We present a compactification of the moduli space of principal $G$-bundles on higher-dimensional complex projective manifolds, which extends the algebro-geometric construction of Balaji of the \it Donaldson--Uhlenbeck \rm compactification. This is achieved by considering semistability calculated with respect to a multipolarization on a projective $n$-fold, consisting of $n-1$ ample integral divisor classes. Moreover, given a curve $C$ that arises as the complete intersection of $(n-1)$ very ample divisors associated with the multipolarization, we construct a modular compactification of the moduli space of principal bundles that are slope-stable with respect to $C$. Furthermore, the geometry of the newly constructed moduli spaces is described by relating them to \it Gieseker \rm moduli spaces.

Proteins are essential for cellular function and for the health of an organism in general. However, their dysfunction can potentially lead to diseases, making them diagnostically informative biomarkers that provide insights into biological processes and various disease mechanisms. Liquid chromatography-mass spectrometry (LC-MS) enables large-scale identification and quantification of proteins, demonstrating immense potential in clinical studies. Discovery LC-MS approaches profiles proteomes, identifies potential biomarkers, which can then be translated into biomarker panels for routine-applicable, absolute quantified targeted approaches. However, challenges such as insufficient quantification and comparability of high-throughput techniques hinders the widespread application of LC-MS in clinics. This thesis addresses these challenges by advancing technologies and integrating discovery and targeted proteomics to achieve a tangible solution that balances sensitivity, selectivity, as well as comparability between platforms with cost efficiency. After an introduction (Chapter I) to the topic, Chapter II introduces the Zeno SWATH method, which improves throughput and analytical coverage while minimising sample input and thus costs. Chapter III describes the development and application of a targeted LC-MRM biomarker panel for the stratification of disease severity and prognosis of COVID-19 plasma cohort. In Chapter IV, discovery and targeted proteomics were employed for the first plasma proteomics analysis of Mpox, demonstrating the value of LC-MS in meeting urgent clinical demands and the versatility of LC-MRM biomarker panel in diverse diseases. To harmonise quantification between LC-MS platforms and methods, Chapter V develops the ‘Charité Open Peptide Standard for Plasma Proteomics (OSPP)’, a panel of 211 stable isotope-labelled peptides, which enables cross-platform comparability at minimal cost and high sample throughput in large-scale clinical plasma-based studies. Overall, this thesis advances LC-MS technologies for blood biomarker studies and their clinical applications, providing tangible solutions for clinical proteomics by introducing streamlined workflows and universal biomarker panels that are adaptable across diseases and analytical platforms, bringing proteomics closer to routine clinical applications.

One Health emphasizes the interconnectedness of animal, human and environmental health. The emerging risk of zoonotic and antibiotic-resistant bacteria in fattening poultry is a significant concern for public health and consumer protection. This underlines the necessity for an integrated approach and comprehensive strategies that encompass veterinary, public health, and environmental perspectives. This thesis comprehensively examines the spread of zoonotic and antibiotic-resistant bacteria among animals, within their immediate environment, and throughout the surrounding areas of barns, as well as other stages in the production chain. Initially, we focused on methicillin-resistant Staphylococcus aureus (MRSA) and later expanded our research to extended-spectrum beta-lactamase/ plasmid-mediated AmpC beta–lactamase Escherichia coli (ESBL-/pAmpC- E. coli). The rising number of antimicrobial resistance (AMR) was and is a highly relevant issue in human and veterinary medicine worldwide. This thesis describes transmission routes for the selected resistant bacteria in broiler chickens and turkeys. The focus is on their spread into the environment as well as their (re-)introduction into herds and their transmission across the broiler production chain. This involved analyzing many different environmental and animal samples. Subsequently, we explored Campylobacter transmission pathways within broiler chicken farms, considering the farm environment. Campylobacteriosis is the most frequently reported foodborne illness in the European Union (EU) in 2021. Across all studies, we conducted additional investigations on isolates from different habitats such as pulsed-field gel electrophoresis (PFGE) or whole genome sequencing (WGS) to reveal epidemiological links. The findings of all 10 publications within this thesis are thematically summarized into two main categories: 1. the dissemination in the environment via air or dust and through fecal associated matrices on broiler chicken and partly turkey farms, and 2. the transmission across the production chain in broiler chickens. The results of the studies show that these bacterial species enter the environment of the farms and can thus be a source of spread or (re)-entry into the production chain. They also illustrate the different behavior of the various bacterial species and show that spread scenarios can occur simultaneously at different stages of the production chain. ESBL-/pAmpC- E. coli pose a significant risk of contamination from feces. Further investigations of the isolates proved a pseudo-vertical transmission of ESBL-/pAmpC- E. coli via contaminated egg surfaces from the parent flock through the hatchery to the fattening flock, and a horizontal transmission between consecutively fattened flocks. Furthermore, the resistant bacteria persist in the barn, surviving even intensive cleaning and disinfection (C&D) measures inside the barns and thus represent a source of colonization for subsequent animals. This shows the crucial role of C&D measures. Critical points for controlling C&D in broiler houses were identified, which should receive more attention in the future. Fragile building structures and mobile equipment are particularly important. Contrarily, MRSA transmission in the environment is less linked to fecal emissions and probably more so to the release of bioaerosols. Investigations revealed that MRSA with the same staphylococcal protein A (spa) types were present on ground surfaces surrounding the barns, sporadically in ambient air samples, in animal samples, and in dust and air samples from inside the broiler chicken and turkey houses. This indicates that MRSA can spread to the outside via the barn air, sediment and persist on the ground. At the time of the study, these were the first investigations on this topic in poultry farming. Thermophilic Campylobacter, similar to E. coli, colonizes the gut. Campylobacter spp. were sporadically found in environmental samples from chicken farms at low concentrations within this thesis. Despite the limited sample size, whole-genome analyses of various isolates revealed a high similarity between those obtained from puddles and water retention basins in the outdoor area and those from the indoor area of the barn, including air samples. Identifying dominant transmission pathways proved challenging, nevertheless, potential scenarios were demonstrated. For the first time, investigations of the the presence of Campylobacter in the viable but non-culturable (VBNC) state, both within the barn and in the surrounding environment, revealed that VBNC Campylobacter (C.) jejuni was predominantly detected in boot swab samples collected from ground surfaces around Campylobacter-positive farms. This was achieved using viability quantitative polymerase chain reaction (v-qPCR) after propidium monoazide (PMA) treatment. Intensive sampling, detailed analysis of isolates, and careful evaluation of metadata are crucial for accurately describing transmission routes. Applying modern methods to analyze and compare isolates from various habitats, which were not available during the initial studies of this thesis, promises to yield further insights. While this work focuses on specific environmental aspects of conventional fattening poultry houses, the One Health concept opens up additional interesting areas for future research, in particular concerning different animal housing systems.

