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Markovian randomized equilibria in games of stopping
Get PDFThe thesis introduces two games of stopping based on a common stochastic model. For both games, equilibria in pure strategies are introduced. Then, Markovian randomized strategies are defined, discussed with respect to their properties and classified as a mathematical concept. Finally, we extend the equilibrium definitions of pure strategies to Markovian randomized strategies. This is followed by the three scientific contributions of the work. Chapter 3 contains a proof of the existence of Markov-perfect equilibria in general nonzero-sum Dynkin games of war-of-attrition type, driven by a 1-dimensional Ito diffusion. This establishes Markovian randomized stopping times as the canonical type of equilibrium in the game. Another main contribution lies in the development of topologies for Markovian randomized stopping times on the basis of which the existence of equilibria can be proved by means of fixed point and general compactness arguments. In Chapter 4 we study a version of the equilibrium problem with randomized strategies that arises from the problem of optimally stopping a 1-dimensional Ito diffusion, subject to an expectation constraint on the time until stopping. We derive a verification theorem and necessary conditions for equilibria, which together basically characterize all equilibria. Furthermore, additional structural properties of equilibria are obtained to feed a possible guess-and-verify approach. It turns out that in order to determine the reward functional by the previously derived properties, we also need differentiability in order to have a sufficient number of conditions. The required differentiability result is provided in Chapter 5. In addition, we conduct a full investigation of the continuity and smoothness of reward functionals associated with Markovian randomized stopping times. These properties can be used to apply a common approach to derive analytic expressions for the reward functional
Phänotypische Wirkstoffentwicklung für kardiale Hypertrophie: Entwicklung und Anwendung einer Hochdurchsatz- und multiparametrischen Screening-Plattform
Get PDFThis thesis presents a high-throughput phenotypic screening platform tailored for cardiac hypertrophy that enables efficient lead optimisation and facilitates translation into in vivo models. A mixed neonatal rat cardiac cell culture was established to analyse cardiomyocytes and non-cardiomyocytes responses in parallel. A self-developed CellProfiler pipeline generated a multi-parametric 'Hypertrophy Score' for phenotypic evaluation. The platform was first applied to investigate a G protein-coupled receptor kinase 5 (GRK5) inhibitor library. The assay platform generated meaningful cellular structure-activity relationships (SAR) to correlate with biochemical IC50 values and physicochemical features. GRK5 inhibitor 4a emerged as a highly effective, non-toxic anti-hypertrophic agent, with its inactive optical antipode 4b serving as an ideal negative control. Secondly, the role of L-2-hydroxyglutarate (L-2HG) as a novel pro-hypertrophic metabolite was investigated. Given its metabolic link to glutamine, small-molecule inhibitors targeting glutaminase (GLS1) and glutamine uptake were systematically profiled for their anti-hypertrophic and anti-proliferative effects. Lastly, the screening platform was leveraged to explore the tumour-heart axis by assessing cardiomyocyte responses to serum from colorectal cancer patients. Patient serum induced proliferative effects across cell populations but suppressed hypertrophic markers, suggesting circulating tumour-derived factors with cardiodepressive properties. Collectively, this thesis introduces a novel multiparametric platform for cardiac drug discovery, demonstrating the power of combining high-content phenotyping, translational models and targeted interventions to address unmet clinical needs in cardiac hypertrophy
The Impact of Digital Technologies on Companies’ International Business Activities
Get PDFDigital technologies have been increasingly argued to increase the efficiency of business operations. This represents an even more relevant subject for international companies due to global competition and the added complexity of their foreign activities, since being active in many countries requires a higher level of coordination as well as competitiveness, whereby advanced technologies are believed to be beneficial. However, the extant research in this field does not shed sufficient light on the way international companies can benefit from deploying digital technologies regarding their international business activities. Hence, this project aims to explore if and to which extent digital technologies influence the afore-mentioned foreign operations and help international companies increase their performance in foreign markets. To address this issue, interviews have been conducted with top managers of German companies having foreign activities. During the interviews, interviewees were asked questions identified based on the literature and theoretical reasoning. These questions form four groups of research topics: Location of activities, internationalization-specific decision-making, foreign subsidiaries and their roles, and governance/management/coordination. The preliminary results illustrate the importance of talent acquisition, automation of routine international operations, and regulatory requirements in different markets. Regarding the latter, China has established itself as one of the most important markets for most of the interviewed companies with its own specific requirements for developing and employing digital technologies. Furthermore, interviewees emphasized the role of digital platforms in the digital era
