The generation of movements is a fundamental function of the central nervous system. The neural circuits responsible for the execution of motor commands are distributed throughout the spinal cord and regulate the coordinated activation of multiple muscles across different joints and body regions, in response to motor and sensory stimuli. Therefore, effective communication between different spinal segments is essential for ensuring a synchronized motor performance. Recent studies have highlighted the importance of long-projecting spinal interneurons, known as propriospinal neurons (PN), in coupling distant spinal circuits to guarantee limb coordination and postural stability during locomotion. However, their subtype identity and precise functions are not yet completely understood. Here, we set out to systematically characterize PN from an anatomical, molecular, and functional perspective. First, by using rabies retrograde tracing, we studied the anatomical organization of ascending (a) and descending (d) PN. Second, we performed transcriptional analysis to reveal their molecular signatures. In particular, we characterized three different populations of aPN whose properties are consistent with two ventral cardinal interneuron subtypes (V0G and V3) and a specific subset of neurons expressing Sst, residing in a stereotyped and conserved position in the lateral deep dorsal horn. Finally, by taking advantage of the identified anatomical and molecular features, we designed intersectional strategies to unravel the functional roles of V0G and Sst+ aPN subtypes in vivo. Our results show that V0G aPN play a crucial role in modulating corrective motor reflexes, while Sst+ aPN appear to be involved in regulating sensorimotor integration. Taken together, our findings provide new insights into the anatomical and molecular diversity of PN subtypes and pave the way for future research into their functional significance for motor and sensorimotor control.

Inflammation, followed by an anti-inflammatory phase mediated by immune cells, is essential for tissue healing. Prolonged inflammation caused by severe injuries can impair regeneration. Elderly patients suffering from major trauma, such as a hip fracture, are at high risk for delayed healing due to excessive inflammation. This leads to muscle loss and fibrosis post-surgery, which reduces the quality of life and increases mortality in this cohort. Cell therapy could support patients in their regenerative process. This thesis investigates the immunomodulatory effects of placenta derived stroma cell (PLX-PAD) therapy on muscle repair in a Phase III study. PLX-PAD promotes the differentiation and migration of muscle precursor cells in vitro. Their unique properties counteract pro-inflammatory stimuli from activated immune cells. Injection of PLX-PAD during surgery resulted in improved muscle strength and volume, highlighting their therapeutic potential. Fracture healing shares similarities with muscle regeneration, where prolonged inflammation can lead to delayed healing and non-union of bones. This process is influenced by the individual immune cell composition in the local hematoma, bone marrow, and peripheral blood. This work reveals how fracture hematoma is a distinct and transient tissue with diverse immune cell subsets, including B cells. B cells appear to play a role in fracture healing, but their role in trauma has not been characterized well. B cells in the fracture situation shed the complement receptor CR2/CD21, likely triggered by cell-free DNA released from damaged cells. Fracture hematoma also induced the dsDNA Toll-like receptor 9 in vitro. This activation may help clear cellular debris and promote an anti-inflammatory environment. As described in the literature, the expected antibody response upon CD21/TLR9 activation did not yield conclusive results in this study and corresponding cell cultures. Due to the unpredictable nature of trauma, patient-specific research is challenging. A bone and bone marrow organ-on-a-chip system was developed to replicate the immune composition of patients and predict clinical outcomes, such as the impact of metal implant debris. This system will be further refined to study fracture healing over time while preserving individual donor variability. In summary, this thesis emphasizes the importance of modulating the local microenvironment for musculoskeletal regeneration by interacting with pro-inflammatory immune cells and fostering an anti-inflammatory milieu necessary for successful healing.

