This thesis presents a systematic approach to the synthesis of highly electrophilic fluorinated dialkyl halonium ions, enabled by strong oxidizing noble gas compounds derived from Lewis superacidic systems. The study begins with the synthesis and characterization of Ga(OTeF5)3, a rare gallium-based Lewis superacid, obtained in quantitative yield via a solvent-free reaction between GaCl3 and ClOTeF5. In SO2ClF solution, Ga(OTeF5)3 forms a monomeric solvent adduct, while it adopts a dimeric structure in the solid state. Quantum-chemical calculations classify the free acid, its dimer, and the SO2ClF solvent adduct as Lewis superacids. This superacidity was further exploited to enhance the oxidative strength of Xe(OTeF5)2, enabling the oxidation of chloromethane and the subsequent formation of the dimethyl chloronium salt [Cl(CH3)2][Ga(OTeF5)4], highlighting the potential of Ga(OTeF5)3 in the synthesis of reactive cationic species. Building on this foundation, the thesis explores the synthesis and reactivity of the fluorinated dialkyl chloronium salts [Cl(CH2CF3)2][E(OTeF5)n] (E = Al, n = 4; E = Sb, n = 6), prepared via oxidation of CH2ClCF3 with [XeOTeF5][E(OTeF5)n]. The chloronium compounds were fully characterized by NMR and IR spectroscopy, as well as by single-crystal X-ray diffraction. Reactivity studies revealed that the chloronium ion can act as a CH2CF3 transfer reagent to weak nucleophiles or as a hydride abstraction reagent capable of activating linear aliphatic alkanes. The resulting branched carbocations, stabilized by the weakly coordinating [Sb(OTeF5)6]− anion, were characterized by NMR spectroscopy and the molecular structures of the tert-butyl and isopentyl cations were determined by single-crystal X-ray diffraction. The reactivity of the chloronium system was further used in the synthesis of other fluorinated dialkyl halonium ions, including [Br(CH2CF3)2]+, [I(CH2CF3)2]+, and [I(CH2CHF2)2]+. These compounds were characterized by NMR and IR spectroscopy as well as single-crystal X-ray diffraction. Additionally, the synthesis of fluorinated dipropyl halonium salts [Br(CH2CH2CF3)2]+ and [I(CH2CH2CF3)2]+ was achieved via oxidation or fluoroalkylation of the corresponding haloalkanes. A similar reaction, the oxidation of 2-chloro-1,1,1-trifluoropropane CHCl(CH3)(CF3), led to the formation of a highly reactive species capable of activating isobutane to generate the tert-butyl cation. Although the reaction product could not be directly observed due to its thermal instability and low solubility, quantum-chemical calculations support the formation of an asymmetric chloronium ion. Overall, this work introduces new synthetic routes to structurally diverse and highly electrophilic halonium ions and shows their utility in C‒H bond activation and carbocation formation, offering fundamental insights into the stabilization of reactive main-group species.

Derivatives of the pentafluoroorthotellurate group (OTeF5) bearing fluorinated and non-fluorinated aryl substituents have been developed as ligand systems for the synthesis of strong Lewis acids and weakly coordinating anions. The acid cis –PhTeF4OH was obtained on a gram scale and subsequently converted into Ag[cis –PhTeF4O], which served as an efficient cis –PhTeF4O transfer reagent, for instance, in the preparation of [PPh4][cis –PhTeF4O]. More importantly, the synthesis of trans –(C6F5)2TeF3OH (abbreviated as HOTeR) was achieved by fluorination of (C6F5)2Te with the TCICA/KF system to give trans –(C6F5)2TeF4, followed by selective hydrolysis in a MeCN/H2O mixture. Quantum-chemical calculations revealed that HOTeR possesses both a higher acidity and an enhanced resistance towards fluoride abstraction compared to cis –PhTeF4OH, and was therefore selected as building block for further syntheses. The boron-based Lewis acid B(OTeR)3 was synthesized by reacting HOTeR with either BCl3 or BCl3 ·SMe2. This compound exhibits exceptional thermal stability up to 300 °C and represents one of the most sterically encumbered boron centers reported to date, as evidenced by a buried volume analysis. Theoretical and experimental investigations showed that B(OTeR)3 possesses a Lewis acidity comparable to that of the well-known B(C6F5)3. The affinity of B(OTeR)3 towards pyridine was determined by isothermal titration calorimetry (ITC), which resulted to be slightly lower compared to B(OTeF5)3 and B(C6F5)3. The ligand-transfer reactivity of B(OTeR)3 was demonstrated by its reaction with fluoride precursors, affording the Au(III) complex [PPh4][(CF3)3Au(OTeR)] and a hypervalent iodine(III) species. Lastly, investigations on the aluminum analogue Al(OTeR)3 revealed that it is a Lewis superacid according to fluoride ion affinity (FIA) calculations. Complementary analysis using the Gutmann–Beckett method via formation of the Al(OTeR)3·OPEt3 adduct rendered similar results, yet for the heavier Ga analogue only GaEt(OTeR)2 · OPEt3 was obtained. The isolation of free Al(OTeR)3 proved challenging due to its intrinsic reactivity towards fluoride abstraction from its own ligands, as shown by quantum-chemical calculations. As a consequence, the Lewis superacid was stabilized as acid-base adducts with tetrahydrofuran and dimethyl carbonate, which remained synthetically useful. Derived from the Al(OTeR)3 moitey, two weakly coordinating anions, the fluoride adduct [FAl(OTeR)3]– and the even less coordinating mixed anion [(F5TeO)Al(OTeR)3]– were synthesized. Among them, the synthetically versatile silver salt Ag[(F5TeO)Al(OTeR)3] stands out, which could be used to generate a strong Brønsted acid as well as the [Ph3C]+ cation. Electrostatic potential surface analysis shows improved charge delocalization and oxygen shielding in [(F5TeO)Al(OTeR)3]– compared to [FAl(OTeR)3]– and [Al(OTeF5)4]– .

