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Development of Nuclear In-Situ Sequencing (NIS-Seq) : A method for the identification of immune signalling components by imaging-based functional genomics
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Determinants and correlates of lipid profiles and their relation with human health
No full textLipids are one of the most abundant and diverse molecules in the human body; our lipid profile consists of thousands of unique lipids. Everyone's profile is unique, and is the result of internal processes, genetics, and the external environment. As such, it provides a wealth of information on someone's past exposures, current health, and future disease risk. Indeed, lipids have been linked to various diseases, including cardiometabolic and neurological diseases.
Despite the growing interest in lipids, much remains unknown about this relatively new field, including the determinants of circulating lipids and their effects on human health. In particular, there is a need for cohort studies covering the disease continuum, rather than focusing on a single condition. This thesis uses data from the community-based Rhineland Study to (I) study genetic and environmental factors influencing lipids, and (II) evaluate the relation between lipids and human health.
We reveal novel gene-lipid loci in a genome-wide association study (GWAS), which were validated using gene expression data. Using this data, we provide new insights into the heritability of lipids. Furthermore, we show the impact of toxic human-made chemicals in a study relating per- and polyfluoralkyl substances (PFAS) to lipids. Specifically, even low exposure levels of these toxic chemicals were found to be related to a potentially harmful lipid profile – i.e. a higher lipid content of lipoproteins.
Additionally, we found that a lipid's fatty acid tail was crucial for its effect on biological ageing and brain health. For example, 16-carbon carrying lipids were related to a higher biological age and worse brain health. In contrast, dairy-derived odd-chained fatty acids seemed beneficial. Importantly, we also found sex-specific effects of certain lipids as ceramides were related more strongly to white matter lesions in women than in men.
This thesis provides important insights into determinants of lipids and their health impacts, highlighting the potential in improving disease understanding, prevention and treatment
Agroforestry adoption and adaptation: A farmer-centric case study in Son La, Vietnam
No full textAgroforestry is promoted in northwestern Vietnam for enhancing environmental sustainability and supporting livelihoods, particularly in resource-constrained settings. By integrating trees into agricultural landscapes, agroforestry fosters beneficial economic and ecological interactions, offering a broad array of ecosystem services and environmental benefits. Despite these advantages, the adoption of agroforestry has not reached the level necessary to fully realize the potential benefits. This stagnation can be attributed to inherent uncertainties in agroforestry planning and implementation, which may pose risks for farmers considering its adoption. While research and development programs have concentrated on identifying and mitigating barriers to initial uptake, the adoption of agroforestry is recognized as a non-linear and dynamic process where farmers adapt practices based on their perceptions and circumstances. Using northwestern Vietnam as a case study, this dissertation investigates the multifaceted processes of agroforestry adoption, focusing on the dynamics influencing decision-making among resource-poor farmers and the implications for policy and practice.
The research comprises four main studies, organized in four main chapters:
• Chapter 2 integrates uncertainty into long-term benefit projections for agroforestry interventions by applying Decision Analysis and a probabilistic modeling approach. It reveals that while agroforestry offers promising long-term profitability, high upfront costs combined with uncertainties in discount rate, crop yields and prices significantly affect farmer preferences, often favoring annual monocultures over agroforestry. Addressing these knowledge gaps could enhance decision-making clarity for farmers and offer more targeted guidance for agencies promoting agroforestry adoption.
• Chapter 3 examines the factors influencing agroforestry adoption decisions using an expert-informed Bayesian Network approach. It reveals a complex network of interrelated drivers, with markets and incentives playing a particularly strong role in shaping adoption. Through adoption pathway analysis, the study also explores the diverse trajectories farmers follow, highlighting the adaptive and non-linear nature of the adoption process. The findings underscore the importance of coordinated, holistic strategies, along with sustained support mechanisms that are responsive to farmers' evolving needs and decision-making contexts.
• Chapter 4 employs Q methodology and systems thinking to explore farmers' perceptions and management decisions within the whole-farm context. The analysis reveals three dominant discourses among farmers regarding agroforestry and a shared mental model that reflects their systemic approaches to integrating agroforestry into farm operations. The study highlights the importance of understanding farmers' perspectives and reasoning processes deeply embedded in real-world contexts and offers insights that can inform innovation and policy development.
• Chapter 5 adopts a participatory approach to develop a farm typology that differentiates farmers based on farm structure and agroforestry adoption behaviors. The study identifies three distinct farm archetypes, each characterized by specific constraints, opportunities and support needs related to agroforestry adoption. By combining these archetype profiles with insights gathered from participatory workshops, the study facilitates a more targeted understanding of farmer diversity. The work supports the design of context-specific strategies to address the varying needs of different agroforestry archetypes.