Genome function relies on the dynamic regulation of chromatin, encompassing both its structural organization and epigenetic landscape. This thesis explores the roles of two crucial chromatin regulators, the chromatin remodeler HELLS and the structural protein complex cohesin, in safeguarding chromatin integrity and modulating genome function. In the first part of this work, we explore the role of HELLS in regulating DNA methylation in human pluripotent stem cells. Through genome-wide profiling of DNA methylation and chromatin accessibility in HELLS knockout cells, we reveal that HELLS is indispensable for maintaining DNA methylation, particularly at pericentromeric satellite repeats across all chromosomes, though not all classes are equally affected. Beyond these repeat regions, HELLS plays a broader role in sustaining global DNA methylation. It appears to act in synergy with DNMT3A and DNMT3B to maintain methylation levels, especially in compact chromatin regions where DNMT1-mediated maintenance is less efficient. Despite substantial disruptions to the chromatin landscape, human pluripotent stem cells exhibit a remarkable resilience to HELLS depletion, maintaining their ability to differentiate into all three germ layers. In contrast, HELLS knockout in mice results in more severe DNA methylation defects, emphasizing the critical developmental role of HELLS with perinatal lethality as a consequence of its absence. In the second part of this thesis, we investigate the role of cohesin in enhancer-promoter interactions by analyzing how the absence of cohesin impacts 3D chromatin contacts and enhancer function. Our findings reveal that enhancer-promoter contact frequency directly modulates gene expression, with cohesin loss significantly reducing enhancer-driven transcriptional activity. Notably, distal enhancers are particularly dependent on cohesin, exhibiting substantial decreases in activity upon cohesin depletion, whereas proximal enhancers remain largely unaffected. These results highlight the crucial role of cohesin in facilitating distal enhancer-promoter interactions and highlight the consequences of disrupting these interactions on gene expression. Interestingly, we find that most genes are regulated by proximal enhancers, which explains why the global transcriptional impact of cohesin loss is relatively modest. Only genes reliant on cohesin-dependent distal enhancers experience transcriptional changes, broadening our understanding of the relationship between chromatin architecture and enhancer function.

This paper examines the evolution and implementation of North Korea's digital distance education (DDE) system, tracing its historical trajectory from its foundational roots under Kim Il Sung to its institutionalization under Kim Jong Un. While the global COVID-19 pandemic has accelerated the adoption of digital learning worldwide, North Korea’s DDE system reflects over two decades of strategic planning and development, making it a cornerstone of the nation’s knowledge-based economy initiative. The study explores the motivations behind North Korea’s sustained investment in DDE, emphasizing its integration into the state’s broader socio-economic framework. Underpinned by policies promoting the informatization of education and the development of human resources in science and technology, DDE emerged as a critical tool for addressing urban-rural disparities, enhancing workforce skills, and modernizing various sectors, including healthcare, economic management, and epidemic prevention. Far from being an isolated response to the pandemic, DDE reflects a deliberate strategy to align education with national development goals, as evidenced by the adoption of the Distance Education Law and the expansion of DDE to millions of learners. Using an analytic framework, this paper examines the major components of North Korea’s DDE system, including discourse and policy, partnerships, technological infrastructure, curriculum development, student support services, and assessment mechanisms. It highlights the system’s flexibility in adapting to challenges, such as economic sanctions and the pandemic’s constraints, through innovative solutions like real-time distance lectures, localized learning platforms, and multimedia resources. Additionally, the paper explores how DDE principles were applied beyond education to other fields, demonstrating its role in North Korea’s digital transformation strategy. By analyzing DDE's historical evolution, the paper challenges oversimplified narratives that portray North Korea’s digital education efforts as reactive measures to crises. Instead, it positions DDE as a forward-looking initiative shaped by long-term planning and a vision for societal modernization. This study contributes to a nuanced understanding of how North Korea has leveraged digital education not only as a means of learning but as a strategic tool for national development.

Die Lungenseuche des Rindes, verursacht durch Mycoplasma mycoides subsp. mycoides (Mmm), ist eine bedeutende Respirationskrankheit der Rinderartigen. Ziel dieser Studie war es, erste Mechanismen des Immunsystems der bovinen Wirtszelle nach Kontakt mit Mmm darzulegen, um gezielte weiterführende Untersuchungen zu ermöglichen. Hierzu wurden sowohl eine permanente bovine Lungenepithelzelllinie (EBL) als auch über magnetische Zellseparation aufgereinigte bovine CD14+ -Zellen mit Mmm und seinem nächsten Verwandten Mycoplasma mycoides subsp. capri (Mmc), ein Pathogen kleiner Wiederkäuer, ko-kultiviert. Die Dauer der Ko-Kultur betrug für die mit den EBL-Zellen durchgeführten Experimente 4 h und 24 h. Die CD14+ -Zellen wurden für 24 h mit Mmm bzw. Mmc ko-kultiviert. Zusätzlich wurde der Einfluss der Ko-Kultur mit dem jeweiligen Mykoplasmenstamm auf die Zellvitalität bestimmt und eine Duplex qPCR etabliert, um die Erreger-Wirtszell-Ratio zu bestimmen. Anschließend wurden die durch die Ko-Kulturen induzierten Transkriptomveränderungen ausgewertet. Sowohl die Mykoplasmen des verwendeten Mmm-Stamms, Afadé, als auch die Mykoplasmen des verwendeten Mmc-Stamms, Y-Goat, adhärierten an den bovinen Zellen. Unabhängig von der Wirtspezifität der Mykoplasmen wurde eine hohe Anzahl ähnlich regulierter Transkripte nach Kontakt der EBL-Zellen sowie der CD14+ -Zellen mit Mmm bzw. Mmc nachgewiesen. Es wurde eine proinflammatorische Antwort initiiert und auch das angeborene Immunsystem aktiviert. Die hervorgerufenen Transkriptomveränderungen waren in beiden verwendeten bovinen Zelltypen in der Ko-Kultur mit Mmm deutlich stärker ausgeprägt als in der Ko-Kultur mit Mmc. Die mit Mmc ko-kultivierten Zellen zeigten keinen Zellvitalitätsverlust. In der Ko-Kultur mit Mmm verringerte sich die Zellvitalität sowohl der EBL-Zellen als auch der CD14+ -Zellen um etwa 30 %. Durch die Analyse der Transkriptregulation, welche beide Stämme auslösten, wurden Gemeinsamkeiten in der durch die Ko-Kultur induzierte Wirtsantwort gezeigt. Beide Mykoplasmen schienen einen intensiven Kontakt zur bovinen Lungenepithelzelle aufgebaut zu haben. Es wurden Transkripte, welche in die Cholesterol-Biosynthese involviert sind, sowie Transkripte für verschiedene Membrantransporter hochreguliert. Es ist zu vermuten, dass beide Mykoplasmenstämme Nährstoffe aus der bovinen Zelle bezogen. Die gemeinsame Antwort war durch eine Aktivierung des angeborenen Immunsystems und der Aktivierung sowie Rekrutierung Neutrophiler gekennzeichnet. Es kam zu oxidativem Stress, welchem sinnvoll entgegen reguliert wurde. Um die Zellintegrität zu erhalten, wurden DNA-Reparatur- und Apoptose-Mechanismen eingeleitet. Es wurden Transkripte reguliert, welche eine antiinflammatorische Immunantwort initiieren könnten. In der Ko-Kultur der EBL-Zellen mit Mmc wurden Transkripte reguliert, welche zunächst zu einem Zellzyklusarrest führen könnten. Es erfolgte ein kontrollierter Umgang mit Zellschäden. Durch die Herunterregulation verschiedener Tumorsuppressor-Transkripte und Verstärkung der negativen Regulation des programmierten Zelltods wurde das Zellwachstum gefördert und die Integrität der Epithelzellschicht blieb erhalten. Diese Ergebnisse lassen vermuten, dass die EBL-Zellen adäquat auf die Ko-Kultur mit Mmc reagierten und es in der Folge nicht zu einem Zellvitalitätsverlust kam. Bei der Ko-Kultur mit Mmm hingegen konnte keine gezielte Orchestrierung der Immunantwort beobachtet werden. Bereits nach 4 h war neben einem ausgeprägten DNA-Schadensstimulus und dem damit verbundenem Zellzyklusarrest und der Apoptose eine starke proinflammatorische Antwort zu erkennen. Diese blieb auch nach 24 h Ko-Kultur bestehen. Neben der deutlichen Aktivierung und Rekrutierung Neutrophiler wurden Transkripte für die Aktivierung weiterer Effektorzellen reguliert. Es schien zu einer überschießenden Immunantwort zu kommen. Diese war sowohl in eine Th1- als auch in eine Th17-Antwort involviert. Sowohl die Ko-Kultur mit dem ziegenpathogenen Mykoplasmenstamm Mmc als auch die Ko- Kultur mit dem rinderpathogenen Mykoplasmenstamm Mmm führten zu einer ausgeprägten Immunantwort der bovinen Monozyten. Die mykoplasmenspezifische Antwort der CD14+ - Zellen zeigte sowohl proinflammatorische und bakterizide Aspekte als auch eine sinnvolle antiinflammatorische Seite mit Schutz vor Dysregulation des Immunsystems und unkontrollierter Entzündung. Ein Teil der herunterregulierten Transkripte könnte ein mykoplasmen-induzierter Schutzmechanismus zum Umgehen der Immunantwort des Wirtes sein. Es wurden verschiedene Transkripte, welche für Gene, die die Aktivierung und die Anlockung von Neutrophilen codieren, herunterreguliert. Auch die mRNA-Mengen von anti- viral und anti-bakteriell wirksamen Transkripten waren sowohl in mit Mmm als auch in mit Mmc ko-kultivierten CD14+ -Zellen herunterreguliert. Die Mmc-spezifische Antwort der CD14+ -Zellen war sehr gering und die Veränderungen in der Transkriptregulation waren von geringer Intensität. Mmc schien keine weitere Bedrohung darzustellen, die eine besondere Abwehr benötigte. Im Fokus der Transkriptregulation lag die Aufrechterhaltung des Zellzyklus. Hingegen war die Antwort der CD14+ -Zellen auf die Ko-Kultur mit Mmm die bei allen Experimenten am stärksten ausgeprägte Reaktion. Dies betraf sowohl die Anzahl der regulierten Transkripte als auch deren Regulationsintensität sowie die Anzahl der detektierten angereicherten biologischen Prozesse. Die Mmm-spezifische Antwort war von einer großen Anzahl proinflammatorischer Zytokine geprägt. Die Aktivierung, das Wachstum sowie die Migration von Neutrophilen waren hierbei wichtige Facetten. Ein Teil der regulierten Transkripte interagierte auch mit T-Zellen, B-Zellen und dendritischen Zellen. Der Großteil der proinflammatorischen Zytokine wies auf eine überschießende Immunantwort hin. Dieser standen einzelne antiinflammatorische Transkripte gegenüber. Die Ko-Kultur mit Mmm führte zu ausgeprägten Zellschädigungen mit Stress des endoplasmatischen Retikulums sowie pro- und anti-apoptotischer Zellzyklus-Regulation. In der Ko-Kultur der CD14+ -Zellen mit Mmm waren verschiedene biologische Prozesse angereichert, welche die Antwort auf ungefaltete Proteine (UPR) betreffen. In den Ko-Kulturen der bovinen Epithelzelllinie waren hingegen sowohl in mit Mmm als auch in mit Mmc ko-kultivierten EBL-Zellen biologische Prozesse, welche in die UPR involviert waren, angereichert. Die Ergebnisse dieser Arbeit zeigen, dass sowohl Lungenepithelzellen als auch bovine Monozyten in zukünftige immunpathologische Betrachtungen zur Lungenseuche der Rinder einbezogen werden sollten.