Renal cell carcinoma (RCC) is a complex disease with remarkable immune and metabolic heterogeneity. In this thesis, proteomic, epigenomic and transcriptomic analyses on a cohort of patients spanning three main RCC subtypes were utilized to better characterize the altered proteomic and epigenomic landscape of RCC. The analysis revealed significant disruptions in the proteomic and epigenomic landscapes in tumor tissue compared to normal adjacent tissue (NAT) in clear cell RCC (ccRCC), papillary RCC (pRCC) and chromophobe RCC (chRCC) subtypes. Stark and global loss of 5-hydroxymethylcytosine (5hmC) in tumor tissue compared to NAT in all three subtypes was observed. Furthermore, it was demonstrated that in the gene body and enhancer regions, loss of 5hmC is correlated with gain of 5- methylcytosine (5mC). Through integration of transcriptome and proteome data, it was demonstrated that loss of 5hmC in gene body and enhancer regions is an epigenetic hallmark for all three of main RCC subtypes and may be associated with cancer progression. Proteomic analysis revealed significant dysregulation of many protein regulons in all three subtypes, with several epigenetic regulators particularly affected and differentially expressed in tumor compared to matched normal tissue. Integration of proteomic and epigenomic approaches highlights the myriad of regulators and networks that are dysregulated in ccRCC, pRCC and chRCC, which can assist in refining the molecular characterization of these subtypes and facilitate the improvement of therapeutic responses.

The level of complexity encountered in biological systems often demands the introduction of generalizations and refinements of classical physical models. Spanning a wide range of length scales, we study a few different biologically relevant systems, namely the molecular diffusion of water, the elasticity of the basement membrane, and surface waves on viscoelastic interfaces surrounded by viscoelastic media, where generalizations to existing theoretical models are introduced systematically. Using molecular dynamics simulations, we study the self-diffusion of water in the laboratory frame as well as in the anisotropic molecular frame via calculations of the water viscosity and the translational and rotational diffusion coefficients. Instead of interpreting the results as deviations from the Stokes-Einstein(-Debye) relations, we describe the diffusivities of water molecules by three models of increasing complexity. We discuss successes and limitations of stick sphere and stick ellipsoid models, and finally show that a heuristic spherical model with tensorial slip lengths and hydrodynamic radii simultaneously describes the isotropic translational and rotational diffusivities in the laboratory frame, as well as, in a restricted viscosity range, the anisotropic molecular-frame diffusivities. We present a coarse-grained elastic model of the laminin network of the basement membrane to simulate the modulation of the elasticity of the basement membrane under influence of netrin-4, and apply our model to longitudinal and transversal deformation scenarios of the basement membrane. We show that the laminin network with defects due to the presence of netrin-4 has a nonlinear stress-strain relationship, and we further extract from our simulations the relevant elastic parameters. To compare with experiments, we develop a method to associate extracted model parameters with measured elastic moduli of bulk samples, and show that our model yields good agreement with experimental data. We derive the general dispersion relation for interfacial waves along a planar viscoelastic boundary that separates two viscoelastic bulk media, which unifies and generalizes existing results for surface waves, such as Rayleigh waves, capillary-gravity-flexural waves, Lucassen waves, bending waves in elastic plates, and the standard dispersion-free sound waves. We apply our general theory to study interfacial waves at water-water and air-water interfaces, as well as at interfaces of viscoelastic Kelvin-Voigt and Maxwell media. In all scenarios, we study how material properties determine the crossovers, scaling, and existence regimes of the various interfacial waves.

This medical historical habilitation thesis analyzes unpublished and publishes sources, medical records, and oral history interviews to complicate a notion of health activism, clinical routines, and bureaucratic practices as discrete cultures with separate thought styles. The welfare state cases of HIV/AIDS policy and trans medicine show that subcultures and clinical cultures, lay and professional expertise have converged and shaped each other in reciprocal ways. The thesis develops the concepts of “amphibious activism” and “welfare state medicine” to characterize this dialectical relationship as a particular way of thinking and practicing medicine in the clinic and in the bureaucracy in the late twentieth century.

Our ecosystems are threatened by the consequences of the global biodiversity crisis: habitat loss and fragmentation, overexploitation, pollution, and climate change drive species, ecosystem, and genetic diversity losses. Freshwater ecosystems are highly diverse, harboring 12 % of all described species (fungi, plants, invertebrates, and vertebrates) condensed on just 2 % of the world's surface (Albert et al. 2021). Yet, they are also among the most endangered and vulnerable ecosystems. Globally, aquatic insects have declined by 33 % (Sánchez-Bayo and Wyckhuys 2019). Ponds, in particular, host high macrophyte and macroinvertebrate diversity as well as high numbers of rare and endangered species, making them biodiversity hotspots (Williams et al. 2004). However, ponds are highly susceptible to biotic and abiotic stressors and remain understudied compared to larger water bodies (Ulrich et al. 2022). Addressing this research gap is urgent given accelerating freshwater biodiversity loss (Sánchez-Bayo and Wyckhuys 2019; Darwall et al. 2018; Kelly-Quinn et al. 2017; Reid et al. 2019). To support effective conservation and management, this thesis focuses on assessing water and habitat quality of small water bodies (SWBs) in agricultural landscapes, given that the main causes of biodiversity loss include pollution and the destruction and fragmentation of habitats, using benthic macroinvertebrates as indicator organisms.

