TY - JOUR A1 - Üçeyler, Nurcan A1 - Schließer, Mira A1 - Evdokimov, Dimitar A1 - Radziwon, Jakub A1 - Feulner, Betty A1 - Unterecker, Stefan A1 - Rimmele, Florian A1 - Walter, Uwe T1 - Reduced midbrain raphe echogenicity in patients with fibromyalgia syndrome JF - PloS One N2 - Objectives The pathogenesis of fibromyalgia syndrome (FMS) is unclear. Transcranial ultrasonography revealed anechoic alteration of midbrain raphe in depression and anxiety disorders, suggesting affection of the central serotonergic system. Here, we assessed midbrain raphe echogenicity in FMS. Methods Sixty-six patients underwent transcranial sonography, of whom 53 were patients with FMS (27 women, 26 men), 13 patients with major depression and physical pain (all women), and 14 healthy controls (11 women, 3 men). Raphe echogenicity was graded visually as normal or hypoechogenic, and quantified by digitized image analysis, each by investigators blinded to the clinical diagnosis. Results Quantitative midbrain raphe echogenicity was lower in patients with FMS compared to healthy controls (p<0.05), but not different from that of patients with depression and accompanying physical pain. Pain and FMS symptom burden did not correlate with midbrain raphe echogenicity as well as the presence and severity of depressive symptoms. Conclusion We found reduced echogenicity of the midbrain raphe area in patients with FMS and in patients with depression and physical pain, independent of the presence or severity of pain, FMS, and depressive symptoms. Further exploration of this sonographic finding is necessary before this objective technique may enter diagnostic algorithms in FMS and depression. KW - midbrain KW - fibromyalgia KW - depression KW - pain KW - ultrasound imaging KW - neuropathic pain KW - diagnostic medicine KW - migraine Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300639 VL - 17 IS - 11 ER - TY - THES A1 - Üreyen, Soner T1 - Multivariate Time Series for the Analysis of Land Surface Dynamics - Evaluating Trends and Drivers of Land Surface Variables for the Indo-Gangetic River Basins T1 - Multivariate Zeitreihen zur Analyse von Landoberflächendynamiken - Auswertung von Trends und Treibern von Landoberflächenvariablen für Flusseinzugsgebiete der Indus-Ganges Ebene N2 - The investigation of the Earth system and interplays between its components is of utmost importance to enhance the understanding of the impacts of global climate change on the Earth's land surface. In this context, Earth observation (EO) provides valuable long-term records covering an abundance of land surface variables and, thus, allowing for large-scale analyses to quantify and analyze land surface dynamics across various Earth system components. In view of this, the geographical entity of river basins was identified as particularly suitable for multivariate time series analyses of the land surface, as they naturally cover diverse spheres of the Earth. Many remote sensing missions with different characteristics are available to monitor and characterize the land surface. Yet, only a few spaceborne remote sensing missions enable the generation of spatio-temporally consistent time series with equidistant observations over large areas, such as the MODIS instrument. In order to summarize available remote sensing-based analyses of land surface dynamics in large river basins, a detailed literature review of 287 studies was performed and several research gaps were identified. In this regard, it was found that studies rarely analyzed an entire river basin, but rather focused on study areas at subbasin or regional scale. In addition, it was found that transboundary river basins remained understudied and that studies largely focused on selected riparian countries. Moreover, the analysis of environmental change was generally conducted using a single EO-based land surface variable, whereas a joint exploration of multivariate land surface variables across spheres was found to be rarely performed. To address these research gaps, a methodological framework enabling (1) the preprocessing and harmonization of multi-source time series as well as (2) the statistical analysis of a multivariate feature space was required. For development and testing of a methodological framework that is transferable in space and time, the transboundary river basins Indus, Ganges, Brahmaputra, and Meghna (IGBM) in South Asia were selected as study area, having a size equivalent to around eight times the size of Germany. These basins largely depend on water resources from monsoon rainfall and High Mountain Asia which holds the largest ice mass outside the polar regions. In total, over 1.1 billion people live in this region and in parts largely depend on these water resources which are indispensable for the world's largest connected irrigated croplands and further domestic needs as well. With highly heterogeneous geographical settings, these river basins allow for a detailed analysis of the interplays between multiple spheres, including the anthroposphere, biosphere, cryosphere, hydrosphere, lithosphere, and atmosphere. In this thesis, land surface dynamics over the last two decades (December 2002 - November 2020) were analyzed using EO time series on vegetation condition, surface water area, and snow cover area being based on MODIS imagery, the DLR Global WaterPack and JRC Global Surface Water Layer, as well as the DLR Global SnowPack, respectively. These data were evaluated in combination with further climatic, hydrological, and anthropogenic variables to estimate their influence on the three EO land surface variables. The preprocessing and harmonization of the time series was conducted using the implemented framework. The resulting harmonized feature space was used to quantify and analyze land surface dynamics by means of several statistical time series analysis techniques which were integrated into the framework. In detail, these methods involved (1) the calculation of trends using the Mann-Kendall test in association with the Theil-Sen slope estimator, (2) the estimation of changes in phenological metrics using the Timesat tool, (3) the evaluation of driving variables using the causal discovery approach Peter and Clark Momentary Conditional Independence (PCMCI), and (4) additional correlation tests to analyze the human influence on vegetation condition and surface water area. These analyses were performed at annual and seasonal temporal scale and for diverse spatial units, including grids, river basins and subbasins, land cover and land use classes, as well as elevation-dependent zones. The trend analyses of vegetation condition mostly revealed significant positive trends. Irrigated and rainfed croplands were found to contribute most to these trends. The trend magnitudes were particularly high in arid and semi-arid regions. Considering surface water area, significant positive trends were obtained at annual scale. At grid scale, regional and seasonal clusters with significant negative trends were found as well. Trends for snow cover area mostly remained stable at annual scale, but significant negative trends were observed in parts of the river basins during distinct seasons. Negative trends were also found for the elevation-dependent zones, particularly at high altitudes. Also, retreats in the seasonal duration of snow cover area were found in parts of the river basins. Furthermore, for the first time, the application of the causal discovery algorithm on a multivariate feature space at seasonal temporal scale revealed direct and indirect links between EO land surface variables and respective drivers. In general, vegetation was constrained by water availability, surface water area was largely influenced by river discharge and indirectly by precipitation, and snow cover area was largely controlled by precipitation and temperature with spatial and temporal variations. Additional analyses pointed towards positive human influences on increasing trends in vegetation greenness. The investigation of trends and interplays across spheres provided new and valuable insights into the past state and the evolution of the land surface as well as on relevant climatic and hydrological driving variables. Besides the investigated river basins in South Asia, these findings are of great value also for other river basins and geographical regions. N2 - Die Untersuchung von Erdsystemkomponenten und deren Wechselwirkungen ist von großer Relevanz, um das Prozessverständnis sowie die Auswirkungen des globalen Klimawandels auf die Landoberfläche zu verbessern. In diesem Zusammenhang liefert die Erdbeobachtung (EO) wertvolle Langzeitaufnahmen zu einer Vielzahl an Landoberflächenvariablen. Diese können als Indikator für die Erdsystemkomponenten genutzt werden und sind essenziell für großflächige Analysen. Flusseinzugsgebiete sind besonders geeignet um Landoberflächendynamiken mit multivariaten Zeitreihen zu analysieren, da diese verschiedene Sphären des Erdsystems umfassen. Zur Charakterisierung der Landoberfläche stehen zahlreiche EO-Missionen mit unterschiedlichen Eigenschaften zur Verfügung. Nur einige wenige Missionen gewährleisten jedoch die Erstellung von räumlich und zeitlich konsistenten Zeitreihen mit äquidistanten Beobachtungen über großräumige Untersuchungsgebiete, wie z.B. die MODIS Sensoren. Um bisherige EO-Analysen zu Landoberflächendynamiken in großen Flusseinzugsgebieten zu untersuchen, wurde eine Literaturrecherche durchgeführt, wobei mehrere Forschungslücken identifiziert wurden. Studien untersuchten nur selten ein ganzes Einzugsgebiet, sondern konzentrierten sich lediglich auf Teilgebietsgebiete oder regionale Untersuchungsgebiete. Darüber hinaus wurden transnationale Einzugsgebiete nur unzureichend analysiert, wobei sich die Studien größtenteils auf ausgewählte Anrainerstaaten beschränkten. Auch wurde die Analyse von Umweltveränderungen meistens anhand einer einzigen EO-Landoberflächenvariable durchgeführt, während eine synergetische Untersuchung von sphärenübergreifenden Landoberflächenvariablen kaum unternommen wurde. Um diese Forschungslücken zu adressieren, ist ein methodischer Ansatz notwendig, der (1) die Vorverarbeitung und Harmonisierung von Zeitreihen aus mehreren Quellen und (2) die statistische Analyse eines multivariaten Merkmalsraums ermöglicht. Für die Entwicklung und Anwendung eines methodischen Frameworks, das raum-zeitlich übertragbar ist, wurden die transnationalen Einzugsgebiete Indus, Ganges, Brahmaputra und Meghna (IGBM) in Südasien, deren Größe etwa der achtfachen Fläche von Deutschland entspricht, ausgewählt. Diese Einzugsgebiete hängen weitgehend von den Wasserressourcen des Monsunregens und des Hochgebirges Asiens ab. Insgesamt leben über 1,1 Milliarden Menschen in dieser Region und sind zum Teil in hohem Maße von diesen Wasserressourcen abhängig, die auch für die größten zusammenhängenden bewässerten Anbauflächen der Welt und auch für weitere inländische Bedarfe unerlässlich sind. Aufgrund ihrer sehr heterogenen geographischen Gegebenheiten ermöglichen diese Einzugsgebiete eine detaillierte sphärenübergreifende Analyse der Wechselwirkungen, einschließlich der Anthroposphäre, Biosphäre, Kryosphäre, Hydrosphäre, Lithosphäre und Atmosphäre. In dieser Dissertation wurden Landoberflächendynamiken der letzten zwei Jahrzehnte anhand von EO-Zeitreihen zum Vegetationszustand, zu Oberflächengewässern und zur Schneebedeckung analysiert. Diese basieren auf MODIS-Aufnahmen, dem DLR Global WaterPack und dem JRC Global Surface Water Layer sowie dem DLR Global SnowPack. Diese Zeitreihen wurden in Kombination mit weiteren klimatischen, hydrologischen und anthropogenen Variablen ausgewertet. Die Harmonisierung des multivariaten Merkmalsraumes ermöglichte die Analyse von Landoberflächendynamiken unter Nutzung von statistischen Methoden. Diese Methoden umfassen (1) die Berechnung von Trends mittels des Mann-Kendall und des Theil-Sen Tests, (2) die Berechnung von phänologischen Metriken anhand des Timesat-Tools, (3) die Bewertung von treibenden Variablen unter Nutzung des PCMCI Algorithmus und (4) zusätzliche Korrelationstests zur Analyse des menschlichen Einflusses auf den Vegetationszustand und die Wasseroberfläche. Diese Analysen wurden auf jährlichen und saisonalen Zeitskalen und für verschiedene räumliche Einheiten durchgeführt. Für den Vegetationszustand wurden weitgehend signifikant positive Trends ermittelt. Analysen haben gezeigt, dass landwirtschaftliche Nutzflächen am meisten zu diesen Trends beitragen haben. Besonders hoch waren die Trends in ariden Regionen. Bei Oberflächengewässern wurden auf jährlicher Ebene signifikant positive Trends festgestellt. Auf Pixelebene wurden jedoch sowohl regional als auch saisonal Cluster mit signifikant negativen Trends identifiziert. Die Trends für die Schneebedeckung blieben auf jährlicher Ebene weitgehend stabil, jedoch wurden in Teilen der Einzugsgebiete zu bestimmten Jahreszeiten signifikant negative Trends beobachtet. Die negativen Trends wurden auch für höhenabhängige Zonen festgestellt, insbesondere in hohen Lagen. Außerdem wurden in Teilen der Einzugsgebiete Rückgänge bei der saisonalen Dauer der Schneebedeckung ermittelt. Darüber hinaus ergab die Untersuchung des multivariaten Merkmalsraums auf kausale Zusammenhänge auf saisonaler Ebene erstmals Aufschluss über direkte und indirekte Relationen zwischen EO-Landoberflächenvariablen und den entsprechenden Einflussfaktoren. Zusammengefasst wurde die Vegetation durch die Wasserverfügbarkeit, die Oberflächengewässer durch den Abfluss und indirekt durch den Niederschlag sowie die Schneebedeckung durch Niederschlag und Temperatur mit räumlichen und saisonalen Unterschieden kontrolliert. Zusätzliche Analysen wiesen auf einen positiven Zusammenhang zwischen dem menschlichen Einfluss und den zunehmenden Trends in der Vegetationsfläche hin. Diese sphärenübergreifenden Untersuchungen zu Trends und Wechselwirkungen liefern neue und wertvolle Einblicke in den vergangenen Zustand von Landoberflächendynamiken sowie in die relevanten klimatischen und hydrologischen Einflussfaktoren. Neben den untersuchten Einzugsgebieten in Südasien sind diese Erkenntnisse auch für weitere Einzugsgebiete und geographische Regionen von großer Bedeutung. KW - Multivariate Analyse KW - Zeitreihe KW - Fernerkundung KW - Geographie KW - Multivariate Time Series KW - River Basins KW - Earth Observation KW - Remote Sensing Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-291941 ER - TY - THES A1 - Ünzelmann, Maximilian T1 - Interplay of Inversion Symmetry Breaking and Spin-Orbit Coupling – From the Rashba Effect to Weyl Semimetals T1 - Zusammenspiel aus Inversionssymmetriebruch und Spin-Bahn-Kopplung – Vom Rashba-Effekt zu Weyl-Halbmetallen N2 - Breaking inversion symmetry in crystalline solids enables the formation of spin-polarized electronic states by spin-orbit coupling without the need for magnetism. A variety of interesting physical phenomena related to this effect have been intensively investigated in recent years, including the Rashba effect, topological insulators and Weyl semimetals. In this work, the interplay of inversion symmetry breaking and spin-orbit coupling and, in particular their general influence on the character of electronic states, i.e., on the spin and orbital degrees of freedom, is investigated experimentally. Two different types of suitable model systems are studied: two-dimensional surface states for which the Rashba effect arises from the inherently broken inversion symmetry at the surface, and a Weyl semimetal, for which inversion symmetry is broken in the three-dimensional crystal structure. Angle-resolved photoelectron spectroscopy provides momentum-resolved access to the spin polarization and the orbital composition of electronic states by means of photoelectron spin detection and dichroism with polarized light. The experimental results shown in this work are also complemented and supported by ab-initio density functional theory calculations and simple model considerations. Altogether, it is shown that the breaking of inversion symmetry has a decisive influence on the Bloch wave function, namely, the formation of an orbital angular momentum. This mechanism is, in turn, of fundamental importance both for the physics of the surface Rashba effect and the topology of the Weyl semimetal TaAs. N2 - Wird die Inversionssymmetrie kristalliner Festkörper gebrochen, ermöglicht dies die Ausbildung von spinpolarisierten elektronischen Zuständen durch Spin-Bahn-Kopplung ohne die Notwendigkeit von Magnetismus. In den vergangenen Jahren wurde eine Vielzahl interessanter physikalischer Phänomene diskutiert, die mit diesem Effekt zusammenhängen, darunter der Rashba-Effekt, topologische Isolatoren sowie Weyl-Halbmetalle. In dieser Arbeit wird das Zusammenspiel von Inversionssymetriebruch und Spin-Bahn-Kopplung sowie insbesondere deren Einfluss auf die Eigenschaften der elektronischen Zustände, also auf die Spin- und Orbital-Freiheitsgrade, experimentell untersucht. Zwei verschiedene Arten geeigneter Modellsysteme werden dazu betrachtet: zweidimensionale Oberflächenzustände, in denen der Rashba-Effekt aufgrund der an der Oberfläche inhärent gebrochenen Inverisonssymetrie auftritt, und ein Weyl-Halbmetall, dessen dreidimensionale Kristallstruktur kein Inversionszentrum besitzt. Winkelaufgelöste Photoelektronenspektroskopie bietet einen impulsaufgelösten Zugang zur Spinpolarisation sowie zur orbitalen Zusammensetzung der elektronischen Zustände mittels Photoelektronenspindetektion und Dichroismus mit polarisiertem Licht. Die in dieser Arbeit gezeigten experimentellen Ergebnisse werden außerdem durch ab-initio Dichtefunktionaltheorierechnungen sowie einfachen Modellbetrachtungen ergänzt und untermauert. Insgesamt zeigt sich, dass das Brechen von Inversionssymmetrie einen entscheidenden Einfluss auf die Bloch-Wellenfunktion hat, nämlich die Ausbildung eines orbitalen Bahndrehimpulses. Dieser Mechanismus ist wiederum von grundlegender Bedeutung sowohl für die Physik des Oberflächen- Rashba-Effekts als auch für die Topologie desWeyl-Halbmetalls TaAs. KW - Rashba-Effekt KW - Inversion Symmetry Breaking KW - Topologie KW - ARPES KW - Spin-Orbit Coupling KW - Orbital Angular Momentum Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-283104 ER - TY - JOUR A1 - Özdağ Acarlı, Ayşe Nur A1 - Klein, Thomas A1 - Egenolf, Nadine A1 - Sommer, Claudia A1 - Üçeyler, Nurcan T1 - Subepidermal Schwann cell counts correlate with skin innervation - an exploratory study JF - Muscle & Nerve N2 - Introduction/Aims Schwann cell clusters have been described at the murine dermis-epidermis border. We quantified dermal Schwann cells in the skin of patients with small-fiber neuropathy (SFN) compared with healthy controls to correlate with the clinical phenotype. Methods Skin punch biopsies from the lower legs of 28 patients with SFN (11 men, 17 women; median age, 54 [range, 19-73] years) and 9 healthy controls (five men, four women, median age, 34 [range, 25-69] years) were immunoreacted for S100 calcium-binding protein B as a Schwann cell marker, protein-gene product 9.5 as a pan-neuronal marker, and CD207 as a Langerhans cell marker. Intraepidermal nerve fiber density (IENFD) and subepidermal Schwann cell counts were determined. Results Skin samples of patients with SFN showed lower IENFD (P < .05), fewer Schwann cells per millimeter (P < .01), and fewer Schwann cell clusters per millimeter (P < .05) than controls. When comparing SFN patients with reduced (n = 13; median age, 53 [range, 19-73] years) and normal distal (n = 15, median age, 54 [range, 43-68] years) IENFD, the number of solitary Schwann cells per millimeter (p < .01) and subepidermal nerve fibers associated with Schwann cell branches (P < .05) were lower in patients with reduced IENFD. All three parameters correlated positively with distal IENFD (P < .05 to P < .01), whereas no correlation was found between Schwann cell counts and clinical pain characteristics. Discussion Our data raise questions about the mechanisms underlying the interdependence of dermal Schwann cells and skin innervation in SFN. The temporal course and functional impact of Schwann cell presence and kinetics need further investigation. KW - intraepidermal nerve fiber density KW - small-fiber neuropathy KW - skin punch biopsy KW - Schwann cell KW - neuropathic pain KW - innervation Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-318726 VL - 65 IS - 4 SP - 471 EP - 479 ER - TY - THES A1 - Züfle, Marwin Otto T1 - Proactive Critical Event Prediction based on Monitoring Data with Focus on Technical Systems T1 - Proaktive Vorhersage kritischer Ereignisse auf der Grundlage von Beobachtungsdaten mit Schwerpunkt auf technischen Systemen N2 - The importance of proactive and timely prediction of critical events is steadily increasing, whether in the manufacturing industry or in private life. In the past, machines in the manufacturing industry were often maintained based on a regular schedule or threshold violations, which is no longer competitive as it causes unnecessary costs and downtime. In contrast, the predictions of critical events in everyday life are often much more concealed and hardly noticeable to the private individual, unless the critical event occurs. For instance, our electricity provider has to ensure that we, as end users, are always supplied with sufficient electricity, or our favorite streaming service has to guarantee that we can watch our favorite series without interruptions. For this purpose, they have to constantly analyze what the current situation is, how it will develop in the near future, and how they have to react in order to cope with future conditions without causing power outages or video stalling. In order to analyze the performance of a system, monitoring mechanisms are often integrated to observe characteristics that describe the workload and the state of the system and its environment. Reactive systems typically employ thresholds, utility functions, or models to determine the current state of the system. However, such reactive systems cannot proactively estimate future events, but only as they occur. In the case of critical events, reactive determination of the current system state is futile, whereas a proactive system could have predicted this event in advance and enabled timely countermeasures. To achieve proactivity, the system requires estimates of future system states. Given the gap between design time and runtime, it is typically not possible to use expert knowledge to a priori model all situations a system might encounter at runtime. Therefore, prediction methods must be integrated into the system. Depending on the available monitoring data and the complexity of the prediction task, either time series forecasting in combination with thresholding or more sophisticated machine and deep learning models have to be trained. Although numerous forecasting methods have been proposed in the literature, these methods have their advantages and disadvantages depending on the characteristics of the time series under consideration. Therefore, expert knowledge is required to decide which forecasting method to choose. However, since the time series observed at runtime cannot be known at design time, such expert knowledge cannot be implemented in the system. In addition to selecting an appropriate forecasting method, several time series preprocessing steps are required to achieve satisfactory forecasting accuracy. In the literature, this preprocessing is often done manually, which is not practical for autonomous computing systems, such as Self-Aware Computing Systems. Several approaches have also been presented in the literature for predicting critical events based on multivariate monitoring data using machine and deep learning. However, these approaches are typically highly domain-specific, such as financial failures, bearing failures, or product failures. Therefore, they require in-depth expert knowledge. For this reason, these approaches cannot be fully automated and are not transferable to other use cases. Thus, the literature lacks generalizable end-to-end workflows for modeling, detecting, and predicting failures that require only little expert knowledge. To overcome these shortcomings, this thesis presents a system model for meta-self-aware prediction of critical events based on the LRA-M loop of Self-Aware Computing Systems. Building upon this system model, this thesis provides six further contributions