular information $per$ $definitionem$.\\ Consequently, SMLM transitioned from its origin as pure high-resolution imaging instrument towards quantitative microscopy, where the key information medium is no longer the highly resolved image itself, but the raw localization data set.\\ The work presented in this thesis is part of the ongoing effort to translate those $per$ $se$ molecular information gained by SMLM imaging to insights into the structural organization of the targeted protein or even beyond. Although largely consistent in their objectives, the general distinction between global or segmentation clustering approaches on one side and particle averaging or meta-analyses techniques on the other is usually made.\\ During the course of my thesis, I designed, implemented and employed numerous quantitative approaches with varying degrees of complexity and fields of application.\\ \\ In my first major project, I analyzed the localization distribution of the integral protein gp210 of the nuclear pore complex (NPC) with an iterative \textit{k}-means algorithm. Relating the distinct localization statistics of separated gp210 domains to isolated fluorescent signals led, among others, to the conclusion that the anchoring ring of the NPC consists of 8 homo-dimers of gp210.\\ This is of particular significance, both because it answered a decades long standing question about the nature of the gp210 ring and it showcased the possibility to gain structural information well beyond the resolution capabilities of SMLM by crafty quantification approaches.\\ \\ The second major project reported comprises an extensive study of the synaptonemal complex (SNC) and linked cohesin complexes. Here, I employed a multi-level meta-analysis of the localization sets of various SNC proteins to facilitate the compilation of a novel model of the molecular organization of the major SNC components with so far unmatched extend and detail with isotropic three-dimensional resolution.\\ In a second venture, the two murine cohesin components SMC3 and STAG3 connected to the SNC were analyzed. Applying an adapted algorithm, considering the disperse nature of cohesins, led to the realization that there is an apparent polarization of those cohesin complexes in the SNC, as well as a possible sub-structure of STAG3 beyond the resolution capabilities of SMLM.\\ \\ Other minor projects connected to localization quantification included the study of plasma membrane glycans regarding their overall localization distribution and particular homogeneity as well as the investigation of two flotillin proteins in the membrane of bacteria, forming clusters of distinct shapes and sizes.\\ \\ Finally, a novel approach to three-dimensional SMLM is presented, employing the precise quantification of single molecule emitter intensities. This method, named TRABI, relies on the principles of aperture photometry which were improved for SMLM.\\ With TRABI it was shown, that widely used Gaussian fitting based localization software underestimates photon counts significantly. This mismatch was utilized as a $z$-dependent parameter, enabling the conversion of 2D SMLM data to a virtual 3D space. Furthermore it was demonstrated, that TRABI can be combined beneficially with a multi-plane detection scheme, resulting in superior performance regarding axial localization precision and resolution.\\ Additionally, TRABI has been subsequently employed to photometrically characterize a novel dye for SMLM, revealing superior photo-physical properties at the single-molecule level.\\ Following the conclusion of this thesis, the TRABI method and its applications remains subject of diverse ongoing research. N2 - Seit ihrer ersten experimentellen Umsetzung in 2005 hat sich die Einzel-Molekül Lokalisations-Mikroskopie (\textit{engl.} single-molecule localization microscopy (SMLM)) als vielseitig einsetzbares Verfahren in der biologischen Bildgebung etabliert, vor allem aufgrund ihres hohen Auflösungsvermögens im Nanometer Bereich. Bis heute wurde eine Reihe neuer Erkenntnisse bezüglich der sub- und inter- zellulären Organisation durch den Einsatz der SMLM erlangt.\\ Aufgrund der Tatsache, dass alle SMLM Techniken auf dem Prinzip basieren, isolierte Fluorophore zu detektieren und zu analysieren, beinhalten SMLM Daten $per$ $definitionem$ molekulare Informationen.\\ Folgerichtig entwickelte sich das Feld der SMLM vom reinen Bildgebungsinstrument mit Nanometer-Auflösung hin zu quantitativer Mikroskopie, bei welcher der Fokus nicht länger vornehmlich auf dem hochaufgelöstem Bild, sondern vielmehr auf den Lokalisationsdaten liegt.\\ Die vorliegende Arbeit ist als Teil der anhaltenden Bestrebungen zu sehen, aus den $per$ $se$ molekularen Informationen der SMLM weiterführende Erkenntnisse über die strukturelle Organisation der markierten Proteine zu gewinnen. Obwohl mit der gleichen prinzipiellen Zielsetzung versehen, unterscheiden sich hierbei globale oder Segmentierungs- Clusteranalysen von Lokalisations-Meta-Analysen oder so genannten \textit{particle averaging} Ansätzen.\\ Während meiner Doktorarbeit habe ich verschiedene Quantifizierungs Ansätze entworfen, implementiert und angewendet, mit unterschiedlichen Graden an Komplexität und Breite des Anwendungsgebietes.\\ \\ In meinem ersten wesentlichem Projekt analysierte ich mit einem iterativen \textit{k}-means Algorithmus die Lokalisationsverteilung des integralen Proteins gp210, welches Teil des Kernporenkomplexes ist (\textit{engl.} nuclear pore complex (NPC)). Durch den Vergleich der charakteristischen Lokalisations-Statistik von separierten gp210 Domänen mit isolierten Fluoreszenzmarkern konnte unter anderem festgestellt werden, dass der Verankerungsring des NPC aus acht gp210 Homodimeren bestehen muss.\\ Diese Erkenntnis beantwortet zum einen eine jahrzehntealte Frage nach der Zusammensetzung des gp210 Rings und zum anderen liefert sie ein Beispiel dafür, dass durch eine geschickte Analyse der Lokalisationsstatistik strukturelle Informationen erlangt werden können, die jenseits des räumlichen Auflösungsvermögens von SMLM liegen.\\ \\ Das zweite hier vorgestellte wesentliche Projekt beinhaltet eine umfassende Studie des Synaptonemalen Komplexes (\textit{engl.} synaptonemal complex (SNC)) und damit verbundenen Cohesin Komplexen. Um die molekulare Organisation des SNC zu untersuchen, implementierte ich eine multi-level Meta-Analyse der Lokalisationsdaten mehrerer SNC Komponenten. Aus dessen Ergebnissen konnte ein neues drei dimensionales molekulares Modell des SNC erstellt werden.\\ Nachfolgend wurden die beiden murinen Cohesine SMC3 und STAG3 mit adaptierter Methodik untersucht. Hierbei musste die starke intrinsische Dispersion der Cohesin-Signale berücksichtigt werden. Die Analyse ergab deutliche Hinweise auf eine Polarisation der Cohesine innerhalb des SNC. Zudem zeigte sich eine mögliche Substruktur in der Organisation von STAG3, die unterhalb der Auflösungsgrenze von SMLM liegt.\\ \\ Weitere Nebenprojekte im Zusammenhang mit quantitativer Lokalisationsanalyse umfassten die Untersuchung der Lokalisationsverteilung von Plasma-Membran Glykanen, sowie zweier Flotillin Proteine in den Membranen von Bakterien, welche Cluster unterschiedlicher Form und Größe aufzeigten.\\ \\ Schließlich wird ein neuartiger Ansatz für dreidimensionale SMLM vorge-stellt, die auf der genauen Bestimmung von Einzel-Molekül Intensitäten basiert. Diese Methode, genannt TRABI, stützt sich auf die Prinzipien der Apertur Photometrie, welche für die SMLM angepasst und verbessert wurden.\\ Mit TRABI konnte gezeigt werden, dass weit verbreitete Lokalisations-Software, die auf $Gaussian-Fitting$ basiert, die Photonenzahl von Emittern oftmals stark unterschätzt. Diese Diskrepanz kann als $z$-abhängiger Parameter verwendet werden um z.B. einen 2D SMLM Datenatz in einen virtuellen 3D Raum zu überführen. Außerdem wird gezeigt, dass TRABI vorteilhaft mit einem multi-plane Detektionsschema kombiniert werden kann und dabei höhere axiale Lokalisationsgenauigkeiten und Auflösungen er-reicht.\\ Zudem wurde TRABI eingesetzt, um einen neuen Fluoreszenzfarbstoff für SMLM zu charakterisieren und dessen verbesserte photo-physikalische Eigenschaften auf Einzel-Molekül Basis zu demonstrieren.\\ Auch nach Abschluss dieser Arbeit ist die TRABI Methode und deren Anwendung weiterhin Gegenstand diverser Forschungen. KW - Einzelmolekülmikroskopie KW - Quantitative Mikroskopie KW - dSTORM Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-156355 ER - TY - THES A1 - Frank, Erik Thomas T1 - Behavioral adaptations in the foraging behaviour of \(Megaponera\) \(analis\) T1 - Verhaltensanpassungen im Furagierverhalten von \(Megaponera\) \(analis\) N2 - An efficient foraging strategy is one of the most important traits for the fitness of animals. The theory of optimal foraging tries to predict foraging behaviour through the overarching question: how animals should forage so as to minimize costs while maximizing profits? Social insects, having occupied nearly every natural niche through widely different strategies, offer themselves as an ideal group to study how well optimal foraging theory can explain their behaviour and success. Specialization often leads to unique adaptations in morphology and behaviour. I therefore decided to investigate the behaviour of Megaponera analis. This ponerine ant species is specialized on hunting only termites of the subfamily Macrotermitinae at their foraging sites. Their foraging behaviour is regulated by a handful of individual scouts (10-20) that search for termite foraging sites before returning to the nest to recruit a large number of nestmates (200-500 ants). These ants then follow the scout in a column formation to the termites and after the hunt return together to the nest, these raids occur two to five times per day. Predators of highly defensive prey likely develop cost reducing adaptations. The evolutionary arms race between termites and ants led to various defensive mechanisms in termites, e.g. a caste specialized in fighting predators. As M. analis incurs high injury/mortality risks when preying on termites, some risk mitigating adaptations have evolved. I show that a unique rescue behaviour in M. analis, consisting of injured nestmates being carried back to the nest, reduces combat mortality. These injured ants “call for help” with pheromones present in their mandibular gland reservoirs. A model accounting for this rescue behaviour identifies the drivers favouring its evolution and estimates that rescuing allows for maintaining a 29% larger colony size. Heavily injured ants that lost too many legs during the fight on the other hand are not helped. Interestingly, this was regulated not by the helper but by the uncooperativeness of the injured ant. I further observed treatment of the injury by nestmates inside the nest through intense allogrooming directly at the wound. Lack of treatment increased mortality from 10% to 80% within 24 hours, with the cause of death most likely being infections. Collective decision-making is one of the main mechanisms in social insects through which foraging is regulated. However, individual decision-making can also play an important role, depending on the type of foraging behaviour. In M. analis only a handful of individuals (the scouts) hold all the valuable information about foraging sites. I therefore looked at predictions made by optimal foraging theory to better understand the interplay between collective and individual decision-making in this obligate group-raiding predator. I found a clear positive relation between raid size and termite abundance at the foraging site. Furthermore, selectivity of the food source increased with distance. The confirmation of optimal foraging theory suggests that individual scouts must be the main driver behind raid size, choice and raiding behaviour. Therefore most central place foraging behaviours in M. analis were not achieved by collective decisions but rather by individual decisions of scout ants. Thus, 1% of the colony (10–20 scouts) decided the fate and foraging efficiency of the remaining 99%. Division of labour is one of the main reasons for the success of social insects. Worker polymorphism, age polyethism and work division in more primitive ants, like the ponerines, remain mostly unexplored though. Since M. analis specializes on a defensive prey, adaptations to reduce their foraging costs can be expected. I found that the work division, task allocation and column-formation during the hunt were much more sophisticated than was previously thought. The column-formation was remarkably stable, with the same ants resuming similar positions in subsequent raids and front ants even returning to their positions if displaced in the same raid. Most of the raid tasks were not executed by predetermined members of the raid but were filled out as need arose during the hunt, with a clear preference for larger ants to conduct most tasks. I show that specialization towards a highly defensive prey can lead to very unique adaptations in the foraging behaviour of a species. I explored experimentally the adaptive value of rescue behaviour focused on injured nestmates in social insects. This was not only limited to selective rescuing of lightly injured individuals by carrying them back (thus reducing predation risk) but moreover includes a differentiated treatment inside the nest. These observations will help to improve our understanding of the evolution of rescue behaviour in animals. I further show that most optimal foraging predictions are fulfilled and regulated by a handful of individuals in M. analis. Lastly, I propose that the continuous allometric size polymorphism in M. analis allows for greater flexibility in task allocation, necessary due to the unpredictability of task requirements in an irregular system such as hunting termites in groups. All of my observations help to further understand how a group-hunting predator should forage so as to minimize costs while maximizing profits. N2 - Ein effizientes Furagierverhalten ist eine der wesentlichsten Voraussetzungen für die Überlebensfähigkeit von Tieren. Die Theorie des „Optimal Foraging“ versucht, das Furagierverhalten durch die übergreifende Frage zu verstehen: Wie sollten Tiere nach Futter suchen/jagen, um die Kosten zu minimieren und gleichzeitig die Gewinne zu maximieren? Soziale Insekten, die fast jede natürliche Nische durch diverse Strategien besetzt haben, bieten sich als ideale Gruppe an, um zu untersuchen, wie gut „Optimal Foraging“ ihr Verhalten und ihren Erfolg erklären kann. Da Spezialisierung oft zu einzigartigen Anpassungen in Morphologie und Verhalten führt, war das Jagdverhalten von Megaponera analis diesbezüglich sehr vielversprechend. Diese Ponerinae Ameisenart ist spezialisiert auf die Jagd von Termiten der Unterfamilie Macrotermitinae an ihren Futterstellen. Ihr Jagdverhalten wird durch eine Handvoll von einzelner Späher (10-20) geregelt, die nach Termiten-Futterstellen suchen, bevor sie zum Nest zurückkehren, um eine große Anzahl von Nestgenossinnen (200-500 Ameisen) zu rekrutieren. Die Ameisen folgen dann dem Späher in einer Kolonne zu den Termiten und zurück, diese Überfälle finden zwei bis fünf Mal am Tag statt. Es ist wahrscheinlich, dass Prädatoren von defensiver Beute kostenreduzierende Anpassungen entwickeln. Das evolutionäre Wettrüsten zwischen Termiten und Ameisen führte zu verschiedenen Abwehrmechanismen bei Termiten, z.B. eine Soldaten-Kaste, die sich auf die Bekämpfung von Raubtieren spezialisiert hat. Da M. analis ein hohes Verletzungsrisiko durch Termitensoldaten hat, haben sich bei ihr einige kostenreduzierende Anpassungen entwickelt. Ich zeige, dass ein einzigartiges Rettungsverhalten bei M. analis, bestehend aus verletzten Nestgenossinnen, die zum Nest zurückgetragen werden, die Mortalität reduziert. Diese verletzten Ameisen „rufen“ um Hilfe mit Pheromonen, die in ihren mandibularen Drüsenreservoirs vorhanden sind. Ein Modell, das dieses Rettungsverhalten berücksichtigt, hilft dabei die wichtigsten Faktoren zu identifizieren, welche die Evolution dieses Rettungsverhaltens begünstigen. Ferner wird schwerverletzten Ameisen, die während des Kampfes zu viele Beine verloren haben, nicht geholfen. Interessanterweise wird dies nicht durch den Helfer reguliert, sondern durch die mangelnde Kooperation der verletzten Ameise. Des Weiteren beobachtete ich die Behandlung der Verletzten durch Nestgenossinnen im Nest durch intensives „Allogrooming“/lecken direkt an der Wunde. Eine Unterbindung der Behandlung erhöhte die Mortalität von 10% auf 80% innerhalb von 24 Stunden, höchstwahrscheinlich aufgrund von Infektionen. Die kollektive Entscheidungsfindung ist einer der Hauptmechanismen bei sozialen Insekten, durch die die Futtersuche reguliert wird. Allerdings spielt die individuelle Entscheidungsfindung, je nach Art des Furagierverhaltens, auch eine wichtige Rolle. In M. analis haben nur eine Handvoll von Individuen (die Späher) alle Informationen über die Futterstellen. Ich betrachtete daher die Vorhersagen, die durch „Optimal Foraging“ gemacht werden, um das Zusammenspiel von kollektiver und individueller Entscheidungsfindung bei diesem obligaten Gruppenjäger besser zu verstehen. Ich fand eine klare positive Beziehung zwischen Raubzugsgröße und Termitenabundanz an der Futterstelle. Außerdem erhöhte sich die Selektivität der Futterstelle mit der Entfernung zum Nest. Die Bestätigung der „Optimalen Foraging“ Theorie deutet darauf hin, dass einzelne Späher der Haupttreiber hinter Raubzugsgröße, Wahl und Raubzugsverhalten sein müssen. Dies bedeutet, dass in M. analis das Furagierverhalten nicht durch kollektive Entscheidungen, sondern durch individuelle Entscheidungen der Späher reguliert wird. So entschied 1% der Kolonie (10-20 Späher) das Schicksal und die Furagier-Effizienz der restlichen 99%. Die Arbeitsteilung ist einer der Hauptgründe des Erfolgs sozialer Insekten. Arbeiterpolymorphismus, Alterspolyethismus und Arbeitsteilung bei primitiveren Ameisen, wie den Ponerinen, blieben bisher jedoch meist unerforscht. Da M. analis sich auf eine defensive Beute spezialisiert hat, sind Anpassungen zur Reduzierung ihrer Furagierkosten zu erwarten. Ich zeige, dass die Arbeitsteilung und Kolonnenformation während der Jagd viel anspruchsvoller ist, als bisher angenommen. Die Kolonnenformation war bemerkenswert stabil: dieselben Ameisen nahmen ähnliche Positionen in späteren Raubzügen ein und die vorderen Ameisen kehrten sogar zu ihrer Position zurück, wenn diese absichtlich verändert wurde. Dies weist auf unbekannte Regulationsmechanismen für die Bildung der Kolonne hin. Darüber hinaus wurden die meisten der Raubzugsaufgaben nicht von vorgegebenen Mitgliedern des Raubzugs ausgeführt, sondern wurden je nach Bedarf während der Jagd verteilt. Meine Versuche zeigen, dass die Spezialisierung auf eine hoch defensive Beute zu sehr einzigartigen Anpassungen im Furagierverhalten einer Art führen kann. Ich erforschte experimentell den adaptiven Wert eines Rettungsverhaltens, das auf verletzte Nestgenossinnen bei sozialen Insekten fokussiert war. Dies beschränkte sich nicht nur auf die selektive Rettung von leicht verletzten Individuen, welche zurückgetragen wurden (wodurch das Prädationsrisiko reduziert wurde), sondern umfasst darüber hinaus eine differenzierte Behandlung im Nest. Ich zeige weiter, dass die meisten „Optimal Foraging“ Vorhersagen von einer Handvoll Individuen in M. analis erfüllt und reguliert werden. Schließlich postuliere ich die Hypothese, dass der kontinuierliche allometrische Größenpolymorphismus in M. analis eine größere Flexibilität bei der Aufgabenverteilung ermöglicht, die aufgrund der Unberechenbarkeit der Aufgabenanforderungen in einem unregelmäßigen System wie dem Jagen von Termiten in Gruppen Erforderlich ist. Alle meine Beobachtungen verbessern unser Verständnis des Verhaltens eines Gruppenjägers, das während der Jagd die Kosten zu minimieren und die Gewinne zu maximieren hat. KW - Stechameisen KW - Nahrungserwerb KW - Verhalten KW - Optimal foraging KW - Rescue behaviour KW - Myrmecology KW - Behaviour KW - Ecology Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-156544 ER - TY - THES A1 - Fleischmann, Pauline Nikola T1 - Starting foraging life: Early calibration and daily use of the navigational system in \(Cataglyphis\) ants T1 - Start in den Außendienst: Zur anfänglichen Kalibrierung und alltäglichen Nutzung des Navigationssystem in \(Cataglyphis\)-Ameisen N2 - Cataglyphis ants are famous for their navigational abilities. They live in hostile habitats where they forage as solitary scavengers covering distances of more than hundred thousand times their body lengths. To return to their nest with a prey item – mainly other dead insects that did not survive the heat – Cataglyphis ants constantly keep track of their directions and distances travelled. The navigational strategy is called path integration, and it enables an ant to return to the nest in a straight line using its home vector. Cataglyphis ants mainly rely on celestial compass cues, like the position of the sun or the UV polarization pattern, to determine directions, and they use an idiothetic step counter and optic flow to measure distances. In addition, they acquire information about visual, olfactory and tactile landmarks, and the wind direction to increase their chances of returning to the nest safe and sound. Cataglyphis’ navigational performance becomes even more impressive if one considers their life style. Most time of their lives, the ants stay underground and perform tasks within the colony. When they start their foraging careers outside the nest, they have to calibrate their compass systems and acquire all information necessary for navigation during subsequent foraging. This navigational toolkit is not instantaneously available, but has to be filled with experience. For that reason, Cataglyphis ants perform a striking behavior for up to three days before actually foraging. These so-called learning walks are crucial for the success as foragers later on. In the present thesis, both the ontogeny and the fine-structure of learning walks has been investigated. Here I show with displacement experiments that Cataglyphis ants need enough space and enough time to perform learning walks. Spatially restricted novices, i. e. naïve ants, could not find back to the nest when tested as foragers later on. Furthermore, ants have to perform several learning walks over 1-3 days to gain landmark information for successful homing as foragers. An increasing number of feeder visits also increases the importance of landmark information, whereas in the beginning ants fully rely on their path-integration vector. Learning walks are well-structured. High-speed video analysis revealed that Cataglyphis ants include species-specific rotational elements in their learning walks. Greek Cataglyphis ants (C. noda and C. aenescens) inhabiting a cluttered pine forest perform voltes, small walked circles, and pirouettes, tight turns about the body axis with frequent stopping phases. During the longest stopping phases, the ants gaze back to their nest entrance. The Tunisian Cataglyphis fortis ants inhabiting featureless saltpans only perform voltes without directed gazes. The function of voltes has not yet been revealed. In contrast, the fine structure of pirouettes suggests that the ants take snapshots of the panorama towards their homing direction to memorize the nest’s surroundings. The most likely hypothesis was that Cataglyphis ants align the gaze directions using their path integrator, which gets directional input from celestial cues during foraging. To test this hypothesis, a manipulation experiment was performed changing the celestial cues above the nest entrance (no sun, no natural polarization pattern, no UV light). The accurately directed gazes to the nest entrance offer an easily quantifiable readout suitable to ask the ants where they expect their nest entrance. Unexpectedly, all novices performing learning walks under artificial sky conditions looked back to the nest entrance. This was especially surprising, because neuronal changes in the mushroom bodies and the central complex receiving visual input could only be induced with the natural sky when comparing test animals with interior workers. The behavioral findings indicated that Cataglyphis ants use another directional reference system to align their gaze directions during the longest stopping phases of learning walk pirouettes. One possibility was the earth’s magnetic field. Indeed, already disarraying the geomagnetic field at the nest entrance with an electromagnetic flat coil indicated that the ants use magnetic information to align their looks back to the nest entrance. To investigate this finding further, ants were confronted with a controlled magnetic field using a Helmholtz coil. Elimination of the horizontal field component led to undirected gaze directions like the disarray did. Rotating the magnetic field about 90°, 180° or -90° shifted the ants’ gaze directions in a predictable manner. Therefore, the earth’s magnetic field is a necessary and sufficient reference system for aligning nest-centered gazes during learning-walk pirouettes. Whether it is additionally used for other navigational purposes, e. g. for calibrating the solar ephemeris, remains to be tested. Maybe the voltes performed by all Cataglyphis ant species investigated so far can help to answer this question.. N2 - Cataglyphis-Ameisen sind für ihre Navigationsfähigkeiten berühmt. Sie bewohnen lebens- feindliche Regionen in denen sie einzeln und über weite Strecken Futter suchen müssen. Um mit Beute (meist ein totes Insekt, das die große Hitze nicht überlebt hat) zu ihrem Nest zurückzukehren, bedienen sie sich einer Navigationsstrategie, die als Wegintegration beze- ichnet wird. Dabei müssen die Ameisen die zurückgelegten Distanzen messen und jeden Richtungswechsel registrieren, um schließlich in gerader Linie nachhause zurückkehren zu können. Als Kompass nutzen sie Himmelsinformationen, wie den Stand der Sonne oder das UV-Polarisationsmuster, und für die Distanzmessung verwenden sie einen inneren Schrittzäh- ler sowie optischen Fluss. Außerdem nutzen sie alle weiteren Informationen, die hilfreich sein könnten, um sicher zum Nest zurückzukehren. Dazu gehören visuelle, olfaktorische und taktile Landmarken sowie die Richtung des Windes. Die Navigationsleistungen von Cataglyphis-Ameisen sind insbesondere dann bemerkenswert, wenn man sich bewusst macht, dass sie die meiste Zeit ihres Lebens unter der Erde verbringen. Dort übernehmen sie Auf- gaben im Nest bis sie dann schließlich alt genug sind, um draußen Futter zu suchen. Dann müssen sie ihre Kompasssysteme kalibrieren und alle Informationen lernen, die sie für eine erfolgreiche Futtersuche brauchen. Dieses sogenannte Navigations-Toolkit steht den Ameisen nicht automatisch zur Verfügung, vielmehr müssen sie es mit eigener Erfahrung füllen. Dafür nutzen sie die ersten ein bis drei Tage außerhalb des Nestes. Während dieser Zeit suchen sie kein Futter, sondern vollführen sogenannte Lernläufe. Lernläufe sind unabdingbar, um später als Fourageur erfolgreich zu sein. In der vorliegenden Doktorarbeit wurde sowohl die zeitliche und räumliche Entwicklung der Lernläufe als auch deren Feinstruktur untersucht. Mit Versetzungsexperimenten konnte ich zeigen, dass Ameisen genügend Zeit und Raum brauchen, um Lernläufe durchzuführen. Wurden Neulinge während ihrer Lernläufe räumlich eingeschränkt, so konnten sie nicht zum Nest zurückfinden, wenn sie als erfahrene Fourageure getestet wurden. Außerdem brauchen die Ameisen ein bis drei Tage Zeit, um ein Landmarkenpanorama zu erlernen, das sie dann später erfolgreich zur Landmarkenorientierung nutzen können. Eine größere Anzahl an Besuchen am Futterplatz erhöht die Wichtigkeit von Landmarkeninformation für die Ameisen, die anfangs nur ihren Wegintegrator nutzen. Lernläufe weisen eine beeindruckende Struktur auf. Mit High-Speed-Videoaufnahmen konnte gezeigt werden, dass Cataglyphis-Ameisen artspezifische Drehungen während der Lernläufe vollführen. Die griechischen Cataglyphis-Ameisen (C. noda und C. aenescens) leben in einem Pinienwald, der ihnen ein vielfältiges und landmarkenreiches Panorama bietet. Ihre Lernläufe beinhalten zwei Drehungsformen, nämlich sogenannte Volten (kleine gelaufene Kreise) und Pirouetten (enge Drehungen um die eigene Körperachse mit häufigen Stoppphasen). Während der längsten Stoppphase einer Pirouette schauen die Ameisen zurück in die Richtung ihres Nesteingangs, obwohl sie ihn nicht direkt sehen können. Die tunesischen Cataglyphis-Ameisen (C. fortis ) leben auf einem landmarkenarmen Salzsee. Sie vollführen nur Volten und machen keine Pirouetten während ihrer Lernläufe. Die Funktion von Volten ist noch unbekannt, wohingegen die Feinstruktur der Pirouetten die Vermutung nahelegt, dass die Ameisen sogenannte Schnappschüsse von der Umgebung ihres Nestes machen, um dorthin zurückkehren zu können. Es schien wahrscheinlich, dass die Ameisen ihren Wegintegrator nutzen, um ihre Blickrich- tungen zum Nest auszurichten. Während der Futtersuche bekommt der Wegintegrator seine Richtungsinformationen vom Himmelskompass. Daher wurde ein Experiment geplant und durchgeführt bei dem die Himmelsinformationen über dem Nesteingang manipuliert wurden (keine Sicht auf die Sonne, kein natürliches Polarisationsmuster oder kein UV-Licht). Die nest- zentrierten Blickrichtungen der Ameisen ermöglichen es relativ einfach zu überprüfen, ob die Ameisen die Position des Nesteingangs kennen. Überraschenderweise schauten die Ameisen unter allen Bedingungen weiterhin zurück zum Nesteingang. Dies war insbesondere be- merkenswert, da die Himmelsmanipulation neuronale Veränderungen in den Pilzkörpern und dem Zentralkomplex (das sind Regionen im Gehirn der Ameisen, die visuelle Informationen verarbeiten) bewirkten bzw. diese verhinderten. Nur unter natürlichen Bedingungen, also bei freiem Blick auf die Sonne, gab es Unterschiede auf neuronaler Ebene zwischen den Testtieren und den Innendiensttieren, die als Kontrolle dienten. Die Ergebnisse des Verhaltensversuchs deuteten darauf hin, dass die Ameisen ein anderes direktionales Referenzsystem nutzen, um ihre Blickrichtungen zu kontrollieren. Eine Möglichkeit war das Erdmagnetfeld. Tatsächlich zeigte schon die experimentelle Streuung des Magnetfelds am Nesteingang mittels einer elektromagnetischen Flachspule, dass die Ameisen tatsächlich Magnetinformationen nutzen, um ihre Blicke auszurichten. Die Blickrichtungen während der längsten Stoppphasen waren nicht mehr zum Nesteingang gerichtet. Um dies genauer zu untersuchen wurden die Ameisen mit dem kontrollierten Magnetfeld einer Helmholtzspule konfrontiert. Die Eliminierung der Horizontalkomponente des Magnetfelds bewirkte wiederum, dass die Ameisen nicht zum Nesteingang zurückschauten. Wurde die Horizontalkomponente jedoch um 90◦, 180◦ oder -90◦ gedreht, so folgten die Blickrichtungen der Ameisen dieser Drehung voraussagbar im selben Winkel. Dies zeigt, dass das Erdmagnetfeld tatsächlich das Referenzsystem für die Ausrichtungen der Blicke während der Lernlaufpirouetten darstellt. Ob es auch noch an- deren Navigationszwecken, wie beispielsweise der Kalibrierung der solaren Ephemeris dient, muss zukünftig überprüft werden. Vielleicht können die Volten, die alle bisher untersuchten KW - Cataglyphis KW - Learning walk Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-159951 ER - TY - THES A1 - Flechsenhar, Aleya Felicia T1 - The Ubiquity of Social Attention – a Detailed Investigation of the Underlying Mechanisms T1 - Die Allgegenwärtigkeit Sozialer Aufmerksamkeit – eine Detaillierte Erforschung Zugrundeliegender Mechanismen N2 - This dissertation highlights various aspects of basic social attention by choosing versatile approaches to disentangle the precise mechanisms underlying the preference to focus on other human beings. The progressive examination of different social processes contrasted with aspects of previously adopted principles of general attention. Recent research investigating eye movements during free exploration revealed a clear and robust social bias, especially for the faces of depicted human beings in a naturalistic scene. However, free viewing implies a combination of mechanisms, namely automatic attention (bottom-up), goal-driven allocation (top-down), or contextual cues and inquires consideration of overt (open exploration using the eyes) as well as covert orienting (peripheral attention without eye movement). Within the scope of this dissertation, all of these aspects have been disentangled in three studies to provide a thorough investigation of different influences on social attention mechanisms. In the first study (section 2.1), we implemented top-down manipulations targeting non-social features in a social scene to test competing resources. Interestingly, attention towards social aspects prevailed, even though this was detrimental to completing the requirements. Furthermore, the tendency of this bias was evident for overall fixation patterns, as well as fixations occurring directly after stimulus onset, suggesting sustained as well as early preferential processing of social features. Although the introduction of tasks generally changes gaze patterns, our results imply only subtle variance when stimuli are social. Concluding, this experiment indicates that attention towards social aspects remains preferential even in light of top-down demands. The second study (section 2.2) comprised of two separate experiments, one in which we investigated reflexive covert attention and another in which we tested reflexive as well as sustained overt attention for images in which a human being was unilaterally located on either the left or right half of the scene. The first experiment consisted of a modified dot-probe paradigm, in which peripheral probes were presented either congruently on the side of the social aspect, or incongruently on the non-social side. This was based on the assumption that social features would act similar to cues in traditional spatial cueing paradigms, thereby facilitating reaction times for probes presented on the social half as opposed to the non-social half. Indeed, results reflected such congruency effect. The second experiment investigated these reflexive mechanisms by monitoring eye movements and specifying the location of saccades and fixations for short as well as long presentation times. Again, we found the majority of initial saccades to be congruently directed to the social side of the stimulus. Furthermore, we replicated findings for sustained attention processes with highest fixation densities