TY - INPR A1 - Hennig, Thomas A1 - Prusty, Archana B. A1 - Kaufer, Benedikt A1 - Whisnant, Adam W. A1 - Lodha, Manivel A1 - Enders, Antje A1 - Thomas, Julius A1 - Kasimir, Francesca A1 - Grothey, Arnhild A1 - Herb, Stefanie A1 - Jürges, Christopher A1 - Meister, Gunter A1 - Erhard, Florian A1 - Dölken, Lars A1 - Prusty, Bhupesh K. T1 - Selective inhibition of microRNA processing by a herpesvirus-encoded microRNA triggers virus reactivation from latency N2 - Herpesviruses have mastered host cell modulation and immune evasion to augment productive infection, life-long latency and reactivation thereof 1,2. A long appreciated, yet elusively defined relationship exists between the lytic-latent switch and viral non-coding RNAs 3,4. Here, we identify miRNA-mediated inhibition of miRNA processing as a novel cellular mechanism that human herpesvirus 6A (HHV-6A) exploits to disrupt mitochondrial architecture, evade intrinsic host defense and drive the latent-lytic switch. We demonstrate that virus-encoded miR-aU14 selectively inhibits the processing of multiple miR-30 family members by direct interaction with the respective pri-miRNA hairpin loops. Subsequent loss of miR-30 and activation of miR-30/p53/Drp1 axis triggers a profound disruption of mitochondrial architecture, which impairs induction of type I interferons and is necessary for both productive infection and virus reactivation. Ectopic expression of miR-aU14 was sufficient to trigger virus reactivation from latency thereby identifying it as a readily drugable master regulator of the herpesvirus latent-lytic switch. Our results show that miRNA-mediated inhibition of miRNA processing represents a generalized cellular mechanism that can be exploited to selectively target individual members of miRNA families. We anticipate that targeting miR-aU14 provides exciting therapeutic options for preventing herpesvirus reactivations in HHV-6-associated disorders like myalgic encephalitis/chronic fatigue syndrome (ME/CFS) and Long-COVID. KW - Herpesvirus KW - HHV-6 KW - miRNA processing KW - miR-30 KW - mitochondria KW - fusion and fission KW - type I interferon KW - latency KW - virus reactivation Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-267858 UR - https://doi.org/10.21203/rs.3.rs-820696/v1 ET - submitted version ER - TY - THES A1 - Qureischi, Musga T1 - Selective modulation of alloreactive T cells in preclinical models of acute Graft-versus-Host Disease T1 - Selektive Modulation von alloreaktiven T-Zellen in präklinischen Modellen der akuten Graft-versus-Host Erkrankung N2 - Hematopoietic cell transplantation (HCT) is a curative therapy for the treatment of malignant and non-malignant bone marrow diseases. The major complication of this treatment is a highly inflammatory reaction called Graft-versus-Host Disease (GvHD). Here, transplanted donor T cells cause massive tissue destruction and inflammation in the main target organs liver, skin and the intestine. Currently, this inflammatory reaction can be treated successfully using strong immunosuppressive agents. One efficient group of immunosuppressants are calcineurin inhibitors such as Cyclosporin A (CsA) and Tacrolimus (FK506). These treatment strategies target all T lymphocytes subsets equally and do not separate GvH from the desirable Graft-versus-Leukemia (GvL) effect. Therefore, we aimed to find immunological targets on alloreactive T cells in order to develop novel treatment strategies, which selectively modulates alloreactive T cells without impairing the GvL effect or hematopoietic immune reconstitution. The aim of this thesis was to develop a predictive marker panel to track alloreactive T cells in the peripheral blood (PB) of murine allo-HCT recipients. In clinically relevant model of aGvHD we demonstrated that alloreactive T cells have a distinct surface marker expression profile and can be detected in the PB before aGvHD manifestation. Based on our data, we propose a combinatory panel consisting of 4 surface markers (a4b7 integrin, CD162E, CD162P und CD62L) on circulating CD8+ T cells to identify the risk of aGvHD after allo-HCT. Since tumor necrosis factor receptor superfamily (TNFR SF) members are involved in several immunological processes, we did extensive surface marker expression analysis of several TNFR superfamily members and other immunomodulatory molecules on conventional and regulatory T cells (Tcons vs. Tregs) on different time points during aGvHD progression. The aim of this study was to find subset-specific immunomodulatory molecules on recently activated Tcons and Tregs. We found that GITR, 4-1BB and CD27 were highly expressed on alloreactive and naïve Tregs. In contrast, PD1 expression was highly upregulated on recently activated alloreactive Tcons. The data of this study serves as basis for future approaches, which aim to develop T cell subset specific therapeutic antibody fusion proteins. a4b7 integrin and CD162P (P-Selectin ligand) are highly upregulated on alloreactive T cells and mediate the infiltration of these cells into GvHD target organs. We developed recombinant (antibody) fusion proteins to target these two homing molecules and could show that antibody-based fusion proteins are superior to ligand-based fusion proteins regarding production efficiency and binding affinity. Therefore, we propose for future studies to focus on the described antibody-based fusion proteins for the selective targeting of T cells. Since the widely used calcineurin inhibitors are impairing the desirable GvL effect, we investigated if selective NFATc1 inhibition might be a novel strategy to prevent or reduce alloreactivity, while hopefully maintaining the GvL effect. In particular, we addressed the role of the isoform NFATc1 and inhibited its posttranslational modification by SUMO (Small Ubiquitin-related Modifier). Indeed, inhibition of NFATc1 SUMOylation resulted in reduced inflammation and increased Treg frequencies in a murine MHC major mismatch aGvHD model. Conclusively, we showed that alloreactive T cells can be identified by their surface profile in the PB of allo-HCT recipients before aGvHD symptoms appeared. Furthermore, we introduced a approach to selectively target alloreactive T cells by antibody fusion proteins, which might serve as a novel strategy to separate GvH from GvL. Additionally, we demonstrated that averted posttranslational modification of NFATc1 by SUMOylation serves as potential target to reduce alloreactivity of T cells. N2 - Die hämatopoetische Stammzelltransplantation ist eine weltweite Therapiemaßnahme für die Behandlung von malignen und nicht-malignen Knochenmarkserkrankungen(z. B. Leukämien). Eine schwerwiegende Komplikation dieser Therapieform ist die Transplantat-gegen-Wirt Erkrankung (engl. Graft-versus-Host Disease, GvHD). Hierbei greifen Spender-T-Lymphozyten den Körper des Empfängers an und verursachen massive Entzündungsreaktionenin den GvHD Zielorganen Leber, Haut und Darm. Diese überschießende Immunreaktion kann klinisch behandelt werden, indem starkimmunsuppressive Medikamente wie Cyclosporin A (CsA) und Tacrolimus (FK506) eingesetzt werden. Jedoch greifen diese Medikamente alle T-Zellen gleichermaßen an und vermindern ebenfalls die gewünschte anti-Tumorantwort der Spender-T-Lymphozyten(engl. Graft-versus-Leukemiaeffect, GvL effect). Ein Ziel dieser Arbeit war die Entwicklung eines prädiktiven FACS Tests, um T-Zellen im peripheren Blut (PB) von Stammzellenempfängern anhand ihrer Oberflächenmoleküle zu identifizieren. Dazu haben wir ein klinisch relevantes Mausmodell für aGvHD herangezogen und konnten zeigen, dass eine Kombination von Migrations- und Aktivierungsmolekülen (a4b7-Integrin, CD162E, CD162P und CD62L) alloreaktive T-Zellen im Blut eindeutig identifizieren konnten,bevor aGvHD Symptome entstanden. Einige Proteine der TNFR Superfamilie sind auf Immunzellen exprimiert und regulieren diverseimmunologische Prozesse. Wir haben konventionelle T-Zellen (Tcons) und regulatorische T-Zellen (Treg) an unterschiedlichen Zeitpunkten aus transplantierten Mäusenisoliert und die Expression von Proteinen der TNFR Superfamilie untersucht, um potenzielletherapeutische Zielstrukturen auf Spender-Lymphozytenzu identifizieren. Wir konnten zeigen, dass GITR,4-1BB und CD27 auf aktivierten, alloreaktiven wie auch auf naiven Tregs exprimiert wurde. Wohingegen, die PD1 Expression vor allem auf aktivierten Tcons induziert wurde. Die Daten dieser Studie dienen als Grundlage für künftige Strategien um T-Zellen mit Hilfe von Antikörper Fusionsproteinen selektiv zu modulieren. Unsere Daten zeigten, dass die Expression von 4 7-Integrin und CD162P auf alloreaktiven T Zellen im Zuge der aGvHD-Pathogenese induziert wird. Weiterhin erstellten wir rekombinante therapeutische Antikörper Fusionsproteinegegen dieoben genannten Migrationsmoleküle. Wir zeigten hier, dass Produktionseffizienz und Bindungsaffinität von Antikörperformaten besser waren als von Liganden-basierten Fusionsproteinen. Demnachempfehlen wir für künftige Studien Antikörperformate heranzuziehen und die hier aufgeführten Antikörper Konstrukteweiter zu entwickeln.Calcineurin Inhibitoren sind potente Immunsupressiva, die zur Behandlung von aGvHD eingesetzt werden. Diese Immunsuppressiva beeinträchtigen jedoch den GvL Effektsignifikant. Da Calcineurin Inhibitoren indirekt den NFAT Signalweg hemmen, haben wir hier dieselektive Inhibition von NFATin alloreaktiven T-Zellen untersucht. Wir zeigten, dass eine fehlende posttranslationale Modifikation von NFATc1 über SUMOylierung (Small Ubiquitin-related MOdifier) zu einer verminderten Alloreaktivität von T-Zellen führte. Diese Spender-T-Zellen zeigten eine verringerte Effektorfunktion, wobei die protektiven Tregs durch die fehlende SUMOylierung nicht beeinflusst wurden. Zusammenfassend konnte gezeigt werden, dass alloreaktive T-Zellen über ihr spezifisches Oberflächenmarkerprofil im Blut identifiziertwerden konnten bevor aGvHD Symptome entstanden. Weiterhin beschreiben wir eine neue Strategie, um alloreaktive T-Zellen mittels Antikörper-basierten Fusionsproteinen spezifisch zu modulieren. Darüber hinaus zeigten wir, dass eine Verhinderung der NFATc1 SUMOylierung die Alloreaktivität von T-Zellen deutlich reduzierte, ohne den protektiven Effekt von Tregs zu vermindern. KW - GvHD Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236031 ER - TY - INPR A1 - Heidenreich, Julius F. A1 - Gassenmaier, Tobias A1 - Ankenbrand, Markus J. A1 - Bley, Thorsten A. A1 - Wech, Tobias T1 - Self-configuring nnU-net pipeline enables fully automatic infarct segmentation in late enhancement MRI after myocardial infarction N2 - Purpose To fully automatically derive quantitative parameters from late gadolinium enhancement (LGE) cardiac MR (CMR) in patients with myocardial infarction and to investigate if phase sensitive or magnitude reconstructions or a combination of both results in best segmentation accuracy. Methods In this retrospective single center study, a convolutional neural network with a U-Net architecture with a self-configuring framework (“nnU-net”) was trained for segmentation of left ventricular myocardium and infarct zone in LGE-CMR. A database of 170 examinations from 78 patients with history of myocardial infarction was assembled. Separate fitting of the model was performed, using phase sensitive inversion recovery, the magnitude reconstruction or both contrasts as input channels. Manual labelling served as ground truth. In a subset of 10 patients, the performance of the trained models was evaluated and quantitatively compared by determination of the Sørensen-Dice similarity coefficient (DSC) and volumes of the infarct zone compared with the manual ground truth using Pearson’s r correlation and Bland-Altman analysis. Results The model achieved high similarity coefficients for myocardium and scar tissue. No significant difference was observed between using PSIR, magnitude reconstruction or both contrasts as input (PSIR and MAG; mean DSC: 0.83 ± 0.03 for myocardium and 0.72 ± 0.08 for scars). A strong correlation for volumes of infarct zone was observed between manual and model-based approach (r = 0.96), with a significant underestimation of the volumes obtained from the neural network. Conclusion The self-configuring nnU-net achieves predictions with strong agreement compared to manual segmentation, proving the potential as a promising tool to provide fully automatic quantitative evaluation of LGE-CMR. KW - Deep learning KW - CMR KW - Segmentation KW - Myocardial infarction KW - Scar KW - nnU-net Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-323418 UR - https://doi.org/10.1016/j.ejrad.2021.109817 ET - accepted version ER - TY - JOUR A1 - Krishna, Anand A1 - Rodrigues, Johannes A1 - Mitschke, Vanessa A1 - Eder, Andreas B. T1 - Self-reported mask-related worrying reduces relative avoidance bias toward unmasked faces in individuals with low Covid19 anxiety syndrome JF - Cognitive Research: Principles and Implications N2 - Facial masks have become and may remain ubiquitous. Though important for preventing infection, they may also serve as a reminder of the risks of disease. Thus, they may either act as cues for threat, priming avoidance-related behavior, or as cues for a safe interaction, priming social approach. To distinguish between these possibilities, we assessed implicit and explicit evaluations of masked individuals as well as avoidance bias toward relatively unsafe interactions with unmasked individuals in an approach-avoidance task in an online study. We further assessed Covid19 anxiety and specific attitudes toward mask-wearing, including mask effectiveness and desirability, hindrance of communication from masks, aesthetic appeal of masks, and mask-related worrying. Across one sample of younger (18–35 years, N = 147) and one of older adults (60+ years, N = 150), we found neither an average approach nor avoidance bias toward mask-wearing compared to unmasked individuals in the indirect behavior measurement task. However, across the combined sample, self-reported mask-related worrying correlated with reduced avoidance tendencies toward unmasked individuals when Covid19 anxiety was low, but not when it was high. This relationship was specific to avoidance tendencies and was not observed in respect to explicit or implicit preference for mask-wearing individuals. We conclude that unsafe interaction styles may be reduced by targeting mask-related worrying with public interventions, in particular for populations that otherwise have low generalized Covid19 anxiety. KW - approach-avoidance KW - Covid19 KW - masks KW - anxiety Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265720 VL - 6 ER - TY - JOUR A1 - Yuan, Yijun A1 - Borrmann, Dorit A1 - Hou, Jiawei A1 - Ma, Yuexin A1 - Nüchter, Andreas A1 - Schwertfeger, Sören T1 - Self-Supervised point set local descriptors for Point Cloud Registration JF - Sensors N2 - Descriptors play an important role in point cloud registration. The current state-of-the-art resorts to the high regression capability of deep learning. However, recent deep learning-based descriptors require different levels of annotation and selection of patches, which make the model hard to migrate to new scenarios. In this work, we learn local registration descriptors for point clouds in a self-supervised manner. In each iteration of the training, the input of the network is merely one unlabeled point cloud. Thus, the whole training requires no manual annotation and manual selection of patches. In addition, we propose to involve keypoint sampling into the pipeline, which further improves the performance of our model. Our experiments demonstrate the capability of our self-supervised local descriptor to achieve even better performance than the supervised model, while being easier to train and requiring no data labeling. KW - point cloud registration KW - descriptors KW - self-supervised learning Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223000 SN - 1424-8220 VL - 21 IS - 2 ER - TY - JOUR A1 - Schembri, Tim A1 - Kim, Jin Hong A1 - Liess, Andreas A1 - Stepanenko, Vladimir A1 - Stolte, Matthias A1 - Würthner, Frank T1 - Semitransparent Layers of Social Self‐Sorting Merocyanine Dyes for Ultranarrow Bandwidth Organic Photodiodes JF - Advanced Optical Materials N2 - Two dipolar merocyanines consisting of the same π‐conjugated chromophore but different alkyl substituents adopt very different packing arrangements in their respective solid state with either H‐ or J‐type exciton coupling, leading to ultranarrow absorption bands at 477 and 750 nm, respectively, due to exchange narrowing. The social self‐sorting behavior of these push‐pull chromophores in their mixed thin films is evaluated and the impact on morphology as well as opto‐electronical properties is determined. The implementation of this well‐tuned two‐component material with tailored optical features allows to optimize planar heterojunction organic photodiodes with fullerene ​(C\(_{60}\)) with either dual or single wavelength selectivity in the blue and NIR spectral range with ultranarrow bandwidths of only 11 nm (200 cm\(^{-1}\)) and an external quantum efficiency of up to 18% at 754 nm under 0 V bias. The application of these photodiodes as low‐power consuming heart rate monitors is demonstrated by a reflectance‐mode photoplethysmography (PPG) sensor. KW - exciton coupling KW - merocyanine dyes/pigments KW - narrow bandwidth KW - organic photodiodes KW - social self‐sorting Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-244762 VL - 9 IS - 15 ER - TY - JOUR A1 - Salvador, Ellaine A1 - Burek, Malgorzata A1 - Löhr, Mario A1 - Nagai, Michiaki A1 - Hagemann, Carsten A1 - Förster, Carola Y. T1 - Senescence and associated blood-brain barrier alterations in vitro JF - Histochemistry and Cell Biology N2 - Progressive deterioration of the central nervous system (CNS) is commonly associated with aging. An important component of the neurovasculature is the blood-brain barrier (BBB), majorly made up of endothelial cells joined together by intercellular junctions. The relationship between senescence and changes in the BBB has not yet been thoroughly explored. Moreover, the lack of in vitro models for the study of the mechanisms involved in those changes impede further and more in-depth investigations in the field. For this reason, we herein present an in vitro model of the senescent BBB and an initial attempt to identify senescence-associated alterations within. KW - senescence KW - in vitro model KW - aging KW - CNS diseases KW - blood–brain barrier Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-267435 SN - 1432-119X VL - 156 IS - 3 ER - TY - JOUR A1 - Ankenbrand, Markus J. A1 - Shainberg, Liliia A1 - Hock, Michael A1 - Lohr, David A1 - Schreiber, Laura M. T1 - Sensitivity analysis for interpretation of machine learning based segmentation models in cardiac MRI JF - BMC Medical Imaging N2 - Background Image segmentation is a common task in medical imaging e.g., for volumetry analysis in cardiac MRI. Artificial neural networks are used to automate this task with performance similar to manual operators. However, this performance is only achieved in the narrow tasks networks are trained on. Performance drops dramatically when data characteristics differ from the training set properties. Moreover, neural networks are commonly considered black boxes, because it is hard to understand how they make decisions and why they fail. Therefore, it is also hard to predict whether they will generalize and work well with new data. Here we present a generic method for segmentation model interpretation. Sensitivity analysis is an approach where model input is modified in a controlled manner and the effect of these modifications on the model output is evaluated. This method yields insights into the sensitivity of the model to these alterations and therefore to the importance of certain features on segmentation performance. Results We present an open-source Python library (misas), that facilitates the use of sensitivity analysis with arbitrary data and models. We show that this method is a suitable approach to answer practical questions regarding use and functionality of segmentation models. We demonstrate this in two case studies on cardiac magnetic resonance imaging. The first case study explores the suitability of a published network for use on a public dataset the network has not been trained on. The second case study demonstrates how sensitivity analysis can be used to evaluate the robustness of a newly trained model. Conclusions Sensitivity analysis is a useful tool for deep learning developers as well as users such as clinicians. It extends their toolbox, enabling and improving interpretability of segmentation models. Enhancing our understanding of neural networks through sensitivity analysis also assists in decision making. Although demonstrated only on cardiac magnetic resonance images this approach and software are much more broadly applicable. KW - deep learning KW - neural networks KW - cardiac magnetic resonance KW - sensitivity analysis KW - transformations KW - augmentation KW - segmentation Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259169 VL - 21 IS - 1 ER - TY - JOUR A1 - Widowski, Helene A1 - Reynaert, Niki L. A1 - Ophelders, Daan R. M. G. A1 - Hütten, Matthias C. A1 - Nikkels, Peter G. J. A1 - Severens-Rijvers, Carmen A. H. A1 - Cleutjens, Jack P. M. A1 - Kemp, Matthew W. A1 - Newnham, John P. A1 - Saito, Masatoshi A1 - Usuda, Haruo A1 - Payne, Matthew S. A1 - Jobe, Alan H. A1 - Kramer, Boris W. A1 - Delhaas, Tammo A1 - Wolfs, Tim G. A. M. T1 - Sequential Exposure to Antenatal Microbial Triggers Attenuates Alveolar Growth and Pulmonary Vascular Development and Impacts Pulmonary Epithelial Stem/Progenitor Cells JF - Frontiers in Medicine N2 - Perinatal inflammatory stress is strongly associated with adverse pulmonary outcomes after preterm birth. Antenatal infections are an essential perinatal stress factor and contribute to preterm delivery, induction of lung inflammation and injury, pre-disposing preterm infants to bronchopulmonary dysplasia. Considering the polymicrobial nature of antenatal infection, which was reported to result in diverse effects and outcomes in preterm lungs, the aim was to examine the consequences of sequential inflammatory stimuli on endogenous epithelial stem/progenitor cells and vascular maturation, which are crucial drivers of lung development. Therefore, a translational ovine model of antenatal infection/inflammation with consecutive exposures to chronic and acute stimuli was used. Ovine fetuses were exposed intra-amniotically to Ureaplasma parvum 42 days (chronic stimulus) and/or to lipopolysaccharide 2 or 7 days (acute stimulus) prior to preterm delivery at 125 days of gestation. Pulmonary inflammation, endogenous epithelial stem cell populations, vascular modulators and morphology were investigated in preterm lungs. Pre-exposure to UP attenuated neutrophil infiltration in 7d LPS-exposed lungs and prevented reduction of SOX-9 expression and increased SP-B expression, which could indicate protective responses induced by re-exposure. Sequential exposures did not markedly impact stem/progenitors of the proximal airways (P63+ basal cells) compared to single exposure to LPS. In contrast, the alveolar size was increased solely in the UP+7d LPS group. In line, the most pronounced reduction of AEC2 and proliferating cells (Ki67+) was detected in these sequentially UP + 7d LPS-exposed lambs. A similar sensitization effect of UP pre-exposure was reflected by the vessel density and expression of vascular markers VEGFR-2 and Ang-1 that were significantly reduced after UP exposure prior to 2d LPS, when compared to UP and LPS exposure alone. Strikingly, while morphological changes of alveoli and vessels were seen after sequential microbial exposure, improved lung function was observed in UP, 7d LPS, and UP+7d LPS-exposed lambs. In conclusion, although sequential exposures did not markedly further impact epithelial stem/progenitor cell populations, re-exposure to an inflammatory stimulus resulted in disturbed alveolarization and abnormal pulmonary vascular development. Whether these negative effects on lung development can be rescued by the potentially protective responses observed, should be examined at later time points. KW - polymicrobial infection KW - vascular disturbances KW - adverse pulmonary outcomes KW - endogenous pulmonary stem cells KW - bronchopulmonary dysplasia KW - preterm birth KW - antenatal inflammation Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229695 SN - 2296-858X VL - 8 ER - TY - JOUR A1 - Kanzow, Christian A1 - Raharja, Andreas B. A1 - Schwartz, Alexandra T1 - Sequential optimality conditions for cardinality-constrained optimization problems with applications JF - Computational Optimization and Applications N2 - Recently, a new approach to tackle cardinality-constrained optimization problems based on a continuous reformulation of the problem was proposed. Following this approach, we derive a problem-tailored sequential optimality condition, which is satisfied at every local minimizer without requiring any constraint qualification. We relate this condition to an existing M-type stationary concept by introducing a weak sequential constraint qualification based on a cone-continuity property. Finally, we present two algorithmic applications: We improve existing results for a known regularization method by proving that it generates limit points satisfying the aforementioned optimality conditions even if the subproblems are only solved inexactly. And we show that, under a suitable Kurdyka–Łojasiewicz-type assumption, any limit point of a standard (safeguarded) multiplier penalty method applied directly to the reformulated problem also satisfies the optimality condition. These results are stronger than corresponding ones known for the related class of mathematical programs with complementarity constraints. KW - augmented Lagrangian method KW - cardinality constraints KW - sequential optimality condition KW - conecontinuity type constraint qualification KW - relaxation method Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-269052 SN - 1573-2894 VL - 80 IS - 1 ER - TY - JOUR A1 - Aboagye, B. A1 - Weber, T. A1 - Merdian, H. L. A1 - Bartsch, D. A1 - Lesch, K. P. A1 - Waider, J. T1 - Serotonin deficiency induced after brain maturation rescues consequences of early life adversity JF - Scientific Reports N2 - Brain serotonin (5-HT) system dysfunction is implicated in depressive disorders and acute depletion of 5-HT precursor tryptophan has frequently been used to model the influence of 5-HT deficiency on emotion regulation. Tamoxifen (TAM)-induced Cre/loxP-mediated inactivation of the tryptophan hydroxylase-2 gene (Tph2) was used to investigate the effects of provoked 5-HT deficiency in adult mice (Tph2 icKO) previously subjected to maternal separation (MS). The efficiency of Tph2 inactivation was validated by immunohistochemistry and HPLC. The impact of Tph2 icKO in interaction with MS stress (Tph2 icKOxMS) on physiological parameters, emotional behavior and expression of 5-HT system-related marker genes were assessed. Tph2 icKO mice displayed a significant reduction in 5-HT immunoreactive cells and 5-HT concentrations in the rostral raphe region within four weeks following TAM treatment. Tph2 icKO and MS differentially affected food and water intake, locomotor activity as well as panic-like escape behavior. Tph2 icKO prevented the adverse effects of MS stress and altered the expression of the genes previously linked to stress and emotionality. In conclusion, an experimental model was established to study the behavioral and neurobiological consequences of 5-HT deficiency in adulthood in interaction with early-life adversity potentially affecting brain development and the pathogenesis of depressive disorders. KW - emotion KW - molecular medicine KW - neuroscience Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-258626 SN - 2045-2322 VL - 11 IS - 1 ER - TY - JOUR A1 - Stein, Kiera A1 - Maruf, Abdullah Al A1 - Müller, Daniel J. A1 - Bishop, Jeffrey R. A1 - Bousman, Chad A. T1 - Serotonin transporter genetic variation and antidepressant response and tolerability: a systematic review and meta-analysis JF - Journal of Personalized Medicine N2 - Antidepressants are used to treat several psychiatric disorders; however, a large proportion of patients do not respond to their first antidepressant therapy and often experience adverse drug reactions (ADR). A common insertion–deletion polymorphism in the promoter region (5-HTTLPR) of the serotonin transporter (SLC6A4) gene has been frequently investigated for its association with antidepressant outcomes. Here, we performed a systematic review and meta-analysis to assess 5-HTTLPR associations with antidepressants: (1) response in psychiatric disorders other than major depressive disorder (MDD) and (2) tolerability across all psychiatric disorders. Literature searches were performed up to January 2021, yielding 82 studies that met inclusion criteria, and 16 of these studies were included in the meta-analyses. Carriers of the 5-HTTLPR LL or LS genotypes were more likely to respond to antidepressant therapy, compared to the SS carriers in the total and European ancestry-only study populations. Long (L) allele carriers taking selective serotonin reuptake inhibitors (SSRIs) reported fewer ADRs relative to short/short (SS) carriers. European L carriers taking SSRIs had lower ADR rates than S carriers. These results suggest the 5-HTTLPR polymorphism may serve as a marker for antidepressant outcomes in psychiatric disorders and may be particularly relevant to SSRI treatment among individuals of European descent. KW - 5-HTTLPR KW - genotype KW - pharmacogenetics KW - antidepressant KW - efficacy KW - tolerability KW - SLC6A4 Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-252294 SN - 2075-4426 VL - 11 IS - 12 ER - TY - JOUR A1 - Jansch, Charline A1 - Ziegler, Georg C. A1 - Forero, Andrea A1 - Gredy, Sina A1 - Wäldchen, Sina A1 - Vitale, Maria Rosaria A1 - Svirin, Evgeniy A1 - Zöller, Johanna E. M. A1 - Waider, Jonas A1 - Günther, Katharina A1 - Edenhofer, Frank A1 - Sauer, Markus A1 - Wischmeyer, Erhard A1 - Lesch, Klaus-Peter T1 - Serotonin-specific neurons differentiated from human iPSCs form distinct subtypes with synaptic protein assembly JF - Journal of Neural Transmission N2 - Human induced pluripotent stem cells (hiPSCs) have revolutionized the generation of experimental disease models, but the development of protocols for the differentiation of functionally active neuronal subtypes with defined specification is still in its infancy. While dysfunction of the brain serotonin (5-HT) system has been implicated in the etiology of various neuropsychiatric disorders, investigation of functional human 5-HT specific neurons in vitro has been restricted by technical limitations. We describe an efficient generation of functionally active neurons from hiPSCs displaying 5-HT specification by modification of a previously reported protocol. Furthermore, 5-HT specific neurons were characterized using high-end fluorescence imaging including super-resolution microscopy in combination with electrophysiological techniques. Differentiated hiPSCs synthesize 5-HT, express specific markers, such as tryptophan hydroxylase 2 and 5-HT transporter, and exhibit an electrophysiological signature characteristic of serotonergic neurons, with spontaneous rhythmic activities, broad action potentials and large afterhyperpolarization potentials. 5-HT specific neurons form synapses reflected by the expression of pre- and postsynaptic proteins, such as Bassoon and Homer. The distribution pattern of Bassoon, a marker of the active zone along the soma and extensions of neurons, indicates functionality via volume transmission. Among the high percentage of 5-HT specific neurons (~ 42%), a subpopulation of CDH13 + cells presumably designates dorsal raphe neurons. hiPSC-derived 5-HT specific neuronal cell cultures reflect the heterogeneous nature of dorsal and median raphe nuclei and may facilitate examining the association of serotonergic neuron subpopulations with neuropsychiatric disorders. KW - neuropsychiatric disorders KW - human induced pluripotent stem cell (hiPSC) KW - serotonin-specific neurons KW - median and dorsal raphe KW - synapse formation KW - Cadherin-13 (CDH13) Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-268519 SN - 1435-1463 VL - 128 IS - 2 ER - TY - JOUR A1 - Janzen, Dieter A1 - Slavik, Benedikt A1 - Zehe, Markus A1 - Sotriffer, Christoph A1 - Loos, Helene M. A1 - Buettner, Andrea A1 - Villmann, Carmen T1 - Sesquiterpenes and sesquiterpenoids harbor modulatory allosteric potential and affect inhibitory GABA\(_{A}\) receptor function in vitro JF - Journal of Neurochemistry N2 - Naturally occurring compounds such as sesquiterpenes and sesquiterpenoids (SQTs) have been shown to modulate GABA\(_{A}\) receptors (GABA\(_{A}\)Rs). In this study, the modulatory potential of 11 SQTs at GABA\(_{A}\)Rs was analyzed to characterize their potential neurotropic activity. Transfected HEK293 cells and primary hippocampal neurons were functionally investigated using electrophysiological whole-cell recordings. Significantly different effects of β-caryophyllene and α-humulene, as well as their respective derivatives β-caryolanol and humulol, were observed in the HEK293 cell system. In neurons, the concomitant presence of phasic and tonic GABA\(_{A}\)R configurations accounts for differences in receptor modulation by SQTs. The in vivo presence of the γ\(_{2}\) and δ subunits is important for SQT modulation. While phasic GABA\(_{A}\) receptors in hippocampal neurons exhibited significantly altered GABA-evoked current amplitudes in the presence of humulol and guaiol, negative allosteric potential at recombinantly expressed α\(_{1}\)β\(_{2}\)γ\(_{2}\) receptors was only verified for humolol. Modeling and docking studies provided support for the binding of SQTs to the neurosteroid-binding site of the GABA\(_{A}\)R localized between transmembrane segments 1 and 3 at the (\(^{+}\)α)-(\(^{-}\)α) interface. In sum, differences in the modulation of GABA\(_{A}\)R isoforms between SQTs were identified. Another finding is that our results provide an indication that nutritional digestion affects the neurotropic potential of natural compounds. KW - allosteric modulation KW - GABA\(_{A}\) receptor KW - patch clamp recording Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259546 VL - 159 IS - 1 ER - TY - JOUR A1 - Notz, Quirin A1 - Lotz, Christopher A1 - Herrmann, Johannes A1 - Vogt, Marius A1 - Schlesinger, Tobias A1 - Kredel, Markus A1 - Muellges, Wolfgang A1 - Weismann, Dirk A1 - Westermaier, Thomas A1 - Meybohm, Patrick A1 - Kranke, Peter T1 - Severe neurological complications in critically ill COVID‑19 patients JF - Journal of Neurology N2 - No abstract available. KW - COVID-19 KW - neurological complications Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232429 SN - 0340-5354 ER - TY - JOUR A1 - Strekalova, Tatyana A1 - Veniaminova, Ekaterina A1 - Svirin, Evgeniy A1 - Kopeikina, Ekaterina A1 - Veremeyko, Tatyana A1 - Yung, Amanda W. Y. A1 - Proshin, Andrey A1 - Tan, Shawn Zheng Kai A1 - Khairuddin, Sharafuddin A1 - Lim, Lee Wei A1 - Lesch, Klaus-Peter A1 - Walitza, Susanne A1 - Anthony, Daniel C. A1 - Ponomarev, Eugene D. T1 - Sex-specific ADHD-like behaviour, altered metabolic functions, and altered EEG activity in sialyltransferase ST3GAL5-deficient mice JF - Biomolecules N2 - A deficiency in GM3-derived gangliosides, resulting from a lack of lactosylceramide-alpha-2,3-sialyltransferase (ST3GAL5), leads to severe neuropathology, including epilepsy and metabolic abnormalities. Disruption of ganglioside production by this enzyme may also have a role in the development of neuropsychiatric disorders. ST3Gal5 knock-out (St3gal5\(^{−/−}\)) mice lack a-, b-, and c-series gangliosides, but exhibit no overt neuropathology, possibly owing to the production of compensatory 0-series glycosphingolipids. Here, we sought to investigate the possibility that St3gal5\(^{−/−}\) mice might exhibit attention-deficit/hyperactivity disorder (ADHD)-like behaviours. In addition, we evaluated potential metabolic and electroencephalogram (EEG) abnormalities. St3gal5\(^{−/−}\) mice were subjected to behavioural testing, glucose tolerance tests, and the levels of expression of brain and peripheral A and B isoforms of the insulin receptor (IR) were measured. We found that St3gal5\(^{−/−}\) mice exhibit locomotor hyperactivity, impulsivity, neophobia, and anxiety-like behavior. The genotype also altered blood glucose levels and glucose tolerance. A sex bias was consistently found in relation to body mass and peripheral IR expression. Analysis of the EEG revealed an increase in amplitude in St3gal5\(^{−/−}\) mice. Together, St3gal5\(^{−/−}\) mice exhibit ADHD-like behaviours, altered metabolic and EEG measures providing a useful platform for better understanding of the contribution of brain gangliosides to ADHD and associated comorbidities. KW - lactosylceramide alpha-2,3-sialyltransferase (ST3GAL5) KW - attention-deficit/hyperactivity disorder (ADHD) KW - insulin receptor (IR) KW - sex differences KW - electroencephalogram (EEG) KW - mice Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-250071 SN - 2218-273X VL - 11 IS - 12 ER - TY - JOUR A1 - Grob, Robin A1 - Heinig, Niklas A1 - Grübel, Kornelia A1 - Rössler, Wolfgang A1 - Fleischmann, Pauline N. T1 - Sex-specific and caste-specific brain adaptations related to spatial orientation in Cataglyphis ants JF - Journal of Comparative Neurology N2 - Cataglyphis desert ants are charismatic central place foragers. After long-ranging foraging trips, individual workers navigate back to their nest relying mostly on visual cues. The reproductive caste faces other orientation challenges, i.e. mate finding and colony foundation. Here we compare brain structures involved in spatial orientation of Cataglyphis nodus males, gynes, and foragers by quantifying relative neuropil volumes associated with two visual