The first publication focuses on pesticides, showing their presence in SWBs across large spatial and detailed temporal scales. Eight pesticides were frequently detected regionally, and it was determined that a constant herbicide contamination negatively affects ecosystems. The second publication focuses on the biology and it was found that habitat type most strongly shapes community composition, while structural biodiversity indices are insufficient for depicting the influence of agricultural stressors. Thus, the third publication links indirect pesticide effects to benthic macroinvertebrate diversity, introducing a new multimetric indicator that reveals these impacts. The fourth publication applies a functional approach, using stable carbon and nitrogen isotope ratios to assess agricultural effects on the isotopic niches of six functional feeding groups in ponds and ditches. No differences were found between the two water body types (pond and ditch) and their different exposure to the agricultural stress factor (pesticides) for the isotope niches of the functional feeding groups. The small and unstable systems studied are more affected by strong fluctuations in abiotic and biotic factors. Results from the case study indicate that benthic macroinvertebrates respond to the stressors in complex ways.

By integrating chemical and biological analysis from both taxonomic and functional perspectives, this thesis aims to provide a more holistic and nuanced understanding of biodiversity patterns in SWBs and the challenges of detecting changes in communities due to agricultural stressors, with the ultimate goal of informing conservation policy.

This cumulative thesis presents the results of Schaar et al. (2024, 2025) and Spiegl et al. (2022) in a broader framework plus additional results on cosmogenic beryllium as a proxy for solar and atmospheric dynamics. Schaar et al. (2024) describe in detail the atmospheric transport and deposition of Beryllium-10 from the CE 774/775 SPE and GCR in dependence on the seasonal appearance of the SPE and GCR. Furthermore, the paper discusses the detectability of the CE 774/775 SPE depending on different GCR background conditions, the seasonal timing of the SPE occurrence, the size distribution of aerosols and the respective phase of the 11-year solar cycle during the SPE. In Schaar et al. (2025) the impact of ENSO on near-surface Beryllium-7 is investigated, as ENSO is one of the most important climate phenomena. The results for the different phases of ENSO (La Niña, El Niño and neutral) are compared to data from IMS stations of the CTBTO in the ENSO region and also future projections of ENSO signatures in near-surface Beryllium-7 are shown. Spiegl et al. (2022) has been the starting point for the simulations leading to Schaar et al. (2024).

IBD represents a relevant inflammatory disorder of the gastrointestinal tract that requires an interdisciplinary collaboration of gastroenterologists and visceral surgeons to provide precise and individualized treatment options. Especially adequate management of chronic symptoms and an effective therapy of complications are crucial, but also highly challenging in the overall treatment plan of these patients. Therefore, the present study focused on abdominal pain typically resulting from intestinal inflammation and displaying one of the leading symptoms in IBD and on the other hand on malignant transformation, especially the occurrence of CRC as one of the most incisive complications in this inflammatory disorder. In the first part of the present work, we therefore started to investigate nociceptive signaling which comprises a complex network of diverse areas, neurons and interacting neurotransmitter systems with special regard to the GABAergic and the opioidergic system. We initially examined the role of GABAergic neurotransmission with respect to GABABR-mediated effects in multiple in vitro experiments which should serve as a basis for future in-depth studies. However, besides GABAergic transmission, administration of opioids and subsequent activation of the opioidergic system still represents the mainstay in clinical practice to inhibit nociceptive signaling thus providing adequate pain relief in many inflammatory disorders, especially in IBD. Nevertheless, the powerful analgesic actions of opioids are counteracted by their severe side effects which markedly limit their prevalent use hence indicating the need for new potent analgesic drugs with low side effect profiles. NFEPP, a fentanyl analogue, typifies such a novel compound which was designed to activate MORs only in acidic microenvironments thereby providing potent analgesia without opioid-typical side effects (Spahn et al., 2017). We next examined the actions of the potential alternative NEPP in a murine model of colonic inflammation employing multiple in vivo and in vitro experiments combined with a translational approach in human colonic tissue. Interestingly, we found that during a colonic inflammation which closely mimics the inflammatory state of ulcerative colitis, repeated treatment with NFEPP effectively inhibited visceral nociception without inducing opioid-typical adverse events and its actions were strictly confined to acidic areas which corresponded to sites of histologically verified inflammation within the inflamed colonic wall. Moreover, in our murine model of IBD, we additionally revealed that NFEPP maintained its antinociceptive actions over time and did not induce analgesic tolerance compared to fentanyl when applied at the same dose and dosing intervals. Finally, we substantiated our results by proving that NFEPP was also able to inhibit human colonic nociceptors under acidic conditions likely indicating its potential future transition into clinical practice as a novel safe and effective analgesic drug for adequate pain control in inflammatory gastrointestinal disorders such as IBD. In the second part, we then investigated sporadic and IBD-related CRC. Identification of distinctive tumor characteristics will likely codetermine therapeutical procedures and survival predictions. In this context, primary tumor sidedness is assumed to be of predictive value based on diverse clinicopathological characteristics found in right- and left-sided tumor localizations. Thus, we first examined an unselected population of patients with sporadic CC stage I-IV at our institution and did not reveal an association of primary tumor sidedness with survival outcomes in our cohort although demonstrating diverse clinicopathological characteristics in the right- and left-sided group. We next conducted a multicentric study of IBD-related non-metastatic CRC and similarly disclosed that primary tumor sidedness did not affect overall and recurrence-free survival, but also found that clinicopathological features were equally distributed among a right- and left-sided tumor localization in these patients likely referring to a unique nature of IBD-related CRC. Interestingly, CEA levels and parameters that were related to lymph node status significantly impacted the overall outcome in sporadic and IBD-related CRC highlighting the relevance of common tumor load and affection of lymph nodes for patient mortality. Nevertheless, our results point out the imperative of future high-power and in-depth studies to clarify the question if primary tumor sidedness could ultimately dictate diverse therapeutical approaches in patients with sporadic and IBD-related CRC.