for the head region of the displayed human being. The third study (section 2.3), tackled the other mechanism proposed in the attention dichotomy, the bottom-up influence. Specifically, we reduced the available contextual information of a scene by using a gaze-contingent display, in which only the currently fixated regions would be visible to the viewer, while the remaining image would remain masked. Thereby, participants had to voluntarily change their gaze in order to explore the stimulus. First, results revealed a replication of a social bias in free-viewing displays. Second, the preference to select social features was also evident in gaze-contingent displays. Third, we find higher recurrent gaze patterns for social images compared to non-social ones for both viewing modalities. Taken together, these findings imply a top-down driven preference for social features largely independent of contextual information. Importantly, for all experiments, we took saliency predictions of different computational algorithms into consideration to ensure that the observed social bias was not a result of high physical saliency within these areas. For our second experiment, we even reduced the stimulus set to those images, which yielded lower mean and peak saliency for the side of the stimulus containing the social information, while considering algorithms based on low-level features, as well as pre-trained high-level features incorporated in deep learning algorithms. Our experiments offer new insights into single attentional mechanisms with regard to static social naturalistic scenes and enable a further understanding of basic social processing, contrasting from that of non-social attention. The replicability and consistency of our findings across experiments speaks for a robust effect, attributing social attention an exceptional role within the general attention construct, not only behaviorally, but potentially also on a neuronal level and further allowing implications for clinical populations with impaired social functioning. N2 - Diese Dissertation beschäftigt sich mit verschiedenen Aspekten grundlegender sozialer Aufmerksamkeitsprozesse. Insbesondere werden durch vielseitige Herangehensweisen einzelne Mechanismen untersucht, die der bevorzugten Betrachtung von Menschen zugrunde liegen. Die progressive Untersuchung unterschiedlicher sozialer Vorgänge widerspricht einiger zuvor angenommener Grundlagen allgemeiner Aufmerksamkeitsprozesse. So zeigen beispielsweise Probanden bei freier Betrachtung naturalistischer Bilder eine klare Präferenz für abgebildete Menschen, v.a. deren Gesichter. Allerdings beinhaltet die freie Betrachtung eine Kombination aus mehreren Vorgängen, wie automatische (engl. bottom-up) und zielorientierte, willentliche Aufmerksamkeitslenkung (engl. top-down), als auch den Einfluss von Kontextzusammenhängen. Dies bedingt weiter die Berücksichtigung offener (engl. overt; Exploration mittels Augenbewegungen), als auch verdeckter Aufmerksamkeit (engl. covert; periphere Erkundung ohne Augenbewegungen). Im Rahmen der Dissertation werden alle genannten Aspekte anhand von drei Studien behandelt, wodurch eine sorgfältige Untersuchung verschiedener Einflüsse sozialer Aufmerksamkeitsprozesse erfolgt. In der ersten Studie (Abschnitt 2.1) wurden zielgerichtete Manipulationen in Form von Aufgabenstellungen vorgenommen, welche die Aufmerksamkeit innerhalb einer sozialen Szene spezifisch auf nicht-soziale Reize lenken sollten, um kompetitive Ressourcen von sozialer und zielgerichteter Aufmerksamkeit zu untersuchen. Interessanterweise überwog die Tendenz, soziale Aspekte zu betrachten, obwohl dies nachteilig für das Lösen der Aufgaben war. Diese Neigung erwies sich für die allgemeine Fixationsverteilung als auch für Fixationen, die unmittelbar nach Erscheinen der Stimuli auftraten. Dieser Befund impliziert, dass soziale Reize sowohl bei dauerhaften als auch frühen Aufmerksamkeitsprozessen bevorzugt werden. Obwohl es einen allgemeinen Konsens gibt, dass eine Implementierung von Aufgaben zu verändertem Blickverhalten führt, deuten unsere Ergebnisse lediglich auf subtile Abweichungen hin, wenn die Stimuli sozialer Natur sind. Abschließend indiziert dieses Experiment, dass auch mit steigender Bedeutung anderer top-down Modulationen bevorzugt soziale Aspekte betrachtet werden. Die zweite Studie (Abschnitt 2.2) bestand aus zwei separaten Experimenten, welche verdeckte und offene Aufmerksamkeit auf soziale Reize untersuchten. Hierfür wurden in beiden Studien dieselben Bilder verwendet, in denen ein Mensch unilateral, entweder auf der rechten oder linken Hälfte abgebildet war. Das erste Experiment bestand aus einer modifizierten Variante des Dot-Probe Paradigmas, bei dem periphere Zielreize entweder kongruent auf der Seite des sozialen Stimulus erschienen, oder inkongruent auf der nicht sozialen Seite präsentiert wurden. Diese Zuteilung basierte auf der Annahme, dass soziale Merkmale auf ähnliche Weise fungieren wie Hinweisreize in traditionellen Spatial-Cueing-Paradigmen, indem sie Reaktionszeiten auf Zielobjekte, die auf der sozialen Seite präsentiert werden, beschleunigen. Tatsächlich wiesen unsere Ergebnisse einen solchen Kongruenzeffekt auf. Das zweite Experiment überprüfte die reflexiven Vorgänge durch die Messung von Augenbewegungen mittels Spezifizierung der Sakkadenrichtung und Fixationsdichte für kurze als auch lange Präsentationszeiten. Wiederum stellte sich heraus, dass die Mehrzahl der initialen Sakkaden kongruent zum sozialen Reiz gerichtet waren. Darüber hinaus wurden die Ergebnisse für kontinuierliche Aufmerksamkeitsprozesse durch eine erhöhte Fixationsdichte auf Kopfregionen der abgebildeten Menschen repliziert. Die dritte Studie (Abschnitt 2.3) behandelte den umgekehrten Mechanismus der Aufmerksamkeitsdichotomie, nämlich den bottom-up Einfluss. Durch die Verwendung eines blickkongruenten Paradigmas, konnte der kontextuelle Informationsgehalt der Szenen so reduziert werden, dass nur noch der aktuell betrachtete Bereich sichtbar war, während der Rest des Bildes maskiert blieb. Somit mussten die Teilnehmer willentlich ihren Blick verändern, um die Szene zu erkunden. Erstens zeigten die Ergebnisse eine Replikation des sozialen Bias bei freier Betrachtung. Zweitens scheint die Präferenz, soziale Aspekte zu selektieren, in der blickkongruenten Darstellung bestehen zu bleiben. Drittens zeigte sich ein erhöhtes wiederkehrendes Blickmuster bei sozialen im Vergleich zu nicht sozialen Bildern für beide Betrachtungsmodalitäten. Zusammenfassend implizieren diese Ergebnisse eine zielgerichtete Präferenz für soziale Reize, welche größtenteils kontextunabhängig ist. Hervorzuheben ist auch, dass bei allen Experimenten Salienzprädiktoren verschiedener Algorithmen in Betracht gezogen wurden, um sicher zu stellen, dass die Tendenz soziale Reize zu bevorzugen nicht alleine durch hohe physikalische Salienz in diesen Bereichen bedingt wurde. Insbesondere für die zweite Studie (Abschnitt 2.2) wurden Algorithmen verwendet, die sowohl untergeordnete Merkmale als Prädiktoren integrierten als auch Deep Learning Algorithmen, welche vortrainierte, übergeordnete Merkmale definieren, um Vorhersagen zu treffen. So wurde das verwendete Stimulusmaterial reduziert, so dass nur Bilder mit niedriger mittlerer als auch maximaler Salienz auf der nicht-sozialen Seite analysiert wurden. Diese Experimente geben Aufschluss auf einzelne Aufmerksamkeitsprozesse bei der Betrachtung von statischen, sozialen, naturalistischen Szenen und ermöglichen ein tiefergehendes Verständnis für grundlegende soziale Verarbeitung, welche sich von nicht-sozialer Aufmerksamkeit abhebt. Die Replizierbarkeit und Konsistenz der Experimente implizieren einen robusten Effekt und suggerieren eine gesonderte Rolle der sozialen Aufmerksamkeit innerhalb des allgemeinen Aufmerksamkeitskonstrukts. Dies basiert nicht nur auf Verhaltensparametern, sondern potentiell auch auf neuronaler Ebene und enthält darüber hinaus auch Implikationen für klinische Populationen mit beeinträchtigten sozialen Funktionen. KW - Aufmerksamkeit KW - Soziale Wahrnehmung KW - Mechanisms of Social Attention Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-184528 ER - TY - THES A1 - Fink, Mario T1 - Unconventional and topological superconductivity in correlated non-centrosymmetric systems with spin-orbit coupling T1 - Unkonventionelle und topologische Supraleitung in (nicht)zentrosymmetrischen korrelierten System mit Spin-Bahn-Kopplung N2 - Despite its history of more than one hundred years, the phenomenon of superconductivity has not lost any of its allure. During that time the concept and perception of the superconducting state - both from an experimental and theoretical point of view - has evolved in way that has triggered increasing interest. What was initially believed to simply be the disappearance of electrical resistivity, turned out to be a universal and inevitable result of quantum statistics, characterized by many more aspects apart from its zero resistivity. The insights of BCS-theory eventually helped to uncover its deep connection to particle physics and consequently led to the formulation of the Anderson-Higgs-mechanism. The very core of this theory is the concept of gauge symmetry (breaking). Within the framework of condensed-matter theory, gauge invariance is only one of several symmetry groups which are crucial for the description and classification of superconducting states. \\ In this thesis, we employ time-reversal, inversion, point group and spin symmetries to investigate and derive possible Hamiltonians featuring spin-orbit interaction in two and three spatial dimensions. In particular, this thesis aims at a generalization of existing numerical concepts to open up the path to spin-orbit coupled (non)centrosymmetric superconductors in multi-orbital models. This is done in a two-fold way: On the one hand, we formulate - based on the Kohn-Luttinger effect - the perturbative renormalization group in the weak-coupling limit. On the other hand, we define the spinful flow equations of the effective action in the framework of functional renormalization, which is valid for finite interaction strength as well. Both perturbative and functional renormalization groups produce a low-energy effective (spinful) theory that eventually gives rise to a particular superconducting state, which is investigated on the level of the irreducible two-particle vertex. The symbiotic relationship between both perturbative and functional renormalization can be traced back to the fact that, while the perturbative renormalization at infinitesimal coupling is only capable of dealing with the Cooper instability, the functional renormalization can investigate a plethora of instabilities both in the particle-particle and particle-hole channels. \\ Time-reversal and inversion are the two key symmetries, which are being used to discriminate between two scenarios. If both time-reversal and inversion symmetry are present, the Fermi surface will be two-fold degenerate and characterized by a pseudospin degree of freedom. In contrast, if inversion symmetry is broken, the Fermi surface will be spin-split and labeled by helicity. In both cases, we construct the symmetry allowed states in the particle-particle as well as the particle-hole channel. The methods presented are formally unified and implemented in a modern object-oriented reusable and extendable C++ code. This methodological implementation is employed to one member of both families of pseudospin and helicity characterized systems. For the pseudospin case, we choose the intriguing matter of strontium ruthenate, which has been heavily investigated for already twenty-four years, but still keeps puzzling researchers. Finally, as the helicity based application, we consider the oxide heterostructure LaAlO$_{3}$/SrTiO$_{3}$, which became famous for its highly mobile two- dimensional electron gas and is suspected to host topological superconductivity. N2 - Trotz seiner über hundertjährigen Geschichte seit seiner Entdeckung hat das Phänomen der Supraleitung nichts von seiner ursprünglichen Faszination eingebüßt. Vielmehr hat sich in der Zwischenzeit der Begriff und das Verständnis des supraleitenden Zustandes in einer Weise weiterentwickelt, die das Interesse daran eher hat zunehmen lassen. Was anfänglich ausschließlich für ein Verschwinden des elektrischen Widerstands gehalten wurde, ist tatsächlich ein universelles und unvermeidliches Resultat der Quantenstatistik und besitzt viel mehr bemerkenswerte Eigenschaften als nur den widerstandslosen elektrischen Transport. Die Erkenntnisse der BCS-Theorie haben schließlich dazu geführt die tiefe Verbindung zur Teilchenphysik zu offenbaren und trugen entscheidend zur Formulierung des Anderson-Higgs-Mechanismus bei. Der wichtigste Baustein dieser Theorie ist das Konzept der (Brechung der) Eichsymmetrie. Im Rahmen der Festkörperphysik ist die Eichsymmetrie nur eine von mehreren Symmetrien, die eine essentielle Rolle für die Beschreibung und Einordnung von Phänomenen der Supraleitung spielen. \\ In dieser Arbeit wenden wir Zeitumkehr-, (räumliche) Inversions-, Punktgruppen- und Spin-Symmetrien an, um mögliche Hamilton-Operatoren in zwei und drei räumlichen Dimensionen, welche Spin-Bahn-Kopplung enthalten, herzuleiten und zu untersuchen. Diese Arbeit zielt auf eine Verallgemeinerung von existierenden numerischen Konzepten ab und erschließt den Weg die supraleitenden Eigenschaften von Modellen mit starker Spin-Bahn-Kopplung und mit oder ohne Inversionszentrum zu untersuchen. Dies geschieht mit Hilfe zweier methodischer Ansätze. Erstens formulieren wir aufbauend auf dem Kohn-Luttinger Effekt die störungstheoretische Renormierungsgruppe im Limes schwacher Kopplung. Zweitens verwenden wir die spinaufgelösten Flussgleichungen der effektiven Wirkung im Rahmen der funktionalen Renormierungsgruppe, die auch für endliche Wechselwirkungsstärke gültig sind. Die symbiotische Ergänzung der perturbativen und funktionalen Renormierungsgruppen ist darauf zurückzuführen, dass es mit der perturbativen Methode zwar möglich ist die Cooper Instabilität bei infinitesimaler Wechselwirkung numerisch exakt zu berechnen, aber nur die funktionale Renormierungsgruppe auch Teilchen-Loch Kondensate zugänglich macht. \\ Zeitumkehr- und Inversionssymmetrie sind die beiden Schlüsselsymmetrien, die verwendet werden, um zwei Szenarien zu unterscheiden. Falls sowohl Zeitumkehr- als auch Inversionssymmetrie gültig sind, sind die Fermiflächen zweifach entartet und durch einen Pseudospin-Freiheitsgrad charakterisiert. Im Gegensatz dazu führt der Verlust der Inversionssymmetrie zur Spinaufspaltung der Fermiflächen, die dann durch die sogenannte Helizität gekennzeichnet sind. In beiden Fällen leiten wir alle symmetrie-erlaubten Zustände her, welche die entsprechenden Teilchen-Teilchen und Teilchen-Loch Kondensate beschreiben. Die vorstellten und verallgemeinerten Methoden sind im Rahmen dieser Arbeit formal miteinander verbunden und in einem modernen objektorientierten C++ Quellcode implementiert worden. \\ Als erste vorläufige Anwendungen für diese methodische Implementierung betrachten wir zwei Systeme, die jeweils einer der beiden Familien zugeordnet werden können. Zum einen berechnen wir in der Pseudospin-Formulierung der perturbativen und funktionalen Renormierungsgruppen die Instabilitäten eines Dreiorbital-Modells für Strontiumruthenat, das seit seiner erstmaligen Synthese trotz intensiver Forschung immer noch Rätsel aufgibt. Zum anderen betrachten wir das zweidimensionale Elektronengas, das sich an der Schnittstelle zwischen LaAlO$_{3}$ und SrTiO$_{3}$ bildet und welches durch seine hohe Ladungsträgermobilität bekannt geworden ist. KW - Quanten-Vielteilchensysteme KW - Korrelierte Fermionen KW - Spin-Bahn-Kopplung KW - Perturbative/Funktionale Renormierungsgruppe KW - Unkonventionelle/Topologische Supraleitung KW - Quantum many-body systems KW - Correlated Fermions KW - Spin-Orbit interaction KW - Unconventional/Topological superconductivity KW - Perturbative/Functional Renormalization Group Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-175034 ER - TY - JOUR A1 - Figueiredo, Ludmilla A1 - Krauss, Jochen A1 - Steffan-Dewenter, Ingolf A1 - Cabral, Juliano Sarmento T1 - Understanding extinction debts: spatio-temporal scales, mechanisms and a roadmap for future research JF - Ecography N2 - Extinction debt refers to delayed species extinctions expected as a consequence of ecosystem perturbation. Quantifying such extinctions and investigating long‐term consequences of perturbations has proven challenging, because perturbations are not isolated and occur across various spatial and temporal scales, from local habitat losses to global warming. Additionally, the relative importance of eco‐evolutionary processes varies across scales, because levels of ecological organization, i.e. individuals, (meta)populations and (meta)communities, respond hierarchically to perturbations. To summarize our current knowledge of the scales and mechanisms influencing extinction debts, we reviewed recent empirical, theoretical and methodological studies addressing either the spatio–temporal scales of extinction debts or the eco‐evolutionary mechanisms delaying extinctions. Extinction debts were detected across a range of ecosystems and taxonomic groups, with estimates ranging from 9 to 90% of current species richness. The duration over which debts have been sustained varies from 5 to 570 yr, and projections of the total period required to settle a debt can extend to 1000 yr. Reported causes of delayed extinctions are 1) life‐history traits that prolong individual survival, and 2) population and metapopulation dynamics that maintain populations under deteriorated conditions. Other potential factors that may extend survival time such as microevolutionary dynamics, or delayed extinctions of interaction partners, have rarely been analyzed. Therefore, we propose a roadmap for future research with three key avenues: 1) the microevolutionary dynamics of extinction processes, 2) the disjunctive loss of interacting species and 3) the impact of multiple regimes of perturbation on the payment of debts. For their ability to integrate processes occurring at different levels of ecological organization, we highlight mechanistic simulation models as tools to address these knowledge gaps and to deepen our understanding of extinction dynamics. KW - Anthropocene KW - biotic interaction KW - extinction dynamics KW - mechanistic modelling KW - time lag KW - transient dynamics Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-204859 VL - 42 IS - 12 ER - TY - JOUR A1 - Fiedler, David A1 - Hirsch, Daniela A1 - El Hajj, Nady A1 - Yang, Howard H. A1 - Hu, Yue A1 - Sticht, Carsten A1 - Nanda, Indrajit A1 - Belle, Sebastian A1 - Rueschoff, Josef A1 - Lee, Maxwell P. A1 - Ried, Thomas A1 - Haaf, Thomas A1 - Gaiser, Timo T1 - Genome‐wide DNA methylation analysis of colorectal adenomas with and without recurrence reveals an association between cytosine‐phosphate‐guanine methylation and histological subtypes JF - Genes, Chromosomes and Cancer N2 - Aberrant methylation of DNA is supposed to be a major and early driver of colonic adenoma development, which may result in colorectal cancer (CRC). Although gene methylation assays are used already for CRC screening, differential epigenetic alterations of recurring and nonrecurring colorectal adenomas have yet not been systematically investigated. Here, we collected a sample set of formalin‐fixed paraffin‐embedded colorectal low‐grade adenomas (n = 72) consisting of primary adenomas without and with recurrence (n = 59), recurrent adenomas (n = 10), and normal mucosa specimens (n = 3). We aimed to unveil differentially methylated CpG positions (DMPs) across the methylome comparing not only primary adenomas without recurrence vs primary adenomas with recurrence but also primary adenomas vs recurrent adenomas using the Illumina Human Methylation 450K BeadChip array. Unsupervised hierarchical clustering exhibited a significant association of methylation patterns with histological adenoma subtypes. No significant DMPs were identified comparing primary adenomas with and without recurrence. Despite that, a total of 5094 DMPs (false discovery rate <0.05; fold change >10%) were identified in the comparisons of recurrent adenomas vs primary adenomas with recurrence (674; 98% hypermethylated), recurrent adenomas vs primary adenomas with and without recurrence (241; 99% hypermethylated) and colorectal adenomas vs normal mucosa (4179; 46% hypermethylated). DMPs in cytosine‐phosphate‐guanine (CpG) islands were frequently hypermethylated, whereas open sea‐ and shelf‐regions exhibited hypomethylation. Gene ontology analysis revealed enrichment of genes associated with the immune system, inflammatory processes, and cancer pathways. In conclusion, our methylation data could assist in establishing a more robust and reproducible histological adenoma classification, which is a prerequisite for improving surveillance guidelines. KW - adenoma KW - DNA methylation KW - epigenetics KW - histological subtype KW - recurrence Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-212676 VL - 58 IS - 11 SP - 783 EP - 797 ER - TY - JOUR A1 - Ferreira, Manuel A. A1 - Gamazon, Eric R. A1 - Al-Ejeh, Fares A1 - Aittomäki, Kristiina A1 - Andrulis, Irene L. A1 - Anton-Culver, Hoda A1 - Arason, Adalgeir A1 - Arndt, Volker A1 - Aronson, Kristan J. A1 - Arun, Banu K. A1 - Asseryanis, Ella A1 - Azzollini, Jacopo A1 - Balmaña, Judith A1 - Barnes, Daniel R. A1 - Barrowdale, Daniel A1 - Beckmann, Matthias W. A1 - Behrens, Sabine A1 - Benitez, Javier A1 - Bermisheva, Marina A1 - Bialkowska, Katarzyna A1 - Blomqvist, Carl A1 - Bogdanova, Natalia V. A1 - Bojesen, Stig E. A1 - Bolla, Manjeet K. A1 - Borg, Ake A1 - Brauch, Hiltrud A1 - Brenner, Hermann A1 - Broeks, Annegien A1 - Burwinkel, Barbara A1 - Caldés, Trinidad A1 - Caligo, Maria A. A1 - Campa, Daniele A1 - Campbell, Ian A1 - Canzian, Federico A1 - Carter, Jonathan A1 - Carter, Brian D. A1 - Castelao, Jose E. A1 - Chang-Claude, Jenny A1 - Chanock, Stephen J. A1 - Christiansen, Hans A1 - Chung, Wendy K. A1 - Claes, Kathleen B. M. A1 - Clarke, Christine L. A1 - Couch, Fergus J. A1 - Cox, Angela A1 - Cross, Simon S. A1 - Czene, Kamila A1 - Daly, Mary B. A1 - de la Hoya, Miguel A1 - Dennis, Joe A1 - Devilee, Peter A1 - Diez, Orland A1 - Dörk, Thilo A1 - Dunning, Alison M. A1 - Dwek, Miriam A1 - Eccles, Diana M. A1 - Ejlertsen, Bent A1 - Ellberg, Carolina A1 - Engel, Christoph A1 - Eriksson, Mikael A1 - Fasching, Peter A. A1 - Fletcher, Olivia A1 - Flyger, Henrik A1 - Friedman, Eitan A1 - Frost, Debra A1 - Gabrielson, Marike A1 - Gago-Dominguez, Manuela A1 - Ganz, Patricia A. A1 - Gapstur, Susan M. A1 - Garber, Judy A1 - García-Closas, Montserrat A1 - García-Sáenz, José A. A1 - Gaudet, Mia M. A1 - Giles, Graham G. A1 - Glendon, Gord A1 - Godwin, Andrew K. A1 - Goldberg, Mark S. A1 - Goldgar, David E. A1 - González-Neira, Anna A1 - Greene, Mark H. A1 - Gronwald, Jacek A1 - Guenél, Pascal A1 - Haimann, Christopher A. A1 - Hall, Per A1 - Hamann, Ute A1 - He, Wei A1 - Heyworth, Jane A1 - Hogervorst, Frans B. L. A1 - Hollestelle, Antoinette A1 - Hoover, Robert N. A1 - Hopper, John L. A1 - Hulick, Peter J. A1 - Humphreys, Keith A1 - Imyanitov, Evgeny N. A1 - Isaacs, Claudine A1 - Jakimovska, Milena A1 - Jakubowska, Anna A1 - James, Paul A. A1 - Janavicius, Ramunas A1 - Jankowitz, Rachel C. A1 - John, Esther M. A1 - Johnson, Nichola A1 - Joseph, Vijai A1 - Karlan, Beth Y. A1 - Khusnutdinova, Elza A1 - Kiiski, Johanna I. A1 - Ko, Yon-Dschun A1 - Jones, Michael E. A1 - Konstantopoulou, Irene A1 - Kristensen, Vessela N. A1 - Laitman, Yael A1 - Lambrechts, Diether A1 - Lazaro, Conxi A1 - Leslie, Goska A1 - Lester, Jenny A1 - Lesueur, Fabienne A1 - Lindström, Sara A1 - Long, Jirong A1 - Loud, Jennifer T. A1 - Lubiński, Jan A1 - Makalic, Enes A1 - Mannermaa, Arto A1 - Manoochehri, Mehdi A1 - Margolin, Sara A1 - Maurer, Tabea A1 - Mavroudis, Dimitrios A1 - McGuffog, Lesley A1 - Meindl, Alfons A1 - Menon, Usha A1 - Michailidou, Kyriaki A1 - Miller, Austin A1 - Montagna, Marco A1 - Moreno, Fernando A1 - Moserle, Lidia A1 - Mulligan, Anna Marie A1 - Nathanson, Katherine L. A1 - Neuhausen, Susan L. A1 - Nevanlinna, Heli A1 - Nevelsteen, Ines A1 - Nielsen, Finn C. A1 - Nikitina-Zake, Liene A1 - Nussbaum, Robert L. A1 - Offit, Kenneth A1 - Olah, Edith A1 - Olopade, Olufunmilayo I. A1 - Olsson, Håkan A1 - Osorio, Ana A1 - Papp, Janos A1 - Park-Simon, Tjoung-Won A1 - Parsons, Michael T. A1 - Pedersen, Inge Sokilde A1 - Peixoto, Ana A1 - Peterlongo, Paolo A1 - Pharaoh, Paul D. P. A1 - Plaseska-Karanfilska, Dijana A1 - Poppe, Bruce A1 - Presneau, Nadege A1 - Radice, Paolo A1 - Rantala, Johanna A1 - Rennert, Gad A1 - Risch, Harvey A. A1 - Saloustros, Emmanouil A1 - Sanden, Kristin A1 - Sawyer, Elinor J. A1 - Schmidt, Marjanka K. A1 - Schmutzler, Rita K. A1 - Sharma, Priyanka A1 - Shu, Xiao-Ou A1 - Simard, Jaques A1 - Singer, Christian F. A1 - Soucy, Penny A1 - Southey, Melissa C. A1 - Spinelli, John J. A1 - Spurdle, Amanda B. A1 - Stone, Jennifer A1 - Swerdlow, Anthony J. A1 - Tapper, William J. A1 - Taylor, Jack A. A1 - Teixeira, Manuel R. A1 - Terry, Mary Beth A1 - Teulé, Alex A1 - Thomassen, Mads A1 - Thöne, Kathrin A1 - Thull, Darcy L. A1 - Tischkowitz, Marc A1 - Toland, Amanda E. A1 - Torres, Diana A1 - Truong, Thérèse A1 - Tung, Nadine A1 - Vachon, Celine M. A1 - van Asperen, Christi J. A1 - van den Ouweland, Ans M. W. A1 - van Rensburg, Elizabeth J. A1 - Vega, Ana A1 - Viel, Alexandra A1 - Wang, Qin A1 - Wappenschmidt, Barbara A1 - Weitzel, Jeffrey N. A1 - Wendt, Camilla A1 - Winqvist, Robert A1 - Yang, Xiaohong R. A1 - Yannoukakos, Drakoulis A1 - Ziogas, Argyrios A1 - Kraft, Peter A1 - Antoniou, Antonis C. A1 - Zheng, Wei A1 - Easton, Douglas F. A1 - Milne, Roger L. A1 - Beesley, Jonathan A1 - Chenevix-Trench, Georgia T1 - Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer JF - Nature Communications N2 - Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer. KW - cancer KW - genetics Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228024 VL - 10 ER - TY - JOUR A1 - Feldheim, Jonas A1 - Kessler, Almuth F. A1 - Monoranu, Camelia M. A1 - Ernestus, Ralf-Ingo A1 - Löhr, Mario A1 - Hagemann, Carsten T1 - Changes of O\(^6\)-Methylguanine DNA Methyltransferase (MGMT) promoter methylation in glioblastoma relapse—a meta-analysis type literature review JF - Cancers N2 - Methylation of the O6-methylguanine DNA methyltransferase (MGMT) promoter has emerged as strong prognostic factor in the therapy of glioblastoma multiforme. It is associated with an improved response to chemotherapy with temozolomide and longer overall survival. MGMT promoter methylation has implications for the clinical course of patients. In recent years, there have been observations of patients changing their MGMT promoter methylation from primary tumor to relapse. Still, data on this topic are scarce. Studies often consist of only few patients and provide rather contrasting results, making it hard to draw a clear conclusion on clinical implications. Here, we summarize the previous publications on this topic, add new cases of changing MGMT status in relapse and finally combine all reports of more than ten patients in a statistical analysis based on the Wilson score interval. MGMT promoter methylation changes are seen in 115 of 476 analyzed patients (24%; CI: 0.21–0.28). We discuss potential reasons like technical issues, intratumoral heterogeneity and selective pressure of therapy. The clinical implications are still ambiguous and do not yet support a change in clinical practice. However, retesting MGMT methylation might be useful for future treatment decisions and we encourage clinical studies to address this topic KW - glioblastoma multiforme (GBM) KW - glioma KW - relapse KW - temozolomide KW - MGMT promoter methylation KW - therapy KW - resistance KW - recurrence Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193040 SN - 2072-6694 VL - 11 IS - 12 ER - TY - JOUR A1 - Fayez, Shaimaa A1 - Feineis, Doris A1 - Aké Assi, Laurent A1 - Seo, Ean-Jeong A1 - Efferth, Thomas A1 - Bringmann, Gerhard T1 - Ancistrobreveines A–D and related dehydrogenated naphthylisoquinoline alkaloids with antiproliferative activities against leukemia cells, from the West African liana Ancistrocladus abbreviatus JF - RSC Advances N2 - A unique series of six biaryl natural products displaying four different coupling types (5,10 , 7,10 , 7,80 , and 5,80) were isolated from the roots of the West African liana Ancistrocladus abbreviatus (Ancistrocladaceae). Although at first sight structurally diverse, these secondary metabolites all have in common that they belong to the rare group of naphthylisoquinoline alkaloids with a fully dehydrogenated isoquinoline portion. Among the African Ancistrocladus species, A. abbreviatus is so far only the second one that was found to produce compounds with such a molecular entity. Here, we report on four new representatives, named ancistrobreveines A–D (12–14, and 6). They were identified along with the two known alkaloids 6-O-methylhamateine (4) and entdioncophylleine A (10). The two latter naphthylisoquinolines had so far only been detected in Ancistrocladus species from Southeast Asia. All of these fully dehydrogenated alkaloids have in common being optically active despite the absence of stereogenic centers, due to the presence of the rotationally hindered biaryl axis as the only element of chirality. Except for ent-dioncophylleine A (10), which lacks an oxygen function at C-6, the ancistrobreveines A–D (12–14, and 6) and 6-O-methylhamateine (4) are 6-oxygenated alkaloids, and are, thus, typical ‘Ancistrocladaceae-type’ compounds. Ancistrobreveine C (14), is the first – and so far only – example of a 7,80-linked fully dehydrogenated naphthylisoquinoline discovered in nature that is configurationally stable at the biaryl axis. The stereostructures of the new alkaloids were established by spectroscopic (in particular HRESIMS, 1D and 2D NMR) and chiroptical (electronic circular dichroism) methods. Ancistrobreveine C (14) and 6-O-methylhamateine (4) exhibited strong antiproliferative activities against drug-sensitive acute lymphoblastic CCRF-CEM leukemia cells and their multidrugresistant subline, CEM/ADR5000. KW - chemistry Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201686 VL - 9 IS - 28 ER - TY - JOUR A1 - Fathy, Moustafa A1 - Fawzy, Michael Atef A1 - Hintzsche, Henning A1 - Nikaido, Toshio A1 - Dandekar, Thomas A1 - Othman, Eman M. T1 - Eugenol exerts apoptotic effect and modulates the sensitivity of HeLa cells to cisplatin and radiation JF - Molecules N2 - Eugenol is a phytochemical present in different plant products, e.g., clove oil. Traditionally, it is used against a number of different disorders and it was suggested to have anticancer activity. In this study, the activity of eugenol was evaluated in a human cervical cancer (HeLa) cell line and cell proliferation was examined after treatment with various concentrations of eugenol and different treatment durations. Cytotoxicity was tested using lactate dehydrogenase (LDH) enzyme leakage. In order to assess eugenol’s potential to act synergistically with chemotherapy and radiotherapy, cell survival was calculated after eugenol treatment in combination with cisplatin and X-rays. To elucidate its mechanism of action, caspase-3 activity was analyzed and the expression of various genes and proteins was checked by RT-PCR and western blot analyses. Eugenol clearly decreased the proliferation rate and increased LDH release in a concentration- and time-dependent manner. It showed synergistic effects with cisplatin and X-rays. Eugenol increased caspase-3 activity and the expression of Bax, cytochrome c (Cyt-c), caspase-3, and caspase-9 and decreased the expression of B-cell lymphoma (Bcl)-2, cyclooxygenase-2 (Cox-2), and interleukin-1 beta (IL-1β) indicating that eugenol mainly induced cell death by apoptosis. In conclusion, eugenol showed antiproliferative and cytotoxic effects via apoptosis and also synergism with cisplatin and ionizing radiation in the human cervical cancer cell line. KW - eugenol KW - HeLa cells KW - cisplatin KW - radiation KW - apoptosis Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193227 SN - 1420-3049 VL - 24 IS - 21 ER - TY - JOUR A1 - Farrell, Jeffrey M. A1 - Grande, Vincenzo A1 - Schmidt, David A1 - Würthner, Frank T1 - A Highly Warped Heptagon-Containing sp\(^2\) Carbon Scaffold via Vinylnaphthyl π-Extension JF - Angewandte Chemie International Edition N2 - A new strategy is demonstrated for the synthesis of warped, negatively curved, all‐sp\(^2\)‐carbon π‐scaffolds. Multifold C−C coupling reactions are used to transform a polyaromatic borinic acid into a saddle‐shaped polyaromatic hydrocarbon (2 ) bearing two heptagonal rings. Notably, this Schwarzite substructure is synthesized in only two steps from an unfunctionalized alkene. A highly warped structure of 2 was revealed by X‐ray crystallographic studies and pronounced flexibility of this π‐scaffold was ascertained by experimental and computational studies. Compound 2 exhibits excellent solubility, visible range absorption and fluorescence, and readily undergoes two reversible one‐electron oxidations at mild potentials. KW - arenes KW - carbon KW - C-C coupling KW - curvature KW - polycyclic aromatic hydrocarbons Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-206682 VL - 58 IS - 46 ER - TY - JOUR A1 - Fan, Sook-Ha A1 - Ebner, Patrick A1 - Reichert, Sebstian A1 - Hertlein, Tobias A1 - Zabel, Susanne A1 - Lankapalli, Aditya Kumar A1 - Nieselt, Kay A1 - Ohlsen, Knut A1 - Götz, Friedrich T1 - MpsAB is important for Staphylococcus aureus virulence and growth at atmospheric CO2 levels JF - Nature Communications N2 - The mechanisms behind carbon dioxide (CO2) dependency in non-autotrophic bacterial isolates are unclear. Here we show that the Staphylococcus aureus mpsAB operon, known to play a role in membrane potential generation, is crucial for growth at atmospheric CO2 levels. The genes mpsAB can complement an Escherichia coli carbonic anhydrase (CA) mutant, and CA from E. coli can complement the S. aureus delta-mpsABC mutant. In comparison with the wild type, S. aureus mps mutants produce less hemolytic toxin and are less virulent in animal models of infection. Homologs of mpsA and mpsB are widespread among bacteria and are often found adjacent to each other on the genome. We propose that MpsAB represents a dissolved inorganic carbon transporter, or bicarbonate concentrating system, possibly acting as a sodium bicarbonate