Flüchtlingslager sind der Inbegriff von Displacement. Sie gelten als geschlossene und isolierte Räume, die vom ökonomischen, kulturellen und sozialen Austausch mit der Aufnahmegesellschaft und weiterreichenden Netzwerken abgeschnitten sind. Sie werden als »Nicht-Orte« wahrgenommen, an denen Menschen nur vorübergehend zusammenkommen, ohne eine Beziehung zueinander oder zu diesem Ort zu entwickeln. Die Vorstellung, dass Flüchtlinge in Lagern in einem sozialen »Schwebezustand« leben, hat zudem zu der Annahme geführt, dass kollektive Veränderungsprozesse an diesen Orten zum Stillstand gekommen sind. In meiner Arbeit zeige ich jedoch, dass Flüchtlingslager auch Orte des Emplacement sein können, an denen neue kollektive soziale, politische und räumliche Zugehörigkeiten entstehen. Emplacement bezeichnet den Prozess, in dem Menschen sich einen unwirtlichen Ort aneignen und ihn mit der Zeit in einen Ort der Zugehörigkeit transformieren. Ich untersuche diesen Prozess am Beispiel der saharauischen Flüchtlingslager in Algerien, eine der langwierigsten Flüchtlingssituationen weltweit. Die Lager sind charakterisiert durch den Kampf der saharauischen Bevölkerung um die noch immer ausstehende Dekolonisierung ihres Landes, der Westsahara, und durch tiefgreifende sozioökonomische Veränderungen. In diesen Prozessen spielt Mobilität eine wichtige Rolle. Sie ist in den letzten Jahrzehnten sehr facettenreich, zirkulär und transnational geworden und erstreckt sich über die Flüchtlingslager, Nordwestafrika, Europa, Asien und die Amerikas. In meiner Arbeit zeige ich auf, wie sich die sozialen, politischen und räumlichen Zugehörigkeiten saharauischer Flüchtlinge in diesem Kontext entwickelt haben, und gehe insbesondere auf die Erfahrungen der zweiten Flüchtlingsgeneration ein. Damit trage ich zu einem erweiterten Verständnis des Zusammenhangs von Ort und Zugehörigkeit in langwierigen Flüchtlingslagern bei.