pathways, and numbers and volumes of antennal lobe (AL) olfactory glomeruli. Furthermore, we determined absolute numbers of synaptic complexes in visual and olfactory regions of the mushroom bodies (MB) and a major relay station of the sky-compass pathway to the central complex (CX). Both female castes possess enlarged brain centers for sensory integration, learning, and memory, reflected in voluminous MBs containing about twice the numbers of synaptic complexes compared with males. Overall, male brains are smaller compared with both female castes, but the relative volumes of the optic lobes and CX are enlarged indicating the importance of visual guidance during innate behaviors. Male ALs contain greatly enlarged glomeruli, presumably involved in sex-pheromone detection. Adaptations at both the neuropil and synaptic levels clearly reflect differences in sex-specific and caste-specific demands for sensory processing and behavioral plasticity underlying spatial orientation. KW - antennal lobe KW - synaptic plasticity KW - polymorphism KW - optic lobes KW - mushroom bodies KW - learning and memory KW - central complex Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-257299 VL - 529 IS - 18 ER - TY - JOUR A1 - Freitag‐Wolf, Sandra A1 - Munz, Matthias A1 - Junge, Olaf A1 - Graetz, Christian A1 - Jockel‐Schneider, Yvonne A1 - Staufenbiel, Ingmar A1 - Bruckmann, Corinna A1 - Lieb, Wolfgang A1 - Franke, Andre A1 - Loos, Bruno G. A1 - Jepsen, Søren A1 - Dommisch, Henrik A1 - Schaefer, Arne S. T1 - Sex‐specific genetic factors affect the risk of early‐onset periodontitis in Europeans JF - Journal of Clinical Periodontology N2 - Aims Various studies have reported that young European women are more likely to develop early‐onset periodontitis compared to men. A potential explanation for the observed variations in sex and age of disease onset is the natural genetic variation within the autosomal genomes. We hypothesized that genotype‐by‐sex (G × S) interactions contribute to the increased prevalence and severity. Materials and methods Using the case‐only design, we tested for differences in genetic effects between men and women in 896 North‐West European early‐onset cases, using imputed genotypes from the OmniExpress genotyping array. Population‐representative 6823 controls were used to verify that the interacting variables G and S were uncorrelated in the general population. Results In total, 20 loci indicated G × S associations (P < 0.0005), 3 of which were previously suggested as risk genes for periodontitis (ABLIM2, CDH13, and NELL1). We also found independent G × S interactions of the related gene paralogs MACROD1/FLRT1 (chr11) and MACROD2/FLRT3 (chr20). G × S‐associated SNPs at CPEB4, CDH13, MACROD1, and MECOM were genome‐wide‐associated with heel bone mineral density (CPEB4, MECOM), waist‐to‐hip ratio (CPEB4, MACROD1), and blood pressure (CPEB4, CDH13). Conclusions Our results indicate that natural genetic variation affects the different heritability of periodontitis among sexes and suggest genes that contribute to inter‐sex phenotypic variation in early‐onset periodontitis. KW - alveolar bone loss KW - gene × sex interaction KW - genetic risk KW - heritability KW - inflammation Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262445 VL - 48 IS - 11 SP - 1404 EP - 1413 ER - TY - THES A1 - Heller, Aline T1 - Sicherheit und Effektivität von Amisulprid zur Therapie von Übelkeit und Erbrechen nach Narkosen T1 - Safety and efficacy of amisulpride for the treatment of postoperative nausea and vomiting N2 - PONV stellt mit einer Inzidenz von circa 30 % ein relevantes Problem in der postoperativen Phase dar. Amisulprid ist ein atypisches Neuroleptikum, das zur Behandlung der Schizophrenie verwendet wird und gehört zur Gruppe der D2-Rezeptor-Antagonisten. Hierüber wirkt Amisulprid antiemetisch. Ziel der Studie war, die Sicherheit und Effektivität einer intravenösen Einmalgabe von Amisulprid in den Dosierungen 5 mg und 10 mg zur Therapie von PONV, nach Versagen einer PONV-Prophylaxe, untereinander und gegenüber einem Placebo zu vergleichen. Es handelte sich hierbei um eine multizentrische, randomisierte, doppelblinde Phase-III-Studie. Amisulprid zeigte ein benignes Nebenwirkungsprofil. Amisulprid zeigte in der Dosierung 10 mg eine statistisch signifikante Überlegenheit gegenüber Placebo sowohl zur Therapie von PONV, als auch im Auftreten signifikanter Übelkeit und im Gebrauch einer Rescue-Medikation. Eine weitere interessante Fragestellung wäre der Vergleich der Sicherheit und Effektivität von Amisulprid mit einem weiteren Antiemetikum. N2 - With an incidence of about 30%, PONV is a relevant problem in the postoperative phase. Amisulpride is an atypical neuroleptic that is used to treat schizophrenia and belongs to the group of D2 receptor antagonists. Amisulpride has an anti-emetic effect. The aim of the study was to compare the safety and effectiveness of a single intravenous dose of amisulpride in doses of 5 mg and 10 mg for the treatment of PONV after failure of a PONV prophylaxis. This was a multicenter, randomized, double-blind phase III study. Amisulpride showed a benign side effect profile. Amisulpride in the dose of 10 mg showed a statistically significant superiority over placebo both for the therapy of PONV, as well as in the occurrence of significant nausea and in the use of rescue medication. Another interesting question would be to compare the safety and effectiveness of amisulpride with another antiemetic. KW - Amisulprid KW - Übelkeit KW - Erbrechen KW - PONV Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-241762 ER - TY - THES A1 - Raban, Rebecca Emmi Hildegard T1 - Sicherheit und Wirksamkeit von intrathekalem Triamcinolon bei Patienten mit chronisch-progredienter Multipler Sklerose : eine retrospektive Longitudinalstudie T1 - Safety and efficacy of intrathecal triamcinolone in chronic progressive multiple sclerosis - a retrospective longitudinal study N2 - Im Zeitraum von 2004 bis 2016 erhielten an der Neurologischen Universitätsklinik Würzburg Patienten mit einer chronisch progredienten Multiplen Sklerose insgesamt 595 Injektionen von intrathekalem Triamcinolonacetonid. Diese Arbeit befasst sich mit Sicherheit, Nebenwirkungen und Wirksamkeit der intrathekalen Therapieform. N2 - In the period from 2004 to 2016 patients with chronic progressive multiple sclerosis at the Neurological University Clinic Würzburg received a total of 595 injections of intrathecal triamcinolone acetonide. This work deals with safety, side effects and effectiveness of intrathecal therapy. KW - Intrathekale Applikation KW - Triamcinolon KW - Multiple Sklerose KW - intrathekal KW - intrathecal KW - Volon A KW - chronische Multiple Sklerose KW - triamcinolone acetonide KW - progressive multiple sclerosis Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-220478 ER - TY - JOUR A1 - Machata, Silke A1 - Sreekantapuram, Sravya A1 - Hünniger, Kerstin A1 - Kurzai, Oliver A1 - Dunker, Christine A1 - Schubert, Katja A1 - Krüger, Wibke A1 - Schulze-Richter, Bianca A1 - Speth, Cornelia A1 - Rambach, Günter A1 - Jacobsen, Ilse D. T1 - Significant Differences in Host-Pathogen Interactions Between Murine and Human Whole Blood JF - Frontiers in Immunology N2 - Murine infection models are widely used to study systemic candidiasis caused by C. albicans. Whole-blood models can help to elucidate host-pathogens interactions and have been used for several Candida species in human blood. We adapted the human whole-blood model to murine blood. Unlike human blood, murine blood was unable to reduce fungal burden and more substantial filamentation of C. albicans was observed. This coincided with less fungal association with leukocytes, especially neutrophils. The lower neutrophil number in murine blood only partially explains insufficient infection and filamentation control, as spiking with murine neutrophils had only limited effects on fungal killing. Furthermore, increased fungal survival is not mediated by enhanced filamentation, as a filament-deficient mutant was likewise not eliminated. We also observed host-dependent differences for interaction of platelets with C. albicans, showing enhanced platelet aggregation, adhesion and activation in murine blood. For human blood, opsonization was shown to decrease platelet interaction suggesting that complement factors interfere with fungus-to-platelet binding. Our results reveal substantial differences between murine and human whole-blood models infected with C. albicans and thereby demonstrate limitations in the translatability of this ex vivo model between hosts. KW - whole blood ex vivo model KW - host-pathogen interaction KW - neutrophils KW - mice Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-222575 SN - 1664-3224 VL - 11 ER - TY - THES A1 - Riensch, Nicolas Alexander T1 - Silicon/Boron Exchange Routes to Novel Inorganic-Organic Hybrid Molecules, Oligomers, Polymers and Macrocycles T1 - Silizium/Bor Austauschrouten zu Neuartigen Anorganisch-Organischen Hybridmolekülen, Oligomeren, Polymeren und Makrozyklen N2 - Industrially used semiconducting materials, building blocks of modern electronics and computer industry, are mostly based on inorganic, crystalline solids, which have the drawback of relatively high production costs. As an alternative, organic pi-conjugated systems show enhanced flexibility and processability as well as the opportunity to obtain light-weight materials. They have emerged as attractive candidates, especially since elements beyond hydrogen and carbon can be used to create pi-conjugated frameworks. In recent years, pi-conjugated oligomers and polymers with tricoordinate boron centers incorporated into the main chain of such organic polymers have attracted considerable attention as the interaction of the vacant p orbital on boron with an adjacent pi system of the chain leads to extended conjugated materials. These materials show intriguing optical and electronic properties and potential applications in organic electronics and optoelectronics (OLEDs, OFETs, photovoltaics) or as sensory materials. In this thesis, a catalytic Si/B exchange reaction protocol is used as a facile and highly effective B-C bond formation method to synthesize organoboron molecules, oligomers, polymers and macrocycles. This reaction is applied to synthesize a series of thienyl- and furylborane based materials. Special focus is on furylborane based materials, which, in general, have been only scarcely explored so far. This is mainly due to synthetic challenges since furan decomposes readily in the presence of light and oxygen. Our mild and highly selective reaction protocol in combination with sufficient kinetic protection of the boron centers gives access to a series of extended organoboranes featuring furylborane units in the main chain. Furthermore, kinetically stabilized furylboranes are established as highly robust and versatile building blocks for pi conjugated materials. The obtained materials reveal remarkable luminescence properties. The scope of potential starting materials was investigated by a catalyst screening, demonstrating that the Si/B exchange reaction can also be performed for less reactive aryldichloroboranes. Furthermore, borazine-based hybrid cyclomatrix microspheres have been synthesized via a Si/B exchange condensation reaction under precipitation polymerization conditions. Finally, synthetic routes to tetrabora- and diboraporphyrinogens were attempted in a multi-step reaction procedure. In the case for tetraboraporphyrinogens, the final macrocyclization reaction under pseudo high-dilution conditions afforded a mixture of macrocycles with different ring sizes. UV-vis and fluorescence spectroscopic analysis indicated significant differences in comparison to their linear congeners. N2 - Industriell eingesetzte Halbleitermaterialien können als Bausteine der modernen Elektronik- und Computerindustrie beschrieben werden und basieren meist auf anorganischen, kristallinen Festkörpern, die relativ hohe Herstellungskosten als Nachteil haben. Als Alternative bieten pi-konjugierte Systeme eine höhere Flexibilität und Verarbeitbarkeit sowie die Möglichkeit, leichte Materialien zu erhalten. Sie haben sich als attraktive Kandidaten erwiesen, zumal auch Elemente jenseits von Wasserstoff und Kohlenstoff zur Herstellung von pi konjugierten Gerüsten verwendet werden können. In den letzten Jahren haben pi-konjugierte Oligomere und Polymere mit dreifach koordinierten Bor-Zentren, die in der Hauptkette solcher organischen Polymere eingebaut sind, große Aufmerksamkeit erregt, da die Wechselwirkung des vakanten p-Orbitals am Bor mit einem benachbarten pi-System der Kette zu ausgedehnten konjugierten Materialien führt. Diese Materialien zeigen faszinierende optische und elektronische Eigenschaften und potenzielle Anwendungen in der organischen Elektronik und Optoelektronik (OLEDs, OFETs, Photovoltaik) oder als Sensormaterialien. In dieser Arbeit wird ein katalytisches Si/B-Austauschreaktionsprotokoll als einfache und hocheffektive Methode zur Bildung von B-C-Bindungen verwendet, um Organobor-Moleküle, Oligomere, Polymere und Makrozyklen zu synthetisieren. Diese Reaktion wird zur Synthese einer Reihe von Materialien auf Thienyl- und Furylboranbasis eingesetzt. Besonderes Augenmerk liegt dabei auf furylboranbasierten Materialien, die im Allgemeinen bisher nur wenig erforscht sind. Dies ist vor allem auf synthetische Herausforderungen zurückzuführen, da Furan in Gegenwart von Licht und Sauerstoff leicht zersetzt wird. Unser mildes und hochselektives Reaktionsprotokoll in Kombination mit einem ausreichenden kinetischen Schutz der Bor-Zentren ermöglicht den Zugang zu einer Reihe von ausgedehnten Organoboranen, die Furylboran-Einheiten in der Hauptkette besitzen. Darüber hinaus werden kinetisch stabilisierte Furylborane als sehr robuste und vielseitige Bausteine für konjugierte Materialien etabliert. Die erhaltenen Materialien weisen bemerkenswerte Lumineszenz-eigenschaften auf. Die Bandbreite möglicher Ausgangsmaterialien wurde durch ein Katalysator-Screening untersucht. Dabei zeigte sich, dass die Si/B-Austauschreaktion auch für weniger reaktive Aryldichlorborane durchgeführt werden kann. Weiterhin wurden Borazin-basierte Hybrid-Cyclomatrix-Mikrokugel über eine Si/B-Austauschkondensationsreaktion unter Fällungspolymerisationsbedingungen synthetisiert. Abschließend wurden Synthesewege zu Tetrabora- und Diboraporphyrinogenen in einem mehrstufigen Reaktionsverfahren untersucht. Im Falle der Tetraboraporphyrinogene ergab die abschließende Makrozyklisierungsreaktion unter Pseudo-Hochverdünnungsbedingungen ein Gemisch von Makrozyklen mit unterschiedlichen Ringgrößen. Die UV-Vis- und fluoreszenzspektroskopische Analyse zeigte signifikante Unterschiede im Vergleich zu ihren linearen Verwandten. KW - Bororganische Verbindungen KW - Konjugierte Polymere KW - Borazin KW - Silizium-Boraustausch KW - Silicon-Boron Exchange KW - Furylborane KW - Organoboron Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-238657 ER - TY - JOUR A1 - Rokhafrouz, Mohammad A1 - Latifi, Hooman A1 - Abkar, Ali A. A1 - Wojciechowski, Tomasz A1 - Czechlowski, Mirosław A1 - Naieni, Ali Sadeghi A1 - Maghsoudi, Yasser A1 - Niedbała, Gniewko T1 - Simplified and hybrid remote sensing-based delineation of management zones for nitrogen variable rate application in wheat JF - Agriculture N2 - Enhancing digital and precision agriculture is currently inevitable to overcome the economic and environmental challenges of the agriculture in the 21st century. The purpose of this study was to generate and compare management zones (MZ) based on the Sentinel-2 satellite data for variable rate application of mineral nitrogen in wheat production, calculated using different remote sensing (RS)-based models under varied soil, yield and crop data availability. Three models were applied, including (1) a modified “RS- and threshold-based clustering”, (2) a “hybrid-based, unsupervised clustering”, in which data from different sources were combined for MZ delineation, and (3) a “RS-based, unsupervised clustering”. Various data processing methods including machine learning were used in the model development. Statistical tests such as the Paired Sample T-test, Kruskal–Wallis H-test and Wilcoxon signed-rank test were applied to evaluate the final delineated MZ maps. Additionally, a procedure for improving models based on information about phenological phases and the occurrence of agricultural drought was implemented. The results showed that information on agronomy and climate enables improving and optimizing MZ delineation. The integration of prior knowledge on new climate conditions (drought) in image selection was tested for effective use of the models. Lack of this information led to the infeasibility of obtaining optimal results. Models that solely rely on remote sensing information are comparatively less expensive than hybrid models. Additionally, remote sensing-based models enable delineating MZ for fertilizer recommendations that are temporally closer to fertilization times. KW - precision agriculture KW - management zones KW - remote sensing KW - Sentinel-2 KW - clustering KW - winter wheat KW - drought KW - digital agriculture Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-250033 SN - 2077-0472 VL - 11 IS - 11 ER - TY - JOUR A1 - Graetz, Jonas T1 - Simulation study towards quantitative X-ray and neutron tensor tomography regarding the validity of linear approximations of dark-field anisotropy JF - Scientific Reports N2 - Tensor tomography is fundamentally based on the assumption of a both anisotropic and linear contrast mechanism. While the X-ray or neutron dark-field contrast obtained with Talbot(-Lau) interferometers features the required anisotropy, a preceding detailed study of dark-field signal origination however found its specific orientation dependence to be a non-linear function of the underlying anisotropic mass distribution and its orientation, especially challenging the common assumption that dark-field signals are describable by a function over the unit sphere. Here, two approximative linear tensor models with reduced orientation dependence are investigated in a simulation study with regard to their applicability to grating based X-ray or neutron dark-field tensor tomography. By systematically simulating and reconstructing a large sample of isolated volume elements covering the full range of feasible anisotropies and orientations, direct correspondences are drawn between the respective tensors characterizing the physically based dark-field model used for signal synthesization and the mathematically motivated simplified models used for reconstruction. The anisotropy of freely rotating volume elements is thereby confirmed to be, for practical reconstruction purposes, approximable both as a function of the optical axis' orientation or as a function of the interferometer's grating orientation. The eigenvalues of the surrogate models' tensors are found to exhibit fuzzy, yet almost linear relations to those of the synthesization model. Dominant orientations are found to be recoverable with a margin of error on the order of magnitude of 1 degrees. Although the input data must adequately address the full orientation dependence of dark-field anisotropy, the present results clearly support the general feasibility of quantitative X-ray dark-field tensor tomography within an inherent yet acceptable statistical margin of uncertainty. KW - applied mathematics KW - applied physics KW - imaging techniques Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-261844 VL - 11 ER - TY - JOUR A1 - Winter, Patrick M. A1 - Andelovic, Kristina A1 - Kampf, Thomas A1 - Hansmann, Jan A1 - Jakob, Peter Michael A1 - Bauer, Wolfgang Rudolf A1 - Zernecke, Alma A1 - Herold, Volker T1 - Simultaneous measurements of 3D wall shear stress and pulse wave velocity in the murine aortic arch JF - Journal of Cardiovascular Magnetic Resonance N2 - Purpose Wall shear stress (WSS) and pulse wave velocity (PWV) are important parameters to characterize blood flow in the vessel wall. Their quantification with flow-sensitive phase-contrast (PC) cardiovascular magnetic resonance (CMR), however, is time-consuming. Furthermore, the measurement of WSS requires high spatial resolution, whereas high temporal resolution is necessary for PWV measurements. For these reasons, PWV and WSS are challenging to measure in one CMR session, making it difficult to directly compare these parameters. By using a retrospective approach with a flexible reconstruction framework, we here aimed to simultaneously assess both PWV and WSS in the murine aortic arch from the same 4D flow measurement. Methods Flow was measured in the aortic arch of 18-week-old wildtype (n = 5) and ApoE\(^{−/−}\) mice (n = 5) with a self-navigated radial 4D-PC-CMR sequence. Retrospective data analysis was used to reconstruct the same dataset either at low spatial and high temporal resolution (PWV analysis) or high spatial and low temporal resolution (WSS analysis). To assess WSS, the aortic lumen was labeled by semi-automatically segmenting the reconstruction with high spatial resolution. WSS was determined from the spatial velocity gradients at the lumen surface. For calculation of the PWV, segmentation data was interpolated along the temporal dimension. Subsequently, PWV was quantified from the through-plane flow data using the multiple-points transit-time method. Reconstructions with varying frame rates and spatial resolutions were performed to investigate the influence of spatiotemporal resolution on the PWV and WSS quantification. Results 4D flow measurements were conducted in an acquisition time of only 35 min. Increased peak flow and peak WSS values and lower errors in PWV estimation were observed in the reconstructions with high temporal resolution. Aortic PWV was significantly increased in ApoE\(^{−/−}\) mice compared to the control group (1.7 ± 0.2 versus 2.6 ± 0.2 m/s, p < 0.001). Mean WSS magnitude values averaged over the aortic arch were (1.17 ± 0.07) N/m\(^2\) in wildtype mice and (1.27 ± 0.10) N/m\(^2\) in ApoE\(^{−/−}\) mice. Conclusion The post processing algorithm using the flexible reconstruction framework developed in this study permitted quantification of global PWV and 3D-WSS in a single acquisition. The possibility to assess both parameters in only 35 min will markedly improve the analyses and information content of in vivo measurements. KW - 4D flow KW - pulse wave velocity KW - wall shear stress KW - radial KW - self-navigation KW - mouse KW - aortic arch KW - atherosclerosis KW - mice KW - flow KW - plaque KW - CMR KW - quantification KW - microscopy Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259152 VL - 23 IS - 1 ER - TY - JOUR A1 - Tufarelli, Tommaso A1 - Friedrich, Daniel A1 - Groß, Heiko A1 - Hamm, Joachim A1 - Hess, Ortwin A1 - Hecht, Bert T1 - Single quantum emitter Dicke enhancement JF - Physical Review Research N2 - Coupling N identical emitters to the same field mode is a well-established method to enhance light-matter interaction. However, the resulting √N boost of the coupling strength comes at the cost of a “linearized” (effectively semiclassical) dynamics. Here, we instead demonstrate a new approach for enhancing the coupling constant of a single quantum emitter, while retaining the nonlinear character of the light-matter interaction. We consider a single quantum emitter with N nearly degenerate transitions that are collectively coupled to the same field mode. We show that in such conditions an effective Jaynes-Cummings model emerges with a boosted coupling constant of order √N. The validity and consequences of our general conclusions are analytically demonstrated for the instructive case N=2. We further observe that our system can closely match the spectral line shapes and photon autocorrelation functions typical of Jaynes-Cummings physics, proving that quantum optical nonlinearities are retained. Our findings match up very well with recent broadband plasmonic nanoresonator strong-coupling experiments and will, therefore, facilitate the control and detection of single-photon nonlinearities at ambient conditions. KW - Cavity quantum electrodynamics KW - Collective effects in quantum optics KW - Quantum optics with artificial atoms KW - Superradiance & subradiance Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-261459 VL - 3 ER - TY - JOUR A1 - Krüger, Timothy A1 - Maus, Katharina A1 - Kreß, Verena A1 - Meyer-Natus, Elisabeth A1 - Engstler, Markus T1 - Single-cell motile behaviour of Trypanosoma brucei in thin-layered fluid collectives JF - The European Physical Journal E N2 - We describe a system for the analysis of an important unicellular eukaryotic flagellate in a confining and crowded environment. The parasite Trypanosoma brucei is arguably one of the most versatile microswimmers known. It has unique properties as a single microswimmer and shows remarkable adaptations (not only in motility, but prominently so), to its environment during a complex developmental cycle involving two different hosts. Specific life cycle stages show fascinating collective behaviour, as millions of cells can be forced to move together in extreme confinement. Our goal is to examine such motile behaviour directly in the context of the relevant environments. Therefore, for the first time, we analyse the motility behaviour of trypanosomes directly in a widely used assay, which aims to evaluate the parasites behaviour in collectives, in response to as yet unknown parameters. In a step towards understanding whether, or what type of, swarming behaviour of trypanosomes exists, we customised the assay for quantitative tracking analysis of motile behaviour on the single-cell level. We show that the migration speed of cell groups does not directly depend on single-cell velocity and that the system remains to be simplified further, before hypotheses about collective motility can be advanced. KW - Trypanosoma brucei KW - motile behaviour KW - fluid collectives Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-273022 SN - 1292-895X VL - 44 IS - 3 ER - TY - JOUR A1 - Klemmt, Chantal A1 - König, Sarah T1 - Situational Judgement Test als Unterrichtsmethode für die kritische Diskussion zu wissenschaftlicher Praxis und Fehlverhalten T1 - Situational judgement test as teaching method for the critical discussion on scientific practice and misconduct JF - Wiener Medizinische Wochenschrift N2 - Wissenschaftskompetenz ist eine Schlüsselqualifikation für jede ärztliche Tätigkeit und sollte ebenso wie die Auseinandersetzung mit Entscheidungsprozessen von Beginn an ins Medizinstudium integriert werden. Ziel der Studie war, die Themen der guten wissenschaftlichen Praxis und des wissenschaftlichen Fehlverhaltens zu vermitteln. Ferner wurde durch die methodische Intervention „Gruppendiskussion“ eine Reflexion im Kontext der wissenschaftlichen Angemessenheit herbeigeführt. Hierfür wurde der Situational Judgement Test (SJT) von den Studierenden (N = 743) (individuell und in der Gruppe) bearbeitet, und dessen Resultate wurden mit den Antworten von Expert/innen/en (N = 23) verglichen. Nach der Gruppendiskussion näherten sich die Ergebnisse in der Verteilung und Reihenfolge den Antwortmöglichkeiten der Expert/innen/en an. Jedoch tendierten die Studierenden signifikant häufiger zu jenen Antworten, die hilfesuchende, passive und verantwortungsübertragende Optionen bedeuteten. Insgesamt hat sich der SJT als didaktische Intervention bewährt. Die Studierenden setzten sich aktiv mit den Themen auseinander, eine Diskussion konnte angeregt und das eigene Verhalten kritisch reflektiert werden. N2 - Scientific competence and decision-making processes are key qualifications in undergraduate medical education and should be integrated into medical studies from the very beginning. The aim of the study was to convey the topics of good scientific practice and scientific misconduct. Furthermore, the methodological intervention “group discussion” enabled a productive reflection in the context of scientific appropriateness. For this purpose, the situational judgement test (SJT) was employed at different didactic activity levels of students (N = 743) (individually and as a group). The rating results were compared with the answers of experts (N = 23). Following group discussions, the answers of students shifted (distribution and order of answer options) towards those of the experts; however, students were more likely to choose response options that implied seeking help, allowing a passive stance and transferring responsibility. Overall, the SJT was a successful didactic intervention. The students actively reviewed the topics, discussed the subjects deeply and thereby critically reflected their own behavior. KW - Medizinische Ausbildung KW - Wissenschaftskompetenz KW - Gruppendiskussion KW - Formative Prüfung KW - Entscheidungsfindung KW - medical education KW - scientific competency KW - group discussions KW - fromative assessment KW - decision making Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235304 SN - 0043-5341 VL - 171 ER - TY - JOUR A1 - Hojsgaard, Diego A1 - Schartl, Manfred T1 - Skipping sex: A nonrecombinant genomic assemblage of complementary reproductive modules JF - BioEssays N2 - The unusual occurrence and developmental diversity of asexual eukaryotes remain a puzzle. De novo formation of a functioning asexual genome requires a unique assembly of sets of genes or gene states to disrupt cellular mechanisms of meiosis and gametogenesis, and to affect discrete components of sexuality and produce clonal or hemiclonal offspring. We highlight two usually overlooked but essential conditions to understand the molecular nature of clonal organisms, that is, a nonrecombinant genomic assemblage retaining modifiers of the sexual program, and a complementation between altered reproductive components. These subtle conditions are the basis for physiologically viable and genetically balanced transitions between generations. Genomic and developmental evidence from asexual animals and plants indicates the lack of complementation of molecular changes in the sexual reproductive program is likely the main cause of asexuals' rarity, and can provide an explanatory frame for the developmental diversity and lability of developmental patterns in some asexuals as well as for the discordant time to extinction estimations. KW - amphimixis KW - apomixis KW - automixis KW - gynogenesis KW - hybridogenesis KW - parthenogenesis Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225818 VL - 43 IS - 1 ER - TY - THES A1 - Lang, Konstantin T1 - SLC6A2-regulierende microRNAs bei Angsterkrankungen: Genexpressions- und Assoziationsuntersuchungen T1 - SLC6A2-regulating microRNAs in anxiety disorders: Genexpression and association studies N2 - Angsterkrankungen sind häufige Krankheitsbilder mit bislang nicht vollständig geklärter multifaktorieller Ätiologie. Neben Umwelt- und psychosozialen Faktoren zeigen Studien eine signifikante familiäre Häufung und lassen eine genetische Komponente mit einer Heritabilität in einem Bereich von 30-60 % vermuten. Da hierbei am ehesten von einem komplexen Zusammenspiel verschiedenster Gene mit unterschiedlicher Relevanz auszugehen ist, stellen miRNAs eine bedeutende Größe dar, da sie es vermögen auf transkriptioneller Ebene Einfluss auf die Regulierung einer Vielzahl von Genen zu nehmen. Verschiedene Aspekte liefern Hinweise darauf, dass eine Neurotransmitterdysregulation eine wichtige Komponente in der Pathogenese von Angsterkrankungen einnimmt – insbesondere veränderte noradrenerge Signalwege sind hierbei entscheidend beteiligt. Dies macht den Noradrenalin-Transporter bzw. SLC6A2 zu einem interessanten Kandidatengen, und stellt die Bezugsgröße der angestellten Untersuchungen in dieser Arbeit dar. miRNAs, welche die SLC6A2-Expression modulieren, können somit Einfluss auf zentrale Verarbeitungswege von Angst nehmen. Im ersten Teil der vorliegenden Arbeit wurden potentielle miRNA-Regulatoren von SLC6A2 in silico ermittelt und in einem weiteren Schritt in vitro überprüft. Zehn der miRNAs (hsa-miR-378g, hsa-miR-330-5p, hsa-miR-4781-5p, hsa-miR664b-3p, hsa-miR-4715-3p, hsa-miR-579-3p, hsa-miR-3921, hsa-miR-3622b-5p, hsa-miR-4773, hsa-miR-532-3p) zeigten hierbei eine relevante Abnahme der Luciferase-Aktivität als Hinweis auf ihre funktionelle Relevanz und stellen damit die Basis der nachfolgenden Untersuchungen dar. Im zweiten Teil der Arbeit wurden Einzelbasenpolymorphismen im Bereich der zuvor ermittelten miRNA-Gene sowie eines SNP innerhalb der 3’-UTR von SLC6A2 mittels Fall-Kontroll-Studie in einer Population von Patienten mit Panikstörung und entsprechenden Kontrollen untersucht. Eine nominelle Assoziation ließ sich für das (minor) T-Allel von rs2910931 (stromaufwärts von MIR579) (p-allel = 0,004) sowie das (major) A-Allel von rs2582372 (p-allel = 0,023) feststellen. In Einklang hiermit ließ sich weiterhin für rs2910931 eine signifikante Assoziation zwischen der Anzahl der (minor) T-Allele und dem ASI-Wert (β = 0,371, p = 0,029, 95 %-CI 0,039-0,702) sowie dem ACQ-Wert (β = 0,012, p = 0,041, 95 %-CI 0,000-0,023) ermitteln. Somit zeigt sich eine Einflussnahme der genetischen Variante um MIR579 auf die Feinmodulation der Noradrenalin-Homöostase als möglichem ätiopathogenetischen Faktor von Angsterkrankungen. N2 - Anxiety disorders are common conditions with a multifactorial etiology that has not yet been fully understood. In addition to environmental and psychosocial factors, studies show a significant familial clustering and suggest a genetic component with a heritability in the range of 30-60%. Since a complex interaction of various genes with different relevance can be assumed, miRNAs are an important factor, since they are able to influence the regulation of a large number of genes at the transcriptional level. Various aspects provide evidence that neurotransmitter dysregulation is an important component in the pathogenesis of anxiety disorders - in particular, altered noradrenergic signaling pathways are crucially involved. This makes the norepinephrine transporter, or SLC6A2, an interesting candidate gene, and represents the reference parameter for the studies conducted in this work. miRNAs that modulate SLC6A2 expression can thus influence central processing pathways of anxiety. In the first part of the present work, potential miRNA regulators of SLC6A2 were identified in silico and, in a further step, tested in vitro. Ten of the miRNAs (hsa-miR-378g, hsa-miR-330-5p, hsa-miR-4781-5p, hsa-miR664b-3p, hsa-miR-4715-3p, hsa-miR-579-3p, hsa-miR-3921, hsa-miR-3622b-5p, hsa-miR-4773, hsa-miR-532-3p) here showed a relevant decrease in luciferase activity as an indication of their functional relevance and thus form the basis of subsequent studies. In the second part of the work, single base polymorphisms in the region of the previously identified miRNA genes as well as a SNP within the 3'-UTR of SLC6A2 were investigated by case-control study in a population of patients with panic disorder and corresponding controls. A nominal association could be detected for the (minor) T allele of rs2910931 (upstream of MIR579) (pallel = 0.004) as well as the (major) A allele of rs2582372 (pallel = 0.023). Consistent with this, a significant association between the number of (minor) T alleles and the ASI value (β = 0.371, p = 0.029, 95%-CI 0.039-0.702) as well as the ACQ value (β = 0.012, p = 0.041, 95%-CI 0.000-0.023) could further be determined for rs2910931. Thus, an influence of the genetic variant around MIR579 on the fine modulation of noradrenaline homeostasis as a possible etiopathogenetic factor of anxiety disorders is revealed. KW - Angsterkrankungen KW - Angstsyndrom KW - miRNS KW - Small RNA KW - Paniksyndrom KW - Panikstörung KW - Assoziationsuntersuchung KW - microRNA KW - anxiety Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230939 ER - TY - THES A1 - Venturini, Elisa T1 - Small proteins in \(Salmonella\): an updated annotation and a global analysis to find new regulators of virulence T1 - Kleine Proteine in \(Salmonella\): Eine aktualisierte Annotation und eine globale Analyse, um neue Regulatoren der Virulenz zu finden N2 - Small proteins, often defined as shorter than 50 amino acids, have been implicated in fundamental cellular processes. Despite this, they have been largely understudied throughout all domains of life, since their size often makes their identification and characterization challenging. This work addressed the knowledge gap surrounding small proteins with a focus on the model bacterial pathogen Salmonella Typhimurium. In a first step, new small proteins were identified with a combination of computational and experimental approaches. Infection-relevant datasets were then investigated with the updated Salmonella annotation to prioritize promising candidates involved in virulence. To implement the annotation of new small proteins, predictions from the algorithm sPepFinder were merged with those derived from Ribo-seq. These were added to the Salmonella annotation and used to (re)analyse different datasets. Information regarding expression during infection (dual RNA-seq) and requirement for virulence (TraDIS) was collected for each given coding sequence. In parallel, Grad-seq data were mined to identify small proteins engaged in intermolecular interactions. The combination of dual RNA-seq and TraDIS lead to the identification of small proteins with features of virulence factors, namely high intracellular induction and a virulence phenotype upon transposon insertion. As a proof of principle of the power of this approach in highlighting high confidence candidates, two small proteins were characterized in the context of Salmonella infection. MgrB, a known regulator of the PhoPQ two-component system, was shown to be essential for the infection of epithelial cells and macrophages, possibly via its stabilizing effect on flagella or by interacting with other sensor kinases of twocomponent systems. YjiS, so far uncharacterized in Salmonella, had an opposite role in infection, with its deletion rendering