cotransporter. KW - bacterial physiology KW - bacteriology KW - pathogens Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227624 VL - 10 ER - TY - JOUR A1 - Fahmy-Garcia, Shorouk A1 - Farrell, Eric A1 - Witte-Bouma, Janneke A1 - Robbesom-van den Berge, Iris A1 - Suarez, Melva A1 - Mumcuoglu, Didem A1 - Walles, Heike A1 - Kluijtmans, Sebastiaan G. J. M. A1 - van der Eerden, Bram C. J. A1 - van Osch, Gerjo J. V. M. A1 - van Leeuwen, Johannes P. T. M. A1 - van Driel, Marjolein T1 - Follistatin Effects in Migration, Vascularization, and Osteogenesis in vitro and Bone Repair in vivo JF - Frontiers in Bioengineering and Biotechnology N2 - The use of biomaterials and signaling molecules to induce bone formation is a promising approach in the field of bone tissue engineering. Follistatin (FST) is a glycoprotein able to bind irreversibly to activin A, a protein that has been reported to inhibit bone formation. We investigated the effect of FST in critical processes for bone repair, such as cell recruitment, osteogenesis and vascularization, and ultimately its use for bone tissue engineering. In vitro, FST promoted mesenchymal stem cell (MSC) and endothelial cell (EC) migration as well as essential steps in the formation and expansion of the vasculature such as EC tube-formation and sprouting. FST did not enhance osteogenic differentiation of MSCs, but increased committed osteoblast mineralization. In vivo, FST was loaded in an in situ gelling formulation made by alginate and recombinant collagen-based peptide microspheres and implanted in a rat calvarial defect model. Two FST variants (FST288 and FST315) with major differences in their affinity to cell-surface proteoglycans, which may influence their effect upon in vivo bone repair, were tested. In vitro, most of the loaded FST315 was released over 4 weeks, contrary to FST288, which was mostly retained in the biomaterial. However, none of the FST variants improved in vivo bone healing compared to control. These results demonstrate that FST enhances crucial processes needed for bone repair. Further studies need to investigate the optimal FST carrier for bone regeneration. KW - follistatin 315 (FST315) KW - follistatin 288 (FST288) KW - migration KW - vascularization KW - osteogenesis KW - injectable in situ gelling slow release system KW - bone tissue engineering KW - regenerative medicine Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227617 VL - 7 ER - TY - JOUR A1 - Evers, Ann-Kristin A1 - Veeh, Julia A1 - McNeill, Rhiannon A1 - Reif, Andreas A1 - Kittel-Schneider, Sarah T1 - C-reactive protein concentration in bipolar disorder: association with genetic variants JF - International Journal of Bipolar Disorders N2 - Background Several recent studies have investigated the role of C-reactive protein (CRP) in bipolar disorder (BD), but few studies have directly investigated the interaction between CRP genetic variants and peripheral CRP concentration across different phases of BD. In this study, we aimed to replicate previous findings that demonstrated altered CRP levels in BD, and to investigate whether there is an association of peripheral protein expression with genetic variants in the CRP gene. Methods 221 patients were included in the study, of which 183 (all episodes, 46 not medicated, 174 medicated) were genotyped for CRP single-nucleotide polymorphisms (SNPs) shown to influence peripheral CRP protein expression (rs1800947, rs2808630, rs1417938, rs1205). Results There were no differences in CRP levels associated with the genotypes, only regarding the rs1205 SNP there were significantly different CRP protein expression between the genotypes when taking body mass index, age, BD polarity, subtype and leukocyte number into account. However, we could show significantly elevated CRP protein expression in manic patients compared to euthymic and depressed patients, independent from genotype. Medication was found to have no effect on CRP protein expression. Conclusions These results indicate that low grade inflammation might play a role in mania and might be rather a state than a trait marker of bipolar disorder. KW - Bipolar disorder KW - Genotype KW - C-reactive protein KW - Biomarke KW - Inflammatio Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202289 VL - 7 ER - TY - JOUR A1 - Evdokimov, Dimitar A1 - Frank, Johanna A1 - Klitsch, Alexander A1 - Unterecker, Stefan A1 - Warrings, Bodo A1 - Serra, Jordi A1 - Papagianni, Aikaterini A1 - Saffer, Nadine A1 - Meyer zu Altenschildesche, Caren A1 - Kampik, Daniel A1 - Malik, Rayaz A. A1 - Sommer, Claudia A1 - Üceyler, Nurcan T1 - Reduction of skin innervation is associated with a severe fibromyalgia phenotype JF - Annals of Neurology N2 - Objective: To assess patterns and impact of small nerve fiber dysfunction and pathology in patients with fibromyalgia syndrome (FMS). Methods: One hundred seventeen women with FMS underwent neurological examination, questionnaire assessment, neurophysiology assessment, and small fiber tests: skin punch biopsy, corneal confocal microscopy, microneurography, quantitative sensory testing including C-tactile afferents, and pain-related evoked potentials. Data were compared with those of women with major depressive disorder and chronic widespread pain (MD-P) and healthy women. Results: Intraepidermal nerve fiber density (IENFD) was reduced at different biopsy sites in 63% of FMS patients (MDP: 10%, controls: 18%; p < 0.001 for each). We found 4 patterns of skin innervation in FMS: normal, distally reduced, proximally reduced, and both distally and proximally reduced (p < 0.01 for each compared to controls). Microneurography revealed initial activity-dependent acceleration of conduction velocity upon low frequencies of stimulation in 1A fibers, besides 1B fiber spontaneous activity and mechanical sensitization in FMS patients. FMS patients had elevated warm detection thresholds (p < 0.01), impaired C-tactile afferents (p < 0.05), and reduced amplitudes (p < 0.001) of pain-related evoked potentials compared to controls. Compared to FMS patients with normal skin innervation, those with generalized IENFD reduction had higher pain intensity and impairment due to pain, higher disease burden, more stabbing pain and paresthesias, and more anxiety (p < 0.05 for each). FMS patients with generalized IENFD reduction also had lower corneal nerve fiber density (p < 0.01) and length (p < 0.05). Interpretation: The extent of small fiber pathology is related to symptom severity in FMS. This knowledge may have implications for the diagnostic classification and treatment of patients with FMS. KW - fibromyalgia Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-206168 VL - 86 IS - 4 ER - TY - INPR A1 - Englert, Lukas A1 - Stoy, Andreas A1 - Arrowsmith, Merle A1 - Müssig, Jonas H. A1 - Thaler, Melanie A1 - Deißenberger, Andrea A1 - Häfner, Alena A1 - Böhnke, Julian A1 - Hupp, Florian A1 - Seufert, Jens A1 - Mies, Jan A1 - Damme, Alexander A1 - Dellermann, Theresa A1 - Hammond, Kai A1 - Kupfer, Thomas A1 - Radacki, Krzysztof A1 - Thiess, Torsten A1 - Braunschweig, Holger T1 - Stable Lewis Base Adducts of Tetrahalodiboranes: Synthetic Methods and Structural Diversity T2 - Chemistry - A European Journal N2 - A series of 22 new bis(phosphine), bis(carbene) and bis(isonitrile) tetrahalodiborane adducts has been synthesized, either by direct adduct formation with highly sensitive B2X4 precursors (X = Cl, Br, I) or by ligand exchange at stable B2X4(SMe2)2 precursors (X = Cl, Br) with labile dimethylsulfide ligands. The isolated compounds have been fully characterized using NMR spectroscopic, (C,H,N)- elemental and, for 20 of these compounds, X-ray crystallographic analysis, revealing an unexpected variation in the bonding motifs. Besides the classical B2X4L2 diborane(6) adducts, some of the more sterically demanding carbene ligands induce a halide displacement leading to the first halide-bridged monocationic diboron species, [B2X3L2]A (A = BCl4, Br, I). Furthermore, low-temperature 1:1 reactions of B2Cl4 with sterically demanding N-heterocyclic carbenes led to the formation of kinetically unstable mono-adducts, one of which was structurally characterized. A comparison of the NMR and structural data of new and literature-known bis-adducts shows several trends pertaining to the nature of the halides and the stereoelectronic properties of the Lewis bases employed. KW - diborane(6) KW - Lewis-base adducts KW - ligand exchange KW - crystallography KW - NMR spectroscopy Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-184888 N1 - This is the pre-peer reviewed version of the following article: L. Englert, A. Stoy, M. Arrowsmith, J. H. Muessig, M. Thaler, A. Deißenberger, A. Häfner, J. Böhnke, F. Hupp, J. Seufert, J. Mies, A. Damme, T. Dellermann, K. Hammond, T. Kupfer, K. Radacki, T. Thiess, H. Braunschweig, Chem. Eur. J. 2019, 25, 8612. https://doi.org/10.1002/chem.201901437, which has been published in final form at https://doi.org/10.1002/chem.201901437. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. ER - TY - JOUR A1 - Engel, Florian A. A1 - Wagner, Matthias Oliver A1 - Schelhorn, Franziska A1 - Deubert, Felix A1 - Leutzsch, Sascha A1 - Stolz, Alexander A1 - Sperlich, Billy T1 - Classroom-Based Micro-Sessions of Functional High-Intensity Circuit Training Enhances Functional Strength but Not Cardiorespiratory Fitness in School Children — A Feasibility Study JF - Frontiers in Public Health N2 - The present study assessed the short-term effect of 6 min classroom-based micro-sessions of multi-joint functional high-intensity circuit training (FunctionalHIIT) performed by students during regular classes on parameters related to functional strength and cardiorespiratory fitness. In this randomized controlled 4-week study, 17 students (11 male; 6 female; age: 11.6 ± 0.2 years) performed 6 min of FunctionalHIIT (targeting >17 on the Borg scale) 4 days per week during regular school classes and 18 students (11 male; 7 female; age: 11.7 ± 0.3 years) served as control group (CG) without any additional in-class physical activity. The FunctionalHIIT group completed 86% of all planned sessions (mean duration: 6.0 ± 1.5 min) with a mean RPE of 17.3 ± 2.1. Body height, mass and BMI did not differ between the groups at baseline or between pre- and post-testing (p > 0.05; eta2 ≤ 0.218). The performances in lateral jumping (p < 0.000; part eta2 = 0.382; Δ% 4.6 ± 8.6), sit-ups (p < 0.000; part eta2 = 0.485; Δ% 3.1 ± 8.6) and 20-m sprints (p < 0.000; part eta2 = 0.691; Δ% 15.8 ± 5.4) improved in both groups with greater increase following FunctionalHIIT. No baseline differences and no interaction effects occurred in performance of 6 min run, flexibility, push-ups, balance, and long jump. Classroom-based FunctionalHIIT sessions, performed 4 days per week during 4 weeks did not improve variables related to aerobic endurance performance but enhanced certain parameters of functional strength in schoolchildren. As time is limited in the educational system of schools, FunctionalHIIT during regular school classes could offer a new perspective for increasing functional strength in schoolchildren. KW - aerobic fitness KW - exercise intervention KW - functional training KW - interval training KW - physical activity promotion Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-195669 SN - 2296-2565 VL - 7 IS - 291 ER - TY - THES A1 - Endres, Ralph Julian T1 - Networks of fear: Functional connectivity of the amygdala, the insula and the anterior cingulate cortex in two subtypes of specific phobia T1 - Netzwerke der Angst: Funktionelle Konnektivität der Amygdala, der Insula und des anterioren cingulären Cortex in zwei Subtypen der spezifischen Phobie N2 - Neuroimaging research has highlighted the relevance of well-balanced functional brain interactions as an essential basis for efficient emotion regulation. In contrast, abnormal coupling of fear-processing regions such as the amygdala, the anterior cingulate cortex (ACC) and the insula could be an important feature of anxiety disorders. Although activity alterations of these regions have been frequently reported in specific phobia, little is known about their functional interactions during phobogenic stimulus processing. To explore these interrelationships in two subtypes of specific phobia – i.e., the blood-injection-injury subtype and the animal subtype – functional connectivity (FC) was analyzed in three fMRI studies. Two studies examined fear processing in a dental phobia group (DP), a snake phobia group (SP) and a healthy control group (HC) during visual phobogenic stimuli presentation while a third study investigated differences between auditory and visual stimuli presentation in DP and HC. Due to a priori hypotheses of impaired interactions between the amygdala, the ACC and the insula, a first analysis was conducted to explore the FC within these three regions of interest. Based on emerging evidence of functionally diverse subregions, the ACC was further divided into a subgenual, pregenual and dorsal ACC and the insula was divided into a ventral-anterior, dorsal-anterior and posterior region. Additionally, an exploratory seed-to-voxel analysis using the amygdala, ACC and insula as seeds was conducted to scan for connectivity patterns across the whole brain. The analyses revealed a negative connectivity of the ACC and the amygdala during phobogenic stimulus processing in controls. This connectivity was predominantly driven by the affective ACC subdivision. By contrast, SP was characterized by an increased mean FC between the examined regions. Interestingly, this phenomenon was specific for auditory, but not visual symptom provocation in DP. During visual stimulus presentation, however, DP exhibited further FC alterations of the ACC and the insula with pre- and orbitofrontal regions. These findings mark the importance of balanced interactions between fear-processing regions in specific phobia, particularly of the inhibitory connectivity between the ACC and the amygdala. Theoretically, this is assumed to reflect top-down inhibition by the ACC during emotion regulation. The findings support the suggestion that SP particularly is characterized by excitatory, or missing inhibitory, (para-) limbic connectivity, reflecting an overshooting fear response based on evolutionary conserved autonomic bottom-up pathways. Some of these characteristics applied to DP as well but only under the auditory stimulation, pointing to stimulus dependency. DP was further marked by altered pre- and orbitofrontal coupling with the ACC and the insula which might represent disturbances of superordinate cognitive control on basal emotion processes. These observations strengthen the assumption that DP is predominantly based on evaluation-based fear responses. In conclusion, the connectivity patterns found may depict an intermediate phenotype that possibly confers risks for inappropriate phobic fear responses. The findings presented could also be of clinical interest. Particularly the ACC – amygdala circuit may be used as a predictive biomarker for treatment response or as a promising target for neuroscience-focused augmentation strategies as neurofeedback or repetitive transcranial magnetic stimulation. N2 - Neurowissenschaftliche Erkenntnisse der letzten Jahre verdeutlichten die Relevanz intakter neuronaler Netzwerke als Grundlage adäquater Emotionsregulationsmechanismen. Funktionelle Dysregulationen zwischen angstverarbeitenden Regionen wie der Amygdala, der Insula oder dem anterioren cingulären Cortex (ACC) könnten hingegen einen wichtigen pathophysiologischen Mechanismus von Angststörungen darstellen. Obwohl Aktivitätsunterschiede dieser Regionen wiederholt für spezifische Phobien beschrieben wurden, sind deren funktionelle Interaktionen während phobischer Stimulusverarbeitung kaum erforscht. Zur Untersuchung dieser Interaktionen in zwei Subtypen der spezifischen Phobie – dem Blut-Spritzen-Verletzungs-Typus und dem Tier-Typus – wurden im Rahmen dieser Arbeit funktionelle Konnektivitäts-Analysen (FK) anhand dreier fMRT- (funktionelle Magnetresonanztomographie) Studien durchgeführt. Zwei Studien untersuchten die neurale Verarbeitung visueller phobischer Stimuli in einer dentalphobischen Gruppe (DP), einer schlangenphobischen Gruppe (SP) sowie einer Kontrollgruppe (KG). Ergänzend verglich eine dritte Studie den Einfluss visueller und akustischer Stimuli für die DP und eine KG. Basierend auf der a priori-Hypothese einer veränderten FK zwischen der Amygdala, der Insula und dem ACC wurden deren spezifische Konnektivitätsmuster untersucht. Aufgrund funktionell unterschiedlicher Subregionen erfolgte eine Untergliederung des ACC in eine subgenuale, perigenuale und dorsalen Region. Analog dazu wurde die Insula in eine ventral-anteriore, dorsal-anteriore und posteriore Region unterteilt. Um darüberhinausgehender Konnektivitätsmuster über das gesamte Gehirn zu ermitteln, wurde eine abschließende Seed-to-Voxel-Analyse mit den Seeds Amygdala, Insula und ACC durchgeführt. In der Auswertung zeigte sich eine negative FK der Amygdala und des ACC während phobischer Stimulusverarbeitung in der KG, die insbesondere auf die ventrale Division des ACC zurückzuführen war. Die phobischen Gruppen hingegen waren im Vergleich zu der Kontrollgruppe durch eine erhöhte Konnektivität der untersuchten Regionen gekennzeichnet. Dieser Effekt war bei der DP spezifisch für die akustische Stimulusmodalität. Bei visueller Stimuluspräsentation zeigten sich hingegen veränderte Konnektivitätsmuster des ACC und der Insula mit prä- und orbitofrontalen Regionen. Insbesondere die negative FK der Amygdala und des ACC, die theoretisch auf einer top-down-Inhibition des ACC über die Amygdala basiert, erscheint einen wichtigen Bestandteil einer effektiven emotionalen Kontrolle darzustellen. In beiden phobischen Gruppen fehlte diese Inhibition. Die erhöhte FK (para-)limbischer Konnektivität der SP könnte hingegen die verstärkte Rekrutierung autonomischer bottom-up-Prozesse als zugrundeliegendem Mechanismus der überschießenden und irrationalen Angstreaktion repräsentieren. Diese Charakteristika konnten in der DP nur für die akustische Stimulusmodalität beobachtet werden. Während der visuellen Stimuluspräsentation war die DP durch Dysregulationen prä- und orbitofrontaler Regionen gekennzeichnet, welche eine beeinträchtigte kognitive Kontrolle über grundlegende Emotionsprozesse widerspiegeln könnte. Dies entspricht der Annahme, dass die DP vor allem durch evaluationsbasierte Furchtreaktionen gekennzeichnet ist, während in der SP als Vertreter des Tier-Typus evolutionär konservierte, limbische Prozesse dominieren. Zusammenfassend bestätigen die Ergebnisse die Bedeutung funktioneller Netzwerke in der spezifischen Phobie, wobei die gefundenen Konnektivitätsmuster einen intermediären Phänotyp darstellen könnten, der möglicherweise das Risiko für das Auftreten dysfunktionaler phobischer Angstreaktionen vermittelt. Von klinischem Interesse ist vor allem die Amygdala – ACC-Vernetzung, die als prädiktiver Biomarker für das Therapieansprechen genutzt oder im Rahmen neuromodulatorischer Therapieansätze wie dem Neurofeedback oder der repetitiven transkraniellen Magnetstimulation gezielt angesteuert werden könnte. KW - Kernspintomografie KW - Psychiatrie KW - Phobie KW - fMRT KW - Funktionelle Konnektivität KW - Spezifische Phobien KW - fMRI KW - Functional Connectivity KW - Specific Phobia KW - Neuroimaging KW - Dental Phobia KW - Zahnbehandlungsphobie KW - Angstverarbeitung Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-180950 ER - TY - THES A1 - Elsässer, Sebastian T1 - Lattice dynamics and spin-phonon coupling in the multiferroic oxides Eu(1-x)Ho(x)MnO3 and ACrO2 T1 - Gitterdynamik und Spin-Phonon Kopplung in den multiferroischen Oxiden Eu(1-x)Ho(x)MnO3 und ACrO2 N2 - The focus of this thesis is the investigation of the lattice dynamics and the coupling of magnetism and phonons in two different multiferroic model systems. The first system, which constitutes the main part in this work is the system of multiferroic manganites RMnO$_{3}$, in particular Eu$_{1-x}$Ho$_{x}$MnO$_{3}$ with $0 \le x \le 0.5$. Its cycloidal spin arrangement leads to the emergence of the ferroelectric polarization via the inverse Dzyaloshinskii-Moriya interaction. This system is special among RMnO$_{3}$ as with increasing Ho content $x$, Eu$_{1-x}$Ho$_{x}$MnO$_{3}$ does not only become multiferroic, but due to the exchange interaction with the magnetic Ho-ion, the spin cycloid (and with it the electric polarization) is also flipped for higher Ho contents. This makes it one of the first compounds, where the cycloidal reorientation happens spontaneously, rather than with the application of external fields. On the other hand, there is the delafossite ACrO$_{2}$ system. Here, due to symmetry reasons, the spin-spiral pattern can not induce the polarization according to the inverse Dzyaloshinskii-Moriya interaction mechanism. Instead, it is thought that another way of magnetoelectric coupling is involved, which affects the charge distribution in the $d-p$ hybridized orbitals of the bonds. The lattice vibrations as well as the quasi-particle of the multiferroic phase, the electromagnon, are studied by Raman spectroscopy. Lattice vibrations like the B$_{3g}$(1) mode, which involves vibrations of the Mn-O-Mn bonds modulate the exchange interaction and serve as a powerful tool for the investigation of magnetic correlations effects with high frequency accuracy. Raman spectroscopy acts as a local probe as even local magnetic correlations directly affect the phonon vibration frequency, revealing coupling effects onto the lattice dynamics even in the absence of global magnetic order. By varying the temperature, the coupling is investigated and unveils a renormalization of the phonon frequency as the magnetic order develops. For Eu$_{1-x}$Ho$_{x}$MnO$_{3}$, the analysis of this spin-induced phonon frequency renormalization enables the quantitative determination of the in-plane spin-phonon coupling strengths. This formalism, introduced by Granado et al., is extended here to evaluate the out-of-plane coupling strengths, which is enabled by the identification of a previously elusive feature as a vibrational mode. The complete picture is obtained by studying the lattice- and electromagnon dynamics in the magnetic field. Further emphasis is put towards the development of the cycloidal spin structure and correlations with temperature. A new model of describing the temperature-dependent behavior of said spin correlations is proposed and can consistently explain ordering phenomena which were until now unaddressed. The results are underscored with Monte Carlo based simulations of the spin dynamics with varying temperature. Furthermore, a novel effect of a tentative violation of the Raman selection rules in Eu$_{1-x}$Ho$_{x}$MnO$_{3}$ was discovered. While the phonon modes can be separated and identified by their symmetry by choosing appropriate polarization configurations, in a very narrow temperature range, Eu$_{1-x}$Ho$_{x}$MnO$_{3}$ shows an increase of phonon intensities in polarization configurations where they should be forbidden. This is interpreted as a sign of local disorder, caused by 90° domain walls and could be explained within the model framework. This course of action is followed with the material system of delafossites ACrO$_{2}$. Being a relatively new class of multiferroic materials, the investigations on ACrO$_{2}$ are also of characterizing nature. For this, shell model calculations are performed as a reference to compare the vibrational frequencies obtained by the Raman experiments to. A renormalization of the vibrational frequencies is observed in this system as well and systematically analyzed across the sample series of \textit{A}=Cu, Pd and Ag. Eventually, the effect of applying an external magnetic field is studied. A particularly interesting feature specific for CuCrO$_{2}$ is a satellite peak which appears at lower temperatures. It is presumably related to a deformation of the lattice and therefore going to be discussed in further detail. N2 - Mit der Entdeckung des Riesenmagnetoelektischen Effekts (Giant Magnetoelectric Effect) in TbMnO$_{3}$ durch Kimura et al., im Jahre 2003, erlebte das Forschungsgebiet der multiferroischen Seltenerdmanganate RMnO$_{3}$ einen neuen Aufschwung durch die neuen Möglichkeiten, die sich durch diese Entdeckung offenbarten. \cite{Kimura2003} Der Effekt besteht darin, dass sich durch ein bestimmtes Muster der magnetischen Ordnung eine direkt an dieses Muster gekoppelte ferroelektrische Polarisation ergibt. Die Kopplung von magnetischer und ferroelektrischer Ordnung bewirkt, dass stets beide Parameter simultan beeinflusst werden, wenn ein externes elektrisches oder magnetisches Feld angelegt wird: Wird das Magnetisierungsmuster durch ein externes Magnetfeld beeinflusst, wirkt sich dies direkt auf die elektrische Polarisation aus. Umgekehrt, wenn die Polarisation durch ein elektrisches Feld beeinflusst wird, ist die magnetische Ordnung entsprechend betroffen. Dies erlaubt die vollständige Umordnung der elektrischen Polarisation durch ein magnetisches Feld oder der magnetischen Ordnung durch ein elektrisches Feld. Materialien, die mindestens zwei ferroische Eigenschaften, in diesem Fall eine spontane Magnetisierung und spontane elektrische Polarisation, in der gleichen Phase aufweisen, werden als Multiferroika bezeichnet. Diese allgemeine Klassifikation ist noch zu unterteilen in Typ-I und Typ-II Multiferroika. Zu Typ-I Multiferroika zählen Systeme wie BiFeO$_{3}$, bei denen die ferroelektrische und die magnetische Ordnung weitestgehend unabhängig voneinander und daher bei verschiedenen Temperaturen einsetzen ($T_{C} = 1100$~K für die ferroelektrische, $T_{N}=$ 643~K für die magnetische Ordnung \cite{Khomskii2009}). Dementsprechend sind Magnetisierung und Polarisation in diesem System kaum miteinander gekoppelt. Demgegenüber stehen die hier betrachteten Systeme der orthorhombischen RMnO$_{3}$ Seltenerdmanganate und der ACrO$_{2}$ Delafossite, die der Gruppe der Typ-II Multiferroika angehören. Hier ist die magnetische Ordnung die direkte Ursache der ferroelektrischen Polarisation, d.h. beide Phänomene treten simultan ab der gleichen Ordnungstemperatur auf. Das Ziel von Forschungsbemühungen auf diesem Gebiet der Multiferroika ist zum Einen, neue Materialien zu finden, die solcherlei Kopplungseffekte zeigen. Zum Anderen gilt es, den Effekt besser nutzbar zu machen, sei es durch eine größere Kopplungsstärke oder durch höhere mögliche Ordnungstemperaturen. Um dies zu erreichen ist es von essentieller Bedeutung die zu Grunde liegenden mikroskopischen Mechanismen zu ergründen, diese zu studieren und schließlich ein besseres Verständnis der multiferroischen Kopplungsmechanismen zu erlangen. In dieser Dissertation liegt der Fokus auf der systematischen Untersuchung von Kopplungseffekten zwischen der magnetischen Ordnung und der Dynamik des Kristallgitters mittels Ramanspektroskopie. Insbesondere werden Renormalisierungseffekte der Frequenzen der Gitterschwingungen untersucht, die sich durch die Ausbildung der magnetischen Ordnung und Kopplung derselben an die Gitterdynamik ergeben, die sogenannte Spin-Phonon Kopplung (SPC). Zu diesem Zweck werden die spektroskopischen Experimente mit Augenmerk auf die Polarisations-, Temperatur- und Magnetfeldabhängigkeit der ramanaktiven Moden durchgeführt. Dabei werden Serien von Proben zweier Materialsysteme untersucht, bei denen sich die multiferroische Phase durch unterschiedliche Mechanismen ausbildet: Zum Einen das System Eu$_{1-x}$Ho$_{x}$MnO$_{3}$ ( $0 \le x \le 0.5$), welches zu den orthorhombischen RMnO$_{3}$ Systemen zählt und sowohl multiferroische als auch nicht-multiferroische Proben umfasst. Hierbei beruht der magnetoelektrische Effekt auf der inversen Dzyaloshinskii-Moriya Wechselwirkung. Im Vergleich dazu wird außerdem das System der ACrO$_{2}$ Delafossite mit A= Cu, Ag, Pd untersucht. Dieses System ist im Kontext der Multiferroika noch als relativ neu anzusehen. Hier kann die inverse Dzyaloshinskii-Moriya Wechselwirkung aus Symmetriegründen ausgeschlossen werden, sodass ein neuartiger magnetoelektrischer Kopplungsmechanismus vorliegt. Durch die Spin-Bahn Kopplung verschiebt sich die Gewichtung der Ladungsverteilung der Bindungen und führt dadurch zur Entstehung der elektrischen Polarisation. Im Vergleich der beiden Systeme, werden die Unterschiede der Spin-Phonon Kopplungsstärken und der Einfluss von lokalen Ordnungseffekten diskutiert. KW - Festkörperphysik KW - Gitterdynamik KW - Raman-Spektroskopie KW - Magnon KW - Optik KW - Spin-Phonon Kopplung KW - Elektromagnon KW - Multiferroika KW - Multiferroics KW - Electromagnon KW - Spin-phonon coupling Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-179719 ER - TY - JOUR A1 - Elmaidomy, Abeer H. A1 - Mohammed, Rabab A1 - Hassan, Hossam M. A1 - Owis, Asmaa I. A1 - Rateb, Mostafa E. A1 - Khanfar, Mohammad A. A1 - Krischke, Markus A1 - Mueller, Martin J. A1 - Abdelmohsen, Usama Ramadan T1 - Metabolomic profiling and cytotoxic tetrahydrofurofuran lignans investigations from Premna odorata Blanco JF - Metabolites N2 - Metabolomic profiling of different Premna odorata Blanco (Lamiaceae) organs, bark, wood, young stems, flowers, and fruits dereplicated 20, 20, 10, 20, and 20 compounds, respectively, using LC–HRESIMS. The identified metabolites (1–34) belonged to different chemical classes, including iridoids, flavones, phenyl ethanoids, and lignans. A phytochemical investigation of P. odorata bark afforded one new tetrahydrofurofuran lignan, 4β-hydroxyasarinin 35, along with fourteen known compounds. The structure of the new compound was confirmed using extensive 1D and 2D NMR, and HRESIMS analyses. A cytotoxic investigation of compounds 35–38 against the HL-60, HT-29, and MCF-7 cancer cell lines, using the MTT assay showed that compound 35 had cytotoxic effects against HL-60 and MCF-7 with IC50 values of 2.7 and 4.2 µg/mL, respectively. A pharmacophore map of compounds 35 showed two hydrogen bond acceptor (HBA) aligning the phenoxy oxygen atoms of benzodioxole moieties, two aromatic ring features vectored on the two phenyl rings, one hydrogen bond donor (HBD) feature aligning the central hydroxyl group and thirteen exclusion spheres which limit the boundaries of sterically inaccessible regions of the target’s active site. KW - Premna KW - lignan KW - metabolomic KW - cytotoxic KW - pharmacophore map Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193187 SN - 2218-1989 VL - 9 IS - 10 ER - TY - JOUR A1 - Elhfnawy, Ahmed Mohamed A1 - Volkmann, Jens A1 - Schliesser, Mira A1 - Fluri, Felix T1 - Are cerebral white matter lesions related to the presence of bilateral internal carotid artery stenosis or to the length of stenosis among patients with ischemic cerebrovascular events? JF - Frontiers in Neurology N2 - Background and purpose: Previous studies delivered contradicting results regarding the relation between the presence of an internal carotid artery stenosis (ICAS) and the occurence of white matter lesions (WMLs). We hypothesize that special characteristics related to the ICAS might be related to the WMLs. We examined the relation between the presence of bilateral ICAS, the degree and length of stenosis and ipsi-, contralateral as well as mean white matter lesion load (MWMLL). Methods: In a retrospective cohort, patients with ischemic stroke or transient ischemic attack (TIA) as well as ipsi- and/or contralateral ICAS were identified. The length and degree of ICAS, as well as plaque morphology (hypoechoic, mixed or echogenic), were assessed on ultrasound scans and, if available, the length was also measured on magnetic resonance angiography (MRA) scans, and/or digital subtraction angiography (DSA). The WMLs were assessed in 4 areas separately, (periventricular and deep WMLs on each hemispherer), using the Fazekas scale. The MWMLL was calculated as the mean of these four values. Results: 136 patients with 177 ICAS were identified. A significant correlation between age and MWMLL was observed (Spearman correlation coefficient, ρ = 0.41, p < 0.001). Before adjusting for other risk factors, a significantly positive relation was found between the presence of bilateral ICAS and MWMLL (p = 0.039). The length but not the degree of ICAS showed a very slight trend toward association with ipsilateral WMLs and with MWMLL. In an age-adjusted multivariate logistic regression with MWMLL ≥2 as the outcome measure, atrial fibrillation (OR 3.54, 95% CI 1.12–11.18, p = 0.03), female sex (OR 3.11, 95% CI 1.19–8.11, p = 0.02) and diabetes mellitus (OR 2.76, 95% CI 1.16–6.53, p = 0.02) were significantly related to WMLs, whereas the presence of bilateral stenosis showed a trend toward significance (OR 2.25, 95% CI 0.93–5.45, p = 0.074). No relation was found between plaque morphology and MWMLL, periventricular, or deep WMLs. Conclusion: We have shown a slight correlation between the length of stenosis and the presence of WMLs which might be due to microembolisation originating from the carotid plaque. However, the presence of bilateral ICAS seems also to be related to WMLs which may point to common underlying vascular risk factors contributing to the occurrence of WML. KW - stroke KW - transient ischemic attack KW - white matter lesions KW - internal carotid artery stenosis KW - bilateral internal carotid artery stenosis KW - degree of stenosis KW - length of stenosis Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201241 VL - 10 IS - 919 ER - TY - JOUR A1 - Elhfnawy, Ahmed Mohamed A1 - Volkmann, Jens A1 - Schliesser, Mira A1 - Fluri, Felix T1 - Symptomatic vs. asymptomatic 20–40% internal carotid artery stenosis: Does the plaque size matter? JF - Frontiers in Neurology N2 - Background: Around 9–15% of ischemic strokes are related to internal carotid artery (ICA)-stenosis ≥50%. However, the extent to which ICA-stenosis <50% causes ischemic cerebrovascular events is uncertain. We examined the relation between plaque cross-sectional area and length and the risk of ischemic stroke or TIA among patients with ICA-stenosis of 20–40%. Methods: We retrospectively identified patients admitted to the Department of Neurology, University Hospital of Würzburg, from January 2011 until September 2016 with ischemic stroke or TIA and concomitant ICA-stenosis of 20–40%, either symptomatic or asymptomatic. Plaque length and cross-sectional area were assessed on ultrasound scans. Results: We identified 41 patients with ischemic stroke or TIA and ICA-stenosis of 20–40%; 14 symptomatic and 27 asymptomatic. The plaque cross-sectional area was significantly larger among