The COVID-19 pandemic created challenges across biological scales and scientific disciplines, spanning from molecular virology to population-scale epidemiology. This thesis presents a body of work that develops and applies quantitative and computational methods to study SARS-CoV-2 across biological scales, from viral replication within individual hosts to infection control strategies at the population level. Each component of this research arose from a distinct phase of the pandemic and addresses a key scientific challenge of that period.

In the early phase, when no vaccines or antivirals were available, we developed stochastic models of inter-host SARS-CoV-2 infection dynamics to evaluate non-pharmaceutical interventions (NPIs) such as testing, quarantine, and isolation. These models describe infection progression in pre-detectable, infectious, and post-infectious stages and integrate empirical data on viral load dynamics and test performance to estimate transmission risk under different intervention schemes. The models were implemented in the open-source software COVIDStrategyCalculator, enabling policymakers and health authorities to compare NPI strategies in real time. Post-hoc validation with the first SARS-CoV-2 human challenge study confirmed the model’s predictive accuracy, and the framework has since been adapted to other pathogens, including the Monkeypox virus.

With the advent of vaccines, attention shifted from epidemiological control to the characterization of molecular mechanisms of viral replication and immune modulation. The success of mRNA vaccines underscored the importance of RNA chemistry, particularly the stabilizing role of modified nucleosides, in achieving effective expression without triggering excessive innate immunity. This highlighted the broader need to characterize RNA modifications and other epitranscriptomic features that influence viral behavior and vaccine design. Nanopore direct RNA sequencing (dRNA-seq) emerged as a promising method for studying these features, as it allows native RNA molecules to be read directly, including their post-transcriptional modifications. However, the technology posed considerable computational challenges related to signal interpretation and throughput.

This thesis advances nanopore dRNA-seq as a tool for analyzing viral and host RNA biology. A systematic characterization of dRNA-seq signal and sequencing errors defined the limits of current sequencing accuracy and informed new algorithms for detecting RNA modifications. Building on this foundation, a novel barcoding and barcode-inference framework, WarpDemuX, was developed to enable the pooled sequencing of multiple RNA samples within a single run. This method eliminates batch effects, reduces cost and turnaround time, and supports longitudinal and comparative studies of viral transcriptomes. Application of this approach to SARS-CoV-2 revealed time-resolved viral replication patterns, stable subgenomic RNA hierarchies, and dynamic regulation of poly(A) tail lengths during infection. As a methodological stress test, the same framework was extended to the pooled sequencing of tRNAs, demonstrating its generalizability to short and heavily modified RNA molecules.

Taken together, these advances demonstrate how computational modeling and sequencing advances can jointly resolve questions related to viral dynamics and support epidemic response. Mechanistic models convert limited early data into actionable guidance, while sequencing frameworks reveal the RNA-level processes that govern replication and adaptation. In combination, they establish a robust, generalizable foundation for rapid analysis, modeling, and control of emerging RNA viruses, delivering methods that can be applied beyond SARS-CoV-2 and support future global health preparedness and mRNA-based biotechnology.

In this work, electron paramagnetic resonance (EPR) spectroscopy is employed to probe spins of charge carriers in electroactive polymer films used as electrodes in rechargeable organic batteries based on organic radicals. With electron spins as microscopic structural probes, EPR provided detailed insights into the electrodes’ molecular structure during charging and discharging cycles.

A significant challenge in applying EPR to working electrochemical cells arises from the strong microwave absorption by battery components. To overcome this, EPR-compatible electrochemical cells were successfully designed. These cells enabled real-time monitoring of spin concentrations, detection of by-products and identification of electrochemically inactive domains in the electrode. Combined, the quantitative EPR and electrochemical data were used to identify the molecular degradation mechanism of the electroactive polymer, to figure out in which part of the polymer charge carriers are stored, and to formulate a hypothesis of the formation of electrically disconnected domains in an electroactive polymer film. Electron spin echo was detected in a charged electrode film using pulsed EPR techniques. The effect of Instantaneous Diffusion caused by the broadband, short microwave pulses was considered and the corresponding distortions of the echo-detected EPR spectra were simulated. Simulations of echo-detected EPR spectra allowed for estimating spin concentrations in the film without any additional measurements such as the volume of the film. Transient analysis of the spin echo decay revealed multiple decay components that were attributed to the charge–storing domains with distinct spin concentrations.

In summary, MRI and CT are excellent diagnostic tools in the acute phase of stroke, providing valuable information that is crucial for understanding individual stroke pathology. The discussed studies highlight the potential of various imaging biomarkers, including thrombus characteristics on CT, FLAIR hyperintense vessels, vessel size determined on VSI, and underlying small vessel disease, all of which provide imaging-based physiological information to assess the patientspecific risk-benefit profile. There is still a strong need for the definitions of these imaging biomarkers to be standardized across centers and sites. Only in this way can the true diagnostic and prognostic value of these biomarkers be tested in a multicenter, controlled setting and the actual clinical utility be sufficiently assessed. Nonetheless, the multitude of information gained through different acute imaging modalities can be explored in smaller cohort studies like ours. These findings contribute to both our pathophysiological understanding of ischemic stroke and move us towards a more imaging-based and targeted treatment concept in all-around stroke care.