Salmonella hypervirulent. The mechanism underlying this, though still obscure, likely relies on the interaction with inner-membrane proteins. Overall, this work provides a global description of Salmonella small proteins in the context of infection with a combinatorial approach that expedites the identification of interesting candidates. Different high-throughput datasets available for a broad range of organisms can be analysed in a similar manner with a focus on small proteins. This will lead to the identification of key factors in the regulation of various processes, thus for example providing targets for the treatment of bacterial infections or, in the case of commensal bacteria, for the modulation of the microbiota composition. N2 - Kleine Proteine, oft definiert als kürzer als 50 Aminosäuren, sind in fundamentale zelluläre Prozesse involviert. Trotzdem sind sie in allen Domänen des Lebens noch weitgehend unerforscht, da ihre Größe ihre Identifizierung und Charakterisierung oft schwierig macht. Diese Arbeit adressiert die Wissenslücke um kleine Proteine mit einem Fokus auf das bakterielle Modellpathogen Salmonella Typhimurium. In einem ersten Schritt wurden neue kleine Proteine mit einer Kombination aus bioinformatischen und experimentellen Ansätzen identifiziert. Anschließend wurden infektionsrelevante Datensätze mit der aktualisierten Salmonella-Annotation untersucht, um vielversprechende Kandidaten zu priorisieren, die an der Virulenz beteiligt sind. Um die Annotation neuer kleiner Proteine zu implementieren, wurden die Vorhersagen aus dem Algorithmus sPepFinder mit denen aus Ribo-seq kombiniert. Diese wurden der Salmonella-Annotation hinzugefügt und zur (Re-)Analyse verschiedener Datensätze verwendet. Für jede gegebene kodierende Sequenz wurden Informationen zur Expression während der Infektion (duale RNA-seq) und zum Beitrag zur Virulenz (TraDIS) gesammelt. Parallel dazu wurden Grad-seq-Daten ausgewertet, um kleine Proteine zu identifizieren, die an intermolekularen Interaktionen beteiligt sind. Die Kombination von dualer RNA-seq und TraDIS führte zur Identifizierung von kleinen Proteinen mit Merkmalen von Virulenzfaktoren, nämlich einer hohen intrazellulären Induktion und einem Virulenz-Phänotyp nach Transposon- Insertion. Als Beweis für die Leistungsfähigkeit dieses Ansatzes Identifikation von vielversprechenden Kandidaten wurden zwei kleine Proteine im Kontext einer Salmonella-Infektion charakterisiert. MgrB, ein bekannter Regulator des PhoPQ-Zweikomponentensystems, erwies sich als ein für die Infektion von Epithelzellen und Makrophagen essentielles Protein, möglicherweise über seine stabilisierende Wirkung von Flagellen oder durch Interaktion mit Sensorkinasen von Zweikomponentensystemen. YjiS, das in Salmonella bisher nicht charakterisiert wurde, hatte eine entgegengesetzte Rolle bei der Infektion, wobei seine Deletion Salmonella hypervirulent macht. Der Mechanismus, der dem zugrunde liegt, ist zwar noch unklar, beruht aber wahrscheinlich auf der Interaktion mit inneneren Membranproteinen. Insgesamt liefert diese Arbeit eine globale Beschreibung der kleinen Salmonella- Proteine im Kontext der Infektion mit einem kombinatorischen Ansatz, der die Identifizierung interessanter Kandidaten beschleunigt. Verschiedene Hochdurchsatz- Datensätze, die für ein breites Spektrum von Organismen verfügbar sind, können auf ähnliche Weise mit einem Fokus auf kleine Proteine analysiert werden. Dies wird zur Identifizierung von Schlüsselfaktoren in der Regulation verschiedener Prozesse führen und damit z. B. Targets für die Behandlung bakterieller Infektionen oder, im Falle kommensaler Bakterien, für die Modulation der Mikrobiota- Zusammensetzung liefern. KW - Salmonella Typhimurium KW - Kleine Proteine KW - small proteins KW - dual RNA-seq KW - TraDIS KW - MgrB Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-247029 ER - TY - JOUR A1 - Pernitzsch, Sandy R. A1 - Alzheimer, Mona A1 - Bremer, Belinda U. A1 - Robbe-Saule, Marie A1 - De Reuse, Hilde A1 - Sharma, Cynthia M. T1 - Small RNA mediated gradual control of lipopolysaccharide biosynthesis affects antibiotic resistance in Helicobacter pylori JF - Nature Communications N2 - The small, regulatory RNA RepG (Regulator of polymeric G-repeats) regulates the expression of the chemotaxis receptor TlpB in Helicobacter pylori by targeting a variable G-repeat in the tlpB mRNA leader. Here, we show that RepG additionally controls lipopolysaccharide (LPS) phase variation by also modulating the expression of a gene (hp0102) that is co-transcribed with tlpB. The hp0102 gene encodes a glycosyltransferase required for LPS O-chain biosynthesis and in vivo colonization of the mouse stomach. The G-repeat length defines a gradual (rather than ON/OFF) control of LPS biosynthesis by RepG, and leads to gradual resistance to a membrane-targeting antibiotic. Thus, RepG-mediated modulation of LPS structure might impact host immune recognition and antibiotic sensitivity, thereby helping H. pylori to adapt and persist in the host. The small RNA RepG modulates expression of chemotaxis receptor TlpB in Helicobacter pylori by targeting a length-variable G-repeat in the tlpB mRNA. Here, Pernitzsch et al. show that RepG also gradually controls lipopolysaccharide biosynthesis, antibiotic susceptibility, and in-vivo colonization of the stomach, by regulating a gene that is co-transcribed with tlpB. KW - bacterial genetics KW - bacterial immune evasion KW - pathogens KW - small RNAs Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-261536 VL - 12 IS - 1 ER - TY - JOUR A1 - Letunic, Ivica A1 - Khedkar, Supriya A1 - Bork, Peer T1 - SMART: recent updates, new developments and status in 2020 JF - Nucleic Acids Research N2 - SMART (Simple Modular Architecture Research Tool) is a web resource (https://smart.embl.de) for the identification and annotation of protein domains and the analysis of protein domain architectures. SMART version 9 contains manually curatedmodels formore than 1300 protein domains, with a topical set of 68 new models added since our last update article (1). All the new models are for diverse recombinase families and subfamilies and as a set they provide a comprehensive overview of mobile element recombinases namely transposase, integrase, relaxase, resolvase, cas1 casposase and Xer like cellular recombinase. Further updates include the synchronization of the underlying protein databases with UniProt (2), Ensembl (3) and STRING (4), greatly increasing the total number of annotated domains and other protein features available in architecture analysis mode. Furthermore, SMART's vector-based protein display engine has been extended and updated to use the latest web technologies and the domain architecture analysis components have been optimized to handle the increased number of protein features available. KW - SMART KW - SMART version 9 KW - protein domains KW - protein domain architectures Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-363816 VL - 49 IS - D1 ER - TY - JOUR A1 - Qi, Yanyan A1 - Bruch, Dorothee A1 - Krop, Philipp A1 - Herrmann, Martin J. A1 - Latoschik, Marc E. A1 - Deckert, Jürgen A1 - Hein, Grit T1 - Social buffering of human fear is shaped by gender, social concern, and the presence of real vs virtual agents JF - Translational Psychiatry N2 - The presence of a partner can attenuate physiological fear responses, a phenomenon known as social buffering. However, not all individuals are equally sociable. Here we investigated whether social buffering of fear is shaped by sensitivity to social anxiety (social concern) and whether these effects are different in females and males. We collected skin conductance responses (SCRs) and affect ratings of female and male participants when they experienced aversive and neutral sounds alone (alone treatment) or in the presence of an unknown person of the same gender (social treatment). Individual differences in social concern were assessed based on a well-established questionnaire. Our results showed that social concern had a stronger effect on social buffering in females than in males. The lower females scored on social concern, the stronger the SCRs reduction in the social compared to the alone treatment. The effect of social concern on social buffering of fear in females disappeared if participants were paired with a virtual agent instead of a real person. Together, these results showed that social buffering of human fear is shaped by gender and social concern. In females, the presence of virtual agents can buffer fear, irrespective of individual differences in social concern. These findings specify factors that shape the social modulation of human fear, and thus might be relevant for the treatment of anxiety disorders. KW - human behaviour KW - physiology Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265782 VL - 11 ER - TY - JOUR A1 - Hein, Grit A1 - Gamer, Matthias A1 - Gall, Dominik A1 - Gründahl, Marthe A1 - Domschke, Katharina A1 - Andreatta, Marta A1 - Wieser, Matthias J. A1 - Pauli, Paul T1 - Social cognitive factors outweigh negative emotionality in predicting COVID-19 related safety behaviors JF - Preventive Medicine Reports N2 - Emotion-motivation models propose that behaviors, including health behaviors, should be predicted by the same variables that also predict negative affect since emotional reactions should induce a motivation to avoid threatening situations. In contrast, social cognitive models propose that safety behaviors are predicted by a different set of variables that mainly reflect cognitive and socio-structural aspects. Here, we directly tested these opposing hypotheses in young adults (N = 4134) in the context of COVID-19-related safety behaviors to prevent infections. In each participant, we collected measures of negative affect as well as cognitive and socio-structural variables during the lockdown in the first infection wave in Germany. We found a negative effect of the pandemic on emotional responses. However, this was not the main predictor for young adults’ willingness to comply with COVID-19-related safety measures. Instead, individual differences in compliance were mainly predicted by cognitive and socio-structural variables. These results were confirmed in an independent data set. This study shows that individuals scoring high on negative affect during the pandemic are not necessarily more likely to comply with safety regulations. Instead, political measures should focus on cognitive interventions and the societal relevance of the health issue. These findings provide important insights into the basis of health-related concerns and feelings as well as behavioral adaptations. KW - social cognitive KW - negative affect KW - safety behavior KW - survey KW - COVID-19 Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265008 VL - 24 ER - TY - THES A1 - Aydinli, Muharrem T1 - Software unterstützte Analyse von regulatorischen Elementen in Promotoren mittels AIModules T1 - Software backed Analysis of regulatory Elements of Promoters with AIModules N2 - Die Regulation der Genexpression steht am Anfang vieler zellbiologischer Prozesse wie beispielsweise dem Zellwachstum oder der Differenzierung. Gene werden an Promotoren transkribiert, wobei ein Promotor selbst aus vielen logischen Einheiten aufgebaut ist, den Transkriptionsfaktorbindestellen (TFBSs). Diese können sehr nah beieinander liegen, aber auch weit entfernt voneinander sein. Sie werden spezifisch von Transkriptionsfaktoren (TFs) gebunden, die die Transkritptionsrate z.B. verstärken (Enhancer) oder schwächen (Silencer) können. Zwei oder mehr dieser TFBSs mit bestimmtem Abstand werden als "Module" zusammengefasst, die über Spezies hinweg konserviert sein können. Typischerweise findet man Module in Zellen mit einem Zellkern. Spezies mit gemeinsamen Modulen können ein Hinweis auf die gemeinsame phylogenetische Abstammung darstellen, aber auch gemeinsame Funktionsmechanismen von TFs über Gene hinweg aufdecken. Heutzutage sind verschiedene Anwendungen verfügbar, mit denen nach TFBSs in DNA gesucht werden kann. Zum Zeitpunkt des Verfassens dieser Arbeit sind aber nur zwei kommerzielle Produkte bekannt, die nicht nur TFBSs, sondern auch Module erkennen. Deshalb stellen wir hier die freie und quelloffene Lösung "AIModules" vor, die diese Lücke füllt und einen Webservice zur Verfügung stellt, der es erlaubt nach TFBSs sowie nach Modulen auf DNA- und auf RNA-Abschnitten zu suchen. Für die Motivesuche werden entweder Matrizen aus der Jaspar Datenbank oder Matrizen vom Anwender verwendet. Darüberhinaus zeigen wir, dass unser Tool für die TF Suche nur Sekunden benötigt, wohingegen conTraV3 mindestens eine Stunde für dieselbe Analyse braucht. Zusätzlich kann der Anwender bei unserem Tool den Grad der Konserviertheit für TFs mit angeben und wir zeigen, dass wir mit unserer Lösung, die die Jaspar Datenbank heranzieht, mehr Module finden, als ein kommerziell verfügbares Produkt. Weiterhin kann mit unserer Lösung auch auf RNA-Sequenzen nach regulatorischen Motiven gesucht werden, wenn der Anwender die dafür nötigen Matrizen liefert. Wir zeigen dies am Beispiel von Polyadenylierungsstellen. Zusammenfassend stellen wir ein Werkzeug vor, das erstens frei und quelloffen ist und zweitens entweder auf Servern veröffentlicht werden kann oder On-Site auf einem Notebook läuft. Unser Tool erlaubt es Promotoren zu analysieren und nach konservierten Modulen sowie TFBSs in Genfamilien sowie nach regulatorischen Elementen in mRNA wie z.B. Polyadenylierungsstellen oder andere regulatorische Elemente wie beispielsweise Enhancern oder Silencern in genomischer DNA zu suchen. N2 - Regulation of gene expression is at the root of many processes in cellular biology such as cell growth and differentiation. Promotors are the starting points for the transcription of a gene. The promotor itself consists of transcription factor binding sites (TFBSs) which can be closely located or vastly apart. They are recognized and bound by transcription factors (TFs) which themselves can e.g. enhance or silence the transcribing process by the RNA polymerases. Two or more of those transcription factor binding sites within a certain range are called a "module". Typically, those are found in cells with a nucleus and they may be conserved throughout species. The knowledge of modules may indicate a phylogenetic relationship among species but may also provide insight into the concerted actions of TFs on different genes. Currently there are a number of tools available that can enable a user to find TFBSs on DNA. But at the time of assembling this thesis, there are only two commercial software products available, that can not only detect TFs but also modules. Therefore, we present a free and open source solution that fills this gap by providing a web service that searches for TFBSs and modules on DNA as well as RNA stretches, called "AIModules". For that, matrices from the Jaspar database or user input matrices are used for motif discovery. Additionally, we show that our tool does TF analysis in seconds, whereas tools like conTraV3 took at least an hour. Furthermore, for the module search the user can specify the degree of conservation of the TFs. We show that with our solution using the JASPAR database we find more modules than a commercially available tool. Moreover, with our application RNA stretches can also be searched for regulatory motifs if suitable matrices are provided. We illustrate this for polyadenylation sites. Thus, our solution is free and open source, and can be deployed on servers as well as provided on-site on a notebook. We provide a tool to analyze promotors and search for conserved modules as well as common TFBSs in gene families, search for regulatory elements in mRNA such as polyadenylation sites or other regulatory elements such as enhancers or silencers in genomic DNA. KW - Genregulation KW - Promotor KW - Transkriptionsfaktor KW - Modulsuche KW - RNA Motivsuche KW - Modul KW - Module search KW - RNA motiv serach KW - module search Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-248025 ER - TY - JOUR A1 - Turkin, Arthur A1 - Holzapfel, Marco A1 - Agarwal, Mohit A1 - Fischermeier, David A1 - Mitric, Roland A1 - Schweins, Ralf A1 - Gröhns, Franziska A1 - Lambert, Christoph T1 - Solvent Induced Helix Folding of Defined Indolenine Squaraine Oligomers JF - Chemistry—A European Journal N2 - A protecting group strategy was employed to synthesise a series of indolenine squaraine dye oligomers up to the nonamer. The longer oligomers show a distinct solvent dependence of the absorption spectra, that is, either a strong blue shift or a strong red shift of the lowest energy bands in the near infrared spectral region. This behaviour is explained by exciton coupling theory as being due to H- or J-type coupling of transition moments. The H-type coupling is a consequence of a helix folding in solvents with a small Hansen dispersity index. DOSY NMR, small angle neutron scattering (SANS), quantum chemical and force field calculations agree upon a helix structure with an unusually large pitch and open voids that are filled with solvent molecules, thereby forming a kind of clathrate. The thermodynamic parameters of the folding process were determined by temperature dependent optical absorption spectra. KW - UV/Vis spectroscopy KW - dye chemistry KW - solvent effects KW - superstructure KW - supramolecular folding Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-256869 VL - 27 IS - 32 ER - TY - JOUR A1 - Herget, Ann-Kristin A1 - Bötzl, Franziska T1 - Sounds Like Respect. The Impact of Background Music on the Acceptance of Gay Men in Audio-Visual Advertising JF - Frontiers in Psychology N2 - Companies increasingly seek to use gay protagonists in audio-visual commercials to attract a new affluent target group. There is also growing demand for the diversity present in society to be reflected in media formats such as advertising. Studies have shown, however, that heterosexual consumers (especially men), who may be part of the company's loyal consumer base, tend to react negatively to gay-themed advertising campaigns. Searching for an instrument to mitigate this unwanted effect, the present study investigated whether carefully selected background music can shape the perceived gender of gay male advertising protagonists. In a 2 × 2 between-subjects online experiment (musical connotation × gender of the participant), 218 heterosexual participants watched a commercial promoting engagement rings that featured gay male protagonists, scored with feminine- or masculine-connoted background music. As expected, women generally reacted more positively than men to the advertising. Men exposed to the masculine-connoted background music rated the promoted brand more positively, and masculine music also enhanced (at least in the short term) these men's acceptance of gay men in general (low and medium effect sizes) more than was the case for feminine background music. Carefully selected background music affecting the perceived gender of gay male advertising protagonists may prevent negative reactions from heterosexual audiences and, therefore, motivate companies to use gay protagonists in television commercials on a more regular basis. KW - music KW - perception KW - advertising KW - musical stereotypes KW - acceptance of gay men Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-237236 SN - 1664-1078 VL - 12 ER - TY - JOUR A1 - Wienrich, Carolin A1 - Komma, Philipp A1 - Vogt, Stephanie A1 - Latoschik, Marc E. T1 - Spatial Presence in Mixed Realities – Considerations About the Concept, Measures, Design, and Experiments JF - Frontiers in Virtual Reality N2 - Plenty of theories, models, measures, and investigations target the understanding of virtual presence, i.e., the sense of presence in immersive Virtual Reality (VR). Other varieties of the so-called eXtended Realities (XR), e.g., Augmented and Mixed Reality (AR and MR) incorporate immersive features to a lesser degree and continuously combine spatial cues from the real physical space and the simulated virtual space. This blurred separation questions the applicability of the accumulated knowledge about the similarities of virtual presence and presence occurring in other varieties of XR, and corresponding outcomes. The present work bridges this gap by analyzing the construct of presence in mixed realities (MR). To achieve this, the following presents (1) a short review of definitions, dimensions, and measurements of presence in VR, and (2) the state of the art views on MR. Additionally, we (3) derived a working definition of MR, extending the Milgram continuum. This definition is based on entities reaching from real to virtual manifestations at one time point. Entities possess different degrees of referential power, determining the selection of the frame of reference. Furthermore, we (4) identified three research desiderata, including research questions about the frame of reference, the corresponding dimension of transportation, and the dimension of realism in MR. Mainly the relationship between the main aspects of virtual presence of immersive VR, i.e., the place-illusion, and the plausibility-illusion, and of the referential power of MR entities are discussed regarding the concept, measures, and design of presence in MR. Finally, (5) we suggested an experimental setup to reveal the research heuristic behind experiments investigating presence in MR. The present work contributes to the theories and the meaning of and approaches to simulate and measure presence in MR. We hypothesize that research about essential underlying factors determining user experience (UX) in MR simulations and experiences is still in its infancy and hopes this article provides an encouraging starting point to tackle related questions. KW - mixed reality KW - virtual-reality-continuum KW - spatial presence KW - place-illusion KW - plausibility-illusion KW - transportation KW - realism Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-260328 VL - 2 ER - TY - JOUR A1 - Brodehl, Andreas A1 - Milting, Hendrik A1 - Gerull, Brenda T1 - Special Issue “Cardiovascular Genetics” JF - Genes N2 - No abstract available KW - cardiovascular genetics Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234229 SN - 2073-4425 VL - 12 IS - 4 ER - TY - JOUR A1 - Meintrup, David A1 - Borgmann, Stefan A1 - Seidl, Karlheinz A1 - Stecher, Melanie A1 - Jakob, Carolin E. M. A1 - Pilgram, Lisa A1 - Spinner, Christoph D. A1 - Rieg, Siegbert A1 - Isberner, Nora A1 - Hower, Martin A1 - Vehreschild, Maria A1 - Göpel, Siri A1 - Hanses, Frank A1 - Nowak-Machen, Martina T1 - Specific risk factors for fatal outcome in critically ill COVID-19 patients: results from a European multicenter study JF - Journal of Clinical Medicine N2 - (1) Background: The aim of our study was to identify specific risk factors for fatal outcome in critically ill COVID-19 patients. (2) Methods: Our data set consisted of 840 patients enclosed in the LEOSS registry. Using lasso regression for variable selection, a multifactorial logistic regression model was fitted to the response variable survival. Specific risk factors and their odds ratios were derived. A nomogram was developed as a graphical representation of the model. (3) Results: 14 variables were identified as independent factors contributing to the risk of death for critically ill COVID-19 patients: age (OR 1.08, CI 1.06–1.10), cardiovascular disease (OR 1.64, CI 1.06–2.55), pulmonary disease (OR 1.87, CI 1.16–3.03), baseline Statin treatment (0.54, CI 0.33–0.87), oxygen saturation (unit = 1%, OR 0.94, CI 0.92–0.96), leukocytes (unit 1000/μL, OR 1.04, CI 1.01–1.07), lymphocytes (unit 100/μL, OR 0.96, CI 0.94–0.99), platelets (unit 100,000/μL, OR 0.70, CI 0.62–0.80), procalcitonin (unit ng/mL, OR 1.11, CI 1.05–1.18), kidney failure (OR 1.68, CI 1.05–2.70), congestive heart failure (OR 2.62, CI 1.11–6.21), severe liver failure (OR 4.93, CI 1.94–12.52), and a quick SOFA score of 3 (OR 1.78, CI 1.14–2.78). The nomogram graphically displays the importance of these 14 factors for mortality. (4) Conclusions: There are risk factors that are specific to the subpopulation of critically ill COVID-19 patients. KW - COVID-19 KW - SARS-CoV-2 KW - risk factors KW - critically ill patients KW - comorbidities KW - lasso regression KW - nomogram Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-245191 SN - 2077-0383 VL - 10 IS - 17 ER - TY - JOUR A1 - Brunkhorst-Kanaan, Nathalie A1 - Trautmann, Sandra A1 - Schreiber, Yannick A1 - Thomas, Dominique A1 - Kittel-Schneider, Sarah A1 - Gurke, Robert A1 - Geisslinger, Gerd A1 - Reif, Andreas A1 - Tegeder, Irmgard T1 - Sphingolipid and endocannabinoid profiles in adult attention deficit hyperactivity disorder JF - Biomedicines N2 - Genes encoding endocannabinoid and sphingolipid metabolism pathways were suggested to contribute to the genetic risk towards attention deficit hyperactivity disorder (ADHD). The present pilot study assessed plasma concentrations of candidate endocannabinoids, sphingolipids and ceramides in individuals with adult ADHD in comparison with healthy controls and patients with affective disorders. Targeted lipid analyses of 23 different lipid species were performed in 71 mental disorder patients and 98 healthy controls (HC). The patients were diagnosed with adult ADHD (n = 12), affective disorder (major depression, MD n = 16 or bipolar disorder, BD n = 6) or adult ADHD with comorbid affective disorders (n = 37). Canonical discriminant analysis and CHAID analyses were used to identify major components that predicted the diagnostic group. ADHD patients had increased plasma concentrations of sphingosine-1-phosphate (S1P d18:1) and sphinganine-1-phosphate (S1P d18:0). In addition, the endocannabinoids, anandamide (AEA) and arachidonoylglycerol were increased. MD/BD patients had increased long chain ceramides, most prominently Cer22:0, but low endocannabinoids in contrast to ADHD patients. Patients with ADHD and comorbid affective disorders displayed increased S1P d18:1 and increased Cer22:0, but the individual lipid levels were lower than in the non-comorbid disorders. Sphingolipid profiles differ between patients suffering from ADHD and affective disorders, with overlapping patterns in comorbid patients. The S1P d18:1 to Cer22:0 ratio may constitute a diagnostic or prognostic tool. KW - attention deficit hyperactivity disorder KW - endocannabinoids KW - ceramides KW - bipolar disorder KW - major depression KW - tandem mass spectrometry Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-246080 SN - 2227-9059 VL - 9 IS - 9 ER - TY - JOUR A1 - Schneider-Schaulies, Sibylle A1 - Schumacher, Fabian A1 - Wigger, Dominik A1 - Schöl, Marie A1 - Waghmare, Trushnal A1 - Schlegel, Jan A1 - Seibel, Jürgen A1 - Kleuser, Burkhard T1 - Sphingolipids: effectors and Achilles heals in viral infections? JF - Cells N2 - As viruses are obligatory intracellular parasites, any step during their life cycle strictly depends on successful interaction with their particular host cells. In particular, their interaction with cellular membranes is of crucial importance for most steps in the viral replication cycle. Such interactions are initiated by uptake of viral particles and subsequent trafficking to intracellular compartments to access their replication compartments which provide a spatially confined environment concentrating viral and cellular components, and subsequently, employ cellular membranes for assembly and exit of viral progeny. The ability of viruses to actively modulate lipid composition such as sphingolipids (SLs) is essential for successful completion of the viral life cycle. In addition to their structural and biophysical properties of cellular membranes, some sphingolipid (SL) species are bioactive and as such, take part in cellular signaling processes involved in regulating viral replication. It is especially due to the progress made in tools to study accumulation and dynamics of SLs, which visualize their compartmentalization and identify interaction partners at a cellular level, as well as the availability of genetic knockout systems, that the role of particular SL species in the viral replication process can be analyzed and, most importantly, be explored as targets for therapeutic intervention. KW - glycosphingolipids KW - ceramides KW - sphingosine 1-phosphate KW - sphingomyelinase KW - HIV KW - SARS-CoV-2 KW - measles Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-245151 SN - 2073-4409 VL - 10 IS - 9 ER - TY - JOUR A1 - Gottscholl, Andreas A1 - Diez, Matthias A1 - Soltamov, Victor A1 - Kasper, Christian A1 - Krauße, Dominik A1 - Sperlich, Andreas A1 - Kianinia, Mehran A1 - Bradac, Carlo A1 - Aharonovich, Igor A1 - Dyakonov, Vladimir T1 - Spin defects in hBN as promising temperature, pressure and magnetic field quantum sensors JF - Nature Communications N2 - Spin defects in solid-state materials are strong candidate systems for quantum information technology and sensing applications. Here we explore in details the recently discovered negatively charged boron vacancies (V\(_B\)\(^−\)) in hexagonal boron nitride (hBN) and demonstrate their use as atomic scale sensors for temperature, magnetic fields and externally applied pressure. These applications are possible due to the high-spin triplet ground state and bright spin-dependent photoluminescence of the V\(_B\)\(^−\). Specifically, we find that the frequency shift in optically detected magnetic resonance measurements is not only sensitive to static magnetic fields, but also to temperature and pressure changes which we relate to crystal lattice parameters. We show that spin-rich hBN films are potentially applicable as intrinsic sensors in heterostructures made of functionalized 2D materials. KW - electronic properties and materials KW - qubits Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-261581 VL - 12 IS - 1 ER - TY - THES A1 - Elias dos Santos, Graciely T1 - Spin-Orbit Torques and Galvanomagnetic Effects Generated by the 3D Topological Insulator HgTe T1 - Spin-Orbit Torques und galvanomagnetische Effekte, erzeugt durch den 3D-topologischen Isolator HgTe N2 - In meiner Dissertation beschäftigte ich mich mit der Frage, ob der 3D topologische Isolator Quecksilbertellurid (3D TI HgTe) ein geeignetes Material für Spintronik-Anwendungen ist. Wir untersuchten Spin-Bahn-Drehmomente, die auf Elektronen beim Tunneln zwischen HgTe und einem angrenzenden Ferromagneten (Permalloy) einwirken. Zunächst setzten wir die Methode der Ferromagnetresonanz (SOT-FMR) für diese Untersuchungen ein. Im ersten Teil der Dissertation werden die Leser in die mathematische Beschreibung von Spin- Bahn-Drehmomenten in einem Hybridsystem bestehend aus topologischem Isolator (TI) und Ferromagnet (FM) eingeführt. Des Weiteren werden die Probenherstellung und der Messaufbau für SOT-FMR Messungen besprochen. Unsere SOT-FMR Messungen ergaben, dass bei tiefen Temperaturen (T = 4.2 K) die Normalkomponente (bezogen auf der TI-Oberfläche) des Drehmoments groß war. Bei Raumtemperatur konnten im Signal beide Komponenten (parallel und normal zur TI-Oberfläche) beobachtet werden. Aus der Symmetrie der Mixing-Spannung (Abbildungen 3.14 und 3.15) schlossen wir, dass 3D TI HgTe ein Spin-Bahn-Drehmoment auf das Elektronensystem des Permalloys überträgt. Unsere Untersuchungen zeigten darüber hinaus, dass die Effizienz dieser Übertragung mit der anderer vorhandener topologischen Isolatoren vergleichbar ist (siehe Abb. 3.17). Abschließend wurden parasitäre Effekte bei der Abschätzung des Spin-Bahn-Drehmoments bzw. andere Interpretationen des Messsignals und seiner Komponenten (z.B., Thermospannungen) ausführlich diskutiert. Obwohl die hier gezeigten Ergebnisse vermehrt darauf hinweisen, dass der 3D TI HgTe möglicherweise effizient für die Anwendung von Spin-Drehmomenten in angrezenden Ferromagneten ist [1], wird dem Leser weiderholt klargemacht, dass parasitäre Effekte eventuelle das korrekte Schreiben und Lesen der Information in Ferromagneten verunreignigt. Diese sollten auch bei der Interpretation von publizierten Resultaten besonders hohen Spin-Bahn-Drehmomentübertragungen in der Literatur berücksichtigt werden [1–3]. Die Nachteile der SOT-FMR-Messmethode führten zu einerWeiterentwicklung unseres Messkonzepts, bei dem der Ferromagnet durch eine Spin-Valve-Struktur ersetzt wurde. In dieser Messanordnung ist der Stromfluss durch den 3D TI im Gegensatz zu den vorangegangenen Messungen bekannt und die Widerstandsänderung der Spin-Valve-Struktur kann durch den GMR-Effekt ausgelesen werden. Die Ausrichtung der Magnetisierung des Ferromagneten in den SOT-FMR-Experimenten erforderte es, ein magnetisches Feld von bis zu 300 mT parallel zur TI-Oberfläche anzulegen. Motiviert durch diesen Umstand, untersuchten wir den Einfluss eines parallelen Magnetfelds auf den Magnetowiderstand in 3D TI HgTe. Die überraschenden Resultate dieser Messungen werden im zweiten Teil der Dissertation beschrieben. Obwohl nichtmagnetisches Quecksilbertellurid untersucht wurde, oszillierte der transversale Magnetowiderstand (Rxy) mit dem Winkel � zwischen der Magnetfeldrichtung (parallel zur Oberfläche) und der elektrischen Stromflussrichtung im topologischen Isolator. Dieser Effekt ist eine typische Eigenschaft von ferromagnetischen Materialien und wird planarer Hall-Effekt (PHE) genannt[4, 5]. Magnetowiderstands- (MR-)Oszillationen wurden ebenfalls sowohl im Längswiderstand (Rxx) und im transversalen Widerstand (Rxy) über einen weiten Bereich von magnetischen Feldstärken und Ladungsträgerdichten des topologischen Isolators beobachtet. Der PHE wurde bereits zuvor in einem anderen TI-Material (Bi2−xSbxTe3) beschrieben [6]. Als physikalischer Mechanismus wurde von den Autoren Elektronenstreuung an magnetisch polarisierten Streuzentren vorgeschlagen. Wir diskutierten sowohl diesen Erklärungsansatz als auch andere Theorievorschläge in der Literatur [7, 8] kritisch. In dieser Doktorarbeit haben wir versucht, der PHE des 3D TI HgTe durch die Asymmetrie in der Bandstruktur dieses Materials zu erklären. In k.p Bandstrukturrechnungen mit einer 6-Orbital-Basis zeigten wir, dass das Zwischenspiel von Rashba- und Dresselhaus-Spin-Bahn- Wechselwirkung mit dem magnetischen Feld parallel zur TI-Oberfläche zu einer Verformung der Fermikontur des Valenzbands von 3D TI-HgTe führt, welche ihrerseits eine Anisotropie des Leitfähigkeit bedingt. Die benötigten Magnetfeldstärken in diesem Modell waren mit bis zu 40 T jedoch etwa eine Größenordnung größer als jene in unseren Experimenten. Des Weiteren lieferte eine direkte Berechnung der Zustandsdichten für Bin k I und Bin ? I bisher keine klaren Resultate. Die komplizierte Abhängigkeit der Rashba-Spin-Bahn-Kopplung für p-leitendes HgTe [9] machte es außerdem schwierig, diesen Term in die Bandstrukturrechnung zu inkludieren. Trotz umfangreicher Bemühungen, den Ursprung der galvanomagnetischen Effekte im 3D TI HgTe zu verstehen, konnte in dieser Arbeit der Mechanismus des PHE und der MR-Oszillationen nicht eindeutig bestimmt werden. Es gelang jedoch, einige aus der Literatur bekannte Theorien für den PHE und die MR-Oszillationseffekte in topologischen Isolatoren auszuschließen. Die Herausforderung, eine vollständige theoretische Beschreibung zu entwickeln, die allen experimentellen Aspekten (PHE, Gatespannungsabhängigkeit und MR-Oszillationen) gerecht wird, bleibt weiter bestehen. Abschließend möchte die Autorin ihre Hoffnung ausdrücken, den Lesern die Komplexität der Fragestellung näher gebracht zu haben und sie in die Kunst elektrischer Messungen an topologischen Isolatoren bei angelegtem parallelem Magnetfeld initiiert zu haben. N2 - Nature shows us only the tail of the lion. But I have no doubt that the lion belongs with it even if he cannot reveal himself all at once. Albert Einstein In my dissertation, I addressed the question of whether the 3D topological insulator mercury telluride (3D TI HgTe) is a suitable material for spintronics applications. This question was addressed by investigating the SOTs generated by the 3D TI HgTe in an adjacent ferromagnet (Permalloy) by using the ferromagnetic resonance technique (SOT-FMR). In the first part of the dissertation, the reader was introduced to the mathematical description of the SOTs of a hybrid system consisting of a topological insulator (TI) and a ferromagnet (FM). Furthermore, the sample preparation and the measurement setup for the SOT-FMR measurements were discussed. Our SOT-FMR measurements showed that at low temperatures (T = 4.2 K) the out-of-plane component of the torque is dominant. At room temperature, both in-plane and out-of-plane components of the torque could be observed. From the symmetry of the mixing voltage (Figs. 3.14 and 3.15) we could conclude that the 3D TI HgTe may be efficient for the generation of spin torques in the permalloy [1]. The investigations reported here showed that the SOT efficiencies generated by the 3D TI HgTe are comparable with other existent topological insulators (see Fig. 3.17). We also discussed in detail the parasitic effects (such as thermovoltages) that can contribute to the correct interpretation of the spin torque efficiencies. Although the results reported here provide several indications that the 3D TI HgTe might be efficient in exerting spin-torques in adjacent ferromagnets [2], the reader was repeatedly made aware that parasitic effects might contaminate the correct writing and reading of the information in the ferromagnet. These effects should be taken into consideration when interpreting results in the published literature claiming high spin-orbit torque efficiencies [2–4]. The drawbacks of the SOT-FMR measurement method led to a further development of our measurement concept, in which the ferromagnet on top of the 3D TI HgTe was replaced by a spin-valve structure. In contrast with our measurements, in this measurement setup, the current flowing through the HgTe is known and changes in the spin-valve resistance can be read via the GMR effect. Moreover, the SOT-FMR experiments required the application of an in-plane magnetic field up to 300 mT to define the magnetization direction in the