symptomatic than asymptomatic ICA-stenosis; median values (IQR) were 0.45 (0.21–0.69) cm2 and 0.27 (0.21–0.38) cm2, p = 0.03, respectively. A plaque cross-sectional area ≥0.36 cm2 had a sensitivity of 71% and a specificity of 76% for symptomatic compared with asymptomatic ICA-stenosis. In a sex-adjusted multivariate logistic regression, a plaque cross-sectional area ≥0.36 cm2 and a plaque length ≥1.65 cm were associated with an OR (95% CI) of 5.54 (1.2–25.6), p = 0.028 and 1.78 (0.36–8.73), p = 0.48, respectively, for symptomatic ICA-stenosis. Conclusion: Large plaques might increase the risk of ischemic stroke or TIA among patients with low-grade ICA-stenosis of 20–40%. Sufficiently powered prospective longitudinal cohort studies are needed to definitively test the stroke risk stratification value of carotid plaque length and cross-sectional area in the setting of current optimal medical treatment. KW - ischemic stroke KW - carotid atherosclerosis KW - carotid stenosis KW - plaque cross-sectional area KW - length of stenosis KW - carotid ultrasound Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201262 VL - 10 IS - 960 ER - TY - JOUR A1 - Elhfnawy, Ahmed Mohamed A1 - Heuschmann, Peter U. A1 - Pham, Mirko A1 - Volkmann, Jens A1 - Fluri, Felix T1 - Stenosis length and degree interact with the risk of cerebrovascular events related to internal carotid artery stenosis JF - Frontiers in Neurology N2 - Background and Purpose: Internal carotid artery stenosis (ICAS)≥70% is a leading cause of ischemic cerebrovascular events (ICVEs). However, a considerable percentage of stroke survivors with symptomatic ICAS (sICAS) have <70% stenosis with a vulnerable plaque. Whether the length of ICAS is associated with high risk of ICVEs is poorly investigated. Our main aim was to investigate the relation between the length of ICAS and the development of ICVEs. Methods: In a retrospective cross-sectional study, we identified 95 arteries with sICAS and another 64 with asymptomatic internal carotid artery stenosis (aICAS) among 121 patients with ICVEs. The degree and length of ICAS as well as plaque echolucency were assessed on ultrasound scans. Results: A statistically significant inverse correlation between the ultrasound-measured length and degree of ICAS was detected for sICAS≥70% (Spearman correlation coefficient ρ = –0.57, p < 0.001, n = 51) but neither for sICAS<70% (ρ = 0.15, p = 0.45, n = 27) nor for aICAS (ρ = 0.07, p = 0.64, n = 54). The median (IQR) length for sICAS<70% and ≥70% was 17 (15–20) and 15 (12–19) mm (p = 0.06), respectively, while that for sICAS<90% and sICAS 90% was 18 (15–21) and 13 (10–16) mm, respectively (p < 0.001). Among patients with ICAS <70%, a cut-off length of ≥16 mm was found for sICAS rather than aICAS with a sensitivity and specificity of 74.1% and 51.1%, respectively. Irrespective of the stenotic degree, plaques of the sICAS compared to aICAS were significantly more often echolucent (43.2 vs. 24.6%, p = 0.02). Conclusion: We found a statistically insignificant tendency for the ultrasound-measured length of sICAS<70% to be longer than that of sICAS≥70%. Moreover, the ultrasound-measured length of sICAS<90% was significantly longer than that of sICAS 90%. Among patients with sICAS≥70%, the degree and length of stenosis were inversely correlated. Larger studies are needed before a clinical implication can be drawn from these results. KW - ischemic stroke KW - carotid stenosis KW - carotid atherosclerosis KW - length of stenosis KW - degree of stenosis KW - carotid ultrasound KW - outcome Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196225 SN - 1664-2295 VL - 10 IS - 317 ER - TY - THES A1 - Elhfnawy, Ahmed T1 - Relation between the length of the internal carotid stenotic segment and ischemic cerebrovascular events as well as white matter lesion load T1 - Zusammenhang zwischen der Stenoselänge der Arteria carotis interna und ischämischen zerebrovaskulären Ereignissen sowie der Läsionslast der weißen Substanz N2 - Background and Purpose: Internal carotid artery stenosis ≥70% is a leading cause of ischemic cerebrovascular events. However, a considerable percentage of stroke survivors with symptomatic internal carotid artery stenosis have <70% stenosis with a vulnerable plaque. Whether the length of internal carotid artery stenosis is associated with high risk of ischemic cerebrovascular events or with white matter lesions is poorly investigated. Our main aim was to investigate the relation between the length of internal carotid artery stenosis and the development of ischemic cerebrovascular events as well as ipsi-, contralateral as well as mean white matter lesion load. Methods: In a retrospective cross-sectional study, 168 patients with 208 internal carotid artery stenosis were identified. The degree and length of internal carotid artery stenosis as well as plaque morphology (hypoechoic, mixed or echogenic) were assessed on ultrasound scans. The white matter lesions were assessed in 4 areas separately, (periventricular and deep white matter lesions on each hemisphere), using the Fazekas scale. The mean white matter lesions load was calculated as the mean of these four values. Results: A statistically significant inverse correlation between the ultrasound-measured length and degree of internal carotid artery stenosis was detected for symptomatic internal carotid artery stenosis ≥70% (Spearman correlation coefficient ρ = –0.57, p < 0.001, n = 51) but neither for symptomatic internal carotid artery stenosis <70% (ρ = 0.15, p = 0.45, n = 27) nor for asymptomatic internal carotid artery stenosis (ρ = 0.07, p = 0.64, n = 54). The median (IQR) length for symptomatic internal carotid artery stenosis <70% and ≥70% was 17 (15–20) and 15 (12–19) mm (p = 0.06), respectively, while that for symptomatic internal carotid artery stenosis <90% and symptomatic internal carotid artery stenosis 90% was 18 (15–21) and 13 (10–16) mm, respectively (p < 0.001). Among patients with internal carotid artery stenosis <70%, a cut-off length of ≥16 mm was found for symptomatic internal carotid artery stenosis rather than asymptomatic internal carotid artery stenosis with a sensitivity and specificity of 74.1% and 51.1%, respectively. Irrespective of the stenotic degree, plaques of the symptomatic internal carotid artery stenosis compared to asymptomatic internal carotid artery stenosis were significantly more often echolucent (43.2 vs. 24.6%, p = 0.02). The length but not the degree of internal carotid artery stenosis showed a very slight trend toward association with ipsilateral white matter lesions and with mean white matter lesions load. Conclusion: We found a statistically insignificant tendency for the ultrasound-measured length of symptomatic internal carotid artery stenosis <70% to be longer than that of symptomatic internal carotid artery stenosis ≥70%. Moreover, the ultrasound-measured length of symptomatic internal carotid artery stenosis <90% was significantly longer than that of symptomatic internal carotid artery stenosis 90%. Among patients with symptomatic internal carotid artery stenosis ≥70%, the degree and length of stenosis were inversely correlated. Furthermore, we have shown that a slight correlation exists between the length of stenosis and the presence of ipsilateral white matter lesions which might be due to microembolisation originating from the carotid plaque. Larger studies are needed before a clinical implication can be drawn from these results. N2 - Hintergrund: Stenose der A. carotis interna ≥70% ist eine der führenden Ursachen für ischämische zerebrovaskuläre Ereignisse. Ein beträchtlicher Prozentsatz der Schlaganfall-Überlebenden mit symptomatischer Stenose der A. carotis interna weist jedoch eine Stenose <70% mit einer „vulnerable Plaque“ auf. Ob die Länge der Stenose der A. carotis interna mit einem hohen Risiko für ischämische zerebrovaskuläre Ereignisse oder mit Läsionen der weißen Substanz verbunden ist, wird nur unzureichend untersucht. Unser Hauptziel war es, den Zusammenhang zwischen der Länge der Stenose der Aerteria carotis interna und der Entwicklung von ischämischen zerebrovaskulären Ereignissen sowie der ipsi-, kontralateralen und mittleren Läsionslast der weißen Substanz zu untersuchen. Methode: In einer retrospektiven Querschnittsstudie wurden 168 Patienten mit 208 Stenosen der A. carotis interna identifiziert. Der Stenosegrad und die Stenoselänge sowie die Plaquemorphologie (echoarm, gemischt oder echogen) wurden mittels Ultraschall untersucht. Die Läsionen der weißen Substanz wurden in 4 Bereichen (periventrikuläre und subkortilae Läsionen der weißen Substanz, jeweils auf jeder Hemisphäre) mittels Fazekas-Skala bewertet. Der mittlere dieser vier Werte wurde ebenso berechnet. Ergebnisse: Eine statistisch signifikante inverse Korrelation zwischen der mit Ultraschall gemessenen Länge und dem Stenosegrad der A. carotis interna wurde für eine symptomatische Stenose der A. carotis interna von ≥ 70% festgestellt (Spearman-Korrelationskoeffizient ρ = –0,57, p <0,001, n = 51), jedoch keine bei symptomatischer Stenose der A. carotis interna <70% (ρ = 0,15, p = 0,45, n = 27) und bei asymptomatischer Stenose der A. carotis interna (ρ = 0,07, p = 0,64, n = 54). Die mediane Länge (IQR) für symptomatische Stenosen der A. carotis interna <70% und ≥ 70% betrug 17 (15–20) bzw. 15 (12–19) mm (p = 0,06), die für symptomatische Stenosen der A. carotis interna <90% und symptomatische Stenose der A. carotis interna 90% betrugen 18 (15–21) bzw. 13 (10–16) mm (p <0,001). Bei Patienten mit einer Stenose der A. carotis interna <70% wurde für eine symptomatische Stenose der A. carotis interna einen Grenzwert von ≥ 16 mm gefunden, und nicht für eine asymptomatische Stenose der A. carotis interna mit einer Sensitivität und Spezifität von 74,1% bzw. 51,1%. Unabhängig vom stenotischen Grad waren Plaques der symptomatischen Stenose der A. carotis interna im Vergleich zur asymptomatischen Stenose der A. carotis interna signifikant häufiger echoarm (43,2 vs. 24,6%, p = 0,02). Die Stenoselänge, aber nicht der Stenosegrad der A. carotis interna zeigte einen sehr geringen Trend zur Assoziation mit ipsilateralen Läsionen der weißen Substanz und mit der mittleren Läsionslast der weißen Substanz. Schlussfolgerung: Es wurde eine statistisch nicht signifikante Tendenz gefunden, dass die ultraschallgemessene Länge der symptomatischen Stenose der A. carotis interna <70% länger ist als die der symptomatischen Stenose der A. carotis interna ≥ 70%. Darüber hinaus war die durch Ultraschall gemessene Länge der symptomatischen Stenose der A. carotis interna <90% signifikant länger als die der symptomatischen Stenose der A. carotis interna 90%. Bei Patienten mit symptomatischer Stenose der A. carotis interna ≥ 70% waren Stenosegrad und Stenoselänge invers korreliert. Darüber hinaus haben wir gezeigt, dass eine leichte Korrelation zwischen der Stenoselänge und der ipsilateralen Läsionen der weißen Substanz besteht, die möglicherweise auf eine Mikroembolisation zurückzuführen sind, die vom Carotis-Plaque herrührt. Größere Studien sind erforderlich, bevor aus diesen Ergebnissen eine klinische Implikation abgeleitet werden kann. KW - Carotisstenose KW - Schlaganfall KW - White matter lesions KW - Stenosis length KW - Stenosis degree Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-191616 ER - TY - JOUR A1 - El-Mesery, Mohamed A1 - Rosenthal, Tina A1 - Rauert-Wunderlich, Hilka A1 - Schreder, Martin A1 - Stühmer, Thorsten A1 - Leich, Ellen A1 - Schlosser, Andreas A1 - Ehrenschwender, Martin A1 - Wajant, Harald A1 - Siegmund, Daniela T1 - The NEDD8-activating enzyme inhibitor MLN4924 sensitizes a TNFR1+ subgroup of multiple myeloma cells for TNF-induced cell death JF - Cell Death & Disease N2 - The NEDD8-activating enzyme (NAE) inhibitor MLN4924 inhibits cullin-RING ubiquitin ligase complexes including the SKP1-cullin-F-box E3 ligase βTrCP. MLN4924 therefore inhibits also the βTrCP-dependent activation of the classical and the alternative NFĸB pathway. In this work, we found that a subgroup of multiple myeloma cell lines (e.g., RPMI-8226, MM.1S, KMS-12BM) and about half of the primary myeloma samples tested are sensitized to TNF-induced cell death by MLN4924. This correlated with MLN4924-mediated inhibition of TNF-induced activation of the classical NFκB pathway and reduced the efficacy of TNF-induced TNFR1 signaling complex formation. Interestingly, binding studies revealed a straightforward correlation between cell surface TNFR1 expression in multiple myeloma cell lines and their sensitivity for MLN4924/TNF-induced cell death. The cell surface expression levels of TNFR1 in the investigated MM cell lines largely correlated with TNFR1 mRNA expression. This suggests that the variable levels of cell surface expression of TNFR1 in myeloma cell lines are decisive for TNF/MLN4924 sensitivity. Indeed, introduction of TNFR1 into TNFR1-negative TNF/MLN4924-resistant KMS-11BM cells, was sufficient to sensitize this cell line for TNF/MLN4924-induced cell death. Thus, MLN4924 might be especially effective in myeloma patients with TNFR1+ myeloma cells and a TNFhigh tumor microenvironment. KW - cancer therapy KW - tumour-necrosis factors Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226666 VL - 10 ER - TY - JOUR A1 - El-Helou, Sabine M. A1 - Biegner, Anika-Kerstin A1 - Bode, Sebastian A1 - Ehl, Stephan R. A1 - Heeg, Maximilian A1 - Maccari, Maria E. A1 - Ritterbusch, Henrike A1 - Speckmann, Carsten A1 - Rusch, Stephan A1 - Scheible, Raphael A1 - Warnatz, Klaus A1 - Atschekzei, Faranaz A1 - Beider, Renata A1 - Ernst, Diana A1 - Gerschmann, Stev A1 - Jablonka, Alexandra A1 - Mielke, Gudrun A1 - Schmidt, Reinhold E. A1 - Schürmann, Gesine A1 - Sogkas, Georgios A1 - Baumann, Ulrich H. A1 - Klemann, Christian A1 - Viemann, Dorothee A1 - Bernuth, Horst von A1 - Krüger, Renate A1 - Hanitsch, Leif G. A1 - Scheibenbogen, Carmen M. A1 - Wittke, Kirsten A1 - Albert, Michael H. A1 - Eichinger, Anna A1 - Hauck, Fabian A1 - Klein, Christoph A1 - Rack-Hoch, Anita A1 - Sollinger, Franz M. A1 - Avila, Anne A1 - Borte, Michael A1 - Borte, Stephan A1 - Fasshauer, Maria A1 - Hauenherm, Anja A1 - Kellner, Nils A1 - Müller, Anna H. A1 - Ülzen, Anett A1 - Bader, Peter A1 - Bakhtiar, Shahrzad A1 - Lee, Jae-Yun A1 - Heß, Ursula A1 - Schubert, Ralf A1 - Wölke, Sandra A1 - Zielen, Stefan A1 - Ghosh, Sujal A1 - Laws, Hans-Juergen A1 - Neubert, Jennifer A1 - Oommen, Prasad T. A1 - Hönig, Manfred A1 - Schulz, Ansgar A1 - Steinmann, Sandra A1 - Klaus, Schwarz A1 - Dückers, Gregor A1 - Lamers, Beate A1 - Langemeyer, Vanessa A1 - Niehues, Tim A1 - Shai, Sonu A1 - Graf, Dagmar A1 - Müglich, Carmen A1 - Schmalzing, Marc T. A1 - Schwaneck, Eva C. A1 - Tony, Hans-Peter A1 - Dirks, Johannes A1 - Haase, Gabriele A1 - Liese, Johannes G. A1 - Morbach, Henner A1 - Foell, Dirk A1 - Hellige, Antje A1 - Wittkowski, Helmut A1 - Masjosthusmann, Katja A1 - Mohr, Michael A1 - Geberzahn, Linda A1 - Hedrich, Christian M. A1 - Müller, Christiane A1 - Rösen-Wolff, Angela A1 - Roesler, Joachim A1 - Zimmermann, Antje A1 - Behrends, Uta A1 - Rieber, Nikolaus A1 - Schauer, Uwe A1 - Handgretinger, Rupert A1 - Holzer, Ursula A1 - Henes, Jörg A1 - Kanz, Lothar A1 - Boesecke, Christoph A1 - Rockstroh, Jürgen K. A1 - Schwarze-Zander, Carolynne A1 - Wasmuth, Jan-Christian A1 - Dilloo, Dagmar A1 - Hülsmann, Brigitte A1 - Schönberger, Stefan A1 - Schreiber, Stefan A1 - Zeuner, Rainald A1 - Ankermann, Tobias A1 - Bismarck, Philipp von A1 - Huppertz, Hans-Iko A1 - Kaiser-Labusch, Petra A1 - Greil, Johann A1 - Jakoby, Donate A1 - Kulozik, Andreas E. A1 - Metzler, Markus A1 - Naumann-Bartsch, Nora A1 - Sobik, Bettina A1 - Graf, Norbert A1 - Heine, Sabine A1 - Kobbe, Robin A1 - Lehmberg, Kai A1 - Müller, Ingo A1 - Herrmann, Friedrich A1 - Horneff, Gerd A1 - Klein, Ariane A1 - Peitz, Joachim A1 - Schmidt, Nadine A1 - Bielack, Stefan A1 - Groß-Wieltsch, Ute A1 - Classen, Carl F. A1 - Klasen, Jessica A1 - Deutz, Peter A1 - Kamitz, Dirk A1 - Lassy, Lisa A1 - Tenbrock, Klaus A1 - Wagner, Norbert A1 - Bernbeck, Benedikt A1 - Brummel, Bastian A1 - Lara-Villacanas, Eusebia A1 - Münstermann, Esther A1 - Schneider, Dominik T. A1 - Tietsch, Nadine A1 - Westkemper, Marco A1 - Weiß, Michael A1 - Kramm, Christof A1 - Kühnle, Ingrid A1 - Kullmann, Silke A1 - Girschick, Hermann A1 - Specker, Christof A1 - Vinnemeier-Laubenthal, Elisabeth A1 - Haenicke, Henriette A1 - Schulz, Claudia A1 - Schweigerer, Lothar A1 - Müller, Thomas G. A1 - Stiefel, Martina A1 - Belohradsky, Bernd H. A1 - Soetedjo, Veronika A1 - Kindle, Gerhard A1 - Grimbacher, Bodo T1 - The German national registry of primary immunodeficiencies (2012-2017) JF - Frontiers in Immunology N2 - Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs. Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel. Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1-25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0-88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE-syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%-subcutaneous; 29%-intravenous; 1%-unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy. Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment. KW - registry for primary immunodeficiency KW - primary immunodeficiency (PID) KW - German PID-NET registry KW - PID prevalence KW - European Society for Immunodeficiencies (ESID) KW - IgG substitution therapy KW - CVID Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226629 VL - 10 ER - TY - JOUR A1 - El-Hawary, Seham S. A1 - Sayed, Ahmed M. A1 - Mohammed, Rabab A1 - Hassan, Hossam M. A1 - Rateb, Mostafa E. A1 - Amin, Elham A1 - Mohammed, Tarek A. A1 - El-Mesery, Mohamed A1 - Bin Muhsinah, Abdullatif A1 - Alsayari, Abdulrhman A1 - Wajant, Harald A1 - Anany, Mohamed A. A1 - Abdelmohsen, Usama Ramadan T1 - Bioactive brominated oxindole alkaloids from the Red Sea sponge Callyspongia siphonella JF - Marine Drugs N2 - In the present study, LC-HRESIMS-assisted dereplication along with bioactivity-guided isolation led to targeting two brominated oxindole alkaloids (compounds 1 and 2) which probably play a key role in the previously reported antibacterial, antibiofilm, and cytotoxicity of Callyspongia siphonella crude extracts. Both metabolites showed potent antibacterial activity against Gram-positive bacteria, Staphylococcus aureus (minimum inhibitory concentration (MIC) = 8 and 4 µg/mL) and Bacillus subtilis (MIC = 16 and 4 µg/mL), respectively. Furthermore, they displayed moderate biofilm inhibitory activity in Pseudomonas aeruginosa (49.32% and 41.76% inhibition, respectively), and moderate in vitro antitrypanosomal activity (13.47 and 10.27 µM, respectively). In addition, they revealed a strong cytotoxic effect toward different human cancer cell lines, supposedly through induction of necrosis. This study sheds light on the possible role of these metabolites (compounds 1 and 2) in keeping fouling organisms away from the sponge outer surface, and the possible applications of these defensive molecules in the development of new anti-infective agents. KW - Callyspongia siphonella KW - LC-HRESIMS KW - metabolomic profiling KW - oxindole alkaloids KW - tisindoline KW - antibacterial KW - antibiofilm KW - antitrypanosomal KW - anticancer Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201485 VL - 17 IS - 8 ER - TY - JOUR A1 - Eisenreich, Wolfgang A1 - Rudel, Thomas A1 - Heesemann, Jürgen A1 - Goebel, Werner T1 - How viral and intracellular bacterial pathogens reprogram the metabolism of host cells to allow their intracellular replication JF - Frontiers in Cellular and Infection Microbiology N2 - Viruses and intracellular bacterial pathogens (IBPs) have in common the need of suitable host cells for efficient replication and proliferation during infection. In human infections, the cell types which both groups of pathogens are using as hosts are indeed quite similar and include phagocytic immune cells, especially monocytes/macrophages (MOs/MPs) and dendritic cells (DCs), as well as nonprofessional phagocytes, like epithelial cells, fibroblasts and endothelial cells. These terminally differentiated cells are normally in a metabolically quiescent state when they are encountered by these pathogens during infection. This metabolic state of the host cells does not meet the extensive need for nutrients required for efficient intracellular replication of viruses and especially IBPs which, in contrast to the viral pathogens, have to perform their own specific intracellular metabolism to survive and efficiently replicate in their host cell niches. For this goal, viruses and IBPs have to reprogram the host cell metabolism in a pathogen-specific manner to increase the supply of nutrients, energy, and metabolites which have to be provided to the pathogen to allow its replication. In viral infections, this appears to be often achieved by the interaction of specific viral factors with central metabolic regulators, including oncogenes and tumor suppressors, or by the introduction of virus-specific oncogenes. Less is so far known on the mechanisms leading to metabolic reprogramming of the host cell by IBPs. However, the still scant data suggest that similar mechanisms may also determine the reprogramming of the host cell metabolism in IBP infections. In this review, we summarize and compare the present knowledge on this important, yet still poorly understood aspect of pathogenesis of human viral and especially IBP infections. KW - metabolic adaptation KW - viruses KW - intracellular bacterial pathogens KW - metabolism of infected and uninfected host cells KW - reprogamming of host cell metabolism Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-197188 SN - 2235-2988 VL - 9 ER - TY - JOUR A1 - Eder, Andreas B. A1 - Dignath, David T1 - Expected value of control and the motivational control of habitual action JF - Frontiers in Psychology N2 - A hallmark of habitual actions is that, once they are established, they become insensitive to changes in the values of action outcomes. In this article, we review empirical research that examined effects of posttraining changes in outcome values in outcome-selective Pavlovian-to-instrumental transfer (PIT) tasks. This review suggests that cue-instigated action tendencies in these tasks are not affected by weak and/or incomplete revaluation procedures (e.g., selective satiety) and substantially disrupted by a strong and complete devaluation of reinforcers. In a second part, we discuss two alternative models of a motivational control of habitual action: a default-interventionist framework and expected value of control theory. It is argued that the default-interventionist framework cannot solve the problem of an infinite regress (i.e., what controls the controller?). In contrast, expected value of control can explain control of habitual actions with local computations and feedback loops without (implicit) references to control homunculi. It is argued that insensitivity to changes in action outcomes is not an intrinsic design feature of habits but, rather, a function of the cognitive system that controls habitual action tendencies. KW - habit KW - outcome devaluation KW - Pavlovian-to-instrumental transfer KW - default-interventionist framework KW - expected value of control KW - cognitive control Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-195703 SN - 1664-1078 VL - 10 IS - 1812 ER - TY - THES A1 - Eckstein, Klaus T1 - Linear and Nonlinear Spectroscopy of Doped Carbon Nanotubes T1 - Lineare und Nichtlineare Spektroskopie von dotierten Kohlenstoffnanoröhren N2 - Doping plays a decisive role for the functionality of semiconductor-based (opto-)electronic devices. Hence, the technological utilization of semiconductors necessitates control and a fundamental understanding of the doping process. However, for low-dimensional systems like carbon nanotubes, neither concentration nor distribution of charge carriers is currently well known. The research presented in this thesis investigated the doping of semiconducting carbon nanotubes by spectroscopic methods. Samples of highly purified, intrinsic (6,5) single-wall carbon nanotubes were fabricated using polymer stabilization. Chapter 4 showed that both electro- and redox chemical $p$-doping lead to identical bleaching, blueshift, broadening and asymmetry of the S$_1$ exciton absorption band. The similar spectral changes induced by both doping schemes suggest that optical spectra can not be used to infer what process was used for doping. Perhaps more importantly, it also indicates that the distribution of charges and the character of the charge transfer states does not depend on the method by which doping was achieved. The detailed analysis of the doping-induced spectral changes in chapter 5 suggests that surplus charges are distributed inhomogeneously. The hypothesis of carrier localization is consistent with the high sensitivity of the S$_1$ exciton photoluminescence to additional charge carriers and with the stretched-exponential decay of the exciton population following ultrafast excitation. Both aspects are in good agreement with diffusion-limited contact quenching of excitons at localized charges. Moreover, localized charges act – similar to structural defects – as perturbations to the bandstructure as evidenced by a doping-induced increase of the D-band antiresonance in the mid-infrared spectrum. Quantum mechanical model calculations also suggest that counterions play a crucial role in carrier localization. Counterion adsorption at the nanotube surface is thus believed to induce charge traps of more than 100 meV depth with a carrier localization length on the order of 3 - 4 nm. The doping-induced bleach of interband absorption is accompanied by an absorption increase in the IR region below 600 meV. The observed shift of the IR peak position indicates a continuous transition from localized to rather delocalized charge carriers. This transition is caused by the increase of the overlap of charge carrier wavefunctions at higher charge densities and was modeled by classical Monte-Carlo simulations of intraband absorption. Chapter 6 discussed the spectroscopy of heavily (degenerately) doped nanotubes, which are characterized by a Drude-response of free-carrier intraband absorption in the optical conductivity spectrum. In the NIR spectral region, the S$_1$ exciton and X$+^_1$ trion absorption is replaced by a nearly 1 eV broad and constant absorption signal, the so-called H-band. The linear and transient absorption spectra of heavily doped nanotubes suggest that the H-band can be attributed to free-carrier interband transitions. Chapter 7 dealt with the quantification of charge carrier densities by linear absorption spectroscopy. A particularly good measure of the carrier density is the S$_1$ exciton bleach. For a bleach below about 50 %, the carrier density is proportional to the bleach. At higher doping levels, deviations from the linear behavior were observed. For doping levels exceeding a fully bleached S$_1$ band, the determination of the normalized oscillator strength f$\text{1st}$ over the whole first subband region (trion, exciton, free e-h pairs) is recommended for quantification of carrier densities. Based on the nanotube density of states, the carrier density $n$ can be estimated using $n = 0.74\,\text{nm}^{−1} \cdot (1 − f_\text{1st})$. In the last part of this thesis (chapter 8), the time-resolved spectroelectrochemistry was extended to systems beyond photostable carbon nanotube films. The integration of a flowelectrolysis cell into the transient absorption spectrometer allows the investigation of in-situ electrochemically generated but photounstable molecules due to a continuous exchange of sample volume. First time-resolved experiments were successfully performed using the dye methylene blue and its electrochemically reduced form leucomethylene blue. N2 - Die Dotierung von Halbleitern spielt eine entscheidende Rolle für die Funktionsweise von halbleiterbasierten (opto-)elektronischen Bauteilen. Deshalb erfordert die technische Nutzbarmachung von Halbleitern die Kontrolle und ein fundamentales Verständnis des Dotierungsprozesses. Für niederdimensionale Halbleiter, wie Kohlenstoffnanoröhren, ist momentan weder die Dichte noch die Verteilung von Ladungsträgern genau bekannt. In dieser Arbeit wurde die Dotierung von halbleitenden Kohlenstoffnanoröhren mittels spektroskopischer Methoden untersucht. Proben hochreiner, intrinsischer und einwandiger (6,5)Kohlenstoffnanoröhren wurden durch Polymerstabilisierung hergestellt. In Kapitel 4 wurde gezeigt, dass sowohl die elektro-, als auch die redoxchemische $p$-Dotierung zu einem identischen Bleichen, einer Blauverschiebung, Verbreiterung und Asymmetrie der Absorptionsbande des S$_1$ Exzitons führt. Die ähnlichen spektralen Änderungen, die durch beide Dotierungsverfahren induziert wurden, legen den Schluss nahe, dass optische Spektren nicht zur Identifikation des Dotierungsverfahrens genutzt werden können. Möglicherweise wichtiger ist die Schlussfolgerung, dass die Ladungsverteilung und der Charakter der Ladungen nicht davon abhängt mittels welcher Methode die Dotierung erreicht wurde. Die detaillierte Analyse der durch Dotierung hervorgerufenen spektralen Änderungen in Kapitel 5 deutet eine inhomogene Verteilung der Überschussladungen an. Die Hypothese der Ladungsträgerlokalisierung ist konsistent mit der hohen Sensitivität der Photolumineszenz des S$_1$-Exzitons auf zusätzliche Ladungen und mit dem gestreckt-exponentiellen Zerfall der Exzitonenpopulation nach ultrakurzer Anregung. Beide Aspekte sind in guter Übereinstimmung mit dem diffusionslimitierten Kontaktlöschen von Exzitonen an lokalisierten Ladungen. Weiterhin wirken lokalisierte Ladungen – ähnlich zu strukturellen Defekten – als Störungen der Bandstruktur. Dies wurde durch den dotierungsbedingten Anstieg der D-Bandenantiresonanz im mittleren Infrarot nachgewiesen. Quantenmechanische Modellrechnungen deuten weiterhin darauf hin, dass Gegenionen eine entscheidende Rolle bei der Ladungsträgerlokalisierung spielen. Die Adsorption von Gegenionen an der Nanorohroberfläche induziert Fallenzustände für Ladungen, die mehr als 100 meV tief sind. Weiterhin ergibt sich eine Lokalisierungslänge der Ladungsträger von ungefähr 3 - 4 nm. Das dotierungsbedingte Bleichen der Interbandabsorption wird begleitet von einem Anstieg der Absorption im IR-Bereich unterhalb von 600 meV. Die beobachtete Verschiebung der IR-Peakposition deutet einen kontinuierlichen Übergang von lokalisierten zu delokalisierten Ladungsträgern an. Dieser Übergang wird durch den steigenden Überlapp der Ladungsträgerwellenfunktionen bei höheren Ladungsdichten verursacht und wurde durch klassische Monte-Carlo-Simulationen der Intrabandabsorption modelliert. In Kapitel 6 wurde die Spektroskopie stark dotierter (entartet dotierter) Nanoröhren diskutiert. Dieses zeichnen sich durch eine Drude-Antwort der Intrabandabsorption freier Ladungsträger im Spektrum der optischen Leitfähigkeit aus. Im NIR-Spektralbereich wird die Absorption des S$_1$-Exzitons und des X$^+_1$ -Trions durch ein beinahe 1 eV breites und konstantes Absorptionssignal, die sogenannte H-Bande, ersetzt. Die linearen und transienten Absorptionsspektren stark dotierter Nanoröhren legt den Schluss nahe, dass die H-Bande Interbandübergängen freier Ladungsträger zugeordnet werden kann. Kapitel 7 beschäftigte sich mit der Quantifizierung von Ladungsträgerdichten mittels linearer Absorptionsspektroskopie. Ein besonders gutes Maß für die Ladungsträgerdichte ist das Bleichen des S$_1$ Exzitons. Für ein Bleichen unterhalb von ungefähr 50% ist die Ladungsträgerdichte proportional zum Bleichen. Bei höherer Dotierung wurden Abweichungen vom linearen Verhalten beobachtet. Für Dotierungen jenseits einer vollständig gebleichten S$_1$-Bande wird zur Quantifizierung der Ladungsträgerdichte die Bestimmung der normierten Oszillatorstärke über den gesamten ersten Subbandbereich (Trion, Exziton, freie e-h-Paare) empfohlen. Basierend auf der Zustandsdichte der Nanoröhren kann die Ladungsträgerdichte $n$ mittels $n = 0.74\,\text{nm}^{−1} \cdot (1 − f_\text{1st})$ abgeschätzt werden. Im letzten Teil dieser Arbeit (Kapitel 8) wurde die zeitaufgelöste Spektroelektrochemie auf Systeme jenseits photostabiler Kohlenstoffnanoröhren ausgeweitet. Der Einbau einer Flusselektrolysezelle in das transiente Absorptionsspektrometer erlaubt die Untersuchung von elektrochemisch in-situ hergestellten aber photoinstabilen Molekülen durch einen kontinuierlichen Austausch des Probenvolumens. Die ersten zeitaufgelösten Experimente wurden erfolgreich anhand des Farbstoffs Methylenblau und dessen reduzierter Form Leukomethylenblau durchgeführt. KW - Dotierung KW - Einwandige Kohlenstoff-Nanoröhre KW - Spektroskopie KW - Lokalisation KW - Ladungsträger KW - Ladungsträgerlokalisation KW - zeitaufgelöste Spektroskopie KW - charge carrier localization KW - time-resolved spectroscopy Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188975 ER - TY - JOUR A1 - Ebner, Florian A1 - Wöckel, Achim A1 - Schwentner, Lukas A1 - Blettner, Maria A1 - Janni, Wolfgang A1 - Kreienberg, Rolf A1 - Wischnewsky, Manfred T1 - Does the number of removed axillary lymphnodes in high risk breast cancer patients influence the survival? JF - BMC Cancer N2 - Background The decision making process for axillary dissection has changed in recent years for patients with early breast cancer and positive sentinel lymph nodes (LN). The question now arises, what is the optimal surgical treatment for patients with positive axillary LN (pN+). This article tries to answer the following questions: (1) Is there a survival benefit for breast cancer patients with 3 or more positive LN (pN3+) and with more than 10 removed LN? (2) Is there a survival benefit for high risk breast cancer patients (triple negative or Her2 + breast cancer) and with 3 or more positive LN (pN3+) with more than 10 removed LN? (3) In pN + patients is the prognostic value of the lymph node ratio (LNR) of pN+/pN removed impaired if 10 or less LN are removed? Methods A retrospective database analysis of the multi center cohort database BRENDA (breast cancer under evidence based guidelines) with data from 9625 patients from 17 breast centers was carried out. Guideline adherence was defined by the 2008 German National consensus guidelines. Results 2992 out of 9625 patients had histological confirmed positive lymph nodes. The most important factors for survival were intrinsic sub types, tumor size and guideline adherent chemo- and hormonal treatment (and age at diagnosis for overall survival (OAS)). Uni-and multivariable analyses for recurrence free survival (RFS) and OAS showed no