Situational judgment tests (SJTs) are widely used tools in personnel selection, yet their theoretical foundations remain debated. While traditionally described as contextualized simulations that capture dynamic person-situation processes, recent work has raised doubts about whether SJTs actually require situation construal or rather rely on structural item properties. In my dissertation, I develop and test a working model of SJT responding that integrates person factors (e.g., trait social desirability), item components (e.g., situation descriptions, response options, trait-relevant cues), and the psychological interpretation of the situation (situation construal via ATIC, DIAMONDS, situational strength, and social desirability perceptions). First, I examine ATIC as an individual difference in inferring evaluation criteria, extending its application to SJTs and testing its predictive power under varying incentive conditions. Second, I manipulate SJT item versions to isolate situation descriptions and response options, showing that response options carry most of the construct and criterion validity. Third, I directly test whether construal ratings predict performance across item versions, with results pointing to weak and inconsistent links. Together, these findings suggest that the “situationality” of SJTs lies less in dynamic construal processes and more in their structural design, particularly the information embedded in response options. The dissertation contributes to theory by reframing SJTs as structurally contextualized assessments and to practice by highlighting design properties such as cue quality and construct alignment.

Emerging zoonotic viruses such as SARS-CoV-2, which are capable of crossing the species barrier to humans, highlight the need for robust human model systems to study viral infection mechanisms. The aim of this work was to gain new insights into SARS CoV 2 pathogenesis by developing in vitro models of the upper and lower respiratory tract to simulate infections and evaluate antiviral strategies. Ex vivo infection of human lung tissue serves as an important model to investigate host-pathogen interactions in the distal airways and alveoli. While preserving native tissue architecture, including parenchyma and resident immune cells, the application of human lung tissue is limited by short cultivation time and restricted availability. In this study, alveolar-like organoids were established and optimized for SARS-CoV-2 infection to analyze host-pathogen-interactions while leveraging the advantages of organoid systems. Viral tropism, replication kinetics, and the expression of key entry factors such as ACE2, TMPRSS2, and FURIN were characterized on both genetic and protein levels. To study the tropism of different SARS-CoV-2 strains in the upper respiratory tract, primary human nasal and bronchial epithelial cells were cultured under air-liquid interface (ALI) conditions. Single-cell RNA sequencing and spectral confocal microscopy revealed pronounced infection of basal cells, cell type-specific expression of viral entry factors, and distinct immune responses. Treatment with the protease inhibitor Camostat mesylate significantly reduced viral load and immune activation. By focusing on SARS-CoV-2, this work highlights the value of advanced human in vitro 3D models for studying respiratory pathogens and testing therapeutic interventions. Targeted modelling of various regions of the respiratory tract provides a basis for improved pandemic preparedness.

This thesis demonstrates ultrafast optical control over spins, valleys, and excitons in 2D semiconductors transition metal dichalcogenides (TMDs), advancing their potential for valleybased information processing. Modern scientific research and technology thrives on the ability to control and manipulate quantum degrees of freedom for information storage and transfer. With the discovery of 2D van der Waals materials, “valleys” — the band structure extrema in the momentum space—have emerged as a new degree of freedom for information transfer. TMDs stand out as promising valleytronic materials with valley-selective optical selection rules, spin/valley locking, and excitons with large binding energies. Our key idea is to leverage the two-dimensionality of TMDs, which allows easy manipulation of the valley degree of freedom through techniques such as interfacial engineering and mechanical strain.

The first group of results in this thesis relates to ultrafast tunneling and depolarization of spin/valley-polarized excitation in TMD heterostructures probed by time-resolved Kerr rotation spectroscopy. We demonstrate spin-conserving charge transport across a TMD heterostructure interface and establish control over ultrafast spin relaxation dynamics through Rashba interactions. In TMD heterostructures, interlayer excitons — layer-separated electron-hole pairs with permanent out-of-plane dipoles — serve as a straightforward tool to control Rashba interactions through a self-induced electric field. By systematically varying excitation fluence, sample temperature, and external electric fields in a MoS2/MoSe2 heterostructure, we establish Rashba interactions as a dominant spin relaxation mechanism for T > 70 K, with the spin/valley depolarization rate tunable by an order of magnitude.

Next, we bring together fields of optics and nanomechanics to identify the momentum configuration of excitons, discovering previously inaccessible intervalley excitons associated with the Γ and Q valleys in monolayers of WSe2 and WS2. We demonstrate that ‘strain fingerprinting’ can be used as a general tool to determine the valley configuration of quasiparticles in 2D semiconductors. We also reveal a new class of valley-polarized hybrid excitons in monolayer TMDs with their electronic wavefunctions delocalized across K, K’, Q, and other valleys. By modulating the intervalley energy separation through strain, we achieve a hundredfold reduction in the valley depolarization rate and up to a fivefold increase in the steady state valley polarization for the valley-hybridized excitons compared to previously studied excitons.

To summarize, we advanced ultrafast control of spins and valleys in TMDs through interfacial engineering and mechanical strain. Our results reveal the emergence of new, robust valleybased information carriers, extending TMD valleytronics beyond the conventional K and K’ valleys, paving ways for realizing alternative degrees of freedom in a diverse class of 2D semiconductors.