Background Women are at two to three times higher risk of developing posttraumatic stress disorder (PTSD) compared to men. However, systematic knowledge about the mechanisms underlying this risk difference is lacking. Therefore, the aim of the present dissertation was to take a sex- and gendersensitive perspective on PTSD development to increase our systematic understanding of sex and gender aspects in PTSD etiology. Methods Summarizing prospective studies on PTSD development, study 1, a systematic review and meta-analysis, examines how sex and gender aspects are currently considered in trauma research. Study 2 introduces a systematic framework to disentangle how three distinct sex/gender-related pathways might contribute to sex/gender differences in PTSD risk. Using data from n = 2924 acutely traumatized individuals (61.8% female, 38.2% male) study 2 examines pathway (a) sex/genderdependent prevalence/severity differences in PTSD risk factors. Using the same data set, study 3 explores pathway (b) sex/gender-dependent vulnerability differences to PTSD risk factors. Analyzing data from clinical interviews with n = 182 individuals with an unintended pregnancy, study 4 presents as an example for considering pathway (c) sex/gender-specific aspects in PTSD etiology. It investigated how experiences of childhood maltreatment are associated with changes in PTSD symptoms from pre- to post-pregnancy. Study 5 is the first systematic review and meta-analysis that examines how women and men differ in risk factors for PTSD. It leverages the proposed framework towards meta-analytic evidence and investigates all three of the proposed pathways collectively. Study 6 broadens the perspective on geographic and gender diversity by comparing trauma-related symptoms among women, men, and non-binary participants from six world regions (k = 115 countries, n = 8675). Results Examining the status quo of sex and gender considerations in prospective trauma research, study 1 revealed various shortcomings along the research process, including – amongst others – an underrepresentation of women in high-quality research on PTSD development as well as a lack of analyses suited to examine the mechanisms underlying this sex/gender difference in PTSD risk. Investigating the role of sex/gender in risk pathways, results of study 2, 3 and 5 paint a coherent picture. While women showed greater prevalence/severity of PTSD risk factors, they did not appear to be more vulnerable to risk factors than men. On the contrary, for some risk factors men showed stronger associations with later PTSD symptoms than women. Sex-/gender-specific issues were found to be particularly understudied (study 2, 3 and 5), although they might be highly relevant. Here, study 4 revealed that almost one in five participants listed traumatic childbirth as their index trauma. Finally, study 6 illustrated that not only women, but also gender minorities, are at increased risk of severe trauma-related symptoms, as well as sexual and physical assault. Discussion The collection of studies presented in this dissertation contributes to advancing our understanding of women’s higher PTSD risk as well as further sexand gender-related aspects in PTSD development. The results illustrate that considering patient heterogeneity can foster our understanding of differential risk mechanisms. Such knowledge can inform personalized clinical psychological interventions that take into account individual patient characteristics to optimize intervention plans and outcomes. Against this background, this dissertation advocates for a greater consideration of sex- and gender-sensitive as well as intersectional perspectives to mitigate existing health disparities and to ensure that all individuals receive optimal care.

Data is the fundamental resource required for training deep learning models. The availability and collection of massive datasets, combined with increasing computational power, has enabled the training of large models that learn complex tasks with human-level proficiency. However, the abundance of data is not universal across all domains. This thesis addresses data scarcity issues in deep learning, focusing on two domains: medicine and recommender systems. In medicine, data scarcity stems from the prohibitive costs of annotating medical data for model training and stringent privacy regulations that limit data sharing. Conversely, recommender systems face cold-start problems, which arise when a new user or item enters the system without sufficient historical data for informed recommendations. To reduce the dependency on costly electrocardiogram (ECG) annotations for training heart arrhythmia classifiers, we employed transfer learning methods to teach the models foundational knowledge about ECG signals. We developed novel pre-training tasks to acquire this knowledge using one of the largest public ECG databases. By fine-tuning these pre-trained models on small datasets, we improved performance across specialized ECG classification tasks by up to +6.57% over models trained from scratch. To address privacy concerns regarding data sharing, we employed federated learning, which enables collaborative model training among medical institutions by sharing locally computed updates to the model instead of raw training data. In a large study using a diverse collection of ECG databases, we demonstrated that ECG classifiers trained via federated learning outperform models trained in isolation on local data. Furthermore, on out-of-distribution data from foreign institutions, these classifiers nearly match the performance of models trained with shared data. Addressing item cold-start issues in sequential recommender systems, we developed a novel dynamic storage model that maintains a latent memory of user-item interactions without requiring gradient updates or side information, ensuring efficient representation and timely recommendation of new items during inference. Our proposed model outperforms a similar approach by more than 29% on recommendation tasks and demonstrates the ability to adapt to entirely new datasets without any fine-tuning in zero-shot transfer scenarios. Collectively, our contributions tackle various data scarcity issues in selected domains, advancing contemporary deep learning methodologies in data-limited scenarios.