Das Ziel der Studie war es, verschiedene diagnostische Möglichkeiten zur Bewertung des Säuren-Basen-Status (SBS) bei Milchkühen unter den Bedingungen der landwirtschaftlichen Praxis zu evaluieren, um fütterungsabhängige, subklinische Störungen des SBS in einer Tier- bzw. Fütterungsgruppe frühzeitig zu erkennen. In Teilstudie 1 wurde die seit mehreren Jahrzehnten etablierte Harnanalyse zur indirekten Beurteilung des SBS mittels drei Verfahren zur titrimetrischen Bestimmung der Netto-Säuren-Basen-Ausscheidung (NSBA) im Harn angewandt, sodass der SBS von 127 Kuhgruppen anhand der einfachen NSBA nach Kutas, der differenzierten NSBA nach Lachmann und Schäfer sowie des vereinfachten NSBA-Siebtestes mit reduziertem Probenvolumen nach Furcht und Grätsch bewertet wurde. Berücksichtigt wurden dabei die Einzeltierergebnisse von 855 Milchkühen der Rasse „Deutsch Holstein“ aus 43 Thüringer Milchviehbetrieben. Die Tiere wurden im Rahmen eines Gesundheitsmonitorings in verschiedenen Laktationsstadien als „Trockensteher“ (21 bis sieben Tage ante partum), „Frischabkalber“ (zwei bis 10 Tage post partum) oder „laktierende Kuh“ (30 bis 100 Tage post partum) beprobt. Die Beurteilung der Ergebnisse von Poolproben aus drei bis 10 Einzeltieren eines Laktationsstadiums wurde der Bewertung anhand der Einzeltierergebnisse gegenübergestellt. Als Referenz galt die Bewertung des Basen-Säuren-Quotienten im Harn nach Lachmann und Schäfer, da dieser Quotient von der Harnkonzentration unabhängig ist und damit den Goldstandard für die Bewertung des SBS im Harn darstellt. Die einfache NSBA nach Kutas auf Einzeltierbasis erwies sich als geeignet, um Abweichungen des SBS in einer Tiergruppe zu detektieren. Azidotisch belastete Kuhgruppen wurden mit einer Sensitivität von 87 % bei einer Spezifität von 71 % und alkalisch belastete Kuhgruppen mit einer Sensitivität und Spezifität von je 83 % erkannt. Die Beurteilung des SBS im Harn mittels differenzierter NSBA wies lediglich in dem eingeschränkten Bereich von 20 – 200 mmol/l einen linearen Zusammenhang zwischen dem errechneten Mittelwert einer Kuhgruppe und dem gemessenem Poolwert auf. Die differenzierte NSBA als Poolwert zeigte eine mäßige Sensitivität (74 %) zur Erkennung azidotisch belasteter Kuhgruppen und eine schlechte Sensitivität (48 %) zur Erkennung alkalisch belasteter Kuhgruppen. Die NSBA-Siebtest-Methode erwies sich aufgrund einer schlechten Sensitivität (57 %) und Spezifität (63 %) zur Erkennung alkalisch belasteter Kuhgruppen als nicht geeignet zur Überwachung des SBS einer Milchviehherde. In der Teilstudie 2 wurden an einem Teil der Studientiere (n = 145 aus 14 Betrieben) die Harnparameter zur Bewertung des SBS über eine hierarchische Clusteranalyse mit im peripheren Blut gemessenen metabolischen Parametern und den Ergebnissen der venösen Blutgasanalyse verknüpft. Die Variablen der traditionellen SBS-Analyse nach Henderson-Hasselbalch, die Bikarbonat-Konzentration, der Base Excess und die Anionenlücke (AG), wurden den Variablen des Strong-Ion Konzeptes nach Stewart und Constable gegenübergestellt. Studieninterne Referenzwerte wurden hierfür aus einer Stichprobe von metabolisch unauffälligen Kühen ermittelt. Subklinische, gemischte Störungen des SBS konnten durch die Berechnung und Bewertung der Variablen Strong Ion Difference (SID) und Acid Total (Atot) sicher erkannt und differenziert werden, wobei der Einfluss von Laktationsstand und Rationszusammensetzung auf diese Variablen nachweisbar war. Anhand einer kleinen Kuhgruppe (n = 5 Tiere) wurde zudem deutlich, dass sich eine ketotische Belastung nur im SBS-Modell nach Constable widerspiegelt, indem die Variable SIG (strong ion gap) signifikant erniedrigt war. Die venöse Blutgas- und Elektrolytanalyse mit der Einbeziehung des Strong-Ion-Konzeptes erwies sich als eine sinnvolle diagnostische Ergänzung zum Auffinden von subklinischen Störungen des SBS von Milchkühen. Aufgrund der präanalytischen Anforderungen, die unter landwirtschaftlichen Praxisbedingungen nur schwer erfüllbar sind, wird sie in der Routinediagnostik jedoch keine Alternative für die herkömmliche Beurteilung des SBS im Harn der Kühe darstellen können. Das Fehlen von validen Referenzwerten für die Variablen SID, Atot und SIG für Milchkühe stellt zudem ein Problem für die Anwendung des Strong-Ion-Konzeptes zur Beurteilung des SBS von Milchviehherden dar und sollte durch künftige Studien behoben werden. Zusammenfassend ist festzustellen, dass die Bestimmung der einfachen NSBA im Harn nach Kutas eine in der Praxis valide diagnostische Möglichkeit darstellt, um den SBS von Milchviehherden zu überwachen und fütterungsbedingte, subklinische Störungen in der Herde zu erkennen. Die Bewertung von Poolproben zur Beurteilung des SBS einer Kuhgruppe ist dabei nur eingeschränkt möglich, sodass der Bestimmung und Beurteilung von Einzeltier-proben der Vorzug zu geben ist. Bei Bedarf und unter Einhaltung der präanalytischen Voraussetzungen kann die Harnanalyse sinnvoll durch venöse Blutanalysen und Ein¬beziehung der Variablen des Strong-Ion-Konzeptes ergänzt werden.

Die Fontan-assoziierte Lebererkrankung (Fontan-associated liver disease, FALD) ist eine der häufigsten Sekundärorganerkrankungen bei Patientinnen und –Patienten mit einer Fontan-Zirkukation. Unter FALD werden alle strukturellen, laborchemischen und funktionellen hepatischen Abnormalitäten zusammengefasst, welche durch die unphysiologische Fontan-Zirkulation entstehen. Im Konsens wird von einer multifaktoriellen Pathogenese basierend auf den hämodynamischen Charakteristika des Fontan-Kreislaufes und den hieraus resultierenden Veränderungen der hepatischen Zirkulation ausgegangen. In der vorliegenden Arbeit wurden sechs Publikationen zu dem Thema Langzeitkomplikationen der univentrikulären Palliation mit dem Schwerpunkt der FALD vorgestellt. Die Arbeiten umfassten Querschnittstudien zur Erfassung der morphologischen und funktionellen Merkmale der FALD. Den Schwerpunkt der Studien stellten die Untersuchung der Einflussparameter auf die Entstehung und den Progress dieser Sekundärorganerkrankung dar.