This dissertation underscores the complexity of agroforestry adoption processes. Together, the four studies presented here offer strategic insights for designing support mechanisms that align with the dynamic and varied contexts of smallholder farmers in northwestern Vietnam
Amtliche Bekanntmachungen 56. Jahrgang, Nr. 1
No full textOrdnung zur Änderung der Prüfungsordnung für den Bachelorstudiengang „Chemie“ der Mathematisch-Naturwissenschaftlichen Fakultät der Rheinischen Friedrich-Wilhelms-Universität Bonn vom 22. Dezember 202
q-Hodge filtrations, Habiro cohomology, and ku
Full text linkPeter Scholze has raised the question whether some variant of the q-de Rham complex is already defined over the Habiro ring. Such a variant should then be called Habiro cohomology.
In Part I of this thesis we show that Habiro cohomology exists whenever the q-de Rham complex can be equipped with a q-Hodge filtration: a q-deformation of the Hodge filtration, subject to some reasonable conditions. To any such q-Hodge filtration we associate a small modification of the q-de Rham complex, which we call the q-Hodge complex, and show that it descends canonically to the Habiro ring. This construction recovers and generalises the Habiro ring of a number field from work of Garoufalidis-Scholze-Wheeler-Zagier and it is closely related to the q-de Rham-Witt complexes from previous work of the author.
While there is no canonical q-Hodge filtration in general, we show that such a filtration does exist in many cases of interest. For example, for a smooth scheme X over the integers, a canonical choice of q-Hodge filtration does exist as soon as one inverts all primes up to the dimension of X.
In Part II, we explain how another large class of examples arises from homotopy theory: If R is a quasisyntomic ring which admits an E2-lift to the sphere spectrum, one can use the even filtration on topological negative cyclic homology over the complex K-theory spectra ku and KU to obtain a q-Hodge filtration and the associated q-Hodge complex for R. We also explain how the Habiro descent of the q-Hodge complex can be recovered using genuine equivariant homotopy theory.
In Part III, which is based on joint work with Samuel Meyer, we study a refinement of topological Hochschild/negative cyclic homology (THH/TC-), constructed by Efimov and Scholze as a consequence of Efimov's theorem on the rigidity of localising motives. Using the results from Part II, we'll compute refined TC- in an interesting special case
Programmed cell death regulation during <em>Salmonella</em> Typhimurium infections
No full textProgrammed cell death (PCD) is a highly regulated process that is vital for the development and homeostasis of multicellular organisms. It functions as an essential mechanism to remove dispensable or unfavourable cells in a coordinated manner under physiological as well as pathophysiological conditions. Importantly, this type of cellular suicide also serves as an effective defence strategy to control intracellular pathogens that aim to repurpose host cells as replicative niche and to evade extracellular immune responses. Recent findings indicate that host cells utilise multiple PCD pathways to fight invading pathogens. However, the organisation and regulation of this complex cell death network consisting of pyroptosis, apoptosis and necroptosis and their relative importance for the control and clearance of intracellular infection is not completely understood. In this thesis, we systematically investigated the cellular and molecular requirements for PCD induction and the contribution of different PCD pathways to immunity against intracellular bacteria.
We infected novel genetically modified mouse strains deficient for various combinations of PCD mediators, such as different cysteine-dependent aspartate-directed proteases (caspases), with the bacterial model organism Salmonella enterica serovar Typhimurium (S. Typhimurium) to analyse their ability to control intracellular infections. Additionally, we established in vitro assays to disentangle the complex interactions of the PCD network by analysing the cell death kinetics of bone-marrow derived macrophages obtained from various mouse strains in real-time and determining the intracellular bacterial burden following infection with S. Typhimurium. Our findings unveiled that the PCD pathways pyroptosis and apoptosis are highly interconnected and regulated with a remarkable level of redundancy. We identified that pyroptosis and apoptosis are essential for the control of S. Typhimurium and that molecular components of these pathways, such as caspase-1 and -8, can be used interchangeably to counteract bacterial evasion strategies. Furthermore, we investigated the underlying mechanisms that coordinate the flexible induction of pyroptosis and apoptosis during S. Typhimurium infection. We demonstrated that caspase-2 neither plays a significant primary nor compensatory role in the regulation of cell death and control of intracellular infections. Upon excluding caspase-2 as link between PCD pathways, we evaluated means of extracellular cell death induction. The results presented in this thesis imply critical functions for cytotoxic CD4+ T cells and interferon gamma (IFN-γ) in extrinsic apoptosis induction of S. Typhimurium infected cells.