to critical event prediction. While the first two contributions address critical event prediction based on univariate data via time series forecasting, the three subsequent contributions address critical event prediction for multivariate monitoring data using machine and deep learning algorithms. Finally, the last contribution addresses the update procedure of the system model. Specifically, the seven main contributions of this thesis can be summarized as follows: First, we present a system model for meta self-aware prediction of critical events. To handle both univariate and multivariate monitoring data, it offers univariate time series forecasting for use cases where a single observed variable is representative of the state of the system, and machine learning algorithms combined with various preprocessing techniques for use cases where a large number of variables are observed to characterize the system’s state. However, the two different modeling alternatives are not disjoint, as univariate time series forecasts can also be included to estimate future monitoring data as additional input to the machine learning models. Finally, a feedback loop is incorporated to monitor the achieved prediction quality and trigger model updates. We propose a novel hybrid time series forecasting method for univariate, seasonal time series, called Telescope. To this end, Telescope automatically preprocesses the time series, performs a kind of divide-and-conquer technique to split the time series into multiple components, and derives additional categorical information. It then forecasts the components and categorical information separately using a specific state-of-the-art method for each component. Finally, Telescope recombines the individual predictions. As Telescope performs both preprocessing and forecasting automatically, it represents a complete end-to-end approach to univariate seasonal time series forecasting. Experimental results show that Telescope achieves enhanced forecast accuracy, more reliable forecasts, and a substantial speedup. Furthermore, we apply Telescope to the scenario of predicting critical events for virtual machine auto-scaling. Here, results show that Telescope considerably reduces the average response time and significantly reduces the number of service level objective violations. For the automatic selection of a suitable forecasting method, we introduce two frameworks for recommending forecasting methods. The first framework extracts various time series characteristics to learn the relationship between them and forecast accuracy. In contrast, the other framework divides the historical observations into internal training and validation parts to estimate the most appropriate forecasting method. Moreover, this framework also includes time series preprocessing steps. Comparisons between the proposed forecasting method recommendation frameworks and the individual state-of-the-art forecasting methods and the state-of-the-art forecasting method recommendation approach show that the proposed frameworks considerably improve the forecast accuracy. With regard to multivariate monitoring data, we first present an end-to-end workflow to detect critical events in technical systems in the form of anomalous machine states. The end-to-end design includes raw data processing, phase segmentation, data resampling, feature extraction, and machine tool anomaly detection. In addition, the workflow does not rely on profound domain knowledge or specific monitoring variables, but merely assumes standard machine monitoring data. We evaluate the end-to-end workflow using data from a real CNC machine. The results indicate that conventional frequency analysis does not detect the critical machine conditions well, while our workflow detects the critical events very well with an F1-score of almost 91%. To predict critical events rather than merely detecting them, we compare different modeling alternatives for critical event prediction in the use case of time-to-failure prediction of hard disk drives. Given that failure records are typically significantly less frequent than instances representing the normal state, we employ different oversampling strategies. Next, we compare the prediction quality of binary class modeling with downscaled multi-class modeling. Furthermore, we integrate univariate time series forecasting into the feature generation process to estimate future monitoring data. Finally, we model the time-to-failure using not only classification models but also regression models. The results suggest that multi-class modeling provides the overall best prediction quality with respect to practical requirements. In addition, we prove that forecasting the features of the prediction model significantly improves the critical event prediction quality. We propose an end-to-end workflow for predicting critical events of industrial machines. Again, this approach does not rely on expert knowledge except for the definition of monitoring data, and therefore represents a generalizable workflow for predicting critical events of industrial machines. The workflow includes feature extraction, feature handling, target class mapping, and model learning with integrated hyperparameter tuning via a grid-search technique. Drawing on the result of the previous contribution, the workflow models the time-to-failure prediction in terms of multiple classes, where we compare different labeling strategies for multi-class classification. The evaluation using real-world production data of an industrial press demonstrates that the workflow is capable of predicting six different time-to-failure windows with a macro F1-score of 90%. When scaling the time-to-failure classes down to a binary prediction of critical events, the F1-score increases to above 98%. Finally, we present four update triggers to assess when critical event prediction models should be re-trained during on-line application. Such re-training is required, for instance, due to concept drift. The update triggers introduced in this thesis take into account the elapsed time since the last update, the prediction quality achieved on the current test data, and the prediction quality achieved on the preceding test data. We compare the different update strategies with each other and with the static baseline model. The results demonstrate the necessity of model updates during on-line application and suggest that the update triggers that consider both the prediction quality of the current and preceding test data achieve the best trade-off between prediction quality and number of updates required. We are convinced that the contributions of this thesis constitute significant impulses for the academic research community as well as for practitioners. First of all, to the best of our knowledge, we are the first to propose a fully automated, end-to-end, hybrid, component-based forecasting method for seasonal time series that also includes time series preprocessing. Due to the combination of reliably high forecast accuracy and reliably low time-to-result, it offers many new opportunities in applications requiring accurate forecasts within a fixed time period in order to take timely countermeasures. In addition, the promising results of the forecasting method recommendation systems provide new opportunities to enhance forecasting performance for all types of time series, not just seasonal ones. Furthermore, we are the first to expose the deficiencies of the prior state-of-the-art forecasting method recommendation system. Concerning the contributions to critical event prediction based on multivariate monitoring data, we have already collaborated closely with industrial partners, which supports the practical relevance of the contributions of this thesis. The automated end-to-end design of the proposed workflows that do not demand profound domain or expert knowledge represents a milestone in bridging the gap between academic theory and industrial application. Finally, the workflow for predicting critical events in industrial machines is currently being operationalized in a real production system, underscoring the practical impact of this thesis. N2 - Die Bedeutung einer proaktiven und rechtzeitigen Vorhersage von kritischen Ereignissen nimmt immer weiter zu, sei es in der Fertigungsindustrie oder im Privatleben. In der Vergangenheit wurden Maschinen in der Fertigungsindustrie oft auf der Grundlage eines regelmäßigen Zeitplans oder aufgrund von Grenzwertverletzungen gewartet, was heutzutage nicht mehr wettbewerbsfähig ist, da es unnötige Kosten und Ausfallzeiten verursacht. Im Gegensatz dazu sind die Vorhersagen von kritischen Ereignissen im Alltag oft wesentlich versteckter und für die Privatperson kaum spürbar, es sei denn das kritische Ereignis tritt ein. So muss zum Beispiel unser Stromanbieter dafür sorgen, dass wir als Endverbraucher immer ausreichend mit Strom versorgt werden, oder unser Streaming-Dienst muss garantieren, dass wir unsere Lieblingsserie jederzeit ohne Unterbrechungen anschauen können. Hierzu müssen diese ständig analysieren wie der aktuelle Zustand ist, wie er sich in naher Zukunft entwickeln wird und wie sie reagieren müssen, um die zukünftigen Bedingungen zu bewältigen, ohne dass es zu Stromausfällen oder Videoabbrüchen kommt. Zur Analyse der Leistung eines Systems werden häufig Überwachungsmechanismen integriert, um Merkmale zu beobachten, die die Arbeitslast und den Zustand des Systems und seiner Umgebung abbilden. Reaktive Systeme verwenden typischerweise Schwellenwerte, Nutzenfunktionen oder Modelle, um den aktuellen Zustand des Systems zu bestimmen. Allerdings können solche reaktiven Systeme zukünftige Ereignisse nicht proaktiv abschätzen, sondern lediglich sobald diese eintreten. Bei kritischen Ereignissen ist die reaktive Bestimmung des aktuellen Systemzustands jedoch zwecklos, während ein proaktives System dieses Ereignis im Voraus hätte vorhersagen und rechtzeitig Gegenmaßnahmen einleiten können. Um Proaktivität zu erreichen, benötigt das System Abschätzungen über zukünftige Systemzustände. Angesichts der Kluft zwischen Entwurfszeit und Laufzeit ist es typischerweise nicht möglich Expertenwissen zu verwenden, um alle Situationen zu modellieren, auf die ein System zur Laufzeit stoßen könnte. Daher müssen Vorhersagemethoden in das System integriert werden. Abhängig von den verfügbaren Überwachungsdaten und der Komplexität der Vorhersageaufgabe müssen entweder Zeitreihenprognosen in Kombination mit Schwellenwerten oder ausgefeiltere Modelle des „Machine Learning“ und „Deep Learning“ trainiert werden. Obwohl in der Literatur schon zahlreiche Zeitreihenprognosemethoden vorgeschlagen wurden, haben alle diese Methoden in Abhängigkeit der Eigenschaften der betrachteten Zeitreihen ihre Vor- und Nachteile. Daher ist Expertenwissen erforderlich, um zu entscheiden, welche Zeitreihenprognosemethode gewählt werden sollte. Da jedoch die zur Laufzeit beobachteten Zeitreihen zur Entwurfszeit nicht bekannt sein können, lässt sich ein solches Expertenwissen nicht im System integrieren. Zusätzlich zur Auswahl einer geeigneten Zeitreihenprognosemethode sind mehrere Zeitreihenvorverarbeitungsschritte erforderlich, um eine zufriedenstellende Prognosegenauigkeit zu erreichen. In der Literatur wird diese Vorverarbeitung oft manuell durchgeführt, was für autonome Computersysteme, wie z. B. „Self-Aware Computing Systems“, nicht praktikabel ist. Hinsichtlich der Vorhersage kritischer Ereignisse auf der Grundlage multivariater Überwachungsdaten wurden in der Literatur auch bereits mehrere Ansätze unter Verwendung von „Machine Learning“ und „Deep Learning“ vorgestellt. Diese Ansätze sind jedoch typischerweise sehr domänenspezifisch, wie z. B. für finanzielle Zusammenbrüche, Lagerschäden oder Produktfehler. Aus diesem Grund erfordern sie umfassendes Expertenwissen. Durch den spezifischen Zuschnitt auf die jeweilige Domäne können diese Ansätze nicht vollständig automatisiert werden und sind nicht auf andere Anwendungsfälle übertragbar. Somit fehlt es in der Literatur an verallgemeinerbaren Ende-zu-Ende Prozessen zur Modellierung, Erkennung und Vorhersage von Ausfällen, die lediglich wenig Expertenwissen erfordern. Um diese Unzulänglichkeiten zu überwinden, wird in dieser Arbeit ein Systemmodell zur meta-selbstbewussten Vorhersage kritischer Ereignisse vorgestellt, das auf der LRA-M-Schleife von „Self-Aware Computing Systems“ basiert. Aufbauend auf diesem Systemmodell liefert diese Arbeit sechs weitere Beiträge zur Vorhersage kritischer Ereignisse. Während sich die ersten beiden Beiträge mit der Vorhersage kritischer Ereignisse auf der Basis univariater Daten mittels Zeitreihenprognose befassen, adressieren die drei folgenden Beiträge die Vorhersage kritischer Ereignisse für multivariate Überwachungsdaten unter Verwendung von „Machine Learning“ und „Deep Learning“ Algorithmen. Der letzte Beitrag schließlich behandelt das Aktualisierungsverfahren des Systemmodells. Im Einzelnen lassen sich die sieben Hauptbeiträge dieser Arbeit wie folgt zusammenfassen: Zunächst stellen wir ein Systemmodell für die meta-selbstbewusste Vorhersage von kritischen Ereignissen vor. Um sowohl univariate als auch multivariate Überwachungsdaten verarbeiten zu können, bietet es univariate Zeitreihenprognosen für Anwendungsfälle, in denen eine einzelne Beobachtungsgröße repräsentativ für den Zustand des Systems ist, sowie „Machine Learning“ und „Deep Learning“ Algorithmen in Kombination mit verschiedenen Vorverarbeitungstechniken für Anwendungsfälle, in denen eine große Anzahl von Variablen beobachtet wird, um den Zustand des Systems zu charakterisieren. Die beiden unterschiedlichen Modellierungsalternativen sind jedoch nicht disjunkt, da auch univariate Zeitreihenprognosen einbezogen werden können, um zukünftige Überwachungsdaten als zusätzliche Eingabe für die „Machine Learning“ und „Deep Learning“ Modelle zu schätzen. Schließlich ist eine Rückkopplungsschleife eingebaut, die die erreichte Vorhersagequalität überwacht und gegebenenfalls Modellaktualisierungen auslöst. Wir präsentieren eine neuartige, hybride Zeitreihenvorhersagemethode für univariate, saisonale Zeitreihen, die wir Telescope nennen. Telescope verarbeitet die Zeitreihe automatisch vor, führt eine Art „Divide-and-Conquer“ Technik durch, welche die Zeitreihe in mehrere Komponenten unterteilt, und leitet zusätzliche kategoriale Informationen ab. Anschließend prognostiziert es die Komponenten und kategorialen Informationen getrennt voneinander mit einer spezifischen Methode für jede Komponente. Abschließend setzt Telescope die einzelnen Vorhersagen wieder zusammen. Da Telescope alle Vorverarbeitungsschritte und Vorhersagen automatisch durchführt, stellt es einen vollständigen Ende-zu-Ende Ansatz für univariate, saisonale Zeitreihenvorhersagen dar. Experimentelle Ergebnisse zeigen, dass Telescope eine verbesserte Vorhersagegenauigkeit, zuverlässigere Vorhersagen und eine erhebliche Beschleunigung erreicht. Darüber hinaus wenden wir Telescope für die Vorhersage kritischer Ereignisse bei der automatischen Skalierung von virtuellen Maschinen an. Die Ergebnisse belegen, dass Telescope die durchschnittliche Antwortzeit erheblich reduziert und die Anzahl der Verletzungen der Service Level Zielvorgaben signifikant verringert. Für die automatische Auswahl einer geeigneten Zeitreihenprognosemethode führen wir zwei Empfehlungssysteme ein. Das erste System extrahiert verschiedene Zeitreihencharakteristika, um die Beziehung zwischen ihnen und der Prognosegenauigkeit zu erlernen. Im Gegensatz dazu unterteilt das zweite System die historischen Beobachtungen in interne Trainings- und Validierungsteile, um die am besten geeignete Zeitreihenprognosemethode zu schätzen. Außerdem beinhaltet letzteres System auch Zeitreihenvorverarbeitungsschritte. Vergleiche zwischen den vorgeschlagenen Empfehlungssystemen für Zeitreihenprognosemethoden und den einzelnen Prognosemethoden sowie dem Ansatz zur Empfehlung von Zeitreihenprognosemethoden nach dem Stand der Technik ergeben, dass die vorgeschlagenen Systeme die Prognosegenauigkeit erheblich verbessern. Im Hinblick auf multivariate Überwachungsdaten stellen wir zunächst einen Ende-zu-Ende Prozess vor, mit dem kritische Ereignisse in technischen Systemen in Form von anomalen Maschinenzuständen erkannt werden können. Der Ende-zu-Ende Entwurf umfasst die Rohdatenverarbeitung, die Phasensegmentierung, das Datenresampling, die Merkmalsextraktion und die Maschinenanomalieerkennung. Darüber hinaus stützt sich der Prozess explizit nicht auf tiefgreifendes Domänenwissen oder spezifische Überwachungsgrößen, sondern setzt lediglich gängige Maschinenüberwachungsdaten voraus. Wir evaluieren den Ende-zu-Ende Prozess anhand von Daten einer realen CNC-Maschine. Die Ergebnisse zeigen, dass die konventionelle Frequenzanalyse die kritischen Maschinenzustände nicht gut erkennt, während unser Prozess die kritischen Ereignisse mit einem F1-Wert von fast 91% sehr gut identifiziert. Um kritische Ereignisse vorherzusagen, anstatt sie nur reaktiv zu erkennen, vergleichen wir verschiedene Modellierungsalternativen für die Vorhersage kritischer Ereignisse im Anwendungsfall der Vorhersage der Zeit bis zum nächsten Fehler von Festplattenlaufwerken. Da Fehlerdatensätze typischerweise wesentlich seltener sind als Instanzen, die den Normalzustand repräsentieren, setzen wir verschiedene Strategien zum Erzeugen künstlicher Fehlerinstanzen ein. Im nächsten Schritt vergleichen wir die Vorhersagequalität der binären Klassenmodellierung mit der herunterskalierten Mehrklassenmodellierung. Des Weiteren integrieren wir die univariate Zeitreihenprognose in den Merkmalsgenerierungsprozess, um so die zukünftigen Überwachungsdaten zu schätzen. Schließlich modellieren wir die Zeit bis zum nächsten Fehler nicht nur mithilfe von Klassifikationsmodellen, sondern auch mit Regressionsmodellen. Die Ergebnisse legen nahe, dass die Mehrklassenmodellierung die insgesamt beste Vorhersagequalität hinsichtlich praktischer Anforderungen liefert. Außerdem belegen wir, dass die Prognose der Merkmale des Vorhersagemodells mittels univariater Zeitreihenprognose die Qualität der Vorhersage kritischer Ereignisse signifikant verbessert. Wir stellen einen Ende-zu-Ende Prozess für die Vorhersage kritischer Ereignisse von Industriemaschinen vor. Auch dieser Ansatz verlässt sich nicht auf Expertenwissen, mit Ausnahme der Definition von Überwachungsdaten, und stellt daher einen verallgemeinerbaren Prozess für die Vorhersage kritischer Ereignisse von Industriemaschinen dar. Der Prozess umfasst Merkmalsextraktion, Merkmalsverarbeitung, Zielklassenzuordnung und Modelllernen mit integrierter Hyperparameter-Abstimmung mittels einer Gittersuchtechnik. Ausgehend von den Ergebnissen des vorherigen Beitrags modelliert der Prozess die Vorhersage der Zeit bis zum nächsten Fehler in Form mehrerer Klassen, wobei wir verschiedene Beschriftungsstrategien für die Mehrklassenklassifizierung vergleichen. Die Evaluierung anhand realer Produktionsdaten einer großen Industriepresse demonstriert, dass der Prozess in der Lage ist, sechs verschiedene Zeitfenster für bevorstehende Fehler mit einem Makro F1-Wert von 90% vorherzusagen. Wenn man die Klassen der Zeit bis zum nächsten Fehler auf eine binäre Vorhersage von kritischen Ereignissen herunterskaliert, steigt der F1-Wert sogar auf über 98%. Schließlich stellen wir vier Aktualisierungsauslöser vor, um zu bestimmen, wann Modelle zur Vorhersage kritischer Ereignisse während der Online-Anwendung neu trainiert werden sollten. Ein solches Neutraining ist bspw. aufgrund von Konzeptdrift erforderlich. Die in dieser Arbeit vorgestellten Aktualisierungsauslöser berücksichtigen die Zeit, die seit der letzten Aktualisierung verstrichen ist, die auf den aktuellen Testdaten erreichte Vorhersagequalität und die auf den vorangegangenen Testdaten erreichte Vorhersagequalität. Wir vergleichen die verschiedenen Aktualisierungsstrategien miteinander und mit dem statischen Ausgangsmodell. Die Ergebnisse veranschaulichen die Notwendigkeit von Modellaktualisierungen während der Online-Anwendung und legen nahe, dass die Aktualisierungsauslöser, die sowohl die Vorhersagequalität der aktuellen als auch der vorangegangenen Testdaten berücksichtigen, den besten Kompromiss zwischen Vorhersagequalität und Anzahl der erforderlichen Aktualisierungen erzielen. Wir sind der festen Überzeugung, dass die Beiträge dieser Arbeit sowohl für die akademische Forschungsgemeinschaft als auch für die praktische Anwendung wichtige Impulse darstellen. Zuallererst sind wir unseres Wissens nach die ersten, die eine vollautomatische, hybride, komponentenbasierte, Ende-zu-Ende Prognosemethode für saisonale Zeitreihen vorschlagen, die auch die Zeitreihenvorverarbeitung beinhaltet. Durch die Verbindung einer zuverlässig hohen Vorhersagegenauigkeit mit einer zuverlässig niedrigen Zeit bis zum Ergebnis eröffnet diese viele neue Möglichkeiten für Anwendungen, die genaue Vorhersagen innerhalb eines festen Zeitraums erfordern, um rechtzeitig Gegenmaßnahmen ergreifen zu können. Darüber hinaus bieten die vielversprechenden Ergebnisse der Empfehlungssysteme für Zeitreihenprognosemethoden neue Ansätze zur Verbesserung der Vorhersageleistung für alle Arten von Zeitreihen, nicht nur für saisonale Zeitreihen. Ferner sind wir die ersten, die die Schwachstellen des bisherigen Stands der Technik bei der Empfehlung von Zeitreihenprognosemethoden aufgedeckt haben. Hinsichtlich der Beiträge zur Vorhersage kritischer Ereignisse mittels multivariater Überwachungsdaten haben wir bereits eng mit Industriepartnern zusammengearbeitet,wodurch die hohe praktische Relevanz der Beiträge dieser Arbeit verdeutlicht wird. Der automatisierte Ende-zu-Ende Entwurf der vorgeschlagenen Prozesse, die kein tiefes Domänen- oder Expertenwissen erfordern, stellt einen Meilenstein in der Überbrückung der Kluft zwischen akademischer Theorie und industrieller Anwendung dar. Diese Tatsache wird insbesondere dadurch untermauert, dass der Prozess zur Vorhersage kritischer Ereignisse in Industriemaschinen derzeit bereits in einem realen Produktionssystem operationalisiert wird. KW - Prognose KW - Automation KW - Zeitreihe KW - Forecasting KW - Zeitreihenvorhersage KW - Failure Prediction KW - Fehlervorhersage KW - End-to-End Automation KW - Ende-zu-Ende Automatisierung Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-255757 ER - TY - JOUR A1 - Zyberaj, Jetmir A1 - Seibel, Sebastian A1 - Schowalter, Annika F. A1 - Pötz, Lennart A1 - Richter-Killenberg, Stefanie A1 - Volmer, Judith T1 - Developing sustainable careers during a pandemic: the role of psychological capital and career adaptability JF - Sustainability N2 - The Coronavirus disease 2019 (COVID-19) has not only had negative effects on employees' health, but also on their prospects to gain and maintain employment. Using a longitudinal research design with two measurement points, we investigated the ramifications of various psychological and organizational resources on employees' careers during the COVID-19 pandemic. Specifically, in a sample of German employees (N = 305), we investigated the role of psychological capital (PsyCap) for four career-related outcomes: career satisfaction, career engagement, coping with changes in career due to COVID-19, and career-related COVID-19 worries. We also employed leader–member exchange (LMX) as a moderator and career adaptability as a mediating variable in these relationships. Results from path analyses revealed a positive association between PsyCap and career satisfaction and career coping. Furthermore, PsyCap was indirectly related to career engagement through career adaptability. However, moderation analysis showed no moderating role of LMX on the link between PsyCap and career adaptability. Our study contributes to the systematic research concerning the role of psychological and organizational resources for employees' careers and well-being, especially for crisis contexts. KW - psychological capital KW - career adaptability KW - LMX KW - career engagement KW - career satisfaction KW - career coping KW - COVID-19 Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-267286 SN - 2071-1050 VL - 14 IS - 5 ER - TY - JOUR A1 - Zupanc, Günther K. H. A1 - Rössler, Wolfgang T1 - Government funding of research beyond biomedicine: challenges and opportunities for neuroethology JF - Journal of Comparative Physiology A N2 - Curiosity-driven research is fundamental for neuroethology and depends crucially on