Alzheimer’s disease (AD), the most common cause of dementia, was the seventh-leading cause of death globally in 2021. As of 2023, dementia affected approximately 55 million people worldwide. AD is a slow-progressing neurodegenerative disorder that primarily impacts memory, cognitive abilities, and daily functioning. The two main pathological hallmarks of AD are extracellular amyloid-beta deposition, forming neuritic plaques, and intracellular hyperphosphorylated tau accumulation, resulting in neurofibrillary tangles (NFTs). These pathological features are believed to drive the degenerative processes in the brain. Emerging evidence highlights the medial temporal lobe as the earliest brain region affected by AD, particularly through the formation of NFTs. As the disease progresses, the associated damages spread throughout the brain in a predictable pattern of distribution. AD is a multifactorial and highly complex disorder, with numerous contributing factors that complicate the understanding of its mechanisms and hinder the development of effective treatments. Bridging these knowledge gaps remains a critical goal in AD research. In this study, I employed systems biology approaches, specifically gene co-expression network analysis, to investigate the complexity of gene interactions underlying AD pathology. Particular focus was placed on long non-coding RNAs (lncRNAs), which remained poorly characterized in the context of AD despite their potential regulatory roles. Additionally, I explored how disease progression is reflected at the level of gene networks between the temporal cortex and frontal cortex. RNA-seq data from two independent studies were used, comprising five datasets with a total of 396 individuals from two human brain regions: the temporal cortex and frontal cortex. Weighted topological overlap was applied to construct gene co-expression networks, and their reliability was enhanced by integrating them into consensus networks. The study aimed to uncover critical genes, pathways, and molecular mechanisms contributing to AD pathology. Differential co-expression analysis revealed significant network rewiring under AD conditions, with shifts in hub genes and the emergence of new key players specific to the disease. Region-specific differences were observed, with the temporal cortex exhibiting more pronounced network alterations compared to the frontal cortex, consistent with the established progression of AD pathology. The temporal cortex showed significant adaptive rewiring of gene interactions, whereas the frontal cortex predominantly displayed a loss of healthy correlations, reflecting different stages of vulnerability and compensation in these brain regions. In the temporal cortex, 46 protein-coding genes were identified as occupying critical positions in the AD network, potentially contributing to the observed disruptions and extensive rewiring. A key objective of this study was to predict lncRNA functions and their associations with AD. The Random Walk with Restart (RWR) algorithm was applied to infer potential functions for lncRNAs by evaluating their proximity to functional protein-coding genes. Using this approach, more than 100 lncRNAs were assigned to biological processes under both AD and non-AD conditions. Of these, 27 lncRNAs were identified as potential key players in AD pathology within the temporal cortex. These findings offered a more comprehensive understanding of the molecular interactions in AD and presented new candidate protein-coding and lncRNA genes for future experimental validation and therapeutic exploration.

This thesis proposes a novel approach for controlling and optimizing the optoelectronic properties of single-walled carbon nanotubes (SWCNTs) through functional groups for covalent functionalization and, ultimately, building photonic devices at the nanoscale. The carbon nanotube community demonstrated through decades of experiments the exceptional optoelectronic properties of SWCNTs. Semiconducting SWCNTs specifically have transitions that allow near infrared (NIR) fluorescence experiments for imaging purposes. To safeguard the fluorescence properties of the nanotube, Setaro et al. developed the first nondestructive covalent π-preserving functionalization (NCF) of SWCNTs using electron poor aromatic nitrenes (based on trichlorotriazine, called triazine in the following) via a [2+1] cycloaddition reaction in 2017. With additional spiropyran photoswitching groups, they could reversibly shift the Fermi level and facilitate charge transfer without introducing defect states that localize excitons, but preserving their diffusion along the tube. The functionalization approach required to replace the chlorine atoms of the grafted triazine already on the nanotube sidewall with molecular species (e.g. the spiropyran switch). The number of attached switches on the triazine could not be precisely controlled, making it challenging to obtain reproducibly a specific concentration of charges transferred between the nanotube and the organic molecule for optimal optoelectronic features. In this thesis, I worked on changing the synthetic approach of the molecular species attached on the SWCNTs in a fundamental way. Instead of attaching the targeted molecular species onto triazine on the SWCNTs, I developed a pre-functionalization strategy, in which I designed novel triazine derivatives with the desired chemical species replacing one or two chlorine atoms before grafting them onto the tubes. In this way, a successful grafting of the triazine onto the SWCNTs automatically ensures the presence and number of desired chemical species attached within the functional hybrids. I synthesized, characterized, and studied a defined set of charge transfer agents (CTAs) with a cyanuric chloride (triazine) backbone and varying substituents number and orientation that can withdraw or donate charges to the SWCNTs. The correlation between the optical properties and functionality of these CTAs was studied through experiments and simulations. Using the NCF approach, I covalently functionalized SWCNTs with these CTAs without destroying the sp2 crystalline network of the tube. Depending on the structural design of the CTAs, I observed the Fermi level position of the SWCNTs shift up or down by donating or withdrawing charges, as observed by Raman and XPS spectroscopy and confirmed by DFT predictions. As a result, the fluorescence intensity of the nanotubes is either quenched or enhanced, as evidenced by photoluminescence experiments. Effect of the reaction temperature used in the covalent functionalization strategy was also examined. Using only triazine molecule on SWCNTs, the impact of the functionalization temperature was found to directly influence the density of triazine molecules covalently attached to the SWCNTs, with 1 triazine molecule to 24 carbon atoms of the SWCNT at 150 oC and 1 triazine molecule to 155 carbon atoms of SWCNT at 25 oC. Across this temperature range, Raman studies at 638 nm laser pump show no increase of defectivity in the nanotube’s sp2 π network, as indicated by ID/IG ratios, while safeguarding the emission of different nanotube species in the photoluminescence spectra. The last part of this thesis builds upon the same pre-functionalization strategy and involves the stepwise synthesis of a novel photoactive triazine-spiropyran molecular complex, (1'-(4,6-dichloro-1,3,5-triazin-2-yl)-3',3'-dimethyl-6-nitrospiro[chromene-2,2'-indoline]), by attaching electron poor triazine to the nitrogen position of indoline moiety. Single crystal XRD and other spectroscopic analysis confirm the successful synthesis of triazine-spiropyran complex. UV absorption experiments show that triazine substituent strongly impacts the optical response of the complex during isomerization. Protonation followed by UV irradiation resulted in decreased absorptivity and appearance of a new absorption band at 390 nm. Subsequently, I covalently functionalized the triazine-spiropyran complex onto the SWCNTs, with Raman ID/IG ratios (measured using a 638 nm laser pump) indicating the preservation of the nanotube’s sp2 π-conjugated network. Activation of the triazine-spiropyran functionalized SWCNTs using UV photons induces reversible change in the nanotube’s EF, leading to ~52 % emission quenching, which is reversed upon thermal activation.