ferromagnet. Motivated by this fact, we investigated the influence of an in-plane magnetic field in the magnetoresistance of the 3D TI HgTe. The surprising results of these measurements are described in the second part of the dissertation. Although the TI studied here is non-magnetic, its transversal MR (Rxy) showed an oscillating behavior that depended on the angle between the in-plane magnetic field and the electrical current. This effect is a typical property of ferromagnetic materials and is called planar Hall effect (PHE) [5, 6]. Moreover, it was also shown that the PHE amplitude (Rxy) and the longitudinal resistance (Rxx) oscillate as a function of the in-plane magnetic field amplitude for a wide range of carrier densities of the topological insulator. The PHE was already described in another TI material (Bi2−xSbxTe3) [7]. The authors suggested as a possible mechanism the scattering of the electron off impurities that are polarized by an in-plane magnetic field. We critically discussed this and other theoretical proposed mechanisms existent in the literature [8, 9]. In this thesis, we attempted to explain the origin of the PHE in the 3D TI HgTe by anisotropies in the band structure of this material. The k.p calculations based on 6-orbitals were able to demonstrate that an interplay between Rashba, Dresselhaus, and in-plane magnetic field deforms the Fermi contours of the camel back band of the 3D TI HgTe, which could lead to anisotropies in its conductivity. However, the magnetic fields needed to experimentally observe this effect are as high as 40 T, i.e., one order of magnitude higher than reported in our experiments. Additionally, calculations of the DoS to assess if there is a difference in the states for Bin parallel and Bin perpendicular to the current were, so far, inconclusive. Moreover, the complicated dependence of Rashba in the p-conducting regime of HgTe [10] makes it not straightforward the inclusion of this term in the band structure calculations. Despite the extensive efforts to understand the origin of the galvanomagnetic effects in the 3D TI HgTe, we could not determine a clear mechanism for the origin of the PHE and the MR oscillations studied in this thesis. However, our work clarifies and excludes a few mechanisms reported in the literature as the origin of these effects in the 3D TI HgTe. The major challenge, which still needs to be overcome, is to find a model that simultaneously explains the PHE, the gate dependence, and the oscillations in the magnetoresistance of the 3D TI HgTe as a function of the in-plane magnetic field. To conclude, the author would like to express her hope to have brought the reader closer to the complexity of the questions addressed in this thesis and to have initiated them into the art of properly conducting electrical transport measurements on topological insulators with in-plane magnetic fields. KW - Electrical transport KW - Topologischer Isolator KW - Spintronics KW - Topological Insulators KW - Spin-Orbit-Torque Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-247971 ER - TY - JOUR A1 - Fischhaber, Natalie A1 - Faber, Jessica A1 - Bakirci, Ezgi A1 - Dalton, Paul D. A1 - Budday, Silvia A1 - Villmann, Carmen A1 - Schaefer, Natascha T1 - Spinal Cord Neuronal Network Formation in a 3D Printed Reinforced Matrix-A Model System to Study Disease Mechanisms JF - Advanced Healthcare Materials N2 - 3D cell cultures allow a better mimicry of the biological and mechanical environment of cells in vivo compared to 2D cultures. However, 3D cell cultures have been challenging for ultrasoft tissues such as the brain. The present study uses a microfiber reinforcement approach combining mouse primary spinal cord neurons in Matrigel with melt electrowritten (MEW) frames. Within these 3D constructs, neuronal network development is followed for 21 days in vitro. To evaluate neuronal development in 3D constructs, the maturation of inhibitory glycinergic synapses is analyzed using protein expression, the complex mechanical properties by assessing nonlinearity, conditioning, and stress relaxation, and calcium imaging as readouts. Following adaptation to the 3D matrix-frame, mature inhibitory synapse formation is faster than in 2D demonstrated by a steep increase in glycine receptor expression between days 3 and 10. The 3D expression pattern of marker proteins at the inhibitory synapse and the mechanical properties resemble the situation in native spinal cord tissue. Moreover, 3D spinal cord neuronal networks exhibit intensive neuronal activity after 14 days in culture. The spinal cord cell culture model using ultrasoft matrix reinforced by MEW fibers provides a promising tool to study and understand biomechanical mechanisms in health and disease. KW - 3D cell cultures KW - spinal cord neurons KW - neuronal networks KW - mouse Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-256353 VL - 10 IS - 19 ER - TY - JOUR A1 - Bunzmann, Nikolai A1 - Krugmann, Benjamin A1 - Weissenseel, Sebastian A1 - Kudriashova, Liudmila A1 - Ivaniuk, Khrystyna A1 - Stakhira, Pavlo A1 - Cherpak, Vladyslav A1 - Chapran, Marian A1 - Grybauskaite‐Kaminskiene, Gintare A1 - Grazulevicius, Juozas Vidas A1 - Dyakonov, Vladimir A1 - Sperlich, Andreas T1 - Spin‐ and Voltage‐Dependent Emission from Intra‐ and Intermolecular TADF OLEDs JF - Advanced Electronic Materials N2 - Organic light emitting diodes (OLEDs) based on thermally activated delayed fluorescence (TADF) utilize molecular systems with a small energy splitting between singlet and triplet states. This can either be realized in intramolecular charge transfer states of molecules with near‐orthogonal donor and acceptor moieties or in intermolecular exciplex states formed between a suitable combination of individual donor and acceptor materials. Here, 4,4′‐(9H,9′H‐[3,3′‐bicarbazole]‐9,9′‐diyl)bis(3‐(trifluoromethyl) benzonitrile) (pCNBCzoCF\(_{3}\)) is investigated, which shows intramolecular TADF but can also form exciplex states in combination with 4,4′,4′′‐tris[phenyl(m‐tolyl)amino]triphenylamine (m‐MTDATA). Orange emitting exciplex‐based OLEDs additionally generate a sky‐blue emission from the intramolecular emitter with an intensity that can be voltage‐controlled. Electroluminescence detected magnetic resonance (ELDMR) is applied to study the thermally activated spin‐dependent triplet to singlet up‐conversion in operating devices. Thereby, intermediate excited states involved in OLED operation can be investigated and the corresponding activation energy for both, intra‐ and intermolecular based TADF can be derived. Furthermore, a lower estimate is given for the extent of the triplet wavefunction to be ≥ 1.2 nm. Photoluminescence detected magnetic resonance (PLDMR) reveals the population of molecular triplets in optically excited thin films. Overall, the findings allow to draw a comprehensive picture of the spin‐dependent emission from intra‐ and intermolecular TADF OLEDs. KW - color tuning KW - exciplexes KW - organic light emitting diodes KW - spin KW - triplets Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224434 VL - 7 IS - 3 ER - TY - JOUR A1 - Nguemeni, Carine A1 - Hiew, Shawn A1 - Kögler, Stefanie A1 - Homola, György A. A1 - Volkmann, Jens A1 - Zeller, Daniel T1 - Split-belt training but not cerebellar anodal tDCS improves stability control and reduces risk of fall in patients with multiple sclerosis JF - Brain Sciences N2 - The objective of this study was to examine the therapeutic potential of multiple sessions of training on a split-belt treadmill (SBT) combined with cerebellar anodal transcranial direct current stimulation (tDCS) on gait and balance in People with Multiple Sclerosis (PwMS). Twenty-two PwMS received six sessions of anodal (PwMS\(_{real}\), n = 12) or sham (PwMS\(_{sham}\), n = 10) tDCS to the cerebellum prior to performing the locomotor adaptation task on the SBT. To evaluate the effect of the intervention, functional gait assessment (FGA) scores and distance walked in 2 min (2MWT) were measured at the baseline (T0), day 6 (T5), and at the 4-week follow up (T6). Locomotor performance and changes of motor outcomes were similar in PwMS\(_{real}\) and PwMS\(_{sham}\) independently from tDCS mode applied to the cerebellum (anodal vs. sham, on FGA, p = 0.23; and 2MWT, p = 0.49). When the data were pooled across the groups to investigate the effects of multiple sessions of SBT training alone, significant improvement of gait and balance was found on T5 and T6, respectively, relative to baseline (FGA, p < 0.001 for both time points). The FGA change at T6 was significantly higher than at T5 (p = 0.01) underlining a long-lasting improvement. An improvement of the distance walked during the 2MWT was also observed on T5 and T6 relative to T0 (p = 0.002). Multiple sessions of SBT training resulted in a lasting improvement of gait stability and endurance, thus potentially reducing the risk of fall as measured by FGA and 2MWT. Application of cerebellar tDCS during SBT walking had no additional effect on locomotor outcomes. KW - multiple sclerosis KW - split-belt treadmill KW - cerebellar tDCS KW - gait KW - balance KW - risk of fall Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-252179 SN - 2076-3425 VL - 12 IS - 1 ER - TY - JOUR A1 - Petritsch, Bernhard A1 - Pannbecker, Pauline A1 - Weng, Andreas M. A1 - Grunz, Jan-Peter A1 - Veldhoen, Simon A1 - Bley, Thorsten A. A1 - Kosmala, Aleksander T1 - Split-filter dual-energy CT pulmonary angiography for the diagnosis of acute pulmonary embolism: a study on image quality and radiation dose JF - Quantitative Imaging in Medicine and Surgery N2 - Background: Computed tomography (CT) pulmonary angiography is the diagnostic reference standard in suspected pulmonary embolism (PE). Favorable results for dual-energy CT (DECT) images have been reported for this condition. Nowadays, dual-energy data acquisition is feasible with different technical options, including a single-source split-filter approach. Therefore, the aim of this retrospective study was to investigate image quality and radiation dose of thoracic split-filter DECT in comparison to conventional single-energy CT in patients with suspected PE. Methods: A total of 110 CT pulmonary angiographies were accomplished either as standard single-energy CT with automatic tube voltage selection (ATVS) (n=58), or as split-filter DECT (n=52). Objective [pulmonary artery CT attenuation, signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR)] and subjective image quality [four-point Likert scale; three readers (R)] were compared among the two study groups. Size-specific dose estimates (SSDE), dose-length-product (DLP) and volume CT dose index (CTDIvol) were assessed for radiation dose analysis. Results: Split-filter DECT images yielded 67.7% higher SNR (27.0 vs. 16.1; P<0.001) and 61.9% higher CNR (22.5 vs. 13.9; P<0.001) over conventional single-energy images, whereas CT attenuation was significantly lower (344.5 vs. 428.2 HU; P=0.013). Subjective image quality was rated good or excellent in 93.0%/98.3%/77.6% (R1/R2/R3) of the single-energy CT scans, and 84.6%/82.7%/80.8% (R1/R2/R3) of the split-filter DECT scans. SSDE, DLP and CTDIvol were significantly lower for conventional single-energy CT compared to split-filter DECT (all P<0.05), which was associated with 26.7% higher SSDE. Conclusions: In the diagnostic workup of acute PE, the split-filter allows for dual-energy data acquisition from single-source single-layer CT scanners. The existing opportunity to assess pulmonary “perfusion” based on analysis of iodine distribution maps is associated with higher radiation dose in terms of increased SSDE than conventional single-energy CT with ATVS. Moreover, a proportion of up to 3.8% non-diagnostic examinations in the current reference standard test for PE is not negligible. KW - dual-energy KW - CT-angiography KW - vascular KW - pulmonary arteries KW - embolism/thrombosis Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-231456 VL - 11 IS - 5 ER - TY - JOUR A1 - Voelker, Johannes A1 - Voelker, Christine A1 - Engert, Jonas A1 - Goemann, Nikolas A1 - Hagen, Rudolf A1 - Rak, Kristen T1 - Spontaneous Calcium Oscillations through Differentiation: A Calcium Imaging Analysis of Rat Cochlear Nucleus Neural Stem Cells JF - Cells N2 - Causal therapies for the auditory-pathway and inner-ear diseases are still not yet available for clinical application. Regenerative medicine approaches are discussed and examined as possible therapy options. Neural stem cells could play a role in the regeneration of the auditory pathway. In recent years, neural stem and progenitor cells have been identified in the cochlear nucleus, the second nucleus of the auditory pathway. The current investigation aimed to analyze cell maturation concerning cellular calcium activity. Cochlear nuclei from PND9 CD rats were microscopically dissected and propagated as neurospheres in free-floating cultures in stem-cell medium (Neurobasal, B27, GlutaMAX, EGF, bFGF). After 30 days, the dissociation and plating of these cells took place under withdrawal of the growth factors and the addition of retinoic acid, which induces neural cell differentiation. Calcium imaging analysis with BAPTA-1/Oregon Green was carried out at different times during the differentiation phase. In addition, the influence of different voltage-dependent calcium channels was analyzed through the targeted application of inhibitors of the L-, N-, R- and T-type calcium channels. For this purpose, comparative examinations were performed on CN NSCs, and primary CN neurons. As the cells differentiated, a significant increase in spontaneous neuronal calcium activity was demonstrated. In the differentiation stage, specific frequencies of the spontaneous calcium oscillations were measured in different regions of the individual cells. Initially, the highest frequency of spontaneous calcium oscillations was ascertainable in the maturing somata. Over time, these were overtaken by calcium oscillations in the axons and dendrites. Additionally, in the area of the growth cones, an increasing activity was determined. By inhibiting voltage-dependent calcium channels, their expression and function in the differentiation process were confirmed. A comparable pattern of maturation of these channels was found in CN NSCs and primary CN neurons. The present results show that neural stem cells of the rat cochlear nucleus differentiated not only morphologically but also functionally. Spontaneous calcium activities are of great relevance in terms of neurogenesis and integration into existing neuronal structures. These functional aspects of neurogenesis within the auditory pathway could serve as future targets for the exogenous control of neuronal regeneration. KW - neurogenesis KW - neural stem cells KW - neuronal oscillations KW - neuronal maturation KW - auditory pathway KW - regenerative capacity Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-248482 SN - 2073-4409 VL - 10 IS - 10 ER - TY - THES A1 - Auer, Jonas T1 - Sportverletzungen durch Indoor-Bouldern T1 - Sports injuries caused by indoor bouldering N2 - Bouldern ist eine noch relativ junge Trendsportart aus der Familie des Klettersports, die in den letzten Jahren starken Zuwachs gewonnen hat. Es gibt bisher wenig Literatur zu Verletzungen durch Bouldern generell und insbesondere zu Indoor-Bouldern. Das Ziel dieser Studie war Daten zu Verletzungshäufigkeit, -schwere und -lokalisation durch Indoor-Bouldern zu erheben sowie den Einfluss von potenziell das Verletzungsrisiko modulierenden Faktoren zu untersuchen. Mittels eines Online-Fragebogens wurden Boulderer retrospektiv zu anthropometrischen Daten, potenziell risikomodulierendem Verhalten sowie Verletzungen in der Vergangenheit befragt. Anschließend wurde monatlich prospektiv über ein Jahr das Auftreten neuer Verletzungen erhoben. Zusätzlich wurden Patienten der Notaufnahme und Klettersprechstunde mit Verletzungen durch Indoor-Bouldern zu Diagnose, Unfallhergang sowie potenziell risikomodulierendem Verhalten befragt. Knapp 60% aller Probanden hatten in der Vergangenheit bereits mindestens eine Verletzung erlitten, 44% eine Verletzung, die eine ärztliche Konsultation erforderte. Während der prospektiv beobachteten 12 Monate trat bei 44% der Probanden mindestens eine Verletzung durch Indoor-Bouldern auf, davon 78% im UIAA Schweregrad 1, 19% im Schweregrad 2 und 3% im Schweregrad 3. Die obere Extremität war von 63% aller Verletzungen betroffen, die untere Extremität von 23%. Verletzungen der unteren Extremität waren häufiger im UIAA Schweregrad ≥ 2 klassifiziert (p = 0,007). Probanden, die Bouldern erst seit maximal einem Jahr betrieben, hatten ein erhöhtes Risiko für Verletzungen der unteren Extremität (p = 0,027). Keine der untersuchten protektiven Maßnahmen inklusive Spotten konnten das Verletzungsrisiko senken. Das Nutzen von Kletterschuhen mit starkem Downturn und Vorspann erhöhte das Risiko für Verletzungen im UIAA Schweregrad ≥ 2 (p = 0,003). Verletzungen der Patienten aus Notaufnahme und Klettersprechstunde waren in 5,1% im UIAA Schweregrad 1, 48,7% im Schweregrad 2 und 46,2% im Schweregrad 3. Verletzungen der unteren Extremität waren häufiger im Schweregrad 3 (p = 0,015). Verletzungen durch Indoor Bouldern sind häufig, der Großteil erfordert jedoch keine medizinische Behandlung. Verletzungen der unteren Extremität sind gehäuft in einem höheren Schweregrad. Die untersuchten Präventivmaßnahmen senkten das Verletzungsrisiko nicht. Einsteigerkurse sollten insbesondere sicheres Abspringen und Stürzen trainieren. Das Nutzen eines weiteren Paares Kletterschuhe ohne starken Downturn und Vorspann für das Training scheint ratsam. Zukünftige Forschung sollte sich der Verletzungsprävention insbesondere durch Stürzen und Abspringen widmen. N2 - Bouldering is a relatively young trend sport from the family of climbing sports, which has become very popular in recent years. There is little literature on injuries caused by bouldering in general and indoor bouldering in particular. The aim of this study was to collect data on injury frequency, severity, and localization of injuries caused by indoor bouldering and to investigate the influence of risk modulating factors. Using an online questionnaire, boulderers were retrospectively surveyed about anthropometric data, potential risk modulating behavior, and past injuries. The incidence of new injuries was assessed on a monthly basis over one year. In addition, patients in the emergency department and climbing consultations with injuries caused by indoor bouldering were asked about diagnosis, accident history, and potential risk-modulating behavior. Nearly 60% of all subjects had at least one previous injury, 44% an injury that required medical consultation. During the prospectively observed 12 months, 44% of subjects experienced at least one indoor bouldering injury, of which 78% were UIAA severity 1, 19% severity 2, and 3% severity 3. The upper extremity was affected by 63% of all injuries, and the lower extremity by 23%. Injuries of the lower extremity were more often classified UIAA severity ≥ 2 (p = 0.007). Subjects who had only been bouldering for one year or less had an increased risk for lower extremity injuries (p = 0.027). None of the investigated protective measures including spotting were able to reduce the risk of injury. The use of climbing shoes with strong downturn increased the risk of injuries ≥ UIAA severity 2 (p = 0.003). 5,1% of injuries of patients from the emergency department and climbing consultations were UIAA severity 1, 48.7% severity 2, and 46.2% severity 3. Injuries to the lower extremity were more often severity 3 (p = 0.015). Injuries from indoor bouldering are common, but the majority do not require medical treatment. Injuries of the lower extremity are of a higher severity. The preventive measures investigated did not reduce the risk of injury. Beginners' courses should especially train safe jumping off and fall training. The use of a second pair of climbing shoes without strong downturn for training seems advisable. Future research should investigate methods to prevent injury, especially from falls and jumps. KW - Sportverletzung KW - Sporttraumatologie KW - Bouldern KW - Sporthalle KW - Indoor Bouldering Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-242329 ER - TY - THES A1 - Schummer, Bernhard T1 - Stabilisierung von CdS Nanopartikeln mittels Pluronic P123 T1 - Stabilization of CdS nanoparticles using Pluronic P123 N2 - Ziel dieser Arbeit war die Stabilisierung von Cadmiumsulfid CdS mit Pluronic P123, einem Polymer. CdS ist ein Halbleiter, der zum Beispiel in der Photonik und bei optischen Anwendungen eingesetzt wird und ist deshalb äußerst interessant, da seine Bandlücke als Nanopartikel verschiebbar ist. Für die Photovoltaik ist es ein attraktives Material, da es im sichtbaren Licht absorbiert und durch die Bandlückenverschiebung effektiver absorbieren kann. Dies ist unter dem Namen Quantum Size Effekt bekannt. Als Feststoff ist CdS für einen solchen Anwendungsbereich weniger geeignet, zumal der Effekt der Bandlückenverschiebung dort nicht auftritt. Wissenschaftler bemühen sich deshalb CdS als Nanopartikeln zu stabilisieren, weil CdS in wässrigen Lösungen ein stark aggregierendes System, also stark hydrophob ist. Es wurden zwei Kriterien für die erfolgreiche Stabilisierung von CdS festgelegt. Zum einen muss das Cds homogen im Medium verteilt sein und darf nicht agglomerieren. Zum anderen, müssen die CdS Nanopartikel kleiner als 100 A sein. In meiner Arbeit habe ich solche Partikel hergestellt und stabilisiert, d.h. verhindert, dass die Partikel weiterwachsen und gleichzeitig ihre Bandlücke verschoben wird. Die Herausforderung liegt nicht in der Herstellung, aber in der Lösung von CdS im Trägerstoff, da CdS in den meisten Flüssigkeiten nicht löslich ist und ausfällt. Die Stabilisierung in wässrigen Lösungen wurde das erste Mal durch Herrn Prof. Dr. Rempel mit Ethylendiamintetraessigsäure EDTA erfolgreich durchgeführt. Mit EDTA können jedoch nur sehr kleine Konzentrationen stabilisiert werden. Zudem können Parameter wie Größe und Geschwindigkeit der Reaktion beim Stabilisieren der CdS-Nanopartikel nicht angepasst oder beeinflusst werden. Dieses Problem ist dem, vieler medizinischer Wirkstoffe sehr ähnlich, die in hohen Konzentrationen verabreicht werden sollen, aber nicht oder nur schwer in Wasser löslich sind (Bsp. Kurkumin). Ein vielversprechender Lösungsweg ist dort, die Wirkstoffe in große Trägerpartikel (sog. Mizellen) einzuschleusen, die ihrerseits gut löslich sind. In meiner Arbeit habe ich genau diesen Ansatz für CdS verfolgt. Als Trägerpartikel/Mizelle wurde das bekannte Copolymer Pluronic P123 verwendet. Aus dieser Pluronic Produktreihe wird P123 gewählt, da es die größte Masse bei gleichzeitig höchstem Anteil von Polypropylenoxid PPO im Vergleich zur Gesamtkettenlänge hat. P123 ist ein ternäres Polyether oder Dreiblockkopolymer und wird von BASAF industriell produziert. Es besteht aus drei Böcken, dem mittlere Block Polypropylenoxid PPO und den beiden äußeren Blöcken Polyethylenoxid PEO. Der Buchstabe P steht für pastös, die ersten beiden Ziffern in P123 mit 300 multipliziert ergeben das molare Gewicht und die letzte Ziffer mit 10 multipliziert entspricht dem prozentualen Gewichtsanteil PEO. Die Bildung von Mizellen aus den P123 Molekülen kann bewusst über geringe Temperaturänderungen gesteuert werden. Bei ungefähr Raumtemperatur liegen Mizellen vor, die sich bei höheren Temperaturen von sphärischen in wurmartige Mizellen umwandeln. Oberhalb einer Konzentration von 30 Gewichtsprozent wtp bilden die Mizellen außerdem einen Flüssigkristall. Ich habe in meiner Arbeit zunächst P123 mit Hilfe von Röntgenstreuung untersucht. Anders als andere Methoden gibt Röntgenstreuung direkten Aufschluss über die Morphologie der Stoffe. Röntgenstreuung kann die Mischung von P123 mit CdS abbilden und lässt darauf schließen, ob das Ziel erreicht werden konnte, stabile CdS Nanopartikel in P123 zu binden. Für die Stabilisierung der Nanopartikel ist es zunächst notwendig die richtigen Temperaturen für die Ausgangslösungen und gemischten Lösungen zu finden. Dazu muss P123 viel genauer untersucht werden, als der momentane Kenntnisstand in der Literatur. Zu diesem Zweck als auch für die Analyse des stabilisierten CdS habe ich ein neues Instrument am LRM entwickelt, sowie eine temperierbare Probenumgebung für Flüssigkeiten fürs Vakuum, um morphologische Eigenschaften aus Streuamplituden und -winkeln zu entschlüsseln. Diese Röntgenstreuanlage wurde konzipiert und gebaut, um auch im Labor P123 in kleinen Konzentrationen messen zu können. Röntgenkleinwinkelstreuung eignet sich besonders als Messmethode, da die Probe mit einer hohen statistischen Relevanz in Flüssigkeit und in verschiedenen Konzentrationen analysiert werden kann. Für die Konzentrationen 5, 10 und 30 wtp konnte das temperaturabhängige Verhalten von P123 präzise mit Röntgenkleinwinkelstreuung SAXS gemessen und dargestellt werden. Für 5 wtp konnten die Größen der Unimere und Mizellen bestimmt werden. Trotz der nicht vorhandenen Absolutkalibration für diese Konzentration konnten dank des neu eingeführten Parameters kappa eine Dehydrierung der Mizellen mit steigender Temperatur abgeschätzt, sowie eine Hysterese zwischen dem Heizen und Abkühlen festgestellt werden. Für die Konzentration von 10 wtp wurden kleinere Temperaturschritte gewählt und die Messungen zusätzlich absolut kalibriert. Es wurden die Größen und Streulängendichten SLD der Unimere und Mizellen präzise bestimmt und ein vollständiges Form-Phasendiagramm erstellt. Auch für diese Konzentration konnte eine Hysterese eindeutig an der Größe, SLD und am Parameter kappa gezeigt werden, sowie eine Dehydrierung des Mizellenkerns. Dies beweist, dass der Parameter kappa geeignet ist, um bei nicht absolut kalibrierten Messungen, Aussagen über die Hydrierung und Hysterese komplexer Kern-Hülle Modelle zu machen. Für die Konzentration von 30 wtp konnte zwischen 23°C und 35°C eine FCC Struktur nachgewiesen werden. Dabei vergrößert sich die Gitterkonstante der FCC Struktur von 260 A auf 289 A in Abhängigkeit der Temperatur. Durch das Mischen zweier Lösungen, zum einen CdCl2 und 30 wtp P123 und zum anderen Na2S und 30 wtp P123, konnte CdS erfolgreich stabilisiert werden. Mit einer Kamera wurde die Gelbfärbung der Lösung, und somit die Bildung des CdS, in Abhängigkeit der Zeit untersucht. Es konnte festgestellt werden, dass das Bilden der CdS Nanopartikel je nach Konzentration und Temperierprogramm zwischen 30 und 300 Sekunden dauert und einer logistischen Wachstumsfunktion folgt. Höhere Konzentrationen CdS bewirken einen schnelleren Anstieg der Wachstumsfunktion. Mittels UV-Vis Spektroskopie konnte gezeigt werden, dass die Bandlücke von CdS mit steigender Konzentration konstant bei 2,52 eV bleibt. Eine solche Verschiebung der Bandlücke von ungefähr 0,05 eV im Vergleich zum Festkörper, deutet auf einen CdS Partikeldurchmesser von 80A hin. Mit SAXS konnte gezeigt werden, dass sich die flüssigkristalline Struktur des P123 bei zwei verschiedenen Konzentrationen CdS, von 0,005 und 0,1 M, nicht ändert. Das CdS wird zwischen den Mizellen, also durch die Bildung des Flüssigkristalls, und im Kern der Mizelle aufgrund seiner Hydrophobizität stabilisiert. Die Anfangs definierten Kriterien für eine erfolgreiche Stabilisierung wurden erfüllt. P123 ist ein hervorragend geeignetes Polymer, um hydrophobes CdS, sowohl durch die Bildung eines Flüssigkristalls, als auch im Kern der Mizelle zu stabilisieren. N2 - Aim of this work was the stabilization of cadmium sulphide CdS with Pluronic P123, a polymer. CdS is a semiconductor, which is used for photonics and for optical applications. It is highly interesting since its band gap can be shifted if it has the size of a nanoparticle. Due to this band gap shift and the fact that CdS is absorbing in the visible range, it is highly attractive material. This is known as the quantum size effect. As a solid, CdS is less interesting in this area because of the non-existing band gap shift. Scientists endeavor to stabilize CdS as a nanoparticle, since CdS is hydrophobic in aqueous solutions and thus a strongly aggregating system. Two criteria of a successful stabilization process were set. Firstly, CdS has to be homogeneously distributed in the solution and must not aggregate. Secondly, the nanoparticles must be smaller then 100A. During my thesis I produced such particles and stabilized them homogeneously in an aqueous solution, which meant to hinder the further growth of those nanopaticles while shifting their band gap. The challenge is not the production, but the encapsulation of CdS in a carrier, since CdS is not soluble in most solutions and precipitates. Such a stabilization in an aqueous solution was succeeded by Prof. Dr. Rempel with ethylenediaminetetraacetic acid EDTA as a stabilizer for the first time. But with EDTA only very small concentrations of CdS can be stabilized. Moreover, properties like size and reaction speed during the stabilization of the CdS nanoparticles cannot be adjusted or influenced. This problem is also known from medical agents, which should be administered in high doses, but are not or barely soluble in water like Curcumin. A promising solution is to encapsulate these medical agents in big carrier, so-called micelles, which themselves are soluble in water. In my thesis I followed this approach for CdS. As a carrier/micelle the well known copolymer Pluronic P123 was used. Compared to other Pluronics, P123 was chosen since it offers the biggest mass with the highest proportion of polypropylene oxide PPO compared to the total chain length. P123 is a ternary polyether and is produced industrially by BASF. It consists of three blocks, where the middle one is PPO and the outer blocks are polyethylene oxide PEO. The letter P stands for pasty while the first two numbers in P123 multiplied with 300 equal the molar mass and the last number multiplied with 10 equals the mass proportion of PEO. The formation of micelles can be triggered on purpose with a change in temperature. Micelles are present at approximately room temperature \cite{Manet2011}, which transform from spherical to worm-like micelles at higher temperatures. Above a certain concentration of 30 weight percent, the micelles will form a liquid crystal. In my work I first examined P123 with X-ray scattering. Unlike other methods, X-ray scattering gives direct information about the morphology of the substances. X-ray scattering can also be used to study the mixture of P123 with CdS and indicates, whether the goal of encapsulate stable CdS nanoparticles in P123 could be achieved. To stabilize the nanoparticles, it is first necessary to find the right temperatures for both the staring point and the end point of the stabilization process. For this purpose, P123 has to be examined much more precisely than the current state of knowledge in the literature. For this purpose as well as for the analysis of the stabilized CdS, I have developed a new instrument at the chair of X-ray microscopy, as well as a temperature controllable sample holder for liquids in vacuum to decipher morphological properties from scattering amplitudes and angles. This X-ray scattering system was designed and built in order to be able to measure P123 in small concentrations in the laboratory. Small-angle X-ray scattering is particularly suitable as a measurement method, since the sample can be analyzed with a high statistical relevance in liquid and in various concentrations. For the concentrations 5, 10 and 30 wtp, the temperature-dependent behavior of P123 could be precisely measured and presented using small-angle X-ray scattering. The sizes of the unimers and micelles could be determined for 5 wtp without an absolute calibration. With a newly introduced parameter kappa, the dehydration of the micelles with increasing temperature could be estimated, despite the lack of the absolute calibration for this concentration, as well as a hysteresis between heating and cooling. Smaller temperature steps were chosen for the concentration of 10 wtp, furthermore the measurements were also absolutely calibrated. The sizes and scattering length densities SLDs of the unimers and micelles were precisely determined and a complete shape-phase diagram was created. Also for this concentration, a hysteresis was clearly shown in terms of size, SLD and the parameter kappa, as well as dehydration of the micellar nucleus. This proves that the parameter kappa is suitable for making statements about the hydrogenation and hysteresis of complex core-shell models in the case of measurements that are not absolutely calibrated. For the concentration of 30 wtp an FCC structure could be detected between 23°C and 35°C. The lattice constant of the FCC structure increases from 260 A to 289 A depending on the temperature. By mixing two solutions, CdCl2 in a 30 wtp P123 and Na2S in 30 wtp P123, CdS could be successfully stabilized. The yellow coloration of the solution, and thus the formation of CdS, was examined as a function of time with the help of a camera. It was found that the formation of the CdS nanoparticles takes between 30 and 300 seconds, depending on the concentration and temperature protocol and follows a logistical growth function. Higher concentrations of CdS cause a more rapid increase in growth function. Using UV-Vis spectroscopy it could be shown that the band gap of CdS remains constant at 2.52 eV with increasing concentration. The shift in the band gap of approximately 0.05 eV compared to the solid state, indicates a CdS particle diameter of 80 A. With SAXS it could be shown that the liquid-crystalline structure of the P123 does not change at two different concentrations of CdS, of 0.005 and 0.1 M. The CdS is stabilized between the micelles due to the formation of the liquid crystal and in the core of the micelles due to their hydrophobicity. The initially defined criteria for successful stabilization were met. P123 is an excellent polymer to stabilize hydrophobic CdS nanoparticles, both through the formation of a liquid crystal and in the core of the micelles. KW - Röntgen-Kleinwinkelstreuung KW - Polymere KW - Cadmiumsulfid KW - Röntgen-Weitwinkelstreuung KW - Nanopartikel KW - Stabilisierung Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-238443 ER - TY - JOUR A1 - Schneider, Leon N. A1 - Tanzer Krauel, Eva-Maria A1 - Deutsch, Carl A1 - Urbahns, Klaus A1 - Bischof, Tobias A1 - Maibom, Kristina A. M. A1 - Landmann, Johannes A1 - Keppner, Fabian A1 - Kerpen, Christoph A1 - Hailmann, Michael A1 - Zapf, Ludwig A1 - Knuplez, Tanja A1 - Bertermann, Rüdiger A1 - Ignat'ev, Nikolai V. A1 - Finze, Maik T1 - Stable and Storable N(CF\(_{3}\))\(_{2}\) Transfer Reagents JF - Chemistry—A European Journal N2 - Fluorinated groups are essential for drug design, agrochemicals, and materials science. The bis(trifluoromethyl)amino group is an example of a stable group that has a high potential. While the number of molecules containing perfluoroalkyl, perfluoroalkoxy, and other fluorinated groups is steadily increasing, examples with the N(CF\(_{3}\))\(_{2}\) group are rare. One reason is that transfer reagents are scarce and metal-based storable reagents are unknown. Herein, a set of Cu\(^{I}\) and Ag\(^{I}\) bis(trifluoromethyl)amido complexes stabilized by N- and P-donor ligands with unprecedented stability are presented. The complexes are stable solids that can even be manipulated in air for a short time. They are bis(trifluoromethyl)amination reagents as shown by nucleophilic substitution and Sandmeyer reactions. In addition to a series of benzylbis(trifluoromethyl)amines, 2-bis(trifluoromethyl)amino acetate was obtained, which, upon hydrolysis, gives the fluorinated amino acid N,N-bis(trifluoromethyl)glycine. KW - silver KW - amination KW - copper KW - fluorinated ligands KW - N ligands Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-256890 VL - 27 IS - 42 ER - TY - JOUR A1 - Liang, Chunguang A1 - Rios-Miguel, Ana B. A1 - Jarick, Marcel A1 - Neurgaonkar, Priya A1 - Girard, Myriam A1 - François, Patrice A1 - Schrenzel, Jacques A1 - Ibrahim, Eslam S. A1 - Ohlsen, Knut A1 - Dandekar, Thomas T1 - Staphylococcus aureus transcriptome data and metabolic modelling investigate the interplay of Ser/Thr kinase PknB, its phosphatase Stp, the glmR/yvcK regulon and the cdaA operon for metabolic adaptation JF - Microorganisms N2 - Serine/threonine kinase PknB and its corresponding phosphatase Stp are important regulators of many cell functions in the pathogen S. aureus. Genome-scale gene expression data of S. aureus strain NewHG (sigB\(^+\)) elucidated their effect on physiological functions. Moreover, metabolic modelling from these data inferred metabolic adaptations. We compared wild-type to deletion strains lacking pknB, stp or both. Ser/Thr phosphorylation of target proteins by PknB switched amino acid catabolism off and gluconeogenesis on to provide the cell with sufficient components. We revealed a significant impact of PknB and Stp on peptidoglycan, nucleotide and aromatic amino acid synthesis, as well as catabolism involving aspartate transaminase. Moreover, pyrimidine synthesis was dramatically impaired by stp deletion but only slightly by functional loss of PknB. In double knockouts, higher activity concerned genes involved in peptidoglycan, purine and aromatic amino acid synthesis from glucose but lower activity of pyrimidine synthesis from glucose compared to the wild type. A second transcriptome dataset from S. aureus NCTC 8325 (sigB\(^−\)) validated the predictions. For this metabolic adaptation, PknB was found to interact with CdaA and the yvcK/glmR regulon. The involved GlmR structure and the GlmS riboswitch were modelled. Furthermore, PknB phosphorylation lowered the expression of many virulence factors, and the study shed light on S. aureus infection processes. KW - metabolism KW - flux balance analysis KW - phosphorylation KW - regulation KW - riboswitch KW - PknB KW - Stp KW - yvcK/glmR operon Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-248459 SN - 2076-2607 VL - 9 IS - 