governmental funding. Here, we highlight similarities and differences in funding of curiosity-driven research across countries by comparing two major funding agencies—the National Science Foundation (NSF) in the United States and the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG). We interviewed representatives from each of the two agencies, focusing on general funding trends, levels of young investigator support, career-life balance, and international collaborations. While our analysis revealed a negative trend in NSF funding of biological research, including curiosity-driven research, German researchers in these areas have benefited from a robust positive trend in DFG funding. The main reason for the decrease in curiosity-driven research in the US is that the NSF has only partially been able to compensate for the funding gap resulting from the National Institutes of Health restricting their support to biomedical research using select model organisms. Notwithstanding some differences in funding programs, particularly those relevant for scientists in the postdoctoral phase, both the NSF and DFG clearly support curiosity-driven research. KW - German Research Foundation KW - Government research funding KW - National Science Foundation KW - Deutsche Forschungsgemeinschaft KW - neuroethology Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-325113 VL - 208 IS - 3 ER - TY - JOUR A1 - Zoran, Tamara A1 - Seelbinder, Bastian A1 - White, Philip Lewis A1 - Price, Jessica Sarah A1 - Kraus, Sabrina A1 - Kurzai, Oliver A1 - Linde, Joerg A1 - Häder, Antje A1 - Loeffler, Claudia A1 - Grigoleit, Goetz Ulrich A1 - Einsele, Hermann A1 - Panagiotou, Gianni A1 - Loeffler, Juergen A1 - Schäuble, Sascha T1 - Molecular profiling reveals characteristic and decisive signatures in patients after allogeneic stem cell transplantation suffering from invasive pulmonary aspergillosis JF - Journal of Fungi N2 - Despite available diagnostic tests and recent advances, diagnosis of pulmonary invasive aspergillosis (IPA) remains challenging. We performed a longitudinal case-control pilot study to identify host-specific, novel, and immune-relevant molecular candidates indicating IPA in patients post allogeneic stem cell transplantation (alloSCT). Supported by differential gene expression analysis of six relevant in vitro studies, we conducted RNA sequencing of three alloSCT patients categorized as probable IPA cases and their matched controls without Aspergillus infection (66 samples in total). We additionally performed immunoassay analysis for all patient samples to gain a multi-omics perspective. Profiling analysis suggested LGALS2, MMP1, IL-8, and caspase-3 as potential host molecular candidates indicating IPA in investigated alloSCT patients. MMP1, IL-8, and caspase-3 were evaluated further in alloSCT patients for their potential to differentiate possible IPA cases and patients suffering from COVID-19-associated pulmonary aspergillosis (CAPA) and appropriate control patients. Possible IPA cases showed differences in IL-8 and caspase-3 serum levels compared with matched controls. Furthermore, we observed significant differences in IL-8 and caspase-3 levels among CAPA patients compared with control patients. With our conceptual work, we demonstrate the potential value of considering the human immune response during Aspergillus infection to identify immune-relevant molecular candidates indicating IPA in alloSCT patients. These human host candidates together with already established fungal biomarkers might improve the accuracy of IPA diagnostic tools. KW - host response KW - invasive pulmonary aspergillosis KW - alloSCT patients KW - galectin-2 KW - caspase-3 KW - matrix metallopeptidase-1 Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262105 SN - 2309-608X VL - 8 IS - 2 ER - TY - THES A1 - Zoran, Tamara T1 - Multilevel analysis of the human immune response to \(Aspergillus\) \(fumigatus\) infection: Characteristic molecular signatures and individual risk factors T1 - Analysen der humanen Immunantwort auf eine Infektion mit \(Aspergillus\) \(fumigatus\): Charakteristische molekulare Signaturen und individuelle Risikofaktoren N2 - Although the field of fungal infections advanced tremendously, diagnosis of invasive pulmonary aspergillosis (IPA) in immunocompromised patients continues to be a challenge. Since IPA is a multifactorial disease, investigation from different aspects may provide new insights, helpful for improving IPA diagnosis. This work aimed to characterize the human immune response to Aspergillus fumigatus in a multilevel manner to identify characteristic molecular candidates and risk factors indicating IPA, which may in the future support already established diagnostic assays. We combined in vitro studies using myeloid cells infected with A. fumigatus and longitudinal case-control studies investigating patients post allogeneic stem cell transplantation (alloSCT) suffering from IPA and their match controls. Characteristic miRNA and mRNA signatures indicating A. fumigatus-infected monocyte-derived dendritic cells (moDCs) demonstrated the potential to differentiate between A. fumigatus and Escherichia coli infection. Transcriptome and protein profiling of alloSCT patients suffering from IPA and their matched controls revealed a distinctive IPA signature consisting of MMP1 induction and LGAL2 repression in combination with elevated IL-8 and caspase-3 levels. Both, in vitro and case-control studies, suggested cytokines, matrix-metallopeptidases and galectins are important in the immune response to A. fumigatus. Identified IPA characteristic molecular candidates are involved in numerous processes, thus a combination of these in a distinctive signature may increase the specificity. Finally, low monocyte counts, severe GvHD of the gut (grade ≥ 2) and etanercept administration were significantly associated with IPA diagnosis post alloSCT. Etanercept in monocyte-derived macrophages (MDM) infected with A. fumigatus downregulates genes involved in the NF-κB and TNF-α pathway and affects the secretion of CXCL10. Taken together, identified characteristic molecular signatures and risk factors indicating IPA may in the future in combination with established fungal biomarkers overcome current diagnostic challenges and help to establish tailored antifungal therapy. Therefore, further multicentre studies are encouraged to evaluate reported findings. N2 - Obwohl im Bereich der Erforschung invasiver Pilzinfektionen aktuell enorme Fortschritte erzielt wurden, stellt die Diagnose der Invasiven Pulmonalen Aspergillose (IPA) bei immunsupprimierten Patienten weiterhin eine grosse Herausforderung dar. Da es sich bei der IPA um eine multifaktorielle Erkrankung handelt, können Untersuchungen unter verschiedenen Fragestellungen neue Erkenntnisse liefern, die zur Verbesserung der IPA Diagnose beitragen. In dieser Arbeit wurde die humane Immunantwort auf Aspergillus fumigatus auf mehreren Ebenen untersucht, um charakteristische molekulare Kandidaten und Risikofaktoren zu identifizieren, die auf eine IPA hinweisen um so in Zukunft bereits etablierte diagnostische Tests unterstützen zu können. Wir kombinierten in vitro Studien mit A. fumigatus infizierten, myeloischen Zellen mit longitudinalen Case-Control-Studien, in denen an IPA erkrankte Patienten und ihre passenden Kontrollpatienten nach allogener Stammzelltransplantation (alloSZT) untersucht wurden. Charakteristische miRNA und mRNA Signaturen von A. fumigatus-infizierten Monozyten-abgeleiteten dendritischen Zellen (moDCs) zeigten das Potenzial, zwischen A. fumigatus und Escherichia coli Infektionen zu unterscheiden. Transkriptom- und Protein- Analysen von alloSZT Patienten, die an einer IPA erkrankten, und den passenden Kontrollpatienten ergaben charakteristische IPA Signaturen, bestehend aus einer MMP1 Induktion und einer LGALS2 Repression, in Kombination mit erhöhten IL-8 und Caspase-3 Konzentrationen. Sowohl die in vitro Daten als auch die Fall-Kontroll- Studien zeigten, dass Zytokine, Matrix-Metallopeptidasen und Galectine eine wichtige Rolle bei der Immunantwort auf A. fumigatus spielen. Die in IPA identifizierten charakteristischen molekularen Kandidaten sind an mehreren Prozessen beteiligt, so dass eine Kombination dieser molekularen Kandidaten die Spezifität mittels charakteristischer Signatur erhöhen könnte. Schließlich waren niedrige Monozytenzahlen, eine schwere GvHD des Darms (Grad ≥ 2) und die Anwendung von Etanercept signifikant mit einer IPA Diagnose nach alloSZT assoziiert. Etanercept in Makrophagen, die mit A. fumigatus ko-kultiviert wurden, reguliert Gene herunter, die am NF-κB- und TNF-α-Signalweg beteiligt sind, und beeinflusst die Sekretion von CXCL10. Zusammenfassend lässt sich festhalten, dass die identifizierten charakteristischen molekularen Signaturen und Risikofaktoren, die auf eine IPA hinweisen, in Zukunft in Kombination mit etablierten Pilz-Biomarkern die derzeitigen diagnostischen Limitationen überwinden könnten und dazu beitragen könnten, eine patientenindividuelle antimykotische Therapie zu etablieren. Es werden jedoch weitere multizentrische Studien notwendig sein, um diese Ergebnisse umfassend zu bewerten. KW - Aspergillus fumigatus KW - Immunantwort KW - Risikofaktoren KW - invasive pulmonary aspergillosis KW - immune response KW - risk factors KW - transcriptome profiling Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-298512 ER - TY - JOUR A1 - Zink, Miriam A1 - Seewald, Anne A1 - Rohrbach, Mareike A1 - Brodehl, Andreas A1 - Liedtke, Daniel A1 - Williams, Tatjana A1 - Childs, Sarah J. A1 - Gerull, Brenda T1 - Altered expression of TMEM43 causes abnormal cardiac structure and function in zebrafish JF - International Journal of Molecular Sciences N2 - Arrhythmogenic cardiomyopathy (ACM) is an inherited heart muscle disease caused by heterozygous missense mutations within the gene encoding for the nuclear envelope protein transmembrane protein 43 (TMEM43). The disease is characterized by myocyte loss and fibro-fatty replacement, leading to life-threatening ventricular arrhythmias and sudden cardiac death. However, the role of TMEM43 in the pathogenesis of ACM remains poorly understood. In this study, we generated cardiomyocyte-restricted transgenic zebrafish lines that overexpress eGFP-linked full-length human wild-type (WT) TMEM43 and two genetic variants (c.1073C>T, p.S358L; c.332C>T, p.P111L) using the Tol2-system. Overexpression of WT and p.P111L-mutant TMEM43 was associated with transcriptional activation of the mTOR pathway and ribosome biogenesis, and resulted in enlarged hearts with cardiomyocyte hypertrophy. Intriguingly, mutant p.S358L TMEM43 was found to be unstable and partially redistributed into the cytoplasm in embryonic and adult hearts. Moreover, both TMEM43 variants displayed cardiac morphological defects at juvenile stages and ultrastructural changes within the myocardium, accompanied by dysregulated gene expression profiles in adulthood. Finally, CRISPR/Cas9 mutants demonstrated an age-dependent cardiac phenotype characterized by heart enlargement in adulthood. In conclusion, our findings suggest ultrastructural remodeling and transcriptomic alterations underlying the development of structural and functional cardiac defects in TMEM43-associated cardiomyopathy. KW - TMEM43 KW - arrhythmogenic cardiomyopathy KW - zebrafish KW - CRISPR/Cas9 Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286025 SN - 1422-0067 VL - 23 IS - 17 ER - TY - JOUR A1 - Zimny, Sebastian A1 - Koob, Dennis A1 - Li, Jingguo A1 - Wimmer, Ralf A1 - Schiergens, Tobias A1 - Nagel, Jutta A1 - Reiter, Florian Paul A1 - Denk, Gerald A1 - Hohenester, Simon T1 - Hydrophobic bile salts induce pro-fibrogenic proliferation of hepatic stellate cells through PI3K p110 alpha signaling JF - Cells N2 - Bile salts accumulating during cholestatic liver disease are believed to promote liver fibrosis. We have recently shown that chenodeoxycholate (CDC) induces expansion of hepatic stellate cells (HSCs) in vivo, thereby promoting liver fibrosis. Mechanisms underlying bile salt-induced fibrogenesis remain elusive. We aimed to characterize the effects of different bile salts on HSC biology and investigated underlying signaling pathways. Murine HSCs (mHSCs) were stimulated with hydrophilic and hydrophobic bile salts. Proliferation, cell mass, collagen deposition, and activation of signaling pathways were determined. Activation of the human HSC cell line LX 2 was assessed by quantification of α-smooth muscle actin (αSMA) expression. Phosphatidyl-inositol-3-kinase (PI3K)-dependent signaling was inhibited both pharmacologically and by siRNA. CDC, the most abundant bile salt accumulating in human cholestasis, but no other bile salt tested, induced Protein kinase B (PKB) phosphorylation and promoted HSC proliferation and subsequent collagen deposition. Pharmacological inhibition of the upstream target PI3K-inhibited activation of PKB and pro-fibrogenic proliferation of HSCs. The PI3K p110α-specific inhibitor Alpelisib and siRNA-mediated knockdown of p110α ameliorated pro-fibrogenic activation of mHSC and LX 2 cells, respectively. In summary, pro-fibrogenic signaling in mHSCs is selectively induced by CDC. PI3K p110α may be a potential therapeutic target for the inhibition of bile salt-induced fibrogenesis in cholestasis. KW - cholestasis KW - HSC KW - myofibroblast KW - chenodeoxycholate KW - phosphatidyl-inositol-3-kinase p110 alpha KW - Alpelisib KW - liver fibrosis Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-281806 SN - 2073-4409 VL - 11 IS - 15 ER - TY - JOUR A1 - Zimmermann, Marcus A1 - Richter, Anne A1 - Weick, Stefan A1 - Exner, Florian A1 - Mantel, Frederick A1 - Diefenhardt, Markus A1 - Fokas, Emmanouil A1 - Kosmala, Rebekka A1 - Flentje, Michael A1 - Polat, Bülent T1 - Acute toxicities of patients with locally advanced rectal cancer treated with intensified chemoradiotherapy within the CAO/ARO/AIO-12 trial: comparing conventional versus VMAT planning at a single center JF - Scientific Reports N2 - In locally advanced rectal cancer (LARC) neoadjuvant chemoradiotherapy is regarded as standard treatment. We assessed acute toxicities in patients receiving conventional 3D-conformal radiotherapy (3D-RT) and correlated them with dosimetric parameters after re-planning with volumetric modulated arc therapy (VMAT). Patients were randomized within the multicenter CAO/ARO/AIO-12 trial and received 50.4 Gy in 28 fractions and simultaneous chemotherapy with fluorouracil and oxaliplatin. Organs at risk (OAR) were contoured in a standardized approach. Acute toxicities and dose volume histogram parameters of 3D-RT plans were compared to retrospectively calculated VMAT plans. From 08/2015 to 01/2018, 35 patients with LARC were treated at one study center. Thirty-four patients were analyzed of whom 1 (3%) was UICC stage II and 33 (97%) patients were UICC stage III. Grade 3 acute toxicities occurred in 5 patients (15%). Patients with acute grade 1 cystitis (n = 9) had significantly higher D\(_{mean}\) values for bladder (29.4 Gy vs. 25.2 Gy, p < 0.01) compared to patients without bladder toxicities. Acute diarrhea was associated with small bowel volume (grade 2: 870.1 ccm vs. grade 0–1: 647.3 ccm; p < 0.01) and with the irradiated volumes V5 to V50. Using VMAT planning, we could reduce mean doses and irradiated volumes for all OAR: D\(_{mean}\) bladder (21.9 Gy vs. 26.3 Gy, p < 0.01), small bowel volumes V5–V45 (p < 0.01), D\(_{mean}\) anal sphincter (34.6 Gy vs. 35.6 Gy, p < 0.01) and D\(_{mean}\) femoral heads (right 11.4 Gy vs. 25.9 Gy, left 12.5 Gy vs. 26.6 Gy, p < 0.01). Acute small bowel and bladder toxicities were dose and volume dependent. Dose and volume sparing for all OAR could be achieved through VMAT planning and might result in less acute toxicities. KW - radiotherapy KW - rectal cancer Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-301255 VL - 12 ER - TY - JOUR A1 - Ziegler, Alice A1 - Meyer, Hanna A1 - Otte, Insa A1 - Peters, Marcell K. A1 - Appelhans, Tim A1 - Behler, Christina A1 - Böhning-Gaese, Katrin A1 - Classen, Alice A1 - Detsch, Florian A1 - Deckert, Jürgen A1 - Eardley, Connal D. A1 - Ferger, Stefan W. A1 - Fischer, Markus A1 - Gebert, Friederike A1 - Haas, Michael A1 - Helbig-Bonitz, Maria A1 - Hemp, Andreas A1 - Hemp, Claudia A1 - Kakengi, Victor A1 - Mayr, Antonia V. A1 - Ngereza, Christine A1 - Reudenbach, Christoph A1 - Röder, Juliane A1 - Rutten, Gemma A1 - Schellenberger Costa, David A1 - Schleuning, Matthias A1 - Ssymank, Axel A1 - Steffan-Dewenter, Ingolf A1 - Tardanico, Joseph A1 - Tschapka, Marco A1 - Vollstädt, Maximilian G. R. A1 - Wöllauer, Stephan A1 - Zhang, Jie A1 - Brandl, Roland A1 - Nauss, Thomas T1 - Potential of airborne LiDAR derived vegetation structure for the prediction of animal species richness at Mount Kilimanjaro JF - Remote Sensing N2 - The monitoring of species and functional diversity is of increasing relevance for the development of strategies for the conservation and management of biodiversity. Therefore, reliable estimates of the performance of monitoring techniques across taxa become important. Using a unique dataset, this study investigates the potential of airborne LiDAR-derived variables characterizing vegetation structure as predictors for animal species richness at the southern slopes of Mount Kilimanjaro. To disentangle the structural LiDAR information from co-factors related to elevational vegetation zones, LiDAR-based models were compared to the predictive power of elevation models. 17 taxa and 4 feeding guilds were modeled and the standardized study design allowed for a comparison across the assemblages. Results show that most taxa (14) and feeding guilds (3) can be predicted best by elevation with normalized RMSE values but only for three of those taxa and two of those feeding guilds the difference to other models is significant. Generally, modeling performances between different models vary only slightly for each assemblage. For the remaining, structural information at most showed little additional contribution to the performance. In summary, LiDAR observations can be used for animal species prediction. However, the effort and cost of aerial surveys are not always in proportion with the prediction quality, especially when the species distribution follows zonal patterns, and elevation information yields similar results. KW - biodiversity KW - species richness KW - LiDAR KW - elevation KW - partial least square regression KW - arthropods KW - birds KW - bats KW - predictive modeling Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262251 SN - 2072-4292 VL - 14 IS - 3 ER - TY - JOUR A1 - Zhou, Xiang A1 - Ruckdeschel, Anna A1 - Peter, Jessica A1 - Böckle, David A1 - Hornburger, Hannah A1 - Danhof, Sophia A1 - Steinhardt, Maximilian Johannes A1 - Heimeshoff, Larissa A1 - Einsele, Hermann A1 - Kortüm, Klaus Martin A1 - Rasche, Leo T1 - Salvage therapy with "Dara-KDT-P(A)CE" in heavily pretreated, high-risk, proliferative, relapsed/refractory multiple myeloma JF - Hematological Oncology N2 - The multi-agent therapy “VDT-PACE” represents an established regimen in relapsed/refractory multiple myeloma (RRMM). Here, we report on our experience with a “modified VDT-PACE” incorporating new generation anti-MM agents daratumumab and carfilzomib (“Dara-KDT-P(A)CE”). We retrospectively analyzed 38 patients with RRMM treated with “Dara-KDT-P(A)CE”. The median age was 62 (range 45–82) years, and the patients were heavily pretreated with a median of 5 (range 2–12) prior lines of therapy. Twenty-one (55%) patients suffered from penta-refractory MM. High-risk cytogenetics was present in 31 (81%) patients. The patients received a median of 2 (range 1–10) cycles of this therapy, and the overall response rate (ORR) was 70%. Patients with penta-refractory MM and high-risk cytogenetics showed similar ORR of 65% and 79%, respectively. The median progression-free survival (PFS) and overall survival were 4.1 (95% CI 2.7–5.4) and 8.4 (95% CI 6.7–10.0) months, respectively. Patients with lactate dehydrogenase >250 IU/L showed significantly shorter PFS in comparison with others patients (p = 0.006). We used this regimen as bridging therapy prior to chimeric antigen receptor T-cell infusion in four patients. In conclusion, “Dara-KDT-P(A)CE” is an effective salvage therapy for patients with heavily pretreated, multi-refractory, high-risk RRMM lacking alternative options. KW - Dara-KDT-P(A)CE KW - multiple myeloma KW - refractory KW - salvage Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-257495 VL - 40 IS - 2 ER - TY - JOUR A1 - Zhang, Xiaolei A1 - Friedrich, Alexandra A1 - Marder, Todd B. T1 - Copper-Catalyzed Borylation of Acyl Chlorides with an Alkoxy Diboron Reagent: A Facile Route to Acylboron Compounds JF - Chemistry—A European Journal N2 - Herein, the copper-catalyzed borylation of readily available acyl chlorides with bis(pinacolato)diboron, (B\(_{2}\)pin\(_{2}\)) or bis(neopentane glycolato)diboron (B\(_{2}\)neop\(_{2}\)) is reported, which provides stable potassium acyltrifluoroborates (KATs) in good yields from the acylboronate esters. A variety of functional groups are tolerated under the mild reaction conditions (room temperature) and substrates containing different carbon-skeletons, such as aryl, heteroaryl and primary, secondary, tertiary alkyl are applicable. Acyl N-methyliminodiacetic acid (MIDA) boronates can also been accessed by modification of the workup procedures. This process is scalable and also amenable to the late-stage conversion of carboxylic acid-containing drugs into their acylboron analogues, which have been challenging to prepare previously. A catalytic mechanism is proposed based on in situ monitoring of the reaction between p-toluoyl chloride and an NHC-copper(I) boryl complex as well as the isolation of an unusual lithium acylBpinOBpin compound as a key intermediate. KW - boronate KW - catalysis KW - borylation KW - carbonyl KW - copper Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-318318 VL - 28 IS - 42 ER - TY - JOUR A1 - Zhang, Chonghe A1 - Liu, Xiaocui A1 - Wang, Junyi A1 - Ye, Qing T1 - A Three-Dimensional Inorganic Analogue of 9,10-Diazido-9,10-Diboraanthracene: A Lewis Superacidic Azido Borane with Reactivity and Stability JF - Angewandte Chemie N2 - Herein, we report the facile synthesis of a three-dimensional (3D) inorganic analogue of 9,10-diazido-9,10-dihydrodiboraantracene, which turned out to be a monomer in both the solid and solution state, and thermally stable up to 230 °C, representing a rare example of azido borane with boosted Lewis acidity and stability in one. Apart from the classical acid-base and Staudinger reactions, E−H bond activation (E=B, Si, Ge) was investigated. While the reaction with B−H (9-borabicyclo[3.3.1]nonane) led directly to the 1,1-addition on N\(_{α}\) upon N\(_{2}\) elimination, the Si−H (Et\(_{3}\)SiH, PhMe\(_{2}\)SiH) activation proceeded stepwise via 1,2-addition, with the key intermediates 5\(_{int}\) and 6\(_{int}\) being isolated and characterized. In contrast, the cooperative Ge−H was reversible and stayed at the 1,2-addition step. KW - E-H bond activation KW - boracycle KW - azido borane KW - lewis superacid KW - structure elucidation Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-318322 VL - 61 IS - 36 ER - TY - JOUR A1 - Zaum, Ann‐Kathrin A1 - Nanda, Indrajit A1 - Kress, Wolfram A1 - Rost, Simone T1 - Detection of pericentric inversion with breakpoint in DMD by whole genome sequencing JF - Molecular Genetics & Genomic Medicine N2 - Background Dystrophinopathies caused by variants in the DMD gene are a well‐studied muscle disease. The most common type of variant in DMD are large deletions. Very rarely reported forms of variants are chromosomal translocations, inversions and deep intronic variants (DIVs) because they are not detectable by standard diagnostic techniques (sequencing of coding sequence, copy number variant detection). This might be the reason that some clinically and histologically proven dystrophinopathy cases remain unsolved. Methods We used whole genome sequencing (WGS) to screen the entire DMD gene for variants in one of two brothers suffering from typical muscular dystrophy with strongly elevated creatine kinase levels. Results Although a pathogenic DIV could not be detected, we were able to identify a pericentric inversion with breakpoints in DMD intron 44 and Xq13.3, which could be confirmed by Sanger sequencing in the index as