Cancer is among the leading diseases and causes for deaths worldwide. Even with a rise of treatment options in the last century, cancer therapy can still be limited and insufficient due to side-effects and drug resistances. Therefore, novel approaches have to be explored to overcome these limitations. In recent years, the development and application of antibody-drug conjugates, a combination of a highly cytotoxic payload with a target specific monoclonal antibody, have been receiving increasing attention. The majority of employed payloads in these antibody-drug conjugates can be considered as natural products or derivatives of these. Natural products make an important source for the development of novel anti-cancer drugs. Recently, microcystins, cyanobacterial cyclic heptapeptides, have been discussed as leads for the development of anti-cancer drug substances. Microcystins exhibit a high target toxicity by inhibiting eukaryotic serine/threonine protein phosphatases 1 and 2A. Unlike many cytotoxins that can cross cell membranes by passive diffusion, they depend on active uptake via organic anion transporting polypeptides 1B1 or 1B3, which are especially expressed by liver cells. This leads to a hepatotoxicity of microcystins and might limit the direct use of natural occuring microcystins as payloads. The aim of this thesis was to find optimized microcystins for use as payloads in antibodydrug conjugates. To maximize effectivity in targeted cells while reducing side-effects through uncontrolled uptake, these derivatives should display a high protein phosphatase inhibition potential but an overall low uptake by their transporters. As both phosphatase inhibition and transportability strongly depend on the structure of the individual microcystin, so-called clickable microcystins were modified with chemically diverse small molecules using click chemistry and tested for their bioactivity. A workflow for synthesis of new microcystins derivatives, structural confirmation, isolation, and quantification was developed. Two different kinds of click reactions, coppercatalyzed and strain-promoted, were used for synthesis. Different chromatographic approaches were chosen depending on the chromatographic issue, including solid-phase extraction, preparative, semi preparative, and analytical HPLC. Also, different detection methods depending on the analytical problem were used, e.g., mass spectrometry and tandem mass spectrometry for structural confirmation and an evaporative light-scattering detector for structure-independent quantification. 46 new microcystin derivatives were obtained and characterized through this workflow. In a second step, the influence of the small molecules on the bioactivity profile of microcystins was evaluated: an already established cytotoxicity assay was used to test for transportability, and a protein phosphatase 1 inhibition assay was established to test for target toxicity. The inhibition assay was complemented by a pharmacophore modeling approach. The results revealed that target inhibition and transportability of microcystins can independently be influenced by the physicochemical properties especially of the residue located in position 2 of the microcystin. The selectivity of the two transporters was evaluated to understand similarities and differences in substrates. Moreover, a ratio of transportability over inhibition potential was calculated to find optimized microcystins with high target toxicity but overall low transportability. It was shown that derivatization with small carboxylic acids or amino acids resulted in microcystins with a favorable ratio of inhibition to transportability, making these derivatives potentially suitable for application as payloads in antibody-drug conjugates.

Bei der Alzheimer-Krankheit handelt es sich um eine nicht aufzuhaltende, stetig fortschreitende neurodegenerative Erkrankung, deren frühzeitige Diagnose entscheidend für den weiteren Krankheitsverlauf ist. Aktuell angewandte, Liquor-basierte Biomarker sind zwar etabliert, weisen jedoch mitunter Limitationen hinsichtlich Frühdiagnose und Invasivität auf. Diese Arbeit widmet sich daher der systematischen Glykoanalytik von Liquor und Serum mit dem Ziel, Glykan-basierte Biomarker für die Frühdiagnose der Alzheimer-Krankheit zu identifizieren.

Ein neu entwickeltes Protokoll ermöglichte erstmals eine vollständige Analyse des Liquorglykoms hinsichtlich der darin vorkommenden freien, N- und O-Glykane mittels MALDI-TOF-Massenspektrometrie. Im Rahmen eines Screenings von 262 Liquorproben zeigten sich signifikante Unterschiede hinsichtlich spezifischer Glykanstrukturen zwischen Alzheimer-Patient:innen und Kontrollpatient:innen. Parallel dazu wurde eine innovative, datenunabhängige Massenspektrometrie-Technik zur Analyse von Glykopeptiden in 90 Liquorproben ohne deren vorherige Anreicherung angewandt. Aus über 11.000 generierten Peptiden konnten 498 Proteine, darunter 274 Glykoproteine, identifiziert werden. Dabei handelte es sich unter anderem auch um zahlreiche mit der Alzheimer-Krankheit assoziierte Proteine mit auffälligen Glykosylierungsmustern.

Zusätzlich dazu wurde ein robustes und reproduzierbares Analyseprotokoll für die Detektion von Glykosaminoglykanen mittels MALDI-TOF-MS entwickelt. Dieses soll nachfolgend ebenfalls bei der Entwicklung eines Glykan-basierten Biomarkers für die Frühdiagnose der Alzheimer-Krankheit angewendet werden. Durchgeführte Vorversuche zeigten vielversprechende Ergebnisse hinsichtlich der Unterscheidung von Alzheimer-Patient:innen und Kontrollpatient:innen.

Die Ergebnisse dieser Arbeit bilden die Grundlage für die Entwicklung neuartiger, Glykan-basierter Biomarker für die Frühdiagnose der Alzheimer-Krankheit.

Organoboron compounds play a central role in the chemical sciences. The classical approach to access this class of molecules entails incorporation of the boron motif in an advanced intermediate and has been implemented in a variety of different transforms, from the venerable Brown hydroboration to innovative platforms like C─H borylation. Alternatively, a core scaffold already containing a boron moiety can be subjected to further functionalization. In order to avoid side reactions at the boron center, protecting groups are generally employed. This has the drawback of adding additional steps to the synthetic sequence. The resulting inefficiency can be overcome by relying on methodologies capable of selectively manipulating multifunctional units that contain and retain an unprotected boron handle. This thesis describes the development of transforms of this latter kind. By relying on either photochemistry or transition metal catalysis, the expedient conversion of multifunctional boron reagents into complex 2D and 3D organoboron compounds could be achieved. Chapter 2 details the development of a method that generates α-boryl radicals from α-iodo boronic acid pinacol esters without the need for catalysts. Interception of the generated open shell species with styrenes afforded E-allylic boronic esters. The mild conditions of the protocol, which requires only a simple Lewis base additive and visible light, showed broad functional group tolerance and allowed its strategic alignment with energy transfer catalysis to access the Z-stereoisomers of the products. Chapter 3 describes the expansion of this chemoselective activation platform to a trifunctional reagent, featuring an additional nucleophilic handle (Si, Ge or B based). C─I bond homolysis yielded an α-bimetalloid radical of increased electrophilicity. Thanks to this, a wider array of SOMOphiles could be engaged, producing valuable 3D borylated scaffolds. These, in turn, could unlock a vast portion of chemical space via the chemoselective manipulation of the two installed nucleophilic moieties. Finally, the mechanism was interrogated via in depth experimental and computational investigations. Chapter 4 describes the development of a transition metal catalysed method for the synthesis of complex 2D organoboron scaffolds. A regioselective Suzuki-Miyaura cross coupling/cyclization reaction between readily available vicinal diborylated alkenes and 2- halophenols allowed the synthesis of 3-substituted benz(oxa/aza)borines, heterocycles that have been receiving increasing attention from medicinal chemists. The modular nature of the protocol provided rapid access to a Xeruborbactam derivative and its functional group tolerance allowed incorporation of multiple synthetic handles. These were exploited in downstream chemoselective manipulations and to install biomolecular probes.