significant survival benefit when removing more than 10 lymph nodes even for high-risk patients. The mean and median of LNR were significantly higher in the pN+ patients with ≤10 excised LN compared to patients with > 10 excised LN. LNR was in both, uni-and multivariable, analysis a highly significant prognostic factor for RFS and OAS in both subgroups of pN + patients with less respective more than 10 excised LN. Multivariable COX regression analysis was adjusted by age, tumor size, intrinsic sub types and guideline adherent adjuvant systemic therapy. Conclusion The removal of more than 10 LN did not result in a significant survival benefit even in high risk pN + breast cancer patients. KW - advanced breast cancer KW - axillary dissection KW - lymph nodes KW - number of KW - sentinel KW - survival KW - guideline adherent treatment Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226445 VL - 19 ER - TY - CHAP A1 - Dürbeck, Gabriele T1 - Empathy, Violence, and Guilt in a Girl-Chimp Experiment: An Analysis of Human-Animal Relations in Karen Joy Fowler’s Novel We Are Completely Beside Ourselves (2013) T2 - Texts, Animals, Environments: Zoopoetics and Ecopoetics N2 - No abstract available. KW - Animal Studies KW - Cultural Animal Studies KW - Cultural Studies KW - Ecocriticism KW - Environmental Humanities KW - Human-Animal Studies KW - Literary Studies Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-178131 UR - https://www.rombach-verlag.de/buecher/suchergebnis/rombach/buch/details/texts-animals-environments.html PB - Rombach Druck- und Verlagshaus CY - Freiburg i. Br. ER - TY - JOUR A1 - Dörk, Thilo A1 - Peterlongo, Peter A1 - Mannermaa, Arto A1 - Bolla, Manjeet K. A1 - Wang, Qin A1 - Dennis, Joe A1 - Ahearn, Thomas A1 - Andrulis, Irene L. A1 - Anton-Culver, Hoda A1 - Arndt, Volker A1 - Aronson, Kristan J. A1 - Augustinsson, Annelie A1 - Beane Freeman, Laura E. A1 - Beckmann, Matthias W. A1 - Beeghly-Fadiel, Alicia A1 - Behrens, Sabine A1 - Bermisheva, Marina A1 - Blomqvist, Carl A1 - Bogdanova, Natalia V. A1 - Bojesen, Stig E. A1 - Brauch, Hiltrud A1 - Brenner, Hermann A1 - Burwinkel, Barbara A1 - Canzian, Federico A1 - Chan, Tsun L. A1 - Chang-Claude, Jenny A1 - Chanock, Stephen J. A1 - Choi, Ji-Yeob A1 - Christiansen, Hans A1 - Clarke, Christine L. A1 - Couch, Fergus J. A1 - Czene, Kamila A1 - Daly, Mary B. A1 - dos-Santos-Silva, Isabel A1 - Dwek, Miriam A1 - Eccles, Diana M. A1 - Ekici, Arif B. A1 - Eriksson, Mikael A1 - Evans, D. Gareth A1 - Fasching, Peter A. A1 - Figueroa, Jonine A1 - Flyger, Henrik A1 - Fritschi, Lin A1 - Gabrielson, Marike A1 - Gago-Dominguez, Manuela A1 - Gao, Chi A1 - Gapstur, Susan M. A1 - García-Closas, Montserrat A1 - García-Sáenz, José A. A1 - Gaudet, Mia M. A1 - Giles, Graham G. A1 - Goldberg, Mark S. A1 - Goldgar, David E. A1 - Guenél, Pascal A1 - Haeberle, Lothar A1 - Haimann, Christopher A. A1 - Håkansson, Niclas A1 - Hall, Per A1 - Hamann, Ute A1 - Hartman, Mikael A1 - Hauke, Jan A1 - Hein, Alexander A1 - Hillemanns, Peter A1 - Hogervorst, Frans B. L. A1 - Hooning, Maartje J. A1 - Hopper, John L. A1 - Howell, Tony A1 - Huo, Dezheng A1 - Ito, Hidemi A1 - Iwasaki, Motoki A1 - Jakubowska, Anna A1 - Janni, Wolfgang A1 - John, Esther M. A1 - Jung, Audrey A1 - Kaaks, Rudolf A1 - Kang, Daehee A1 - Kapoor, Pooja Middha A1 - Khusnutdinova, Elza A1 - Kim, Sung-Won A1 - Kitahara, Cari M. A1 - Koutros, Stella A1 - Kraft, Peter A1 - Kristensen, Vessela N. A1 - Kwong, Ava A1 - Lambrechts, Diether A1 - Le Marchand, Loic A1 - Li, Jingmei A1 - Lindström, Sara A1 - Linet, Martha A1 - Lo, Wing-Yee A1 - Long, Jirong A1 - Lophatananon, Artitaya A1 - Lubiński, Jan A1 - Manoochehri, Mehdi A1 - Manoukian, Siranoush A1 - Margolin, Sara A1 - Martinez, Elena A1 - Matsuo, Keitaro A1 - Mavroudis, Dimitris A1 - Meindl, Alfons A1 - Menon, Usha A1 - Milne, Roger L. A1 - Mohd Taib, Nur Aishah A1 - Muir, Kenneth A1 - Mulligan, Anna Marie A1 - Neuhausen, Susan L. A1 - Nevanlinna, Heli A1 - Neven, Patrick A1 - Newman, William G. A1 - Offit, Kenneth A1 - Olopade, Olufunmilayo I. A1 - Olshan, Andrew F. A1 - Olson, Janet E. A1 - Olsson, Håkan A1 - Park, Sue K. A1 - Park-Simon, Tjoung-Won A1 - Peto, Julian A1 - Plaseska-Karanfilska, Dijana A1 - Pohl-Rescigno, Esther A1 - Presneau, Nadege A1 - Rack, Brigitte A1 - Radice, Paolo A1 - Rashid, Muhammad U. A1 - Rennert, Gad A1 - Rennert, Hedy S. A1 - Romero, Atocha A1 - Ruebner, Matthias A1 - Saloustros, Emmanouil A1 - Schmidt, Marjanka K. A1 - Schmutzler, Rita K. A1 - Schneider, Michael O. A1 - Schoemaker, Minouk J. A1 - Scott, Christopher A1 - Shen, Chen-Yang A1 - Shu, Xiao-Ou A1 - Simard, Jaques A1 - Slager, Susan A1 - Smichkoska, Snezhana A1 - Southey, Melissa C. A1 - Spinelli, John J. A1 - Stone, Jennifer A1 - Surowy, Harald A1 - Swerdlow, Anthony J. A1 - Tamimi, Rulla M. A1 - Tapper, William J. A1 - Teo, Soo H. A1 - Terry, Mary Beth A1 - Toland, Amanda E. A1 - Tollenaar, Rob A. E. M. A1 - Torres, Diana A1 - Torres-Mejía, Gabriela A1 - Troester, Melissa A. A1 - Truong, Thérèse A1 - Tsugane, Shoichiro A1 - Untch, Michael A1 - Vachon, Celine M. A1 - van den Ouweland, Ans M. W. A1 - van Veen, Elke M. A1 - Vijai, Joseph A1 - Wendt, Camilla A1 - Wolk, Alicja A1 - Yu, Jyh-Cherng A1 - Zheng, Wei A1 - Ziogas, Argyrios A1 - Ziv, Elad A1 - Dunnig, Alison A1 - Pharaoh, Paul D. P. A1 - Schindler, Detlev A1 - Devilee, Peter A1 - Easton, Douglas F. T1 - Two truncating variants in FANCC and breast cancer risk JF - Scientific Reports N2 - Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44–1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants. KW - oncology KW - risk factors Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-222838 VL - 9 ER - TY - JOUR A1 - Duque, Laura A1 - Poelman, Erik H. A1 - Steffan-Dewenter, Ingolf T1 - Plant-mediated effects of ozone on herbivores depend on exposure duration and temperature JF - Scientific Reports N2 - Abiotic stress by elevated tropospheric ozone and temperature can alter plants’ metabolism, growth, and nutritional value and modify the life cycle of their herbivores. We investigated how the duration of exposure of Sinapis arvensis plants to high ozone and temperature levels affect the life cycle of the large cabbage white, Pieris brassicae. Plants were exposed to ozone-clean (control) or ozone-enriched conditions (120 ppb) for either 1 or 5 days and were afterwards kept in a greenhouse with variable temperature conditions. When given the choice, P. brassicae butterflies laid 49% fewer eggs on ozone-exposed than on control plants when the exposure lasted for 5 days, but showed no preference when exposure lasted for 1 day. The caterpillars took longer to hatch on ozone-exposed plants and at lower ambient temperatures. The ozone treatment had a positive effect on the survival of the eggs. Ozone decreased the growth of caterpillars reared at higher temperatures on plants exposed for 5 days, but not on plants exposed for 1 day. Overall, longer exposure of the plants to ozone and higher temperatures affected the life cycle of the herbivore more strongly. With global warming, the indirect impacts of ozone on herbivores are likely to become more common. KW - Ecology KW - Environmental impact Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202805 VL - 9 ER - TY - JOUR A1 - Duan, Xiaodong A1 - Nagel, Georg A1 - Gao, Shiqiang T1 - Mutated channelrhodopsins with increased sodium and calcium permeability JF - Applied Sciences N2 - (1) Background: After the discovery and application of Chlamydomonas reinhardtii channelrhodopsins, the optogenetic toolbox has been greatly expanded with engineered and newly discovered natural channelrhodopsins. However, channelrhodopsins of higher Ca\(^{2+}\) conductance or more specific ion permeability are in demand. (2) Methods: In this study, we mutated the conserved aspartate of the transmembrane helix 4 (TM4) within Chronos and PsChR and compared them with published ChR2 aspartate mutants. (3) Results: We found that the ChR2 D156H mutant (XXM) showed enhanced Na\(^+\) and Ca\(^{2+}\) conductance, which was not noticed before, while the D156C mutation (XXL) influenced the Na\(^+\) and Ca\(^{2+}\) conductance only slightly. The aspartate to histidine and cysteine mutations of Chronos and PsChR also influenced their photocurrent, ion permeability, kinetics, and light sensitivity. Most interestingly, PsChR D139H showed a much-improved photocurrent, compared to wild type, and even higher Na+ selectivity to H\(^+\) than XXM. PsChR D139H also showed a strongly enhanced Ca\(^{2+}\) conductance, more than two-fold that of the CatCh. (4) Conclusions: We found that mutating the aspartate of the TM4 influences the ion selectivity of channelrhodopsins. With the large photocurrent and enhanced Na\(^+\) selectivity and Ca\(^{2+}\) conductance, XXM and PsChR D139H are promising powerful optogenetic tools, especially for Ca\(^{2+}\) manipulation. KW - optogenetics KW - channelrhodopsins KW - sodium KW - calcium KW - DC gate Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-197435 SN - 2076-3417 VL - 9 IS - 4 ER - TY - THES A1 - Du, Yiqiang T1 - Gauge/Gravity Duality with Backreacting Background T1 - Eich-Gravitations-Dualität in gravitationell rückgewirkten Hintergründen N2 - The topic of this thesis is generalizations of the Anti de Sitter/Conformal Field Theory (AdS/CFT) correspondence, often referred to as holography, and their application to models relevant for condensed matter physics. A particular virtue of AdS/CFT is to map strongly coupled quantum field theories, for which calculations are inherently difficult, to more tractable classical gravity theories. I use this approach to study the crossover between Bose-Einstein condensation (BEC) and the Bardeen-Cooper-Schrieffer (BCS) superconductivity mechanism. I also study the phase transitions between the AdS black hole and AdS soliton spacetime in the presence of disorder. Moreover, I consider a holographic model of a spin impurity interacting with a strongly correlated electron gas, similar to the Kondo model. In AdS/CFT, the BEC/BCS crossover is modeled by a soliton configuration in the dual geometry and we study the BEC and BCS limits. The backreaction of the matter field on the background geometry is considered, which provides a new approach to study the BEC/BCS crossover. The behaviors of some physical quantities such as depletion of charge density under different strength of backreaction are presented and discussed. Moreover, the backreaction enables us to obtain the effective energy density of the soliton configurations, which together with the surface tension of the solitons leads to an argument for the occurrence of so called snake instability for dark solitons, i.e. for the solitons to form a vortex-like structures. Disordering strongly coupled and correlated quantum states of matter may lead to new insights into the physics of many body localized (MBL) strongly correlated states, which may occur in the presence of strong disorder. We are interested in potential insulator-metal transitions induced by disorder, and how disorder affects the Hawking-Page phase transition in AdS gravity in general. We introduce a metric ansatz and numerically construct the corresponding disordered AdS soliton and AdS black hole solutions, and discuss the calculation of the free energy in these states. In the Kondo effect, the rise in resistivity in metals with scarce magnetic impurities at low temperatures can be explained by the RG flow of the antiferromagnetic coupling between the impurity and conduction electrons in CFT. The generalizations to SU(N) in the large N limit make the treatment amenable to the holographic approach. We add a Maxwell term to a previously existing holographic model to study the conductivity of the itinerant electrons. Our goal is to find the log(T) behavior in the DC resistivity. In the probe limit, we introduce junction conditions to connect fields crossing the defect. We then consider backreactions, which give us a new metric ansatz and new junction conditions for the gauge fields. N2 - Das Thema dieser Arbeit sind Verallgemeinerungen der Anti-de-Sitter/Conformal Field Theory Korrespondenz (AdS/CFT-Korrespondenz), die oft auch als Holographie bezeichnet wird, und deren Anwendung auf Modelle, die für die Physik der kondensierten Materie relevant sind. Ein besonderer Vorteil von AdS / CFT ist die Abbildung stark gekoppelter Quantenfeldtheorien, für die Berechnungen insbesondere in fermionischen Systemen von Natur aus schwierig sind, auf leichter zu fassende klassische Gravitationstheorien. Mit diesem Zugang untersuche ich den Übergang zwischen der Bose-Einstein-Kondensation (BEC) und dem Supraleitungsmechanismus nach Bardeen- Cooper-Schrieffer (BCS). Ich untersuche auch die Phasenübergänge zwischen dem schwarzen Loch in der Anti de Sitter Raumzeit und der AdS - Solitonenraumzeit in der Vorhandensein von Unordnung. Außerdem betrachte ich ein holographisches Modell ähnlich dem Kondo-Modell, welches eine Spin-Störstelle, die mit einem stark korrelierten Elektronengas interagiert, beschreibt. In AdS / CFT wird der BEC/BCS-Übergang durch eine Solitonenkonfiguration in der dualen Geometrie modelliert, und wir untersuchen die asymptotischen BEC- und BCS-Grenzfälle. Die Rückwirkung des Materiefelds auf die Hintergrundgeometrie wird berücksichtigt, was eine neue Richtung zur Untersuchung des holographischen BEC / BCS-Übergangs eröffnet. Das Verhalten einiger physikalischer Größen wie z.B. der Ladungsdichte bei unterschiedlicher Stärke der Rückwirkung werden vorgestellt und diskutiert. Die Rückwirkung ermöglicht es uns außerdem, die effektive Energiedichte der Solitonen-Konfigurationen zu bestimmen, was zusammen mit der Oberflächenspannung der Solitonen zu einem Argument für das Auftreten einer sogenannten Schlangeninstabilität für dunkle Solitonen führt, d. h. für die Solitonen, die wirbel-ähnliche Strukturen bilden. Die Unordnung stark gekoppelter und korrelierter Quantenzustände der Materie kann zu neuen Erkenntnissen über die Physik vielteilchenlokalisierter stark korrelierter Zustände führen, die im Grenzfall starker Unordnung auftreten können. Ich untersuche mögliche Isolator-Metall-Übergänge, die durch die Unordnung induziert werden, sowie die Auswirkung von Unordnung auf den Hawking-Page-Phasenübergang in der AdS-Raumzeit im Allgemeinen. Wir führen einen metrischen Ansatz ein und konstruieren numerisch die entsprechenden ungeordneten AdS-Solitonen- und AdS-Schwarzloch-Lösungen, und diskutieren die Berechnung der freien Energie in diesen Zuständen. Der Anstieg des spezifischen Widerstands in Metallen mit vereinzelten magnetischen Verunreinigungen bei niedrigen Temperaturen lässt sich mit dem RG-Fluss der antiferromagnetischen Kopplung zwischen den Verunreinigungs- und Leitungselektronen erklären. Die Verallgemeinerungen zu SU(N)-Spins in Limes großer N machen die Behandlung durch den holographischen Zugang möglich. Wir fügen einem zuvor existierenden holographischen Modell einen Maxwell-Term hinzu, um die Leitfähigkeit der Leitungselektronen zu untersuchen. Unser Ziel ist es, das logT-Verhalten im Gleichstromwiderstand zu finden. Im Limes verschwindender Rückwirkung auf die Hintergrundgeometrie führen wir Übergangsbedingungen ein, um die gravitationellen Felder über dem Defekt, welcher holographisch die magnetische Verunreinigung beschreibt, zu verbinden. Dann betrachten wir die Rückwirkung auf die Geometrie, die uns einen neuen metrischen Ansatz und neue Übergangsbedingungen für die Eichfelder gibt. KW - AdS/CFT correspondence KW - gauge/gravity duality KW - back reaction Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187869 ER - TY - JOUR A1 - Du, Kang A1 - Wuertz, Sven A1 - Adolfi, Mateus A1 - Kneitz, Susanne A1 - Stöck, Matthias A1 - Oliveira, Marcos A1 - Nóbrega, Rafael A1 - Ormanns, Jenny A1 - Kloas, Werner A1 - Feron, Romain A1 - Klopp, Christophe A1 - Parrinello, Hugues A1 - Journot, Laurent A1 - He, Shunping A1 - Postlethwait, John A1 - Meyer, Axel A1 - Guiguen, Yann A1 - Schartl, Manfred T1 - The genome of the arapaima (Arapaima gigas) provides insights into gigantism, fast growth and chromosomal sex determination system JF - Scientific Reports N2 - We have sequenced the genome of the largest freshwater fish species of the world, the arapaima. Analysis of gene family dynamics and signatures of positive selection identified genes involved in the specific adaptations and unique features of this iconic species, in particular it’s large size and fast growth. Genome sequences from both sexes combined with RAD-tag analyses from other males and females led to the isolation of male-specific scaffolds and supports an XY sex determination system in arapaima. Whole transcriptome sequencing showed that the product of the gland-like secretory organ on the head surface of males and females may not only provide nutritional fluid for sex-unbiased parental care, but that the organ itself has a more specific function in males, which engage more in parental care. KW - Genome KW - Genomics Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201333 VL - 9 ER - TY - CHAP A1 - Driscoll, Kári T1 - “Il n’y a pas de chats”: Feline Absence and/as the Space of Zoopoetics T2 - Texts, Animals, Environments: Zoopoetics and Ecopoetics N2 - No abstract available. KW - Animal Studies KW - Cultural Animal Studies KW - Cultural Studies KW - Ecocriticism KW - Environmental Humanities KW - Human-Animal Studies KW - Literary Studies Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-178019 UR - https://www.rombach-verlag.de/buecher/suchergebnis/rombach/buch/details/texts-animals-environments.html PB - Rombach Druck- und Verlagshaus CY - Freiburg i. Br. ER - TY - JOUR A1 - Drescher, Nora A1 - Klein, Alexandra-Maria A1 - Schmitt, Thomas A1 - Leonhardt, Sara Diana T1 - A clue on bee glue: New insight into the sources and factors driving resin intake in honeybees (Apis mellifera) JF - PLoS ONE N2 - Honeybees (Apis mellifera) are threatened by numerous pathogens and parasites. To prevent infections they apply cooperative behavioral defenses, such as allo-grooming and hygiene, or they use antimicrobial plant resin. Resin is a chemically complex and highly variable mixture of many bioactive compounds. Bees collect the sticky material from different plant species and use it for nest construction and protection. Despite its importance for colony health, comparatively little is known about the precise origins and variability in resin spectra collected by honeybees. To identify the botanical resin sources of A. mellifera in Western Europe we chemically compared resin loads of individual foragers and tree resins. We further examined the resin intake of 25 colonies from five different apiaries to assess the effect of location on variation in the spectra of collected resin. Across all colonies and apiaries, seven distinct resin types were categorized according to their color and chemical composition. Matches between bee-collected resin and tree resin indicated that bees used poplar (Populus balsamifera, P. x canadensis), birch (Betula alba), horse chestnut (Aesculus hippocastanum) and coniferous trees (either Picea abies or Pinus sylvestris) as resin sources. Our data reveal that honeybees collect a comparatively broad and variable spectrum of resin sources, thus assuring protection against a variety of antagonists sensitive to different resins and/or compounds. We further unravel distinct preferences for specific resins and resin chemotypes, indicating that honeybees selectively search for bioactive resin compounds. KW - Honey bees KW - Poplars KW - Trees KW - Forests KW - Chemical composition KW - Bees KW - Conifers KW - Phenols Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200935 VL - 14 IS - 2 ER - TY - JOUR A1 - Drayß, Maria A1 - Claus, Heike A1 - Hubert, Kerstin A1 - Thiel, Katrin A1 - Berger, Anja A1 - Sing, Andreas A1 - van der Linden, Mark A1 - Vogel, Ulrich A1 - Lâm, Thiên-Trí T1 - Asymptomatic carriage of Neisseria meningitidis, Haemophilus influenzae, Streptococcus pneumoniae, Group A Streptococcus and Staphylococcus aureus among adults aged 65 years and older JF - PLoS ONE N2 - Objective The aim of this study was to determine the prevalence of Neisseria meningitidis, Haemophilus influenzae, Streptococcus pneumoniae, group A Streptococcus (GAS), and Staphylococcus aureus in asymptomatic elderly people and to unravel risk factors leading to colonization. Methods A multi-centre cross-sectional study was conducted including 677 asymptomatic adults aged 65 years or more, living at home or in nursing homes. Study areas were Greater Aachen (North-Rhine-Westphalia) and Wuerzburg (Bavaria), both regions with medium to high population density. Nasal and oropharyngeal swabs as well as questionnaires were collected from October 2012 to May 2013. Statistical analysis included multiple logistic regression models. Results The carriage rate was 1.9% ([95%CI: 1.0–3.3%]; 13/677) for H. influenzae, 0.3% ([95%CI: 0–1.1%]; 2/677) for N. meningitidis and 0% ([95% CI: 0–0.5%]; 0/677) for S. pneumoniae and GAS. Staphylococcus aureus was harboured by 28.5% of the individuals ([95% CI: 25.1–32.1%]; 193/677) and 0.7% ([95% CI: 0.2–1.7%]; 5/677) were positive for methicillin-resistant S. aureus. Among elderly community-dwellers colonization with S. aureus was significantly associated with higher educational level (adjusted OR: 1.905 [95% CI: 1.248–2.908]; p = 0.003). Among nursing home residents colonization was associated with being married (adjusted OR: 3.367 [1.502–7.546]; p = 0.003). Conclusion The prevalence of N. meningitidis, H. influenzae, S. pneumoniae and GAS was low among older people in Germany. The S. aureus rate was expectedly high, while MRSA was found in less than 1% of the individuals. KW - Geriatric care KW - Geriatrics KW - Elderly KW - Staphylococcus aureus KW - Nursing homes KW - Haemophilus influenzae KW - Neisseria meningitidis KW - Methicillin-resistant Staphylococcus aureus Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201042 VL - 14 IS - 2 ER - TY - JOUR A1 - Draganov, Dobrin D. A1 - Santidrian, Antonio F. A1 - Minev, Ivelina A1 - Duong, Nguyen A1 - Kilinc, Mehmet Okyay A1 - Petrov, Ivan A1 - Vyalkova, Anna A1 - Lander, Elliot A1 - Berman, Mark A1 - Minev, Boris A1 - Szalay, Aladar A. T1 - Delivery of oncolytic vaccinia virus by matched allogeneic stem cells overcomes critical innate and adaptive immune barriers JF - Journal of Translational Medicine N2 - Background Previous studies have identified IFNγ as an important early barrier to oncolytic viruses including vaccinia. The existing innate and adaptive immune barriers restricting oncolytic virotherapy, however, can be overcome using autologous or allogeneic mesenchymal stem cells as carrier cells with unique immunosuppressive properties. Methods To test the ability of mesenchymal stem cells to overcome innate and adaptive immune barriers and to successfully deliver oncolytic vaccinia virus to tumor cells, we performed flow cytometry and virus plaque assay analysis of ex vivo co-cultures of stem cells infected with vaccinia virus in the presence of peripheral blood mononuclear cells from healthy donors. Comparative analysis was performed to establish statistically significant correlations and to evaluate the effect of stem cells on the activity of key immune cell populations. Results Here, we demonstrate that adipose-derived stem cells (ADSCs) have the potential to eradicate resistant tumor cells through a combination of potent virus amplification and sensitization of the tumor cells to virus infection. Moreover, the ADSCs demonstrate ability to function as a virus-amplifying Trojan horse in the presence of both autologous and allogeneic human PBMCs, which can be linked to the intrinsic immunosuppressive properties of stem cells and their unique potential to overcome innate and adaptive immune barriers. The clinical application of ready-to-use ex vivo expanded allogeneic stem cell lines, however, appears significantly restricted by patient-specific allogeneic differences associated with the induction of potent anti-stem cell cytotoxic and IFNγ responses. These allogeneic responses originate from both innate (NK)- and adaptive (T)- immune cells and might compromise therapeutic efficacy through direct elimination of the stem cells or the induction of an anti-viral state, which can block the potential of the Trojan horse to amplify and deliver vaccinia virus to the tumor. Conclusions Overall, our findings and data indicate the feasibility to establish simple and informative assays that capture critically important patient-specific differences in the immune responses to the virus and stem cells, which allows for proper patient-stem cell matching and enables the effective use of off-the-shelf allogeneic cell-based delivery platforms, thus providing a more practical and commercially viable alternative to the autologous stem cell approach. KW - vaccinia KW - cancer KW - stem Cells KW - oncolysis KW - oncolytic virus KW - virotherapy KW - immunity KW - immunotherapy Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226312 SN - 100 VL - 17 ER - TY - JOUR A1 - Doppler, Kathrin A1 - Schuster, Yasmin A1 - Appeltshauser, Luise A1 - Biko, Lydia A1 - Villmann, Carmen A1 - Weishaupt, Andreas A1 - Werner, Christian A1 - Sommer, Claudia T1 - Anti-CNTN1 IgG3 induces acute conduction block and motor deficits in a passive transfer rat model JF - Journal of Neuroinflammation N2 - Background: Autoantibodies against the paranodal protein contactin-1 have recently been described in patients with severe acute-onset autoimmune neuropathies and mainly belong to the IgG4 subclass that does not activate complement. IgG3 anti-contactin-1 autoantibodies are rare, but have been detected during the acute onset of disease in some cases. There is evidence that anti-contactin-1 prevents adhesive interaction, and chronic exposure to anti-contactin-1 IgG4 leads to structural changes at the nodes accompanied by neuropathic symptoms. However, the pathomechanism of acute onset of disease and the pathogenic role of IgG3 anti-contactin-1 is largely unknown. Methods: In the present study, we aimed to model acute autoantibody exposure by intraneural injection of IgG of patients with anti-contacin-1 autoantibodies to Lewis rats. Patient IgG obtained during acute onset of disease (IgG3 predominant) and IgG from the chronic phase of disease (IgG4 predominant) were studied in comparison. Results: Conduction blocks were measured in rats injected with the “acute” IgG more often than after injection of “chronic” IgG (83.3% versus 35%) and proved to be reversible within a week after injection. Impaired nerve conduction was accompanied by motor deficits in rats after injection of the “acute” IgG but only minor structural changes of the nodes. Paranodal complement deposition was detected after injection of the “acute IgG”. We did not detect any inflammatory infiltrates, arguing against an inflammatory cascade as cause of damage to the nerve. We also did not observe dispersion of paranodal proteins or sodium channels to the juxtaparanodes as seen in patients after chronic exposure to anti-contactin-1. Conclusions: Our data suggest that anti-contactin-1 IgG3 induces an acute conduction block that is most probably mediated by autoantibody binding and subsequent complement deposition and may account for acute onset of disease in these patients. This supports the notion of anti-contactin-1-associated neuropathy as a paranodopathy with the nodes of Ranvier as the site of pathogenesis. KW - complement deposition KW - paranodopathy KW - anti-contactin-1 KW - CIDP KW - passive transfer KW - autoantibody Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200476 VL - 16 IS - 73 ER - TY - JOUR A1 - Doppler, Christopher E. J. A1 - Meyer, Linda A1 - Dovern, Anna A1 - Stühmer-Beckh, Jaro A1 - Weiss, Peter H. A1 - Fink, Gereon R. T1 - Differential impact of social and monetary reward on procedural learning and consolidation in aging and its structural correlates JF - Frontiers in Aging Neuroscience N2 - In young (n = 36, mean +/- SD: 24.8 +/- 4.5 years) and older (n = 34, mean +/- SD: 65.1 +/- 6.5 years) healthy participants, we employed a modified version of the Serial Reaction Time task to measure procedural learning (PL) and consolidation while providing monetary and social reward. Using voxel-based morphometry (VBM), we additionally determined the structural correlates of reward-related motor performance (RMP) and PL. Monetary reward had a beneficial effect on PL in the older subjects only. In contrast, social reward significantly enhanced PL in the older and consolidation in the young participants. VBM analyses revealed that motor performance related to monetary reward was associated with larger grey matter volume (GMV) of the left striatum in the young, and motor performance related to social reward with larger GMV of the medial orbitofrontal cortex in the older group. The differential effects of social reward in young (improved consolidation) and both social and monetary rewards in older (enhanced PL) healthy subjects point to the potential of rewards for interventions targeting aging-associated motor decline or stroke-induced motor deficits. KW - serial reaction time task KW - procedural learning KW - reinforcement learning KW - voxel-based morphometry KW - motor aging Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-222394 VL - 11 ER - TY - JOUR A1 - Djuzenova, Cholpon S. A1 - Fiedler, Vanessa A1 - Memmel, Simon A1 - Katzer, Astrid A1 - Sisario, Dmitri A1 - Brosch, Philippa K. A1 - Göhrung, Alexander A1 - Frister, Svenja A1 - Zimmermann, Heiko A1 - Flentje, Michael A1 - Sukhorukov, Vladimir L. T1 - Differential effects of the Akt inhibitor MK-2206 on migration and radiation sensitivity of glioblastoma cells JF - BMC Cancer N2 - Background Most tumor cells show aberrantly activated Akt which leads to increased cell survival and resistance to cancer radiotherapy. Therefore, targeting Akt can be a promising strategy for radiosensitization. Here, we explore the impact of the Akt inhibitor MK-2206 alone and in combination with the dual PI3K and mTOR inhibitor PI-103 on the radiation sensitivity of glioblastoma cells. In addition, we examine migration of drug-treated cells. Methods Using single-cell tracking and wound healing migration tests, colony-forming assay, Western blotting, flow cytometry and electrorotation we examined the effects of MK-2206 and PI-103 and/or irradiation on the migration, radiation sensitivity, expression of several marker proteins, DNA damage, cell cycle progression and the plasma membrane properties in two glioblastoma (DK-MG and SNB19) cell lines, previously shown to differ markedly in their migratory behavior and response to PI3K/mTOR inhibition. Results We found that MK-2206 strongly reduces the migration of DK-MG but only moderately reduces the migration of SNB19 cells. Surprisingly, MK-2206 did not cause radiosensitization, but even increased colony-forming ability after irradiation. Moreover, MK-2206 did not enhance the radiosensitizing effect of PI-103. The results appear to contradict the strong depletion of p-Akt in MK-2206-treated cells. Possible reasons for the radioresistance of MK-2206-treated cells could be unaltered or in case of SNB19 cells even increased levels of p-mTOR and p-S6, as compared to the reduced expression of these proteins in PI-103-treated samples. We also found that MK-2206 did not enhance IR-induced DNA damage, neither did it cause cell cycle distortion, nor apoptosis nor excessive autophagy. Conclusions Our study provides proof that MK-2206 can effectively inhibit the expression of Akt in two glioblastoma cell lines. However, due to an aberrant activation of mTOR in response to Akt inhibition in PTEN mutated cells, the therapeutic window needs to be carefully defined, or a combination of Akt and mTOR inhibitors should be considered. KW - DNA damage KW - glioblastoma multiforme KW - histone H2AX KW - irradiation KW - migration KW - mTOR KW - PTEN KW - p53 KW - radiation sensitivity KW - wound healing Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200290 VL - 19 ER - TY - JOUR A1 - Djebko, Kirill A1 - Puppe, Frank A1 - Kayal, Hakan T1 - Model-based fault detection and diagnosis for spacecraft with an application for the SONATE triple cube nano-satellite JF - Aerospace N2 - The correct behavior of spacecraft components is the foundation of unhindered mission operation. However, no technical system is free of wear and degradation. A malfunction of one single component might significantly alter the behavior of the whole spacecraft and may even lead to a complete mission failure. Therefore, abnormal component behavior must be detected early in order to be able to perform counter measures. A dedicated fault detection system can be employed, as opposed to classical health monitoring, performed by human operators, to decrease the response time to a malfunction. In this paper, we present a generic model-based diagnosis system, which detects faults by analyzing the spacecraft’s housekeeping data. The observed behavior of the spacecraft components, given by the housekeeping data is compared to their expected behavior, obtained through simulation. Each discrepancy between the observed and the expected behavior of a component generates a so-called symptom. Given the symptoms, the diagnoses are derived by computing sets of components whose malfunction might cause the observed discrepancies. We demonstrate the applicability of the diagnosis system by using modified housekeeping data of the qualification model of an actual spacecraft and outline the advantages and drawbacks of our approach. KW - fault detection KW - model-based diagnosis KW - nano-satellite Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-198836 SN - 2226-4310 VL - 6 IS - 10 ER - TY - JOUR A1 - Dirimanov, Stoyan A1 - Högger, Petra T1 - Screening of inhibitory effects of polyphenols on Akt-phosphorylation in endothelial cells and determination of structure-activity features JF - Biomolecules N2 - Polyphenols exert beneficial effects in type 2 diabetes mellitus (T2DM). However, their mechanism of action remains largely unknown. Endothelial Akt-kinase plays a key role in the pathogenesis of cardiovascular complications in T2DM and therefore the modulation of its activity is of interest. This work aimed to characterize effects of structurally different polyphenols on Akt-phosphorylation (pAkt) in endothelial cells (Ea.hy926) and to describe structure-activity features. A comprehensive screening via ELISA quantified the effects of 44 polyphenols (10 µM) on pAkt Ser473. The most pronounced inhibitors