10 ER - TY - JOUR A1 - Krones, David A1 - Rühling, Marcel A1 - Becker, Katrin Anne A1 - Kunz, Tobias C. A1 - Sehl, Carolin A1 - Paprotka, Kerstin A1 - Gulbins, Erich A1 - Fraunholz, Martin T1 - Staphylococcus aureus α-Toxin Induces Acid Sphingomyelinase Release From a Human Endothelial Cell Line JF - Frontiers in Microbiology N2 - Staphylococcus aureus (S. aureus) is well known to express a plethora of toxins of which the pore-forming hemolysin A (α-toxin) is the best-studied cytolysin. Pore-forming toxins (PFT) permeabilize host membranes during infection thereby causing concentration-dependent effects in host cell membranes ranging from disordered ion fluxes to cytolysis. Host cells possess defense mechanisms against PFT attack, resulting in endocytosis of the breached membrane area and delivery of repair vesicles to the insulted plasma membrane as well as a concurrent release of membrane repair enzymes. Since PFTs from several pathogens have been shown to recruit membrane repair components, we here investigated whether staphylococcal α-toxin is able to induce these mechanisms in endothelial cells. We show that S. aureus α-toxin induced increase in cytosolic Ca2+ in endothelial cells, which was accompanied by p38 MAPK phosphorylation. Toxin challenge led to increased endocytosis of an extracellular fluid phase marker as well as increased externalization of LAMP1-positive membranes suggesting that peripheral lysosomes are recruited to the insulted plasma membrane. We further observed that thereby the lysosomal protein acid sphingomyelinase (ASM) was released into the cell culture medium. Thus, our results show that staphylococcal α-toxin triggers mechanisms in endothelial cells, which have been implicated in membrane repair after damage of other cell types by different toxins. KW - acid sphingomyelinase KW - staphylococcal alpha-toxin KW - sphingomyelinase release KW - lysosomal recruitment KW - Staphylococcus aureus Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-244843 SN - 1664-302X VL - 12 ER - TY - JOUR A1 - Krishna, Anand A1 - Ried, Sophia A1 - Meixner, Marie T1 - State-trait interactions in regulatory focus determine impulse buying behavior JF - PLoS One N2 - Little research has focused on motivational state-trait interactions to explain impulse buying. Although the trait chronic regulatory focus has been linked to impulse buying, no evidence yet exists for an effect of situational regulatory focus and no research has examined whether the fit of chronic and situational regulatory focus can influence impulse buying with actual consumptive consequences rather than purchase intentions. Two laboratory experiments (total N = 250) manipulated situational regulatory focus before providing opportunities for impulse buying. In addition, cognitive constraint was manipulated as a potential boundary condition for regulatory focus effects. Situational promotion focus increased impulse buying relative to situational prevention focus in participants with strong chronic promotion, consistent with regulatory fit theory and independently of cognitive constraint. Surprisingly, situational promotion focus also increased impulse buying in participants with strong chronic prevention, but only under low cognitive constraint. These results may be explained by diverging mediating cognitive processes for promotion vs. prevention focus' effect on impulse buying. Future research must focus more on combining relevant states and traits in predicting consumer behavior. Marketing implications are discussed. KW - behavior KW - cognition KW - cognitive psychology KW - motivation KW - open science KW - emotions KW - marketing KW - owls Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-261206 VL - 16 IS - 7 ER - TY - JOUR A1 - Zottnick, Sven H. A1 - Sprenger, Jan A. P. A1 - Finze, Maik A1 - Müller‐Buschbaum, Klaus T1 - Statistic Replacement of Lanthanide Ions in Bis‐salicylatoborate Coordination Polymers for the Deliberate Control of the Luminescence Chromaticity JF - ChemistryOpen N2 - Based on the strand‐like coordination polymer (CP) type \(^{1}\)\(_{∞}\)[Ln(BSB)\(_{3}\)(py)\(_{2}\)], [BSB]−=bis‐salicylatoborate anion, mixed Eu/Tb‐containing compounds of the constitution \(^{1}\)\(_{∞}\)[Eu\(_{x}\)Tb\(_{1-x}\)(BSB)\(_{3}\)(py)\(_{2}\)] were synthesised ionothermally for a phase width of (x=0.25–0.75) and characterized regarding structure and optical properties. Previously, known only for other lanthanides, the mixed 1D−Eu/Tb‐CPs show excellent options for statistic replacement of the Ln‐cations during synthesis yielding solid solutions. The products are highly luminescent, with the chromaticity being a direct function of the amount of the respective Ln‐ions. Corresponding to an overall addition of emission intensities, the green Tb\(^{3+}\) emission and the red Eu\(^{3+}\) emission allow for a chromaticity control that also includes yellow emission. Control of the luminescence colour renders them suitable examples of the versatility of statistic replacement of metal ions in coordination chemistry. In addition, crystallization of [EMIm]\(_{2}\)[YCl\(_{5}\)(py)] illuminates possible other products of the ionothermal reactions of [EMIm][BSB] with LnCl\(_{3}\) constituted by components not being part of the main CPs. KW - borates KW - coordination polymers KW - ionic liquids KW - lanthanides KW - luminescence Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239953 VL - 10 IS - 2 SP - 164 EP - 170 ER - TY - JOUR A1 - Schönbrodt-Stitt, Sarah A1 - Ahmadian, Nima A1 - Kurtenbach, Markus A1 - Conrad, Christopher A1 - Romano, Nunzio A1 - Bogena, Heye R. A1 - Vereecken, Harry A1 - Nasta, Paolo T1 - Statistical Exploration of SENTINEL-1 Data, Terrain Parameters, and in-situ Data for Estimating the Near-Surface Soil Moisture in a Mediterranean Agroecosystem JF - Frontiers in Water N2 - Reliable near-surface soil moisture (θ) information is crucial for supporting risk assessment of future water usage, particularly considering the vulnerability of agroforestry systems of Mediterranean environments to climate change. We propose a simple empirical model by integrating dual-polarimetric Sentinel-1 (S1) Synthetic Aperture Radar (SAR) C-band single-look complex data and topographic information together with in-situ measurements of θ into a random forest (RF) regression approach (10-fold cross-validation). Firstly, we compare two RF models' estimation performances using either 43 SAR parameters (θNov\(^{SAR}\)) or the combination of 43 SAR and 10 terrain parameters (θNov\(^{SAR+Terrain}\)). Secondly, we analyze the essential parameters in estimating and mapping θ for S1 overpasses twice a day (at 5 a.m. and 5 p.m.) in a high spatiotemporal (17 × 17 m; 6 days) resolution. The developed site-specific calibration-dependent model was tested for a short period in November 2018 in a field-scale agroforestry environment belonging to the “Alento” hydrological observatory in southern Italy. Our results show that the combined SAR + terrain model slightly outperforms the SAR-based model (θNov\(^{SAR+Terrain}\) with 0.025 and 0.020 m3 m\(^{−3}\), and 89% compared to θNov\(^{SAR}\) with 0.028 and 0.022 m\(^3\) m\(^{−3}\, and 86% in terms of RMSE, MAE, and R2). The higher explanatory power for θNov\(^{SAR+Terrain}\) is assessed with time-variant SAR phase information-dependent elements of the C2 covariance and Kennaugh matrix (i.e., K1, K6, and K1S) and with local (e.g., altitude above channel network) and compound topographic attributes (e.g., wetness index). Our proposed methodological approach constitutes a simple empirical model aiming at estimating θ for rapid surveys with high accuracy. It emphasizes potentials for further improvement (e.g., higher spatiotemporal coverage of ground-truthing) by identifying differences of SAR measurements between S1 overpasses in the morning and afternoon. KW - near-surface soil moisture KW - Sentinel-1 single-look complex data KW - SAR backscatters KW - terrain parameters KW - Alento hydrological observatory KW - Mediterranean environment Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259062 VL - 3 ER - TY - JOUR A1 - Seufert, Michael T1 - Statistical methods and models based on quality of experience distributions JF - Quality and User Experience N2 - Due to biased assumptions on the underlying ordinal rating scale in subjective Quality of Experience (QoE) studies, Mean Opinion Score (MOS)-based evaluations provide results, which are hard to interpret and can be misleading. This paper proposes to consider the full QoE distribution for evaluating, reporting, and modeling QoE results instead of relying on MOS-based metrics derived from results based on ordinal rating scales. The QoE distribution can be represented in a concise way by using the parameters of a multinomial distribution without losing any information about the underlying QoE ratings, and even keeps backward compatibility with previous, biased MOS-based results. Considering QoE results as a realization of a multinomial distribution allows to rely on a well-established theoretical background, which enables meaningful evaluations also for ordinal rating scales. Moreover, QoE models based on QoE distributions keep detailed information from the results of a QoE study of a technical system, and thus, give an unprecedented richness of insights into the end users’ experience with the technical system. In this work, existing and novel statistical methods for QoE distributions are summarized and exemplary evaluations are outlined. Furthermore, using the novel concept of quality steps, simulative and analytical QoE models based on QoE distributions are presented and showcased. The goal is to demonstrate the fundamental advantages of considering QoE distributions over MOS-based evaluations if the underlying rating data is ordinal in nature. KW - statistical methods KW - quality of experience Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235733 SN - 2366-0139 VL - 6 ER - TY - JOUR A1 - Brenzinger, Kristof A1 - Costa, Ohana Y. A. A1 - Ho, Adrian A1 - Koorneef, Guusje A1 - Robroek, Bjorn A1 - Molenaar, Douwe A1 - Korthals, Gerard A1 - Bodelier, Paul L. E. T1 - Steering microbiomes by organic amendments towards climate-smart agricultural soils JF - Biology and Fertility of Soils N2 - We steered the soil microbiome via applications of organic residues (mix of cover crop residues, sewage sludge + compost, and digestate + compost) to enhance multiple ecosystem services in line with climate-smart agriculture. Our result highlights the potential to reduce greenhouse gases (GHG) emissions from agricultural soils by the application of specific organic amendments (especially digestate + compost). Unexpectedly, also the addition of mineral fertilizer in our mesocosms led to similar combined GHG emissions than one of the specific organic amendments. However, the application of organic amendments has the potential to increase soil C, which is not the case when using mineral fertilizer. While GHG emissions from cover crop residues were significantly higher compared to mineral fertilizer and the other organic amendments, crop growth was promoted. Furthermore, all organic amendments induced a shift in the diversity and abundances of key microbial groups. We show that organic amendments have the potential to not only lower GHG emissions by modifying the microbial community abundance and composition, but also favour crop growth-promoting microorganisms. This modulation of the microbial community by organic amendments bears the potential to turn soils into more climate-smart soils in comparison to the more conventional use of mineral fertilizers. KW - greenhouse gases KW - agricultural soils KW - organic amendment KW - flux measurements KW - microbial community abundance and compositions KW - plant growth Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-326930 VL - 57 IS - 8 ER - TY - THES A1 - Lüthen, Julia T1 - Stellenwert des Heavy Light Chain Assays in Diagnostik und Therapiemonitoring des Multiplen Myeloms – Vergleich mit konventionellen Analysen und minimaler Resterkrankung T1 - Benefit of using the Heavy Light Chain Assay in diagnosis and therapy monitoring of multiple myeloma patients - comparison with conventional methods and minimal residual disease assessment N2 - Das Multiple Myelom ist eine komplexe Erkrankung, dessen Tumorbiologie noch immer nicht in Gänze verstanden ist. Mit dem Heavy Light Chain Assay (Hevylite®) war es erstmals möglich, mit spezifischen Antikörpern nicht nur zwischen den Klassen intakter Immunglobuline, sondern auch zwischen kappa- und lambda-Isotyp zu differenzieren. Dies ist in der Behandlung von Patient*innen mit Multiplem Myelom sehr nützlich, um das vom Tumor produzierte klonale Immunglobulin von den funktionalen Immunglobulinen getrennt zu quantifizieren. Dadurch sollen die Tumorlast und die einhergehende Immunsuppression genauer erfasst werden. Den zusätzlichen Nutzen für Diagnostik und Therapiemonitoring des Multiplen Myeloms untersuchen wir in dieser Arbeit anhand von Daten einer multizentrischen, randomisierten Phase 3- Medikamentenstudie (DSMM XIV) mit dem Vorteil, hierdurch eine große und weitgehend einheitlich behandelte Kohorte und Zugang zu modernen Messmethoden zu haben. Wir bestätigen, dass das Heavy Light Chain Assays insbesondere zur Erkennung von IgA-Myelomen eine hohe Sensitivität bei negativer Serumproteinelektrophorese hat. Weiterhin zeigen wir, dass je nach Zeitpunkt in der Therapie das Heavy Light Chain Assay ein höheres Risiko für einen Progress vorhersagt als bisher verwendete Methoden. Signifikante Unterschiede im progressionsfreien Überleben finden wir nicht nur je nach Höhe der kappa/lambda Heavy Light Chain-Ratio des involvierten Immunglobulins, sondern auch bei Suppression der nicht involvierten Heavy Light Chain. Zudem beschreiben wir eine hohe Korrelation zwischen hoch abnormaler kappa/lambda Heavy Light Chain-Ratio des involvierten Immunglobulins und positivem Minimal Residual Disease Status in der Durchflusszytometrie. Wir empfehlen daher anhand unserer Ergebnisse, dass das Heavy Light Chain Assay einen Platz in der diagnostischen Routine erhält und als prognostischer Faktor zusätzlich in die Response-Kriterien integriert wird. N2 - Multiple myeloma is a complex disease, whose the tumor biology is not yet fully understood. Using specific antibodies of the Heavy Light Chain Assay (Hevylite®) it was possible for the first time to not only differentiate between the classes of intact immunoglobuline but also between kappa- and lambda- isotype. This is very useful in the treatment of patients with multiple myeloma, in order to quantify the tumor-induced clonal immunoglobulin and the functional immunoglobulins separately. It allows assessing the tumor burden and the associated immunosuppression more precisely. In this paper we are investigating the additional benefit for diagnosis and therapy monitoring of multiple myeloma patients based on data from a multicentric, randomized phase 3 drug study (DSMM XIV). This gives us the advantage of having a large and overall uniformly treated cohort and access to modern measurement methods. We confirm that the Heavy Light Chain Assay has a high sensitivity, especially for the detection of IgA myeloma with negative serum protein electrophoresis. Furthermore, we show that depending on the point in time in therapy, the Heavy Light Chain Assay predicts a higher risk of progression than previously used methods. We found significant differences in the progression-free survival not only depending on the level of the kappa/lambda Heavy Light Chain Ratio of the involved immunoglobulin, but also depending on the suppression of the non-involved Heavy Light Chain. We also describe a high correlation between highly abnormal kappa/lambda Heavy Light Chain Ratio of the involved immunoglobulin and a positive status in minimal residual disease analysis through flow cytometry. Based on our results, we recommend that the Heavy Light Chain Assay should have a place in the diagnostic routine and be integrated into the response criteria as a prognostic factor. KW - Multiples Myelom KW - Immunglobuline KW - Immunassay KW - Minimale Resterkrankung KW - Multiple myeloma KW - Immunoglobulins KW - Minimal residual disease KW - Immunoassay KW - Heavy Light Chain Assay KW - DSMM XIV Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-242223 ER - TY - THES A1 - Martellotta, Donato Daniel T1 - Stellenwert von CXCL12 und CXCR4 in der Pathogenese des Vestibularisschwannomes T1 - Significance of CXCL12 and CXCR4 in the pathogenesis of vestibular schwannoma N2 - CXCR4 ist der spezifische Rezeptor für das Chemokin CXCL12 und ist überexprimiert in Vestibularisschwannomzellen. Das Ziel dieser Arbeit war es den Effekt des spezifischen Inhibitors AMD3100 auf die CXCR4 vermittelte Proliferation und Migration der Vestibularisschwannomzellen in verschiedenen Zellkuturmodellen zu analysieren. Die nachgewiesene Inhibition von CXCR4 deutet auf einen möglichen Einsatz von AMD3100 in der systemischen Therapie von NF-2 Patienten hin. N2 - CXCR4 is the specific receptor for the chemokine CXCL12 and is hyperexpressed in vestibular schwannoma cells. The aim was to analyse the influence of the specific inhibitor AMD 3100 on the CXCR4 stimulated proliferation and migration of vestibular schwannoma cells in different cell culture models. The demonstrated inhibition of CXCR4 suggests the use of AMD3100 in the systemic therapy of NF-2 patients. KW - CXCL12 KW - Vestibularisschwannom KW - CXCR4 KW - NF-2 KW - 3D-Modell Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-241454 ER - TY - THES A1 - Eckhardt, Carolin T1 - Sterol O-Acyltransferasen als Zielmoleküle in der Tumortherapie sowie die klinische Relevanz ihrer Expression beim Prostatakarzinom T1 - Sterol-O-Acyl transferases as target molecules in tumor therapy and the clinical relevance of their expression in prostate cancer N2 - Sterol O-Acyltransferasen (SOATs) spielen eine zentrale Rolle im Cholesterinstoffwechsel von Zellen, indem sie die Veresterung von freiem Cholesterin und Speicherung in Lipid droplets katalysieren. In Tumorzellen findet häufig eine Aktivierung alternativer Pfade des Energiestoffwechsels, unter anderem des Lipidstoffwechsels statt. Präklinische und klinische Daten unterstützen den Mechanismus der SOAT-Inhibierung als Therapiekonzept für bestimmte Tumore. Eine genaue Kenntnis sowohl dieser Inhibitoren als auch der Expression des Zielmoleküls ist Voraussetzung für eine klinische Anwendung. Im ersten Teil dieser Arbeit wurde ein in-vitro SOAT-Aktivitätsassay etabliert und auf Grundlage dessen ein Vergleich der mittleren Hemmstärken ausgewählter SOAT-Inhibitoren gezogen. SOAT-transfizierte AD-293 Zellen sowie NCI-H295R Nebennieren-Zellen wurden mit dem fluoreszierenden 22-NBD-Cholesterin sowie den SOAT-Inhibitoren inkubiert und die Veresterung des Lipid-Analogons dann zunächst mikroskopisch und anschließend quantitativ mittels chromatographischer Auftrennung untersucht. Mitotane stellte sich mit einer IC50 von 1,3x10⁻⁶ M als schwächster SOAT-Inhibitor dar, gefolgt von Sandoz58-035 (IC50=1,4x10\(^{-8}\) M), ATR101 (IC50=3,1x10\(^{-9}\) M) und schließlich AZD3988 (IC50=8,8x10\(^{-10}\) M). Im zweiten Teil dieser Arbeit wurde die SOAT-Expression in Prostatektomiepräparaten von Hochrisiko Prostatakarzinom-Patienten mittels Immunhistochemie bestimmt. Eine starke SOAT1 Expression (SOAT H-Score 3) war sowohl in der univariaten als auch in der multivariaten Analyse hoch signifikant mit einem kürzeren biochemisch progressfreien Überleben der Patienten assoziiert unabhängig von etablierten Prognoseparametern [HR für den biochemischen Progress 2,33 (95%KI 1,48-3,68), p<0,001)]. Für SOAT2 war dies erwartungsgemäß nicht der Fall. SOAT1 scheint bei diesem bestimmten Kollektiv einen vielversprechenden Stellenwert als prognostischer Marker zu haben und könnte darüber hinaus zukünftig als Zielmolekül im Rahmen einer individualisierten Therapie des Prostatakarzinoms in Frage kommen. N2 - Sterol-O-Acyl transferases (SOATs) play a central role in cellular cholesterol metabolism by catalyzing the esterification of free cholesterol and storage in lipid droplets. In tumor cells, activation of alternative pathways of energy metabolism, including lipid metabolism, frequently occurs. Preclinical and clinical data support the mechanism of SOAT inhibition as a therapeutic concept for certain tumors. Accurate knowledge of both these inhibitors and the expression of the target molecule is a prerequisite for clinical application. In the first part of this work, an in vitro SOAT activity assay was established and a comparison of the mean inhibitory strengths of selected SOAT inhibitors was drawn based on this. SOAT-transfected AD-293 cells as well as NCI-H295R adrenal cells were incubated with the fluorescent 22-NBD cholesterol as well as the SOAT inhibitors, and the esterification of the lipid analogue was then examined first microscopically and then quantitatively by chromatographic separation. Mitotane turned out to be the weakest SOAT inhibitor with an IC50 of 1.3x10⁻⁶ M, followed by Sandoz58-035 (IC50=1.4x10\(^{-8}\) M), ATR101 (IC50=3.1x10\(^{-9}\) M) and finally AZD3988 (IC50=8.8x10\(^{-10}\) M). In the second part of this work, SOAT expression in prostatectomy specimens from high-risk prostate cancer patients was determined by immunohistochemistry. Strong SOAT1 expression (SOAT H-score 3) was highly significantly associated with shorter biochemical progression-free survival of patients independent of established prognostic parameters in both univariate and multivariate analysis [HR for biochemical progression 2.33 (95%CI 1.48-3.68), p<0.001)]. As expected, this was not the case for SOAT2. SOAT1 appears to have promising value as a prognostic marker in this particular collective and, moreover, could be considered as a future target in the context of individualized therapy of prostate cancer. KW - Sterol O-Acyltransferasen KW - SOAT KW - Hochrisiko Prostatakarzinom KW - SOAT Inhibitoren KW - Sterol-O-Acyl transferases KW - High risk prostate cancer KW - Cholesterol metabolism Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-243002 ER - TY - THES A1 - Rauschenberger, Vera T1 - Stiff-person syndrome - Pathophysiological mechanisms of glycine receptor autoantibodies T1 - Stiff-Person Syndrom - Pathophysiologische Mechanismen von Glyzinrezeptor Autoantikörpern N2 - The Stiff-person syndrome (SPS) is a rare autoimmune disease that is characterized by symptoms including stiffness in axial and limb muscles as well as painful spasms. Different variants of SPS are known ranging from moderate forms like the stiff-limb syndrome to the most severe form progressive encephalomyelitis with rigidity and myoclonus (PERM). SPS is elicited by autoantibodies that target different pre- or postsynaptic proteins. The focus of the present work is on autoantibodies against the glycine receptor (GlyR). At start of the present thesis, as main characteristic of the GlyR autoantibody pathology, receptor cross-linking followed by enhanced receptor internalization and degradation via the lysosomal pathway was described. If binding of autoantibodies modulates GlyR function and therefore contributes to the GlyR autoantibody pathology has not yet been investigated. Moreover, not all patients respond well to plasmapheresis or other treatments used in the clinic. Relapses with even higher autoantibody titers regularly occur. In the present work, further insights into the disease pathology of GlyRα autoantibodies were achieved. We identified a common GlyRα1 autoantibody epitope located in the far N-terminus including amino acids A1-G34 which at least represent a part of the autoantibody epitope. This part of the receptor is easily accessible for autoantibodies due to its location at the outermost surface of the GlyRα1 extracellular domain. It was further investigated if the glycosylation status of the GlyR interferes with autoantibody binding. Using a GlyRα1 de-glycosylation mutant exhibited that patient autoantibodies are able to detect the de-glycosylated GlyRα1 variant as well. The direct modulation of the GlyR analyzed by electrophysiological recordings demonstrated functional alterations of the GlyR upon autoantibody binding. Whole cell patch clamp recordings revealed that autoantibodies decreased the glycine potency, shown by increased EC50 values. Furthermore, an influence on the desensitization behavior of the receptor was shown. The GlyR autoantibodies, however, had no impact on the binding affinity of glycine. These issues can be explained by the localization of the GlyR autoantibody epitope. The determined epitope has been exhibited to influence GlyR desensitization upon binding of allosteric modulators and differs from the orthosteric binding site for glycine, which is localized much deeper in the structure at the interface between two adjacent subunits. To neutralize GlyR autoantibodies, two different methods have been carried out. Transfected HEK293 cells expressing GlyRα1 and ELISA plates coated with the GlyRα1 extracellular domain were used to efficiently neutralize the autoantibodies. Finally, the successful passive transfer of GlyRα1 autoantibodies into zebrafish larvae and mice was shown. The autoantibodies detected their target in spinal cord and brain regions rich in GlyRs of zebrafish and mice. A passive transfer of human GlyRα autoantibodies to zebrafish larvae generated an impaired escape behavior in the animals compatible with the abnormal startle response in SPS or PERM patients. N2 - Das Stiff-person Syndrom (SPS) ist eine seltene Autoimmunerkrankung, die sich durch Symptome wie Steifheit in Muskeln des Rumpfes und der Gliedmaßen sowie schmerzhafte Spasmen auszeichnet. Vom SPS sind verschiedene Varianten bekannt, die von mäßigen Formen, wie dem Stiff-limb Syndrom (limb von engl. Extremitäten), bis zur schwersten Variante, der progressiven Enzephalomyelitis mit Steifheit und Myoklonus (PERM, vom engl. progressive encephalomyelitis with rigidity and myoclonus), reichen. Ausgelöst wird das SPS durch Autoantikörper, die an verschiedene prä- und postsynaptische Proteine binden. Der Fokus in dieser Arbeit liegt dabei auf Autoantikörpern, die gegen den Glyzinrezeptor (GlyR) gerichtet sind. Zu Beginn dieser Thesis galten als Hauptcharakteristika der Pathologie von Autoantikörpern die Quervernetzung von Rezeptoren gefolgt von einer verstärkten Rezeptor Internalisierung und dem Abbau über das Lysosom. Allerdings wurde bisher noch nicht untersucht, ob die GlyR Funktion durch eine Autoantikörperbindung verändert wird. Darüber hinaus sprechen nicht alle Patienten gut auf Plasmapheresen oder andere Therapien an. Rückfälle mit noch viel höheren Autoantikörpertitern treten regelmäßig auf. Die vorliegende Arbeit erweitert die Kenntnisse der pathophysiologischen Mechanismen, die durch GlyRα Autoantikörper ausgelöst werden. Wir konnten ein Epitop der GlyRα1 Autoantikörper im N-terminalen Bereich ausfindig machen, wobei die Aminosäuren A1-G34 zumindest einen Teil des Epitops bilden. Dieser GlyR Bereich kann durch die Autoantikörper sehr leicht erreicht werden, weil er sich an der Oberfläche der extrazellulären Domäne des GlyRs befindet. Weiterhin wurde untersucht, ob die Glykosylierung des GlyRs die Autoantikörperbindung beeinflusst. Mit Hilfe von Mutanten, bei denen die Glykosylierungsstelle entfernt wurde, konnte gezeigt werden, dass Patientenautoantikörper die nicht-glykosylierte Variante des GlyRα1 ebenfalls detektieren können. Elektrophysiologische Messungen ergaben, dass die Funktionalität des GlyRs durch die Bindung von Autoantikörpern beeinträchtigt wird. Erhöhte EC50 Werte zeigen, dass Autoantikörper die Wirksamkeit von Glyzin in niedrigeren Konzentrationen auf den Rezeptor verringern. Außerdem beeinflussen die Autoantikörper die Desensitisierung des Rezeptors. Allerdings waren die Glyzin-Wirksamkeit in sättigenden Konzentrationen und die Affinität von Glyzin zum Rezeptor unverändert. Diese Ergebnisse können durch die Lokalisierung des GlyR Autoantikörper-Epitops erklärt werden. Das ermittelte Epitop ist bekannt dafür, dass dort allosterische Modulatoren binden können und dadurch die Desensitisierung beeinflusst wird. Außerdem unterscheidet sich das Epitop von der orthosterischen Bindestelle von Glyzin, welche viel tiefer in der Struktur an der Grenze zweier benachbarter Untereinheiten liegt. Um die GlyR Autoantikörper zu neutralisieren, wurden zwei verschiedene Methoden entwickelt. Transfizierte HEK293 Zellen, die den GlyRα1 exprimieren, und ELISA Platten, die mit der extrazellulären Domäne des GlyRα1 beschichtet waren, wurden zur effizienten Neutralisation der Autoantikörper verwendet. Abschließend konnte in der vorliegenden Arbeit die erfolgreiche passive Übertragung von GlyRα1 Autoantikörpern in Zebrafischlarven und Mäusen gezeigt werden. In Zebrafischen und Mäusen detektierten die Autoantikörper ihr Antigen im Rückenmark und in Gehirnregionen, in denen der GlyR zahlreich exprimiert ist. Ein passiver Transfer von menschlichen GlyRα Autoantikörpern in Zebrafischlarven beeinträchtigte das Fluchtverhalten der Tiere, welches kompatibel mit dem krankhaften Startle Reflex in SPS- oder PERM-Patienten ist. KW - Glycinrezeptor KW - Autoantikörper KW - Pathophysiologie KW - Stiff-person syndrome KW - Stiff-Person Syndrom KW - Pathophysiologische Mechanismen KW - pathophysiological mechanisms Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-209588 ER - TY - JOUR A1 - Böckler, Anne A1 - Rennert, Annika A1 - Raettig, Tim T1 - Stranger, Lover, Friend? BT - The Pain of Rejection Does Not Depend JF - Social Psychology N2 - Social exclusion, even from minimal game-based interactions, induces negative consequences. We investigated whether the nature of the relationship with the excluder modulates the effects of ostracism. Participants played a virtual ball-tossing game with a stranger and a friend (friend condition) or a stranger and their romantic partner (partner condition) while being fully included, fully excluded, excluded only by the stranger, or excluded only by their close other. Replicating previous findings, full exclusion impaired participants’ basic-need satisfaction and relationship evaluation most severely. While the degree of exclusion mattered, the relationship to the excluder did not: Classic null hypothesis testing and Bayesian statistics showed no modulation of ostracism effects depending on whether participants were excluded by a stranger, a friend, or their partner. KW - interpersonal relationships KW - ostracism KW - rejection KW - social exclusion KW - social interaction Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-238721 SN - 1864-9335 SN - 2151-2590 VL - 52 IS - 3 ER - TY - JOUR A1 - Appel, Alexandra A1 - Hardaker, Sina T1 - Strategies in Times of Pandemic Crisis — Retailers and Regional Resilience in Würzburg, Germany JF - Sustainability N2 - Research on the COVID-19 crisis and its implications on regional resilience is still in its infancy. To understand resilience on its aggregate level it is important to identify (non)resilient actions of individual actors who comprise regions. As the retail sector among others represents an important factor in an urban regions recovery, we focus on the resilience of (textile) retailers within the city of Würzburg in Germany to the COVID-19 pandemic. To address the identified research gap, this paper applies the concept of resilience. Firstly, conducting expert interviews, the individual (textile) retailers’ level and their strategies in coping with the crisis is considered. Secondly, conducting a contextual analysis of the German city of Würzburg, we wish to contribute to the discussion of how the resilience of a region is influenced inter alia by actors. Our study finds three main strategies on the individual level, with retailers: (1) intending to “bounce back” to a pre-crisis state, (2) reorganising existing practices, as well as (3) closing stores and winding up business. As at the time of research, no conclusions regarding long-term impacts and resilience are possible, the results are limited. Nevertheless, detailed analysis of retailers’ strategies contributes to a better understanding of regional resilience. KW - resilience KW - COVID-19 KW - pandemic crisis KW - regional resilience KW - retail KW - owner-operated retailers KW - textile sector KW - Germany Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233991 SN - 2071-1050 VL - 13 IS - 5 ER - TY - JOUR A1 - Rubo, Marius A1 - Gamer, Matthias T1 - Stronger reactivity to social gaze in virtual reality compared to a classical laboratory environment JF - British Journal of Psychology N2 - People show a robust tendency to gaze at other human beings when viewing images or videos, but were also found to relatively avoid gaze at others in several real‐world situations. This discrepancy, along with theoretical considerations, spawned doubts about the appropriateness of classical laboratory‐based experimental paradigms in social attention research. Several researchers instead suggested the use of immersive virtual scenarios in eliciting and measuring naturalistic attentional patterns, but the field, struggling with methodological challenges, still needs to establish the advantages of this approach. Here, we show using eye‐tracking in a complex social scenario displayed in virtual reality that participants show enhanced attention towards the face of an avatar at near distance and demonstrate an increased reactivity towards her social gaze as compared to participants who viewed the same scene on a computer monitor. The present study suggests that reactive virtual agents observed in immersive virtual reality can elicit natural modes of information processing and can help to conduct ecologically more valid experiments while maintaining high experimental control. KW - reactive virtual agents KW - social attention KW - social gaze KW - virtual reality Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-215972 VL - 112 IS - 1 SP - 301 EP - 314 ER - TY - JOUR A1 - Britz, Sebastian A1 - Markert, Sebastian Matthias A1 - Witvliet, Daniel A1 - Steyer, Anna Maria A1 - Tröger, Sarah A1 - Mulcahy, Ben A1 - Kollmannsberger, Philip A1 - Schwab, Yannick A1 - Zhen, Mei A1 - Stigloher, Christian T1 - Structural Analysis of the Caenorhabditis elegans Dauer Larval Anterior Sensilla by Focused Ion Beam-Scanning Electron Microscopy JF - Frontiers in Neuroanatomy N2 - At the end of the first larval stage, the nematode Caenorhabditis elegans developing in harsh environmental conditions is able to choose an alternative developmental path called the dauer diapause. Dauer larvae exhibit different physiology and behaviors from non-dauer larvae. Using focused ion beam-scanning electron microscopy (FIB-SEM), we volumetrically reconstructed the anterior sensory apparatus of C. elegans dauer larvae with unprecedented precision. We provide a detailed description of some neurons, focusing on structural details that were unknown or unresolved by previously published studies. They include the following: (1) dauer-specific branches of the IL2 sensory neurons project into the periphery of anterior sensilla and motor or putative sensory neurons at the sub-lateral cords; (2) ciliated endings of URX sensory neurons are supported by both ILso and AMso socket cells near the amphid openings; (3) variability in amphid sensory dendrites among dauers; and (4) somatic RIP interneurons maintain their projection into the pharyngeal nervous system. Our results support the notion that dauer larvae structurally expand their sensory system to facilitate searching for more favorable environments. KW - FIB-SEM KW - 3D reconstruction KW - neuroanatomy KW - IL2 branching KW - amphids KW - Caenorhabditis elegans (C. elegans) KW - dauer Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-249622 SN - 1662-5129 VL - 15 ER - TY - THES A1 - Song, Boyuan T1 - Structural and functional studies of \(Saccharomyces\) \(cerevisiae\) Ccr4-Not complex with Electron microscopy T1 - Strukturelle und funktionelle Untersuchungen von \(Saccharomyces\) \(cerevisiae\) Ccr4-Not Komplexen mittels Elektronenmikroskopie N2 - The degradation of poly-adenosine tails of messenger RNAs (mRNAs) in the eukaryotic cells is a determining step in controlling the level of gene expression. The highly conserved Ccr4-Not complex was identified as the major deadenylation complex in all eukaryotic organisms. Plenty of biochemical studies have shown that this complex is also involved in many aspects of the mRNA metabolism, but we are still lacking the detailed structural information about its overall architecture and conformational states that could help to elucidate its multifunction and the way it is coordinated in the cells. Such information can also provide a basis to finding a possible way of intervention since the complex is also involved in some diseases such as cancer and cardiovascular disorders in humans. Meanwhile, the single particle Cryo-EM method has been through a “resolution revolution” recently due to the use of the newly developed direct electron detectors and has since resolved the high-resolution structures of many macromolecular protein complexes in their near-native state. Therefore, it was employed as a suitable method for studying the Ccr4-Not complex here. In this work, the Falcon 3EC direct detector mounted on the 300kV Titan Krios G3i Cryo-EM was evaluated for its practical performance at obtaining high-quality Cryo-EM data from protein samples of different molecular sizes. This served as a proof of principle for this detector’s capabilities and as a data collection guidance for studying the macromolecular complexes, such as the Ccr4-Not, when using an advanced high-performance microscope system. Next, the endogenous yeast Ccr4-Not complex was also purified via the immunoaffinity purification method and evaluated using negative staining EM to assess the conditions of the complex before proceeding to sample preparation for Cryo-EM. This has shown that the complex had an unexpected inherently dynamic property in vitro and