Mass spectrometry-based proteomics allows to take a snapshot of the state of cells on the protein level. In particular, it allows to study the entire proteome in a high-throughput manner with high sensitivity. It is furthermore able to provide insights into peptidoforms, which are peptides that have sequence variations or are post-translationally modified. These play a major role in cell signaling and gene regulation, but can also be linked to certain disorders. So, studying peptidoforms and proteoforms provides fine-grained phenotypic insights that are of high biological relevance. However, the identification of peptidoforms, using mass spectrometry-based proteomics, is challenging from at least two directions. First, the underlying tandem mass spectra contain additional, rare, and potentially hard-to-simulate patterns. Furthermore, contextual knowledge in the form of reference proteomes, which initially contain canonical reference proteins, cannot be extended indefinitely to account for all potential peptidoforms. This is because considering all possible combinations of modifications and sequence variations is not tractable due to combinatorial complexity. Hence, this thesis provides new deep learning methods that improve the identification of peptidoforms in mass spectrometry-based proteomics while being interpretable. First, I introduce AHLF as a new end-to-end trained deep learning model that predicts modified peptides based on their fragmentation tandem mass spectrum (MS/MS) spectra. I am able to show that AHLF’s prediction score boosts peptide identification rates in the context of phosphoproteomics and for cross-linked peptides. AHLF is a temporal convolutional neural network temporal convolutional neural network (TCN), which I trained on 19.2 million of historical peptide-to-spectrum matches. For interpreting AHLF, I estimate feature importances per peak and per spectrum. These peak-level importances show that AHLF is indeed focusing on peptide-specific fragment ions. Additionally, I investigate the prediction performance across varying quality of data, denoting that variation occurs due to instrument type, resolution and dissociation method. In the second part of this work, I present yHydra which is a foundation model that I trained on nearly 20 million peptides and MS/MS spectra. I designed yHydra as a foundation model to be able to implement various downstream sub-tasks. In particular, I demonstrate that yHydra is able to perform closed, open, and error-tolerant searching. Using yHydra, I demonstrate error-tolerant searching of antibody peptide sequences searching and in the context of cross-species searching of chimpanzee plasma samples. Lastly, I demonstrate the of explainability yHydra by visualizing the learned joint embedding of peptides and spectra which reveals a learned manifold that is structured in concordance of physico-chemical properties of embedded peptides.

Unpaired adatom spins on superconductors interact with the Cooper pairs of the substrate and induce Yu-Shiba-Rusinov (YSR) states inside the excitation gap. Using combined scanning tunneling microscopy and spectroscopy (STM/STS) methods, we can probe these states at the single-atom scale. Additionally, adatoms can be moved on surfaces with atomic precision by lateral manipulation using the STM tip. If the YSR wave functions of two impurities overlap, they may hybridize forming a symmetric and an antisymmetric linear combination of the monomer wave functions similar to the linear combination of atomic orbitals when forming molecules. In structures consisting of many magnetic adatoms YSR bands can develop and, for specific parameter ranges, realize topological superconductivity.

We investigate structures of Fe and Mn atoms on the quasi-two dimensional superconductor 2H-NbSe2. We start out by studying symmetry properties of hybridized YSR states. Because the symmetries of YSR wave functions are determined by the crystal field of the corresponding adsorption site of the magnetic atoms as well as the Fermi surface of the substrate, we can employ the symmetries imposed by the substrate to realize chiral, triatomic YSR molecules which cannot be obtained in gas-phase chemistry. Interestingly, we also observe an odd parity ground state in dimers without a mirror plane between both atoms. This ground state makes the dimer a promising start for a chain that may host topological superconductivity. We extend the dimer to a linear chain of 24 atoms and observe the formation of YSR bands. In long chains the YSR bands are influenced by the incommensurate charge-density wave (CDW) that coexists with superconductivity in NbSe2.

Just as YSR bands in chains, the YSR states of individual Fe atoms on NbSe2 are influenced by the CDW. Here, we demonstrate that Fe atoms also influence the CDW. We reversibly switch the CDW-to-lattice alignment around Fe dimers by manipulating additional Fe atoms at a distance of more than 6nm from the dimers and observe significant changes in the YSR states of the dimers upon switching the CDW. Finally, we explore Mn atoms on 2H-NbSe2. We find that the YSR states of individual Mn atoms are less influenced by the CDW than those of Fe atoms. While we do not observe hybridization of YSR states in Mn dimers, we find signatures of spin excitations in chains of densely spaced Mn atoms.

Reconstructing the carbonate chemistry of the past ocean is a central goal of paleoceanography. In this regard, the boron isotope composition of marine carbonates has become a promising and widely used proxy for the pH of ancient seawater. However, a major concern in the application of this proxy is that the isotopic composition of carbonates may have also been influenced by secular changes in the isotope value of seawater (δ11Bsw). The purpose of the present thesis is to address this potential source of bias and investigate the likely changes in δ11Bsw from the Cretaceous to the present.

We do this by first experimentally examining boron adsorption on clay minerals, one of the key mechanisms by which boron isotopes are fractionated in the ocean. Cleaned samples of kaolinite, smectite and illite were suspended for 48 hours in a fixed volume of fluid (with a solid-to-fluid mass ratio of 0.04), containing boron at a known concentration and isotopic composition. The ability of each clay mineral to sorb and isotopically fractionate dissolved boron was determined by measuring the boron content of the fluid before and after interaction with the clay minerals. This basic experimental procedure was repeated multiple times under varying levels of pH, ionic strength, dissolved inorganic carbon (DIC) and major ion concentrations to probe the sensitivity of boron adsorption to fluid chemistry.

When clays are suspended in a pure aqueous boron solution without any other dissolved constituents, boron adsorption is inefficient and approximately constant over a wide range of pH. This is because clay edge surfaces, where most adsorption takes place, remain neutral regardless of the acidity of the surrounding fluid, inhibiting complexation of either B(OH)3 or B(OH)4-. In contrast, clay edges can become charged if the ionic strength of the surrounding fluid is high. Complexation reactions of boron in seawater are therefore strongly dependent on pH, as the pH sets both charge state of clay minerals (positive, neutral, negative) and the speciation of boron (B(OH)3 or B(OH)4-). We identify maximum rates of boron adsorption for all clay minerals in alkaline seawater. At these conditions, adsorbed concentrations of boron can be between six to twelve times higher than those of dissolved boron in the surrounding fluid. Isotope fractionation associated with adsorption is maximized at a pH of 8 (approximately 20 ‰ between fluid and clay) but becomes negligible at very alkaline or acidic conditions (~ 0 ‰). Complexation modeling shows that the isotopic composition of adsorbed boron is consistent with a high affinity of B(OH)4- to the clay surface, in agreement with previously published experimental work. As a result, detrital clay minerals isotopically fractionate seawater by preferentially adsorbing isotopically light B(OH)4-, not because the adsorption process itself induces a specific isotopic fractionation of adsorbed boron.

Moreover, our results demonstrate that adsorption behavior of clay minerals is not clearly altered when adsorption occurs in seawater with a major ionic composition close to that of the Eocene or Cretaceous oceans. Long-term changes in seawater chemistry consequently had little impact on the boron adsorption flux, which was instead set over time by the total mass of sediment entering the ocean as well as its mineral assemblage. To further explore the impact of these parameters on the boron adsorption sink, we model a number of plausible erosion scenarios and the associated sediment discharge for the last 100 million years. The model takes into account changes in terrestrial climate and erosion patterns to predicts the abundances of five boron-adsorbing minerals (kaolinite, chlorite, illite, smectite and iron oxyhydroxides) in the global sedimentary discharge. Our results show that changes in the terrestrial climate had a limited impact on the global-scale abundance of these minerals because a warmer and wetter climate state in the past was balanced by a reduced land mass in tropical latitudes. On the other hand, changes in sediment provenance could have significantly altered the mineral assemblage. Previous studies suggested a lack of mountainous erosion in the Cretaceous and early Paleogene which, according to our erosion model, caused discharged sediment at these times to be composed of 40 % clay minerals (compared to 15 % today). In other words, the large acceleration in sediment discharge thought to occur over the course of the last 40 million years was dominantly comprised of minerals with a small specific surface area that do not adsorb boron in significant quantities. Our results therefore show that the capacity of detrital sediments to adsorb boron from seawater has remained similar to today for most of the Cenozoic.