were luteolin (44 ± 18%), quercetin (36 ± 8%), urolithin A (35 ± 12%), apigenin, fisetin, and resveratrol; (p < 0.01). The results were confirmed by Western blotting and complemented with corresponding experiments in HUVEC cells. A strong positive and statistically significant correlation between the mean inhibitory effects of the tested polyphenols on both Akt-residues Ser473 and Thr308 (r = 0.9478, p = 0.0003) was determined by immunoblotting. Interestingly, the structural characteristics favoring pAkt inhibition partially differed from structural features enhancing the compounds’ antioxidant activity. The present study is the first to quantitatively compare the influence of polyphenols from nine different structural subclasses on pAkt in endothelial cells. These effects might be advantageous in certain T2DM-complications involving over-activation of the Akt-pathway. The suggested molecular mode of action of polyphenols involving Akt-inhibition contributes to understanding their effects on the cellular level. KW - Akt/PKB KW - endothelium KW - diabetes KW - polyphenols KW - in vitro KW - structure-activity relationships KW - screening Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-197333 SN - 2218-273X VL - 9 IS - 6 ER - TY - THES A1 - Dirimanov, Stoyan Dinkov T1 - Molecular Effects of Polyphenols in Experimental Type 2 Diabetes Mellitus and Metabolic Syndrome T1 - Molekulare Effekte von Polyphenolen bei experimentellem Diabetes mellitus Typ 2 und metabolischem Syndrom N2 - The growing prevalence of type 2 diabetes mellitus (T2DM) demands novel therapeutic and adjuvant strategies. Polyphenols (PPs) are plant secondary metabolites. Epidemiological studies demonstrate an inverse relationship between their increased intake and the risk of development of T2DM and cardiovascular complications. However, the PPs’ mechanism of action remains largely unknown. The present work aimed to expand knowledge regarding the effects of PPs on diabetes relevant molecular targets. Pycnogenol® (PYC) is a standardized pine bark extract which consists of oligomeric and monomeric PPs. Its anti-diabetic effects have been demonstrated in clinical trials. As a part of a human study involving 20 healthy volunteers, the extract’s effects on dipeptidyl peptidase IV (DPP IV) were investigated. This protease terminates the insulin secretagogue action of incretins. Its inhibition is a promising strategy in T2DM treatment. This study uncovered that PYC-intake of 100 mg daily over 14 days statistically significantly reduced DPP IV serum concentrations by 8.2 % (n= 38, p= 0.032). Contrary to expectations, this decrease was not paralleled by a reduction in the serum DPP IV enzymatic activity. To the best of our knowledge, the present study was the first investigating the effects of PPs on DPP IV serum concentrations and activities in humans. The finding that PYC is capable of reducing DPP IV serum concentrations might be important with regard to diabetes, where DPP IV levels are increased. Screenings for PPs’ in vitro effects on DPP IV activity were performed employing a purified enzyme. The effects of tested PPs (among which PYC ingredients) at a physiologically relevant concentration of 5 µM were weak (< 10 %) and too small compared to the reference compound sitagliptin, and thus not likely to be clinically relevant. This result is in discordance with some published data, but consistent with the outcome from the present human study. In addition, fluorescence interactions with the experimental setup were registered: under certain conditions urolithin B exhibited an autofluorescence which might mask eventual inhibitory activity. Quercetin quenched the fluorescence slightly which might contribute to false positive results. No statistically significant effects of selected constituents and metabolites of PYC on the total DPP IV protein expression were observed in 3T3-L1 adipocytes. Thus, the lower DPP IV in vivo concentrations after intake of PYC cannot be explained with down-regulation of the DPP IV expression in adipocytes. Akt kinase is responsible for the transmission of insulin signals and its dysregulation is related to insulin resistance and plays an important role in development of cardiovascular complications in T2DM. Thus, the modulation of the phosphorylation status of endothelial Akt-kinase, respectively its activity, might be a promising strategy in the management of these pathologies. This work aimed to uncover the effects of PPs from different structural subclasses on Akt-phosphorylation (pAkt) in endothelial cells (Ea.hy926). Short-term effects (5 – 30 min) were investigated at a concentration of 10 µM. In a pilot study two model PPs induced a moderate, but reproducible inhibition of pAkt Ser473 of 52.37 ± 21.01 % (quercetin; p= 0.006, n= 3) and 37.79 ± 7.14 % (resveratrol; p= 0.021, n= 4) compared to the negative control. A primary screening with Western blot analysis investigated the effects of eight compounds from different subclasses on pAkt Ser473 and Thr308 to reveal whether the observed inhibition PPs a group effect or specific to certain compounds. In addition to resveratrol and quercetin, statistically significant inhibitions of pAkt Ser473 were induced by luteolin (29.96 ± 11.06 %, p< 0.01, n= 6) and apigenin (22.57 ± 10.30 %, p< 0.01, n= 6). In contrast, genistein, 3,4,5-trimethoxystilbene, taxifolin and (+)-catechin caused no inhibition. A strong positive and statistically significant correlation between the mean inhibitory effects of the tested PPs on both Akt-residues Ser473 and Thr308 (r= 0.9478, p= 0.0003) was determined. A comprehensive secondary screening via ELISA involving 44 compounds from nine structural groups quantified the effects of PPs on pAkt Ser473 to uncover potential structure-activity features. The most potent inhibitors were luteolin (44.31 ± 17.95 %), quercetin (35.71 ± 8.33 %), urolithin A (35.28 ± 11.80 %), apigenin (31.79 ± 6.16 %), fisetin (28.09 ± 9.09 %), and resveratrol (26.04 ± 5.58 %). These effects were statistically significant (p< 0.01, n= 3 to 6). Further lead structure optimization might be based on the fact that the effects of luteolin and resveratrol also differed statistically significantly from each other (p= 0.008). To the best of our knowledge, the present study is the first to compare quantitatively the short term effects of PPs from different subclasses on pAkt in endothelial cells. Basic structure-activity relationships revealed that for flavones and flavonols the presence of a C2=C3 double bond (ring C) was essential for inhibitory activity and hydroxylation on the m- and p- positions in the ring B contributed to it. For stilbenoids, three free OH-groups appeared to be optimal. The comparison of the inhibitory potentials of ellagic acid and its microbial metabolites showed that urolithin A was statistically significantly more effective than its progenitor compound. Despite their structural similarities, the only active compound among all urolithins tested was urolithin A, hydroxylated at the C3 and C8 positions. This suggested a specific effect for urolithin A. Based on the common structural determinants and molecular geometry of the most active PPs a pharmacophore model regarding Akt-inhibition was proposed. In summary, the effects of a wide variety of PPs from diverse structural subclasses on the in vitro phosphorylation of endothelial Akt were quantitatively analyzed for the first time, the effects of previously undescribed compounds were determined and structure activity relationships were elucidated. The inhibitory potential of individual PPs might be beneficial in cases of sustained over-activation of Akt-kinase and its substrates such as S6 kinase as reported for certain T2DM-related pathological states, such as insulin resistance, endothelial dysfunction, excessive angiogenesis, vascular calcification, and insulin triggered DNA-damage. The results of the present work suggest potential molecular mechanisms of action of PP involving Akt-inhibition and DPP IV-down-regulation and thus contribute to the understanding of anti-diabetic effects of these compounds on the molecular level. N2 - Diabetes mellitus Typ 2 (DMT2) und seine Spätkomplikationen sind ein maßgeblicher Grund für Morbidität und Mortalität. Die steigende Prävalenz der Krankheit erfordert die Entwicklung neuer therapeutischer und prophylaktischer Strategien. Publizierte Daten deuten darauf hin, dass diätetische Polyphenole (PP) sowohl zur Prävention des Diabetes beitragen als auch therapiebegleitend sinnvoll eingesetzt werden können. Allerdings sind ihre Wirkmechanismen nicht vollständig aufgeklärt. Das Ziel der Arbeit war die Charakterisierung zellulärer Wirkungen von PP, die eine Relevanz in der unterstützenden Behandlung von DMT2 und denen Spätkomplikationen haben könnten. Pycnogenol® (PYC) ist ein standardisierter Kiefernrindenextrakt, der oligomere und monomere PP enthält. PYC hat in klinischen Studien mit Diabetikern viele vorteilhafte anti-diabetische und protektive Effekte gezeigt. Die Wirkungen des Extraktes auf die Serumkonzentration und die enzymatische Aktivität der Dipeptidylpeptidase IV (DPP IV) wurden im Rahmen einer klinischen Studie mit 20 gesunden Probanden untersucht. DPP IV ist eine Serin-Exopeptidase, die Inkretinhormone spaltet und damit deren Wirkung auf die Insulin-Freisetzung beendet. Nach PYC-Einnahme zeigte sich im Vergleich zu dem Kontrollzustand eine statistisch signifikante (p= 0,032, n= 38) Abnahme der DPP-IV-Konzentration von 8.2 %. Allerdings wurden keine deutlichen Änderungen der mittleren DPP-IV-Aktivität durch die PYC-Behandlung hervorgerufen. Nach unserem Wissensstand war die klinische Studie die erste ihrer Art, welche die Effekte von PP auf die Serumkonzentration und die enzymatischen Aktivität von DPP IV im Menschen untersuchte. Da die Serumspiegel von DPP IV bei diabetischen Patienten im Vergleich zu gesunden Menschen erhöht sind, könnte der beobachtete Effekt vorteilhaft sein. Als Nächstes sollten die Effekte von einzelnen PP und ihren Metaboliten auf die enzymatische Aktivität der DPP IV in vitro untersucht werden. Die Ergebnisse zeigten nur eine geringe Hemmung (< 10 %) der DPP IV Aktivität durch die PP (auch Inhaltsstoffe von PYC und deren Metaboliten) in einer Konzentration von 5 µM, verglichen zur initialen 100 %-igen Enzymaktivität. Die Positivkontrolle (50 nM Sitagliptin) verursachte hingegen eine starke Senkung der Aktivität von DPP IV. Es ist daher unwahrscheinlich, dass die Effekte der PP eine klinische Relevanz haben. Die Ergebnisse stehen im Widerspruch zu bisher veröffentlichten Daten, unterstützen aber die Resultate aus der vorliegenden Humanstudie. Zusätzlich durchgeführte Fluoreszenzmessungen deuten darauf hin, dass Quercetin und Urolithin B unter definierten Bedingungen in der Lage sind, die Ergebnisse des DPP IV-Inhibitoren-Screening-Assays unspezifisch zu beeinflussen. In-vitro-Experimente in 3T3-L1 differenzierten Adipozyten zeigten zudem keine statistisch signifikanten Effekte auf die Proteinexpression von DPP IV – weder für einzelne Bestandteile noch für Metabolite von PYC. Somit konnte die beobachtete Abnahme der DPP-IV-Konzentrationen in vivo nach der Einnahme von PYC nicht durch eine Herunterregulierung der DPP-IV-Expression in Adipozyten erklärt werden. Die Akt-Kinase/PKB (Protein Kinase B) spielt eine wesentliche Rolle bei der Vermittlung der Effekte des Insulins auf intrazellulärer Ebene bzw. bei der Pathophysiologie von DMT2 sowie dessen vaskulären Spätfolgen. Die Modulation von Akt in Endothelzellen ist ein vielversprechender Ansatz, um pathophysiologische Veränderungen zu beeinflussen, die für diabetische kardiovaskuläre Spätkomplikationen verantwortlich sind. Daher sollte in der vorliegenden Arbeit der Einfluss von PP aus verschiedenen strukturellen Subklassen auf die Akt-Phosphorylierung (pAkt) an Ser 473 und Thr 308 in Endothelzellen (EA.hy926) in vitro untersucht werden (10 µM, 5 – 30 min). In der Pilotstudie hemmten beide Modellverbindungen die Akt-Phosphorylierung (pAkt Ser473) statistisch signifikant mit 52,37 ± 21,01 % (Quercetin; p= 0,006, n= 3) und 37,79 ± 7,14 % (Resveratrol; p= 0,021, n= 4). Im Primärscreening wurden acht Verbindungen verschiedener Subklassen einbezogen. Die Substanzen, welche neben Quercetin und Resveratrol die stärksten Hemmungsaktivitäten auf pAkt Ser473 (Mittelwert ± Standardabweichung) hatten, waren Luteolin (29,96 ± 11,06 %, p< 0,01, n= 6) und Apigenin (22,57 ± 10,30 %, p< 0,01, n= 6). Im Gegensatz dazu zeigten Genistein, 3,4,5-Trimethoxy-trans-stilben, Taxifolin und (+)-Catechin keine Hemmung. Die inhibierenden Effekte der PP auf pAkt Thr308 und pAkt Ser473 korrelierten positiv und statistisch signifikant miteinander (r= 0,9478, p= 0,0003). In einem sekundären Screening sollten die Effekte diverser PP auf die Phosphorylierung von Akt an Ser 473 in Endothelzellen mittels quantitativen ELISA detailliert untersucht werden. Die Verbindungen mit den größten Hemmungseffekte waren Luteolin (44,31 ± 17,95 %), Quercetin (35,71 ± 8,33 %), Urolithin A (35,28 ± 11,80 %), Apigenin (31,79 ± 6,16 %), Fisetin (28,09 ± 9,09 %), und Resveratrol (26,04 ± 5,58 %). Diese Hemmungen waren statistisch signifikant (p< 0,01, n= 3 - 6). Zusätzlich war die Wirkung von Luteolin und Resveratrol statistisch signifikant verschieden (p= 0,008), was einer weiteren Leitstrukturoptimierung dienen kann. Der quantitative Vergleich der Substanzaktivitäten war die Grundlage für nachfolgende Struktur-Wirkungsuntersuchungen (SAR). Die Doppelbindung C2=C3 (Ring C) war für die Inhibitionseffekte bei Flavonen und Flavon-3-olen von wesentlicher Bedeutung. Die Anwesenheit einer meta- und einer para- OH-Gruppe (Ring B) trug sehr wahrscheinlich zu den Hemmeffekten bei. Bei den Stilbenoiden hingegen waren drei freie OH-Gruppen (bei Resveratrol) optimal für die Aktivität. Der mikrobielle Metabolit der Ellagsäure, Urolithin A, hemmte im Vergleich zur Muttersubstanz die Akt-Phosphorylierung statistisch signifikant. Im Gegensatz dazu zeigten die anderen Urolithine trotz der strukturellen Ähnlichkeit nur geringe Effekte. Dies deutet auf einen spezifischen Effekt von Urolithin A hin. Basierend auf den gemeinsamen Merkmalen, die für die Aktivität wichtig sein können und der molekularen Geometrie der aktivsten PP, wurde ein Pharmakophormodell für die Akt-Hemmung vorgeschlagen. Zusammengefasst ist die vorliegende Studie nach unserem Wissensstand die erste, welche die Auswirkungen einer Vielzahl von PP verschiedener struktureller Subklassen auf die Akt-Phosphorylierung in Endothelzellen quantitativ verglich. Es wurden Effekte von zuvor nicht beschriebenen Verbindungen und Struktur-Aktivitäts-Beziehungen ermittelt. Die hemmenden Eigenschaften einzelner PP auf die Akt-Kinase könnten im Fall einer anhaltenden Überaktivierung der Akt-Kinase und ihren Substraten wie die S6-Kinase vorteilhaft sein. Dieser Zustand wurde bei bestimmten DMT2-verwandten pathologischen Prozessen, wie Insulinresistenz, endotheliale Dysfunktion, übermäßige Angiogenese, vaskuläre Kalzifizierung und Insulin-induzierte-DNA-Schäden beobachtet. Die Ergebnisse der vorliegenden Arbeit deuten darauf hin, dass die Wirkmechanismen von PP die Akt-Inhibierung und DPP IV-Herunterregulierung umfassen könnten, was zum Verständnis der anti-diabetischen und protektiven Wirkungen dieser Verbindungen auf molekularer Ebene beitragen kann. KW - Polyphenole KW - Endothel KW - Struktur-Aktivitäts-Beziehung KW - Diabetes mellitus KW - in vitro KW - endothelium KW - screening KW - structure-activity relationship KW - DPP IV KW - Akt KW - Diabetes mellitus Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-185701 ER - TY - THES A1 - Dindas, Julian T1 - Cytosolic Ca\(^2\)\(^+\), a master regulator of vacuolar ion conductance and fast auxin signaling in \(Arabidopsis\) \(thaliana\) T1 - Zytosolisches Ca\(^2\)\(^+\), ein zentraler Regulator der vakuolären Ionenleitfähigkeit und der schnellen Auxin-Signaltransduktion in \(Arabidopsis\) \(thaliana\) N2 - Das Phytohormon Auxin erfüllt wichtige Funktionen bei der Initiierung von pflanzlichen Geweben und Organen, wie auch in der Steuerung des Wurzelwachstums im Zusammenspiel mit äußeren Reizen wie Schwerkraft, Wasser- und Nähstoffverfügbarkeit. Diese Funktionen basieren dabei vor allem auf der Auxin-abhängigen Regulation von Zellteilung und -streckung. Wichtig für letzteres ist dabei die Kontrolle des Zellturgors durch die Vakuole. Als Speicher für Nährstoffe, Metabolite und Toxine sind Vakuolen von essentieller Bedeutung. Vakuolär gespeicherte Metabolite und Ionen werden sowohl über aktive Transportprozesse, als auch passiv durch Ionenkanäle, über die vakuoläre Membran mit dem Zytoplasma ausgetauscht. In ihrer Funktion als second messenger sind Kalziumionen wichtige Regulatoren, aber auch Gegenstand vakuolärer Transportprozesse. Änderungen der zytosolischen Kalziumkonzentration wirken nicht nur lokal, sie werden auch mit einer Signalweiterleitung über längere Distanzen in Verbindung gebracht. Im Rahmen dieser Arbeit wurden elektrophysiologische Methoden mit bildgebenden Methoden kombiniert um Einblicke in das Zusammenspiel zwischen zytosolischen Kalziumsignalen, vakuolärer Transportprozesse und der Auxin-Physiologie im intakten pflanzlichen Organismus zu gewinnen. Kalziumsignale sind an der Regulierung vakuolärer Ionenkanäle und Transporter beteiligt. Um dies im intakten Organismus zu untersuchen wurden im Modellsystem junger Wurzelhaare von Arabidopsis thaliana Messungen mit intrazellulären Mikroelektroden durchgeführt. Mittels der Zwei-Elektroden-Spannungsklemm-Technik konnte bestätigt werden, dass die vakuoläre Membran der limitierende elektrische Wiederstand während intravakuolärer Messungen ist und so gemessene Ionenströme in der Tat nur die Ströme über die vakuoläre Membran repräsentieren. Die bereits bekannte zeitabhängige Abnahme der vakuolären Leitfähigkeit in Einstichexperimenten konnte weiterhin mit einer einstichbedingten, transienten Erhöhung der zytosolischen Kalziumkonzentration korreliert werden. Durch intravakuoläre Spannungsklemmexperimente in Wurzelhaarzellen von Kalziumreporterpflanzen konnte dieser Zusammenhang zwischen vakuolärer Leitfähigkeit und der zytosolischen Kalziumkonzentration bestätigt werden. Die Vakuole ist jedoch nicht nur ein Empfänger zytosolischer Kalziumsignale. Da die Vakuole den größten intrazellulären Kalziumspeicher darstellt, wird seit Langem diskutiert, ob sie auch an der Erzeugung solcher Signale beteiligt ist. Dies konnte in intakten Wurzelhaarzellen bestätigt werden. Änderungen des vakuolären Membranpotentials wirkten sich auf die zytosolische Kalziumkonzentration in diesen Zellen aus. Während depolarisierende Potentiale zu einer Erhöhung der zytosolischen Kalziumkonzentration führten, bewirkte eine Hyperpolarisierung der vakuolären Membran das Gegenteil. Thermodynamische Überlegungen zum passiven und aktiven Kalziumtransport über die vakuoläre Membran legten dabei den Schluss nahe, dass die hierin beschriebenen Ergebnisse das Verhalten von vakuolären H+/Ca2+ Austauschern wiederspiegeln, deren Aktivität durch die protonenmotorische Kraft bestimmt wird. Im Rahmen dieser Arbeit stellte sich weiterhin heraus, dass zytosolisches Kalzium ebenso ein zentraler Regulator eines schnellen Auxin-induzierten Signalweges ist, über den der polare Transport des Hormons reguliert wird. Im gleichen Modellsystem junger Wurzelhaare konnte gezeigt werden, dass die externe Applikation von Auxin eine sehr schnelle, Auxinkonzentrations- und pH-abhängige Depolarisation des Plasmamembranpotentials zur Folge hat. Synchron zur Depolarisation des Plasmamembranpotentials wurden im Zytosol transiente Kalziumsignale registriert. Diese wurden durch einen von Auxin aktivierten Einstrom von Kalziumionen durch den Ionenkanal CNGC14 hervorgerufen. Experimente an Verlustmutanten als auch pharmakologische Experimente zeigten, dass zur Auxin-induzierten Aktivierung des Kalziumkanals die Auxin-Perzeption durch die F-box Proteine der TIR1/AFB Familie erforderlich ist. Durch Untersuchungen der Auxin-abhängigen Depolarisation wie auch des Auxin-induzierten Einstroms von Protonen in epidermale Wurzelzellen von Verlustmutanten konnte gezeigt werden, dass die sekundär aktive Aufnahme von Auxin durch das hochaffine Transportprotein AUX1 für die schnelle Depolarisation verantwortlich ist. Nicht nur die zytosolischen Kalziumsignale korrelierten mit der CNGC14 Funktion, sondern ebenso die AUX1-vermittelte Depolarisation von Wurzelhaaren. Eine unveränderte Expression von AUX1 in der cngc14 Verlustmutante legte dabei den Schluss nahe, dass die Aktivität von AUX1 posttranslational reguliert werden muss. Diese Hypothese erfuhr Unterstützung durch Experimente, in denen die Behandlung mit dem Kalziumkanalblocker Lanthan zu einer Inaktivierung von AUX1 im Wildtyp führte. Die zytosolische Beladung einzelner epidermaler Wurzelzellen mit Auxin hatte die Ausbreitung lateraler und acropetaler Kalziumwellen zur Folge. Diese korrelierten mit einer Verschiebung des Auxin-Gradienten an der Wurzelspitze und unterstützten somit eine hypothetische Kalziumabhängige Regulation des polaren Auxin Transports. Ein Model für einen schnellen, Auxin induzierten und kalziumabhängigen Signalweg wird präsentiert und dessen Bedeutung für das gravitrope Wurzelwachstum diskutiert. Da die AUX1-vermittelte Depolarisation in Abhängigkeit von der externen Phosphatkonzentration variierte, wird die Bedeutung dieses schnellen Signalwegs ebenso für die Anpassung des Wurzelhaarwachstums an eine nicht ausreichende Verfügbarkeit von Phosphat diskutiert. N2 - The phytohormone auxin performs important functions in the initiation of plant tissues and organs, as well as in the control of root growth in conjunction with external stimuli such as gravity, water and nutrient availability. These functions are based primarily on the auxin-dependent regulation of cell division and elongation. Important for the latter is the control of the cell turgor by the vacuole. As storage for nutrients, metabolites and toxins, vacuoles are of vital importance. Vacuolar stored metabolites and ions are exchanged across the vacuolar membrane with the cytoplasm via active transport processes as well as passively through ion channels. In their function as second messenger, calcium ions are important regulators but also subject to vacuolar transport processes. Changes in the cytosolic calcium concentration not only act locally, but are also associated with signal transduction over longer distances. In this work, electrophysiological methods were combined with imaging techniques to gain insights into the interaction between cytosolic calcium signals, vacuolar transport processes and auxin physiology in the intact plant organism. Calcium signals are involved in the regulation of vacuolar ion channels and transporters. In order to investigate this in the intact organism, intracellular microelectrode measurements were performed in the model system of bulging Arabidopsis thaliana root hairs. By means of the two-electrode voltage-clamp technique, it could be confirmed that the vacuolar membrane is the limiting electrical resistance during intravacuolar measurements and thus measured ion currents actually represent only the currents across the vacuolar membrane. The already known time-dependent decrease of vacuolar conductivity during intravacuolar experiments could be further correlated with an impalement-related, transient increase of the cytosolic calcium concentration. Intravacuolar voltage-clamp experiments in root hair cells of calcium reporter plants confirmed this relationship between vacuolar conductivity and the cytosolic calcium concentration. However, the vacuole is not just a recipient of cytosolic calcium signals. Since the vacuole represents the largest intracellular calcium reservoir, it has long been argued that it is also involved in the generation of such signals. This could be confirmed in intact root hair cells. Changes in the vacuolar membrane potential affected the cytosolic calcium concentration in these cells. While depolarizing potentials led to an increase of the cytosolic calcium concentration, hyperpolarization of the vacuolar membrane caused the opposite. Thermodynamic considerations of passive and active calcium transport across the vacuolar membrane suggested that the results described herein reflect the behaviour of vacuolar H+/Ca2+ exchangers whose activity is determined by the proton motive force. In addition, cytosolic calcium has been shown to be a key regulator of a rapid auxin-induced signaling pathway that regulates polar transport of the hormone. In the same model system of bulging root hairs it could be shown that the external application of auxin results in a very fast, auxin concentration- and pH-dependent depolarization of the plasma membrane potential. Synchronous with the depolarization of the plasma membrane potential, transient calcium signals were recorded in the cytosol. These were caused by an auxin-activated influx of calcium ions through the ion channel CNGC14. Experiments on loss-of-function mutants as well as pharmacological experiments showed that the auxin-induced activation of the calcium channel requires auxin-perception by the F-box proteins of the TIR1/AFB family. Investigations of auxin-dependent depolarization as well as the auxin-induced influx of protons into epidermal root cells of loss-of-function mutants showed that the secondary active uptake of auxin by the high-affinity transport protein AUX1 is responsible for the rapid depolarization Not only the cytosolic calcium signals correlated with CNGC14 function, but also the AUX1-mediated depolarization of root hairs. An unchanged expression of AUX1 in the cngc14 loss-of-function mutant suggested that the activity of AUX1 must be post-translationally regulated. This hypothesis was supported by experiments in which treatment with the calcium channel blocker lanthanum led to inactivation of AUX1 in the wild type. The cytosolic loading of individual epidermal root cells with auxin resulted in the spread of lateral and acropetal calcium waves. These correlated with a shift of the auxin gradient at the root apex and thus supported a hypothetical calcium-dependent regulation of polar auxin transport. A model for a rapid, auxin-induced and calcium-dependent signaling pathway is presented and its importance for gravitropic root growth is discussed. Since AUX1-mediated depolarization varied with external phosphate concentration, the importance of this rapid signaling pathway is also discussed for the adaptation of root hair growth to an inadequate availability of phosphate. KW - Ackerschmalwand KW - Auxine KW - Vakuole KW - Calcium KW - Elektrophysiologie KW - Pflanzenhormone KW - Hormontransport KW - Ionenleitfähigkeit KW - Signaltransduktion KW - Arabidopsis thaliana Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158638 ER - TY - JOUR A1 - Dietrich, Thomas A1 - Krug, Ralf A1 - Krastl, Gabriel A1 - Tomson, Philip L. T1 - Restoring the unrestorable! Developing coronal tooth tissue with a minimally invasive surgical extrusion technique JF - British Dental Journal N2 - Surgical extrusion is a recognised treatment option for teeth that have insufficient coronal tooth structure remaining due to deep caries, resorption or traumatic injury. However, the technique has not been widely adopted, arguably because extraction of a severely compromised tooth may be difficult to achieve in a gentle and predictable way. In this paper, we present our novel approach to surgical extrusion and subsequent management of teeth using a vertical extraction system (Benex), which has become the method of choice in the authors' practice for many teeth that would otherwise be deemed unrestorable. We describe the clinical procedure in detail and discuss the advantages and disadvantages compared to alternative approaches, including surgical crown lengthening and orthodontic extrusion. Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225333 VL - 226 ER - TY - JOUR A1 - Dietrich, Laura A1 - Meister, Julia A1 - Dietrich, Oliver A1 - Notroff, Jens A1 - Kiep, Janika A1 - Heeb, Julia A1 - Beuger, André A1 - Schütt, Brigitta T1 - Cereal processing at Early Neolithic Göbekli Tepe, southeastern Turkey JF - PLoS ONE N2 - We analyze the processing of cereals and its role at Early Neolithic Göbekli Tepe, southeastern Anatolia (10th / 9th millennium BC), a site that has aroused much debate in archaeological discourse. To date, only zooarchaeological evidence has been discussed in regard to the subsistence of its builders. Göbekli Tepe consists of monumental round to oval buildings, erected in an earlier phase, and smaller rectangular buildings, built around them in a partially contemporaneous and later phase. The monumental buildings are best known as they were in the focus of research. They are around 20 m in diameter and have stone pillars that are up to 5.5 m high and often richly decorated. The rectangular buildings are smaller and–in some cases–have up to 2 m high, mostly undecorated, pillars. Especially striking is the number of tools related to food processing, including grinding slabs/bowls, handstones, pestles, and mortars, which have not been studied before. We analyzed more than 7000 artifacts for the present contribution. The high frequency of artifacts is unusual for contemporary sites in the region. Using an integrated approach of formal, experimental, and macro- / microscopical use-wear analyses we show that Neolithic people at Göbekli Tepe have produced standardized and efficient grinding tools, most of which have been used for the processing of cereals. Additional phytolith analysis confirms the massive presence of cereals at the site, filling the gap left by the weakly preserved charred macro-rests. The organization of work and food supply has always been a central question of research into Göbekli Tepe, as the construction and maintenance of the monumental architecture would have necessitated a considerable work force. Contextual analyses of the distribution of the elements of the grinding kit on site highlight a clear link between plant food preparation and the rectangular buildings and indicate clear delimitations of working areas for food production on the terraces the structures lie on, surrounding the circular buildings. There is evidence for extensive plant food processing and archaeozoological data hint at large-scale hunting of gazelle between midsummer and autumn. As no large storage facilities have been identified, we argue for a production of food for immediate use and interpret these seasonal peaks in activity at the site as evidence for the organization of large work feasts. KW - Specimen grinding KW - Archaeology KW - Neolithic period KW - Sediment KW - Equipment KW - Stratigraphy KW - Limestone KW - Meat Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201504 VL - 14 IS - 5 ER - TY - JOUR A1 - Dietrich, Georg A1 - Krebs, Jonathan A1 - Liman, Leon A1 - Fette, Georg A1 - Ertl, Maximilian A1 - Kaspar, Mathias A1 - Störk, Stefan A1 - Puppe, Frank T1 - Replicating medication trend studies using ad hoc information extraction in a clinical data warehouse JF - BMC Medical Informatics and Decision Making N2 - Background Medication trend studies show the changes of medication over the years and may be replicated using a clinical Data Warehouse (CDW). Even nowadays, a lot of the patient information, like medication data, in the EHR is stored in the format of free text. As the conventional approach of information extraction (IE) demands a high developmental effort, we used ad hoc IE instead. This technique queries information and extracts it on the fly from texts contained in the CDW. Methods We present a generalizable approach of ad hoc IE for pharmacotherapy (medications and their daily dosage) presented in hospital discharge letters. We added import and query features to the CDW system, like error tolerant queries to deal with misspellings and proximity search for the extraction of the daily dosage. During the data integration process in the CDW, negated, historical and non-patient context data are filtered. For the replication studies, we used a drug list grouped by ATC (Anatomical Therapeutic Chemical Classification System) codes as input for queries to the CDW. Results We achieve an F1 score of 0.983 (precision 0.997, recall 0.970) for extracting medication from discharge letters and an F1 score of 0.974 (precision 0.977, recall 0.972) for extracting the dosage. We replicated three published medical trend studies for hypertension, atrial fibrillation and chronic kidney disease. Overall, 93% of the main findings could be replicated, 68% of sub-findings, and 75% of all findings. One study could be completely replicated with all main and sub-findings. Conclusion A novel approach for ad hoc IE is presented. It is very suitable for basic medical texts like discharge letters and finding reports. Ad hoc IE is by definition more limited than conventional IE and does not claim to replace it, but it substantially exceeds the search capabilities of many CDWs and it is convenient to conduct replication studies fast and with high quality. KW - data warehouse KW - medication extraction KW - information extraction Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200409 VL - 19 ER - TY - THES A1 - Dietrich, Georg T1 - Ad Hoc Information Extraction in a Clinical Data Warehouse with Case Studies for Data Exploration and Consistency Checks T1 - Ad Hoc Informationsextraktion in einem Klinischen Data-Warehouse mit Fallstudien zur Datenexploration und Konsistenzüberprüfungen N2 - The importance of Clinical Data Warehouses (CDW) has increased significantly in recent years as they support or enable many applications such as clinical trials, data mining, and decision making. CDWs integrate Electronic Health Records which still contain a large amount of text data, such as discharge letters or reports on diagnostic findings in addition to structured and coded data like ICD-codes of diagnoses. Existing CDWs hardly support features to gain information covered in texts. Information extraction methods offer a solution for this problem but they have a high and long development effort, which can only be carried out by computer scientists. Moreover, such systems only exist for a few medical domains. This paper presents a method empowering clinicians to extract information from texts on their own. Medical concepts can be extracted ad hoc from e.g. discharge letters, thus physicians can work promptly and autonomously. The proposed system achieves these improvements by efficient data storage, preprocessing, and with powerful query