extra optimisation procedures were needed to stabilise the complex during the purification and sample preparation. In addition, by using the label-free quantitative Mass spectrometry to examine the coimmunoprecipitated complex via different tagged subunits, it was deduced that two of the subunits (Not3/Not5) that shared some sequence similarity might compete for association with the scaffold subunit of the complex. An uncharacterised protein was also identified coimmunoprecipitating with the Caf130 subunit of the yeast complex. Cryo-EM data from the purified complex provided a low-resolution map that represents a surprisingly smaller partial complex as compared to 3D structures from previous studies, although gel electrophoresis and Mass spectrometry data have identified all of the nine subunits of the Ccr4-Not core complex in the sample. It was concluded that due to the presence of many predicted unstructured regions VI in the subunits and their dynamic composition in solution, the native complex could have been spontaneously denatured at the air/water interface during the sample preparation thus limiting the resolution of the Cryo-EM reconstruction. The purified complex was also examined for its deadenylase and ubiquitin ligase activity by in vitro assays. It was shown that the native complex has a different rate of activity and possibly also a different mode of action compared to the recombinant complexes from other species under similar reaction conditions. The Not4 E3 ligase was also shown to be active in the complex and was likely auto-ubiquitinated in the absence of a substrate. Both types of assays have also shown that the conformational flexibility does not seem to affect the enzymatic reactions when using a chemically crosslinked form of the complex for the assay, which implies that there can be other underlying mechanisms coordinating its structural and functional relationship. The findings from this work have therefore moved our understanding of the Ccr4-Not complex forward by looking at the different structural and functional behaviours of the endogenous complex, especially highlighting the obstacles in sample preparation for the native complex in high-resolution Cryo-EM. This would serve as foundation for future studies on the mechanism of this complex’s catalytic functions and also for optimising the Cryo-EM sample to generate better data that could eventually resolve the structure to a high-resolution. N2 - Der Abbau des Poly(A)-Schwanzes von Messenger-RNAs (mRNA) in den eukaryotischen Zellen ist ein entscheidender Schritt bei der Kontrolle des Niveaus der Genexpression. Der hochkonservierte Ccr4-Not-Komplex wurde in allen eukaryotischen Organismen als der Hauptdeadenylierungskomplex identifiziert. Zahlreiche biochemische Studien haben gezeigt, dass dieser Komplex auch an vielen Aspekten des mRNA-Metabolismus beteiligt ist. Uns fehlen jedoch noch die detaillierten Strukturinformationen über seine Gesamtarchitektur und seine Konformationszustände, die zur Aufklärung seiner Multifunktion und seiner Koordinierung in den Zellen beitragen könnten. Solche Informationen können auch Grundlage für die Suche nach einem möglichen Interventionsweg bieten, da der Komplex auch an einigen Krankheiten wie Krebs und Herz-Kreislauf-Erkrankungen des Menschen beteiligt ist. In der Zwischenzeit hat die Einzelpartikel-Kryo-EM-Methode aufgrund der Verwendung der neu entwickelten direkten Elektronendetektoren kürzlich eine „Auflösungsrevolution“ durchlaufen und seitdem die hochauflösenden Strukturen vieler makromolekularer Proteinkomplexe in ihrem nahezu nativen Zustand aufgelöst. Daher wurde es hier als geeignete Methode zur Untersuchung des Ccr4-Not-Komplexes eingesetzt. In dieser Arbeit wurde der Falcon 3EC-Direktdetektor, der an das 300-kV-Titan Krios G3i Kryo-EM montiert ist, auf seine praktische Leistung bei der Gewinnung hochwertiger Kryo-EM-Daten aus Proteinproben unterschiedlicher Molekülgröße untersucht. Dies diente als Grundsatznachweis für die Fähigkeiten des Detektors und als Leitfaden für die Datenerfassung zur Untersuchung der makromolekularen Komplexe wie Ccr4-Not bei Verwendung eines fortschrittlichen Hochleistungsmikroskopsystems. Als nächstes wurde der endogene Hefe-Ccr4-Not-Komplex auch über das Immunaffinitäts-Reinigungsverfahren gereinigt und unter Verwendung einer negativ gefärbten EM bewertet, um die Bedingungen des Komplexes zu bewerten, bevor mit der Probenvorbereitung für Kryo-EM fortgefahren wurde. Dies hat gezeigt, dass der Komplex in vitro eine unerwartete inhärent dynamische Eigenschaft aufwies und zusätzliche Optimierungsverfahren erforderlich waren, um den Komplex während der Reinigung und Probenvorbereitung zu stabilisieren. Darüber hinaus wurde unter Verwendung der markierungsfreien quantitativen Massenspektrometrie zur Untersuchung des co-immunpräzipitierten Komplexes über verschiedene markierte Untereinheiten abgeleitet, dass zwei der Untereinheiten (Not3 / Not5), die eine gewisse Sequenzähnlichkeit teilen, um die Verbindung mit der Gerüstuntereinheit des Komplexes konkurrieren könnten. Es wurde auch ein nicht charakterisiertes Protein identifiziert, das zusammen mit der Caf130-Untereinheit des Hefekomplexes immunpräzipitiert. Kryo-EM-Daten aus dem gereinigten Komplex lieferten eine Karte mit niedriger Auflösung, die im Vergleich zu 3D-Strukturen aus früheren Studien einen überraschend kleineren Teilkomplex darstellt, obwohl Gelelektrophorese- und Massenspektrometriedaten gezeigt haben, dass alle neun Untereinheiten des Ccr4-Not Kernkomplexware in der Probe vorhanden waren. Daraus kann man schließen, dass aufgrund des Vorhandenseins vieler vorhergesagter unstrukturierter Regionen in den Untereinheiten und ihrer dynamischen Zusammensetzung in Lösung der native Komplex während der Probenvorbereitung an der Luft / Wasser-Grenzfläche spontan denaturiert werden konnte, wodurch die Auflösung des Kryo-EM Wiederaufbaus begrenzt wurde. Der gereinigte Komplex wurde auch durch In-vitro-Tests auf seine Deadenylase- und Ubiquitin-Ligase-Aktivität untersucht. Es wurde aufgezeigt, dass der native Komplex eine andere Aktivitätsrate und möglicherweise auch eine andere Wirkungsweise aufweist als die rekombinanten Komplexe anderer Spezies unter ähnlichen Reaktionsbedingungen. Es wurde auch dargestellt, dass die Not4 E3-Ligase in dem Komplex aktiv ist und wahrscheinlich in Abwesenheit eines Substrats automatisch ubiquitiniert wird. Beide Arten von Assays haben auch gezeigt, dass die Konformationsflexibilität die enzymatischen Reaktionen bei Verwendung einer chemisch vernetzten Form des Komplexes für den Assay nicht zu beeinflussen scheint, was impliziert, dass es andere zugrunde liegende Mechanismen geben kann, die seine strukturelle und funktionelle Beziehung koordinieren. Die Ergebnisse dieser Arbeit haben daher unser Verständnis des Ccr4-Not-Komplexes weiterentwickelt, indem wir die unterschiedlichen strukturellen und funktionellen Verhaltensweisen des endogenen Komplexes untersucht und insbesondere die Hindernisse bei der Probenvorbereitung für den nativen Komplex im hochauflösendem Kryo-EM hervorgehoben haben. Dies würde als Grundlage für zukünftige Forschungen dienen, die Mechanismen seiner katalytischen Funktionen weiter zu untersuchen und auch die Kryo-EM-Probe zu optimieren, um bessere Daten zu generieren, die die Struktur schließlich in eine hohe Auflösung auflösen könnten. KW - CCR4 KW - Ccr4-Not KW - biochemistry KW - electron microscopy Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-216527 ER - TY - JOUR A1 - Schindler, Dorothee A1 - Meza-Chincha, Anna-Lucia A1 - Roth, Maximilian A1 - Würthner, Frank T1 - Structure-Activity Relationship for Di- up to Tetranuclear Macrocyclic Ruthenium Catalysts in Homogeneous Water Oxidation JF - Chemistry—A European Journal N2 - Two di- and tetranuclear Ru(bda) (bda: 2,2′-bipyridine-6,6′-dicarboxylate) macrocyclic complexes were synthesized and their catalytic activities in chemical and photochemical water oxidation investigated in a comparative manner to our previously reported trinuclear congener. Our studies have shown that the catalytic activities of this homologous series of multinuclear Ru(bda) macrocycles in homogeneous water oxidation are dependent on their size, exhibiting highest efficiencies for the largest tetranuclear catalyst. The turnover frequencies (TOFs) have increased from di- to tetranuclear macrocycles not only per catalyst molecule but more importantly also per Ru unit with TOF of 6 \(^{-1}\) to 8.7 \(^{-1}\) and 10.5 s\(^{-1}\) in chemical and 0.6 s\(^{-1}\) to 3.3 \(^{-1}\) and 5.8 \(^{-1}\) in photochemical water oxidation per Ru unit, respectively. Thus, for the first time, a clear structure–activity relationship could be established for this novel class of macrocyclic water oxidation catalysts. KW - homogeneous catalysis KW - water oxidation KW - ruthenium catalysts KW - renewable fuels KW - metallomacrocycles Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-256792 VL - 27 IS - 68 ER - TY - JOUR A1 - Welker, Armin A1 - Kersten, Christian A1 - Müller, Christin A1 - Madhugiri, Ramakanth A1 - Zimmer, Collin A1 - Müller, Patrick A1 - Zimmermann, Robert A1 - Hammerschmidt, Stefan A1 - Maus, Hannah A1 - Ziebuhr, John A1 - Sotriffer, Christoph A1 - Schirmeister, Tanja T1 - Structure‐Activity Relationships of Benzamides and Isoindolines Designed as SARS‐CoV Protease Inhibitors Effective against SARS‐CoV‐2 JF - ChemMedChem N2 - Inhibition of coronavirus (CoV)‐encoded papain‐like cysteine proteases (PL\(^{pro}\)) represents an attractive strategy to treat infections by these important human pathogens. Herein we report on structure‐activity relationships (SAR) of the noncovalent active‐site directed inhibitor (R)‐5‐amino‐2‐methyl‐N‐(1‐(naphthalen‐1‐yl)ethyl) benzamide (2 b), which is known to bind into the S3 and S4 pockets of the SARS‐CoV PL\(^{pro}\). Moreover, we report the discovery of isoindolines as a new class of potent PL\(^{pro}\) inhibitors. The studies also provide a deeper understanding of the binding modes of this inhibitor class. Importantly, the inhibitors were also confirmed to inhibit SARS‐CoV‐2 replication in cell culture suggesting that, due to the high structural similarities of the target proteases, inhibitors identified against SARS‐CoV PL\(^{pro}\) are valuable starting points for the development of new pan‐coronaviral inhibitors. KW - antiviral agents KW - computational chemistry KW - drug design KW - protease inhibitors KW - structure-activity relationships Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225700 VL - 16 IS - 2 SP - 340 EP - 354 ER - TY - THES A1 - Kahr, Philipp Michael T1 - Strukturiertes Feedback im Kommunikationstraining zur präoperativen Aufklärung: unterschiedliche Bewertungsquellen nutzbar machen T1 - Structured Feedback within the Framework of Communication Training in Informed Consent Prior to Surgery N2 - Ärztliche Kommunikation wird vielerorts bereits im Studium eingeübt. Das Aufklärungsgespräch vor einer Operation ist ein spezifischer Kommunikationsanlass, der einer differenzierten Rückmeldung an die Studierenden bedarf. Ziel war es, im Rahmen eines Kommunikationstrainings die Rückmeldung verschiedener Feedbackgeber (ärztlicher Experte, geschulte Tutorinnen und Tutoren, Studierende der Peer Group, Aufklärende selbst und Simulationspersonen) anhand von Bewertungschecklisten zu strukturieren und die Ergebnisse zu vergleichen. 171 Humanmedizinstudierende des 8. Semesters der Universität Würzburg nahmen in Kleingruppen an einem Training zur präoperativen Aufklärung teil. 50 Personen davon führten ein Aufklärungsgespräch und erhielten Feedback. Im Fokus der Gespräche standen „Kommunikation“ sowie „Komplikationen“. Die Studierenden bereiteten sich mittels Unterrichtsmaterialien auf der universitätseigenen E-Learning-Plattform vor. Gegenstand der statistischen Auswertungen waren die Testgüte der Bewertungschecklisten, die Bewertungspunkte in den Skalen und die Übereinstimmung der Bewertungen auf Basis des Intraklassenkorrelationskoeffizienten (ICC). Die Bewertungschecklisten wiesen zufriedenstellende Werte für interne Konsistenz, Itemschwierigkeit und Trennschärfe auf. Die Mittelwerte der Scores zur „Kommunikation“ unterschieden sich teilweise signifikant durch die 5 Bewertungsquellen, wobei hier die Selbsteinschätzung durch die studentischen Aufklärenden am strengsten ausfiel. Die studentischen Tutorinnen und Tutoren bewerteten identisch zum Experten. In Bezug auf die „Komplikationen“ gab es keine signifikanten Abweichungen zwischen den Bewertenden. Es konnte gezeigt werden, dass innerhalb des hochspezifischen Settings eines Simulationstrainings und nach geplanter Vorbereitung geschulte studentische Tutoren/innen eine vergleichbar gute Rückmeldung wie der ärztliche Experte geben können. Bei überwiegenden Übereinstimmungen im strukturierten Feedback darf somit der Rückmeldung durch Tutoren/innen oder Peers zukünftig ein höherer Stellenwert eingeräumt werden. N2 - In many locations, communication between patients and doctors is already actively taught as part of undergraduate medicine at many. Informed consent prior to surgery is a particular reason for communication that calls for differentiated feedback to students.Within the framework of communication training, the aim was to compare the feedback given from 5 different sources (by a medical expert, by tutors, by student peers, by the student obtaining informed consent and by the simulated patients) using evaluation checklists. 171 medical students in their eighth semester at the University of Würzburg participated in a training module in obtaining informed consent prior to surgery. 50 students out of this group conducted a conversation. The emphasis laid on “communication” and “risks”. Students were able to prepare using teaching materials from the Universityʼs own e-learning platform. The statistical evaluation focussed on assessing the test quality of the checklists, the scores in the scales, and interrater agreement based on the intraclass correlation coefficient. The checklists delivered satisfactory test values with respect to internal consistency, item difficulty and discriminatory index. The average scores from the five raters only differed significantly with respect to communicative skills, whereby the students seeking informed consent were strict in their self-assessment. The student raters where highly consistent with the expert rater. With respect to “risks and complications”, there was high agreement between all raters. We were able to demonstrate that, within the highly specific setting of a simulation and after subtile preparation, a trained student tutor can provide just as effective feedback as a medical expert. Feedback from tutors or peers may be furnished with greater prominence in future, given the overall high agreement in the 360-degree feedback. KW - Aufklärungsgespräch KW - informed consent KW - Beurteilerübereinstimmung KW - strukturiertes Feedback KW - interrater agreement KW - structured feedback Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-242546 ER - TY - THES A1 - Stadler, David T1 - Studien zur Inflammation und neuronalem Schaden in genetischen Modellen von progredienter Multipler Sklerose T1 - Studies in inflammation and neuronal damage in genetic models of progressive multiple sclerosis N2 - Multiple Sklerose ist eine der häufigsten neurologischen Erkrankungen, die zu motorischen, sensiblen und vegetativen Einschränkungen führt. Häufig beginnt die Erkrankung mit einem schubförmigen Verlauf, dem eine progrediente Verschlechterung folgt. Trotzdem leiden ca. 15% der Patienten bereits von Beginn an, an einer primär progressiven Variante der MS, die bereits mit der progredienten Phase beginnt. Bis jetzt ist die Pathophysiologie nicht vollständig verstanden. Lange Zeit dachte man, dass MS primär eine reine Autoimmun-Erkrankung darstellt, aber in den letzten Jahren ergab sich die Frage, ob es vor allem in den progressiven Formen, eine zytodegenerative Komponente gibt, auf die eine sekundäre Inflammation folgt. Eine mögliche Ursache stellen hier Mutationen des PLP 1 Gens dar, die normalerweise mit leukodystrophischen Erkrankungen assoziiert sind. Es gab zwei Fallberichte, in denen von Patienten berichtet wurde, die unterschiedliche Mutationen in diesem Gen hatten und den klinischen Phänotyp einer MS zeigten. Diese Arbeit sollte nun die Auswirkungen der Mutationen, beziehungsweise einer Nullmutation des PLP 1 Gens in 18- und zum Teil 12-Monate alten Mausmutanten untersuchen. Hier konnten Myelin-Veränderungen und axonaler Schaden in immunhistochemischen Untersuchungen sowie mittels Elektronenmikroskopie und optischer Kohärenztomographie gezeigt werden. Weiter konnte eine Neuroinflammation und damit einhergehend eine zunehmende Anzahl CD8+ T-Zellen sowie einer erhöhten Anzahl an Mikroglia/Makrophagen gefunden werden. Dies ging mit vergleichsweise reduzierten Leistungen der Mutanten bei der motorischen Rotarod-Analyse einher. Interessanterweise wurde weniger neuraler Schaden in den heterozygoten Varianten gefunden, obwohl das Ausmaß der Entzündung gleichblieb. Dies könnte für eine zielgerichtete immunvermittelte Schädigung der Oligodendrozyten sprechen, die zu neuronalem Schaden führt. So konnte gezeigt werden, dass es durch Punktmutationen in einem Myelinprotein-codierendem Gen zu einer sekundären Entzündung kommen kann, die mit dem klinischen Phänotyp einer progressiven MS einhergeht. Weiter sind diese Mausmodelle ein Beispiel für eine genetische Erkrankung des ZNS, in denen die Klinik maßgeblich durch die begleitende Inflammation und nicht allein durch den genetischen Schaden verursacht wird. N2 - Multiple sclerosis (MS) is one of the most common neurological diseases, leading to motor, sensory and vegetative impairment. Frequently, the disease begins as a relapsing remitting form, which is followed by a progressive stage. Nevertheless about 15% of the patients suffer under a primary progressive multiple sclerosis, which starts with the progressive stage. Until now the pathophysiology is not completely understood. For a long time, multiple sclerosis was thought to be an autoimmune disease, but in the last years the question arose if the underlying cause, especially in the progressive forms (PMS), could be a cytodegenerative component, followed by secondary inflammation. A possible candidate here could be point mutations in the PLP 1 gene, which are usually associated with leukodystrophic disorders. There were two case reports about patients carrying distinct point mutations in this gene, leading to the clinical phenotype of multiple sclerosis. This thesis examines 18- and in part 12-month-old mice, carrying these point mutations or having a Plp 1 null mutation. Here myelin alterations and axonal damage in immunohistochemical stainings could be shown, as well as in the optical coherence tomography and electron microscopy. Furthermore, the occurrence of neuroinflammation comprising recruitment of microglia/macrophages and CD8 positive T-cells could be demonstrated. Also, typical clinical symptoms in the Rotarod test were found. Interestingly, there was less neural damage found in heterozygous females than in homozygous mutant mice, while the extent of inflammation was the same. This could indicate a targeted immune-mediated injury of oligodendrocytes leading to neuronal damage. In summary, this thesis shows that a point mutation of a gene coding for a myelin protein of oligodendrocytes can lead to secondary neuroinflammation and a neurological phenotype comparable to PMS. In addition, the generated mouse models are an example for genetic diseases of the CNS, in which the clinical outcome could be driven by inflammation and not only by the primary gene mutation. KW - Multiple Sklerose KW - Maus KW - Genetik KW - Immunsystem KW - Glia KW - Sekundäre Inflammation KW - Neuroinflammation KW - Neurodegeneration KW - Mikroglia KW - Mausmodell Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236923 ER - TY - THES A1 - Swirski, Thorben T1 - Studies on the Effect of Gas Contaminations in Micromegas Detectors and Production of Micromegas Detectors for the New Small Wheel of the ATLAS Detector T1 - Untersuchung des Einflusses von Gasverunreinigungen auf Micromegas Detektoren und Produktion von Micromegas Detektoren für das New Small Wheel des ATLAS Detektors N2 - This work consists of two parts. On the one hand, it describes simulation and measurement of the effect of contaminations of the detector gas on the performance of particle detectors, with special focus on Micromegas detectors. On the other hand, it includes the setup of a production site for the finalization of drift panels which are going to be used in the ATLAS NSW. The first part augments these two parts to give an introduction into the theoretical foundations of gaseous particle detectors. N2 - Diese Arbeit beinhaltet zwei Teile. Zum einen behandelt sie die Simulation und die Messung des Effekts von Verunreinigungen des Detektorgases auf Teilchen- detektoren, im speziellen vom Typ Micromegas. Zum anderen beinhaltet sie den Aufbau einer Produktionsstätte zur Vollendung von Driftpaneelen, die im ATLAS NSW Einsatz finden werden. Der erste Teil dieser Arbeit nimmt die Rolle eines Einführungsteiles ein, der die theoretischen Grundlagen von gasgefüllten Detekto- ren bespricht. KW - Gasionisationsdetektor KW - ATLAS KW - Micromegas KW - MPGD Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-246405 ER - TY - THES A1 - Aurbach, Katja T1 - Studies on the role of the cytoskeleton in platelet production T1 - Studien über die Rolle des Zytoskeletts in der Produktion von Thrombozyten N2 - Platelets are small anucleated cell fragments that originate from megakaryocytes (MKs), which are large cells located in the bone marrow (BM). MKs extend long cytoplasmic protrusions, a process which is called proplatelet formation, into the lumen of the sinusoidal vessels where platelets are sized by the bloodstream. During the process of platelet biogenesis, segments of the MK penetrate the endothelium and, through cytoskeletal remodeling inside the MK, proplatelet fragments are released. Rho GTPases, such as RhoA and RhoB, are critically involved in cytoskeletal rearrangements of both the actin and the tubulin cytoskeleton. The first part of this thesis concentrated on the protein RhoB and its involvement in cytoskeletal organization in MKs and platelets. Single knockout (KO) mice lacking RhoB had a minor microthrombocytopenia, which means a smaller platelet size and reduced platelet number, accompanied by defects in the microtubule cytoskeleton in both MKs and platelets. In particular, tubulin organization and stability, which is regulated by posttranslational modifications of α-tubulin, were disturbed in RhoB-/- platelets. In contrast, RhoB-/- MKs produced abnormally shaped proplatelets but had unaltered posttranslational modifications of α-tubulin. The second part focused on the influence of RhoA and RhoB on MK localization and platelet biogenesis in murine BM. Many intact RhoA-/- MKs are able to transmigrate through the endothelial layer and stay attached to the vessel wall, whereas only 1% of wildtype (wt) MKs are detectable in the intrasinusoidal space. Concomitant deficiency of RhoA and RhoB reverts this transmigration and results in macrothrombocytopenia, MK clusters around the vessel in the BM and defective MK development. The underlying mechanism that governs MKs to distinct localizations in the BM is poorly understood, thus this thesis suggests that this process may be dependent on RhoB protein levels, as RhoA deficiency is coincided with increased RhoB levels in MKs and platelets. The third part of this thesis targeted the protein PDK1, a downstream effector of Rho GTPases, in regard to MK maturation and polarization throughout thrombopoiesis. MK- and platelet-specific KO in mice led to a significant macrothrombocytopenia, impaired actin cytoskeletal reorganization during MK spreading and proplatelet formation, with defective MK maturation. This was associated with decreased PAK activity and, subsequently, phosphorylation of its substrates LIMK and Cofilin. Together, the observations of this thesis highlight the importance of Rho GTPases and their downstream effectors on the regulation of the MK and platelet cytoskeleton. N2 - Thrombozyten sind kleine Zellfragmente ohne Zellkern, die von Megakaryozyten (MKs) produziert werden. MKs sind riesige Zellen im Knochenmark, welche lange zytoplasmatische Ausläufer in die sinusoidalen Blutgefäße strecken, woraus durch den Blutstrom Thrombozyten abgeschnürt werden. Während der Thrombozyten-Biogenese penetrieren Teile des MKs das Endothel und durch zytoskeletales Umorganisieren innerhalb des MKs werden Proplättchen-Fragmente gebildet. Rho GTPasen wie die Proteine RhoA und RhoB sind maßgebliche Regulatoren des Zytoskeletts, sowohl des Aktins als auch des Tubulin Zytoskeletts. Der erste Teil dieser Thesis konzentrierte sich auf das Protein RhoB und dessen Einfluss auf die Organisation des Zytoskeletts. Mäuse mit einer Defizienz für das Protein RhoB zeigen eine Microthrombozytopenie und eine Reduktion der Thrombozytenzahl und -größe. Dies ist begleitet von Defekten des Mikrotubuli Zytoskeletts sowohl in MKs als auch in Blutplättchen. In Thrombozyten waren insbesondere Tubulin Organisation und Stabilisation betroffen, welche durch posttranslationale Modifizierungen von α-Tubulin bestimmt wurde. RhoB-negative MKs hingegen produzierten abnormal geformte Proplättchen, hatten jedoch unveränderte posttranslationale Modifizierungen von α-Tubulin. Der zweite Teil dieser Thesis fokussierte sich auf den Einfluss von RhoA und RhoB auf die Lokalisation von MKs im Knochenmarkt von Mäusen. Eine große Anzahl von RhoA-negativen MKs können durch das Endothel in die Blutgefäße wandern und bleiben dort adhärent, während nur etwa 1% wildtypischer MKs am Blutgefäß detektierbar sind. Gleichzeitige Defizienz von RhoA und RhoB revertiert die Translokation von RhoA-negativen MKs und führt in Mäusen zu Makrothrombozytopenie, die Formierung von MK Clustern um die Gefäßwand im Knochenmarkt und eine fehlerhafte MK Entwicklung. Der Mechanismus, der MKs zu bestimmten Positionen im Knochenmarkt führt, ist bisher kaum verstanden. In dieser Thesis konnte gezeigt werden, dass dieser Prozess von dem Level an RhoB Protein abhängig sein könnte, da eine Defizienz von RhoA zu einer Hochregulierung von RhoB in MKs und Thrombozyten führte. Der dritte Teil dieser Thesis zielte auf ein Signalprotein der Rho GTPasen ab, dem Protein PDK1. Es wurde die Rolle von PDK1 in der Regulation von MK Reifung und Polarisation während der Bildung von Thrombozyten untersucht. Ein MK und Thrombozyten spezifischer KO von PDK1 führte zu einer signifikanten Makrothrombozytopenie, einem gestörten Aktin Zytoskelett, während des MK Spreadings und der Proplättchen Bildung, begleitet von einer fehlerhaften MK Reifung. Dies war mit einer Reduktion in der Aktivität von PAK und folglich dem Phosphorylierungsstatus seiner Substrate LIMK und Cofilin assoziiert. Die Beobachtungen dieser Doktorarbeit arbeiteten die Relevanz von Rho GTPasen und ihren Signalproteinen für die Regulation des MK und Thrombozyten Zytoskelettes im Maus-Modell hervor. KW - Megakaryozyt KW - Thrombozyt KW - Zellskelett KW - Thrombopoiesis KW - Cytoskeleton Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234669 ER - TY - JOUR A1 - Trinks, Nora A1 - Reinhard, Sebastian A1 - Drobny, Matthias A1 - Heilig, Linda A1 - Löffler, Jürgen A1 - Sauer, Markus A1 - Terpitz, Ulrich T1 - Subdiffraction-resolution fluorescence imaging of immunological synapse formation between NK cells and A. fumigatus by expansion microscopy JF - Communications Biology N2 - Expansion microscopy (ExM) enables super-resolution fluorescence imaging on standard microscopes by physical expansion of the sample. However, the investigation of interactions between different organisms such as mammalian and fungal cells by ExM remains challenging because different cell types require different expansion protocols to ensure identical, ideally isotropic expansion of both partners. Here, we introduce an ExM method that enables super-resolved visualization of the interaction between NK cells and Aspergillus fumigatus hyphae. 4-fold expansion in combination with confocal fluorescence imaging allows us to resolve details of cytoskeleton rearrangement as well as NK cells' lytic granules triggered by contact with an RFP-expressing A. fumigatus strain. In particular, subdiffraction-resolution images show polarized degranulation upon contact formation and the presence of LAMP1 surrounding perforin at the NK cell-surface post degranulation. Our data demonstrate that optimized ExM protocols enable the investigation of immunological synapse formation between two different species with so far unmatched spatial resolution. KW - biological fluorescence KW - fluorescence imaging KW - imaging the immune system KW - infectious diseases KW - super-resolution microscopy Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-264996 VL - 4 IS - 1 ER - TY - JOUR A1 - Marquardt, André A1 - Solimando, Antonio Giovanni A1 - Kerscher, Alexander A1 - Bittrich, Max A1 - Kalogirou, Charis A1 - Kübler, Hubert A1 - Rosenwald, Andreas A1 - Bargou, Ralf A1 - Kollmannsberger, Philip A1 - Schilling, Bastian A1 - Meierjohann, Svenja A1 - Krebs, Markus T1 - Subgroup-Independent Mapping of Renal Cell Carcinoma — Machine Learning Reveals Prognostic Mitochondrial Gene Signature Beyond Histopathologic Boundaries JF - Frontiers in Oncology N2 - Background: Renal cell carcinoma (RCC) is divided into three major histopathologic groups—clear cell (ccRCC), papillary (pRCC) and chromophobe RCC (chRCC). We performed a comprehensive re-analysis of publicly available RCC datasets from the TCGA (The Cancer Genome Atlas) database, thereby combining samples from all three subgroups, for an exploratory transcriptome profiling of RCC subgroups. Materials and Methods: We used FPKM (fragments per kilobase per million) files derived from the ccRCC, pRCC and chRCC cohorts of the TCGA database, representing transcriptomic data of 891 patients. Using principal component analysis, we visualized datasets as t-SNE plot for cluster detection. Clusters were characterized by machine learning, resulting gene signatures were validated by correlation analyses in the TCGA dataset and three external datasets (ICGC RECA-EU, CPTAC-3-Kidney, and GSE157256). Results: Many RCC samples co-clustered according to histopathology. However, a substantial number of samples clustered independently from histopathologic origin (mixed subgroup)—demonstrating divergence between histopathology and transcriptomic data. Further analyses of mixed subgroup via machine learning revealed a predominant mitochondrial gene signature—a trait previously known for chRCC—across all histopathologic subgroups. Additionally, ccRCC samples from mixed subgroup presented an inverse correlation of mitochondrial and angiogenesis-related genes in the TCGA and in three external validation cohorts. Moreover, mixed subgroup affiliation was associated with a highly significant shorter overall survival for patients with ccRCC—and a highly significant longer overall survival for chRCC patients. Conclusions: Pan-RCC clustering according to RNA-sequencing data revealed a distinct histology-independent subgroup characterized by strengthened mitochondrial and weakened angiogenesis-related gene signatures. Moreover, affiliation to mixed subgroup went along with a significantly shorter overall survival for ccRCC and a longer overall survival for chRCC patients. Further research could offer a therapy stratification by specifically addressing the mitochondrial metabolism of such tumors and its microenvironment. KW - kidney cancer KW - pan-RCC KW - machine learning KW - mitochondrial DNA KW - mtDNA KW - mTOR Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232107 SN - 2234-943X VL - 11 ER - TY - JOUR A1 - Kunz, Felix A1 - Hirth, Matthias A1 - Schweitzer, Tilmann A1 - Linz, Christian A1 - Goetz, Bernhard A1 - Stellzig-Eisenhauer, Angelika A1 - Borchert, Kathrin A1 - Böhm, Hartmut T1 - Subjective perception of craniofacial growth asymmetries in patients with deformational plagiocephaly JF - Clinical Oral Investigations N2 - Objectives The present investigation aimed to evaluate the subjective perception of deformational cranial asymmetries by different observer groups and to compare these subjective perceptions with objective parameters. Materials and methods The 3D datasets of ten infants with different severities of deformational plagiocephaly (DP) were presented to 203 observers, who had been subdivided into five different groups (specialists, pediatricians, medical doctors (not pediatricians), parents of infants with DP, and laypersons). The observers rated their subjective perception of the infants’ cranial asymmetries using a 4-point Likert-type scale. The ratings from the observer groups were compared with one another using a multilevel modelling linear regression analysis and were correlated with four commonly used parameters to objectively quantify the cranial asymmetries. Results No significant differences were found between the ratings of the specialists and those of the parents of infants with DP, but both groups provided significantly more asymmetric ratings than did pediatricians, medical doctors, or laypersons. Moreover, the subjective perception of cranial asymmetries correlated significantly with commonly used parameters for objectively quantifying cranial asymmetries. Conclusions Our results demonstrate that different observer groups perceive the severity of cranial asymmetries differently. Pediatricians’ more moderate perception of cranial asymmetries may reduce the likelihood of parents to seek therapeutic interventions for their infants. Moreover, we identified some objective symmetry-related parameters that correlated strongly with the observers’ subjective perceptions. Clinical relevance Knowledge about these findings is important for clinicians when educating parents of infants with DP about the deformity. KW - infants with deformational plagiocephaly (DP) KW - deformational cranial asymmetry KW - subjective perception KW - positionalskull deformities KW - three-dimensional Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232803 SN - 1432-6981 VL - 25 ER - TY - THES A1 - Paul, Rebecca Theodora T1 - Subjektive Krankheitswahrnehmung, Therapieadhärenz und Zufriedenheit mit erhaltenen Informationen bei Patienten mit chronischer Nebenniereninsuffizienz – Zusammenhang mit der Teilnahme an einer standardisierten Patientenschulung T1 - Beliefs about glucocorticoid replacement therapy, medication adherence and satisfaction with information in patients with adrenal insufficiency – relation with a participation in the standardised education programme N2 - Rezente Studien mit kleineren Fallzahlen offenbaren bei Patienten mit chronischer Nebenniereninsuffizienz eine sehr negative Krankheitswahrnehmung, große Ängste und Sorgen hinsichtlich der Substitutionstherapie mit Glucocorticoiden sowie eine geringe Therapieadhärenz. Ziel der vorliegenden Beobachtungsstudie war es daher im Rahmen einer monozentrischen Querschnittstudie nebenniereninsuffiziente Patienten zu Therapieadhärenz, subjektiver Krankheits- und Glucocorticoidwahrnehmung und Zufriedenheit mit erhaltenen Informationen zu befragen. Zudem wurden erstmalig die Zusammenhänge zwischen der Teilnahme an einer standardisierten NNI-Schulung und oben genannten Aspekten im Rahmen einer multizentrischen Längschnittstudie untersucht. Die Ergebnisse der Querschnittstudie zeichnen insgesamt ein deutlich positiveres Bild von der subjektiven Krankheits- und Therapiewahrnehmung als bisher in der Literatur beschrieben. Die subjektive Therapieadhärenz war hoch. Zudem waren Sorgen und Ängste hinsichtlich der Glucocorticoid-Substitution geringer ausgeprägt als erwartet. Nichtsdestotrotz ließ sich konkordant zu früheren Publikationen eine zum Teil sehr große Unzufriedenheit mit erhaltenen Informationen zu möglichen Problemen der Glucocorticoid-Substitution feststellen. Die Ergebnisse der Längschnittstudie deuten darauf hin, dass die standardisierte Patientenschulung ein geeignetes Instrument sein könnte, um die Zufriedenheit von Patienten mit NNI zu steigern, das Selbstmanagement zu stärken und gleichzeitig positiven Einfluss auf die Wahrnehmung der Substitutionstherapie nehmen könnte. N2 - Recent studies in patients with chronic adrenal insufficiency revealed negative illness perceptions, strong concerns regarding glucocorticoid replacement and low medication adherence. In order to further evaluate subjective medication adherence, illness and glucocorticoids perception and satisfaction with information, we conducted a cross-sectional study comprising a larger German sample size. Furthermore, as part of a longitudinal study we aimed at evaluating the relation between the above-mentioned aspects and participation in a standardised education programme. The findings of the cross-sectional study show a more positive perception of adrenal insufficiency and glucocorticoid replacement as than previously described in literature. Self-reported medication adherence was high in this sample. Therapy-related concerns were considerably lower than previously described. Participants reported low satisfaction with the information they received about potential problems of glucocorticoid intake. The results of the longitudinal study indicate that the standardised education programme may be an adequate tool to enhance satisfaction with information, to strengthen the patients` self-management of adrenal insufficiency and to improve the patients` perception of glucocorticoid replacement KW - Nebennierenrindeninsuffizienz KW - Hypoadrenalismus KW - Patientenschulungen KW - Subjektive Krankheitswahrnehmung KW - Therapieadhärenz KW - Patientenzufriedenheit Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235522 ER - TY - THES A1 - Hütz, Barbara T1 - Substantia Nigra-Echogenität als Biomarker für Erkrankungen aus dem psychotischen