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Item type: Item , When Visions Become Reality - Urban Living Labs as a Transition Arena for Sustainable Mobility Culture(2025) Rollin, PhilippAccess to mobility is an important aspect of social inclusion and therefore also a question of social justice. At the same time, the current transport infrastructure in Germany, which is primarily geared towards the car, generates high external costs such as climate-damaging emissions and immissions or massive land consumption. The resulting demand to ensure socially equitable participation in mobility for all members of society, on the one hand, and to make it more climate-friendly and fairer, on the other, inevitably leads to socio-political challenges.<br> Urban Living Labs (ULLs), a participatory method and kind of real-world laboratory, are increasingly being used as a method to realise a socially accepted traffic transition. However, so far this is more assumption than fact, as there is a lack of empirical data on the effectiveness of the method. As a result, this dissertation is based on hypotheses that deal theoretically and empirically with the transformative potential of ULLs in the context of a traffic transition.<br> The thesis shows that a transport transition can be supported by an ULL, as they influence mobility-related social norms. The focus is on mobility culture as a latent construct. It is operationalised along social norms and reflects the perceived mobility-related normality. Empirical evidence shows that it is linked to mobility behaviour and therefore represents a previously underused starting point for the transport transition. The evaluation of a ULL confirms this: Based on repeated cross-sectional data, changes in mobility culture and mobility behaviour become clear that point in a more sustainable direction, i.e. towards a transport transition.<br> The project provides impulses for analysing cultural and normative processes of the transport transition and for evaluating participatory transformation approaches.Item type: Item , Investigating the impact of Caspase-8 and Connexin-43 on metastasis and tumour aggressiveness in human ovarian cancer using an orthotopic mouse model(2024) Aberoumandi, Seyed MohsenOvarian carcinoma is the leading cause of mortality among gynaecological malignancies, primarily due to late-stage diagnosis and the presence of metastatic disease. As most patients present with advanced tumours, an improved understanding of the molecular mechanisms driving tumour progression, metastasis, and therapeutic resistance is required for the development of targeted therapies. Caspase-8 (CASP8), a key regulator of apoptosis, and Connexin-43 (CX43), a gap-junction protein implicated in cell-cell communication and metastasis, have emerged as potential therapeutic targets in ovarian cancer. This PhD project aimed to investigate the functional roles of CASP8 and CX43 in ovarian cancer progression, metastasis, and response to chemotherapy using clinically relevant in vivo and in vitro models. High- grade serous ovarian cancer cell lines (OVCAR8 and OVCAR3) were engineered using CRISPR-Cas9 to generate CASP8 and/or CX43 knockout (KO) models for analysis in an orthotopic mouse model and complementary in vitro assays. In vivo, luciferase-labelled OVCAR8 KO:CASP8 cells exhibited significantly enhanced tumour growth and widespread organ dissemination compared with OVCAR8 WT, highlighting a tumour-suppressive role for CASP8. In vitro, CASP8-deficient cells displayed increased resistance to carboplatin and paclitaxel, with reduced chemotherapy- induced apoptosis relative to WT cells. Immunodetection studies revealed increased CX43 expression following CASP8 loss, suggesting functional crosstalk between these proteins. Functional assays demonstrated that CASP8 depletion enhanced invasion in OVCAR3 cells, while co-depletion of CASP8 and CX43 attenuated this phenotype; however, combined KO increased migratory capacity. Overall, these findings reveal a complex, context-dependent interaction between CASP8 and CX43 in regulating ovarian cancer invasion, migration, and therapeutic response, supporting their potential relevance as targets for improved treatment strategies.Item type: Item , Der Einfluss von Apremilast auf Tumornekrosefaktor-α- aktivierte Endothelzellen(2025) Otto, MarkZiel dieser Arbeit war es, den Effekt des in Deutschland zur Behandlung der Psoriasis vulgaris zugelassenen PDE4-Inhibitors Apremilast auf TNF- aktivierte Endothelzellen in Hinblick auf proatherogene Faktoren und Mechanismen zu untersuchen. Die Psoriasis vulgaris und die Atherosklerose können als Komorbiditäten auftreten, sich gegenseitig bedingen und teilen ähnliche klinische Risikofaktoren. Unter der Therapie mit Apremilast konnte in klinischen Studien bereits beobachtet werden, dass hier protektive Einflüsse auf Risikofaktoren, wie z.B. dem erhöhten BMI oder erhöhte Blutfettwerte (LDL, Triglyceride) vermittelt werden. TNFα als Stimulus der endothelialen Entzündungsreaktion in den durchgeführten Versuchen, kommt in beiden Erkrankungen sowohl in der Initiierung als Unterhaltung eine entscheidende Rolle zu. Unsere Experimente zeigen deutlich, dass Apremilast die Sekretion verschiedener proatherogener Zytokine wie GM-CSG, MCP-1 und IP-10 hemmt. Ähnliche Effekte zeigte