Details of the immune response and impact of the microbiome in murine calcific aortic valve stenosis

(noch nicht zugänglich / not yet accessible

Towards Sustainable Water Use in the Indus River Basin: Assessing Groundwater Dynamics, Environmental Flows, associated Controlling Factors and Management Options

The dissertation highlights the need to release enough discharge as EFs to conserve ecosystems and found that the Chenab, Ravi, and Sutlej Rivers of IRB are particularly vulnerable to the ecosystem as the estimated EFs were not attained during most of the months and seasons of the year during the study period. These findings underscore the urgent need to take appropriate measures for area-specific groundwater monitoring and for ensuring the release of required EFs for conserving the downstream ecosystems. The varied water allocations within the basin are the main controlling factors for groundwater depletion and attainment of EFs in the basin. The dissertation builds a foundation to consider groundwater depletion and EFs (missing aspects in water allocation treaties) to start and support a discussion on revisiting the Indus Water Treaty-1960 and Water Apportionment Accord-1991. The study contributes to the discussion within the scientific community but is also helpful for stakeholders from water management (water users, water administration) and policymakers to include groundwater depletions and EFs in the water allocations

Pharmacologic intervention in macrophage metabolism: Mitochondrial pyruvate carrier inhibition by Mitoglitazone modulates inflammation

Upon Toll-like receptor (TLR) activation, macrophages rapidly change their transcriptional- and translational network and rewire their metabolism. Mitochondrial pyruvate import via the mitochondrial pyruvate carrier (MPC) is essential to the metabolic changes controlling inflammatory responses. Thus, the MPC is a promising target to pharmacologically intervene in inflammatory diseases. Mitoglitazone is an MPC inhibitor currently under clinical investigation for insulin sensitization and amelioration of neurodegeneration. Yet, its effects on macrophage metabolism and inflammation remain undescribed. Here, it is reported that Mitoglitazone inhibits the MPC in macrophages and decreases their inflammatory response following TLR4- or TLR7/8 activation. Metabolic analyses showed rerouting of glucose metabolism and, concomitantly, inhibition of the glycolytic switch and maximal respiration of inflammatory macrophages. Accordingly, Mitoglitazone decreased inflammatory cytokine transcription and release as well as nitric oxide production. Sustained effects of Mitoglitazone under pharmacologic inhibition or in the absence of the nuclear receptor PPARγ emphasize its mode of action via MPC inhibition. In an acute sepsis mouse model Mitoglitazone decreased LPS-induced cytokines, demonstrating its immunomodulatory effect also in vivo. These findings give new insights into the integrative network of macrophage metabolism and their inflammatory response, and highlight the potential of MPC inhibition by Mitoglitazone as a strategy to ameliorate erroneous inflammation

Development of Molecular Chimeras Targeting the NLRP3 Inflammasome and HDAC6

(noch nicht zugänglich / not yet accessible

Lipidic cubic phase crystallization of the adenosine A_2B receptor in complex with antagonists

(noch nicht zugänglich / not yet accessible

Role of the chemokines CCL17 and CCL22 in bacterial infection and IL-33-induced immune responses