Formenkreis und Korrelat psychopharmakologischer Nebenwirkungen bei Jugendlichen und jungen Erwachsenen T1 - Substantia Nigra echogenicity as biomarker for schizophrenic spectrum disorders and neuroleptic-induced extrapyramidal side-effects in adolescents and young adults N2 - Hintergrund: Bei erwachsenen Patient*innen mit Erkrankungen aus dem Schizophrenie-Spektrum konnte im transkraniellen Ultraschall im Vergleich zu gesunden Proband*innen eine signifikant erhöhte Echogenität der Substantia Nigra (SN) nachgewiesen werden. Zudem bestand ein Zusammenhang zwischen der SN-Fläche und stärker ausgeprägten extrapyramidalmotorischen Bewegungsstörungen unter Antipsychotikatherapie. In der vorliegenden Arbeit wurde überprüft, inwiefern die Echogenität der SN auch bei Jugendlichen und jungen Erwachsenen als Biomarker für Erkrankungen aus dem psychotischen Formenkreis und als Korrelat psychopharmakologischer Nebenwirkungen herangezogen werden kann. Des Weiteren wurde der Einfluss von Alter, Krankheitsdauer sowie Antipsychotika-Lebenszeitdosis auf die SN-Echogenität untersucht sowie Zusammenhänge mit peripheren Eisenparametern. Methoden: Hierfür wurden insgesamt 16 stationär behandelte Patient*innen zwischen 14 – 22 Jahren mit Erkrankungen aus dem schizophrenen Formenkreis sowie nach Alter und Geschlecht gematchte gesunde Kontrollen mittels TCS untersucht. Aus peripher entnommenem Blut wurden Parameter des Eisenhaushalts bestimmt. Ergebnisse: Es konnten entgegen der Hypothese keine signifikanten Unterschiede in Bezug auf die Echogenität der SN im Vergleich zur gesunden Kontrollgruppe festgestellt werden. Bezüglich der Schwere der beobachteten EPMS ergab sich entgegen der Hypothese und im Kontrast zu Befunden bei Erwachsenen kein Zusammenhang mit der SN-Echogenität. Das Alter der Proband*innen, die Krankheitsdauer sowie die Dosis der eingenommenen Antipsychotika zeigten keine Zusammenhänge mit der SN-Echogenität. Interessanterweise zeigte sich eine signifikant negative Korrelation zwischen der echogenen Fläche der SN und Eisen sowie Transferrin. Schlussfolgerung: Im Jugend- und jungen Erwachsenenalter eignet sich die SN-Echogenität vermutlich nicht als Biomarker für Erkrankungen aus dem Schizophrenie-Spektrum oder für die Prädiktion von Nebenwirkungen antipsychotischer Medikation. Möglicherweise manifestiert sich eine erhöhte Echogenität der SN, welche als Zeichen für eine Schädigung der dopaminergen Neurone gesehen wird, bei schizophrenen Psychosen erst im Verlauf der Krankheit. Da wir die Studienteilnehmer*innen nur zu einem einzigen Zeitpunkt im Laufe ihrer Krankheitsgeschichte untersuchten, kann keine Aussage über den weiteren Verlauf der SN-Echogenität getroffen werden. Hierfür wären longitudinale Untersuchungen zielführend, da nur so mögliche entwicklungsbedingte Veränderungen festgestellt werden können. N2 - Background: Adult patients with schizophrenic spectrum disorders showed a significantly larger mean echogenic area of the subtantia nigra (SN) in transcranial sonography compared to healthy controls. Also, patients showing larger echogenic SN developed more severe neuroleptic-induced extrapyramidal side-effects. In this study, we examined if SN echogenicity can function as a biomarker for schizophrenic spectrum disorders and as a predictor of neuroleptic-induced extrapyramidal side-effects in adolescents and young adults. Furthermore, we investigated the correlation of age, disease duration, lifetime neuroleptic dose and iron parameters with SN echogenicity. Methods: 16 hospitalized patients who had been diagnosed with schizophrenic spectrum disorders and 16 healthy controls between the ages of 14 – 22 years were examined via transcranial sonography. We also assessed the concentration of iron parameters in peripheral blood samples. Results: In contradiction to our hypothesis, no significant differences regarding SN echogenicity could be found when comparing the two groups. There also was no correlation of severity of extrapyramidal side-effects, age, disease duration or lifetime neuroleptic dose with echogenicity of the SN. Interestingly, we found a significant negative correlation of SN echogenicity with serum iron as well as serum transferrin levels. Conclusion: SN echogenicity apparently cannot be used as a biomarker for schizophrenic spectrum disorders or a predictor of neuroleptic-induced extrapyramidal side-effects in adolescents and young adults. Increased SN echogenicity, which is assumed to be an indicator of nigrostriatal injury, presumably evolves much later in the course of schizophrenic disorders. As our probands underwent examination only once in the course of their disease, we cannot draw conclusions regarding the development of SN echogenicity. Longitudinal studies are needed to shed more light on possible developmental changes in this regard. KW - Substantia nigra KW - Schizophrenie KW - Ultraschalldiagnostik KW - Juvenile Psychose KW - Extrapyramidales System KW - Substantia Nigra - Echogenität KW - Transkranieller Ultraschall KW - Adoleszenz KW - EPMS Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-231713 ER - TY - JOUR A1 - Wagner, Johanna C. A1 - Wetz, Anja A1 - Wiegering, Armin A1 - Lock, Johan F. A1 - Löb, Stefan A1 - Germer, Christoph-Thomas A1 - Klein, Ingo T1 - Successful surgical closure of infected abdominal wounds following preconditioning with negative pressure wound therapy JF - Langenbeck's Archives of Surgery N2 - Purpose Traditionally, previous wound infection was considered a contraindication to secondary skin closure; however, several case reports describe successful secondary wound closure of wounds "preconditioned" with negative pressure wound therapy (NPWT). Although this has been increasingly applied in daily practice, a systematic analysis of its feasibility has not been published thus far. The aim of this study was to evaluate secondary skin closure in previously infected abdominal wounds following treatment with NPWT. Methods Single-center retrospective analysis of patients with infected abdominal wounds treated with NPWT followed by either secondary skin closure referenced to a group receiving open wound therapy. Endpoints were wound closure rate, wound complications (such as recurrent infection or hernia), and perioperative data (such as duration of NPWT or hospitalization parameters). Results One hundred ninety-eight patients during 2013-2016 received a secondary skin closure after NPWT and were analyzed and referenced to 67 patients in the same period with open wound treatment after NPWT. No significant difference in BMI, chronic immunosuppressive medication, or tobacco use was found between both groups. The mean duration of hospital stay was 30 days with a comparable duration in both patient groups (29 versus 33 days, p = 0.35). Interestingly, only 7.7% of patients after secondary skin closure developed recurrent surgical site infection and in over 80% of patients were discharged with closed wounds requiring only minimal outpatient wound care. Conclusion Surgical skin closure following NPWT of infected abdominal wounds is a good and safe alternative to open wound treatment. It prevents lengthy outpatient wound therapy and is expected to result in a higher quality of life for patients and reduce health care costs. KW - open wound treatment KW - surgical site infections KW - secondary skin closure KW - negative pressure wound therapy Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-267541 SN - 1435-2451 VL - 406 IS - 7 ER - TY - THES A1 - Eiring, Patrick T1 - Super-resolution microscopy of plasma membrane receptors T1 - Hochauflösende Mikroskopie von Plasmamembran Rezeptoren N2 - Plasma membrane receptors are the most crucial and most commonly studied components of cells, since they not only ensure communication between the extracellular space and cells, but are also responsible for the regulation of cell cycle and cell division. The composition of the surface receptors, the so-called "Receptome", differs and is characteristic for certain cell types. Due to their significance, receptors have been important target structures for diagnostic and therapy in cancer medicine and often show aberrant expression patterns in various cancers compared to healthy cells. However, these aberrations can also be exploited and targeted by different medical approaches, as in the case of personalized immunotherapy. In addition, advances in modern fluorescence microscopy by so-called single molecule techniques allow for unprecedented sensitive visualization and quantification of molecules with an attainable spatial resolution of 10-20 nm, allowing for the detection of both stoichiometric and expression density differences. In this work, the single molecule sensitive method dSTORM was applied to quantify the receptor composition of various cell lines as well as in primary samples obtained from patients with hematologic malignancies. The focus of this work lies on artefact free quantification, stoichiometric analyses of oligomerization states and co localization analyses of membrane receptors. Basic requirements for the quantification of receptors are dyes with good photoswitching properties and labels that specifically mark the target structure without generating background through non-specific binding. To ensure this, antibodies with a predefined DOL (degree of labeling) were used, which are also standard in flow cytometry. First background reduction protocols were established on cell lines prior analyses in primary patient samples. Quantitative analyses showed clear expression differences between the cell lines and the patient cells, but also between individual patients. An important component of this work is the ability to detect the oligomerization states of receptors, which enables a more accurate quantification of membrane receptor densities compared to standard flow cytometry. It also provides information about the activation of a certain receptor, for example of FLT3, a tyrosine kinase, dimerizing upon activation. For this purpose, different well-known monomers and dimers were compared to distinguish the typical localization statistics of single bound antibodies from two or more antibodies that are in proximity. Further experiments as well as co localization analyses proved that antibodies can bind to closely adjacent epitopes despite their size. These analytical methods were subsequently applied for quantification and visualization of receptors in two clinically relevant examples. Firstly, various therapeutically relevant receptors such as CD38, BCMA and SLAMF7 for multiple myeloma, a malignant disease of plasma cells, were analyzed and quantified on patient cells. Furthermore, the influence of TP53 and KRAS mutations on receptor expression levels was investigated using the multiple myeloma cell lines OPM2 and AMO1, showing clear differences in certain receptor quantities. Secondly, FLT3 which is a therapeutic target receptor for acute myeloid leukemia, was quantified and stoichiometrically analyzed on both cell lines and patient cells. In addition, cells that have developed resistance against midostaurin were compared with cells that still respond to this type I tyrosine-kinase-inhibitor for their FLT3 receptor expression and oligomerization state. N2 - Plasmamembranrezeptoren sind die wohl wichtigsten und meist untersuchten Komponenten einer Zelle, da sie nicht nur die Kommunikation zwischen dem extrazellulären Bereich und den Zellen gewährleisten, sondern auch für die Regulierung des Zellzyklus und der Zellteilung zuständig sind. Dabei unterscheidet sich die Zusammensetzung der Oberflächenrezeptoren, das sogenannte „Rezeptom“, und ist charakteristisch für bestimme Zelltypen. Aufgrund ihrer Bedeutsamkeit sind Rezeptoren wichtige Zielstrukturen für Diagnose und Therapie in der Krebsmedizin, welche häufig bei verschiedensten Krebserkrankungen im Vergleich zu gesunden Zellen aberrante Expressionsmuster aufweisen. Diese Abweichungen können sich allerdings auch zu Nutze gemacht werden und zum Ziel verschiedener medizinischer Behandlungsmethoden, wie es bei der personalisierten Immuntherapie der Fall ist, werden. Zusätzlich hat der Fortschritt in der modernen Fluoreszenzmikroskopie durch sogenannte Einzelmolekültechniken, es auch erlaubt, eine noch nie dagewesene empfindliche Visualisierung und Quantifizierung von Molekülen mit einer räumlichen Auflösung von 10-20 nm zu erreichen, wodurch sowohl stöchiometrische Unterschiede, als auch Unterschiede in der Expressionsdichte detektiert werden können. In dieser Arbeit wurde die einzelmolekülsensitive Methode dSTORM genutzt, um die Rezeptorkomposition von verschiedenen Zelllinien aber auch von primären Patientenzellen mit zugrundeliegenden hämatologischen Erkrankungen zu quantifizieren. Schwerpunkte dieser Arbeit sind dabei die artefaktfreie Quantifizierung, stöchiometrische Analysen von Oligomerisierungszuständen, sowie die Kolokalisationsanalyse von Membranrezeptoren. Grundvoraussetzung für die Quantifizierung von Rezeptoren sind dabei gut schaltbare Farbstoffe, sowie Label, welche die Zielstruktur spezifisch markieren ohne dabei Hintergrund durch unspezifische Bindung zu generieren. Um dies zu gewährleisten, kamen Antikörper mit einem vordefinierten DOL (degree of labeling; engl. für: Markierungsgrad) zum Einsatz, welche auch in der Durchflusszytometrie standardmäßig eingesetzt werden. Protokolle zur Hintergrundreduktion wurden dabei an Zelllinien etabliert, bevor Primärzellen von Krebspatienten analysiert wurden. Durch quantitative Analysen konnten dabei deutliche Expressionsunterschiede zwischen den Zelllinien und den Patientenzellen, aber auch zwischen den verschiedenen Patienten gezeigt werden. Ein wichtiger Bestandteil dieser Arbeit ist die Fähigkeit, den Oligomerisierungszustand von Rezeptoren zu erkennen, was eine genauere Quantifizierung der Membran-rezeptordichten im Vergleich zur Durchflusszytometrie ermöglicht. Allerdings können diese Oligomerisierungszustände auch Informationen über die Aktivierung eines Rezeptors beinhalten, wie zum Beispiel von FLT3, einer Tyrosinkinase, welche zur Aktivierung dimerisieren muss. Hierfür wurden verschiedene bekannte Monomere und Dimere verglichen, um die typische Lokalisationsstatistik von vereinzelten gebundenen Antikörpern mit der von zwei oder mehr Antikörpern, welche nah beieinanderliegen, zu vergleichen. Durch weitere Etablierungsexperimente sowie Kolokalisationsanalysen konnte außerdem bewiesen werden, dass Antikörper trotz ihrer Größe auch an nah benachbarte Epitope binden können. Diese Analyseverfahren wurden im weiteren Verlauf zur Quantifizierung und Visualisierung von Rezeptoren an zwei klinisch relevanten Beispielen angewendet. Zum einen wurden verschiedene therapeutisch relevante Rezeptoren wie z.B. CD38, BCMA und SLAMF7 für das Multiple Myelom, einer malignen Erkrankung von Plasmazellen, auf Patientenzellen analysiert und quantifiziert. Zusätzlich wurde der Einfluss von TP53 und KRAS Mutationen auf die Rezeptorexpressionen anhand der Multiplen Myelom Zelllinien OPM2 und AMO1 untersucht, bei denen eindeutige Unterschiede in der Rezeptorexpression detektiert wurden. Zum anderen wurde FLT3, welches ein therapeutischer Zielrezeptor für die akute myeloische Leukämie ist, sowohl auf Zelllinien als auch auf Patientenzellen quantifiziert und stöchiometrisch analysiert. Hierbei wurden auch Zellen welche eine Midostaurinresistenz entwickelt haben mit Zellen, welche auf diesen Typ I Tyrosinkinase Inhibitor ansprechen, auf ihre FLT3 Rezeptorexpression und ihren Oligomerisierungszustand verglichen. KW - Fluoreszenzmikroskopie KW - Membranrezeptor KW - Hochaufgelöste Fluoreszenzmikroskopie KW - Super-resolution microscopy KW - Membrane receptor Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-250048 ER - TY - THES A1 - Schlegel, Jan T1 - Super-Resolution Microscopy of Sphingolipids and Protein Nanodomains T1 - Hochaufgelöste Mikroskopie von Sphingolipiden und Protein Nanodomänen N2 - The development of cellular life on earth is coupled to the formation of lipid-based biological membranes. Although many tools to analyze their biophysical properties already exist, their variety and number is still relatively small compared to the field of protein studies. One reason for this, is their small size and complex assembly into an asymmetric tightly packed lipid bilayer showing characteristics of a two-dimensional heterogenous fluid. Since membranes are capable to form dynamic, nanoscopic domains, enriched in sphingolipids and cholesterol, their detailed investigation is limited to techniques which access information below the diffraction limit of light. In this work, I aimed to extend, optimize and compare three different labeling approaches for sphingolipids and their subsequent analysis by the single-molecule localization microscopy (SMLM) technique direct stochastic optical reconstruction microscopy (dSTORM). First, I applied classical immunofluorescence by immunoglobulin G (IgG) antibody labeling to detect and quantify sphingolipid nanodomains in the plasma membrane of eukaryotic cells. I was able to identify and characterize ceramide-rich platforms (CRPs) with a size of ~ 75nm on the basal and apical membrane of different cell lines. Next, I used click-chemistry to characterize sphingolipid analogs in living and fixed cells. By using a combination of fluorescence microscopy and anisotropy experiments, I analyzed their accessibility and configuration in the plasma membrane, respectively. Azide-modified, short fatty acid side chains, were accessible to membrane impermeable dyes and localized outside the hydrophobic membrane core. In contrast, azide moieties at the end of longer fatty acid side chains were less accessible and conjugated dyes localized deeper within the plasma membrane. By introducing photo-crosslinkable diazirine groups or chemically addressable amine groups, I developed methods to improve their immobilization required for dSTORM. Finally, I harnessed the specific binding characteristics of non-toxic shiga toxin B subunits (STxBs) and cholera toxin B subunits (CTxBs) to label and quantify glycosphingolipid nanodomains in the context of Neisseria meningitidis infection. Under pyhsiological conditions, these glycosphingolipids were distributed homogenously in the plasma membrane but upon bacterial infection CTxB detectable gangliosides accumulated around invasive Neisseria meningitidis. I was able to highlight the importance of cell cycle dependent glycosphingolipid expression for the invasion process. Blocking membrane accessible sugar headgroups by pretreatment with CTxB significantly reduced the number of invasive bacteria which confirmed the importance of gangliosides for bacterial uptake into cells. Based on my results, it can be concluded that labeling of sphingolipids should be carefully optimized depending on the research question and applied microscopy technique. In particular, I was able to develop new tools and protocols which enable the characterization of sphingolipid nanodomains by dSTORM for all three labeling approaches. N2 - Die Entwicklung von zellulären Lebensformen auf der Erde basiert auf der Entstehung biologischer Lipid-Membranen. Obwohl viele Techniken zur Verfügung stehen, welche es erlauben deren biophysikalische Eigenschaften zu untersuchen, sind die Möglichkeiten, verglichen mit der Analyse von Proteinen, eher eingeschränkt. Ein Grund hierfür, ist die geringe Größe von Lipiden und deren komplexe Zusammenlagerung in eine asymmetrische dicht gepackte Lipiddoppelschicht, welche sich wie eine heterogene zweidimensionale Flüssigkeit verhält. Durch die lokale Anreicherung von Sphingolipiden und Cholesterol sind Membranen in der Lage dynamische, nanoskopische Domänen auszubilden, welche lediglich mit Techniken, welche die optische Auflösungsgrenze umgehen, detailliert untersucht werden können. Ein wesentliches Ziel meiner Arbeit war es, drei Färbeverfahren für Sphingolipide zu vergleichen, erweitern und optimieren, um eine anschliessende Untersuchung mit Hilfe der einzelmolekülsensitiven Technik dSTORM (direct stochastic optical reconstruction microscopy) zu ermöglichen. Zunächst verwendete ich das klassische Färbeverfahren der Immunfluoreszenz, um Sphingolipid-Nanodomänen auf eukaryotischen Zellen mit Hilfe von Farbstoff-gekoppelten Antikörpern zu detektieren und quantifizieren. Dieses Vorgehen ermöglichte es mir, Ceramid-angereicherte Plattformen mit einer Größe von ~ 75nm auf der basalen und apikalen Membran verschiedener Zell-Linien zu identifizieren und charakterisieren. Als nächstes Verfahren verwendete ich die Klick-Chemie, um Sphingolipid-Analoge in lebenden und fixierten Zellen zu untersuchen. Eine Kombination aus Fluoreszenz-Mikroskopie und Anisotropie-Messungen erlaubte es mir Rückschlüsse über deren Zugänglichkeit und Konfiguration innerhalb der Plasmamembran zu ziehen. Hierbei lokalisierten Azid-Gruppen am Ende kurzkettiger Fettsäurereste außerhalb des hydrophoben Membrankerns, wodurch sie mittels membran-undurchlässige Farbstoffe angeklickt werden konnten. Im Gegensatz dazu, waren Azide an längeren Fettsäureresten weniger zugänglich und konjugierte Farbstoffe tauchten tiefer in die Plasmamembran ein. Durch die Einführung photoreaktiver Diazirin-Gruppen oder chemisch modifzierbarer Amin-Gruppen wurden Wege geschaffen, welche eine Immobilisierung und anschließende Analyse mit Hilfe von dSTORM ermöglichen. Schließlich nutzte ich das spezifische Bindeverhalten der nicht toxischen B Untereinheiten von Shiga- (STxB) und Cholera-Toxin (CTxB) aus, um Glycosphingolipid Nanodomänen im Kontext einer Neisseria meningitidis Infektion zu untersuchen. Unter physiologischen Bedingungen waren diese homogen in der Plasmamembran verteilt, jedoch reicherten sich CTxB-detektierbare Ganglioside um eindringende Bakterien an. Darüber hinaus konnte ich einen Zusammenhang zwischen der zellzyklusabhängigen Expression von Glycosphingolipiden und dem Eindringen der Bakterien herstellen. Eine Absättigung der Zucker an der äußeren Membran durch CTxB-Vorbehandlung reduzierte die Anzahl von invasiven Bakterien signifikant und bestätigte die Schlüsselrolle von Gangliosiden bei der Aufnahme von Bakterien. Meine Ergebnisse legen Nahe, dass das Färbeverfahren für Sphingolipide an die jeweilige Fragestellung und Mikroskopietechnik angepasst werden sollte. Im Rahmen dieser Arbeit konnten neue Werkzeuge und Protokolle geschaffen werden, die die Charakterisierung von Sphingolipid-Nanodomänen mittels dSTORM für alle drei Färbeverfahren ermöglichen. KW - Sphingolipide KW - Lipide KW - Einzelmolekülmikroskopie KW - Click-Chemie KW - Lipid Raft KW - super-resolution microscopy KW - sphingolipids KW - labeling techniques KW - dSTORM KW - lipid rafts Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229596 ER - TY - JOUR A1 - Haack, Stephanie A1 - Baiker, Sarah A1 - Schlegel, Jan A1 - Sauer, Markus A1 - Sparwasser, Tim A1 - Langenhorst, Daniela A1 - Beyersdorf, Niklas T1 - Superagonistic CD28 stimulation induces IFN‐γ release from mouse T helper 1 cells in vitro and in vivo JF - European Journal of Immunology N2 - Like human Th1 cells, mouse Th1 cells also secrete IFN‐γ upon stimulation with a superagonistic anti‐CD28 monoclonal antibody (CD28‐SA). Crosslinking of the CD28‐SA via FcR and CD40‐CD40L interactions greatly increased IFN‐γ release. Our data stress the utility of the mouse as a model organism for immune responses in humans. KW - CD28 KW - Th1 cells KW - cytokine release KW - interferon γ KW - Superagonistic antibody Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239028 VL - 51 IS - 3 SP - 738 EP - 741 ER - TY - JOUR A1 - Sputh, Sebastian A1 - Panzer, Sabine A1 - Stigloher, Christian A1 - Terpitz, Ulrich T1 - Superaufgelöste Mikroskopie: Pilze unter Beobachtung JF - BIOspektrum N2 - The diffraction limit of light confines fluorescence imaging of subcellular structures in fungi. Different super-resolution methods are available for the analysis of fungi that we briefly discuss. We exploit the filamentous fungus Fusarium fujikuroi expressing a YFP-labeled membrane protein showing the benefit of correlative light- and electron microscopy (CLEM), that combines structured illumination microscopy (SIM) and scanning election microscopy (SEM). KW - Pilze KW - mikroskopische Untersuchung KW - Abbe-Limit Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270014 SN - 1868-6249 VL - 27 IS - 4 ER - TY - JOUR A1 - Radeloff, Katrin A1 - Ramos Tirado, Mario A1 - Haddad, Daniel A1 - Breuer, Kathrin A1 - Müller, Jana A1 - Hochmuth, Sabine A1 - Hackenberg, Stephan A1 - Scherzad, Agmal A1 - Kleinsasser, Norbert A1 - Radeloff, Andreas T1 - Superparamagnetic iron oxide particles (VSOPs) show genotoxic effects but no functional impact on human adipose tissue-derived stromal cells (ASCs) JF - Materials N2 - Adipose tissue-derived stromal cells (ASCs) represent a capable source for cell-based therapeutic approaches. For monitoring a cell-based application in vivo, magnetic resonance imaging (MRI) of cells labeled with iron oxide particles is a common method. It is the aim of the present study to analyze potential DNA damage, cytotoxicity and impairment of functional properties of human (h)ASCs after labeling with citrate-coated very small superparamagnetic iron oxide particles (VSOPs). Cytotoxic as well as genotoxic effects of the labeling procedure were measured in labeled and unlabeled hASCs using the MTT assay, comet assay and chromosomal aberration test. Trilineage differentiation was performed to evaluate an impairment of the differentiation potential due to the particles. Proliferation as well as migration capability were analyzed after the labeling procedure. Furthermore, the labeling of the hASCs was confirmed by Prussian blue staining, transmission electron microscopy (TEM) and high-resolution MRI. Below the concentration of 0.6 mM, which was used for the procedure, no evidence of genotoxic effects was found. At 0.6 mM, 1 mM as well as 1.5 mM, an increase in the number of chromosomal aberrations was determined. Cytotoxic effects were not observed at any concentration. Proliferation, migration capability and differentiation potential were also not affected by the procedure. Labeling with VSOPs is a useful labeling method for hASCs that does not affect their proliferation, migration and differentiation potential. Despite the absence of cytotoxicity, however, indications of genotoxic effects have been demonstrated. KW - ASCs KW - adipose tissue-derived stromal cells KW - VSOP KW - iron oxide nanoparticles KW - toxicity KW - MRI KW - cell labeling Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-222970 SN - 1996-1944 VL - 14 IS - 2 ER - TY - THES A1 - Wehner, Marius T1 - Supramolecular Polymorphism in Homo- and Heterochiral Supramolecular Polymerizations T1 - Supramolekularer Polymorphismus in homo- und heterochiralen supramolekularen Polymerisationen N2 - The aim of the first part of this thesis was to investigate (R,R)-PBI as a model system for polymorphism at its origin by a supramolecular approach. The pathway complexity of (R,R)-PBI was fine-tuned by experimental parameters such as solvent, temperature and concentration to make several supramolecular polymorphs accessible. Mechanistic and quantum chemical studies on the kinetics and thermodynamics of the supramolecular polymerization of (R,R)-PBI were conducted to shed light on the initial stages of polymorphism. The second part of this work deals with mechanistic investigations on the supramolecular polymerization of the racemic mixture of (R,R)- and (S,S)-PBI with regard to homochiral and heterochiral aggregation leading to conglomerates and a racemic supramolecular polymer, respectively. N2 - Das Ziel des ersten Teils der Dissertation war es, anhand des Modellsystems (R,R)-PBI Polymorphismus mit Hilfe eines supramolekularen Ansatzes an dessen Ursprung zu untersuchen. Durch die Wahl geeigneter experimenteller Parameter wie Lösungsmittel, Temperatur und Konzentration wurden die komplexen Polymerisationspfade von (R,R)-PBI gezielt beeinflusst und verschiedene supramolekulare Polymorphe zugänglich gemacht. Mechanistische und quantenchemische Untersuchungen der Kinetik und Thermodynamik der supramolekularen Polymerisation von (R,R)-PBI wurden durchgeführt, um die Anfangsphase des Polymorphismus zu beleuchten. Der zweite Teil der vorliegenden Arbeit befasst sich mit mechanistischen Untersuchungen der supramolekularen Polymerisation der racemischen Mischung aus (R,R)- und (S,S)-PBI im Hinblick auf homo- und heterochirale Aggregation, welche zu Konglomeraten beziehungsweise einem racemischen supramolekularen Polymer führte. KW - Supramolekulare Chemie KW - Polymorphismus KW - Konglomerat KW - Aggregat KW - Organische Chemie KW - Aggregation Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-211519 ER - TY - JOUR A1 - Kriegel, Peter A1 - Fritze, Michael‐Andreas A1 - Thorn, Simon T1 - Surface temperature and shrub cover drive ground beetle (Coleoptera: Carabidae) assemblages in short‐rotation coppices JF - Agricultural and Forest Entomology N2 - Increasing demand for biomass has led to an on‐going intensification of fuel wood plantations with possible negative effects on open land biodiversity. Hence, ecologists increasingly call for measures that reduce those negative effects on associated biodiversity. However, our knowledge about the efficiency of such measures remains scarce. We investigated the effects of gap implementation in short rotation coppices (SRCs) on carabid diversity and assemblage composition over 3 years, with pitfall traps in gaps, edges and interiors. In parallel, we quantified soil surface temperature, shrub‐ and herb cover. Edges had the highest number of species and abundances per trap, whereas rarefied species richness was significantly lower in short rotation coppice interiors than in other habitat types. Carabid community composition differed significantly between habitat types. The main environmental drivers were temperature for number of species and abundance and shrub cover for rarefied species richness. We found significantly higher rarefied species richness in gaps compared with interiors. Hence, we argue that gap implementation benefits overall diversity in short rotation coppices. Furthermore, the differences in species community composition between habitat types through increased species turnover support carabid diversity in short rotation coppices. These positive effects were largely attributed to microclimate conditions. However, to maintain positive effects, continuous management of herb layer might be necessary. KW - Carabidae KW - fuel wood KW - short‐rotation coppice KW - shrub‐cover KW - temperature Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239873 VL - 23 IS - 4 SP - 400 EP - 410 ER - TY - JOUR A1 - Gil-Sepulcre, Marcos A1 - Lindner, Joachim O. A1 - Schindler, Dorothee A1 - Velasco, Lucía A1 - Moonshiram, Dooshaye A1 - Rüdiger, Olaf A1 - DeBeer, Serena A1 - Stepanenko, Vladimir A1 - Solano, Eduardo A1 - Würthner, Frank A1 - Llobet, Antoni T1 - Surface-promoted evolution of Ru-bda coordination oligomers boosts the efficiency of water oxidation molecular anodes JF - Journal of the American Chemical Society N2 - A new Ru oligomer of formula {[Ru-\(^{II}\)(bda-\(\kappa\)-N\(^2\)O\(^2\))(4,4'-bpy)]\(_{10}\)(4,4'-bpy)}, 10 (bda is [2,2'-bipyridine]-6,6'-dicarbox-ylate and 4,4'-bpy is 4,4'-bipyridine), was synthesized and thoroughly characterized with spectroscopic, X-ray, and electrochemical techniques. This oligomer exhibits strong affinity for graphitic materials through CH-\(\pi\) interactions and thus easily anchors on multiwalled carbon nanotubes (CNT), generating the molecular hybrid material 10@CNT. The latter acts as a water oxidation catalyst and converts to a new species, 10'(H\(_2\)O)\(_2\)@CNT, during the electrochemical oxygen evolution process involving solvation and ligand reorganization facilitated by the interactions of molecular Ru catalyst and the surface. This heterogeneous system has been shown to be a powerful and robust molecular hybrid anode for electrocatalytic water oxidation into molecular oxygen, achieving current densities in the range of 200 mA/cm\(^2\) at pH 7 under an applied potential of 1.45 V vs NHE. The remarkable long-term stability of this hybrid material during turnover is rationalized based on the supramolecular interaction of the catalyst with the graphitic surface. KW - electrodes KW - ligands KW - oligomers KW - surface interactions KW - water oxidation Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-351514 VL - 143 IS - 30 ER - TY - JOUR A1 - Sivarajan, Rinu A1 - Kessie, David Komla A1 - Oberwinkler, Heike A1 - Pallmann, Niklas A1 - Walles, Thorsten A1 - Scherzad, Agmal A1 - Hackenberg, Stephan A1 - Steinke, Maria T1 - Susceptibility of Human Airway Tissue Models Derived From Different Anatomical Sites to Bordetella pertussis and Its Virulence Factor Adenylate Cyclase Toxin JF - Frontiers in Cellular and Infection Microbiology N2 - To study the interaction of human pathogens with their host target structures, human tissue models based on primary cells are considered suitable. Complex tissue models of the human airways have been used as infection models for various viral and bacterial pathogens. The Gram-negative bacterium Bordetella pertussis is of relevant clinical interest since whooping cough has developed into a resurgent infectious disease. In the present study, we created three-dimensional tissue models of the human ciliated nasal and tracheo-bronchial mucosa. We compared the innate immune response of these models towards the B. pertussis virulence factor adenylate cyclase toxin (CyaA) and its enzymatically inactive but fully pore-forming toxoid CyaA-AC\(^-\). Applying molecular biological, histological, and microbiological assays, we found that 1 µg/ml CyaA elevated the intracellular cAMP level but did not disturb the epithelial barrier integrity of nasal and tracheo-bronchial airway mucosa tissue models. Interestingly, CyaA significantly increased interleukin 6, interleukin 8, and human beta defensin 2 secretion in nasal tissue models, whereas tracheo-bronchial tissue models were not significantly affected compared to the controls. Subsequently, we investigated the interaction of B. pertussis with both differentiated primary nasal and tracheo-bronchial tissue models and demonstrated bacterial adherence and invasion without observing host cell type-specific significant differences. Even though the nasal and the tracheo-bronchial mucosa appear similar from a histological perspective, they are differentially susceptible to B. pertussis CyaA in vitro. Our finding that nasal tissue models showed an increased innate immune response towards the B. pertussis virulence factor CyaA compared to tracheo-bronchial tissue models may reflect the key role of the nasal airway mucosa as the first line of defense against airborne pathogens. KW - human nasal epithelial cells KW - human tracheo-bronchial epithelial cells KW - human airway mucosa tissue models KW - adenylate cyclase toxin KW - Bordetella pertussis Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-253302 SN - 2235-2988 VL - 11 ER - TY - JOUR A1 - Bianchi, Maria A1 - Sivarajan, Rinu A1 - Walles, Thorsten A1 - Hackenberg, Stephan A1 - Steinke, Maria T1 - Susceptibility of primary human airway epithelial cells to Bordetella pertussis adenylate cyclase toxin in two- and three-dimensional culture conditions JF - Innate Immunity N2 - The human pathogen Bordetella pertussis targets the respiratory epithelium and causes whooping cough. Its virulence factor adenylate cyclase toxin (CyaA) plays an important role in the course of infection. Previous studies on the impact of CyaA on human epithelial cells have been carried out using cell lines derived from the airways or the intestinal tract. Here, we investigated the interaction of CyaA and its enzymatically inactive but fully pore-forming toxoid CyaA-AC– with primary human airway epithelial cells (hAEC) derived from different anatomical sites (nose and tracheo-bronchial region) in two-dimensional culture conditions. To assess possible differences between the response of primary hAEC and respiratory cell lines directly, we included HBEC3-KT in our studies. In comparative analyses, we studied the impact of both the toxin and the toxoid on cell viability, intracellular cAMP concentration and IL-6 secretion. We found that the selected hAEC, which lack CD11b, were differentially susceptible to both CyaA and CyaA-AC–. HBEC3-KT appeared not to be suitable for subsequent analyses. Since the nasal epithelium first gets in contact with airborne pathogens, we further studied the effect of CyaA and its toxoid on the innate immunity of three-dimensional tissue models of the human nasal mucosa. The present study reveals first insights in toxin–cell interaction using primary hAEC. KW - Adenylate cyclase toxin KW - cyclic adenosine monophosphate KW - human respiratory epithelial cells KW - IL-6 KW - Bordetella pertussis Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-219849 SN - 1753-4259 SN - 1753-4267 VL - 27 IS - 1 SP - 89-98 ER - TY - JOUR A1 - Redlich, Sarah A1 - Martin, Emily A. A1 - Steffan‐Dewenter, Ingolf T1 - Sustainable landscape, soil and crop management practices enhance biodiversity and yield in conventional cereal systems JF - Journal of Applied Ecology N2 - Input‐driven, modern agriculture is commonly associated with large‐scale threats to biodiversity, the disruption of ecosystem services and long‐term risks to food security and human health. A switch to more sustainable yet highly productive farming practices seems unavoidable. However, an integrative evaluation of targeted management schemes at field and landscape scales is currently lacking. Furthermore, the often‐disproportionate influence of soil conditions and agrochemicals on yields may mask the benefits of biodiversity‐driven ecosystem services. Here, we used a real‐world ecosystem approach to identify sustainable management practices for enhanced functional biodiversity and yield on 28 temperate wheat fields. Using path analysis, we assessed direct