features. Negations in texts are recognized and automatically excluded, as well as the context of information is determined and undesired facts are filtered, such as historical events or references to other persons (family history). Context-sensitive queries ensure the semantic integrity of the concepts to be extracted. A new feature not available in other CDWs is to query numerical concepts in texts and even filter them (e.g. BMI > 25). The retrieved values can be extracted and exported for further analysis. This technique is implemented within the efficient architecture of the PaDaWaN CDW and evaluated with comprehensive and complex tests. The results outperform similar approaches reported in the literature. Ad hoc IE determines the results in a few (milli-) seconds and a user friendly GUI enables interactive working, allowing flexible adaptation of the extraction. In addition, the applicability of this system is demonstrated in three real-world applications at the Würzburg University Hospital (UKW). Several drug trend studies are replicated: Findings of five studies on high blood pressure, atrial fibrillation and chronic renal failure can be partially or completely confirmed in the UKW. Another case study evaluates the prevalence of heart failure in inpatient hospitals using an algorithm that extracts information with ad hoc IE from discharge letters and echocardiogram report (e.g. LVEF < 45 ) and other sources of the hospital information system. This study reveals that the use of ICD codes leads to a significant underestimation (31%) of the true prevalence of heart failure. The third case study evaluates the consistency of diagnoses by comparing structured ICD-10-coded diagnoses with the diagnoses described in the diagnostic section of the discharge letter. These diagnoses are extracted from texts with ad hoc IE, using synonyms generated with a novel method. The developed approach can extract diagnoses from the discharge letter with a high accuracy and furthermore it can prove the degree of consistency between the coded and reported diagnoses. N2 - Die Bedeutung von Clinical Data Warehouses (CDW) hat in den letzten Jahren stark zugenommen, da sie viele Anwendungen wie klinische Studien, Data Mining und Entscheidungsfindung unterstützen oder ermöglichen. CDWs integrieren elektronische Patientenakten, die neben strukturierten und kodierten Daten wie ICD-Codes von Diagnosen immer noch sehr vielen Textdaten enthalten, sowie Arztbriefe oder Befundberichte. Bestehende CDWs unterstützen kaum Funktionen, um die in den Texten enthaltenen Informationen zu nutzen. Informationsextraktionsmethoden bieten zwar eine Lösung für dieses Problem, erfordern aber einen hohen und langen Entwicklungsaufwand, der nur von Informatikern durchgeführt werden kann. Außerdem gibt es solche Systeme nur für wenige medizinische Bereiche. Diese Arbeit stellt eine Methode vor, die es Ärzten ermöglicht, Informationen aus Texten selbstständig zu extrahieren. Medizinische Konzepte können ad hoc aus Texten (z. B. Arztbriefen) extrahiert werden, so dass Ärzte unverzüglich und autonom arbeiten können. Das vorgestellte System erreicht diese Verbesserungen durch effiziente Datenspeicherung, Vorverarbeitung und leistungsstarke Abfragefunktionen. Negationen in Texten werden erkannt und automatisch ausgeschlossen, ebenso wird der Kontext von Informationen bestimmt und unerwünschte Fakten gefiltert, wie z. B. historische Ereignisse oder ein Bezug zu anderen Personen (Familiengeschichte). Kontextsensitive Abfragen gewährleisten die semantische Integrität der zu extrahierenden Konzepte. Eine neue Funktion, die in anderen CDWs nicht verfügbar ist, ist die Abfrage numerischer Konzepte in Texten und sogar deren Filterung (z. B. BMI > 25). Die abgerufenen Werte können extrahiert und zur weiteren Analyse exportiert werden. Diese Technik wird innerhalb der effizienten Architektur des PaDaWaN-CDW implementiert und mit umfangreichen und aufwendigen Tests evaluiert. Die Ergebnisse übertreffen ähnliche Ansätze, die in der Literatur beschrieben werden. Ad hoc IE ermittelt die Ergebnisse in wenigen (Milli-)Sekunden und die benutzerfreundliche Oberfläche ermöglicht interaktives Arbeiten und eine flexible Anpassung der Extraktion. Darüber hinaus wird die Anwendbarkeit dieses Systems in drei realen Anwendungen am Universitätsklinikum Würzburg (UKW) demonstriert: Mehrere Medikationstrendstudien werden repliziert: Die Ergebnisse aus fünf Studien zu Bluthochdruck, Vorhofflimmern und chronischem Nierenversagen können in dem UKW teilweise oder vollständig bestätigt werden. Eine weitere Fallstudie bewertet die Prävalenz von Herzinsuffizienz in stationären Patienten in Krankenhäusern mit einem Algorithmus, der Informationen mit Ad-hoc-IE aus Arztbriefen, Echokardiogrammbericht und aus anderen Quellen des Krankenhausinformationssystems extrahiert (z. B. LVEF < 45). Diese Studie zeigt, dass die Verwendung von ICD-Codes zu einer signifikanten Unterschätzung (31%) der tatsächlichen Prävalenz von Herzinsuffizienz führt. Die dritte Fallstudie bewertet die Konsistenz von Diagnosen, indem sie strukturierte ICD-10-codierte Diagnosen mit den Diagnosen, die im Diagnoseabschnitt des Arztbriefes beschriebenen, vergleicht. Diese Diagnosen werden mit Ad-hoc-IE aus den Texten gewonnen, dabei werden Synonyme verwendet, die mit einer neuartigen Methode generiert werden. Der verwendete Ansatz kann Diagnosen mit hoher Genauigkeit aus Arztbriefen extrahieren und darüber hinaus den Grad der Übereinstimmung zwischen den kodierten und beschriebenen Diagnosen bestimmen. KW - Information Extraction KW - information extraction KW - information retrieval KW - Clinical Data Warehouse KW - negation detection KW - natural language processing KW - Data-Warehouse-Konzept KW - Klinisches Experiment KW - Data Warehouse Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-184642 ER - TY - JOUR A1 - Diers, J. A1 - Wagner, J. A1 - Baum, P. A1 - Lichthardt, S. A1 - Kastner, C. A1 - Matthes, N. A1 - Löb, S. A1 - Matthes, H. A1 - Germer, C.-T. A1 - Wiegering, A. T1 - Nationwide in-hospital mortality following colonic cancer resection according to hospital volume in Germany JF - BJS Open N2 - Background: Colonic cancer is the most common cancer of the gastrointestinal tract. The aim of this study was to determine mortality rates following colonic cancer resection and the effect of hospital caseload on in-hospital mortality in Germany. Methods: Patients admitted with a diagnosis of colonic cancer undergoing colonic resection from 2012 to 2015 were identifed from a nationwide registry using procedure codes. The outcome measure was in-hospital mortality. Hospitals were ranked according to their caseload for colonic cancer resection, and patients were categorized into five subgroups on the basis of hospital volume. Results: Some 129 196 colonic cancer resections were reviewed. The overall in-house mortality rate was 5⋅8 per cent, ranging from 6⋅9 per cent (1775 of 25 657 patients) in very low-volume hospitals to 4⋅8 per cent (1239 of 25 825) in very high-volume centres (P < 0⋅001). In multivariable logistic regression analysis the risk-adjusted odds ratio for in-house mortality was 0⋅75 (95 per cent c.i. 0⋅66 to 0⋅84) in very high-volume hospitals performing a mean of 85⋅0 interventions per year, compared with that in very low-volume hospitals performing a mean of only 12⋅7 interventions annually, after adjustment for sex, age, co-morbidity, emergency procedures, prolonged mechanical ventilation and transfusion. Conclusion: In Germany, patients undergoing colonic cancer resections in high-volume hospitals had with improved outcomes compared with patients treated in low-volume hospitals Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-204385 VL - 3 IS - 5 ER - TY - JOUR A1 - Diehl-Schmid, Janine A1 - Licata, Abigail A1 - Goldhardt, Oliver A1 - Förstl, Hans A1 - Yakushew, Igor A1 - Otto, Markus A1 - Anderl-Straub, Sarah A1 - Beer, Ambros A1 - Ludolph, Albert Christian A1 - Landwehrmeyer, Georg Bernhard A1 - Levin, Johannes A1 - Danek, Adrian A1 - Fliessbach, Klaus A1 - Spottke, Annika A1 - Fassbender, Klaus A1 - Lyros, Epameinondas A1 - Prudlo, Johannes A1 - Krause, Bernd Joachim A1 - Volk, Alexander A1 - Edbauer, Dieter A1 - Schroeter, Matthias Leopold A1 - Drzezga, Alexander A1 - Kornhuber, Johannes A1 - Lauer, Martin A1 - Grimmer, Timo T1 - FDG-PET underscores the key role of the thalamus in frontotemporal lobar degeneration caused by C9ORF72 mutations JF - Translational Psychiatry N2 - C9ORF72 mutations are the most common cause of familial frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). MRI studies have investigated structural changes in C9ORF72-associated FTLD (C9FTLD) and provided first insights about a prominent involvement of the thalamus and the cerebellum. Our multicenter, 18F-fluorodeoxyglucose positron-emission tomography study of 22 mutation carriers with FTLD, 22 matched non-carriers with FTLD, and 23 cognitively healthy controls provided valuable insights into functional changes in C9FTLD: compared to non-carriers, mutation carriers showed a significant reduction of glucose metabolism in both thalami, underscoring the key role of the thalamus in C9FTLD. Thalamic metabolism did not correlate with disease severity, duration of disease, or the presence of psychotic symptoms. Against our expectations we could not demonstrate a cerebellar hypometabolism in carriers or non-carriers. Future imaging and neuropathological studies in large patient cohorts are required to further elucidate the central role of the thalamus in C9FTLD. KW - diagnostic markers KW - psychiatric disorders Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225308 VL - 9 ER - TY - JOUR A1 - Derakhshani, Shaghayegh A1 - Kurz, Andreas A1 - Japtok, Lukasz A1 - Schumacher, Fabian A1 - Pilgram, Lisa A1 - Steinke, Maria A1 - Kleuser, Burkhard A1 - Sauer, Markus A1 - Schneider-Schaulies, Sibylle A1 - Avota, Elita T1 - Measles virus infection fosters dendritic cell motility in a 3D environment to enhance transmission to target cells in the respiratory epithelium JF - Frontiers in Immunology N2 - Transmission of measles virus (MV) from dendritic to airway epithelial cells is considered as crucial to viral spread late in infection. Therefore, pathways and effectors governing this process are promising targets for intervention. To identify these, we established a 3D respiratory tract model where MV transmission by infected dendritic cells (DCs) relied on the presence of nectin-4 on H358 lung epithelial cells. Access to recipient cells is an important prerequisite for transmission, and we therefore analyzed migration of MV-exposed DC cultures within the model. Surprisingly, enhanced motility toward the epithelial layer was observed for MV-infected DCs as compared to their uninfected siblings. This occurred independently of factors released from H358 cells indicating that MV infection triggered cytoskeletal remodeling associated with DC polarization enforced velocity. Accordingly, the latter was also observed for MV-infected DCs in collagen matrices and was particularly sensitive to ROCK inhibition indicating infected DCs preferentially employed the amoeboid migration mode. This was also implicated by loss of podosomes and reduced filopodial activity both of which were retained in MV-exposed uninfected DCs. Evidently, sphingosine kinase (SphK) and sphingosine-1-phosphate (S1P) as produced in response to virus-infection in DCs contributed to enhanced velocity because this was abrogated upon inhibition of sphingosine kinase activity. These findings indicate that MV infection promotes a push-and-squeeze fast amoeboid migration mode via the SphK/S1P system characterized by loss of filopodia and podosome dissolution. Consequently, this enables rapid trafficking of virus toward epithelial cells during viral exit. KW - dendritic cell KW - cell migration KW - measles virus KW - 3D tissue model KW - sphingosine-1-phosphate Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201818 VL - 10 IS - 1294 ER - TY - THES A1 - Derakhshani, Shaghayegh T1 - Measles virus infection enhances dendritic cell migration in a 3D environment T1 - Die Masernvirusinfektion verstärkt die Migration dendritischer Zellen in einer 3D-Umgebung N2 - The respiratory system is amongst the most important compartments in the human body. Due to its connection to the external environment, it is one of the most common portals of pathogen entry. Airborne pathogens like measles virus (MV) carried in liquid droplets exhaled from the infected individuals via a cough or sneeze enter the body from the upper respiratory tract and travel down to the lower respiratory tract and reach the alveoli. There, pathogens are captured by the resident dendritic cells (DCs) or macrophages and brought to the lymph node where immune responses or, as in case of MV, dissemination via the hematopoietic cell compartment are initiated. Basic mechanisms governing MV exit from the respiratory tract, especially virus transmission from infected immune cells to the epithelial cells have not been fully addressed before. Considering the importance of these factors in the viral spread, a complex close-to-in-vivo 3D human respiratory tract model was generated. This model was established using de-cellularized porcine intestine tissue as a biological scaffold and H358 cells as targets for infection. The scaffold was embedded with fibroblast cells, and later on, an endothelial cell layer seeded at the basolateral side. This provided an environment resembling the respiratory tract where MV infected DCs had to transmigrate through the collagen scaffold and transmit the virus to epithelial cells in a Nectin-4 dependent manner. For viral transmission, the access of infected DCs to the recipient epithelial cells is an essential prerequisite and therefore, this important factor which is reflected by cell migration was analyzed in this 3D system. The enhanced motility of specifically MV-infected DCs in the 3D models was observed, which occurred independently of factors released from the other cell types in the models. Enhanced motility of infected DCs in 3D collagen matrices suggested infection-induced cytoskeletal remodeling, as also verified by detection of cytoskeletal polarization, uropod formation. This enforced migration was sensitive to ROCK inhibition revealing that MV infection induces an amoeboid migration mode in DCs. In support of this, the formation of podosome structures and filopodia, as well as their activity, were reduced in infected DCs and retained in their uninfected siblings. Differential migration modes of uninfected and infected DCs did not cause differential maturation, which was found to be identical for both populations. As an underlying mechanism driving this enforced migration, the role of sphingosine kinase (SphK) and sphingosine-1-phosphate (S1P) was studied in MV-exposed cultures. It was shown in this thesis that MV-infection increased S1P production, and this was identified as a contributing factor as inhibition sphingosine kinase activity abolished enforced migration of MV-infected DCs. These findings revealed that MV infection induces a fast push-and-squeeze amoeboid mode of migration, which is supported by SphK/S1P axis. However, this push-and-squeeze amoeboid migration mode did not prevent the transendothelial migration of MV-infected DCs. Altogether, this 3D system has been proven to be a suitable model to study specific parameters of mechanisms involved in infections in an in vivo-like conditions. N2 - Die respiratorische System ist ein wesentlicher physiologischer Bestandteil. Durch die direkte und konstante Verbindung der Atemwege mit der äußeren Umgebung sind sie einer der häufigsten Pfade für den Eintritt von Krankheitserregern in den Körper. Luftübertragene Krankheitserreger wie das Masern-Virus (MV), das in Flüssigkeitströpfchen mitgeführt und von Patienten durch Husten oder Niesen ausgeatmet wird, können über die oberen Atemwege in den Körper gelangen und sich bis in die unteren Atemwege und bis zu den Alveolen ausbreiten. Dort werden diese Krankheitserreger von den dort residenten dendritischen Zellen (DC) oder Makrophagen erworben und zu sekundären lymphatischen Organen transportiert, in denen sowohl virus-spezifische Immunantworten, aber auch – wie im Falle von MV – die hämatogene Dissemination initiiert wird. Der Austrittsmechanismus des MV aus den Atemwegen, insbesondere dessen Übertragung von infizierten Immunzellen auf die Epithelzellen und die Faktoren, die diesen Ablauf bestimmen, wurden jedoch bisher unzureichend untersucht. In Anbetracht der Bedeutung dieser Faktoren für die Virusausbreitung wurde ein komplexes, realitätsnahes in-vivo 3D-Modell der menschlichen Atemwege erstellt. Dieses Modell wurde unter Verwendung von de-zellularisiertem Schweinedarmgewebe als biologischem Gerüst und H358 Epithelzellen als Empfänger etabliert. Dieses Grundgerüst wurde mit Fibroblastenzellen eingebettet. Später wurde auf der basolateralen Seite der Modelle eine Endothelzellschicht eingebracht, um eine Umgebung zu schaffen, die der der Atemwege ähnelt. Somit mussten die Virus-Donoren, MV-infizierte DC durch das Kollagengerüst wandern und das Virus auf Epithelzellen in einer Nektin-4 abhängigen Weise übertragen. Für die Virusübertragung ist der Zugang infizierter DC zu den Empfänger-Epithelzellen eine wesentliche Voraussetzung, weshalb dieser wichtige Faktor, der sich in der Zellmigration widerspiegelt, in diesem 3D-System analysiert wurde. Eine erhöhte Beweglichkeit spezifisch MV-infizierter DCs wurde in den 3D-Modellen beobachtet. Dies erwies sich als unabhängig von löslichen Faktoren der anderen Zelltypen in den Modellen. Erhöhte Beweglichkeit infizierten DCs wurde auch in 3D-Kollagenmatrizes gesehen, was auf einen infektionsvermittelten zytoskelettalen Umbau hindeutete, der auch anhand von Zytoskelettpolarisation und Uropodbildung bestätigt wurde. Die MV-Infektion induzierte einen schnellen amöboiden Migrationsmodus in den DCs, der sich als sensitiv gegenüber ROCK-Hemmung erwies. Im Gegensatz zu uninfizierten DCs gleichen Reifungsstadiums waren in infizierten DCs Podosomenstrukturen und Filopodien sowie deren Aktivität stark reduziert. Als potentiell zur verstärkten Motilität infizierter DCs beitragender Faktor wurde die Rolle der Sphingosinkinase (SphK) und des Sphingosin-1-phosphats (S1P) in MV-exponierten Kulturen untersucht. In dieser Arbeit wurde gezeigt, dass die S1P-Produktion durch eine MV-Infektion erhöht wurde, und in der Tat zur für infizierte DCs beobachteten erhöhten Geschwindigkeit beitrug, da diese sensitiv gegenüber Hemmung der Sphingosinkinase-Aktivität war. Diese Ergebnisse zeigen, dass die MV-Infektion einen schnellen amöboid-artigen Migrationsmodus induziert, der von der SphK/S1P-Achse unterstützt wird. Dieser Push-and-Squeeze-Amoeboid-Migrationsmodus verhinderte jedoch nicht die transendotheliale Migration von MV-infizierten DCs. Insgesamt hat sich dieses 3D-System als geeignetes Modell erwiesen, um die spezifische Parameter von Mechanismen von Infektionen in einem in-vivo-ähnlichen Zustand zu untersuchen. KW - Dendritische Zelle KW - Zell Migration KW - Masern-Virus KW - 3D-Modell KW - Sphingosine-1-phosphats KW - Dendritic cell KW - Cell migration KW - Measles virus KW - 3D tissue model KW - Tissue engineering KW - Sphingosine-1-phosphate Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-189182 ER - TY - JOUR A1 - Deol, Kirandeep K. A1 - Lorenz, Sonja A1 - Strieter, Eric R. T1 - Enzymatic logic of ubiquitin chain assembly JF - Frontiers in Physiology N2 - Protein ubiquitination impacts virtually every biochemical pathway in eukaryotic cells. The fate of a ubiquitinated protein is largely dictated by the type of ubiquitin modification with which it is decorated, including a large variety of polymeric chains. As a result, there have been intense efforts over the last two decades to dissect the molecular details underlying the synthesis of ubiquitin chains by ubiquitin-conjugating (E2) enzymes and ubiquitin ligases (E3s). In this review, we highlight these advances. We discuss the evidence in support of the alternative models of transferring one ubiquitin at a time to a growing substrate-linked chain (sequential addition model) versus transferring a pre-assembled ubiquitin chain (en bloc model) to a substrate. Against this backdrop, we outline emerging principles of chain assembly: multisite interactions, distinct mechanisms of chain initiation and elongation, optimal positioning of ubiquitin molecules that are ultimately conjugated to each other, and substrate-assisted catalysis. Understanding the enzymatic logic of ubiquitin chain assembly has important biomedical implications, as the misregulation of many E2s and E3s and associated perturbations in ubiquitin chain formation contribute to human disease. The resurgent interest in bifunctional small molecules targeting pathogenic proteins to specific E3s for polyubiquitination and subsequent degradation provides an additional incentive to define the mechanisms responsible for efficient and specific chain synthesis and harness them for therapeutic benefit. KW - ubiquitin KW - E2 conjugating enzyme KW - E3 ligating enzyme KW - sequential addition KW - en bloc transfer Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201731 VL - 10 IS - 835 ER - TY - THES A1 - Demmer, Claudia T1 - Merger-specific Efficiency Gains T1 - Fusionsbedingte Effizienzsteigerungen N2 - The present thesis analyzes whether and - if so - under which conditions mergers result in merger-specific efficiency gains. The analysis concentrates on manufacturing firms in Europe that participate in horizontal mergers as either buyer or target in the years 2005 to 2014. The result of the present study is that mergers are idiosyncratic processes. Thus, the possibilities to define general conditions that predict merger-specific efficiency gains are limited. However, the results of the present study indicate that efficiency gains are possible as a direct consequence of a merger. Efficiency changes can be measured by a Total Factor Productivity (TFP) approach. Significant merger-specific efficiency gains are more likely for targets than for buyers. Moreover, mergers of firms that mainly operate in the same segment are likely to generate efficiency losses. Efficiency gains most likely result from reductions in material and labor costs, especially on a short- and mid-term perspective. The analysis of conditions that predict efficiency gains indicates that firm that announce the merger themselves are capable to generate efficiency gains in a short- and mid-term perspective. Furthermore, buyers that are mid-sized firms are more likely to generate efficiency gains than small or large buyers. Results also indicate that capital intense firms are likely to generate efficiency gains after a merger. The present study is structured as follows. Chapter 1 motivates the analysis of merger-specific efficiency gains. The definition of conditions that reasonably likely predict when and to which extent mergers will result in merger-specific efficiency gains, would improve the merger approval or denial process. Chapter 2 gives a literature review of some relevant empirical studies that analyzed merger-specific efficiency gains. None of the empirical studies have analyzed horizontal mergers of European firms in the manufacturing sector in the years 2005 to 2014. Thus, the present study contributes to the existing literature by analyzing efficiency gains from those mergers. Chapter 3 focuses on the identification of mergers. The merger term is defined according to the EC Merger Regulation and the Horizontal Merger Guidelines. The definition and the requirements of mergers according to legislation provides the framework of merger identification. Chapter 4 concentrates on the efficiency measurement methodology. Most empirical studies apply a Total Factor Productivity (TFP) approach to estimate efficiency. The TFP approach uses linear regression in combination with a control function approach. The estimation of coefficients is done by a General Method of Moments approach. The resulting efficiency estimates are used in the analysis of merger-specific efficiency gains in chapter 5. This analysis is done separately for buyers and targets by applying a Difference-In-Difference (DID) approach. Chapter 6 concentrates on an alternative approach to estimate efficiency, that is a Stochastic Frontier Analysis (SFA) approach. Comparable to the TFP approach, the SFA approach is a stochastic efficiency estimation methodology. In contrast to TFP, SFA estimates the production function as a frontier function instead of an average function. The frontier function allows to estimate efficiency in percent. Chapter 7 analyses the impact of different merger- and firm-specific characteristics on efficiency changes of buyers and targets. The analysis is based on a multiple regression, which is applied for short-, mid- and long-term efficiency changes of buyers and targets. Chapter 8 concludes. N2 - Die Dissertation mit dem Titel 'Merger-specific Efficiency Gains' beschäftigt sich mit der Frage, ob und inwieweit Fusionen zu Effizienzsteigerungen der beteiligten Parteien beitragen. Die Analyse konzentriert sich dabei auf europäische Firmen im verarbeitenden Gewerbe, die im Zeitraum von 2005 bis einschließlich 2014 entweder als Käufer oder als Kaufobjekt an einer horizontalen Fusion beteiligt waren. Ergebnis dieser Dissertation ist, dass Fusionen einzigartige Prozesse sind. Allgemeingültige Aussagen hinsichtlich Zeitpunkt, Zeitraum und Umfang fusionsbedingter Effizienzgewinne sind daher nur bedingt möglich. Die Ergebnisse dieser Dissertation deuten darauf hin, dass Effienzgewinne als direkte Konsequenz einer Fusion möglich sind. Effizienzveränderungen können mithilfe einer Total Factor Productivity (TFP)-Methode gemessen werden. Signifikante fusionsbedingte Effizienzgewinne sind für gekaufte Unternehmen wahrscheinlicher als für Käufer. Desweiteren treten sie frühestens ab dem zweiten Jahr nach einer Fusion auf. Die Verschmelzung von zwei Unternehmen, die beide im gleichen Hauptsegment tätig sind, führt allerdings eher zu Effizienzverlusten als Effizienzgewinnen. Effizienzgewinne werden vor allem kurz- bis mittelfristig durch Veränderungen in den Material- und Personalkosten herbeigeführt. Insgesamt sind fusionsbedingte Effizienzgewinne eher von der Art der Firmen als von der Art der Fusion abhängig. Die Analyse der Gründe für fusionsbedingte Effizienzgewinne zeigt, dass Firmen, die die Information über die Fusion selber veröffentlichen, kurz- bis mittelfristig Effizienzgewinne generieren. Des Weiteren sind mittelgroße Käufer eher in der Lage Effizienzgewinne zu generieren als kleine oder große Käufer. Zudem zeigt die Untersuchung, dass kapitalintensivere Unternehmen häufig Effizienzgewinne nach einer Fusion generieren. Die Arbeit ist wie folgt strukturiert. In der Einleitung werden die Gründe für eine Beschäftigung mit der Frage nach fusionsbedingten Effizienzgewinnen dargelegt. Die Herausarbeitung von Faktoren, anhand derer sich der Zeitpunkt, der Umfang und der Zeitraum fusionsbedingter Effizienzgewinne bestimmen ließe, kann in der Praxis die Entscheidung für oder gegen eine Fusion erleichtern. Das zweite Kapitel beinhaltet einen Literaturüberblick über ausgewählte empirische Studien, die sich mit der Frage nach fusionsbedingten Effizienzgewinnen bereits befasst haben. Eine Studie, die horizontale Fusionen von europäischen Firmen im verarbeitenden Gewerbe zwischen 2005 und 2014 untersucht, liegt bisher nicht vor. Die vorliegende Arbeit leistet mit der Analyse von Effizienzgewinnen eben solcher Fusionen einen Beitrag zur vorhandenen Literatur. Das dritte Kapitel beschäftigt sich mit der Identifizierung von Fusionen. Die Fusionsdefinition entstammt der Europäischen Zusammenschlusskontrolle sowie den Richtlinien zur Bewertung horizontaler Fusionen. Anhand von Begriffsbestimmungen und festgelegten Kriterien schafft der europäische Gesetzgeber einen Rahmen zur Identifizierung von Fusionen. Im Fokus des vierten Kapitels steht die Effizienzschätzmethode. In empirischen Studien wird vorwiegend die TFP-Methode zur Schätzung der Effizienz eingesetzt. Die TFP-Methode bedient sich der ökonometrischen Methode der linearen Regression in Kombination mit einem Kontrollfunktionsansatz. Die Schätzung der Parameter erfolgt mit Hilfe der verallgemeinerten Momentenmethode. Die Ergebnisse der Effizienzschätzung gehen im fünften Kapitel in die Analyse fusionsbedinger Effizienzgewinne ein. Die Analyse erfolgt unter Zuhilfenahme der Difference-In-Difference (DID)-Methode und wird für Käufer und Gekaufte separat durchgeführt. Das sechste Kapitel beschäftigt sich mit einer alternativen Methode zur Effizienzschätzung, der Stochastic Frontier Analysis (SFA)-Methode. Vergleichbar zur TFP-Methode handelt es sich um eine stochastische Methode. Im Gegensatz zur TFP-Methode wird die Produktionsfunktion als Grenzfunktion und nicht als durchschnittliche Funktion geschätzt. So ist es möglich, Effizienz in Prozent auszudrücken. Es folgt im siebten Kapitel eine Analyse des Einflusses verschiedener fusions- und firmenspezifischer Faktoren auf die Effizienzveränderung bei Käufern und Gekauften. Die Analyse erfolgt mittels einer multiplen Regression und wird separat für kurz-, mittel- und langfristige Veränderung der Effizienz von Käufern und Gekauften durchgeführt. Im achten Kapitel folgt die Schlussbetrachtung. KW - Verarbeitende Industrie KW - Merger-specific Efficiency Gains KW - Mergers and Acquisitions KW - Effizienzsteigerung KW - Total Factor Productivity KW - Mergers KW - Efficiency Gains KW - TFP Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-183928 ER - TY - CHAP A1 - Demello, Margo T1 - The Rabbits of Okunoshima: How Feral Rabbits Alter Space, Create Relationships, and Communicate with People and Each Other T2 - Texts, Animals, Environments: Zoopoetics and Ecopoetics N2 - No abstract available. KW - Animal Studies KW - Cultural Animal Studies KW - Cultural Studies KW - Ecocriticism KW - Environmental Humanities KW - Human-Animal Studies KW - Literary Studies Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-178064 UR - https://www.rombach-verlag.de/buecher/suchergebnis/rombach/buch/details/texts-animals-environments.html PB - Rombach Druck- und Verlagshaus CY - Freiburg i. Br. ER - TY - THES A1 - del Olmo Toledo, Valentina T1 - Evolution of DNA binding preferences in a family of eukaryotic transcription regulators T1 - Evolutionäre Entwicklung der Bindeaffinität an bestimmte DNA Sequenzen in einer Familie von eukaryotischen Transkriptionsfaktoren N2 - Regulation of gene expression by the control of transcription is essential for any cell to adapt to the environment and survive. Transcription regulators, i.e. sequence-specific DNA binding proteins that regulate gene expression, are central elements within the gene networks of most organisms. Transcription regulators are grouped into distinct families based on structural features that determine, to a large extent, the DNA sequence(s) that they can recognise and bind. Less is known, however, about how the DNA binding preferences can diversify within transcription regulator families during evolutionary timescales, and how such diversification can affect the biology of the organism. In this dissertation I study the SREBP (sterol regulatory element binding protein) family of transcriptional regulators in yeasts, and in Candida albicans in particular, as an experimental system to address these questions. The SREBPs are conserved from fungi to humans and represent a subgroup of basic helix-loop-helix DNA binding proteins. Early chromatin immunoprecipitation experiments with SREBPs from humans and yeasts showed that these proteins bound in vivo to the canonical DNA sequence, termed E-box, most basic helix-loop-helix proteins bind to. By contrast, most recent analysis carried out with less-studied fungal SREBPs revealed a non-canonical DNA motif to be the most overrepresented sequence in the bound regions. This study aims to establish the intrinsic DNA binding preferences of key branches of this family and to determine how the divergence in DNA binding affinities originated. To this end, I combined phylogenetic and ancestral reconstruction with extensive biochemical characterisation of key SREBP proteins. The results indicated that while the most-studied SREBPs (in mammals) indeed show preference for the E-box, a second branch of the family preferentially binds the non-E-box, and a third one is able to bind both sequences with similar affinity. The preference for one or the other DNA sequence is an intrinsic property of each protein because their purified DNA binding domain was sufficient to recapitulate their in vivo binding preference. The ancestor that gave rise to these two different types of SREBPs (the branch that binds E-box and the one that binds non-E-box DNA) appears to be a protein with a broader DNA binding capability that had a slight preference for the non-canonical motif. Thus, the results imply these two branches originated by either enhancing the original ancestral preference for non-E-box or tilting it towards the E-box DNA and flipping the preference for this sequence. The main function associated with members of the SREBP family in most eukaryotes is the control of lipid biosynthesis. I have further studied the function of these proteins in the lineage that encompasses the human associated yeast C. albicans. Strikingly, the three SREBPs present in the fungus’ genome contribute to the colonisation of the mammalian gut by regulating cellular processes unrelated to lipid metabolism. Here I describe that two of the three C. albicans SREBPs form a regulatory cascade that regulates morphology and cell wall modifications under anaerobic conditions, whereas the third SREBP has been shown to be involved in the regulation of glycolysis genes. Therefore, I posit that the described diversification in DNA binding specificity in these proteins and the concomitant expansion of targets of regulation were key in enabling this fungal lineage to associate with animals. N2 - Für jede Zelle ist es essenziell die Transkription über die Genexpression zu regulieren, um sich an unterschiedliche Lebensbedingungen anzupassen. Regulatoren der Transkription, zum Beispiel sequenzspezifische DNA-binde Proteine, sind ein zentrales Element des Genregulationsnetzwerks in den meisten Organismen. Auf Grund ihres Aufbaus sowie der daraus resultierenden spezifischen Eigenschaften DNA zu binden, werden diese Regulatoren in unterschiedliche Familien unterteilt. Bisher