„TrACES of Time“: Entwicklung eines Verfahrens zur Schätzung des Depositionstageszeitpunkts zur Kontextualisierung biologischer Tatortspuren mittels forensischer Transkriptomanalysen
Get PDFDie DNA-basierte Zuordnung biologischer Spuren zu ihren Verursachern, die das Hauptaufgabengebiet der forensischen Molekularbiologie darstellt, ist alleinstehend häufig nicht ausreichend, um die Abfolge der Geschehnisse und Aktivitäten an einem (Tat-)Ort objektiv rekonstruieren zu können. Möglichkeiten, mittels in biologischem Spurenmaterial enthaltener Information Erkenntnisse über den Kontext der Spurenentstehung zu gewinnen, werden daher in verschiedenen Forschungsprojekten erkundet. Das Transkriptom, dessen Zusammensetzung sich je nach Art und Zustand einer biologischen Spur unterscheidet, weist ein hohes Potential für derartige Untersuchungen auf. Die in dieser Dissertationsschrift aufgeführten Studien befassten sich mit dem Ziel, ein auf der Messung mit der Tageszeit rhythmisch oszillierend exprimierter mRNA-Transkripte basierendes Verfahren zur Schätzung des Tageszeitpunkts der Deposition menschlicher Blut- und Speichelspuren zu entwickeln. Für dieses Ziel wurden zunächst Gesamttranskriptomsequenzierungen zur unvoreingenommenen Identifizierung geeigneter Markerkandidaten durchgeführt. Darauf aufauend wurde ein Verfahren zur gezielten Sequenzierung und Genexpressionsquantifizierung der ausgewählten Kandidaten auf einem Ion-S5-Tischsequenziergerät entwickelt und ein statistisches Modell zur Schätzung des Tagesdepositionszeitpunkts auf Basis von Genexpressionsmessdaten trainiert. Das etablierte Verfahren stellt den ersten Ansatz zur Schätzung des Depositionstageszeitpunkts von Blutspuren auf Basis gezielter RNA-Sequenzierung dar. Während eine umfangreichere Validierung unter zusätzlichen, forensisch relevanten Bedingungen noch aussteht, stellt die vorliegende Arbeit eine essenzielle Grundlage für die Anwendung des Verfahrens zur Schätzung der Depositionstageszeit von Spuren in der forensischen Fallarbeit dar
Biophysikalische Untersuchung von an Biotransformation beteiligten Flavinmonooxygenasen
Get PDFDiese Arbeit beschäftigt sich mit der Expression, Reinigung, Charakterisierung sowie der Kristallisation der ΔhFMO5, einer Variante der humanen Flavin-abhängigen Monooxygenase 5 (hFMO5), bei welcher die Transmembranhelix entfernt wurde. Diese Modifikation ermöglicht die Expression und Reinigung von löslichem Protein ohne Zugabe von Detergenz und resultiert in der Reinigung von aktivem, mit FAD gesättigtem Protein. Die zur Bildung von Aggregat neigende ΔhFMO5 konnte im Glasfermenter im Stamm E. coli Rosetta 2 (DE3) pLysS erfolgreich exprimiert, mittels enzymatischem Zellaufschluss lysiert und mit Affinitäts- und Gelfiltrationschromatographie gereinigt werden. Die Charakterisierung mittels Massenphotometrie zeigt, dass die ΔhFMO5 in Lösung als ein Mix aus unterschiedlichen Oligomerisierungszuständen vorliegt. Dabei überwiegt der Zustand bestehend aus vier Untereinheiten. Der katalytische Zyklus der ΔhFMO5 beinhaltet einen entkoppelten Stoffwechselweg, bei welchem zur Regeneration des Kofaktors FAD ohne die Umsetzung von Substrat NADPH verbraucht wird und Wasserstoffperoxid entsteht. Die iterative Modellierung der Reaktionskinetik der ΔhFMO5 zeigt, dass die Verstoffwechselung von Substrat als Reaktion 2. Ordnung langsamer abläuft als die entkoppelte Reaktion. Die Messung der Aktivität zeigt, dass die Umwandlung von Phenylaceton zu Benzylacetat mit einer Umsetzungsrate von 5,1 % durch die ΔhFMO5 katalysiert wird. Als mögliches endogenes Substrat wurde N-Acetylserotonin ermittelt, welches eine Rolle in der Produktion von Melatonin und Serotonin spielt
Development of a Rat Femoral Fracture Model for Preclinical Investigation of Magnesium-based Orthopedic Implant Materials
Get PDFBackground: Magnesium (Mg) and its alloys exhibit excellent biomechanical properties and osteogenic potential, being considered as promising biomaterials for the treatment of bone fractures. The objective of this project was to establish a rat fracture model for future preclinical evaluation of novel Mg-based implant materials. Methods: Female Sprague-Dawley rats underwent general anesthesia and induction of femoral shaft fractures via osteotomy. In the experimental Mg group, a Mg pin was implanted in the medullary cavity, followed by fracture reduction and external fixation. In the control group, only fracture reduction and external fixation were performed without Mg implantation. The general status and surgical limbs were monitored for 12 weeks. Bone healing and implant degradation were evaluated by micro-CT, and bone samples were collected for histology. Results: No serious complications observed during follow-up. At postoperative week 12, all rats in the Mg group achieved bone union, while nonunion cases were observed in the control group. Quantitative analysis showed lower bone volume and bone mineral content in the Mg group, suggesting potential bone-inhibition associated with long-term retention. Histological analysis showed higher percentage of soft tissue areas including cartilaginous callus in the control group, suggesting an accelerated onset of bone remodeling phase in the presence of Mg implants. Conclusion: The study demonstrated the safety and efficacy of this fracture model for evaluation of Mg implant materials. In addition to the confirmation of beneficial treatment effects from Mg, the imaging analysis also revealed potential bone inhibition associated with long-term retention of Mg implants. Future studies using this model could contribute to a deeper understanding of the biological mechanism and the development of novel Mg-based materials for musculoskeletal disorders