auch Roflumilast, ein weiterer PDE4i. Weiterhin konnte für das Zytokin GM-CSF auf sekretorischer als auch auf transkriptionaler Ebene ein konzentrations- und zeitabhängiger Effekt von Apremilast gezeigt werden. Im nächsten Schritt wurde durch Apremilast die entzündliche Hochregulierung der wichtigen Adhäsionsrezeptoren VCAM-1 und E-Selektin gehemmt werden. Auf Ebene der Signalwege führte eine Behandlung mit Apremilast zur Reduktion der proinflammatorischen Aktivierung von p38 als auch JNK 1/2. Durch weitere Experimente konnten Hinweise für die Beteiligung der Hemmung von p38 und JNK 1/2 durch Apremilast auf die GM -CSF-Sekretion sowie Hochregulierung von VCAM-1 gezeigt werden. Apremilast führte ebenfalls zu einer Hemmung des Transkriptionsfaktors NF-ĸB. Die zeigte sich durch eine verminderte Phosphorylierung, Translokation in den Zellkern als auch tatsächlichen Aktivierung. Ganz entscheidend konnte Apremilast diese Ergebnisse auch auf funktioneller Ebene zeigen, indem es die Adhäsion als auch Transmigration einer Monozytenzelllinie durch eineEndothelzellschichtinhibiert.AlsAusblickkonnteApremilastebenfallsdieSekretion verschiedener proentzündlicher Zytokine, wie IL-6 und MCP-1, in IL-17A-stimulierten Endothelzellen, als auch die Sekretion der MMP-9 in einer Monozytenzelllinie hemmen. Unsere Experimente zeigen eindrucksvoll, dass Apremilast in vitro initiale Schritte der Pathogenese der Atherosklerose, einer relevanten Komorbidität der Psoriasis vulgaris hemmt. Apremilast zeigt somit sowohl klinisch als auch in vitro beeindruckende, protektive Eigenschaften auf wichtige Faktoren der Atherosklerose, eine der häufigsten Todesursachen in der westlichen Welt.Item type: Item , The transcription factor FOXO1 orchestrates growth and maturation of lymphatics(2025) Fasse, Jannik Werner DieterThe lymphatic vascular system is a unidirectional vascular network connecting the extracellular space with the venous blood circulation. It is essential for accurate regulation of homeostasis, intestinal fat absorption and immune response. Accurate development and maturation of these vessels is indispensable for growth and survival of the organism. Increased lymphangiogenesis is a hallmark of many tumor entities, whereas decreased lymphatic function can lead to lymphedema. Previous work from our laboratory has revealed the function of the transcription factor Forkhead Box O1 (FOXO1) in blood endothelial cells as an inductor of quiescence. Using lymphendothelial cell-specific overexpression in vitro and in vivo, we investigate the function of FOXO1 in the development and maturation of the lymphatic vasculature. In vivo, FOXO1 overexpression resulted in a sparse lymphatic network, exhibiting reduced proliferation. In vitro, we demonstrated downregulation of many genes involved in lymphatic vessel maturation. In addition, FOXO1 appears to reduce MYC and mTORC1 signaling and thereby diverse metabolic pathways, such as lipid and sterol biosynthesis, which may explain reduced cell growth. This study reveals FOXO1 as a regulator of proliferation and maturation in the lymphatic vasculature. Our results demonstrate that proper development and maintenance of the lymphatic vascular network requires precise regulation of FOXO1, and alterations lead to defects in proliferation and maturation. Thus, FOXO1 might have a role in the pathogenesis of lymphatic diseases such as hereditary lymphedema and might evolve as an appealing target to treat these disorders.Item type: Item , dsRNA as a novel tool to fight Verticillium diseases - from basics to future applications(2025) Abdeldayem, MohamedVerticillium infections affect a wide range of plant hosts and cause considerable losses for economically relevant crops like cotton, tomatoes, oilseed rape, and many others. The lifestyle of this soil-borne fungal pathogen further complicates the management strategies and is currently limited to cultural practices such as crop rotation and the use of resistant cultivars, aimed to reduce the presence of disease causing microsclerotia resting in the soil. V. longisporum is the latest characterized species with a nearly diploid genome and a narrower host range – in comparison to the better studied species, namely V. dahliae and V. albo-atrum – is a major threat to oilseed rape production in Europe and Canada. The lack of reliable management strategies led to the interest in exploring RNA interference (RNAi) based alternatives, using double-stranded (ds)RNA to target virulence genes identified from the closely related species V. dahliae. The dissertation covers the confirmation of RNAi machinery activity and targeted gene silencing using 450-500 bp (ds)RNA, followed by a hydroponic based infection assay development and in-vitro growth assay in 96-well-plates for scalability. Both assays were used to assess the plant protection potential for the selected gene targets, formulation development for stabilizing (ds)RNA, and (ds)RNA detection assay after spray application. The selected gene targets demonstrated variable effects on growth and virulence, resulting in different in-vitro growth patterns and disease severity after (ds)RNA addition. The results highlighted the necessity of gene target selection framework and revealed the challenges facing this approach to achieve a prolonged plant protection on a larger scale.