and indirect links between soil, crop and landscape management with natural enemies and pests, as well as follow‐on effects on yield quantity and quality. A paired‐field design with a crossed insecticide‐fertilizer experiment allowed us to control for the relative influence of soil characteristics and agrochemical inputs. We demonstrate that biodiversity‐enhancing management options such as reduced tillage, crop rotation diversity and small field size can enhance natural enemies without relying on agrochemical inputs. Similarly, we show that in this system controlling pests and weeds by agrochemical means is less relevant than expected for final crop productivity. Synthesis and applications. Our study highlights soil, crop and landscape management practices that can enhance beneficial biodiversity while reducing agrochemical usage and negative environmental impacts of conventional agriculture. The diversification of cropping systems and conservation tillage are practical measures most farmers can implement without productivity losses. Combining local measures with improved landscape management may also strengthen the sustainability and resilience of cropping systems in light of future global change. KW - crop management KW - ecological intensification KW - landscape heterogeneity KW - natural enemies KW - pests KW - soil characteristics KW - sustainable intensification KW - wheat yield Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228345 VL - 58 IS - 3 SP - 507 EP - 517 ER - TY - THES A1 - Georgiev, Kostadin T1 - Sustainable management of naturally disturbed forests T1 - Nachhaltiges Management von natürlichen Störungen in Wäldern N2 - Owing to climate change, natural forest disturbances and consecutive salvage logging are drastically increasing worldwide, consequently increasing the importance of understanding how these disturbances would affect biodiversity conservation and provision of ecosystem services. In chapter II, I used long-term water monitoring data and mid-term data on α-diversity of twelve species groups to quantify the effects of natural disturbances (windthrow and bark beetle) and salvage logging on concentrations of nitrate and dissolved organic carbon (DOC) in streamwater and α-diversity. I found that natural disturbances led to a temporal increase of nitrate concentrations in streamwater, but these concentrations remained within the health limits recommended by the World Health Organization for drinking water. Salvage logging did not exert any additional impact on nitrate and DOC concentrations, and hence did not affect streamwater quality. Thus, neither natural forest disturbances in watersheds nor associated salvage logging have a harmful effect on the quality of the streamwater used for drinking water. Natural disturbances increased the α-diversity in eight out of twelve species groups. Salvage logging additionally increased the α-diversity of five species groups related to open habitats, but decreased the biodiversity of three deadwood-dependent species groups. In chapter III, I investigated whether salvage logging following natural disturbances (wildfire and windthrow) altered the natural successional trajectories of bird communities. I compiled data on breeding bird assemblages from nine study areas in North America, Europe and Asia, over a period of 17 years and tested whether bird community dissimilarities changed over time for taxonomic, functional and phylogenetic diversity when rare, common and dominant species were weighted differently. I found that salvage logging led to significantly larger dissimilarities than expected by chance and that these dissimilarities persisted over time for rare, common and dominant species, evolutionary lineages, and for rare functional groups. Dissimilarities were highest for rare, followed by common and dominant species. In chapter IV, I investigated how β-diversity of 13 taxonomic groups would differ in intact, undisturbed forests, disturbed, unlogged forests and salvage-logged forests 11 years after a windthrow and salvage logging. The study suggests that both windthrow and salvage logging drive changes in between-treatment β-diversity, whereas windthrow alone seems to drive changes in within-treatment β-diversity. Over a decade after the windthrow at the studied site, the effect of subsequent salvage logging on within-treatment β-diversity was no longer detectable but the effect on between-treatment β-diversity persisted, with more prominent changes in saproxylic groups and rare species than in non-saproxylic groups or common and dominant species. Based on these results, I suggest that salvage logging needs to be carefully weighed against its long-lasting impact on communities of rare species. Also, setting aside patches of naturally disturbed areas is a valuable management alternative as these patches would enable post-disturbance succession of bird communities in unmanaged patches and would promote the conservation of deadwood-dependent species, without posing health risks to drinking water sources. N2 - In Folge des Klimawandels treten in Wäldern vermehrt natürliche Störungen auf, wodurch wiederum die Zahl an nachfolgenden Sanitärhieben (Räumungen) drastisch gestiegen ist. Wie sich natürliche Störungen und Sanitärhiebe auf die biologische Vielfalt und die Bereitstellung von Ökosystemleistungen auswirken können, ist bisher jedoch nur unzureichend bekannt. In Kapitel II nutzte ich langfristige Wassermonitoringdaten und mittelfristige Biodiversitätsdaten über zwölf Artengruppen, um die Effekte von natürlichen Störungen (Windwurf und Borkenkäfer) und Sanitärhieben auf die Konzentrationen von Nitraten und gelöster organischer Kohlenstoffe (GOK) in Bächen und Artenzahl zu quantifizieren. Die Ergebnisse zeigen, heraus, dass natürliche Störungen zu einer temporären Erhöhung der Nitratwerte führen, welche dennoch laut Angaben der Weltgesundheitsorganisation immer noch als unbedenklich eingestuft werden können. Die Sanitärhiebe hatten keinen zusätzlichen Einfluss auf die Nitrat- und GOK-Konzentrationen und daher keinen Einfluss auf die Wasserqualität. Daraus lässt sich schließen, dass sich weder natürliche Waldstörungen in Wassereinzugsgebieten noch die damit verbundenen Sanitärhiebe auf die Trinkwasserqualität aus auswirken. Natürliche Störungen erhöhten die Artenzahlen in acht von zwölf Artengruppen. Zusätzlich erhöhten die Sanitärhiebe die Artenzahlen von fünf Artengruppen, welche auf offene Lebensräume angewiesen sind, verringerte jedoch die Artenzahlen von drei xylobionte Artengruppen. In Kapitel III habe ich untersucht, ob Sanitärhiebe nach natürlichen Waldstörungen zu sukzessiven Veränderungen der Vogelgemeinschaften führen. Hierzu habe ich die taxonomische, funktionelle und phylogenetische Diversität von Brutvogelgemeinschaften aus neun Untersuchungsregionen in Nordamerika, Europa und Asien über die Zeit von 17 Jahren verglichen und analysiert, ob sich das jeweilige Diversitätsmaß verändert, wenn seltene, häufige und dominante Arten unterschiedlich gewichtet werden. Ich konnte zeigen, dass Sanitärhiebe zu signifikant größeren Unterschieden geführt haben als zufällig zu erwarten gewesen sind und dass diese Unterschiede über die Zeit sowohl für seltene, häufige und dominante Arten, als auch für evolutionäre Linien, und funktionelle Gruppen fortdauern. Diese Unterschiede waren am größten für seltene, gefolgt von häufigen und dominanten Arten. In Kapitel IV untersuchte ich wie sich die β-Diversität von 13 taxonomischen Gruppen zwischen ungestörten Wäldern, gestörten und ungeräumten Wäldern sowie gestörten und geräumten Wäldern 11 Jahre nach Windwurf und anschließender Räumung unterscheidet. Die Ergebnisse deuten darauf hin, dass sowohl Windwurf als auch Räumung Änderungen in der β-Diversität bewirken. Windwurf allein jedoch scheint diese Änderungen in der β-Diversität innerhalb der Behandlung bewirken zu können. Über ein Jahrzehnt nach dem Windwurf war der Effekt des Sanitärhiebes auf die β-Diversität innerhalb der Behandlung nicht mehr nachweisbar. Der Effekt auf die β-Diversität zwischen den Behandlungen blieb jedoch bestehen, wobei sich die xylobionten Gruppen und seltenen Arten stärker veränderten als die nicht-xylobionten Gruppen oder häufigen und dominanten Arten. Basierend auf diesen Ergebnissen schlage ich vor, dass der Einsatz von Sanitärhieben sorgfältig gegen ihre langfristigen Auswirkungen auf Gemeinschaften seltener Arten abgewogen werden muss. Zusätzlich, besteht mit dem Belassen von natürlich gestörten Waldgebieten eine wertvolle Managementalternative, da diese Flächen eine natürliche Entwicklung von Vogelgemeinschaften ermöglichen und xylobionte Arten fördern, ohne dass die Trinkwasserqualität negativ beeinträchtigt wird. KW - species richness KW - water quality KW - beta diversity KW - Hill numbers KW - post-disturbance logging KW - biodiversity response KW - ecosystem services Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-242854 ER - TY - THES A1 - Kreß, Theresa T1 - Symptommanagement bei konservativ behandelten Tumorpatienten T1 - Symptom management of conservatively treated cancer patients N2 - Schmerz ist ein häufiges Problem bei Tumorpatienten und nach wie vor nicht ausreichend erkannt oder behandelt. Hierfür werden zunehmend standardisierte Fragebögen basierend auf patient-reported outcomes eingesetzt. QUIPS ist als solcher Fragebogen im perioperativen Bereich etabliert. Analog dazu wurde QUIKS als Fragebogen für das konservative Schmerzmanagement entwickelt. In dieser Studie konnte erstmals die Einsetzbarkeit des QUIKS-Bogens an Tumorpatienten getestet werden. Die Patienten wurden einmalig während ihres stationären Aufenthaltes befragt, ergänzt um den IPOS Fragebogen um ein umfassendes Bild auch des palliativmedizinischen Unterstützungsbedarfs zu erhalten. Die Ergebnisse zeigen, dass Schmerz bei konservativ behandelten Tumorpatienten insgesamt gut kontrolliert ist. Die bestehenden Strukturen sind geeignet, um Schmerzen zu erfassen und zu lindern. Dennoch sollte die Information über Schmerz und Schmerztherapie noch verbessert werden. Aufgrund der umfassenden Erfassung verschiedener Aspekte wie Schmerzintensität, -entwicklung sowie schmerzbedingter Einschränkungen und der Zufriedenheit mit der Schmerztherapie scheint QUIKS ein geeignetes Instrument zur Erfassung der Schmerzsituation bei Tumorpatienten zu sein. Die aufgedeckten Schwächen des Bogens könnten nur durch deutlich höheren Zeit- und Personalaufwand behoben werden. In Kombination mit den Ergebnissen des IPOS Fragebogens konnte die Verlässlichkeit des QUIKS Bogens indirekt bestätigt werden. N2 - Pain in a common problem in cancer patients and still not necessarily identified or treated. In this regard, standardized questionnaires based upon patient-reported outcomes are increasingly used. QUIPS as such a questionnaire is commonly used in perioperative settings. According to this QUIKS as tool for conservative pain management has been developed. During this study QUIKS could be used for the first time to test the usability in cancer patients. Patients were questioned once during their stay in hospital. They also answered the IPOS questionnaire to broadly identify the palliative care needs. The results show that pain in conservatively treated cancer patients is generally well controlled. The existing structures are suitable to register and lessen pain. Still, the information about pain and pain therapy should be improved. Due to the broad registration of many aspects of pain such as pain intensity, development, pain related disabilities and satisfaction with the pain therapy QUIKS seems to be a usable tool to capture the pain situation in cancer patients. The discovered limitations of the questionnaire could only be solved by investing much more time and staff. In combination with the results of the IPOS questionnaire the reliability of the QUIKS questionnaire could be confirmed. KW - Palliativtherapie KW - Schmerz KW - konservative Tumortherapie KW - Schmerzerfassung KW - Symptommanagement Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232879 ER - TY - JOUR A1 - Höhn, Stefan A1 - Frimmel, Hartwig E. A1 - Prince, Westley T1 - Syn-metamorphic sulfidation of the Gamsberg zinc deposit, South Africa JF - Mineralogy and Petrology N2 - The Mesoproterozoic Aggeneys-Gamsberg ore district, South Africa, is one of the world´s largest sulfidic base metal concentrations and well-known as a prime example of Broken Hill-type base metal deposits, traditionally interpreted as metamorphosed SEDEX deposits. Within this district, the Gamsberg deposit stands out for its huge size and strongly Zn-dominated ore ( >14 Mt contained Zn). New electron microprobe analyses and element abundance maps of sulfides and silicates point to fluid-driven sulfidation during retrograde metamorphism. Differences in the chemistry of sulfide inclusions within zoned garnet grains reflect different degrees of interaction of sulfides with high metal/sulfur-ratio with a sulfur-rich metamorphic fluid. Independent evidence of sulfidation during retrograde metamorphism comes from graphic-textured sulfide aggregates that previously have been interpreted as quenched sulfidic melts, replacement of pyrrhotite by pyrite along micro-fractures, and sulfides in phyllic alteration zones. Limited availability of fluid under retrograde conditions caused locally different degrees of segregation of Fe-rich sphalerite into Zn-rich sphalerite and pyrite, and thus considerable heterogeneity in sphalerite chemistry. The invoked sulfur-rich metamorphic fluids would have been able to sulfidize base metal-rich zones in the whole deposit and thus camouflage a potential pre-metamorphic oxidation. These findings support the recently established hypothesis of a pre-Klondikean weathering-induced oxidation event and challenge the traditional explanation of Broken Hill-type deposits as merely metamorphosed SEDEX deposits. Instead, we suggest that the massive sulfide deposits experienced a complex history, starting with initial SEDEX-type mineralization, followed by near-surface oxidation with spatial metal separation, and then sulfidation of this oxidized ore during medium- to high-grade metamorphism. KW - Gamsberg KW - metamorphic sulfidation KW - sulfide inclusions KW - base metal deposit KW - Aggeneys Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-268574 SN - 1438-1168 VL - 115 IS - 6 ER - TY - THES A1 - Ciba, Manuel T1 - Synchrony Measurement and Connectivity Estimation of Parallel Spike Trains from in vitro Neuronal Networks T1 - Messung der Synchronität und Abschätzung der Konnektivität von in-vitro Spike-Trains N2 - The goal of this doctoral thesis is to identify appropriate methods for the estimation of connectivity and for measuring synchrony between spike trains from in vitro neuronal networks. Special focus is set on the parameter optimization, the suitability for massively parallel spike trains, and the consideration of the characteristics of real recordings. Two new methods were developed in the course of the optimization which outperformed other methods from the literature. The first method “Total spiking probability edges” (TSPE) estimates the effective connectivity of two spike trains, based on the cross-correlation and a subsequent analysis of the cross-correlogram. In addition to the estimation of the synaptic weight, a distinction between excitatory and inhibitory connections is possible. Compared to other methods, simulated neuronal networks could be estimated with higher accuracy, while being suitable for the analysis of massively parallel spike trains. The second method “Spike-contrast” measures the synchrony of parallel spike trains with the advantage of automatically optimizing its time scale to the data. In contrast to other methods, which also adapt to the characteristics of the data, Spike-contrast is more robust to erroneous spike trains and significantly faster for large amounts of parallel spike trains. Moreover, a synchrony curve as a function of the time scale is generated by Spike-contrast. This optimization curve is a novel feature for the analysis of parallel spike trains. N2 - Ziel dieser Dissertation ist die Identifizierung geeigneter Methoden zur Schätzung der Konnektivität und zur Messung der Synchronität von in-vitro Spike-Trains. Besonderes Augenmerk wird dabei auf die Parameteroptimierung, die Eignung für große Mengen paralleler Spike-Trains und die Berücksichtigung der Charakteristik von realen Aufnahmen gelegt. Im Zuge der Optimierung wurden zwei neue Methoden entwickelt, die anderen Methoden aus der Literatur überlegen waren. Die erste Methode “Total spiking probability edges” (TSPE) schätzt die effektive Konnektivität zwischen zwei Spike-Trains basierend auf der Berechnung einer Kreuzkorrelation und einer anschließenden Analyse des Kreuzkorrelograms. Neben der Schätzung der synaptischen Ge- wichtung ist eine Unterscheidung zwischen exzitatorischen und inhibitorischen Verbindungen möglich. Im Vergleich zu anderen Methoden, konnten simulierte neuronale Netzwerke mit einer höheren Genauigkeit geschätzt werden. Zudem ist TSPE aufgrund der hohen Rechengeschwindigkeit für große Datenmengen geeignet. Die zweite Methode “Spike-contrast” misst die Synchronität paralleler Spike-Trains mit dem Vorteil, dass die Zeitskala automatisch an die Daten angepasst wird. Im Gegensatz zu anderen Methoden, welche sich ebenfalls an die Daten anpassen, ist Spike-contrast robuster gegenüber fehlerhaften Spike-Trains und schneller für große Datenmengen. Darüber hinaus berechnet Spike-Contrast eine Synchronitätskurve als Funktion der Zeitskala. Diese Kurve ist ein neuartiges Feature zur Analyse paralleler Spike-Trains. KW - Synchronitätsmessung KW - Konnektivitätsschätzung KW - microelectrode array KW - bicuculline KW - similarity KW - distance KW - correlation Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223646 ER - TY - THES A1 - Grebinyk, Anna T1 - Synergistic Chemo- and Photodynamic Treatment of Cancer Cells with C\(_{60}\) Fullerene Nanocomplexes T1 - Synergistische chemo- und photodynamische Behandlung von Krebszellen mit C\(_{60}\)-Fulleren-Nanokomplexen N2 - Recent progress in nanotechnology has attracted interest to a biomedical application of the carbon nanoparticle C60 fullerene (C60) due to its unique structure and versatile biological activity. In the current study the dual functionality of C60 as a photosensitizer and a drug nanocarrier was exploited to improve the efficiency of chemotherapeutic drugs towards human leukemic cells. Pristine C60 demonstrated time-dependent accumulation with predominant mitochondrial localization in leukemic cells. C60’s effects on leukemic cells irradiated with high power single chip LEDs of different wavelengths were assessed to find out the most effective photoexcitation conditions. A C60-based noncovalent nanosized system as a carrier for an optimized drug delivery to the cells was evaluated in accordance to its physicochemical properties and toxic effects. Finally, nanomolar amounts of C60-drug nanocomplexes in 1:1 and 2:1 molar ratios were explored to improve the efficiency of cell treatment, complementing it with photodynamic approach. A proposed treatment strategy was developed for C60 nanocomplexes with the common chemotherapeutic drug Doxorubicin, whose intracellular accumulation and localization, cytotoxicity and mechanism of action were investigated. The developed strategy was revealed to be transferable to an alternative potent anticancer drug – the herbal alkaloid Berberine. Hereafter, a strong synergy of treatments arising from the combination of C60-mediated drug delivery and C60 photoexcitation was revealed. Presented data indicate that a combination of chemo- and photodynamic treatments with C60-drug nanoformulations could provide a promising synergetic approach for cancer treatment. N2 - Kürzliche Fortschritte in der Nanotechnologie haben Interesse an einer biomedizinischen Anwendung des Kohlenstoffnanopartikels C60 Fulleren (C60) aufgrund seiner einzigartigen Struktur und breiten biologischen Aktivität geweckt. In der aktuellen Studie wurde die doppelte Funktionalität von C60 als Photosensibilisator und als Wirkstoff-Nanoträger genutzt, um die Wirkung von Chemotherapeutika auf menschliche Leukämiezellen zu verbessern. C60 alleine zeigte in den Zellen eine zeitabhängige Akkumulation mit vorherrschender mitochondrialer Lokalisation. Die Wirkung von C60 auf Leukämiezellen, die mit unterschiedlicher Wellenlänge bestrahlt wurden, wurde bewertet, um die effektivsten Photoanregungsbedingungen zu finden. Die physikochemischen Eigenschaften und toxischen Wirkungen von C60 auf die Leukämiezellen wurden nach nicht kovalenter Bindung von Arzneistoffen bewertet. Schließlich wurden nanomolare Mengen von C60-Wirkstoff-Nanokomplexen in Molverhältnissen von 1:1 und 2:1 untersucht, um die Effizienz der Behandlung von Zellen zu verbessern und sie durch photodynamischen Ansatz zu ergänzen. Mit dem gängigen Chemotherapeutikum Doxorubicin wurde eine Behandlungsstrategie entwickelt und dessen intrazelluläre Akkumulation und Lokalisation, Zytotoxizität und Wirkmechanismus untersucht wurden. Es wurde gezeigt, dass die entwickelte Strategie auch auf ein alternatives Krebsmedikament übertragbar ist – das pflanzliche Alkaloid Berberin. Die erhaltenen Daten deuten darauf hin, dass eine Kombination von chemo- und photodynamischen Behandlungen mit C60-Nanokomplexen einen vielversprechenden synergetischen Ansatz für die Krebsbehandlung bieten könnte. KW - cancer KW - drug delivery KW - photodynamic therapy KW - fullerene Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-222075 ER - TY - THES A1 - Lang, Katharina T1 - Synthese leitfähiger elastischer Materialkomposite durch Verwendung metallischer Nanodrähte T1 - Synthesis of conductive elastic material composites by using metallic nanowires N2 - Silbernanodrähte (AgNW) wurden in verschiedene Hybridpolymere und in eine als Referenz dienende Silikonzusammensetzung eingebaut. Durch Spincoating konnten transparente leitfähige Filme erhalten werden. Deren jeweilige Nanodrahtverteilung, thermische Aktivierung und visuelle Transparenz wurden charakterisiert. Die Perkolationsschwelle der Filme hängt dabei von der individuellen durchschnittlichen AgNW-Länge ab. Eine beträchtliche Leitfähigkeit wurde während des mechanischen Streckens bis zu 30 % aufrechterhalten. Mikrostrukturierte Hybridpolymer-Verbundfilme wurden durch UV-Lithographie erhalten. ... N2 - In the context of the present work, silver nanowires were successfully synthesized using a modified polyol process according to Sun et al.[43-45]. The reproducibility of the synthesis was increased by adjusting the reaction parameters. Silver nanowires with an average length of the of ~ 12 µm and diameters of around 50 nm were obtained. The investigations of the silver nanowires were carried out on an optical level, using LSM and SEM (Section 5.1 / Section 9). In this work silver nanowire batches of different lengths were used in the manufacture of composite systems with regard to compatibility. Correspondingly, the selected resin systems from chapter 5.2 with different polarities were introduced. ... KW - Verbundwerkstoff KW - Nanodraht KW - Polymere KW - Elastizität KW - Elastizität KW - Hybridpolymere KW - Komposit Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-248253 ER - TY - THES A1 - Wolf, Natalia T1 - Synthese multifunktionaler Farbstoffe und Linker zur Visualisierung biologischer Strukturen T1 - Synthesis of multifunctional dyes and linkers for visualization of biological structures N2 - Durch stetige Entwicklung der Mikroskopiemethoden in den letzten Jahrzehnten ist es nun möglich Strukturen und Abläufe in biologischen Systemen detaillierter darzustellen als mit der von Abbe entdeckten maximalen Auflösungsgrenze. Oft werden dabei Fluoreszenzmarker benutzt, welche die unsichtbare Welt der Mikrobiologie und deren biochemische Prozesse illuminieren. Diese werden entweder durch Expression, wie z.B. das grün fluoreszierende Protein (GFP), in das zu untersuchende Objekt eingebracht oder durch klassische Markierungsmethoden mithilfe von fluoreszierenden Immunkonjugaten installiert. Jedoch gewinnt eine alternative Strategie, die von der interdisziplinären Zusammenarbeit zwischen Chemikern, Physikern und Biologen profitiert, immer mehr an Bedeutung – die bioorthogonale Click-Chemie. Sie ermöglicht eine effiziente Fluoreszenzmarkierung der biologischen Strukturen unter minimalem Eingriff in die Abläufe der Zelle. Dazu müssen allerdings sowohl Farbstoffe als auch die biologisch aktiven Substanzen chemisch modifiziert werden, da nur dadurch die Bioorthogonalität gewährleistet werden kann. Mittlerweile existiert eine breite Palette an fluoreszierenden Farbstoffen, die das komplette sichtbare Spektrum abdecken und sich für diverse Mikroskopiemethoden eignen. Allerdings gibt es zwei Farbstoffklassen, die sich aus der gesamten Fülle abheben und sich für hochauflösende bildgebende Experimente auf Einzelmolekülebene eignen. Zum einen ist es die Farbstofffamilie der Cyanine und insbesondere der wasserlöslichen Pentamethincyanine, die reversibel und kontrolliert zum Photoschalten animiert werden können und in der stochastisch optischen Rekonstruktionsmikroskopie Anwendung finden. Zum anderen ist es die Gruppe, der Rhodamine und Fluoresceine, die zu Xanthenfarbstoffen gehören und sich durch gute photophysikalische Eigenschaften auszeichnen. Trotz der Beliebtheit stellt ihre Darstellung immer noch eine Herausforderung dar und limitiert deren Einsatz. Deshalb war es notwendig im Rahmen der vorliegenden Arbeit Möglichkeiten zur Syntheseoptimierung beider Farbstoffklassen zu finden, damit diese im Folgenden weiterentwickelt und an die biologische Fragestellung angepasst werden können. Die Arbeit unterteilt sich deshalb in Relation an die oben genannten Farbstoffklassen in zwei Bereiche. Im ersten Teil wurden Projekte basierend auf den wasserlöslichen Pentamethincyaninen behandelt. Im zweiten Teil beschäftigte sich die Arbeit mit Projekten, die auf Xanthen-Farbstoffen aufbauen. N2 - Due to steady development in microscopy methods during the last decades its now possible to visualize biological structures in more detail than Abbes low would allow. Frequently fluorescence labeling is used to illuminate the world of microbiology and its processes. There are two classical methods to introduce fluorescent markers to the target of interest. The first way is to use the expression of fluorescent proteins like GFP (green fluorescent protein). The second one is the application of fluorescent immunoconjugates. However, an alternative strategy that benefits from the interdisciplinary cooperation between chemists, physicists and biologists is becoming increasingly important – bioorthogonal click chemistry. It enables efficient fluorescent labelling of biological structures with minimal influence in cell processes. But this requires chemical modification of both dyes and the biologically active substances, as this is the only way to guarantee bioorthogonal click reactions. In the meantime, a wide range of fluorescent dyes is available that cover the entire visible spectrum and are suitable for various microscopy methods. However, there are two classes of dyes that stand out from the rest and are suitable for high-resolution imaging experiments at the single molecule level. On the one hand, there is the dye family of cyanines and in particular the water-soluble pentamethine cyanines, which can be reversibly and in a controlled manner animated to photoswitch. Therefore, they are used in stochastic optical reconstruction microscopy like dStorm. On the other hand, there is the group of rhodamines and fluoresceins, which belong to xanthene dyes and are characterized by good photophysical properties. Despite their popularity, their synthesis still poses a challenge and limits their use. Therefore, it was necessary to find ways to optimize the synthesis of both dye classes within the scope of the present work, so that they can be further developed and adapted to the biological question. This thesis is therefore divided into two parts in relation to the two above mentioned dye classes. In the first part three projects based on the water-soluble pentamethine cyanines were addressed. In the second part the work dealt with projects based on the HMSiR-dyes. KW - Farbstoff KW - Cyanin KW - Rhodaminderivate KW - Click-Chemie KW - Farbstoffsynthese KW - Pentamethincyanine KW - Siliziumrhodaminderivate KW - bioorthogonale Click-Chemie KW - Synthese Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-205312 ER - TY - THES A1 - Thiess, Torsten T1 - Synthese und Reaktivität von 1,4-Diaza-2,3-diborininen T1 - Synthesis and reactivity of 1,4-diaza-2,3-diborinines N2 - In der vorliegenden Arbeit wurde die Synthese, Funktionalisierung und Reaktivität von 1,4,2,3-Diazadiborininen untersucht. Zu Beginn sollten Bis(dimethylamino)-substituierte Diazadiborinine mit unterschiedlichen Resten an den Stickstoffatomen dargestellt werden, deren weitere Funktionalisierung später im Fokus stand. Die Synthese erfolgte durch Reduktion von 1,4-Diazabutadienen mit elementarem Lithium und anschließender Salzeliminierungsreaktion mit B2(NMe2)2Cl2. Dadurch ließen sich die monocyclischen vier N,N’-Diaryl-substituierten Diazadiborinine sowie ein Alkyl-substituiertes Diazadiborinin darstellen. Durch etablierte Methoden der Diboran(4)-Chemie wurden diese in ihre Halogenderivate (Cl, Br, I) überführt. Aus diesen konnten drei 2,3-Diazido-1,4,2,3-diazadiborinine durch Umsetzung mit TMSN3 aus den Dihalogenderivaten dargestellt werden. Diese stellen hierbei die ersten isolierten Diboran(4)azidverbindugen dar. Ebenso gelang die Synthese eines bicyclischen Naphthalinisosters, welches erneut erfolgreich in seine Halogenderivate sowie das Diazdidoderivat überführt werden konnte. Einen Einblick in den Mechanismus der 1,4,2,3-Diazadiborininbildung ermöglichte die Isolierung eines Diazadiboretidinintermediats, welches durch doppelte Salzeliminierung entsteht. Dieses erwies sich jedoch als metastabil und lagerte zum Sechsring Diazadiborinin um. Quantenchemische Berechnungen unterstutzten die experimentellen Befunde. Über Kommutierungsreaktionen konnte eine Vielzahl an B,B‘-unsymmetrisch substituierten Diazadiborininen dargestellt und isoliert werden, wobei je nach verwendeten Startmaterialien entweder Gleichgewichtsreaktionen oder quantitative Umsetzungen beobachtet wurden. Ebenso wurde die Reaktivität der neuartigen Diazidodiborane(4) gegenüber Lewis-Basen untersucht. Sowohl das monocyclische Diazadiborinin, als auch das Benzodiazadiborinin konnten mit NHC-Basen zu den fünf verschiedenen Addukten umgesetzt werden. Unter thermischer Belastung wurde bei den monocyclischen Addukten eine Staudinger-artige Reaktion beobachtet, die unter Freisetzung von N2 zur Bildung von Guanadin-substituierten Diborane(4) führte. Die Benzodiazadiborininaddukte zeigten jedoch eine gänzlich andere Reaktivität. Hier fand eine Ringverkleinerungsreaktion unter Bildung von Diazaborolen statt, welche unter Wanderung einer Azidfunktion auf das NHC-stabilisierte Boratom gebildet wurden. Auf diese Weise konnten drei 1,1-Diamino-2,2-diazidodiborane(5) isoliert werden. Während bei der Umsetzung des Naphtalenderivats mit cAAC keine selektive Reaktion beobachtet wurde, reagierte das monocyclische Diazadiborinin mit zwei Äquivalenten cAAC. Hier bedingte das erste Carbon eine Staudinger-artige Reaktion, die unter Distickstofffreisetzung zu einem Formamidin führte. Die zweite Azidgruppe wurde am $\gamma$-Stickstoffatom von einem weiteren Äquivalent cAAC koordiniert. In weiteren Reaktivitätsstudien wurde die Generierung von transienten Iminoboranen aus Diazidodiazadiborininen untersucht. Die Diazide zeigten bei Temperaturen von über 150 °C ein sehr selektives Reaktionsverhalten und gingen unter Freisetzung von Distickstoff zu 1,3,2,4-Diazadiboretidin über, wobei dies über die Dimerisierung eines intermediär gebildeten siebengliedrigen, endocyclischen Iminoborans verlief. Der Mechanismus zur Bildung der transienten Iminoborane wurde anhand zweier möglicher Bildungswege mit quantenchemischen Methoden untersucht. Im letzten Kapitel wurde die Reaktivität des Dihydrodiazadiborinins gegenüber NHC- und cAAC-Lewis-Basen untersucht. Die Umsetzung mit cAAC führte zu einer B–H-Bindungsaktivierung durch das Carbenkohlenstoffatom, die vermutlich über eine Adduktspezies verläuft. Mit dem gesättigten NHC SIMes wurde ebenfalls keine Adduktbildung beobachtet, auch wenn ein derartiges Intermediat vermutlich durchlaufen wird. Als Produkt der Umsetzung wurde indes ein bicyclisches Molekül identifiziert, welches durch doppelte Ringerweiterung gebildet wurde. Mit ungesättigten NHCs wurden drei Addukte isoliert, welche jedoch nur metastabil waren und beim Erwärmen in bicyclische Verbindungen umlagerten. Die Umlagerungsprodukte konnten weiterhin durch Koordination eines weiteren Äquivalents IMe an die B–H-Funktionalität erneut zu Addukten umgesetzt werden. Die Bildung der zweier bicyclischer Verbindungen wurde ebenfalls mit quantenchemischen Methoden untersucht, wobei ein vierstufiger Prozess durchlaufen wird. Nach der Bildung des NHC-Addukts erfolgt die Übertragung eines Hydrids auf das Carbenkohlenstoffatom. Durch Insertion eines Boratoms in die NC-Bindung des Carbenrings wird eine Spiroverbindung gebildet und im letzten Schritt folgt die Spaltung der BB-Bindung durch Insertion des ehemaligen Carbenkohlenstoffatoms, was zur Bildung der Bicyclen führt. N2 - In the present work the synthesis, functionalization and reactivity of 1,4,2,3-diazadiborinines was investigated. Initially, bis(dimethylamino)-substituted diazadiborinines with different residues on the nitrogen atoms were to be synthesized, whose further functionalization was later in focus. The synthesis was performed by reduction of 1,4-diazabutadienes with elemental lithium and subsequent salt elimination reaction with B2(NMe2)2Cl2. Thus, the monocyclic four N,N'-diaryl-substituted diazadiborinines and one alkyl-substituted diazadiborinine could be prepared. By established methods of diborane(4) chemistry, these were converted into their halogen derivatives (Cl, Br, I). From these, three 2,3-diazido-1,4,2,3-diazadiborinines could be prepared by reaction with TMSN3 from the dihalogen derivatives. These represent the first isolated diborane(4)azide compounds. The synthesis of a bicyclic naphthalene isoster was also successful, which could again be successfully converted into its halogen derivatives as well as the diazdido derivative. An insight into the mechanism of 1,4,2,3-diazadiborinine formation was gained by isolating a diazadiboretidine intermediate, which is formed by double salt elimination. However, this proved to be metastable and rearranged to the six-membered ring of diazadiborinine. Quantum chemical calculations supported the experimental findings. Via commutation reactions, a large number of B,B'-unsymmetrically substituted diazadiborinines could be represented and isolated. Depending on the starting materials used, either equilibrium reactions or quantitative conversions were observed. The reactivity of the novel diazidodiboranes(4) to Lewis bases was also investigated. Both the monocyclic diazadiborinine and the benzodiazadiborinine could be converted with NHC bases to the five different adducts. Under thermal stress a Staudinger-like reaction was observed in the monocyclic adducts, which led to the formation of guanadine-substituted diboranes(4) with the release of N2. However, the benzodiazadiborinine adducts showed a completely different reactivity. Here, a ring reduction reaction took place with formation of diazaborols, which were formed by migration of an azide function to the NHC-stabilized boron atom. In this way, three 1,1-diamino-2,2-diazidodiboranes(5) could be isolated. While no selective reaction was observed during the reaction of the naphthalene derivative with cAAC, the monocyclic diazadiborinine reacted with two equivalents of cAAC. In this case, the first carbon caused a Staudinger-like reaction, which led to the release of dinitrogen to formamidine. The second azide group was coordinated at the $\gamma$ nitrogen atom by another equivalent cAAC. In further reactivity studies the generation of transient iminoboranes from diazidodiazadiborinines was investigated. The diazides showed a highly selective reaction behavior at temperatures above 150 °C and converted to 1,3,2,4-diazadiboretidine with the release of dinitrogen. This was achieved by dimerization of an intermediately formed seven-membered endocyclic iminoborane. The mechanism for the formation of the transient iminoboranes was investigated by quantum chemical methods on the basis of two possible formation pathways. In the last chapter the reactivity of dihydrodiazadiborinine towards NHC and cAAC Lewis bases were investigated. The reaction with cAAC resulted in B-H bond activation by the carbene carbon atom, which is thought to be via an adduct species. No adduct formation was observed with the saturated NHC SIMes either, although such an intermediate is likely to be passed through. However, a bicyclic molecule formed by double ring extension was identified as the product of the reaction. Three adducts were isolated with unsaturated NHCs, but they were only metastable and rearranged into bicyclic compounds upon heating. The rearrangement products were further converted back to adducts by coordinating another equivalent IMe to the B-H functionality. The formation of the two bicyclic compounds was also investigated by quantum chemical methods, whereby a four-step process is used. After formation of the NHC adduct, a hydride is transferred to the carbene carbon atom. By insertion of a boron atom into the NC bond of the carbene ring a spiro compound is formed and in the last step the BB bond is cleaved by insertion of the former carbene carbon atom, which leads to the formation of the bicycles. KW - Heterocyclische Verbindungen KW - Chemie KW - Elementorganik KW - Diazadiborinin Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-214598 ER -