Specialized metabolites have played a central role since ancient times in medicine, culture, and science, from early herbal remedies to groundbreaking antibiotics, and have always been an extraordinary source of new drug leads, shaping modern drug research. Cyanobacterial specialized metabolites possess chemically diverse structures and a broad range of biological activities, which not only affect aquatic ecosystems and human health but also provide promising opportunities to discover new drug leads. This dissertation presents two case studies demonstrating how high-resolution mass spectrometry, enhanced by advanced computational tools, accelerates and streamlines the discovery and characterization of novel halogenated cyanobacterial specialized metabolites by efficiently mining complex datasets. The first study focuses on new analogues of the anhydro congener of the known herbicide cyanobacterin, all isolated from Tolypothrix sp. PCC 9009. Using a mass spectrometry-based chemical-guided screening, 15 new cyanobacterin analogues were isolated and characterized. Based on the known furanolide core assembly and the findings of this study, a biosynthetic pathway is proposed that may explain the tailoring enzyme reactions leading to cyanobacterin formation, with the newly discovered structures incorporated into the pathway. The second study investigates the pentabrominated biindole alkaloid aetokthonotoxin from Aetokthonos hydrillicola causing Vacuolar Myelinopathy. Based on analyses of environmental samples and supplementation studies, brominated, iodinated, and mixed halogenated aetokthonotoxin congeners and biosynthetic intermediates were discovered, highlighting the remarkable substrate flexibility of the involved halogenases and expanding the previously known biosynthetic pathway. Moreover, cytotoxicity assays of the isolated congeners showed that they differ markedly in their cytotoxicity. The third study, a mode-of-action investigation, reveals that the primary targets of aetokthonotoxin intoxication are mitochondria, where it functions as a weakly acidic uncoupler of mitochondrial respiration via its protonophore activity. The thesis demonstrates the diversity of cyanobacterial halogenated specialized metabolites, the indisputable advantages of the mass spectrometry-based tools mentioned, and has developed adaptable workflows to efficiently mine for these compounds.

The formation of blood and immune cells is sustained throughout life by hematopoietic stem cells (HSCs). Yet, a detailed, quantitative understanding of the output and activity of individual human HSCs is only emerging. Here, somatic mitochondrial DNA (mtDNA) mutations were used as natural barcodes to trace clonal output and dynamics for up to three years. Mitochondrial single-cell ATAC sequencing-based (mtscATAC-seq) was applied to matched bone marrow and peripheral blood samples from three patients undergoing allogeneic stem cell transplantation (alloHSCT) to evaluate hematopoietic regeneration. Clonal reconstitution dynamics were compared to longitudinal profiles from blood samples of three healthy individuals, collectively capturing chromatin accessibility and mutational profiles of over 770,000 cells. Stable cell type compositions were observed for healthy individuals over time, highlighting the robustness of homeostatic hematopoiesis. Following alloHSCT, a sequential pattern of immune reconstitution was observed, with innate immune cells, such as monocytes, repopulating the blood earlier than adaptive immune cells. B cells, for example, were detected only months to years post-transplantation. By approximately two years after transplantation, immune cell compositions reached those observed in healthy individuals. Tracking mtDNA variants over time revealed a higher degree of fluctuation in mutational profiles during early post-transplantation time points, likely reflecting a less stable and more dynamic output during initial engraftment. At later time points, clonal outputs appeared more stable and resembled those of healthy individuals. Despite immune cell expansions in both healthy and transplanted individuals, no strong lineage biases were detected, nor was evidence found for selection-driven dominance or absence of single mtDNA variants. Subtle differences in the mitochondrial mutational signature were detected in alloHSCT patients, most likely related to treatment-associated mutagenesis. In addition to its role as a clonal tracking marker, mtDNA showed high sensitivity in chimerism analysis, but also revealed limitations for phylogenetic inference when used in isolation. Together, these findings provide one of the first longitudinal, single-cell resolved assessments of human hematopoietic clonal dynamics under physiological homeostasis and post-transplantation regeneration. By leveraging mtDNA, new insights into human stem cell behavior were generated, while also highlighting important considerations for future lineage tracing and diagnostic applications.

This dissertation is dedicated to developing new approaches for the discretization and analysis of high-dimensional Markov processes, particularly in molecular dynamics, with a focus on their interactions. The four included articles present methods for addressing associated challenges, such as efficient representation of transfer operators and understanding long-term dynamics. The first two articles focus on representing and understanding the interactions of high- dimensional jump processes through their generators. The first article introduces the Augmented Jump Chain, a method to transform time-dependent Markov processes into time-independent Markov chains. The process description through individual space-time jumps allows for a more efficient numerical treatment of time-dependent processes. The second article develops the Ten- sor Square-Root Approximation, a tensor representation of the generator of diffusion processes that can be explicitly derived from the potential and potentially enables efficient calculations by reducing to low-rank tensors. The final two articles offer new approaches for representing the invariant subspaces of stochas- tic processes using the so-called χ functions, which capture the slowest timescales of the process. These are learned through neural networks with ISOKANN, a method that combines traditional numerical methods and machine learning. The third article focuses on the methodological de- velopment of ISOKANN and the combination of optimal control and adaptive sampling, which allow data to be generated efficiently and iteratively improve the neural network training. The fourth article presents a fundamental interpretation of the χ functions as macro-states, which define a temporal structure for macroscopic transitions, thereby offering a new way to extract representative transition paths. Overall, this dissertation provides new theoretical insights, as well as computation- and data- driven methods, for the analysis of high-dimensional Markov processes, opening perspectives for future applications in molecular dynamics.