In conclusion, our results highlight the relative importance, interconnectivity and redundancy of different PCD pathways. This study provides detailed insights into the highly complex network of PCD by unravelling new functions for several of its components and thereby defining novel mechanisms of cell death induction during infections with S. Typhimurium. These findings aid to discover new drug targets and develop novel treatment strategies to fight intracellular infections by enhancing essential host immune responses
Role of TLR2 in immune sensing of gut microbiota in RNA virus induced glomerulonephritis
No full textChronically infected patients with human immune deficiency virus (HIV) are at high risk of developing autoimmune diseases. Despite successful anti-retroviral therapy, autoimmune diseases and renal diseases affect 10–15 % of HIV-infected patients. Due to the lack of appropriate animal models, the pathophysiological mechanisms of HIV-associated glomerulonephritis (GN) remain elusive.
In my thesis, I characterized the murine neoLCMV infection model, which mimics the key hallmarks of HIV infection and allowed me investigating the cellular and molecular mechanisms of HIV-induced GN. Infection of neonatal C57BL/6 mice with the WE-LCMV strain resulted in GN, and reflected most aspects of HIV infection in humans such as, elevated levels of anti-DNA and anti-nucleosome auto-antibodies, cell free circulating DNA and a chronic type I interferons (IFNs) signature. HIV-infected patients suffer from the leaky gut syndrome, which is characterized by the translocation of gut microbiota into the liver, bacterial dissemination and increased inflammation. Clinical investigations in this thesis confirmed elevated levels of leaky gut indicators such as LBP and FABP2, in HIV patients with kidney disease group. These findings were confirmed in the murine neoLCMV infection model. Furthermore, loss of Kupffer cells together with elevated levels of claudin 2 in neoLCMV infected mouse further proved that this mouse model can mimic the leaky gut syndrome found in HIV-infected individuals.
To understand the underlying mechanisms of the leaky gut syndrome, I investigated the role of TLR2 and TLR4, which are known to sense translocated gut microbiota. Loss of TLR2, but not TLR4 resulted in partial protection from GN in neoLCMV-infected mice. TLR2 signaling in neutrophils triggered NETosis which can be the source of self-antigens and might therefore induce autoantibody formation that contributes to LCMV-induced GN. We further provided evidence that neutrophil-recruiting chemokines such as Cxcl2 were produced in a TLR2-dependent manner presumably by macrophages or Kupffer cells in the liver. Cxcl10 expression by hepatocytes, the dominant cell type producing this chemokine, might recruit B cells to the infection site where they encounter NETosis-derived autoantigens, leading to their activation and differentiation to auto-antibody producing plasma cells. Decreased monocyte counts and IL-6 and IL-4 expression in the spleen further indicated the contribution of a Th2 response in LCMV virus-induced GN via TLR2 signaling.
In summary, I could demonstrate how nuclear autoantigens are released by NETosis in the liver of neoLCMV mice and how autoantibodies are induced that can later form deposits in the kidney and thereby contribute to the disease development as a consequence of LCMV infection. Moreover, TLR2 deficiency in the neoLCMV model ameliorated GN and resulted in decreased auto-antibody production. Hence, these findings revealed the importance of TLR2 in the pathogenesis of GN in murine LCMV infection that serves as a model for human HIV infection and its potential contribution to the therapeutic approaches
Recognition of orthoflaviviral RNA in mosquitoes and viral countermeasures
No full textVarious infectious diseases are caused by mosquito-borne orthoflaviviruses affecting people worldwide. Efficient transmission of these viruses highly depends on the pathogen’s ability to overcome the host immune system. Previous studies showed that orthoflaviviruses evade the vertebrate immune system by capping their viral genome via a cap-N1-2’-O-methyltransferase encoded in the non-structural protein NS5. This thesis aimed to analyze whether orthoflaviviruses also escape the insect immune system by modulating their 5’ cap structure via 2’-O-methylation.
Using the yellow fever virus (YFV) vaccine strain (YFV-17D cap1) and a methyltransferase deficient mutant (YFV-17D cap0), this thesis demonstrates that the replication of YFV-17D cap0 is also impaired in mosquito cells. Since YFV-17D is unable to replicate in mosquitoes, a YFV-Asibi cDNA clone was additionally established to compare the respective cap1 and cap0 variants in vitro and in vivo. Similar to YFV-17D cap0, YFV-Asibi cap0 was suppressed in mosquito cells in a Dicer-2 independent manner but to a slightly lower extent. These data indicate that YFV-Asibi counteracts the insect antiviral discrimination mechanism of cap0 RNA. Studies comparing chimeras between YFV-Asibi and YFV-17D aimed to pinpoint the viral genes responsible for counteracting the discrimination mechanism. The results suggest that a synergy of several non-structural proteins is involved in this mechanism. In the case of YFV, the counteraction seems to be linked to a faster viral replication at early time points.