We finally combine these findings on the boron adsorption sink with additional advancements made for other relevant parts of the Earth system to construct a new model for the evolution of δ11Bsw. Critically, our model also includes a self-consistent representation of the lithium isotope value of seawater (δ7Lisw), as both lithium and boron are mechanistically coupled because of their shared dependence on the same geologic processes. These processes include the riverine discharge of water and sediments, precipitation of carbonate and silica in the ocean, marine productivity, early sediment diagenesis and exchange reactions between seawater and the ocean crust. The model allows us to simulate the effect of proposed changes in various lithium and boron fluxes, and test their ability to match available seawater reconstructions. We find that seawater proxy data of both boron and lithium can be explained by a hitherto unrecognized long-term rise in the pH of soil porewaters, which we attribute to aridification of the global land surface. During the Cretaceous and Paleogene, soils were acidic (pH < 7) so secondary minerals forming in soils reincorporate only small amounts of solubilized lithium and boron with a modest isotope fractionation. Rivers at this time consequently delivered large amounts of isotopically light boron and lithium to the ocean. The model produces minimum δ11Bsw values of 36 and 37 ‰ for the late Cretaceous (85 Ma) and early Eocene (50 Ma), respectively. As the planet cooled and land surfaces dried in the latter half of the Cenozoic, soils became more alkaline (pH > 7) and the propensity of soil minerals to reincorporate and isotopically fractionate solubilized boron and lithium increased. This caused the river input and, accordingly, seawater compositions of both elements to become isotopically heavier over time. The δ11Bsw increased at a steady rate of 0.06 ‰ per million years from the early Eocene to the present and did not exceed its modern value of 39.6 ‰ at any time over the last 100 million years.

Turbulence is an important feature of blood flow near the heart. A discretization of moderate resolution must therefore model the interactions between "coarse" resolvable flow behaviors and "fine" subgrid-scale features. We compare several choices of turbulence model in terms of their impact on clinically interesting flow statistics. We also present an investigation of a novel method for augmenting classical turbulence models with machine learning algorithms trained on coarse-fine simulation pairs.

Die empirische Studie untersucht, ob durch historische Auseinandersetzung die Herausbildung europäischer Identität bei Kindern am Ende der Grundschulzeit beeinflusst wird. Dazu wurden Leitfadeninterviews mit Grundschüler*innen (n=19) im Alter von ungefähr zehn Jahren durchgeführt, die anschließend mittels Qualitativer Inhaltsanalyse ausgewertet wurden. Die Ergebnisse zeigen, dass Kinder am Ende der Grundschulzeit über vielfältiges Wissen und unterschiedliche Konzepte zu Europa verfügen, deren Qualität variiert. Dieses Wissen bezieht sich auch auf europäische Vergangenheit und es kann gezeigt werden, dass Kinder über umfangreiche Kompetenzen des historischen Denkens verfügen, die sie befähigen, Europa in historischer Perspektive zu betrachten, was sie auch tun. Besonders häufig formulieren die Kinder die Narration, dass sich Länder zu Europa zusammengeschlossen haben um Kriege zu beenden und Frieden zu schaffen. Die Aneignung von Wissen und historisches Lernen findet dabei hauptsächlich außerschulisch statt. Durch die geschichtliche Auseinandersetzung mit Europa verstärkt sich ein europäisches Bewusstsein der Kinder. Das europäische Bewusstsein ist unterschiedlich stark ausgeprägt. Aufbauend auf diesem Bewusstsein kann eine europäische Identität bei Kindern am Ende der Grundschulzeit als in der Entwicklung beschrieben werden.