Der kardiogene Schock ist trotz moderner Therapieverfahren, wie mechanischer Kreislaufunterstützung, weiterhin mit einer hohen Mortalität assoziiert. Ziel der vorliegenden Arbeit war es, strukturierte Konzepte zur Risikostratifizierung, Therapieallokation und Behandlungsoptimierung zu evaluieren und deren Einfluss auf das klinische Outcome zu untersuchen. Zunächst konnte die SCAI-Klassifikation in einer großen herzchirurgischen Kohorte als valides Instrument zur prognostischen Einschätzung bestätigt werden und bildete die Grundlage für die Implementierung einer ätiologieunabhängigen, standardisierten Behandlungsstrategie. Nach Einführung einer überarbeiteten Standard Operating Procedure mit klar definierten Allokationskriterien für den Einsatz temporärer mechanischer Kreislaufunterstützungsverfahren zeigte sich eine signifikante Verbesserung der Überlebenswahrscheinlichkeit. Über die initiale Therapieentscheidung hinaus adressiert diese Arbeit die Bedeutung der Behandlungsphase unter mechanischer Kreislaufunterstützung, einschließlich der Rolle inflammatorischer Prozesse sowie therapieassoziierter Komplikationen. Dabei konnte gezeigt werden, dass Komplikationen einen wesentlichen Einfluss auf das Outcome haben und dass strukturierte technische und klinische Behandlungskonzepte zur Risikoreduktion beitragen. Zusammenfassend unterstreicht diese Arbeit, dass die Prognose des kardiogenen Schocks nicht allein von der Wahl des Unterstützungssystems abhängt, sondern entscheidend durch standardisierte Behandlungspfade mit strukturierter Patientenselektion, optimierter Therapieführung und konsequentem Komplikationsmanagement geprägt wird.

Schwere zielgerichtete Gewalttaten an Schulen ziehen weitreichende und gravierende Konsequenzen nach sich. Diese wirken sich jedoch nicht allein auf die unmittelbar Geschädigten und deren Familien aus, sondern zusätzlich auf die gesamte Gesellschaft. Insbesondere wenn dabei Menschen physisch verletzt oder gar getötet werden, wird die politische Diskussion sehr emotional und intensiv geführt. Im Nachgang stellt sich häufig heraus, dass der Täter bzw. die Täterin im Vorfeld ein auffälliges Verhalten gezeigt hat sowie gegenüber anderen Personen die Absicht geäußert hat, die Tat zu begehen. Die Gesellschaft stellt bei jedem Vorfall die Frage, ob die Tat hätte verhindert werden können. Es ist belegt, dass Täter*innen Informationen über ihre persönliche Krise und ihre Tatabsichten preisgeben. Es wurde wiederholt festgestellt, dass diese Aussagen häufig nicht ernst genommen werden. Darüber hinaus werden nicht alle Drohungen und Ankündigungen der Polizei oder der Schulleitung gemeldet. Dies erschwert die Umsetzung bestehender Interventionsmaßnahmen. Folglich erhält die betreffende Person meist nicht die Unterstützung, die sie dringend benötigt. Ihre krisenhafte Entwicklung wird nicht abgewendet. Die vorliegende kumulative Dissertation basiert auf drei Manuskripten. Sie befasst sich mit der Frage, wie krisenhafte Entwicklungen bei Schüler*innen besser identifiziert werden können. Das erste Manuskript betrachtet das subjektive Sicherheitsgefühl des Lehrpersonals. Es wird angenommen, dass das subjektive Sicherheitsgefühl die Reaktion des Lehrpersonals auf Drohungen oder Ankündigungen beeinflusst. Da bislang kein Instrument zur Verfügung steht, welches das Sicherheitsgefühl des Schulpersonals bezüglich schwerer zielgerichteter Schulgewalt mit diagnostischen Gütekriterien messen kann, wird im Folgenden ein entsprechendes Instrument entwickelt. Das zweite Manuskript widmet sich der bislang unzureichenden empirischen Fundierung bisheriger Ansätze zur Einschätzung der Ernsthaftigkeit von Drohungen und Ankündigungen. Es wird die Konzeption eines interdisziplinären Aktenanalyseinstruments dargelegt, welches zur systematischen und einheitlichen Erfassung und Analyse von Ankündigungen und Drohungen entwickelt wurde. Mit diesem Instrument wird im dritten Manuskript eine Längsschnittanalyse des Warnverhaltens in deutschen Fällen von schwerer zielgerichteter Schulgewalt durchgeführt. Ziel der Untersuchung ist es, Erkenntnisse über das wahrgenommene Warnverhalten im Verlauf der krisenhaften Entwicklung bis hin zur Tat zu generieren. Die Manuskripte basieren auf den Daten der vom Bundesministerium für Bildung und Forschung (BMBF) geförderten Programme "NETWorks Against School Shootings" (NETWASS) sowie "Tat- und Fallanalysen hochexpressiver zielgerichteter Gewalt" (TARGET) . Die vorliegende Arbeit verwendet Ansätze der Survey- und Einzelfallforschung. Eine Besonderheit des methodischen Vorgehens besteht darin, dass die retrospektiven Analysen der Einzelfälle auf staatsanwaltschaftlichen Akten beruhen. Die durchgeführten Analysen basieren sowohl auf qualitativen als auch auf quantitativen Forschungsdesigns. Die Ergebnisse zeigen, dass sowohl die Furcht als auch die subjektive Einschätzung des Risikos, persönlich durch eine Tat geschädigt zu werden, beim untersuchten Lehrpersonal gering ist. Zudem gehen Lehrer*innen davon aus, dass sie Drohungen und Ankündigungen aktiv ahnden. Dies impliziert, dass Lehrkräfte möglicherweise dazu neigen, eine potentielle Bedrohung voreilig als unbedeutend einzustufen (erstes Manuskript). Es wurde erfolgreich ein Aktenanalyseinstrument entwickelt, das zur systematischen und einheitlichen Erfassung und Analyse von Ankündigungen und Drohungen geeignet ist (zweites Manuskript). Die Längsschnittanalyse zeigt, dass die Täter*innen im Laufe ihrer krisenhaften Entwicklung eine Vielzahl von Warnverhalten preisgeben. Dieses Warnverhalten wird durchaus von anderen Personen wahrgenommen, jedoch häufig nicht als solches erkannt. Da diese Informationen an keiner Stelle miteinander in Verbindung gebracht werden, bleibt das Wissen der einzelnen Akteure über die psychosoziale Krise fragmentiert. In der Konsequenz wird eine krisenhafte Entwicklung bei Schüler*innen nicht erkannt (drittes Manuskript). Ziel muss es sein, Strukturen auszubauen, die die vorhandenen Informationen systematisch zusammenführen und in ihrer Gesamtheit betrachten. Zudem ist es nötig, alle beteiligten Personengruppen darin zu schulen, Warnverhaltensweisen besser identifizieren zu können. Dies wird als große Chance gesehen, krisenhafte Entwicklungen frühzeitig zu erkennen und potentielle Taten zu verhindern.