Pyrrolizidine alkaloids are secondary plant metabolites that are found in herbal medicines and supplements, as contaminants in food such as teas and spices and in livestock feed. Within this structurally diverse group, the 1,2-unsaturated pyrrolizidine alkaloids (PAs) are subject of drug and food safety assessment due to their hepatotoxic, genotoxic and carcinogenic effects. Retrorsine, a prototypic hepatotoxic PA, is one of the most frequently detected PAs in tea samples. Current risk assessment is facing data gaps for PAs including retrorsine not only with regard to their absorption, distribution, metabolism and excretion (ADME) characteristics, but also in vivo dose-response studies that are needed to derive health-based exposure limits for consumers are missing. In addition, cytochrome P450 (CYP) 3A4 induction by drugs increases the formation of toxic CYP3A4 metabolites and thereby potentially enhances PA toxicity. However, a quantitative analysis of PA-drug interactions in humans is lacking. The objectives of this doctoral work were (1) in vitro ADME characterization of PAs (2) development and evaluation of a physiologically-based pharmacokinetic (PBPK) model for PAs including relevant biomarkers for hepatotoxicity, (3) in vitro-to-in vivo extrapolation of cellular hepato-cytotoxicity data by means of reverse PBPK modeling for mice and rats (4) PBPK-based simulation of human PA kinetics with CYP3A4 induction under patient-relevant conditions. Apart from the relevance for food safety, we selected retrorsine as representative PA for PBPK model development due to the availability of in vivo kinetic data of the parent compound and its CYP3A4 metabolites, speciffcally toxic DNA and protein adducts as well as detoxifying glutathione conjugates, in mice and rats. Since key in vitro ADME characteristics for retrorsine like lipophilicity, blood partitioning, plasma protein binding, intestinal absorption, hepatic uptake and metabolism are hitherto unknown, we designed, executed and analyzed corresponding experiments. Lipophilicity and blood partitioning were determined for retrorsine and additional PAs intermedine, lasiocarpine, monocrotaline and their N-oxides (PANOs). Remaining unknown parameters of the retrorsine PBPK model were estimated based on the available in vivo kinetic data using maximum likelihood estimation and Monte Carlo analysis. The PBPK model was evaluated with separate in vivo kinetic data. For extrapolation of liver toxicity, in vitro concentration-response data for retrorsine obtained from cytotoxicity assays with primary mouse and rat hepatocytes were translated to in vivo dose- response data by PBPK-based reverse modeling. We performed benchmark dose modeling of predicted dose-response data to obtain benchmark dose confidence intervals for acute liver toxicity of retrorsine in mice and rats. Regarding CYP3A4 induction, we focused on the antibiotic rifampicin due to its fullly available PBPK characterization for human. Daily intake of retrorsine from herbal tea was simulated for a time span of five weeks accompanied by a daily therapeutic dose of rifampicin for two weeks. PAs and PANOs were hydrophilic and had a low binding affinity toward red blood cells. Plasma protein binding of retrorsine was low indicated by the fraction unbound in plasma of 60.0%. The estimated fraction absorbed from the intestine of retrorsine was high (78.3%). Hepatic uptake of retrorsine showed species differences up to factor 2 between humans, rats and mice (1.02, 0.887 and 0.516 mL/min/g liver, respectively). Species-differences up to factor 4 were observed for the liver metabolic clearance of retrorsine, which was highest in rats, followed by humans and mice (2.07, 1.03 and 0.497 mL/min/g liver, respectively). The PBPK model of retrorsine was based on a generic structure with 13 anatomical compartments. Implementation of the liver compartment according to the extended clearance model allowed to integrate liver metabolism and transport. Unknown PBPK model parameters, speciffically intestinal absorption rate constant, biliary clearance and parameters related to formation and depletion of DNA and protein adducts and glutathione conjugates, were estimated with high precision. The parametrized PBPK model showed convincing predictivity by adequately describing hepatic retrorsine kinetics and its DNA adducts in mice. Translation of measured in vitro hepato-cytotoxicity data to in vivo acute liver toxicity of retrorsine resulted in benchmark dose 90% confidence intervals of 24.1 to 88.5 and 79.9 to 104 mg/kg body weight in mice and rats, i.e. that a single oral dose of retrorsine within this interval leads to a 5% increase in liver toxicity. For the simulated CYP3A4 induction, a reduction of retrorsine plasma 24 h-area under the curve and maximum concentration was observed. This reduction was strongest directly after rifampicin discontinuation (to 67% and 74% compared to rifampicin-free reference, respectively). Retrorsine kinetics returned to baseline 14 days after stop of rifampicin intake. After five weeks, the cumulative formation of toxic CYP3A4 metabolites of retrorsine, increased to 254% (from 10 to 25 nmol) in the intestine due to the impacted metabolism kinetics, but not in the liver (57 nmol). In summary, the developed PBPK model allowed to predict benchmark dose confidence intervals for acute liver toxicity based on in vitro data in absence of in vivo dose-response studies. Furthermore, the PBPK approach was shown to be an efficient tool to explore the interplay of enzyme induction and toxification pathways. Prospectively, the model can be utilized as a flexible tool for extrapolation to other relevant species or other hepatotoxic PAs.