Furthermore, after oral infection of Aedes aegypti mosquitoes, YFV-Asibi cap1 replicated in the mosquito midgut and secondary tissues like legs plus wings. Conversely, replication of YFV-Asibi cap0 was suppressed in the midgut and nearly blocked in secondary tissues. Intriguingly, efficient replication of YFV-Asibi cap0 occurred after intrathoracic infection, indicating the existence of a potential receptor or protein discriminating between cap1 and cap0 RNAs in the midgut or the midgut barrier.
Since the methyltransferase is highly conserved between orthoflaviviruses, DENV cap0 was established as well. Comparative growth curve kinetics revealed that DENV cap0 replication is not suppressed in mosquito cells, implying that DENV also counteracts the insect antiviral discrimination mechanism of cap0 RNA but more strongly than YFV-Asibi.
In summary, the obtained results suggest the existence of an innate 5’ RNA-modification recognizing effector protein in mosquito cells and mosquitoes. Further, orthoflaviviruses counteract this effector protein by different means, leading to different levels of cap0 virus replication
Influence of Cross Linking on the Stability of Functional Emulsion-Derived Polymer Films
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Development of intracellular ligands and targeted protein degraders for chemokine receptors and histone deacetylases
Full text linkChemokine receptors are a subfamily of G protein-coupled receptors (GPCRs) that play a crucial role in the immune system by regulating the migration and positioning of immune cells. They are involved in various physiological and pathological processes, including inflammation, infection, and cancer. Among these receptors, CXCR1, CXCR2, CCR6, and CCR7 have emerged as attractive therapeutic targets due to their roles in immune cell trafficking, tumor progression, and autoimmune diseases. Traditional antagonists have often targeted extracellular sites, but recent studies have highlighted the significance of intracellular allosteric binding sites (IABS), which offer new opportunities for more selective and effective modulation of receptor function.
PROTACs (Proteolysis Targeting Chimeras) represent a novel class of small molecules that induce the degradation of target proteins rather than inhibition. They act by recruiting an E3 ubiquitin ligase to the protein of interest (POI), leading to its ubiquitination and subsequent degradation by the proteasome. This catalytic mechanism offers advantages such as sustained protein knockdown and the potential to target previously “undruggable” proteins. Recently, strategies like PHOTACs (light-controllable PROTACs) have been developed to allow precise spatial and temporal control of protein degradation.
This work aimed to develop novel intracellular allosteric antagonists for the chemokine receptors CXCR1, CXCR2, CCR6, and CCR7. To achieve this, structural modifications were made to two established scaffolds: the squaramide-based structure of navarixin and the thiadiazole-1,1-dioxide scaffold of Cmpd2105. Modifications were done at different molecular regions to generate detailed structure–activity relationship (SAR) data on the affinity and selectivity of the synthesized compounds. Additionally, a propargylamide moiety was introduced to enable late-stage functionalization of the antagonists.
A key focus of the project was the development of NanoBRET-based binding assays. For this purpose, the modified antagonists were functionalized with a TAMRA fluorophore. To this end the chemokine receptors were fused with a nanoluciferase to allow for intracellular binding studies. The NanoBRET system enabled the identification of intracellular allosteric antagonists by measuring the displacement of the fluorescent tracer, resulting in a reduced BRET signal. This platform was used to evaluate both the binding affinities and the receptor selectivity of the synthesized compounds.
The most effective antagonists from each scaffold were then used as protein-of-interest (POI) ligands in the synthesis of PROTACs (proteolysis targeting chimeras). Two PROTAC libraries were developed: one explored various cereblon-targeting thalidomide derivatives to study the influence of the E3 ligase ligand, and the other focused on modifying linker flexibility and physicochemical properties to improve degradation efficiency.
The last part of this project focused on the PHOTAC strategy to achieve precise spatiotemporal control of protein degradation. Three HDAC6 targeting PHOTACs were designed, based on the A6 PROTAC and incorporating a photoswitchable lenalidomide-based recruiter. These PHOTACs were tested for their ability to undergo light-induced trans-to-cis isomerization and were evaluated by western blot for their degradation efficiency in both light-activated and inactive states. This approach demonstrated the potential of light-controlled protein degradation for therapeutic applications