A Magnetoelectric Distance Estimation System for Relative Human Motion Tracking
Get PDFClinical motion analysis plays an important role in the diagnosis and treatment of mobility-limiting diseases. Within this assessment, relative (point-to-point) tracking of extremities could benefit from increased accuracy. Given the limitations of current wearable sensor technology, supplementary spatial data such as distance estimates could provide added value. Therefore, we propose a distributed magnetic tracking system based on early-stage demonstrators of novel magnetoelectric (ME) sensors. The system consists of two body-worn magnetic actuators and four ME sensor arrays (body-worn and fixed). It is enabled by a comprehensive signal processing framework with sensor-specific signal enhancement and a gradient descent-based system calibration. As a pilot study, we evaluated the technical feasibility of the described system for motion tracking in general (Scenario A) and for operation during treadmill walking (Scenario B). At distances of up to 60 cm, we achieved a mean absolute distance error of 0.4 cm during gait experiments. Our results show that the modular system is capable of centimeter-level motion tracking of the lower extremities during treadmill walking and should therefore be investigated for clinical gait parameter assessment
When the Second-Person Perspective is the First: On the Interconnection between Second- and First-Person Perspective regarding an Individual’s Self-Relationship and its Theological Consequences
Get PDFWithin Christian theology, the second-person perspective primarily comes into play when it refers to God ’ s perspective on humanity. In contrast, this article focuses on the second-person perspective as a human perspective and explores its relevance for the development of an individual ’ s self-relationship. Drawing on insights from developmental psychology, it also argues for an intergenerational and social understanding of human sinfulness and advocates for more systematic-theological attention to childhood and adolescence. Overall, the article contributes to strengthening an intersubjective view of the self and to deepening one of the many dimensions of human interdependence
Implementation Methods for Transmission Zeros in Groove Gap Waveguide Filters at W-Band
Get PDFIn this paper, three groove gap waveguide (GGW) filters are presented, which utilize different techniques to create transmission zeros (TZs) in the W-band. First, a fourth-order filter with cross-coupling of non-adjacent cavities realizes five TZs. The filter is implemented using a stacked cavity approach, which simplifies the realization of cross-couplings with positive and negative signs. The source to load cross-coupling realizes one TZ more than predicted from theory. In the second filter, two off-centered posts with partial height are used to realize two TZs. These posts act as strongly frequency-dependent coupling elements and enable the realization of TZs in an inline filter topology. An interdigital-pin implementation has been used since otherwise, the distance between the posts and the sidewalls is too small to allow manufacturing using the Computerized Numerical Control (CNC) milling approach. The third filter is of fourth order and implements two TZs by using a stub-loaded cavity approach. All filters are designed as a proof of concept in the W-band (75–110 GHz) to verify the manufacturability at high-frequency bands. The manufactured components are realized by high-precision CNC milling and measurement results show good agreement with the simulation for all proposed filters
Prognostic scores for predicting overall survival in patients with metastatic renal and urothelial cancer undergoing immunotherapy - which one to use?
Get PDFPurpose Evaluation of the prognostic significance of four different scoring systems in a real-world cohort of patients with metastatic urothelial carcinoma (mUC) or renal cell carcinoma (mRCC) undergoing immunotherapy (IO). Methods For 120 patients with mUC (n = 67) and mRCC (n = 53) who received IO between July 2016 and December 2020 at the tertiary Urological University Medical Centre Mannheim, the following scores were recorded at pre-treatment baseline: modified Glasgow prognostic score (mGPS), systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), neutrophil-to-eosinophil ratio (NER). Overall survival (time between the beginning of IO until the patients' death or last contact) was determined for every patient. Results Kaplan-Meier analyses revealed that high baseline mGPS, SII (> 979) and NLR (> 3) were associated with poor overall survival (OS) (p < 0.05). Cox proportional hazards regression analyses showed that baseline mGPS and NLR had a significant independent prognostic influence on OS (p < 0.05), of which mGPS had a greater significance (p < 0.001, mGPS Score 2 vs. Score 0: HR 4.1, 95% CI 1.9-8.8). Although a high baseline NER (63.9) was associated with poor OS, it did not reach statistical significance. Baseline NER was also not identified as a significant score in the regression analyses. Conclusion mGPS, SII and NLR are scoring systems that are easy to record in routine clinical practice. As they provide good prediction of OS in patients with mUC and mRCC under IO, they may allow identification of patients at high-risk and monitor them more cautiously in addition to imaging