well as in his brother and mother. As this variation affects a major part of DMD it is most likely disease causing. Conclusion Our findings elucidate that WGS is capable of detecting large structural rearrangements and might be suitable for the genetic diagnostics of dystrophinopathies in the future. In particular, inversions might be a more frequent cause for dystrophinopathies as anticipated and should be considered in genetically unsolved dystrophinopathy cases. KW - chromosome inversion KW - Duchenne muscular dystrophy KW - dystrophin KW - genetic diagnostics KW - whole genome sequencing Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-293940 VL - 10 IS - 10 ER - TY - JOUR A1 - Zapf, Ludwig A1 - Peters, Sven A1 - Bertermann, Rüdiger A1 - Radius, Udo A1 - Finze, Maik T1 - Tricyanoborane‐Functionalized Anionic N‐Heterocyclic Carbenes: Adjustment of Charge and Stereo‐Electronic Properties JF - Chemistry – A European Journal N2 - The 1‐methyl‐3‐(tricyanoborane)imidazolin‐2‐ylidenate anion (2) was obtained in high yield by deprotonation of the B(CN)3‐methylimidazole adduct 1. Regarding charge and stereo‐electronic properties, anion 2 closes the gap between well‐known neutral NHCs and the ditopic dianionic NHC, the 1,3‐bis(tricyanoborane)imidazolin‐2‐ylidenate dianion (IIb). The influence of the number of N‐bonded tricyanoborane moieties on the σ‐donating and π‐accepting properties of NHCs was assessed by quantum chemical calculations and verified by experimental data on 2, IIb, and 1,3‐dimethylimidazolin‐2‐ylidene (IMe, IIa). Therefore NHC 2, which acts as a ditopic ligand via the carbene center and the cyano groups, was reacted with alkyl iodides, selenium, and [Ni(CO)\(_{4}\)] yielding alkylated imidazoles 3 and 4, the anionic selenium adduct 5, and the anionic nickel tricarbonyl complex 8, respectively. The results of this study prove that charge, number of coordination sites, buried volume (%V\(_{bur}\)) and σ‐donor and π‐acceptor abilities of NHCs can be effectively fine‐tuned via the number of tricyanoborane substituents. KW - N-heterocyclic carbene KW - anionic carbene KW - boron KW - cyanoborate KW - imidazolate Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-287200 VL - 28 IS - 39 ER - TY - JOUR A1 - Zamò, Alberto A1 - Gerhard-Hartmann, Elena A1 - Ott, German A1 - Anagnostopoulos, Ioannis A1 - Scott, David W. A1 - Rosenwald, Andreas A1 - Rauert-Wunderlich, Hilka T1 - Routine application of the Lymph2Cx assay for the subclassification of aggressive B-cell lymphoma: report of a prospective real-world series JF - Virchows Archiv N2 - The subclassification of diffuse large B-cell lymphoma (DLBCL) into germinal center B-cell-like (GCB) and activated B-cell-like (ABC) subtypes has become mandatory in the 2017 update of the WHO classification of lymphoid neoplasms and will continue to be used in the WHO 5\(^{th}\) edition. The RNA-based Lymph2Cx assay has been validated as a reliable surrogate of high-throughput gene expression profiling assays for distinguishing between GCB and ABC DLBCL and provides reliable results from formalin-fixed, paraffin-embedded (FFPE) material. This test has been previously used in clinical trials, but experience from real-world routine application is rare. We routinely applied the Lymph2Cx assay to day-to-day diagnostics on a series of 147 aggressive B-cell lymphoma cases and correlated our results with the immunohistochemical subclassification using the Hans algorithm and fluorescence in situ hybridization findings using break-apart probes for MYC, BCL2, and BCL6. The routine use of the Lymph2Cx assay had a high technical success rate (94.6%) with a low rate of failure due to poor material and/or RNA quality. The Lymph2Cx assay was discordant with the Hans algorithm in 18% (23 of 128 cases). Discordant cases were mainly classified as GCB by the Hans algorithm and as ABC by Lymph2Cx (n = 11, 8.6%). Only 5 cases (3.9%) were classified as non-GCB by the Hans algorithm and as GCB by Lymph2Cx. Additionally, 5.5% of cases (n = 7) were left unclassified by Lymph2Cx, whereas they were defined as GCB (n = 4) or non-GCB (n = 3) by the Hans algorithm. Our data support the routine applicability of the Lymph2Cx assay. KW - diffuse large B-cell lymphoma KW - Hans algorithm KW - Lymph2Cx assay KW - cell of origin Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324686 VL - 481 IS - 6 ER - TY - JOUR A1 - Zaitseva, Olena A1 - Hoffmann, Annett A1 - Otto, Christoph A1 - Wajant, Harald T1 - Targeting fibroblast growth factor (FGF)-inducible 14 (Fn14) for tumor therapy JF - Frontiers in Pharmacology N2 - Fibroblast growth factor-inducible 14 (Fn14) is a member of the tumor necrosis factor (TNF) receptor superfamily (TNFRSF) and is activated by its ligand TNF-like weak inducer of apoptosis (TWEAK). The latter occurs as a homotrimeric molecule in a soluble and a membrane-bound form. Soluble TWEAK (sTWEAK) activates the weakly inflammatory alternative NF-κB pathway and sensitizes for TNF-induced cell death while membrane TWEAK (memTWEAK) triggers additionally robust activation of the classical NF-κB pathway and various MAP kinase cascades. Fn14 expression is limited in adult organisms but becomes strongly induced in non-hematopoietic cells by a variety of growth factors, cytokines and physical stressors (e.g., hypoxia, irradiation). Since all these Fn14-inducing factors are frequently also present in the tumor microenvironment, Fn14 is regularly found to be expressed by non-hematopoietic cells of the tumor microenvironment and most solid tumor cells. In general, there are three possibilities how the tumor-Fn14 linkage could be taken into consideration for tumor therapy. First, by exploitation of the cancer associated expression of Fn14 to direct cytotoxic activities (antibody-dependent cell-mediated cytotoxicity (ADCC), cytotoxic payloads, CAR T-cells) to the tumor, second by blockade of potential protumoral activities of the TWEAK/Fn14 system, and third, by stimulation of Fn14 which not only triggers proinflammtory activities but also sensitizes cells for apoptotic and necroptotic cell death. Based on a brief description of the biology of the TWEAK/Fn14 system and Fn14 signaling, we discuss the features of the most relevant Fn14-targeting biologicals and review the preclinical data obtained with these reagents. In particular, we address problems and limitations which became evident in the preclinical studies with Fn14-targeting biologicals and debate possibilities how they could be overcome. KW - agonistic antibodies KW - cell death KW - Fn14 KW - NFκB KW - TNF KW - TWEAK Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290238 SN - 1663-9812 VL - 13 ER - TY - THES A1 - Youssef, Almoatazbellah T1 - Fabrication of Micro-Engineered Scaffolds for Biomedical Application T1 - Fabrikation von Scaffolds mit optimierter Mikroarchitektur für biomedizinische Anwendungen N2 - Thermoplastic polymers have a history of decades of safe and effective use in the clinic as implantable medical devices. In recent years additive manufacturing (AM) saw increased clinical interest for the fabrication of customizable and implantable medical devices and training models using the patients’ own radiological data. However, approval from the various regulatory bodies remains a significant hurdle. A possible solution is to fabricate the AM scaffolds using materials and techniques with a clinical safety record, e.g. melt processing of polymers. Melt Electrowriting (MEW) is a novel, high resolution AM technique which uses thermoplastic polymers. MEW produces scaffolds with microscale fibers and precise fiber placement, allowing the control of the scaffold microarchitecture. Additionally, MEW can process medical-grade thermoplastic polymers, without the use of solvents paving the way for the production of medical devices for clinical applications. This pathway is investigated in this thesis, where the layout is designed to resemble the journey of a medical device produced via MEW from conception to early in vivo experiments. To do so, first, a brief history of the development of medical implants and the regenerative capability of the human body is given in Chapter 1. In Chapter 2, a review of the use of thermoplastic polymers in medicine, with a focus on poly(ε-caprolactone) (PCL), is illustrated, as this is the polymer used in the rest of the thesis. This review is followed by a comparison of the state of the art, regarding in vivo and clinical experiments, of three polymer melt AM technologies: melt-extrusion, selective laser sintering and MEW. The first two techniques already saw successful translation to the bedside, producing patient-specific, regulatory-approved AM implants. To follow in the footsteps of these two technologies, the MEW device parameters need to be optimized. The MEW process parameters and their interplay are further discussed in Chapter 3 focusing on the importance of a steady mass flow rate of the polymer during printing. MEW reaches a balance between polymer flow, the stabilizing electric field and moving collector to produce reproducible, high-resolution scaffolds. An imbalance creates phenomena like fiber pulsing or arcing which result in defective scaffolds and potential printer damage. Chapter 4 shows the use of X-ray microtomography (µCT) as a non-destructive method to characterize the pore-related features: total porosity and the pore size distribution. MEW scaffolds are three-dimensional (3D) constructs but have long been treated in the literature as two-dimensional (2D) ones and characterized mainly by microscopy, including stereo- and scanning electron microscopy, where pore size was simply reported as the distance between the fibers in a single layer. These methods, together with the trend of producing scaffolds with symmetrical pores in the 0/90° and 0/60/120° laydown patterns, disregarded the lateral connections between pores and the potential of MEW to be used for more complex 3D structures, mimicking the extracellular matrix. Here we characterized scaffolds in the aforementioned symmetrical laydown patterns, along with the more complex 0/45/90/135° and 0/30/60/90/120/150° ones. A 2D pore size estimation was done first using stereomicroscopy, followed by and compared to µCT scanning. The scaffolds with symmetrical laydown patterns resulted in the predominance of one pore size, while those with more complex patterns had a broader distribution, which could be better shown by µCT scans. Moreover, in the symmetrical scaffolds, the size of 3D pores was not able to reach the value of the fiber spacing due to a flattening effect of the scaffold, where the thickness of the scaffold was less than the fiber spacing, further restricting the pore size distribution in such scaffolds. This method could be used for quality assurance of fabricated scaffolds prior to use in in vitro or in vivo experiments and would be important for a clinical translation. Chapter 5 illustrates a proof of principle subcutaneous implantation in vivo experiment. MEW scaffolds were already featured in small animal in vivo experiments, but to date, no analysis of the foreign body reaction (FBR) to such implants was performed. FBR is an immune reaction to implanted foreign materials, including medical devices, aimed at protecting the host from potential adverse effects and can interfere with the function of some medical implants. Medical-grade PCL was used to melt electrowrite scaffolds with 50 and 60 µm fiber spacing for the 0/90° and 0/60/120° laydown patterns, respectively. These implants were implanted subcutaneously in immunocompetent, outbred mice, with appropriate controls, and explanted after 2, 4, 7 and 14 days. A thorough characterization of the scaffolds before implantation was done, followed by a full histopathological analysis of the FBR to the implants after excision. The scaffolds, irrespective of their pore geometry, induced an extensive FBR in the form of accumulation of foreign body giant cells around the fiber walls, in a manner that almost occluded available pore spaces with little to no neovascularization. This reaction was not induced by the material itself, as the same reaction failed to develop in the PCL solid film controls. A discussion of the results was given with special regard to the literature available on flat surgical meshes, as well as other hydrogel-based porous scaffolds with similar pore sizes. Finally, a general summary of the thesis in Chapter 6 recapitulates the most important points with a focus on future directions for MEW. N2 - Thermoplastische Polymere werden seit Jahrzehnten erfolgreich in der Klinik eingesetzt und für die Herstellung von Medizinprodukten verwendet. Vorangetrieben durch das zunehmende klinische Interesse an additiven Fertigungsverfahren, z.B. zur Herstellung patientenspezifischer Trainingsmodelle und implantierbarer Medizinprodukte, rücken thermoplastische Materialien noch mehr in den Fokus der klinischen Forschung. Allerdings stellt die Marktzulassung durch die verschiedenen Gesundheitsbehörden eine große Hürde dar. Eine mögliche Lösung ist die Gerüstfabrikation mit Materialien und Verfahren, die bereits etablierte Sicherheitsstandards durchlaufen haben, z. B. die Schmelzverarbeitung der Polymere. Ein neuartiges und hochauflösendes additives Fertigungsverfahren, welches die Verarbeitung von Thermoplasten ermöglicht, ist Melt Electrowriting (MEW). Mittels MEW lassen sich Gerüste, die aus Fasern mit Durchmessern im Mikrometerbereich zusammengesetzt sind, herstellen. Neben der hohen Kontrolle über den Faserdurchmesser ermöglicht MEW auch eine genaue Ablage der Fasern und erlaubt dadurch, die Mikroarchitektur der Konstrukte vorzugeben. Zudem kann das Verfahren medizinisch zugelassene thermoplastische Polymere ohne die Verwendung von Lösungsmitteln verarbeiten und ist somit für die Herstellung medizinischer Produkte sehr relevant. Diese Relevanz sollte im Rahmen der vorliegenden Dissertation evaluiert werden, indem der Weg, den ein Medizinprodukt von der Konzeption bis hin zu in vivo Vorversuchen durchlaufen muss, anhand von Konstrukten, die mittels MEW hergestellt wurden, nachgeahmt wurde. Um eine Basis für das Verständnis dieses Prozesses zu schaffen, wird in Kapitel 1 erst die Geschichte der Entwicklung medizinischer Implantate zusammengefasst sowie ein Einblick in die regenerativen Fähigkeiten des menschlichen Körpers gegeben. Das zweite Kapitel befasst sich mit der Anwendung von thermoplastischen Polymeren im Bereich implantierbarer Medizinprodukte, wobei der Hauptfokus auf Poly(ε-caprolactone) (PCL) liegt, da dies der in der vorliegenden Arbeit verwendete Thermoplast ist. Es folgt ein Vergleich von in vivo sowie klinischen Versuchen dreier für die Biomedizin relevanten additiven Fertigungsverfahren, mit denen sich thermoplastische Polymere verarbeiten lassen: Die Mikro-Schmelzextrusion, das selektive Lasersintern und das MEW. Die ersten zwei Verfahren sind bereits erfolgreich in klinischen Anwendungen etabliert und ermöglichen die routinemäßige Herstellung von additiv gefertigten, patientenspezifischen, auf dem Markt zugelassenen Implantaten. Damit MEW in diese Fußstapfen treten kann, müssen die Prozessparameter und deren Zusammenspiel genau analysiert werden. Dieser Thematik widmet sich Kapitel 3, wobei die Untersuchung des Massendurchsatzes des Polymers während des Druckens diskutiert wird. Um den MEW-Prozess kontrollieren zu können, muss eine Balance zwischen Polymerdurchsatz, dem stabilisierenden elektrischen Feld und dem beweglichen Kollektor erreicht werden. Dies ist Grundlage für die reproduzierbare Herstellung hochaufgelöster Konstrukte. Ein Ungleichgewicht der Prozessparameter verursacht Phänomene wie Fiber Pulsing oder sogar elektrischen Durchschlag, welche zu defekten Konstrukten oder sogar zur Schädigung des Druckers führen können. Kapitel 4 zeigt die Anwendung der Röntgenmikrocomputertomographie (µCT) als eine zerstörungsfreie Charakterisierungsmethode für MEW-Konstrukte, die die Quantifizierung charakteristischer Eigenschaften wie der Porosität und der Porengrößenverteilung ermöglicht. MEW-Konstrukte wurden in der Literatur lange als zweidimensional behandelt und hauptsächlich durch mikroskopische Verfahren wie die Stereo- und Rasterelektronmikroskopie charakterisiert. Die zweidimensionale Porengröße wurde hauptsächlich durch die Bestimmung des Faserabstands definiert und daraus errechnet, mit einer Tendenz der Herstellung der Konstrukte mit symmetrischen Poren in 0/90° und 0/60/120° Ablagemustern. Da es sich bei den Konstrukten jedoch um dreidimensionale (3D) Fasergerüste handelt, wurden die seitlichen Verbindungen zwischen den Poren und das Potential der Anwendung des MEW für die Herstellung von komplexeren 3D-Strukturen, wie bei der extrazellulären Matrix mit interkonnektierenden Poren, vernachlässigt. Aus diesem Grund wurden in der vorliegenden Arbeit µCT-Scans verwendet, um die Porosität der Konstrukte besser wiedergeben zu können. Hierzu wurden verschiedene Ablagemuster mit symmetrischen Poren in 0/90° und 0/60/120° Mustern und komplexere Porenstrukturen durch Ablagen von 0/45/90/135° und 0/30/60/90/120/150° Geometrien hergestellt. Diese Konstrukte wurden dann mittels mikroskopischer und tomographischer Aufnahmen charakterisiert und die Ergebnisse miteinander verglichen. Es zeigte sich, dass symmetrische Ablagemuster zu Konstrukten mit der Prädominanz einer Porengröße geführt haben. Bei den komplexeren Strukturen ergab sich jedoch ein klarer Unterschied, weil die interkonnektierenden Poren nur mit Hilfe von µCT-Scans erfasst werden konnten. Dies zeigte sich durch eine breitere Porenverteilung bei der Auswertung der rekonstruierten Scans. Die Porengrößen in den Konstrukten mit den symmetrischen Mustern konnten aufgrund einer Verflachungswirkung nicht die des Faserabstands erreichen. Die Dicke der Konstrukte war geringer als der Faserabstand mit einer weiteren einschränkenden Wirkung auf die Porenverteilung in den symmetrischen Konstrukten. µCT kann deshalb für die Qualitätssicherung von medizinischen Produkten, die mittels MEW hergestellt wurden, eingesetzt werden. Da die Methode zerstörungsfrei ist, könnte sie auch vor in vitro oder in vivo Versuchen verwendet werden. Kapitel 5 präsentiert eine Machbarkeitsstudie eines subkutanen in vivo Implantationsversuchs. Aus der Literatur ist zwar bekannt, dass MEW-Konstrukte bereits in vivo in Kleintierversuchen verwendet wurden, eine Analyse der Fremdkörperreaktion (FKR) zu solchen Implantaten wurde bisher jedoch noch nicht durchgeführt. FKR ist eine Immunreaktion gegen fremde, implantierte Materialien, einschließlich medizinischer Geräte, um den Wirt vor potenziellen Nebenwirkungen zu schützen. Allerdings könnte sie die Funktion verschiedener medizinischer Implantate beeinträchtigen Um dieser Fragestellung nachzugehen, wurde im Rahmen der vorliegenden Dissertation PCL mittels MEW zu Konstrukten mit 50 und 60 µm Fiberabstand in 0/90° bzw. 0/60/120° Ablagemuster verarbeitet. Diese Konstrukte wurden subkutan in immunkompetente, fremdgezüchtete Mäuse mit entsprechenden Kontrollen implantiert und nach 2, 4, 7 und 14 Tagen explantiert. Vor der Implantation wurde die Konstrukte ausführlich charakterisiert, gefolgt von einer vollen histopathologischen Analyse des FKR. Unabhängig von der Porengeometrie haben die Konstrukte eine deutliche Immunreaktion im Sinne einer Ansammlung von Fremdkörperriesenzellen um die Fasern der Konstrukte hervorgerufen. Hierbei wurden die Poren fast komplett verschlossen, ohne dass es zu einer Neovaskularisation kam. Es konnte nachgewiesen werden, dass die deutliche Immunantwort nicht durch das Material hervorgerufen wurde, da sie bei der Implantation von dichtem PCL-Film nicht beobachtet wurde. Eine Diskussion der Ergebnisse erfolgte unter Berücksichtigung aktueller Literatur zu klinischen Versuchen von flachen chirurgischen Netzen sowie porösen Hydrogel-basierten Implantaten mit vergleichbarer Porengröße. Abschließend wird die Arbeit in Kapitel 6 zusammengefasst und die wichtigsten Punkte rekapituliert. Der Fokus des Kapitels liegt hierbei auf dem zukünftigen Potential des MEW als Fabrikationsmethode für medizinische Produkte. KW - melt electrowriting KW - medical device KW - biomaterials KW - subcutaneous implanation KW - x-ray micro computed tomography Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235457 ER - TY - THES A1 - Ye, Mingyu T1 - Immunotherapy with Vaccinia virus co-expressing tumor-associated antigens and mouse IL-2 cytokine in mice with mammary cancer T1 - Immuntherapie von Brustkrebs in tumortragenden Mäusen mit genetisch modifizierten Vaccinia Viren, die simultan Interleukin-2 und tumorassoziierte Antigene exprimieren N2 - Interleukin 2 (IL-2) was the first cytokine applied for cancer treatment in human history. It has been approved as monotherapy for renal cell carcinoma and melanoma by the FDA and does mediate the regression of the tumors in patients. One of the possible mechanisms is that the administration of IL-2 led to T lymphocytes expansion, including CD4+ and CD8+ T cells. In addition, a recent study demonstrated that antigen-specific T cells could also be expanded through the induction of IL-2, which plays a crucial role in mediating tumor regression. However, despite the long-term and extensive use of IL-2 in the clinic, the ratio of patients who get a complete response was still low, and only about one-fifth of patients showed objective tumor regression. Therefore, the function of IL-2 in cancer treatment should continue to be optimized and investigated. A study by Franz O. Smith et al. has shown that the combination treatment of IL-2 and tumor-associated antigen vaccine has a strong trend to increased objective responses compared to patients with melanoma receiving IL-2 alone. Peptide vaccines are anti-cancer vaccines able to induce a powerful tumor antigenspecific immune response capable of eradicating the tumors. According to the type of antigens, peptide vaccines can be classified into two distinct categories: Tumor-associated antigens (TAA) vaccine and tumor-specific neoantigens (TSA) vaccine. Currently, Peptide vaccines are mainly investigated in phase I and phase II clinical trials of human cancer patients with various advanced cancers such as lung cancer, gastrointestinal tumors, and breast cancers. Vaccinia virus (VACV) is one of the safest viral vectors, which has been wildly used in cancer treatment and pathogen prevention. As an oncolytic vector, VACV can carry multiple large foreign genes, which enable the virus to introduce diagnostic and therapeutic agents without dramatically reducing the viral replication. Meanwhile, the recombinant vaccinia virus (rVACV) can be easily generated by homologous recombination. Here, we used the vaccinia virus as the therapeutic cancer vector, expressing mouse Interleukin 2 (IL-2) and tumor-associated antigens simultaneously to investigate the combined effect of anti-tumor immune response in the 4T1 mouse tumor model. As expected, the VACV driven mIL-2 expression remarkably increased both CD4+ and CD8+ populations in vivo, and the virus-expressed tumor-associated peptides successfully elicited theantigen-specific T cell response to inhibit the growth of tumors. Furthermore, the experiments with tumor-bearing animals showed that the mIL-2 plus tumor antigens expressing VACV vector gave a better anti-cancer response than the mIL-2 alone expressing vector. The combinations did significantly more inhibit tumor growth than mIL-2 treatment alone. Moreover, the results confirmed our previous unpublished data that the mIL-2 expression driven by synthetic early/late promoter in the Lister strain VACV could enhance the tumor regression in the 4T1 mouse model. N2 - Interleukin 2 (IL-2) war das erste Zytokin in der Geschichte des Menschen, das zur Krebsbehandlung eingesetzt wurde. Es ist von der FDA als Monotherapie für Nierenzellkarzinome und Melanome zugelassen und kann bei Patienten die Rückbildung von Tumorerkrankungen fördern. Einer der möglichen Mechanismen ist, dass die Verabreichung von IL-2 zu einer T-Zell- Expansion führte. Darüber hinaus zeigte eine aktuelle Studie, dass auch antigenspezifische T- Zellen vermehrt werden können, was eine entscheidende Rolle bei der Vermittlung der Tumorregression spielt. Trotz des langjährigen und umfangreichen Einsatzes von IL-2 in der Klinik war der Anteil der Patienten, die eine komplette Antwort Zeigten, jedoch immer noch gering, und nur etwa ein Fünftel der Patienten