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency affecting one in 250,000 individuals, caused by defects in genes encoding the NADPH oxidase (NOX) complex in phagocytes. X-linked CGD (X-CGD) results from mutations in the CYBB gene encoding the gp91phox subunit, impairing the generation of superoxide required for pathogen elimination. Current treatments include lifelong antimicrobial prophylaxis, interferon-gamma therapy, corticosteroids, and, occasionally, hematopoietic stem cell transplantation (HSCT), though their limitations necessitate new therapeutic strategies. Gene therapy is a promising approach for monogenic diseases like X-CGD, with hematopoietic stem cells (HSCs) offering an ideal target due to their differentiation capacity. However, limited HSC availability and expansion efficiency pose challenges. Mouse models with patient-derived mutations provide an unlimited HSC source for optimizing gene therapy techniques. This study characterizes the first X-CGD mouse model carrying a patient-derived mutation, replicating disease symptoms and phenotype. A CRISPR/Cas9 homology-directed repair (HDR) strategy was developed to correct the Cybb gene mutation, validated through genomic, protein expression, and functional analyses, together with an off-target assessment confirming the specificity and safety of the gene-editing approach. Additionally, the study explored HIROS (homology-independent replacement of sequence) for Cybb gene correction, offering insights despite suboptimal efficiency at the targeted locus in HSCs. These findings contribute to advancing HSC gene therapy. In conclusion, this work deepens the understanding of X-CGD, establishes a mouse model carrying a patient-derived mutation, and develops gene correction strategies, providing a foundation for future therapeutic interventions targeting genetic disorders in hematopoietic stem cells.

The aim of this thesis is to construct efficient numerical solvers for linear saddle point problems arising from discretizations of phase-field models.

We are particularly interested in systems of Cahn–Hilliard and Penrose–Fife types. The numerical approximation of these models leads to large-scale nonsmooth nonlinear saddle point problems that have be solved in each time step. To efficiently treat these nonlinear problems, there is an efficient generalized Newton approach (NSNMG). Our attention then turns to the subproblems generated by the NSNMG method. More precisely, the NSNMG generates large linear saddle point problems whose solutions dominate the total computational time. Classical multigrid methods applied directly to these problems typically lack robustness.

These linear saddle point problems are heterogeneous in the sense that they can be decoupled into an elliptic problem on one part of the domain and a smaller-sized linear saddle point problem with the same structure on the remaining part of the domain. We develop and analyze an efficient and fast-converging domain decomposition algorithm in the context of Cahn–Hilliard equations.

For the (multi-phase) Penrose–Fife equations, we develop a symmetric positive definite Schur complement preconditioner, which is based on a spectrally equivalent approximation of the actual Schur complement.