This work presents projects focusing on the functions of native mucins in physiology and pathology. A variety of functional materials were designed using the outstanding chemical and biological properties of polyglycerol and its derivatives. To advance therapeutic strategies, this work aims to address the modulation of mucin crosslinks implicated in pathological conditions, while simultaneously developing a biomimetic system that accurately mimics the native mucin structure and functions. The first part of this thesis investigated the potential of using polyglycerol-based reducing agents to target disulfide crosslinks in pathological mucus as a potential treatment for muco-obstructive lung diseases. In the first project, thiol functionalities were combined with the anti-inflammatory scaffold dendritic polyglycerol sulfate (dPGS) aiming for a bifunctional compound (dPGS-SH). dPGS-SH induced a significant, dose-dependent chemical reduction of mucin crosslinks in cystic fibrosis sputum, as demonstrated by quantitative western blot analysis. Notably, dPGS-SH showed stronger mucolytic activity than clinically approved N-acetylcysteine (NAC). Moreover, it was proved that mucin multimer degradation relies on thiol-dependent effects using control experiments with the non-sulfated analogue (dPG-SH) and the precursor polymer (dPGS-NH2). Correspondingly, rheological experiments revealed a significant improvement in the viscoelastic properties of CF sputum following dPGS- SH treatment. In addition, no toxicity was observed on primary human nasal epithelial cells up to 5 mM dPGS-SH and the polymer mucolytic was shown to have slower autoxidation of thiols than NAC, even at 37°C. The unique polymeric structure, characterized by high molecular weight and multiple covalently bound thiol groups, distinguishes dPGS-SH from conventional small-molecule mucolytics. The second project aimed to evaluate the mucolytic potential of dithiol- functionalized dendritic polyglycerol (dPG-DTBA) in comparison to the small molecule dithiol reducing agent dithiobutylamine (DTBA). Multiple DTBA functionalities were conjugated to a polyglycerol scaffold via reductive amination. This strategy was intended to minimize alteration of the reducing properties of the dithiol motif, which was approved by determining similar thiol pKa values and disulfide reduction potential (E°’). Notably, the comparison of cell toxic effects on human bronchial epithelia cells revealed a substantially improved cell viability of dPG-DTBA compared to DTBA. Furthermore, it was demonstrated that polymer conjugation decelerates autoxidation and enhances reduction capacity. This was evidenced both by reduction assays using a model disulfide in solution and by macrorheological analysis of a synthetic disulfide hydrogel. Further, it was shown that dPG-DTBA reduces the mucin multimers of CF sputum significantly stronger than NAC with similar potency as unconjugated DTBA. The results obtained in both projects established a strong rationale for continuing the translational efforts of the presented mucolytic polymers. Further steps will focus on evaluating the effects of these compounds on mucus-producing human airway epithelial cells cultured at the air-liquid interface. Particular attention will be paid to mucociliary transport using particle tracking and rheological changes assessed using magnetic microwire rheology. In vivo studies employing bENaC mouse models are planned to further elucidate the therapeutic potential of the polymer mucolytics including mucolytic and anti-inflammatory readouts. Additionally, the pharmacological application parameters, such as compound stability and distribution during nebulization, must be systematically examined to optimize delivery and efficacy in clinical settings. In the third project, a dendronized polysulfate p(G1AAm-OSO3)PDS with an acrylamide- backbone as mucin-inspired polymer (MIP) was synthesized and its potential as inhibitor was evaluated using herpes simplex virus 1 (HSV-1). The morphology and inhibitory activity to its polymethacrylate analogue MIP was evaluated and compared. Both polymers showed mucin-like elongated fiber structure, as revealed in cryo- electron microscopy (cryo-EM) imaging, with similar relative stiffness. This suggests that backbone rigidity is not the determining factor for the worm-like morphology of both polymers. Both polymers showed potent HSV-1 inhibition with half-maximal inhibitory concentration (IC50) values in nanomolar range. Furthermore, the novel MIP displayed high cell compatibility, and prophylactic and therapeutic activities were evaluated using pre- and post-infection inhibition assays, further supporting its potential as an HSV-1 inhibitor. This thesis presented sulfation as initial functionalization of mucin-inspired polymers to integrate mucin function as polyelectrolyte. However, the functions of native mucins rely on complex effects involving charge- and glycan-mediated interactions with pathogens. Future investigations will focus on integrating mucin glycan functions, with the ultimate aim of achieving broad-spectrum inhibitory activity against various types of pathogens. Further, the crosslinking sites of the presented structures will be investigated with respect to their hydrogelation properties via thiol-disulfide interchange reactions. This approach enables the generation of a mucus- mimetic hydrogel system, which can serve as a potential platform to study pathogen interactions in 3D.