weist eine objektive Tumorregression auf. Daher sollte die Funktion von IL-2 in der Krebsbehandlung weiter optimiert und untersucht werden. Eine Studie von Franz O. Smith et al. hat gezeigt, dass die Kombinationsbehandlung von IL-2 und tumorassoziiertem Antigenimpfstoff im Vergleich zu Melanomapatienten, die IL-2 allein erhalten, einen starken Trend zu verstärkten objektiven Reaktionen aufweist. Peptidimpfstoff ist ein Anti- Krebs-Impfstoff, der in der Lage ist, eine starke tumorantigenspezifische Immunantwort zu induzieren, die die Tumore ausrotten kann. Je nach Art der Antigene kann es in zwei verschiedene Kategorien eingeteilt werden: Impfstoff gegen tumorassoziierte Antigene (TAA) und Impfstoff gegen tumorspezifische Neoantigene (TSA). Derzeit werden Peptidimpfstoffe hauptsächlich in klinischen Studien in Phasen I und II an Patienten mit verschiedenen fortgeschrittenen Krebsarten wie Lungenkrebs, Magen-Darm-Tumoren und Brustkrebs untersucht ... KW - Immunotherapy KW - Vaccinia virus Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-253095 ER - TY - JOUR A1 - Yang, Xuting A1 - Yao, Wanqiang A1 - Li, Pengfei A1 - Hu, Jinfei A1 - Latifi, Hooman A1 - Kang, Li A1 - Wang, Ningjing A1 - Zhang, Dingming T1 - Changes of SOC content in China's Shendong coal mining area during 1990–2020 investigated using remote sensing techniques JF - Sustainability N2 - Coal mining, an important human activity, disturbs soil organic carbon (SOC) accumulation and decomposition, eventually affecting terrestrial carbon cycling and the sustainability of human society. However, changes of SOC content and their relation with influential factors in coal mining areas remained unclear. In the study, predictive models of SOC content were developed based on field sampling and Landsat images for different land-use types (grassland, forest, farmland, and bare land) of the largest coal mining area in China (i.e., Shendong). The established models were employed to estimate SOC content across the Shendong mining area during 1990–2020, followed by an investigation into the impacts of climate change and human disturbance on SOC content by a Geo-detector. Results showed that the models produced satisfactory results (R\(^2\) > 0.69, p < 0.05), demonstrating that SOC content over a large coal mining area can be effectively assessed using remote sensing techniques. Results revealed that average SOC content in the study area rose from 5.67 gC·kg\(^{−1}\) in 1990 to 9.23 gC·kg\(^{−1}\) in 2010 and then declined to 5.31 gC·Kg\(^{−1}\) in 2020. This could be attributed to the interaction between the disturbance of soil caused by coal mining and the improvement of eco-environment by land reclamation. Spatially, the SOC content of farmland was the highest, followed by grassland, and that of bare land was the lowest. SOC accumulation was inhibited by coal mining activities, with the effect of high-intensity mining being lower than that of moderate- and low-intensity mining activities. Land use was found to be the strongest individual influencing factor for SOC content changes, while the interaction between vegetation coverage and precipitation exerted the most significant influence on the variability of SOC content. Furthermore, the influence of mining intensity combined with precipitation was 10 times higher than that of mining intensity alone. KW - loess plateau KW - coal mining area KW - SOC content prediction KW - human disturbance KW - vegetation restoration KW - climate change Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-278939 SN - 2071-1050 VL - 14 IS - 12 ER - TY - THES A1 - Yang, Shang T1 - Characterization and engineering of photoreceptors with improved properties for optogenetic application T1 - Charakterisierung und Entwicklung von Photorezeptoren mit verbesserten Eigenschaften für die optogenetische Anwendung N2 - Optogenetics became successful in neuroscience with Channelrhodopsin-2 (ChR2), a light-gated cation channel from the green alga Chlamydomonas reinhardtii, as an easy applicable tool. The success of ChR2 inspired the development of various photosensory proteins as powerful actuators for optogenetic manipulation of biological activity. However, the current optogenetic toolbox is still not perfect and further improvements are desirable. In my thesis, I engineered and characterized several different optogenetic tools with new features. (i) Although ChR2 is the most often used optogenetic actuator, its single-channel conductance and its Ca2+ permeability are relatively low. ChR2 variants with increased Ca2+ conductance were described recently but a further increase seemed possible. In addition, the H+ conductance of ChR2 may lead to cellular acidification and unintended pH-related side effects upon prolonged illumination. Through rational design, I developed several improved ChR2 variants with larger photocurrent, higher cation selectivity, and lower H+ conductance. (ii) The light-activated inward chloride pump NpHR is a widely used optogenetic tool for neural silencing. However, pronounced inactivation upon long time illumination constrains its application for long-lasting neural inhibition. I found that the deprotonation of the Schiff base underlies the inactivation of NpHR. Through systematically exploring optimized illumination schemes, I found illumination with blue light alone could profoundly increase the temporal stability of the NpHR-mediated photocurrent. A combination of green and violet light eliminates the inactivation effect, similar to blue light, but leading to a higher photocurrent and therefore better light-induced inhibition. (iii) Photoactivated adenylyl cyclases (PACs) were shown to be useful for light-manipulation of cellular cAMP levels. I developed a convenient in-vitro assay for soluble PACs that allows their reliable characterization. Comparison of different PACs revealed that bPAC from Beggiatoa is the best optogenetic tool for cAMP manipulation, due to its high efficiency and small size. However, a residual activity of bPAC in the dark is unwanted and the cytosolic localization prevents subcellular precise cAMP manipulation. I therefore introduced point mutations into bPAC to reduce its dark activity. Interestingly, I found that membrane targeting of bPAC with different linkers can remarkably alter its activity, in addition to its localization. Taken together, a set of PACs with different activity and subcellular localization were engineered for selection based on the intended usage. The membrane-bound PM-bPAC 2.0 with reduced dark activity is well-tolerated by hippocampal neurons and reliably evokes a transient photocurrent, when co-expression with a CNG channel. (iv) Bidirectional manipulation of cell activity with light of different wavelengths is of great importance in dissecting neural networks in the brain. Selection of optimal tool pairs is the first and most important step for dual-color optogenetics. Through N- and C-terminal modifications, an improved ChR variant (i.e. vf-Chrimson 2.0) was engineered and selected as the red light-controlled actuator for excitation. Detailed comparison of three two-component potassium channels, composed of bPAC and the cAMP-activated potassium channel SthK, revealed the superior properties of SthK-bP. Combining vf-Chrimson 2.0 and improved SthK-bP “SthK(TV418)-bP” could reliably induce depolarization by red light and hyperpolarization by blue light. A residual tiny crosstalk between vf-Chrimson 2.0 and SthK(TV418)-bP, when applying blue light, can be minimized to a negligible level by applying light pulses or simply lowering the blue light intensity. N2 - Die Optogenetik wurde in den Neurowissenschaften mit Channelrhodopsin-2 (ChR2), einem lichtgesteuerten Kationenkanal aus der Grünalge Chlamydomonas reinhardtii, als leicht anwendbares Werkzeug erfolgreich. Der Erfolg von ChR2 inspirierte die Entwicklung verschiedener photosensorischer Proteine als leistungsstarke Aktuatoren für die optogenetische Manipulation der biologischen Aktivität. Die derzeitige optogenetische Toolbox ist jedoch immer noch nicht perfekt und weitere Verbesserungen sind wünschenswert. In meiner Arbeit habe ich verschiedene optogenetische Werkzeuge mit neuen Funktionen entwickelt und charakterisiert. (i) Obwohl ChR2 der am häufigsten verwendete optogenetische Aktuator ist, sind seine Einzelkanal-Leitfähigkeit und seine Ca2 + -Permeabilität relativ gering. Kürzlich wurden ChR2-Varianten mit erhöhter Ca2 + -Leitfähigkeit beschrieben, eine weitere Verbesserung schien jedoch möglich. Darüber hinaus kann die H+-Leitfähigkeit von ChR2 bei längerer Beleuchtung zu einer Ansäuerung der Zellen und zu unbeabsichtigten Nebenwirkungen im Zusammenhang mit dem pH-Wert führen. Durch rationales Design entwickelte ich mehrere verbesserte ChR2-Varianten mit größerem Photostrom, höherer Kationenselektivität und geringerer H+-Leitfähigkeit. (ii) Die lichtaktivierte Chloridpumpe NpHR ist ein weit verbreitetes optogenetisches Werkzeug für die neuronale Inhibierung. Eine ausgeprägte Inaktivierung bei längerer Beleuchtung schränkt jedoch die Anwendung für eine lang anhaltende neuronale Hemmung ein. Ich konnte zeigen, dass die Deprotonierung der Schiffschen Base der Inaktivierung von NpHR zugrunde liegt. Durch die systematische Untersuchung optimierter Beleuchtungsschemata fand ich heraus, dass die Beleuchtung mit blauem Licht allein die zeitliche Stabilität des NpHR-vermittelten Photostroms erheblich verbessern kann. Eine Kombination aus grünem und violettem Licht eliminiert den Inaktivierungseffekt, ähnlich wie blaues Licht, führt jedoch zu einem höheren Photostrom und deswegen effektiverer Licht-induzierter Inhibierung. (iii) Photoaktivierte Adenylylcyclasen (PACs) erwiesen sich als nützlich für die Lichtmanipulation der zellulären cAMP-Spiegel. Ich habe einen praktischen in-vitro-Test für lösliche PACs entwickelt, der deren zuverlässige Charakterisierung ermöglicht. Ein Vergleich verschiedener PACs ergab, dass bPAC von Beggiatoa aufgrund seiner hohen Effizienz und geringen Größe das beste optogenetische Werkzeug für die cAMP-Manipulation ist. Eine Restaktivität von bPAC im Dunkeln ist jedoch unerwünscht und die cytosolische Lokalisierung verhindert eine subzellulär präzise cAMP-Manipulation. Ich habe daher Punktmutationen in bPAC eingeführt, um dessen Dunkelaktivität zu reduzieren. Interessanterweise fanden Ich heraus, dass das Membrantargeting von bPAC mit verschiedenen „Linkern“ zusätzlich zu seiner Lokalisierung seine Aktivität erheblich verändern kann. Zusammengenommen wurde eine Reihe von PACs mit unterschiedlicher Aktivität und subzellulärer Lokalisation für unterschiedliche Anwendungen konstruiert. Das membrangebundene PM-bPAC 2.0 mit reduzierter Dunkelaktivität wird von Hippocampus-Neuronen gut vertragen und erlaubt, bei gleichzeitiger Expression mit einem CNG-Kanal, zuverlässig einen Licht-induzierten Strom auszulösen. (iv) Die bidirektionale Manipulation der Zellaktivität mit Licht unterschiedlicher Wellenlänge ist für die Dissektion neuronaler Netze im Gehirn von großer Bedeutung. Die Auswahl der optimalen Werkzeugpaare ist der erste und wichtigste Schritt für die zweifarbige Optogenetik. Durch N- und C-terminale Modifikationen wurde eine verbesserte ChR-Variante (d. h. Vf-Chrimson 2.0) entwickelt und als Rotlicht-gesteuerter Aktuator zur Anregung ausgewählt. Ein detaillierter Vergleich von drei Zweikomponenten-Kaliumkanälen, bestehend aus bPAC und dem cAMP-aktivierten Kaliumkanal SthK, ergab die überlegenen Eigenschaften von SthK-bP. Die Kombination von vf-Chrimson 2.0 und verbessertem SthK-bP „SthK(TV418)-bP“ konnte zuverlässig eine Depolarisation durch rotes Licht und eine Hyperpolarisation durch blaues Licht induzieren. Ein restliches, kleines Übersprechen zwischen vf-Chrimson 2.0 und SthK(TV418)-bP kann beim Anlegen von blauem Licht durch Anlegen von Lichtimpulsen oder durch einfaches Verringern der Intensität von blauem Licht auf ein vernachlässigbares Maß minimiert werden. KW - Optogenetics KW - ChR2 KW - NpHR KW - PAC KW - Bidirectional manipulation Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-205273 ER - TY - JOUR A1 - Yan, Zhe T1 - “I tried to control my emotions”: nursing home care workers’ experiences of emotional labor in China JF - Journal of Cross-Cultural Gerontology N2 - Despite dramatic expansions in the Chinese nursing home sector in meeting the increasing care needs of a rapidly aging population, direct care work in China remains largely devalued and socially unrecognized. Consequently, scant attention has been given to the caregiving experiences of direct care workers (DCWs) in Chinese nursing homes. In particular, given the relational nature of care work, there is little knowledge as to how Chinese DCWs manage emotions and inner feelings through their emotional labor. This article examines the emotional labor of Chinese DCWs through ethnographic data collected with 20 DCWs in one nursing home located in an urban setting in central China. Data were analyzed using conventional content analysis and constant comparison. Participants’ accounts of sustaining a caring self, preserving professional identity, and hoping for reciprocity revealed implicit meanings about the often-conflicting nature of emotional labor and the nonreciprocal elements of care work under constrained working conditions. Importantly, the moral-cultural notion of bao (报 norm of reciprocity) was found to be central among DCWs in navigating strained resources and suggested their agency in meaning-construction. However, their constructed moral buffers may be insufficient if emotional labor continues to be made invisible by care organizations. KW - Gerontologie KW - Care-Arbeit KW - Emotionsregulation KW - China KW - Altenpflege KW - China KW - Long-term care KW - Direct care workers KW - Emotional labor KW - Filial piety/xiao KW - Professionalism KW - Reciprocity Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324295 VL - 37 IS - 1 ER - TY - THES A1 - Xu, Wenshan T1 - Regulation of the DNA Damage Response by the Ubiquitin System T1 - Regulierung der DNA-Schadensreaktion durch das Ubiquitin System N2 - DNA damage occurs frequently during normal cellular progresses or by environmental factors. To preserve the genome integrity, DNA damage response (DDR) has evolved to repair DNA and the non-properly repaired DNA induces human diseases like immune deficiency and cancer. Since a large number of proteins involved in DDR are enzymes of ubiquitin system, it is critical to investigate how the ubiquitin system regulates cellular response to DNA damage. Hereby, we reveal a novel mechanism for DDR regulation via activation of SCF ubiquitin ligase upon DNA damage. As an essential step for DNA damage-induced inhibition of DNA replication, Cdc25A degradation by the E3 ligase β-TrCP upon DNA damage requires the deubiquitinase Usp28. Usp28 deubiquitinates β-TrCP in response to DNA damage, thereby promotes its dimerization, which is required for its activity in substrate ubiquitination and degradation. Particularly, ubiquitination at a specific lysine on β-TrCP suppresses dimerization. The key mediator protein of DDR, 53BP1, forms oligomers and associates with β-TrCP to inhibit its activity in unstressed cells. Upon DNA damage, 53BP1 is degraded in the nucleoplasm, which requires oligomerization and is promoted by Usp28 in a β-TrCP-dependent manner. Consequently, 53BP1 destruction releases and activates β-TrCP during DNA damage response. Moreover, 53BP1 deletion and DNA damage promote β-TrCP dimerization and recruitment to chromatin sites that locate in the vicinity of putative replication origins. Subsequently, the chromatin-associated Cdc25A is degraded by β-TrCP at the origins. The stimulation of β-TrCP binding to the origins upon DNA damage is accompanied by unloading of Cdc45, a crucial component of pre-initiation complexes for replication. Loading of Cdc45 to origins is a key Cdk2-dependent step for DNA replication initiation, indicating that localized Cdc25A degradation by β-TrCP at origins inactivates Cdk2, thereby inhibits the initiation of DNA replication. Collectively, this study suggests a novel mechanism for the regulation of DNA replication upon DNA damage, which involves 53BP1- and Usp28-dependent activation of the SCF(β-TrCP) ligase in Cdc25A degradation. N2 - DNA-Schäden treten häufig in Folge zellulären Fortschrittes oder durch externe Faktoren auf. Um die Integrität des Genoms zu bewahren und DNA Schäden zu reparieren, die Ursache für viele Autoimmunkrankheiten und Krebs sind, hat sich ein durch DNA Schäden getriggertes Geflecht aus Reparaturprozessen (englisch: “DNA damage response (DDR)”) entwickelt. Hierbei ist es von großem Interesse zu verstehen, wie das Ubiquitin-Proteasom-System die zelluläre Antwort auf DNA-Schäden reguliert. Wir konnten zeigen, dass die SCF Ubiquitin Ligase β-TrCP durch geschädigte DNA aktiviert wird, was einen bisher unbekannten Mechanismus für die Regulation der DDR darstellt. Für den grundlegenden Schritt der durch DNA Schäden ausgelösten Inhibition der DNA Replikation – der Abbau von Cdc25A durch die E3 Ligase β-TrCP – wird die Deubiquitinase Usp28 benötigt. Diese deubiquitiniert β-TrCP als Antwort auf DNA-Schäden und fördert dadurch seine Dimerisierung, die für die Substrat-Ubiquitinierung und dem anschließenden Abbau erforderlich ist. Hierbei unterdrückt die Ubiquitinierung eines spezifischen Lysin-Rests von β-TrCP dessen Dimerisierung. Das Schlüsselprotein vom DDR, 53BP1, oligomerisiert und assoziiert mit β-TrCP, was seine Aktivität in gesunden Zellen inhibiert. Auf DNA-Schäden hin oligomerisiert 53BP1 und wird mit Hilfe von Usp28 abhängig von β-TrCP im Nukleoplasma abgebaut. Durch den Abbau von 53BP1 wird β-TrCP freigesetzt, aktiviert und kann auf DNA Schäden reagieren. Die Deletion von 53BP1 fördert die Dimerisierung von β-TrCP. Die Reparaturmaschinerie wird daraufhin an Stellen des Chromatins rekrutiert, die in der Nähe von vermeintlichen Replikationsursprüngen liegen. Chromatin-assoziiertes Cdc25A wird dann durch β-TrCP ubiquitiniert. Die Bindung von β-TrCP an die Replikationsursprünge in Folge von DNA Schädigung wird begleitet von der Freisetzung von Cdc45, das eine entscheidende Komponente des Präinitiationskomplexes darstellt. Das Beladen von Cdc45 an die Replikationsursprünge stellt eine Schlüsselfunktion der Cdc25A-abhängigen DNA Replikationsinititation dar. Gezielter Abbau von Cdc25A durch β-TrCP an den Replikationsursprüngen inaktiviert Cdk2 und inhibiert dadurch DNA Replikation. Zusammenfassend lässt sich konstatieren, dass unsere Studien einen neuartigen Mechanismus für die Regulation der DNA Replikation auf DNA Schäden hin aufgezeigt haben, der die 53BP1- und Usp28-abhängige Aktivierung der SCF(β-TrCP) Ubiquitin Ligase im Abbau von Cdc25A beinhaltet. KW - DNS-Schädigung KW - DNS-Reparatur KW - Ubiquitin KW - DNA damage KW - Ubiquitin system Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-160064 ER - TY - JOUR A1 - Wyborski, Paweł A1 - Podemski, Paweł A1 - Wroński, Piotr Andrzej A1 - Jabeen, Fauzia A1 - Höfling, Sven A1 - Sęk, Grzegorz T1 - Electronic and optical properties of InAs QDs grown by MBE on InGaAs metamorphic buffer JF - Materials N2 - We present the optical characterization of GaAs-based InAs quantum dots (QDs) grown by molecular beam epitaxy on a digitally alloyed InGaAs metamorphic buffer layer (MBL) with gradual composition ensuring a redshift of the QD emission up to the second telecom window. Based on the photoluminescence (PL) measurements and numerical calculations, we analyzed the factors influencing the energies of optical transitions in QDs, among which the QD height seems to be dominating. In addition, polarization anisotropy of the QD emission was observed, which is a fingerprint of significant valence states mixing enhanced by the QD confinement potential asymmetry, driven by the decreased strain with increasing In content in the MBL. The barrier-related transitions were probed by photoreflectance, which combined with photoluminescence data and the PL temperature dependence, allowed for the determination of the carrier activation energies and the main channels of carrier loss, identified as the carrier escape to the MBL barrier. Eventually, the zero-dimensional character of the emission was confirmed by detecting the photoluminescence from single QDs with identified features of the confined neutral exciton and biexciton complexes via the excitation power and polarization dependences. KW - molecular beam epitaxy KW - quantum dot KW - metamorphic buffer layer KW - band structure KW - photoluminescence KW - photoreflectance Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297037 SN - 1996-1944 VL - 15 IS - 3 ER - TY - JOUR A1 - Wußmann, Maximiliane A1 - Groeber-Becker, Florian Kai A1 - Riedl, Sabrina A1 - Alihodzic, Dina A1 - Padaric, Daniel A1 - Gerlitz, Lisa A1 - Stallinger, Alexander A1 - Liegl-Atzwanger, Bernadette A1 - Zweytick, Dagmar A1 - Rinner, Beate T1 - In model, in vitro and in vivo killing efficacy of antitumor peptide RDP22 on MUG-Mel2, a patient derived cell line of an aggressive melanoma metastasis JF - Biomedicines N2 - The host defense derived peptide was assessed in different model systems with increasing complexity employing the highly aggressive NRAS mutated melanoma metastases cell line MUG-Mel2. Amongst others, fluorescence microscopy and spectroscopy, as well as cell death studies were applied for liposomal, 2D and 3D in vitro models including tumor spheroids without or within skin models and in vivo mouse xenografts. Summarized, MUG-Mel2 cells were shown to significantly expose the negatively charged lipid phosphatidylserine on their plasma membranes, showing they are successfully targeted by RDP22. The peptide was able to induce cell death in MUG-Mel2 2D and 3D cultures, where it was able to kill tumor cells even inside the core of tumor spheroids or inside a melanoma organotypic model. In vitro studies indicated cell death by apoptosis upon peptide treatment with an LC\(_{50}\) of 8.5 µM and seven-fold specificity for the melanoma cell line MUG-Mel2 over normal dermal fibroblasts. In vivo studies in mice xenografts revealed effective tumor regression upon intratumoral peptide injection, indicated by the strong clearance of pigmented tumor cells and tremendous reduction in tumor size and proliferation, which was determined histologically. The peptide RDP22 has clearly shown high potential against the melanoma cell line MUG-Mel2 in vitro and in vivo. KW - melanoma metastases KW - NRAS mutation KW - antitumor peptide KW - tumor model systems KW - phosphatidylserine Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297525 SN - 2227-9059 VL - 10 IS - 11 ER - TY - JOUR A1 - Wunder, Juliane A1 - Pemp, Daniela A1 - Cecil, Alexander A1 - Mahdiani, Maryam A1 - Hauptstein, René A1 - Schmalbach, Katja A1 - Geppert, Leo N. A1 - Ickstadt, Katja A1 - Esch, Harald L. A1 - Dankekar, Thomas A1 - Lehmann, Leane T1 - Influence of breast cancer risk factors on proliferation and DNA damage in human breast glandular tissues: role of intracellular estrogen levels, oxidative stress and estrogen biotransformation JF - Archives of Toxicology N2 - Breast cancer etiology is associated with both proliferation and DNA damage induced by estrogens. Breast cancer risk factors (BCRF) such as body mass index (BMI), smoking, and intake of estrogen-active drugs were recently shown to influence intratissue estrogen levels. Thus, the aim of the present study was to investigate the influence of BCRF on estrogen-induced proliferation and DNA damage in 41 well-characterized breast glandular tissues derived from women without breast cancer. Influence of intramammary estrogen levels and BCRF on estrogen receptor (ESR) activation, ESR-related proliferation (indicated by levels of marker transcripts), oxidative stress (indicated by levels of GCLC transcript and oxidative derivatives of cholesterol), and levels of transcripts encoding enzymes involved in estrogen biotransformation was identified by multiple linear regression models. Metabolic fluxes to adducts of estrogens with DNA (E-DNA) were assessed by a metabolic network model (MNM) which was validated by comparison of calculated fluxes with data on methoxylated and glucuronidated estrogens determined by GC- and UHPLC-MS/MS. Intratissue estrogen levels significantly influenced ESR activation and fluxes to E-DNA within the MNM. Likewise, all BCRF directly and/or indirectly influenced ESR activation, proliferation, and key flux constraints influencing E-DNA (i.e., levels of estrogens, CYP1B1, SULT1A1, SULT1A2, and GSTP1). However, no unambiguous total effect of BCRF on proliferation became apparent. Furthermore, BMI was the only BCRF to indeed influence fluxes to E-DNA (via congruent adverse influence on levels of estrogens, CYP1B1 and SULT1A2). KW - metabolic network model KW - estrogens KW - human breast KW - multiple linear regression Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265343 SN - 1432-0738 VL - 96 IS - 2 ER - TY - JOUR A1 - Wulf, Maximilian A1 - Barkovits, Katalin A1 - Schork, Karin A1 - Eisenacher, Martin A1 - Riederer, Peter A1 - Gerlach, Manfred A1 - Eggers, Britta A1 - Marcus, Katrin T1 - The proteome of neuromelanin granules in dementia with Lewy bodies JF - Cells N2 - Neuromelanin granules (NMGs) are organelle-like structures present in the human substantia nigra pars compacta. In addition to neuromelanin, NMGs contain proteins, lipids and metals. As NMG-containing dopaminergic neurons are preferentially lost in Parkinson’s disease and dementia with Lewy bodies (DLB), it is assumed that NMGs may play a role in neurodegenerative processes. Until now, this role is not completely understood and needs further investigation. We therefore set up an exploratory proteomic study to identify differences in the proteomic profile of NMGs from DLB patients (n = 5) compared to healthy controls (CTRL, n = 5). We applied a laser microdissection and mass-spectrometry-based approach, in which we used targeted mass spectrometric experiments for validation. In NMG-surrounding (SN\(_{Surr.