Die kumulative Dissertation konzentriert sich vorwiegend auf die Beziehung zwischen rechtsextremen Einstellungen und rechtsextremen Straftaten bei Jugendlichen. Da solche Straftaten jedoch auch bei Jugendlichen nicht isoliert von ihrem sozialen Kontext betrachtet werden können, nimmt die Arbeit das soziale Umfeld der Jugendlichen in den Blick. Somit wird zum einen die Rolle der Einstellungen der den Jugendlichen nahestehenden Personen (Eltern, Freund*innen, Lehrkräfte) in der Beziehung zwischen rechtsextremen Einstellungen und Verhaltensweisen betrachtet. Zum anderen wird die Relevanz von Kontextmerkmalen der Schulklasse und des Landkreises untersucht. Neben der Fokussierung auf das soziale Umfeld wird in der vorliegenden Dissertation noch ein weiterer Themenbereich aufgegriffen. Im Zusammenspiel von Einstellungen und Verhalten stellt sich die Frage, welche weiteren Einstellungen neben der rechtsextremen Einstellung selbst vorliegen müssen, damit diese in entsprechendes Verhalten mündet. Es wird daher zudem die Verschwörungsmentalität als möglicher Katalysator in der Beziehung zwischen rechtsextremen Einstellungen und Straftaten untersucht, da sowohl der jugendliche Verschwörungsglaube an sich als auch seine Rolle im Kontext Rechtsextremismus bisher kaum erforscht sind. Anhand von vier Artikeln werden folgende Forschungsfragen untersucht: 1. Wie verbreitet sind rechtsextreme Einstellungen und Straftaten unter Jugendlichen (alle Studien)? 2. Welche potentiellen Bedingungsfaktoren rechtsextremer Straftaten lassen sich identifizieren (Studie 1)? 3. Inwiefern stehen menschenfeindliche Einstellungen mit der Ausführung politisch motivierter Taten in einem Zusammenhang (Studie 2)? 4. Inwiefern stehen menschenfeindliche Einstellungen und die (hypothetische) Befürwortung einer politisch motivierten Tat im sozialen Umfeld mit der Ausführung politisch motivierter Taten in einem Zusammenhang (Studie 2)? 5. Inwiefern verändert sich der Zusammenhang zwischen eigenen menschenfeindlichen Einstellungen und der Ausführung politisch motivierter Taten, wenn das soziale Umfeld diese (hypothetisch) befürwortet (Studie 2)? 6. Inwiefern verändert sich der Zusammenhang zwischen der (hypothetischen) Reaktion des sozialen Umfelds und der Ausführung politisch motivierter Taten bei unterschiedlicher Ausprägung der eigenen menschenfeindlichen Einstellungen (Studie 2)? 7. Inwieweit hängt der soziale Kontext in Niedersachsen in Form der Landkreise und Schulklasse mit der Ausprägung rechtsextremer Einstellungen von Jugendlichen zusammen und inwiefern unterscheidet sich der Zusammenhang zwischen den Dimensionen von Rechtsextremismus (Studie 3)? 8. Wie verbreitet ist eine Verschwörungsmentalität unter Jugendlichen (Studie 4)? 9. Inwiefern steht eine Verschwörungsmentalität mit der Ausprägung rechtsextremer Einstellungen und diskriminierender Verhaltensweisen gegenüber ausländischen und homosexuellen Personen in einem Zusammenhang (Studie 4)? 10. Welche Rolle spielt die Verschwörungsmentalität in der Beziehung zwischen rechtsextremen Einstellungen und diskriminierenden Verhaltensweisen gegenüber ausländischen und homosexuellen Personen (Studie 4)?