ist wenig darüber bekannt, wie unterschiedlich die DNA Sequenzen sein können, welche von einer Familie von Transkriptionsregulatoren gebunden werden, wie sich diese Diversität der Bindung in der Evolution über die Zeit verändert hat und ob diese unterschiedlichen Bindeaffinitäten die Biologie eines Organismus beeinflussen. In dieser Dissertation befasse ich mich mit der Transkriptionsregulator Familie der SREBPs (sterol regulatory element binding protein) in Hefen, als Modelorganismus diente dabei Candida albicans. Die Familie der SREBPs ist vom Pilz zu den Menschen genetisch weitestgehend konserviert und repräsentiert eine Unterfamilie der Helix-loop-helix DNA-binde Proteine. Erste Chromatin-Immunpräzipitation Experimente der SREBPs in Menschen und Hefen zeigen in vivo eine Bindung an eine kanonische DNA Sequenz genannt E-box, welche von den meisten der Helix-loop-helix Proteine gebunden wird. Im Gegensatz zeigen neuere Analysen, welche mit weniger bekannten SREBPs aus Pilzen durchgeführt wurden, dass hauptsächlich nicht-kanonische DNA Sequenzen gebunden werden. Diese Arbeit versucht die Präferenzen, mit welchen einige der wichtigsten Mitglieder der Familie der SREBPs an bestimmte DNA Sequenzen binden aufzudecken und heraus zu finden wie es innerhalb dieser Gruppe zu unterschiedlichen Bindungsaffinitäten kam. Dafür wurden phylogenetische Rekonstruktionsanalysen und aufwändige biochemische Charakterisierungen einiger der Proteine der SREBP Familie durchgeführt. Die Ergebnisse zeigen, dass die meisten der bisher charakterisierten SREBPs (in Säugetieren) es vorziehen an die E-box Sequenz zu binden, ein anderer Zweig des SREBP Familienstammbaums bevorzugt hingegen die non-E-box Sequenz, ein dritter Zweig des Stammbaums ist in der Lage beide Sequenzen mit gleicher Affinität zu binden. Das Bevorzugen einer der beiden DNA Sequenzen ist eine natürliche Eigenschaft des jeweiligen Proteins, da in Experimenten die isolierte DNA-binde Domäne der Proteine ausreichend war, um die in vivo Bindepräferenzen zu replizieren. Der Ursprung dieser beiden Gruppen (der E-box bindenden Gruppe und der Gruppe die non-E-box Sequenzen bindet) liegt wahrscheinlich in einem Protein, welches beide Sequenzen binden konnte, mit einem Vorzug für die nicht-kanonische Sequenz. Dies impliziert, dass die Gruppen entstanden sind indem sich entweder eine Präferenz des Vorgängerproteins für die nicht-kanonische Sequenz durchgesetzt hat oder, dass sich eine Präferenz für die E-box bindende Sequenz durchgesetzt hat und somit die Affinität dahingehend verschoben wurde. Die Hauptfunktion der meisten Proteine der SREBP Familie in Eukaryoten ist die Kontrolle der Lipid Biosynthese. In meiner Arbeit habe ich mich auf die Erforschung der SREBPs in einer Gruppe von Organismen zugewandt, die auch den mit dem Menschen assoziierten Hefepilz Candida albicans umfasst. Erstaunlicherweise beeinflussen die drei SREBPs die im Candida albicans Genom zu finden sind, die Kolonisierung des Säugetierdarms, jedoch nicht durch die Kontrolle der Lipid Biosynthese. Im Folgenden werde ich beschreiben wie zwei der drei SREBPs aus Candida albicans eine regulatorische Kaskade bilden, welche Einfluss auf die Regulierung der Morphologie und der Zellwandzusammensetzung des Pilzes unter anaeroben Bedingungen hat, wohingegen das dritte Protein der SREBP Familie für die Regulierung der Glykolyse von Bedeutung ist. Ich habe festgestellt, dass die beschriebene Vielfalt mit der diese Proteine an bestimmte DNA Sequenzen binden und die damit einhergehende Expansion der regulierbaren Ziele ein wesentlicher Grund dafür ist, dass Organismen dieses Stammbaums erfolgreich Säugetiere kolonisieren können. KW - Candida albicans KW - SREBP KW - evolution Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187890 ER - TY - JOUR A1 - Dekker, Annelot M. A1 - Diekstra, Frank P. A1 - Pulit, Sara L. A1 - Tazelaar, Gijs H. P. A1 - van der Spek, Rick A. A1 - van Rheenen, Wouter A1 - van Eijk, Kristel R. A1 - Calvo, Andrea A1 - Brunetti, Maura A1 - Van Damme, Philip A1 - Robberecht, Wim A1 - Hardiman, Orla A1 - McLaughlin, Russell A1 - Chiò, Adriano A1 - Sendtner, Michael A1 - Ludolph, Albert C. A1 - Weishaupt, Jochen H. A1 - Pardina, Jesus S. Mora A1 - van den Berg, Leonard H. A1 - Veldink, Jan H. T1 - Exome array analysis of rare and low frequency variants in amyotrophic lateral sclerosis JF - Scientific Reports N2 - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects 1 in ~350 individuals. Genetic association studies have established ALS as a multifactorial disease with heritability estimated at ~61%, and recent studies show a prominent role for rare variation in its genetic architecture. To identify rare variants associated with disease onset we performed exome array genotyping in 4,244 cases and 3,106 controls from European cohorts. In this largest exome-wide study of rare variants in ALS to date, we performed single-variant association testing, gene-based burden, and exome-wide individual set-unique burden (ISUB) testing to identify single or aggregated rare variation that modifies disease risk. In single-variant testing no variants reached exome-wide significance, likely due to limited statistical power. Gene-based burden testing of rare non-synonymous and loss-of-function variants showed NEK1 as the top associated gene. ISUB analysis did not show an increased exome-wide burden of deleterious variants in patients, possibly suggesting a more region-specific role for rare variation. Complete summary statistics are released publicly. This study did not implicate new risk loci, emphasizing the immediate need for future large-scale collaborations in ALS that will expand available sample sizes, increase genome coverage, and improve our ability to detect rare variants associated to ALS. KW - amyotrophic lateral sclerosis KW - genome-wide association studies Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223686 VL - 9 ER - TY - JOUR A1 - Dechaud, Corentin A1 - Volff, Jean-Nicolas A1 - Schartl, Manfred A1 - Naville, Magali T1 - Sex and the TEs: transposable elements in sexual development and function in animals JF - Mobile DNA N2 - Transposable elements are endogenous DNA sequences able to integrate into and multiply within genomes. They constitute a major source of genetic innovations, as they can not only rearrange genomes but also spread ready-to-use regulatory sequences able to modify host gene expression, and even can give birth to new host genes. As their evolutionary success depends on their vertical transmission, transposable elements are intrinsically linked to reproduction. In organisms with sexual reproduction, this implies that transposable elements have to manifest their transpositional activity in germ cells or their progenitors. The control of sexual development and function can be very versatile, and several studies have demonstrated the implication of transposable elements in the evolution of sex. In this review, we report the functional and evolutionary relationships between transposable elements and sexual reproduction in animals. In particular, we highlight how transposable elements can influence expression of sexual development genes, and how, reciprocally, they are tightly controlled in gonads. We also review how transposable elements contribute to the organization, expression and evolution of sexual development genes and sex chromosomes. This underscores the intricate co-evolution between host functions and transposable elements, which regularly shift from a parasitic to a domesticated status useful to the host. KW - Transposable element KW - Sex determination KW - Sexual development and function KW - Germline KW - piRNA KW - Sex chromosome Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202510 VL - 10 ER - TY - JOUR A1 - Deak, Dalma A1 - Pop, Cristina A1 - Zimta, Alina-Andreea A1 - Jurj, Ancuta A1 - Ghiaur, Alexandra A1 - Pasca, Sergiu A1 - Teodorescu, Patric A1 - Dascalescu, Angela A1 - Antohe, Ion A1 - Ionescu, Bogdan A1 - Constantinescu, Catalin A1 - Onaciu, Anca A1 - Munteanu, Raluca A1 - Berindan-Neagoe, Ioana A1 - Petrushev, Bobe A1 - Turcas, Cristina A1 - Iluta, Sabina A1 - Selicean, Cristina A1 - Zdrenghea, Mihnea A1 - Tanase, Alina A1 - Danaila, Catalin A1 - Colita, Anca A1 - Colita, Andrei A1 - Dima, Delia A1 - Coriu, Daniel A1 - Einsele, Hermann A1 - Tomuleasa, Ciprian T1 - Let’s Talk About BiTEs and Other Drugs in the Real-Life Setting for B-Cell Acute Lymphoblastic Leukemia JF - Frontiers in Immunology N2 - Background: Therapy for acute lymphoblastic leukemia (ALL) are currently initially efficient, but even if a high percentage of patients have an initial complete remission (CR), most of them relapse. Recent data shows that immunotherapy with either bispecific T-cell engagers (BiTEs) of chimeric antigen receptor (CAR) T cells can eliminate residual chemotherapy-resistant B-ALL cells. Objective: The objective of the manuscript is to present improvements in the clinical outcome for chemotherapy-resistant ALL in the real-life setting, by describing Romania's experience with bispecific antibodies for B-cell ALL. Methods: We present the role of novel therapies for relapsed B-cell ALL, including the drugs under investigation in phase I-III clinical trials, as a potential bridge to transplant. Blinatumomab is presented in a critical review, presenting both the advantages of this drug, as well as its limitations. Results: Bispecific antibodies are discussed, describing the clinical trials that resulted in its approval by the FDA and EMA. The real-life setting for relapsed B-cell ALL is described and we present the patients treated with blinatumomab in Romania. Conclusion: In the current manuscript, we present blinatumomab as a therapeutic alternative in the bridge-to-transplant setting for refractory or relapsed ALL, to gain a better understanding of the available therapies and evidence-based data for these patients in 2019. KW - blinatumoman KW - acute lymphoblastic leukemia KW - bridge-to-transplant KW - real life setting KW - bispecific antobodies Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193921 SN - 1664-3224 VL - 10 IS - 2856 ER - TY - JOUR A1 - de Nijs, Laurence A1 - Choe, Kyonghwan A1 - Steinbusch, Hellen A1 - Schijns, Olaf E. M. G. A1 - Dings, Jim A1 - van den Hove, Daniel L. A. A1 - Rutten, Bart P. F. A1 - Hoogland, Govert T1 - DNA methyltransferase isoforms expression in the temporal lobe of epilepsy patients with a history of febrile seizures JF - Clinical Epigenetics N2 - Background Temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS) is a common pharmaco-resistant epilepsy referred for adult epilepsy surgery. Though associated with prolonged febrile seizures (FS) in childhood, the neurobiological basis for this relationship is not fully understood and currently no preventive or curative therapies are available. DNA methylation, an epigenetic mechanism catalyzed by DNA methyltransferases (DNMTs), potentially plays a pivotal role in epileptogenesis associated with FS. In an attempt to start exploring this notion, the present cross-sectional pilot study investigated whether global DNA methylation levels (5-mC and 5-hmC markers) and DNMT isoforms (DNMT1, DNMT3a1, and DNMT3a2) expression would be different in hippocampal and neocortical tissues between controls and TLE patients with or without a history of FS. Results We found that global DNA methylation levels and DNMT3a2 isoform expression were lower in the hippocampus for all TLE groups when compared to control patients, with a more significant decrease amongst the TLE groups with a history of FS. Interestingly, we showed that DNMT3a1 expression was severely diminished in the hippocampus of TLE patients with a history of FS in comparison with control and other TLE groups. In the neocortex, we found a higher expression of DNMT1 and DNMT3a1 as well as increased levels of global DNA methylation for all TLE patients compared to controls. Conclusion Together, the findings of this descriptive cross-sectional pilot study demonstrated brain region-specific changes in DNMT1 and DNMT3a isoform expression as well as global DNA methylation levels in human TLE with or without a history of FS. They highlighted a specific implication of DNMT3a isoforms in TLE after FS. Therefore, longitudinal studies that aim at targeting DNMT3a isoforms to evaluate the potential causal relationship between FS and TLE or treatment of FS-induced epileptogenesis seem warranted. KW - febrile seizures KW - temporal lobe epilepsy KW - epigenetics KW - DNA methylation KW - DNA methyltransferases Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223636 VL - 11 ER - TY - JOUR A1 - Dasari, Prasad A1 - Koleci, Naile A1 - Shopova, Iordana A. A1 - Wartenberg, Dirk A1 - Beyersdorf, Niklas A1 - Dietrich, Stefanie A1 - Sahagún-Ruiz, Alfredo A1 - Figge, Marc Thilo A1 - Skerka, Christine A1 - Brakhage, Axel A. A1 - Zipfel, Peter F. T1 - Enolase from Aspergillus fumigatus is a moonlighting protein that binds the human plasma complement proteins factor H, FHL-1, C4BP, and plasminogen JF - Frontiers in Immunology N2 - The opportunistic fungal pathogen Aspergillus fumigatus can cause severe infections, particularly in immunocompromised individuals. Upon infection, A. fumigatus faces the powerful and directly acting immune defense of the human host. The mechanisms on how A. fumigatus evades innate immune attack and complement are still poorly understood. Here, we identify A. fumigatus enolase, AfEno1, which was also characterized as fungal allergen, as a surface ligand for human plasma complement regulators. AfEno1 binds factor H, factor-H-like protein 1 (FHL-1), C4b binding protein (C4BP), and plasminogen. Factor H attaches to AfEno1 via two regions, via short conserved repeats (SCRs) 6–7 and 19–20, and FHL-1 contacts AfEno1 via SCRs 6–7. Both regulators when bound to AfEno1 retain cofactor activity and assist in C3b inactivation. Similarly, the classical pathway regulator C4BP binds to AfEno1 and bound to AfEno1; C4BP assists in C4b inactivation. Plasminogen which binds to AfEno1 via lysine residues is accessible for the tissue-type plasminogen activator (tPA), and active plasmin cleaves the chromogenic substrate S2251, degrades fibrinogen, and inactivates C3 and C3b. Plasmin attached to swollen A. fumigatus conidia damages human A549 lung epithelial cells, reduces the cellular metabolic activity, and induces cell retraction, which results in exposure of the extracellular matrix. Thus, A. fumigatus AfEno1 is a moonlighting protein and virulence factor which recruits several human regulators. The attached human regulators allow the fungal pathogen to control complement at the level of C3 and to damage endothelial cell layers and tissue components. KW - complement factor H KW - moonlighting KW - immune evasion KW - plasminogen KW - blocking phagocytosis Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-195612 SN - 1664-3224 VL - 10 ER - TY - INPR A1 - Dandekar, Thomas T1 - Biological heuristics applied to cosmology suggests a condensation nucleus as start of our universe and inflation cosmology replaced by a period of rapid Weiss domain-like crystal growth N2 - Cosmology often uses intricate formulas and mathematics to derive new theories and concepts. We do something different in this paper: We look at biological processes and derive from these heuristics so that the revised cosmology agrees with astronomical observations but does also agree with standard biological observations. We show that we then have to replace any type of singularity at the start of the universe by a condensation nucleus and that the very early period of the universe usually assumed to be inflation has to be replaced by a period of rapid crystal growth as in Weiss magnetization domains. Impressively, these minor modifications agree well with astronomical observations including removing the strong inflation perturbations which were never observed in the recent BICEP2 experiments. Furthermore, looking at biological principles suggests that such a new theory with a condensation nucleus at start and a first rapid phase of magnetization-like growth of the ordered, physical laws obeying lattice we live in is in fact the only convincing theory of the early phases of our universe that also is compatible with current observations. We show in detail in the following that such a process of crystal creation, breaking of new crystal seeds and ultimate evaporation of the present crystal readily leads over several generations to an evolution and selection of better, more stable and more self-organizing crystals. Moreover, this explains the “fine-tuning” question why our universe is fine-tuned to favor life: Our Universe is so self-organizing to have enough offspring and the detailed physics involved is at the same time highly favorable for all self-organizing processes including life. This biological theory contrasts with current standard inflation cosmologies. The latter do not perform well in explaining any phenomena of sophisticated structure creation or self-organization. As proteins can only thermodynamically fold by increasing the entropy in the solution around them we suggest for cosmology a condensation nucleus for a universe can form only in a “chaotic ocean” of string-soup or quantum foam if the entropy outside of the nucleus rapidly increases. We derive an interaction potential for 1 to n-dimensional strings or quantum-foams and show that they allow only 1D, 2D, 4D or octonion interactions. The latter is the richest structure and agrees to the E8 symmetry fundamental to particle physics and also compatible with the ten dimensional string theory E8 which is part of the M-theory. Interestingly, any other interactions of other dimensionality can be ruled out using Hurwitz compositional theorem. Crystallization explains also extremely well why we have only one macroscopic reality and where the worldlines of alternative trajectories exist: They are in other planes of the crystal and for energy reasons they crystallize mostly at the same time, yielding a beautiful and stable crystal. This explains decoherence and allows to determine the size of Planck´s quantum h (very small as separation of crystal layers by energy is extremely strong). Ultimate dissolution of real crystals suggests an explanation for dark energy agreeing with estimates for the “big rip”. The halo distribution of dark matter favoring galaxy formation is readily explained by a crystal seed starting with unit cells made of normal and dark matter. That we have only matter and not antimatter can be explained as there may be right handed mattercrystals and left-handed antimatter crystals. Similarly, real crystals are never perfect and we argue that exactly such irregularities allow formation of galaxies, clusters and superclusters. Finally, heuristics from genetics suggest to look for a systems perspective to derive correct vacuum and Higgs Boson energies. KW - heuristics KW - inflation KW - cosmology KW - crystallization KW - crystal growth KW - E8 symmetry KW - Hurwitz theorem KW - evolution KW - Lee Smolin Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-183945 ER - TY - JOUR A1 - Dammert, Marcel A. A1 - Brägelmann, Johannes A1 - Olsen, Rachelle R. A1 - Böhm, Stefanie A1 - Monhasery, Niloufar A1 - Whitney, Christopher P. A1 - Chalishazar, Milind D. A1 - Tumbrink, Hannah L. A1 - Guthrie, Matthew R. A1 - Klein, Sebastian A1 - Ireland, Abbie S. A1 - Ryan, Jeremy A1 - Schmitt, Anna A1 - Marx, Annika A1 - Ozretić, Luka A1 - Castiglione, Roberta A1 - Lorenz, Carina A1 - Jachimowicz, Ron D. A1 - Wolf, Elmar A1 - Thomas, Roman K. A1 - Poirier, John T. A1 - Büttner, Reinhard A1 - Sen, Triparna A1 - Byers, Lauren A. A1 - Reinhardt, H. Christian A1 - Letai, Anthony A1 - Oliver, Trudy G. A1 - Sos, Martin L. T1 - MYC paralog-dependent apoptotic priming orchestrates a spectrum of vulnerabilities in small cell lung cancer JF - Nature Communications N2 - MYC paralogs are frequently activated in small cell lung cancer (SCLC) but represent poor drug targets. Thus, a detailed mapping of MYC-paralog-specific vulnerabilities may help to develop effective therapies for SCLC patients. Using a unique cellular CRISPR activation model, we uncover that, in contrast to MYCN and MYCL, MYC represses BCL2 transcription via interaction with MIZ1 and DNMT3a. The resulting lack of BCL2 expression promotes sensitivity to cell cycle control inhibition and dependency on MCL1. Furthermore, MYC activation leads to heightened apoptotic priming, intrinsic genotoxic stress and susceptibility to DNA damage checkpoint inhibitors. Finally, combined AURK and CHK1 inhibition substantially prolongs the survival of mice bearing MYC-driven SCLC beyond that of combination chemotherapy. These analyses uncover MYC-paralog-specific regulation of the apoptotic machinery with implications for genotype-based selection of targeted therapeutics in SCLC patients. KW - genetic engineering KW - oncogenes KW - small-cell lung cancer KW - targeted therapies Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223569 VL - 10 ER - TY - JOUR A1 - Da Vià, Matteo Claudio A1 - Solimando, Antonio Giovanni A1 - Garitano-Trojaola, Andoni A1 - Barrio, Santiago A1 - Munawar, Umair A1 - Strifler, Susanne A1 - Haertle, Larissa A1 - Rhodes, Nadine A1 - Vogt, Cornelia A1 - Lapa, Constantin A1 - Beilhack, Andreas A1 - Rasche, Leo A1 - Einsele, Hermann A1 - Kortüm, K. Martin T1 - CIC Mutation as a Molecular Mechanism of Acquired Resistance to Combined BRAF‐MEK Inhibition in Extramedullary Multiple Myeloma with Central Nervous System Involvement JF - The Oncologist N2 - Combined MEK‐BRAF inhibition is a well‐established treatment strategy in BRAF‐mutated cancer, most prominently in malignant melanoma with durable responses being achieved through this targeted therapy. However, a subset of patients face primary unresponsiveness despite presence of the activating mutation at position V600E, and others acquire resistance under treatment. Underlying resistance mechanisms are largely unknown, and diagnostic tests to predict tumor response to BRAF‐MEK inhibitor treatment are unavailable. Multiple myeloma represents the second most common hematologic malignancy, and point mutations in BRAF are detectable in about 10% of patients. Targeted inhibition has been successfully applied, with mixed responses observed in a substantial subset of patients mirroring the widespread spatial heterogeneity in this genomically complex disease. Central nervous system (CNS) involvement is an extremely rare, extramedullary form of multiple myeloma that can be diagnosed in less than 1% of patients. It is considered an ultimate high‐risk feature, associated with unfavorable cytogenetics, and, even with intense treatment applied, survival is short, reaching less than 12 months in most cases. Here we not only describe the first patient with an extramedullary CNS relapse responding to targeted dabrafenib and trametinib treatment, we furthermore provide evidence that a point mutation within the capicua transcriptional repressor (CIC) gene mediated the acquired resistance in this patient. KW - Multiple myeloma KW - Extramedullary disease KW - Capicua transcriptional repressor KW - Drug resistance KW - BRAF mutation Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-219549 VL - 25 IS - 2 ER - TY - JOUR A1 - Cook, Nigel A1 - Geier, Andreas A1 - Schmid, Andreas A1 - Hirschfeld, Gideon A1 - Kautz, Achim A1 - Schattenberg, Jörn M. A1 - Balp, Maria-Magdalena T1 - The patient perspectives on future therapeutic options in NASH and patient needs JF - Frontiers in Medicine N2 - Background: Non-alcoholic steatohepatitis (NASH) is a chronic liver disease with severe complications and without approved therapies. Currently, there is limited data on the overall burden of the disease for patients or on patient needs and preferences. This study investigates patient preferences in relation to potential future therapies for NASH. In addition, the factors that are relevant to patients and their importance in relation to future treatment options are explored. Method: Telephone in-depth interviews (TDIs) preceded an online 30-min quantitative survey. The online survey included (1) multiple choice questions (MCQs) on NASH diagnosis and disease background. (2) An exercise to determine patients' satisfaction levels with information provided at diagnosis, and to explore symptomatology in detail. (3) Exercises to evaluate potential new products and product attributes, including a "drag and drop" ranking exercise, and an adaptive choice-based conjoint exercise (ACBC). (4) The EQ-5D-5L questionnaire and the Visual Analog Scale (VAS), which measures patients' health status. (5) Collection of socio-demographic data, and (6) Questions to measure patient satisfaction with the survey. Results: There were 166 patients included in this study from Canada [n = 36], Germany [n = 50], the UK [n = 30], and USA [n = 50]. Fifty seven percent of patients [n = 94] had had a liver biopsy for confirmation of NASH. Patients were often unable to link their symptoms to NASH or other conditions. ACBC results showed that efficacy, defined as "impact on liver status" was the single most important attribute of a potential future NASH therapy. Other attributes considered to have secondary importance included impact on weight, symptom control and the presence of side effects. The EQ-5D utility score was 0.81 and VAS = 67.2. Conclusion: "Impact on liver status" is the primary outcome sought. Patients demonstrate a general lack of understanding of their disease and appeared to be unfamiliar with longer-term consequences of NASH. It is necessary to improve patient understanding of NASH and its progressive nature, and there is a need for improving confirmatory diagnosis and monitoring. KW - patient preference KW - non-alcoholic fatty liver disease (NAFLD) KW - non-alcoholic steatohepatitis (NASH) KW - adaptive choice-based conjoint KW - liver disease KW - EQ5D-5L KW - patient-based evidence KW - patient-reported outcomes Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223268 VL - 6 ER - TY - RPRT A1 - Conrad, Christopher A1 - Morper-Busch, Lucia A1 - Netzband, Maik A1 - Teucher, Mike A1 - Schönbrodt-Stitt, Sarah A1 - Schorcht, Gunther A1 - Dukhovny, Viktor T1 - WUEMoCA Water Use Efficiency Monitor in Central Asia Informed Decision-Making in Land and Water Resources Management N2 - WUEMoCA is an operational scientific webmapping tool for the regional monitoring of land and water use efficiency in the irrigated croplands of the transboundary Aral Sea Basin that is shared by Kazakhstan, Kyrgyzstan, Tajikistan, Turkmenistan, Uzbekistan, and Afghanistan. Satellite data on land use, crop pro-duction and water consumption is integrated with hydrological and economic information to provide of a set indicators. The tool is useful for large-scale decisions on water distribution or land use, and may be seen as demonstrator for numerous applications in practice, that require independent area-wide spatial information. KW - Zentralasien KW - Information system KW - Remote Sensing KW - WebGIS KW - Information System KW - Central Asia Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-191934 ER - TY - JOUR A1 - Coelho, Luis Pedro A1 - Alves, Renato A1 - Monteiro, Paulo A1 - Huerta-Cepas, Jaime A1 - Freitas, Ana Teresa A1 - Bork, Peer T1 - NG-meta-profiler: fast processing of metagenomes using NGLess, a domain-specific language JF - Microbiome N2 - Background Shotgun metagenomes contain a sample of all the genomic material in an environment, allowing for the characterization of a microbial community. In order to understand these communities, bioinformatics methods are crucial. A common first step in processing metagenomes is to compute abundance estimates of different taxonomic or functional groups from the raw sequencing data. Given the breadth of the field, computational solutions need to be flexible and extensible, enabling the combination of different tools into a larger pipeline. Results We present NGLess and NG-meta-profiler. NGLess is a domain specific language for describing next-generation sequence processing pipelines. It was developed with the goal of enabling user-friendly computational reproducibility. It provides built-in support for many common operations on sequencing data and is extensible with external tools with configuration files. Using this framework, we developed NG-meta-profiler, a fast profiler for metagenomes which performs sequence preprocessing, mapping to bundled databases, filtering of the mapping results, and profiling (taxonomic and functional). It is significantly faster than either MOCAT2 or htseq-count and (as it builds on NGLess) its results are perfectly reproducible. Conclusions NG-meta-profiler is a high-performance solution for metagenomics processing built on NGLess. It can be used as-is to execute standard analyses or serve as the starting point for customization in a perfectly reproducible fashion. NGLess and NG-meta-profiler are open source software (under the liberal MIT license) and can be downloaded from https://ngless.embl.de or installed through bioconda. KW - metagenomics KW - next-generation sequencing KW - domain-specific language Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223161 VL - 7 IS - 84 ER - TY - JOUR A1 - Claus, Heike A1 - Hubert, Kerstin A1 - Becher, Dörte A1 - Otto, Andreas A1 - Pawlik, Marie-Christin A1 - Lappann, Ines A1 - Strobel, Lea A1 - Vogel, Ulrich A1 - Johswich, Kay T1 - A homopolymeric adenosine tract in the promoter region of nspA influences factor H-mediated serum resistance in Neisseria meningitidis JF - Scientific Reports N2 - Although usually asymptomatically colonizing the human nasopharynx, the Gram-negative bacterium Neisseria meningitidis (meningococcus) can spread to the blood stream and cause invasive disease. For survival in blood, N. meningitidis evades the complement system by expression of a polysaccharide capsule and surface proteins sequestering the complement regulator factor H (fH). Meningococcal strains belonging to the sequence type (ST-) 41/44 clonal complex (cc41/44) cause a major proportion of serogroup B meningococcal disease worldwide, but they are also common in asymptomatic carriers. Proteome analysis comparing cc41/44 isolates from invasive disease versus carriage revealed differential expression levels of the outer membrane protein NspA, which binds fH. Deletion of nspA reduced serum resistance and NspA expression correlated with fH sequestration. Expression levels of NspA depended on the length of a homopolymeric tract in the nspA promoter: A 5-adenosine tract dictated low NspA expression, whereas a 6-adenosine motif guided high NspA expression. Screening German cc41/44 strain collections revealed the 6-adenosine motif in 39% of disease isolates, but only in 3.4% of carriage isolates. Thus, high NspA expression is associated with disease, but not strictly required. The 6-adenosine nspA promoter is most common to the cc41/44, but is also found in other hypervirulent clonal complexes. KW - Meningitis KW - Pathogens Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200956 VL - 9 ER - TY - JOUR A1 - Cecil, Alexander A1 - Gentschev, Ivaylo A1 - Adelfinger, Marion A1 - Dandekar, Thomas A1 - Szalay, Aladar A. T1 - Vaccinia virus injected human tumors: oncolytic virus efficiency predicted by antigen profiling analysis fitted boolean models JF - Bioengineered N2 - Virotherapy on the basis of oncolytic vaccinia virus (VACV) strains is a promising approach for cancer therapy. Recently, we showed that the oncolytic vaccinia virus GLV-1h68 has a therapeutic potential in treating human prostate and hepatocellular carcinomas in xenografted mice. In this study, we describe the use of dynamic boolean modeling for tumor growth prediction of vaccinia virus-injected human tumors. Antigen profiling data of vaccinia virus GLV-1h68-injected human xenografted mice were obtained, analyzed and used to calculate differences in the tumor growth signaling network by tumor type and gender. Our model combines networks for apoptosis, MAPK, p53, WNT, Hedgehog, the T-killer cell mediated cell death, Interferon and Interleukin signaling networks. The in silico findings conform very well with in vivo findings of tumor growth. Similar to a previously published analysis of vaccinia virus-injected canine tumors, we were able to confirm the suitability of our boolean modeling for prediction of human tumor growth after virus infection in the current study as well. In summary, these findings indicate that our boolean models could be a useful tool for testing of the efficacy of VACV-mediated cancer therapy already before its use in human patients. KW - boolean modeling KW - oncolytic virus KW - human xenografted mouse models KW - cancer therapy Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200507 VL - 10 IS - 1 ER - TY - CHAP A1 - Cazajous-Augé, Claire T1 - The Traces Animals Leave: A Zoopoetic Study of Rick Bass’ “Antlers” T2 - Texts, Animals, Environments: Zoopoetics and Ecopoetics N2 - No abstract available. KW - Animal Studies KW - Cultural Animal Studies KW - Cultural Studies KW - Ecocriticism KW - Environmental Humanities KW - Human-Animal Studies KW - Literary Studies Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-178097 UR - https://www.rombach-verlag.de/buecher/suchergebnis/rombach/buch/details/texts-animals-environments.html PB - Rombach Druck- und Verlagshaus CY - Freiburg i. Br. ER - TY - CHAP A1 - Cazaban-Mazerolles, Marie T1 - Narrating le vivant: the Zoe-Poetical Hypothesis T2 - Texts, Animals, Environments: Zoopoetics and Ecopoetics N2 - No abstract available. KW - Animal Studies KW - Cultural Animal Studies KW - Cultural Studies KW - Ecocriticism KW - Environmental Humanities KW - Human-Animal Studies KW - Literary Studies Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-177818 UR - https://www.rombach-verlag.de/buecher/suchergebnis/rombach/buch/details/texts-animals-environments.html PB - Rombach Druck- und Verlagshaus CY - Freiburg i. Br. ER - TY - CHAP A1 - Bühler, Benjamin T1 - Other Environments: Ecocriticism and Science Fiction (Lem, Ballard, Dath) T2 - Texts, Animals, Environments: Zoopoetics and Ecopoetics N2 - No abstract available. KW - Animal Studies KW - Cultural Animal Studies KW - Cultural Studies KW - Ecocriticism KW - Environmental Humanities KW - Human-Animal Studies KW - Literary Studies Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-177973 UR - https://www.rombach-verlag.de/buecher/suchergebnis/rombach/buch/details/texts-animals-environments.html PB - Rombach Druck- und Verlagshaus CY - Freiburg i. Br. ER -