}\)) tissue of DLB patients, we found evidence for ongoing oxidative damage and an impairment of protein degradation. As a potentially disease-related mechanism, we found α-synuclein and protein S100A9 to be enriched in NMGs of DLB cases, while the abundance of several ribosomal proteins was significantly decreased. As S100A9 is known to be able to enhance the formation of toxic α-synuclein fibrils, this finding points towards an involvement of NMGs in pathogenesis, however the exact role of NMGs as either neuroprotective or neurotoxic needs to be further investigated. Nevertheless, our study provides evidence for an impairment of protein degradation, ongoing oxidative damage and accumulation of potentially neurotoxic protein aggregates to be central mechanisms of neurodegeneration in DLB. KW - neuromelanin granules KW - neurodegeneration KW - dementia with Lewy bodies KW - proteomics KW - stress granules KW - substantia nigra pars compacta Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297465 SN - 2073-4409 VL - 11 IS - 22 ER - TY - JOUR A1 - Wu, Zhu A1 - Roldao, Juan Carlos A1 - Rauch, Florian A1 - Friedrich, Alexandra A1 - Ferger, Matthias A1 - Würthner, Frank A1 - Gierschner, Johannes A1 - Marder, Todd B. T1 - Pure Boric Acid Does Not Show Room-Temperature Phosphorescence (RTP) JF - Angewandte Chemie N2 - Boric acid (BA) has been used as a transparent glass matrix for optical materials for over 100 years. However, recently, apparent room-temperature phosphorescence (RTP) from BA (crystalline and powder states) was reported (Zheng et al., Angew. Chem. Int. Ed. 2021, 60, 9500) when irradiated at 280 nm under ambient conditions. We suspected that RTP from their BA sample was induced by an unidentified impurity. Our experimental results show that pure BA synthesized from B(OMe)\(_{3}\) does not luminesce in the solid state when irradiated at 250–400 nm, while commercial BA indeed (faintly) luminesces. Our theoretical calculations show that neither individual BA molecules nor aggregates would absorb light at >175 nm, and we observe no absorption of solid pure BA experimentally at >200 nm. Therefore, it is not possible for pure BA to be excited at >250 nm even in the solid state. Thus, pure BA does not display RTP, whereas trace impurities can induce RTP. KW - boric acid KW - room-temperature phosphorescence (RTP) KW - optical materials Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-318308 VL - 61 IS - 15 ER - TY - JOUR A1 - Wu, Zhu A1 - Dinkelbach, Fabian A1 - Kerner, Florian A1 - Friedrich, Alexandra A1 - Ji, Lei A1 - Stepanenko, Vladimir A1 - Würthner, Frank A1 - Marian, Christel M. A1 - Marder, Todd B. T1 - Aggregation-Induced Dual Phosphorescence from (o-Bromophenyl)-Bis(2,6-Dimethylphenyl)Borane at Room Temperature JF - Chemistry—A European Journal N2 - Designing highly efficient purely organic phosphors at room temperature remains a challenge because of fast non-radiative processes and slow intersystem crossing (ISC) rates. The majority of them emit only single component phosphorescence. Herein, we have prepared 3 isomers (o, m, p-bromophenyl)-bis(2,6-dimethylphenyl)boranes. Among the 3 isomers (o-, m- and p-BrTAB) synthesized, the ortho-one is the only one which shows dual phosphorescence, with a short lifetime of 0.8 ms and a long lifetime of 234 ms in the crystalline state at room temperature. Based on theoretical calculations and crystal structure analysis of o-BrTAB, the short lifetime component is ascribed to the T\(^M_1\) state of the monomer which emits the higher energy phosphorescence. The long-lived, lower energy phosphorescence emission is attributed to the T\(^A_1\) state of an aggregate, with multiple intermolecular interactions existing in crystalline o-BrTAB inhibiting nonradiative decay and stabilizing the triplet states efficiently. KW - AIE KW - luminescence KW - phosphorescence KW - triarylborane KW - triplet Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-318297 VL - 28 IS - 30 ER - TY - THES A1 - Wu, Zhu T1 - Room Temperature Phosphorescence (RTP): Experimental And Theoretical Studies on Boron-Containing Materials T1 - Raumtemperaturphosphoreszenz (RTP): Experimentelle und theoretische Studien zu borhaltigen Materialien N2 - Persistent room temperature phosphorescent (RTP) luminophores have gained remarkable interest recently for a number of applications in security printing, OLEDs, optical storage, time-gated biological imaging and oxygen sensors. We report the first persistent RTP with lifetimes up to 0.5 s from simple triarylboranes which have no lone pairs. We also have prepared 3 isomeric (o, m, p-bromophenyl)-bis(2,6-dimethylphenyl)boranes. Among the 3 isomers (o-, m- and p-BrTAB) synthesized, the ortho-one is the only one which shows dual phosphorescence, with a short lifetime of 0.8 ms and a long lifetime of 234 ms in the crystalline state at room temperature. At last, we checked the RTP properties from the boric acid. We found that the pure boric acid does not show RTP in the solid state. N2 - In letzter Zeit haben Luminophore, die eine effiziente Raumtemperatur-Phosphoreszenz (RTP) zeigen, aufgrund ihrer zahlreichen Anwendungen enormes Interesse gefunden. Die meisten phosphoreszierenden Materialien leiten sich jedoch von Übergangsmetallkomplexen ab, da ihr intrinsisches schnelles Intersystem Crossing (ISC) durch die starke Spin Bahn Kopplung (SOC) des Schwermetalls induziert wird. Metallfreie RTP Materialien sind selten und haben sich zu einem vielversprechenden Gebiet entwickelt, da sie kostengünstig und umweltfreundlich sind. Dieses Kapitel fasst organische molekulare Materialien mit langen Triplett Lebensdauern bei Raumtemperatur aus der Perspektive zusammen, ob sie aus einem molekularen oder Mehrkomponentensystem stammen. Bei rein organischen phosphoreszierenden Materialien werden üblicherweise Heteroatome in das Rückgrat eingeführt, um die Singulett Triplett ISC Geschwindigkeitskonstante zu erhöhen. In Mehrkomponentensystemen wird durch nützliche Strategien wie Wirt-Gast, Polymermatrix, Copolymerisation und supramolekulare Anordnung eine starre Matrixanordnung erreicht, durch die nichtstrahlende Pfade eingeschränkt und so ultralange RTP realisiert wird. ... KW - room temperature phosphorescence Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-260844 ER - TY - JOUR A1 - Woźnicki, Piotr A1 - Laqua, Fabian Christopher A1 - Messmer, Katharina A1 - Kunz, Wolfgang Gerhard A1 - Stief, Christian A1 - Nörenberg, Dominik A1 - Schreier, Andrea A1 - Wójcik, Jan A1 - Ruebenthaler, Johannes A1 - Ingrisch, Michael A1 - Ricke, Jens A1 - Buchner, Alexander A1 - Schulz, Gerald Bastian A1 - Gresser, Eva T1 - Radiomics for the prediction of overall survival in patients with bladder cancer prior to radical cystectomy JF - Cancers N2 - (1) Background: To evaluate radiomics features as well as a combined model with clinical parameters for predicting overall survival in patients with bladder cancer (BCa). (2) Methods: This retrospective study included 301 BCa patients who received radical cystectomy (RC) and pelvic lymphadenectomy. Radiomics features were extracted from the regions of the primary tumor and pelvic lymph nodes as well as the peritumoral regions in preoperative CT scans. Cross-validation was performed in the training cohort, and a Cox regression model with an elastic net penalty was trained using radiomics features and clinical parameters. The models were evaluated with the time-dependent area under the ROC curve (AUC), Brier score and calibration curves. (3) Results: The median follow-up time was 56 months (95% CI: 48–74 months). In the follow-up period from 1 to 7 years after RC, radiomics models achieved comparable predictive performance to validated clinical parameters with an integrated AUC of 0.771 (95% CI: 0.657–0.869) compared to an integrated AUC of 0.761 (95% CI: 0.617–0.874) for the prediction of overall survival (p = 0.98). A combined clinical and radiomics model stratified patients into high-risk and low-risk groups with significantly different overall survival (p < 0.001). (4) Conclusions: Radiomics features based on preoperative CT scans have prognostic value in predicting overall survival before RC. Therefore, radiomics may guide early clinical decision-making. KW - bladder cancer KW - radical cystectomy KW - radiomics KW - outcome prediction Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288098 SN - 2072-6694 VL - 14 IS - 18 ER - TY - JOUR A1 - Woznicki, Piotr A1 - Laqua, Fabian A1 - Bley, Thorsten A1 - Baeßler, Bettina T1 - AutoRadiomics: a framework for reproducible radiomics research JF - Frontiers in Radiology N2 - Purpose Machine learning based on radiomics features has seen huge success in a variety of clinical applications. However, the need for standardization and reproducibility has been increasingly recognized as a necessary step for future clinical translation. We developed a novel, intuitive open-source framework to facilitate all data analysis steps of a radiomics workflow in an easy and reproducible manner and evaluated it by reproducing classification results in eight available open-source datasets from different clinical entities. Methods The framework performs image preprocessing, feature extraction, feature selection, modeling, and model evaluation, and can automatically choose the optimal parameters for a given task. All analysis steps can be reproduced with a web application, which offers an interactive user interface and does not require programming skills. We evaluated our method in seven different clinical applications using eight public datasets: six datasets from the recently published WORC database, and two prostate MRI datasets—Prostate MRI and Ultrasound With Pathology and Coordinates of Tracked Biopsy (Prostate-UCLA) and PROSTATEx. Results In the analyzed datasets, AutoRadiomics successfully created and optimized models using radiomics features. For WORC datasets, we achieved AUCs ranging from 0.56 for lung melanoma metastases detection to 0.93 for liposarcoma detection and thereby managed to replicate the previously reported results. No significant overfitting between training and test sets was observed. For the prostate cancer detection task, results were better in the PROSTATEx dataset (AUC = 0.73 for prostate and 0.72 for lesion mask) than in the Prostate-UCLA dataset (AUC 0.61 for prostate and 0.65 for lesion mask), with external validation results varying from AUC = 0.51 to AUC = 0.77. Conclusion AutoRadiomics is a robust tool for radiomic studies, which can be used as a comprehensive solution, one of the analysis steps, or an exploratory tool. Its wide applicability was confirmed by the results obtained in the diverse analyzed datasets. The framework, as well as code for this analysis, are publicly available under https://github.com/pwoznicki/AutoRadiomics. KW - radiomics KW - radiology KW - machine learning KW - reproducibility KW - workflow KW - image analysis Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284813 SN - 2673-8740 VL - 2 ER - TY - JOUR A1 - Wong, Alex H. K. A1 - Pittig, Andre T1 - A dimensional measure of safety behavior: A non-dichotomous assessment of costly avoidance in human fear conditioning JF - Psychological Research N2 - Safety behavior prevents the occurrence of threat, thus it is typically considered adaptive. However, safety behavior in anxiety-related disorders is often costly, and persists even the situation does not entail realistic threat. Individuals can engage in safety behavior to varying extents, however, these behaviors are typically measured dichotomously (i.e., to execute or not). To better understand the nuances of safety behavior, this study developed a dimensional measure of safety behavior that had a negative linear relationship with the admission of an aversive outcome. In two experiments, a Reward group receiving fixed or individually calibrated incentives competing with safety behavior showed reduced safety behavior than a Control group receiving no incentives. This allowed extinction learning to a previously learnt warning signal in the Reward group (i.e., updating the belief that this stimulus no longer signals threat). Despite the Reward group exhibited extinction learning, both groups showed a similar increase in fear to the warning signal once safety behavior was no longer available. This null group difference was due to some participants in the Reward group not incentivized enough to disengage from safety behavior. Dimensional assessment revealed a dissociation between low fear but substantial safety behavior to a safety signal in the Control group. This suggests that low-cost safety behavior does not accurately reflect the fear-driven processes, but also other non-fear-driven processes, such as cost (i.e., engage in safety behavior merely because it bears little to no cost). Pinpointing both processes is important for furthering the understanding of safety behavior. KW - safety behavior KW - anxiety KW - threat Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-267688 SN - 1430-2772 VL - 86 IS - 1 ER - TY - JOUR A1 - Wolf, Erik A1 - Döllinger, Nina A1 - Mal, David A1 - Wenninger, Stephan A1 - Bartl, Andrea A1 - Botsch, Mario A1 - Latoschik, Marc Erich A1 - Wienrich, Carolin T1 - Does distance matter? Embodiment and perception of personalized avatars in relation to the self-observation distance in virtual reality JF - Frontiers in Virtual Reality N2 - Virtual reality applications employing avatar embodiment typically use virtual mirrors to allow users to perceive their digital selves not only from a first-person but also from a holistic third-person perspective. However, due to distance-related biases such as the distance compression effect or a reduced relative rendering resolution, the self-observation distance (SOD) between the user and the virtual mirror might influence how users perceive their embodied avatar. Our article systematically investigates the effects of a short (1 m), middle (2.5 m), and far (4 m) SOD between users and mirror on the perception of their personalized and self-embodied avatars. The avatars were photorealistic reconstructed using state-of-the-art photogrammetric methods. Thirty participants repeatedly faced their real-time animated self-embodied avatars in each of the three SOD conditions, where they were repeatedly altered in their body weight, and participants rated the 1) sense of embodiment, 2) body weight perception, and 3) affective appraisal towards their avatar. We found that the different SODs are unlikely to influence any of our measures except for the perceived body weight estimation difficulty. Here, the participants perceived the difficulty significantly higher for the farthest SOD. We further found that the participants’ self-esteem significantly impacted their ability to modify their avatar’s body weight to their current body weight and that it positively correlated with the perceived attractiveness of the avatar. Additionally, the participants’ concerns about their body shape affected how eerie they perceived their avatars. The participants’ self-esteem and concerns about their body shape influenced the perceived body weight estimation difficulty. We conclude that the virtual mirror in embodiment scenarios can be freely placed and varied at a distance of one to four meters from the user without expecting major effects on the perception of the avatar. KW - virtual human KW - virtual body ownership KW - agency KW - body image distortion KW - body weight perception KW - body weight modification KW - affective appraisal KW - distance compression Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-299415 SN - 2673-4192 VL - 3 ER - TY - THES A1 - Wohlfart, Jonas T1 - Analysis of Drug Impurities by Means of Chromatographic Methods: Targeted and Untargeted Approaches T1 - Analytik von Verunreinigungen in Arzneimitteln mittels chromatographischer Methoden: Gerichtete und ungerichtete Ansätze N2 - The presented works aimed on the analysis of new impurities in APIs and medicinal products. Different subtypes of LC were coupled to suitable detection methods, i.e. UV and various MS techniques, depending on the chemical natures of the analytes and the analytical task. Unexpected impurities in medicinal products and APIs caused several scandals in the past, concomitant with fatalities or severe side effects in human and veterinary patients. The detection of nitrosamines in sartans led to the discovery of nitrosamines in various other drugs, of which the antibiotic rifampicin was analyzed in this work. An examination of the synthesis of rifampicin revealed a high potential for the formation of 4-methyl-1-nitrosopiperazine (MeNP). An LC-MS/HRMS method suitable for the quantification of MeNP was applied in the analysis of drugs collected from Brazil, Comoros, India, Nepal, and Tanzania, where a single dose of rifampicin is used in the post-exposure prophylaxis of leprosy. All batches were contaminated with MeNP, ranging from 0.7-5.1 ppm. However, application of rifampicin containing up to 5 ppm MeNP was recommended by the regulatory authorities for the post-exposure prophylaxis of leprosy. In the 1990s the aminoglycoside antibiotic gentamicin attracted attention after causing fatalities in the USA, but the causative agent was never identified unequivocally. The related substance sisomicin was recognized as a lead impurity by the Holzgrabe lab at the University of Würzburg: sisomicin was accompanied by a variety of other impurities and batches containing sisomicin had caused the fatalities. In 2016, anaphylactic reactions were reported after application of gentamicin. A contamination of the medicinal products with histamine, an impurity of the raw material fish peptone used upon the production, could be identified as the cause of the adverse effects. Batches of gentamicin sulfate, which had been stored at the University of Würzburg since the earlier investigations, were analyzed regarding their contamination with histamine to determine whether the biogenic amine was responsible for the 1990s fatalities as well. Furthermore, a correlation with the lead impurity sisomicin was checked. Histamine could be detected in all analyzed batches, but at a lower level than in the batches responsible for the anaphylactic reactions. Moreover, there is no correlation of histamine with the lead impurity sisomicin. Hence, the causative agent for the 1990s fatalities was not histamine and remains unknown. Another source of impurities is the reaction of APIs with excipients, e.g. the esterification of naproxen with PEG 600 in soft gel capsules. The influence of the formulation’s composition on this reaction was investigated by means of LC-UV. Therefore, the impurity naproxen-PEG-ester (NPEG) was synthesized and used for the development of a method suitable for the analysis of soft gel capsule formulations. Different formulations were stressed for 7 d at 60 °C and the relative amount of NPEG was determined. The formation of NPEG was influenced by the concentrations of water and lactic acid, the pH, and the drug load of the formulation, which can easily be explained by the chemistry behind esterification reactions. Keeping in mind the huge variety of sources of impurities, it might be impossible to predict all potential impurities of a drug substance/product. Targeted and untargeted approaches were combined in the impurity profiling of bisoprolol fumarate. Eight versions of an LC-HRMS method were developed to enable the detection of a maximum number of impurities: an acidic and a basic buffered LC was coupled to MS detection applying ESI and APCI, both in positive in negative mode. MS and MS/MS data were acquired simultaneously by information dependent acquisition. In the targeted approach, potential impurities were derived from a reaction matrix based on the synthesis route of the API, while the untargeted part was based on general unknown comparative screening to identify additional signals. 18 and 17 impurities were detected in the targeted and the untargeted approach, respectively. The molecular formulae were assessed based on the exact mass and the isotope pattern. Theoretical fragment spectra generated by in silico fragmentation were matched with experimental data to estimate the plausibility of proposed/elucidated structures. Moreover, the detected impurities were quantified with respect to an internal standard. N2 - In den vorgestellten Projekten wurden neue Verunreinigungen in Arzneistoffen und Arzneimitteln untersucht. Verschiedene flüssigchromatographische Methoden wurden mit geeigneten Detektionsverfahren gekoppelt. UV-Detektion und verschiedene massenspektrometrische Techniken wurden in Abhängigkeit der chemischen Eigenschaften der Analyten und der analytischen Herausforderung ausgewählt. Eine Kontamination von Wirkstoffen bzw. humanen und veterinären Arzneimittel mit unerwarteten Verunreinigungen löste mehrere Skandale aus, die mit Todesfällen oder ernsthaften Nebenwirkungen einhergingen. Die Identifikation von Nitrosamin-Verunreinigungen in Sartanen führte zur Entdeckung von Nitrosaminen in verschiedenen anderen Wirkstoffen, z.B. im Antibiotikum Rifampicin, das in dieser Arbeit untersucht wurde. Eine Betrachtung der Rifampicin-Synthese offenbarte ein hohes Potenzial der Bildung von 4-Methyl-1-nitrosopiperazin (MeNP). Arzneimittel aus Brasilien, Indien, Nepal, Tansania und von den Komoren wurden mittels LC-MS/HRMS bezüglich ihres MeNP-Gehaltes analysiert. Alle untersuchten Chargen waren mit MeNP im Bereich von 0.7-5.1 ppm belastet. Rifampicin wird in den genannten Ländern unter anderem als Einzeldosis zur Postexpositionsprophylaxe von Lepra eingesetzt. Für diese Indikation empfehlen die Zulassungsbehörden die Verwendung von Rifampicin mit bis zu 5 ppm MeNP. Das Aminoglycosid-Antibiotikum Gentamicin löste in den 1990er Jahren Todesfälle in den USA aus. Die verantwortliche Verunreinigung wurde nie eindeutig aufgeklärt, doch die verwandte Substanz Sisomicin wurde durch den Arbeitskreis Holzgrabe an der Universität Würzburg als Leitverunreinigung identifiziert: Sisomicin ging mit einer Vielzahl von weiteren Verunreinigungen einher und Sisomicin-reiche Chargen hatten die Todesfälle ausgelöst. 