Continental rifting is a major plate tectonic process in which the lithosphere stretches and thins, eventually causing continents to break apart by creating two conjugate rifted margins. Continental rifts often emerge in places that have been shaped by prior orogeny. The correlation between ancient orogenic belts and young rift systems highlights the importance of orogenic inheritance in shaping the complexities of rift and rifted margins alike. However, there is limited geological data from offshore domains of rifted margins, which challenges the understanding of the role of inherited orogenic structures. In addition, the issue is further complicated by the diverse nature of orogenic inheritance, characterized by variations in thermal state, compositional properties, and structural complexity across multiple scales, along with the superimposed phenomenon of subsequent extensional processes that reactivate inherited structures. This raises the critical question of how orogenic inheritance influences the evolution of rifts and the final architecture of rifted margins. In this thesis, a geodynamic numerical modelling approach is employed, integrating the thermomechanical modelling software ASPECT and the landscape evolution code FastScape to simulate the formation of orogens and rifts within the context of the Wilson Cycle. To this aim, I conduct so-called "accordion models" that involve a first phase of shortening that is followed by a phase of extension. In contrast to geological interpretation, this numerical modelling offers the advantage of generating orogenic inheritance in a self-consistent way that allows to directly quantify geological processes. Furthermore, because this coupled numerical model incorporates erosion and sedimentation, it allows for the exploration of feedback mechanisms between tectonic and surface processes. Finally, all involved parameters can be controlled, enabling detailed analysis of specific types of inheritance over the entire evolution of plate convergence and divergence. I demonstrate the applicability of these numerical models by comparing results to selected natural rifted margins worldwide. The first chapter of this thesis provides a short introduction to the research topic. I summarize main results of previous work and isolate remaining knowledge gaps. In addition, this chapter introduces the numerical modelling software used in this thesis. In the second chapter, I present two-dimensional numerical modelling where I systematically alter the velocity boundary conditions across temporal stages. Hence the model simulates successive phases of continental collision, post-orogenic collapse, continental rifting, and ultimately continental breakup, as observed in the South China Sea (SCS), a marginal basin in South East Asia. I successfully generate rifted margin architectures that align with geophysical observations in the SCS. To explore the role of orogenic inherited structures more broadly, I present alternative model scenarios incorporating variations in shortening velocities, surface erosion efficiency, and lithosphere strength. I analyze these scenarios and find that orogenic inheritance governs the reactivation of thrust faults, with continental breakup consistently occurring in regions formerly characterized by a thick crustal root. Third, I investigate the combined impact of orogenic inheritance and surface processes on the exhumation of lower crust at rifted margins, an enigmatic finding at many rifted margins. I simulate an initial phase of orogeny followed by continental breakup and vary the syn-orogenic erosion efficiencies to understand their influence on rifted margin architecture. These models clearly show that the erosion of mountain belts thins the upper crust, reducing the upper-to-lower crustal ratio prior to rifting. This process facilitates the exhumation of lower crustal material during extension, exposing it at the Earth’s surface along the footwall of normal faults. This finding leads me to propose a new conceptual model to explain lower crustal exhumation observed at rifted margins worldwide, including the northern margin of the South China Sea, the Gulf of Lion, the Aegean Sea, and the Norwegian margin. The fourth thesis chapter, focusses on the comparison of rift evolution in both simple homogeneous lithosphere and accordion models incorporating orogenic inheritance. By varying the rheological properties and surface erosional efficiency, I reproduce a variety of rifted margin architectures. Through quantitative analysis of the model results, I find that models with pre-rift orogenic inheritance reduce the far-field forces required for rift initiation, delay continental breakup, and result in wider rifted margins compared to homogeneous lithosphere models. Additionally, the application of a healing process to eliminate structural inheritance and the incorporation of a phase of tectonic quiescence to remove transient thermal inheritance allows investigation of the relative roles of different types of inheritance: structural inheritance predominantly controls rift initiation forces, margin width, and breakup location, while thermal inheritance governs crust-mantle interactions, significantly influencing rift migration, breakup timing, and margin symmetry. I also find that compositional inheritance, defined by rheological interfaces, consistently dominates, producing asymmetric rifted margins. These findings, validated through comparisons with natural examples, provide new insights into the broader implications of different orogenic inheritance types for rift system evolution. Finally, in Chapter 5, I provide concluding remarks and an outlook for potential future work where I develop 3D modelling approaches. By including a periodic boundary, I could explore rifted margin architectures simultaneously impacted by oblique extension and orogenic inheritance. (See Chapter 5.2). With these findings, I hope to improve our understanding of orogenic inheritance on rifted margin formation. Further development of geodynamic software accounting for even more realistic process in conjunction with detailed comparison with observational data may help to explore the dynamic process interaction that shape rifts and rifted margins.

X-chromosome inactivation (XCI) is the mechanism of dosage compensation in mammals whereby one X-chromosome in every female cell is transcriptionally silenced during early embryonic development to ensure equivalent dosage of X-chromosome-linked genes between males and females. The process of XCI is closely coupled to exit from the pluripotent state. Pluripotency factors inhibit the process of XCI, and conversely the presence of two active X-chromosomes in female cells delays the exit from the pluripotent state. Female mouse embryonic stem cells, that have two active X-chromosomes, have been previously reported to display a more n ̈aive state of pluripotency including higher expression of pluripotency factors, slower kinetics of downregulation of pluripotency factors upon induction of differentiation. Additionally, they show decreased expression of MAPK and GSK3 target genes, but elevated levels of MAPK pathway intermediates such pMEK. However, the molecular mechanisms underlying the observed differences between the mESCs based on differential X-dosage are not well understood. In my doctoral project, I combined systematic perturbation experiments with mathematical modeling to interrogate the signaling network that regulates XCI and pluripotency in mESCs and to find differences in this network based on the differences in X-chromosome dosage. A female mESC line and its subclone that has lost one X-chromosome were used as a model system. I quantified the response of cells with one (XO) or two X chromosomes (XX) to a variety of inhibitors and growth factors. I then built models of the signaling networks in XX and XO cells through a semi-quantitative modeling approach based on modular response analysis (MRA). MRA-based modeling resulted in the discovery of novel links in the network and quantitative comparison of the model parameters using profile likelihood led to identification of the links underlying X-dosage-based differences. A novel negative feedback was identified in the PI3K-AKT pathway through GSK3. Moreover, it was found that the presence of a single active X makes mESCs more sensitive to the differentiation-promoting Activin A signal and leads to a stronger RAF1-mediated negative feedback in the FGF-triggered MAPK pathway. The differential response to these differentiation-promoting pathways can explain the impaired differentiation propensity of female mESCs.