Das deutsche 19. Jahrhundert stand im Zeichen von intensiven Bestrebungen der Nations- und Nationalstaatsbildung. Ihre mit der historisch verankerten föderativen Tradition verbundenen Herausforderungen führten zum Einsatz emotional geprägter Bewältigungsmittel sowohl zur Kristallisierung einer als einheitlich imaginierten Nation als auch zur inneren Konsolidierung des Kaiserreichs von 1871. Darunter ragten seit dem Humanismus im deutschen Nationsdiskurs fest eingebettete und deshalb re-applizierungsfähige sowie auch durch moderne Deutungseliten neukreierte Mythen hervor. Ihre Bedeutung für die Stiftung von Identität, beruhend auf Konstituenten des deutschen Nationalcharakters wie Ethnos, Sprache, Geschichte, Religion, Recht u. a. stand den politischen und militärischen Vorgängen in nichts nach. Mythen halfen Welt- und Geschichtsbilder zu konstruieren, wirkten aktiv bei der Grundlegung eines kollektiven Gedächtnisses mit und trugen zugleich zur wesentlichen Überexponierung des deutschen Volkes als Träger der Nation und deren Staates bei. Zur Avantgarde nationaler Mythenproduktion und -popularisierung gehörte der Juraprofessor und Erfolgsautor Felix Dahn. Mit seinem umfangreichen wissenschaftlichen, vor allem aber literarischen Werk genoss er enormes Ansehen nicht nur bei der deutschen Leserschaft. Dieses stützte sich nicht so sehr auf die ästhetischen Qualitäten seiner Schriften, sondern in erster Linie auf die Symbiose zwischen der Fundierung historischer Kontinuität und der Heraufbeschwörung von Glanz, aber auch von Untergang verheißender äußerer und innerer Bedrohung des germanisch-deutschen Volkstums in seinen ethnischen Merkmalen und Facetten sowie dessen Staatsgebildes. Markante Topoi bilden dabei die gefährdete deutsche Sprache, die Diskrepanz zwischen nationaler Eigenart und „wesensfremden“ Glaubens- und Rechtsformen mit deren Konsequenzen für die Bewährung des Wilhelminischen Reiches und dessen kulturellen Daseins, die Lebensraumerweiterung und die als Krönung des Kriegers stilisierte Ethik des Heldentums in ihrer Funktion, Garant der Volks- respektive der Staatsexistenz zu sein. Vor diesem Hintergrund setzt sich die Studie mit dem Beitrag Dahns zur Etablierung des mythengestützten Nationalismus im ersten deutschen Nationalstaat zwischen 1871 und 1914 auseinander. Die Erschließung der Semantik und der Wirkungssphären seiner mythischen Schöpfungen versteht sie als semiotische Ermittlung von für Dahns Identitätsstiftungsstrategie konstitutiven Vorstellungen, deren Objekte zeichenartige Sinnträger verschiedenen Ranges (Symbole, Mythen) darstellen. Pragmatisch fasst die Semiotik das Zeichen als eine bilaterale Einheit von Bezeichnendem und Bezeichnetem auf. Sie besteht aus der spezifisch materialisierten Form des „Ausdrucks“ und einem bedeutungstragenden „Inhalt“. In semiotischem Sinne weisen Symbole und Mythen dieselbe dualistische Struktur auf. Deshalb eignet sich das Zeichenmodell als Grundlage ihrer theoretischen Erfassung. Den Mythos als spezifische Textsorte charakterisiert vor allem sein symbolischer Kern. Die Narrativität verbindet das mythische Symbolgebilde genealogisch mit dem hier literarischen Medium seiner Exponierung. Im Unterschied zum Symbol präsentiert der Mythos sein Ideengut nicht piktografisch konzentriert, sondern in der Form fabulierter Erzählung mit ausgeprägtem Zeit-Raum-Kontinuum, welche eine doppelschichtige Struktur erkennen lässt. Die in verschiedenen Episoden unter der Beteiligung agierender Figuren in bestimmter Reihenfolge verlaufende Handlung bildet die Oberflächenstruktur. Für die Semantisierung von Merkmalen (Mythemen) der untereinander kooperierenden oder rivalisierenden Aktanten ist die Tiefenstruktur maßgeblich, auf deren Ebene die handelnden Gestalten als Protagonisten bzw. Antagonisten auftreten. Trotz verschiedener Verflechtungen der mythischen Narrationen im Kaiserreich ist eher von diskursiv koexistierenden Mythen als von einer Mythologie im klassischen Sinne zu sprechen. Es werden in Mythologemen gebündelte Mythenstränge zusammengelegt. Als Mythologem bezeichnet diese Untersuchung von Dahns Mythen ein, auf der wiederkehrenden Aufeinanderbeziehung emblematischer Symbole und Mytheme beruhendes Organisationsprinzip, das Mythensysteme mit symbolsemantisch konstruierten Gefügen benennen lässt. In genremäßig unterschiedlichen Texten gelang es Dahn, eine zu nationalistischen Erziehungszwecken einsetzbare mythische Konstruktion mit identitätsstiftender Semantik aufzubauen, deren tragende Elemente zwei Hauptstränge von aufeinander bezogenen fundierenden Mythen aufweisen. Ihre signifikante, mit dem Ethnischen verbundene Blut- respektive für das Kriegerische stehende Eisen-Komponenten beinhaltende Symbol- und Mythem-Substanz, welche anhand der Oberflächen- und Tiefenstrukturen von artifizierten Varianten des Germanenmythos sowie der Mythisierung zeitgeschichtlicher preußischer Personen und Ereignisse mithilfe semiotisch-strukturalistisch orientierter Analysestrategie expliziert wird, ermöglicht die Identifizierung eines diese Mythen zusammenfügenden Mythologems. Es verleiht jener in der Verkettung des germanisch-deutschen Geschichts- und Identitätsbewusstseins mit der heldenhaften Opferbereitschaft für Volk und Staat wurzelnden Mythenwelt des Nationalstaats einen Systemcharakter. Die fokussierte biographische Thematisierung sowie die Erörterung von Dahns philosophischer, politischer und ideologischer Anschauung dient der Orientierung hinsichtlich der schwierigen Einordnung seines Ideenguts und „Blut und Eisen“-Mythologems in das Ideologie-Spektrum des Kaiserreichs. Dahns führende Rolle als herausragender Exponent der Mythisierung des Nationalen für die konstruktivistische Erfindung von nationalen Imaginationen und Identitätsmustern, aber auch sein Engagement bei ihrer Propagierung werden an der intensiven und nachhaltigen zeitgenössischen Rezeption verifiziert. Die Kritik an dessen weitgehend dem Zeitgeist bzw. den Erwartungen des breiten Publikums entsprechenden Gesinnung, die ideologischen Vereinnahmungsversuche und die eigene Verwahrung dagegen deuten auf eine massive und anhaltende Wirkung des durch ihn elaborierten Mythologems hin. Die pointierte Topographierung der Kompatibilität und Divergenz seiner Ansichten mit den ideologischen Fundamenten der sich von den 1890er Jahren an formierenden, breitgefächerten völkischen Bewegung veranschaulicht es, dass der sich in Freikonservatismus transformierende Nationalliberalismus Dahns und sein Deutschtum ihn innerhalb des zwischen Patriotismus und völkischem Radikalismus oszillierenden wilhelminischen Nationalismusdiskurses im Bereich einer auf Sicherstellung des Volks- und Staatserhalts bedachten gemäßigteren nationalistischen Volkstumsideologie verankern ließen.

The thesis examines the management tools introduced by the Safavid shahs to alter the Shrine of Imam Reżā in Mashhad from a mere place of pilgrimage to a center for disseminating Shiʿi con- victions. It furthermore aims to create a deeper comprehension of the multiple functions of the Āstān-e Qods as a cultural, social and economic institution in the years 907/1501 to 1148/1735. It enhances the argument that the foundation for developing the Shrine in this manner was laid by Shah Ṭahmāsb I and that Shah ‘Abbās I increased both the significance and the financial means of the Shrine by undertaking several measures, such as constructing additional buildings, enlarging its architecture and embellishing the city of Mashhad and by establishing endowments and encouraging votive offerings to the Shrine. The main part of this study is based on a large number of unique original documents kept in the Āstān-e Qods, many of which are presented and analyzed here for the first time. The en- dowment deeds reveal the significant increase in the number of endowments in this period and give insight into the motivation of the donors in support of the religious policy of the Safavids, making this dynasty extremely successful in achieving their religious and political goals by the end of the period. We have, moreover, scrutinized the different types of orders issued by the Sa- favid shahs, highlighting the methods by which the shahs managed the Shrine directly, the main role of the ṣadr and his office, the dīvāno’ṣ-ṣedāre (Office of the ṣadr) and the important role of the dīvān-e a‘lā’ (Supreme Government Office) in this context. Subsequently we have focused on the tasks of the motavallīs (custodians) of the Shrine, described their position as deputies of the Shah and attempted to identify them. Another part of the study focuses on the organization of the Āstān-e Qods, predominantly the duties of the official with the title Sarkār Feyż Āsār (lit. “Department of Divine Grace”), and the formation of the secretariat and the daily shifts (kešīk) in the Shrine, which had increased from three to five in the early Safavid period. Besides the analysis of the chancellery documents kept in the Āstān-e Qods, the study also offers insight into the preparation of the record called ṭūmār-e nasaq (“fiscal management instruction scroll”) as a manual for managing the Shrine through the dīvān-e aʿlā’. The main aim is to show how the organization of the Āstān-e Qods functioned by analyzing the development of the Shrine and its endowments under the di- rect management of the Shah and the dīvān-e aʿlāʾ. It highlights the striking similarities between the official structure of the Shrine, as revealed in its administrative manual, and the highest Sa- favid government office. The documents reveal how the organization of the Shrine of Imam Reżā grew due to the establishment of endowments, whose revenue contributed to embellishing the Shrine and played a principal role in supporting the political objectives of the Safavids: rather than remaining only a place for pilgrimage, it became an institution for actively disseminating the Shiʿa by attracting a large number of pilgrims and Shiʿite scholars. This development led in turn to the emergence of other functions, increasing the central importance of the Shrine. The organization of the Āstān-e Qods Rażavī and its endowments expanded under the direct management of the Shah who appointed the Shrine’s motavallī. The Shrine’s fiscal matters and endowments were man- aged by the dīvāno’ṣ-ṣedāre via the central government office, the dīvān-e a‘lā’. The documents of the Safavid administrative system, which have survived in the Āstān-e Qods, are unique origi- nal copies of these financial operations, which clarify the relationship between the Safavid shahs and the motavallīs of the Shrine. They furthermore shed light on the functions of the other high government officials in the management of the Shrine. They show in detail, how the income of the Āstān-e Qods was used to strengthen the country's religious foundation and how its endow- ment policy aimed at expanding the reach of Shiʿite propaganda.