The chemokines CCL17 and CCL22 are primarily expressed by dendritic cells (DC) and macrophages. Both chemokines share the receptor CCR4, which is expressed on DC and macrophages as well as on a variety of different T cell subsets, including Th1 cells, Th2 cells, and regulatory T (Treg) cells. As ligands of CCR4, CCL17 and CCL22 recruit T cells, facilitate the T cell-DC interaction, and sensitise DC for migration. However, CCL17 and CCL22 differ in their distinct signaling pathways and functions, a phenomenon that has been termed biased agonism. CCL17 is involved in the induction and enhancement of numerous allergic and inflammatory diseases. In contrast, CCL22 is rather associated with an immunosuppressive environment. Moreover, CCL17 induces migration and activation of Th1 and Th2 cells as well as sensitising DC migration towards CCR7-ligands, whereas CCL22 facilitates the recruitment of Treg cells. In addition, CCL22 shows higher receptor-binding affinity and induces desensitisation and internalisation of CCR4 more rapidly than CCL17. Although CCL17 and CCL22 were extensively studied in allergic, inflammatory, and autoimmune diseases as well as in the tumor microenvironment, their involvement in infectious diseases has not been well described. Furthermore, IL-33 stimulates the production of CCL17 and CCL22 by DC. In the context of Salmonella infection, IL-33 can be produced by intestinal stroma cells after stimulation with bacterial ligands and IL-33 secretion by pericryptal fibroblasts was shown to be directly protective against the infection. Hence, the aim of this thesis was to elucidate the differential function of CCL17 and CCL22 in the context of Salmonella infection and IL-33-mediated immune responses in organs linked to Salmonella dissemination and beyond. Using a vaccination/challenge Salmonella mouse model, wt, CCL17E/E CCL22-/-, and CCR4-/- mice were investigated for their antigen-specific CD4+ T cell response. Vaccinated CCL17E/E CCL22-/- and CCR4-/- mice were less protected against Salmonella challenge, while vaccinated wt mice survived with 100 %, potentially suggesting an impaired recruitment or positioning of CD4+ T cells and a subsequent defect in clearing the infection. In the context of IL-33-mediated immune responses, CCL22 appeared to play a detrimental role in IL-33-induced adipose tissue fibrosis as adipose tissue morphology XII exhibited less signs of inflammation, indicated by fibrosis and immune cell infiltration, in CCL22-deficient mice. Moreover, CCL17 and CCL22 were involved in adipose tissue homeostasis in the inguinal white adipose tissue as well as the brown adipose tissue in the case of CCL22. Absence of CCL17, CCL22, and CCR4 caused eosinophilia in the blood, potentially due to an impaired recruitment of eosinophils from the bloodstream into the tissue. Additionally, while IL-33 impaired bone marrow erythropoiesis independently of the CCL17/CCL22/CCR4-axis and thereby caused extramedullary erythropoiesis in the spleen, CCL22 promoted the expansion of basophilic erythroblasts in the spleen. Lastly, comparison of CCL17E/E CCL22-/- and CCR4-/- mice revealed certain phenotypic differences, suggesting the existence of a second receptor for CCL17 and CCL22. Using a chemokine-based receptor staining approach, it was confirmed that CCR4-deficient T cells in the thymus and spleen were still able to bind both chemokines. A putative second receptor, however, was not involved in mediating chemotaxis as CCR4-deficiency abrogated migration of primary T cells from the thymus and of the T cell lymphoma cell line BW5147.3. In conclusion, uncovering both protective and detrimental functions of CCL17 and CCL22 as well as an additional player in the CCL17/CCL22/CCR4-axis opens new aspects to consider in future applications, disease studies and even therapeutically approaches

Functions and regulation of synaptopodin-2 isoforms under mechanical stress in muscle cells

(noch nicht zugänglich / not yet accessible

The role of glutaredoxin S15 in the transfer of Fe–S clusters and their consumption by lipoyl synthase in Arabidopsis mitochondria

(noch nicht zugänglich / not yet accessible

Nucleic acid sensing in CD8 T cells and NK cells during viral infections

Pathogens can be detected by a variety of germline encoded pattern recognition receptors (PRR) that recognize highly conserved pathogen-associated molecular patterns (PAMPs). Among these receptors, Retinoic Acid-Inducible Gene I (RIG-I), a type I IFN (IFN-I) inducing sensor of cytosolic pathogen-derived RNA, plays a key role in the immune responses to RNA viruses in macrophages and dendritic cells. However, the specific impact of RIG-I activation on lymphocyte function has remained poorly understood. This in vitro study aimed to investigate the role of RIG-I in human NK and CD8 T cells. Activation of RIG-I by influenza A virus infection or the synthetic RIG-I ligand 3p-dsRNA demonstrated that both stimuli resulted in the production of IFN-I, which not only activated these cytotoxic lymphocytes but also significantly enhanced their degranulation and cytokine production. Pre-stimulation by 3p-dsRNA also significantly reduced the ability of influenza A virus to infect these cells. To further investigate the role of RIG-I receptors and the secreted IFN-I stimulated by influenza A infection and 3p-dsRNA, we employed CRISPR/Cas9-mediated gene editing in primary human lymphocytes. This approach demonstrated the involvement of RIG-I and STAT2 in the signalling pathway leading to the activation of cytotoxic lymphocytes. Altogether, the data shows that RIG-I activation not only protects lymphocytes from infection by inducing cell autonomous antiviral pathways in the lymphocytes themselves but also enhances lymphocyte effector function. This research contributes to our understanding of lymphocyte responses to viral infections, emphasizing the importance of RIG-I as a nucleic acid sensor in lymphocyte effector function and raise the possibility of activating RIG-I to enhance their effector function in cellular therapies

Self-organized branching morphogenesis : Study of a related FKPP-system, and a case study of prostate cancer

(noch nicht zugänglich / not yet accessible