2016 traten anaphylaktische Reaktionen nach Gentamicin-Anwendung auf. Histamin war als Verunreinigung von Fischpepton, einem Ausgangsmaterial der Produktion, in den Wirkstoff gelangt. Um zu überprüfen, ob Histamin auch für die Todesfälle in den 1990er Jahren verantwortlich war, wurden seit den früheren Untersuchungen gelagerte Gentamicin-Chargen bezüglich ihrer Verunreinigung mit Histamin untersucht. Außerdem wurde überprüft, ob es einen Zusammenhang mit dem Sisomicin-Gehalt gibt. In allen untersuchten Proben wurde Histamin gefunden, allerdings in einer geringeren Konzentration als in Chargen, die anaphylaktische Reaktionen ausgelöst hatten. Des Weiteren konnte kein Zusammenhang mit der Leitverunreinigung Sisomicin erkannt werden. Der Auslöser der Todesfälle in den 1990er Jahren war somit nicht Histamin, sondern bleibt weiterhin unbekannt. Ein weiterer Ursprung von Verunreinigungen ist die Reaktion des Wirkstoffs mit Hilfsstoff(en), z.B. die Veresterung von Naproxen mit PEG in Weichkapseln. Der Einfluss von Veränderungen der Formulierung auf diese Reaktion wurde mittels LC-UV untersucht. Die Verunreinigung Naproxen-PEG-Ester (NPEG) wurde synthetisiert und zur Entwicklung einer Methode zur Analyse von Weichkapsel-Formulierungen verwendet. Verschiedene Formulierungen wurden für 7 Tage bei 60 °C gestresst und deren relative Gehalte an NPEG bestimmt. Dabei war die Bildung von NPEG von der Wasser- und der Milchsäure-Konzentration, dem pH und dem Wirkstoffgehalt der Formulierung abhängig. Sämtliche Einflüsse konnten durch die Art der Reaktion (Veresterung) erklärt werden. Vor dem Hintergrund der vielfältigen Quellen für Verunreinigungen erscheint es unmöglich, alle potenziellen Verunreinigungen eines Wirkstoffs/Arzneimittels vorherzusagen. Gerichtete und ungerichtete Ansätze wurden daher für die Erstellung eines Verunreinigungsprofils von Bisoprololfumarat kombiniert. Um eine möglichst große Anzahl von möglichen Substanzen zu detektieren, wurden 8 LC-MS/HRMS-Methoden entwickelt: je eine saure und eine basische mobile Phase der LC wurde mit massenspektrometrischer Detektion mittels ESI und APCI, jeweils im positiv- und negativ-Modus kombiniert. MS- und MS/MS-Daten wurden simultan durch information dependent acquisition aufgenommen. Für den gerichteten Ansatz wurde eine Reaktionsmatrix auf Basis der Synthese des Wirkstoffs angefertigt und ausgehend davon potenzielle Verunreinigungen abgeleitet. Im ungerichteten Ansatz wurden mittels general unknown comparative screening zusätzliche Signale identifiziert. Der gerichtete Ansatz zeigte die Anwesenheit von 18, der ungerichtete von 17 Verunreinigungen. Summenformeln wurden anhand der exakten Masse und des Isotopenmusters der Signale bewertet. Die Plausibilität von Strukturformeln wurde mittels In-silico-Fragmentierung abgeschätzt, wobei experimentelle und theoretische Fragmentspektren in Einklang gebracht wurden. Außerdem wurden alle detektierten Verunreinigungen mittels eines externen Standards quantifiziert. KW - LC-MS KW - Gentamicin KW - Naproxen KW - Bisoprolol KW - Rifampicin KW - Impurity Profiling Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-273878 ER - TY - JOUR A1 - Wobser, Marion A1 - Schummer, Patrick A1 - Appenzeller, Silke A1 - Kneitz, Hermann A1 - Roth, Sabine A1 - Goebeler, Matthias A1 - Geissinger, Eva A1 - Rosenwald, Andreas A1 - Maurus, Katja T1 - Panel sequencing of primary cutaneous B-cell lymphoma JF - Cancers N2 - Background: Primary cutaneous follicular B-cell lymphoma (PCFBCL) represents an indolent subtype of Non-Hodgkin’s lymphomas, being clinically characterized by slowly growing tumors of the skin and common cutaneous relapses, while only exhibiting a low propensity for systemic dissemination or fatal outcome. Up to now, only few studies have investigated underlying molecular alterations of PCFBCL with respect to somatic mutations. Objectives: Our aim was to gain deeper insight into the pathogenesis of PCFBCL and to delineate discriminatory molecular features of this lymphoma subtype. Methods: We performed hybridization-based panel sequencing of 40 lymphoma-associated genes of 10 cases of well-characterized PCFBCL. In addition, we included two further ambiguous cases of atypical B-cell-rich lymphoid infiltrate/B-cell lymphoma of the skin for which definite subtype attribution had not been possible by routine investigations. Results: In 10 out of 12 analyzed cases, we identified genetic alterations within 15 of the selected 40 target genes. The most frequently detected alterations in PCFBCL affected the TNFRSF14, CREBBP, STAT6 and TP53 genes. Our analysis unrevealed novel mutations of the BCL2 gene in PCFBCL. All patients exhibited an indolent clinical course. Both the included arbitrary cases of atypical B-cell-rich cutaneous infiltrates showed somatic mutations within the FAS gene. As these mutations have previously been designated as subtype-specific recurrent alterations in primary cutaneous marginal zone lymphoma (PCMZL), we finally favored the diagnosis of PCMZL in these two cases based on these molecular findings. Conclusions: To conclude, our molecular data support that PCFBCL shows distinct somatic mutations which may aid to differentiate PCFBCL from pseudo-lymphoma as well as from other indolent and aggressive cutaneous B-cell lymphomas. While the detected genetic alterations of PCFBCL did not turn out to harbor any prognostic value in our cohort, our molecular data may add adjunctive discriminatory features for diagnostic purposes on a molecular level. KW - B-cell lymphoma KW - primary cutaneous follicular B-cell lymphoma KW - targeted sequencing Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290330 SN - 2072-6694 VL - 14 IS - 21 ER - TY - JOUR A1 - Winter, Anna A1 - Schulz, Stefan M. A1 - Schmitter, Marc A1 - Brands, Roman C. A1 - Straub, Anton A1 - Kübler, Alexander A1 - Borgmann, Anna A1 - Hartmann, Stefan T1 - Oral-health-related quality of life in patients with medication-related osteonecrosis of the jaw: a prospective clinical study JF - International Journal of Environmental Research and Public Health N2 - Medication-related osteonecrosis of the jaw (MRONJ) represents an adverse side effect of antiresorptive and antiangiogenic medications. It is associated with impaired quality of life, oral health, and oral function and can be classified into various stages. The purpose of this prospective clinical study is to evaluate the impact of stages I and II MRONJ on oral-health-related quality of life (OHRQoL) and related parameters. Patients’ OHRQoL, satisfaction with life, oral discomfort, and oral health were assessed using the German version of the Oral Health Impact Profile (OHIP-G49), visual analog scales (VAS), and Satisfaction with Life Scale (SWLS) at baseline (T0), 10 days (T1), and 3 months after treatment (T2) in 36 patients. Data were analyzed using Kolmogorov–Smirnov test, two-way mixed ANOVAs, and follow-up Mann–Whitney U tests. The impact of treatment effects on the original seven OHIP domain structures and the recently introduced four-dimensional OHIP structure were evaluated using linear regression analysis. Thirty-six patients received surgical MRONJ treatment. Before treatment, patients’ perceived OHRQoL, oral discomfort, oral health, and satisfaction with life were negatively affected by MRONJ. Surgical treatment significantly improved OHRQoL and related parameters (all p ≤ 0.012). This improvement was greater in patients with higher impairment at T0. OHRQoL and oral restrictions were still impaired after treatment in patients who needed prosthetic treatment. The four-dimensional structure revealed valuable information beyond the standard seven OHIP domains. Increased awareness of MRONJ risks and an interdisciplinary treatment approach for MRONJ patients are needed. KW - oral-health-related quality of life KW - satisfaction with life KW - oral health KW - medication-related osteonecrosis of the jaw KW - treatment benefit KW - OHIP-49 KW - SWLS Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288141 SN - 1660-4601 VL - 19 IS - 18 ER - TY - JOUR A1 - Willms, A. G. A1 - Schwab, R. A1 - von Websky, M. W. A1 - Berrevoet, F. A1 - Tartaglia, D. A1 - Sörelius, K. A1 - Fortelny, R. H. A1 - Björck, M. A1 - Monchal, T. A1 - Brennfleck, F. A1 - Bulian, D. A1 - Beltzer, C. A1 - Germer, C. T. A1 - Lock, J. F. T1 - Factors influencing the fascial closure rate after open abdomen treatment: Results from the European Hernia Society (EuraHS) Registry. Surgical technique matters JF - Hernia N2 - Purpose Definitive fascial closure is an essential treatment objective after open abdomen treatment and mitigates morbidity and mortality. There is a paucity of evidence on factors that promote or prevent definitive fascial closure. Methods A multi-center multivariable analysis of data from the Open Abdomen Route of the European Hernia Society included all cases between 1 May 2015 and 31 December 2019. Different treatment elements, i.e. the use of a visceral protective layer, negative-pressure wound therapy and dynamic closure techniques, as well as patient characteristics were included in the multivariable analysis. The study was registered in the International Clinical Trials Registry Platform via the German Registry for Clinical Trials (DRK00021719). Results Data were included from 630 patients from eleven surgical departments in six European countries. Indications for OAT were peritonitis (46%), abdominal compartment syndrome (20.5%), burst abdomen (11.3%), abdominal trauma (9%), and other conditions (13.2%). The overall definitive fascial closure rate was 57.5% in the intention-to-treat analysis and 71% in the per-protocol analysis. The multivariable analysis showed a positive correlation of negative-pressure wound therapy (odds ratio: 2.496, p < 0.001) and dynamic closure techniques (odds ratio: 2.687, p < 0.001) with fascial closure and a negative correlation of intra-abdominal contamination (odds ratio: 0.630, p = 0.029) and the number of surgical procedures before OAT (odds ratio: 0.740, p = 0.005) with DFC. Conclusion The clinical course and prognosis of open abdomen treatment can significantly be improved by the use of treatment elements such as negative-pressure wound therapy and dynamic closure techniques, which are associated with definitive fascial closure. KW - open abdomen KW - peritonitis KW - fascial closure KW - hernia KW - abdominal compartment syndrome KW - abdominal trauma KW - burst abdomen KW - NPWT KW - VAC Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234871 SN - 1265-4906 VL - 26 IS - 1 ER - TY - JOUR A1 - Wildervanck, Martijn J. A1 - Hecht, Reinhard A1 - Nowak-Król, Agnieszka T1 - Synthesis and strong solvatochromism of push-pull thienylthiazole boron complexes JF - Molecules N2 - The solvatochromic behavior of two donor-π bridge-acceptor (D-π-A) compounds based on the 2-(3-boryl-2-thienyl)thiazole π-linker and indandione acceptor moiety are investigated. DFT/TD-DFT calculations were performed in combination with steady-state absorption and emission measurements, along with electrochemical studies, to elucidate the effect of two different strongly electron-donating hydrazonyl units on the solvatochromic and fluorescence behavior of these compounds. The Lippert–Mataga equation was used to estimate the change in dipole moments (Δµ) between ground and excited states based on the measured spectroscopic properties in solvents of varying polarity with the data being supported by theoretical studies. The two asymmetrical D-π-A molecules feature strong solvatochromic shifts in fluorescence of up to ~4300 cm\(^{−1}\) and a concomitant change of the emission color from yellow to red. These changes were accompanied by an increase in Stokes shift to reach values as large as ~5700–5800 cm\(^{−1}\). Quantum yields of ca. 0.75 could be observed for the N,N-dimethylhydrazonyl derivative in nonpolar solvents, which gradually decreased along with increasing solvent polarity, as opposed to the consistently reduced values obtained for the N,N-diphenylhydrazonyl derivative of up to ca. 0.20 in nonpolar solvents. These two push–pull molecules are contrasted with a structurally similar acceptor-π bridge-acceptor (A-π-A) compound. KW - solvatochromism KW - donor–acceptor KW - fluorescence KW - hydrazone KW - Lippert–Mataga plot KW - push–pull thienylthiazole KW - tetracoordinated boron Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286186 SN - 1420-3049 VL - 27 IS - 17 ER - TY - THES A1 - Wilde, Martina T1 - Landslide susceptibility assessment in the Chiconquiaco Mountain Range area, Veracruz (Mexico) T1 - Bewertung der Rutschungssuszeptibilität in der Chiconquiaco Gebirgsregion, Veracruz (Mexiko) N2 - In Mexico, numerous landslides occur each year and Veracruz represents the state with the third highest number of events. Especially the Chiconquiaco Mountain Range, located in the central part of Veracruz, is highly affected by landslides and no detailed information on the spatial distribution of existing landslides or future occurrences is available. This leaves the local population exposed to an unknown threat and unable to react appropriately to this hazard or to consider the potential landslide occurrence in future planning processes. Thus, the overall objective of the present study is to provide a comprehensive assessment of the landslide situation in the Chiconquiaco Mountain Range area. Here, the combination of a site-specific and a regional approach enables to investigate the causes, triggers, and process types as well as to model the landslide susceptibility for the entire study area. For the site-specific approach, the focus lies on characterizing the Capulín landslide, which represents one of the largest mass movements in the area. In this context, the task is to develop a multi-methodological concept, which concentrates on cost-effective, flexible and non-invasive methods. This approach shows that the applied methods complement each other very well and their combination allows for a detailed characterization of the landslide. The analyses revealed that the Capulín landslide is a complex mass movement type. It comprises rotational movement in the upper parts and translational movement in the lower areas, as well as flow processes at the flank and foot area and therefore, is classified as a compound slide-flow according to Cruden and Varnes (1996). Furthermore, the investigations show that the Capulín landslide represents a reactivation of a former process. This is an important new information, especially with regard to the other landslides identified in the study area. Both the road reconstructed after the landslide, which runs through the landslide mass, and the stream causing erosion processes at the foot of the landslide severely affect the stability of the landslide, making it highly susceptible to future reactivation processes. This is particularly important as the landslide is located only few hundred meters from the village El Capulín and an extension of the landslide area could cause severe damage. The next step in the landslide assessment consists of integrating the data obtained in the site-specific approach into the regional analysis. Here, the focus lies on transferring the generated data to the entire study area. The developed methodological concept yields applicable results, which is supported by different validation approaches. The susceptibility modeling as well as the landslide inventory reveal that the highest probability of landslides occurrence is related to the areas with moderate slopes covered by slope deposits. These slope deposits comprise material from old mass movements and erosion processes and are highly susceptible to landslides. The results give new insights into the landslide situation in the Chiconquiaco Mountain Range area, since previously landslide occurrence was related to steep slopes of basalt and andesite. The susceptibility map is a contribution to a better assessment of the landslide situation in the study area and simultaneously proves that it is crucial to include specific characteristics of the respective area into the modeling process, otherwise it is possible that the local conditions will not be represented correctly. N2 - In Mexico ereignen sich jedes Jahr zahlreiche Rutschungen und Veracruz ist der Bundesstaat mit der dritthöchsten Anzahl von solchen Ereignissen. Besonders das Chiconquiaco Gebirge, welches im zentralen Bereich von Veracruz liegt, ist stark von Rutschungen betroffen und trotzdem sind keine detaillierten Informationen zur räumlichen Verbreitung existierender Rutschungen oder zu deren erwarteten, zukünftigen Auftreten verfügbar. Dadurch ist die lokale Bevölkerung mit einer nicht einschätzbaren Bedrohungslage konfrontiert und kann weder auf diese angemessen reagieren noch das potentielle Auftreten von Rutschungen in künftigen Planungsprozessen berücksichtigen. Das übergeordnete Ziel der vorliegenden Arbeit besteht daher darin, eine umfassende Beurteilung der Rutschungssituation im Chiconquiaco Gebirge zu erstellen. Hierbei ermöglicht die Kombination eines standortspezifischen und eines regionalen Ansatzes sowohl die Untersuchung der Ursachen, Auslöser und Prozesstypen, als auch die Modellierung der Rutschanfälligkeit für das gesamte Untersuchungsgebiet. Bei dem standortspezifischen Ansatz liegt der Schwerpunkt auf der Charakterisierung der Capulín Rutschung, bei der es sich um eine der größten Massenbewegungen in dieser Region handelt. In diesem Rahmen besteht die Aufgabe darin, ein multi-methodologisches Konzept zu entwickeln, welches sich hauptsächlich auf kostengünstige, flexible und nicht-invasive Methoden konzentriert. Dieser Ansatz zeigt, dass sich die verwendeten Methoden sehr gut ergänzen und ihre Kombination eine detaillierte Charakterisierung der Rutschung ermöglicht. Die Ergebnisse legen dar, dass die Capulín Rutschung eine komplexe Massenbewegung ist. So umfasst sie Rotationsbewegungen im oberen und Translationsbewegungen im unteren Bereich, sowie Fließprozesse an der Flanke und im Fußbereich und kann daher nach Cruden und Varnes (1996) als Kombination aus Gleit- und Fließprozessen (compound slide-flow) klassifiziert werden. Des Weiteren zeigen die Ergebnisse, dass es sich bei der Capulín Rutschung um eine Reaktivierung einer älteren Rutschung handelt. Das ist eine wichtige neue Erkenntnis besonders im Hinblick auf die anderen Rutschungen, die im Untersuchungsgebiet festgestellt wurden. Sowohl die nach der Rutschung wieder aufgebaute Straße, die durch die Rutschmasse verläuft, als auch der Fluss, der Erosionsprozesse am Fuß der Rutschung verursacht, beeinträchtigen die Stabilität der Capulín Rutschung maßgeblich, was sie sehr anfällig für zukünftige Reaktivierungsprozesse macht. Dies ist besonders wichtig, da die Rutschung nur wenige hundert Meter von dem Ort El Capulín entfernt ist und eine Erweiterung des Rutschgebietes erhebliche Schäden verursachen könnte. Im Anschluss werden die durch den lokalen Ansatz erhaltenen Daten in die regionale Analyse integriert. Der Fokus bei diesem Vorgehen liegt dabei auf der Übertragung der generierten Daten auf das gesamte Untersuchungsgebiet. Das hier entwickelte methodische Konzept erzielt verwertbare Ergebnisse, was durch verschiedene Validierungsansätze bekräftigt werden kann. Sowohl die Suszeptibilitätsmodellierung als auch das Rutschungsinventar zeigen, dass die höchste Wahrscheinlichkeit für das Auftreten von Rutschungen vor allem in den Gebieten mit moderater Hangneigung liegt, welche mit Hangschutt bedeckt sind. Diese Hangablagerungen bestehen aus Material von alten Massenbewegungen und Erosionsprozessen und zeigen eine hohe Anfälligkeit für Rutschungen. Die Ergebnisse liefern neue Erkenntnisse über die Rutschungssituation im Chiconquiaco Gebirge, da vorher das Auftreten von Rutschungen mit den steilen Hängen aus Basalt und Andesit in Verbindung gebracht wurde. Auf Grundlage der generierten Suszeptibilitätskarte ist eine bessere Bewertung der Rutschungssituation im Untersuchungsgebiet möglich. Weiterhin zeigt sie, dass es von entscheidender Bedeutung ist, spezifische Eigenschaften der jeweiligen Untersuchungsgebiete in die Modellierung miteinzubeziehen, da sonst die Gefahr besteht, dass die örtlichen Gegebenheiten fehlerhaft eingeschätzt werden. KW - Naturgefahren KW - Landslide susceptibility modeling KW - Geomorphologie KW - Rutschungen KW - Modellierung KW - Veracruz KW - Mexiko KW - UAV KW - Digital Elevation Model KW - Hangstabilitätsmodellierung Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-276085 ER - TY - THES A1 - Wiese, Teresa T1 - Pharmacological targeting of acid sphingomyelinase increases CD4\(^+\) Foxp3\(^+\) regulatory T cell subsets in patients with major depression T1 - Pharmakologische Hemmung der sauren Sphingomyelinase verstärkt CD4\(^+\) Foxp3\(^+\) regulatorische T-Zell-Subpopulationen bei Patienten mit Depression N2 - Lack of acid sphingomyelinase (ASM) activity, either through genetic deficiency or through pharmacological inhibition, is linked with increased activity and frequency of Foxp3+ regulatory T cells (Treg) among cluster of differentiation (CD) 4+ T cells in mice in vivo and in vitro1. Thus, pharmacological blockade of ASM activity, which catalyzes the cleavage of sphingomyelin to ceramide and phosphocholine, might be used as a new therapeutic mechanism to correct numeric and/ or functional Treg de-ficiencies in diseases like multiple sclerosis or major depression. In the present study, the effect of pharmacological inhibition of ASM in humans, in vitro and in vivo, was analyzed. In the in vitro experiments, peripheral blood mono-nuclear cells (PBMC) of healthy human blood donors were treated with two widely prescribed antidepressants with high (sertraline, Ser) or low (citalopram, Cit) capaci-ty to inhibit ASM activity. Similar to the findings in mice an increase in the frequency of Treg among human CD4+ T cells upon inhibition of ASM activity was observed. For the analysis in vivo, a prospective study of the composition of the CD4+ T cell com-partment of patients treated for major depression was done. The data show that pharmacological inhibition of ASM activity was superior to antidepressants with little or no ASM-inhibitory activity in increasing CD45RA- CD25high effector Treg (efTreg) frequencies among CD4+ T cells to normal levels. Independently of ASM inhibition, correlating the data with the clinical response, i.e. improvement of the Hamilton rat-ing scale for depression (HAMD) by at least 50 per cent (%) after four weeks of treatment, it was found that an increase in efTreg frequencies among CD4+ cells dur-ing the first week of treatment identified patients with a clinical response. Regarding the underlying mechanism, it could be found that the positive effect of ASM inhibition on Treg required CD28 co-stimulation suggesting that enhanced CD28 co-stimulation was the driver of the observed increase in the frequency of Treg among human CD4+ T cells. Inhibition of ASM activity was further associated with changes in the expression and shuttling of CTLA-4, a key inhibitory molecule ex-pressed by Treg, between cellular compartments but the suppressive activity of CTLA-4 through its transendocytosis activity was unaffected by the inhibition of ASM activity. In summary, the frequency of (effector) Treg among CD4+ T cells in mice and in hu-mans is increased after inhibition of ASM activity suggesting that ASM blockade might beneficially modulate autoimmune diseases and depression-promoting in-flammation. N2 - Ein Mangel an Aktivität der sauren Sphingomyelinase (ASM), entweder durch ge-netisches Defizit oder durch pharmakologische Hemmung, ist mit einer erhöhten Aktivität und Häufigkeit von Foxp3+ regulatorischen T-Zellen (Treg) innerhalb der CD4+ (cluster of differentation 4) T-Zellen in Mäusen in vivo und in vitro verbun-den1. Daher könnte die pharmakologische Blockade der ASM-Aktivität, die die Spaltung von Sphingomyelin in Ceramid und Phosphocholin katalysiert, als neuer therapeutischer Mechanismus zur Korrektur von numerischen und/oder funktionel-len Treg-Defiziten bei Erkrankungen wie Multipler Sklerose oder schwerer Depres-sion eingesetzt werden. In der vorliegenden Studie wurde die Wirkung der pharmakologischen Hemmung von ASM beim Menschen, in vitro und in vivo analysiert. In den In-vitro-Experimenten wurden die peripheren mononukleären Blutzellen (PBMC) gesunder menschlicher Blutspender mit zwei weithin verschriebenen Antidepressiva mit ho-her (Sertralin, Ser) oder niedriger (Citalopram, Cit) Fähigkeit zur Hemmung der ASM-Aktivität untersucht. Ähnlich wie bei Mäusen wurde bei Hemmung der ASM-Aktivität ein Anstieg der Häufigkeit von Treg innerhalb der menschlichen CD4+ T-Zellen festgestellt. Für die Analyse in vivo wurde eine prospektive Studie über die Zusammensetzung des CD4+ T-Zellkomplexes bei Patienten, die wegen einer De-pression im Krankenhaus behandelt wurden, durchgeführt. Die Daten zeigen, dass die pharmakologische Hemmung der ASM-Aktivität Antidepressiva mit ge-ringer oder keiner ASM-hemmenden Aktivität überlegen war, was die Vermehrung der CD45RA- CD25hoch-Effektor-Treg (efTreg)-Frequenzen innerhalb der CD4+ T-Zellen betraf. Unabhängig von der Untersuchung zur ASM-Aktivität beobachteten wir, dass die klinische Reaktion (d.h. der Verbesserung der Hamilton-Bewertungsskala für Depressionen (HAMD) um mindestens 50 Prozent (%) nach vierwöchiger Behandlung) mit einem frühen Anstieg der efTreg-Frequenzen unter CD4+-Zellen während der ersten Behandlungswoche positiv korrelierte. Hinsichtlich des zugrunde liegenden Mechanismus konnte festgestellt werden, dass die positive Wirkung der ASM-Hemmung auf Treg eine CD28-Kostimulation erforderte, was darauf hindeutet, dass eine verstärkte CD28-Kostimulation die Ur-sache für den beobachteten Anstieg der Frequenz von Treg innerhalb menschli-cher CD4+ T-Zellen war. Die Hemmung der ASM-Aktivität war darüber hinaus mit Veränderungen in der Expression und im zellulären Umsatz von CTLA-4, einem von Treg exprimierten inhibitorischen Schlüsselmolekül, verbunden. Die suppressi-ve Aktivität von CTLA-4 durch seine Transendozytose-Aktivität wurde jedoch durch die Hemmung der ASM-Aktivität nicht beeinflusst. Zusammenfassend lässt sich sagen, dass die Häufigkeit von (Effektor-)Treg unter-halb der CD4+ T-Zellen in Mäusen und beim Menschen nach Hemmung der ASM-Aktivität erhöht ist, was darauf hindeutet, dass eine ASM-Blockade Autoimmuner-krankungen und depressionsfördernde Entzündungen vorteilhaft modulieren könn-te. KW - Treg KW - CD28 KW - ASM KW - CTLA-4 KW - Major depression KW - Ceramid Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233471 ER - TY - JOUR A1 - Wienrich, Carolin A1 - Carolus, Astrid A1 - Roth-Isigkeit, David A1 - Hotho, Andreas T1 - Inhibitors and enablers to explainable AI success: a systematic examination of explanation complexity and individual characteristics JF - Multimodal Technologies and Interaction N2 - With the increasing adaptability and complexity of advisory artificial intelligence (AI)-based agents, the topics of explainable AI and human-centered AI are moving close together. Variations in the explanation itself have been widely studied, with some contradictory results. These could be due to users’ individual differences, which have rarely been systematically studied regarding their inhibiting or enabling effect on the fulfillment of explanation objectives (such as trust, understanding, or workload). This paper aims to shed light on the significance of human dimensions (gender, age, trust disposition, need for cognition, affinity for technology, self-efficacy, attitudes, and mind attribution) as well as their interplay with different explanation modes (no, simple, or complex explanation). Participants played the game Deal or No Deal while interacting with an AI-based agent. The agent gave advice to the participants on whether they should accept or reject the deals offered to them. As expected, giving an explanation had a positive influence on the explanation objectives. However, the users’ individual characteristics particularly reinforced the fulfillment of the objectives. The strongest predictor of objective fulfillment was the degree of attribution of human characteristics. The more human characteristics were attributed, the more trust was placed in the agent, advice was more likely to be accepted and understood, and important needs were satisfied during the interaction. Thus, the current work contributes to a better understanding of the design of explanations of an AI-based agent system that takes into account individual characteristics and meets the demand for both explainable and human-centered agent systems. KW - explainable AI KW - human-centered AI KW - recommender agent KW - explanation complexity KW - individual differences Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297288 SN - 2414-4088 VL - 6 IS - 12 ER - TY - JOUR A1 - Wiegering, Verena A1 - Riedmeier, Maria A1 - Thompson, Lester D. R. A1 - Virgone, Calogero A1 - Redlich, Antje A1 - Kuhlen, Michaela A1 - Gultekin, Melis A1 - Yalcin, Bilgehan A1 - Decarolis, Boris A1 - Härtel, Christoph A1 - Schlegel, Paul-Gerhardt A1 - Fassnacht, Martin A1 - Timmermann, Beate T1 - Radiotherapy for pediatric adrenocortical carcinoma - Review of the literature JF - Clinical and Translational Radiation Oncology N2 - Background and purpose Pediatric adrenocortical carcinoma (pACC) is a rare disease with poor prognosis. Publications on radiotherapy (RT) are scarce. This review summarizes the current data on RT for pACC and possibly provides first evidence to justify its use in this setting. Materials and methods We searched the PubMed and Embase database for manuscripts regarding RT for pACC. Results We included 17 manuscripts reporting on 76 patients treated with RT, after screening 2961 references and 269 full articles. In addition, we added data of 4 unreported pACC patients treated by co-authors. All reports based on retrospective data. Median age at first diagnosis was 11.1 years (70% female); 78% of patients presented with hormonal activity. RT was mostly performed for curative intent (78%). 88% of RT were administered during primary therapy. The site of RT was predominantly the local tumor bed (76%). Doses of RT ranged from 15 to 62 Gy (median 50 Gy). Information on target volumes or fractionation were lacking. Median follow-up was 6,9 years and 64% of the patients died of disease, with 33% alive without disease. In 16 of 48 patients with available follow-up data after adjuvant RT (33%) no recurrence was reported and in 3 of 9 patients palliative RT seemed to induce some benefit for the patient. Conclusions Our first systematic review on RT for pACC provides too few data for any general recommendation, but adjuvant RT in patients with high risk might be considered. International collaborative studies are urgently needed to establish better evidence on the role of RT in this rare malignancy. KW - pediatric adrenocortical cancer KW - pediatric adrenocortical carcinoma KW - pediatric adrenocortical tumor KW - radiotherapy KW - therapy KW - treatment Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300472 VL - 35 ER - TY - JOUR A1 - Widder, Anna A1 - Kelm, Matthias A1 - Reibetanz, Joachim A1 - Wiegering, Armin A1 - Matthes, Niels A1 - Germer, Christoph-Thomas A1 - Seyfried, Florian A1 - Flemming, Sven T1 - Robotic-assisted versus laparoscopic left hemicolectomy — postoperative inflammation status, short-term outcome and cost effectiveness JF - International Journal of Environmental Research and Public Health N2 - Robotic-assisted colon surgery may contain advantages over the laparoscopic approach, but clear evidence is sparse. This study aimed to analyze postoperative inflammation status, short-term outcome and cost-effectiveness of robotic-assisted versus laparoscopic left hemicolectomy. All consecutive patients who received minimal-invasive left hemicolectomy at the Department of Surgery I at the University Hospital of Wuerzburg in 2021 were prospectively included. Importantly, no patient selection for either procedure was carried out. The robotic-assisted versus laparoscopic approaches were compared head to head for postoperative short-term outcomes as well as cost-effectiveness. A total of 61 patients were included, with 26 patients having received a robotic-assisted approach. Baseline characteristics did not differ among the groups. Patients receiving a robotic-assisted approach had a significantly decreased length of hospital stay as well as lower rates of complications in comparison to patients who received laparoscopic surgery (n = 35). In addition, C-reactive protein as a marker of systemic stress response was significantly reduced postoperatively in patients who were operated on in a robotic-assisted manner. Consequently, robotic-assisted surgery could be performed in a cost-effective manner. Thus, robotic-assisted left hemicolectomy represents a safe and cost-effective procedure and might improve patient outcomes in comparison to laparoscopic surgery. KW - robotic surgery KW - colon resection KW - postoperative inflammation KW - cost-effectiveness KW - left hemicolectomy Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286203 SN - 1660-4601 VL - 19 IS - 17 ER - TY - JOUR A1 - White, P. Lewis A1 - Springer, Jan A1 - Wise, Matt P. A1 - Einsele, Hermann A1 - Löffler, Claudia A1 - Seif, Michelle A1 - Prommersberger, Sabrina A1 - Backx, Matthijs A1 - Löffler, Jürgen T1 - A clinical case of COVID-19-associated pulmonary aspergillosis (CAPA), illustrating the challenges in diagnosis (despite overwhelming mycological evidence) JF - Journal of Fungi N2 - The COVID-19 pandemic has resulted in large numbers of patients requiring critical care management. With the established association between severe respiratory virus infection and invasive pulmonary aspergillosis (7.6% for COVID-19-associated pulmonary aspergillosis (CAPA)), the pandemic places a significant number of patients at potential risk from secondary invasive fungal disease. We described a case of CAPA with substantial supporting mycological evidence, highlighting the need to employ strategic diagnostic algorithms and weighted definitions to improve the accuracy in diagnosing CAPA. KW - COVID-19 KW - CAPA KW - diagnostics KW - Aspergillus Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-302438 SN - 2309-608X VL - 8 IS - 1 ER - TY - JOUR A1 - Westphale, Silke A1 - Backhaus, Joy A1 - Koenig, Sarah T1 - Quantifying teaching quality in medical education: The impact of learning gain calculation JF - Medical Education N2 - Background Student performance is a mirror of teaching quality. The pre-/post-test design allows a pragmatic approach to comparing the effects of interventions. However, the calculation of current knowledge gain scores introduces varying degrees of distortion. Here we present a new metric employing a linear weighting coefficient to reduce skewness on outcome interpretation. Methods We compared and contrasted a number of common scores (raw and relative gain scores) with our new method on two datasets, one simulated and the other empirical from a previous intervention study (n = 180) employing a pre-/post-test design. Results The outcomes of the common scores were clearly different, demonstrating a significant dependency on pre-test scores. Only the new metric revealed a linear relationship to the knowledge baseline, was less skewed on the upper or lower extremes, and proved well suited to allow the calculation of negative learning gains. Employing the empirical dataset, the new method also confirmed the interaction effect of teaching formats with specific subgroups of learner characteristics. Conclusion This work introduces a new weighted metric enabling meaningful comparisons between interventions based on a linear transformation. This method will form the basis to intertwine the calculation of test performance closely with the outcome of learning as an important factor reflecting teaching quality and efficacy. Its regular use can improve the transparency of teaching activities and outcomes, contribute to forming rounded judgements of students' acquisition of knowledge and skills and enable valuable feedforward to develop and enhance curricular concepts. KW - medical education KW - teaching quality KW - student performance KW - comparison Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259576 VL - 56 IS - 3 ER - TY - THES A1 - Wertgen, Andreas Gabriel T1 - The Role of Source Credibility in the Validation of Text Information T1 - Die Rolle der Quellenglaubwürdigkeit bei der Validierung von Textinformationen N2 - Numerous experiments have shown that an evaluative and passive process, known as validation, accompanies activation and integration, which are fundamental processes of text comprehension. During the construction of a mental model, validation implicitly assesses the plausibility of incoming information by checking its consistency with world knowledge, prior beliefs, and contextual information (e.g., the broader discourse context). However, research on potential influences that shape validation processes has just started. One branch of research is investigating how world knowledge and contextual information contribute to integration and validation. World knowledge usually influences validation more strongly because information plausibility is the primary criterion for validation, but strong contextual information can yield influences as well. Contextual information that may be specifically relevant for routine validation is the credibility of a source providing text information. Source credibility bears a strong conceptual relationship to the validity of information. However, a dearth of research has investigated joint effects of plausibility and source credibility for routine validation. To fill this research gap, the aim of the present dissertation was to examine the role of source credibility in routine validation processes of text information. This dissertation argues that both source credibility and plausibility are considered in these processes. In particular, information plausibility is proposed as the primary criterion, but source credibility may modulate validation as an additional criterion. To this end, three studies with five self-paced reading experiments were conducted in which reading times served as an implicit indicator of validation and plausibility judgments as an explicit indicator, and the convergence or divergence between the two indicators was interpreted. The first study examined the interplay of plausibility and source credibility for the validation of world-knowledge consistent versus inconsistent text information embedded in short narratives. This highly plausible or highly implausible information was provided by a high- or low-expertise source. In Study 1, plausibility dominated validation as suggested by faster reading times and higher plausibility judgments for world-knowledge consistent information. Importantly, source credibility modulated the validation of highly implausible information but seemed to not matter for plausible information. High-credible sources increased the implausibility of highly implausible information to a greater extent compared with low-credible sources as indicated by longer reading times and lower plausibility judgments. These results diverged from recent findings from Foy et al. (2017). The second study investigated whether the modulating role of source credibility depends on the degree of implausibility of an information. Thus, Study 2 extended Study 1 by an intermediate, somewhat implausible level of plausibility (comparable to the implausible claims in Foy et al., 2017). Similar to Study 1, plausibility dominated validation as indicated by lower reading times and plausibility judgments with higher world-knowledge inconsistency. Again, source credibility had no effect on the routine validation of plausible information. However, high-credible sources mitigated the implausibility of somewhat implausible information as indicated by faster reading times and higher plausibility judgments but exacerbated the implausibility of highly implausible information as indicated by slower reading times and lower plausibility judgments. In short, Study 2 findings not only integrates the seemingly divergent results of Study 1 and Foy et al. (2017) but also provides strong support for the assumption that the degree of implausibility determines the modulating role of source credibility for validation. The third study examined the relationship of source credibility and plausibility in an ecologically valid social media setting with short Twitter messages varying in world-knowledge and text-belief consistency by trustworthy and untrustworthy sources. In sum, plausibility and to a lesser extent source credibility mattered for routine validation and explicit evaluation of text information as indicated by reading times and plausibility judgments. However, the pattern partly diverged from Study 1 and 2, possibly because the source information was more salient. In sum, the present dissertation yielded three insights. First, the findings further extends evidence for routine validation based on world-knowledge and prior beliefs. Second, the studies suggest that source credibility can modulate validation. Readers used source credibility cues for routine validation and the explicit evaluation of text information in all studies. Third, the impact of source credibility seems to depend on the degree of implausibility of information. The present findings have theoretical implications for theories of validation and text comprehension as well as practical implications for targeting threats associated with the prevalence of inaccurate information, for example, on the World Wide Web. Future research using eye-tracking methodology could further disentangle the routine and strategic underlying processes of the relationship between source credibility and plausibility. N2 - Zahlreiche empirische Untersuchungen konnten zeigen, dass ein passiver und evaluativer Prozess – genannt Validierung – die Aktivierung und Integration von Textinformationen mit leserseitigem Vorwissen und Überzeugungen als grundlegende Prozesse des Textverstehens begleitet. Während der Konstruktion des Situationsmodells erfassen Validierungsprozesse fortlaufend und implizit die Plausibilität einer eingehenden Information, indem sie die Konsistenz mit leserseitigem Vorwissen und Überzeugungen sowie mit Kontextinformationen (z. B. vorherige Textinformationen) überprüfen. Die Erforschung weiterer Einflussgrößen für die Validierung hat jedoch gerade erst begonnen. Ein Forschungszweig beschäftigt sich mit der Frage, wie sich Kontextinformationen und Vorwissen in ihrem Beitrag zu Integrations- und Validierungsprozessen unterscheiden. Ein Befund dabei ist, dass das Vorwissen häufig einen stärkeren Einfluss auf die Validierungsprozesse hat und folglich die Informationsplausibilität das primäre Kriterium für die Validierung von Textinformationen ist. Starke Kontextinformationen können jedoch ebenfalls für die Bewertung von eingehenden Informationen herangezogen werden. Eine spezifische Kontextinformation, die eine konzeptuelle Verbindung zu der Validität einer Information hat und daher eine besondere Relevanz für die Validierung von Textinformationen besitzt, ist die Glaubwürdigkeit der Quelle, die eine Textinformation liefert. Es gibt jedoch nur vereinzelte Studien, die das interaktive Zusammenspiel der Informationsplausibilität und Quellenglaubwürdigkeit für die Validierung von Textinformationen untersucht haben. Die vorliegende Dissertation setzt an dieser Lücke an und untersucht die Rolle der Quellenglaubwürdigkeit für die routinierte Validierung von Textinformationen. Dabei wird angenommen, dass sowohl die Plausibilität als auch die Quellenglaubwürdigkeit in diesen Prozessen berücksichtigt werden. Die Plausibilität einer Information sollte hierbei das primäre Kriterium sein, das zur Validierung herangezogen wird, aber die Quellenglaubwürdigkeit sollte als zusätzliches Kriterium genutzt werden und die Prozesse potentiell zu modulieren. Zur Überprüfung dieser Annahmen wurden drei Lesezeitstudien mit insgesamt fünf Experimenten durchgeführt. Ob implizite und explizite Maße konvergieren oder divergieren ist aufschlussreich für die Untersuchung der Prozesse des Textverstehens. Daher dienten die Lesezeit als implizites Maß für Validierungsprozesse und die Beurteilung der Plausibilität einer Textinformation als explizites Maß in allen Studien. Die erste Studie untersuchte die Beziehung von Plausibilität und Quellenglaubwürdigkeit bei der Validierung von Textinformationen, die konsistent (plausibel) oder inkonsistent (stark unplausibel) mit dem Vorwissen waren. Diese Textinformationen waren eingebettet in kurzen Geschichten und wurden von einer Quelle mit viel bzw. wenig Expertise hinsichtlich des angesprochenen Wissensbereichs geäußert. In Studie 1 führten plausible Textinformationen zu kürzeren Lesezeiten und höheren Plausibilitätsurteilen als stark unplausible Textinformationen. Für plausible Informationen schien die Quellenglaubwürdigkeit keine Rolle zu spielen, jedoch führten glaubwürdige Quellen zu höheren Lesezeiten und niedrigeren Plausibilitätsurteilen bei stark unplausiblen Informationen. Studie 1 legt nahe, dass die Konsistenz mit dem Vorwissen das Hauptkriterium für die Validierung war und die Quellenglaubwürdigkeit als zusätzliches Kriterium die Validierung unplausibler Informationen modulieren kann, jedoch in der Wirkrichtung scheinbar abweichend zu aktuellen Befunden ist (Foy et al., 2017). Die zweite Studie untersuchte, ob die in Studie 1 gefundene, modulierende Rolle der Quellenglaubwürdigkeit für Validierungsprozesse vom Grad der Unplausibilität einer Information abhängt. Hierzu wurden die Konzeption und die Materialien der ersten Studie um eine mittlere Plausibilitätsstufe, die als „etwas unplausibel“ bezeichnet werden kann, erweitert; sonst waren die Studien sehr ähnlich. In Studie 2 zeigte sich ein dreigestufter Plausibilitätseffekt abhängig von der Konsistenz mit dem Vorwissen. Plausible Textinformationen wurden schneller gelesen und als plausibler beurteilt als etwas unplausible Informationen. Diese wiederum wurden schneller gelesen und als plausibler eingeschätzt als stark unplausible Informationen. Erneut wurde die Quellenglaubwürdigkeit während des Lesens plausibler Informationen nicht berücksichtigt, modulierte aber die Validierung unplausibler Informationen. Glaubwürdige Quellen verglichen mit unglaubwürdigen Quellen führten zu kürzeren Lesezeiten und einer höher eingeschätzten Plausibilität für etwas unplausible Informationen, aber verlängerten die Lesezeiten und verringerten die Plausibilitätsurteile stark unplausibler Informationen – letzteres war identisch mit dem Ergebnis von Studie 1. Studie 2 zeigt, dass die Plausibilität einer Information das Hauptkriterium für wissensbasierte Validierungsprozesse war. Wenn Informationen einen gewissen Grad an Unplausibilität erreichen, können glaubwürdige Quellen die Plausibilität eigentlich unplausibler Informationen erhöhen oder sogar weiter verringern. Die Ergebnisse von Studie 2 belegen die Annahme, dass der Grad der Unplausibilität einer Information die modulierende Rolle der Glaubwürdigkeit einer Quelle bestimmt und darüber hinaus werden die Befunde von Studie 1 und Foy et al. (2017) integriert. Die dritte Studie untersuchte die Beziehung von Plausibilität und Quellenglaubwürdigkeit eingebettet in einem sozialen Medium mit kurzen Twitter-Nachrichten als ein ökologisch valider Kontext. Die Nachrichten unterschieden sich in der vom Text vermittelten Überzeugung und der Vorwissenskonsistenz. Diese Nachrichten wurden präsentiert von stark und wenig vertrauenswürdigen Quellen. Zusammenfassend zeigen Lesezeiten und Plausibilitätsurteile, dass die Informationsplausibilität und in einem geringeren Maße die Quellenglaubwürdigkeit für die routinierte Validierung und explizite Bewertung der Textinformationen von Bedeutung waren, aber mit einem teilweise abweichenden Muster zu Studie 1 und 2. Eine mögliche Erklärung könnte in den stark salienten Quelleninformationen in Studie 3 liegen. Zusammengefasst hat die vorliegende Dissertation drei Erkenntnisse erbracht. Erstens, die Befundlage für routinierte Validierungsprozesse basierend auf der Plausibilität einer Information wurde erweitert. Zweitens, die Studien legen nahe, dass die Glaubwürdigkeit einer Quelle dabei auch eine Rolle spielt: in allen Studien nutzten die Leserinnen und Leser die Quellenglaubwürdigkeit als zusätzlichen Hinweis zur Validierung und zur expliziten Plausibilitätsbewertung von Textinformationen. Drittens, die Stärke und die Richtung des Einflusses der Quellenglaubwürdigkeit für die wissensbasierte Validierung von Textinformationen scheint vom Grad der Unplausibilität einer Information abzuhängen. Diese Ergebnisse erlauben Schlussfolgerungen für Theorien der Validierung und des Textverstehens sowie praktische Implikationen für die Bekämpfung von möglichen Folgen, die mit der Verbreitung von Falschinformationen verbunden sind. Zukünftige Experimente basierend auf Blickbewegungen könnten helfen die routinierten und strategischen Prozesse genauer zu trennen, die die Beziehung von Quellenglaubwürdigkeit und Plausibilität für die Validierung bestimmen. KW - Textverstehen KW - Plausibilität KW - Trustworthiness KW - Credibility KW - Validation KW - Source Credibility KW - Text Comprehension KW - Plausibility KW - Sourcing Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288619 ER -