We rely on the Internet as a ubiquitous communications network for critical functions ranging from financial transactions to emergency and crisis alerts. Organizational, policy, and technical efforts have been made to enable users to assess the trustworthiness of the hosts with which they communicate. However, this host-centric approach to trust fails if a network path to the host in question cannot be established. Our research aims to understand trust, decouple it from hosts, and bind it to the data itself to achieve object trust, which ensures trustworthy data exchange even when the source is unavailable.

In this thesis, construct a trust framework for the Web, measure the effectiveness and deployment of security and trust mechanisms on the Web, and assess the suitability of these mechanisms for information-centric networks. Our contributions have operational implications for today's Internet and pave the way for the integration of trust mechanisms into other network paradigms.

Clinical psychoneuroendocrinology (PNE) focuses on identifying dysregulations of the biological stress system in mental disorders, with major depressive disorder (MDD) being one of the most extensively studied. Various studies in MDD samples have demonstrated dysregulations in both arms of the biological stress system, which consists of the autonomic nervous system (ANS), and the hypothalamus pituitary adrenal (HPA) axis, primarily pointing to chronic hyperactivity. However, results are not unequivocal with some researchers reporting stress system hypoactivity in MDD samples. One explanation for these contradictory findings is the substantial methodological heterogeneity in the assessment of stress system markers such as salivary alpha-amylase, and cortisol. These methodological issues pose a significant challenge for clinical PNE, particularly since there appears to be a disconnection affecting the implementation of insights gained from basic research on reliable stress marker assessment in the clinical field. This highlights the need for practical advice on standardization measures and reporting transparency to reduce heterogeneity. These issues are particularly relevant for the investigation of PNE mechanisms of change during psychotherapy. In MDD, the relationship between treatment response and biological stress system regulation has not been established yet. More specifically, it is unclear whether potential pre-intervention dysregulations of the stress system might be alleviated in MDD patients benefiting from psychotherapeutic treatment, compared to patients who do not benefit. A particularly promising approach could be the investigation of single symptom trajectories, as opposed to aggregate symptom scores. Particularly in MDD, aggregate scores often mask divergent symptom manifestations (e.g., insomnia vs. hypersomnia), which may have fundamentally different biological underpinnings. This PhD thesis aims to address the issues outlined above. First, I will present two overview papers, which summarize the current state of psychotherapy PNE research (Chapter two) and offer insights on which cortisol assessment strategies PNE experts consider essential to obtain reliable data (Chapter three). The results of the expert ratings aided in creating the Cortisol Assessment List (CoAL), a weighted instrument to designed to document cortisol assessment strategies prospectively or evaluate cortisol data quality retrospectively, which is also presented in Chapter three. The following two chapters investigate neuroendocrine correlates of treatment response to an internet-based intervention for mild to moderate depression. The results of the first study (Chapter four) show that the pre-intervention diurnal alpha-amylase slope predicted treatment response according to an overall depression score, with nonresponders exhibiting a steeper increase throughout the day. This indicates pre-intervention ANS hyperactivity in these participants. Furthermore, we found an association between the trajectory of subjective sleep quality and the cortisol awakening response (CAR), which I present in Chapter five. At pre-intervention, MDD patients with poor sleep quality exhibited a blunted CAR, compared to MDD patients with better sleep quality. Responder analyses demonstrated that participants with a marked pre-post improvement in long-term sleep quality also showed a significant pre-post increase in the CAR. These results indicate a change-sensitive association between a single symptom of MDD and the biological stress system. In conclusion, papers one and two form an overview cluster with a methodological focus on stress marker assessment in clinical research. They provide the reader with practical advice regarding reliable data collection in clinical PNE. These recommendations form the basis of papers three and four focusing on the association between treatment response and changes in the biological stress system in MDD. Hence, while the methodological cluster enables the transfer of insights from basic research to the clinical field, the clinical cluster demonstrates the feasibility of such an approach. Furthermore, the results of the clinical cluster show an association between psychotherapeutic treatment response and the biological stress system, especially for subjective sleep quality. The meaning of theses results for PNE as a research field and implications for future research are discussed in the final section of this PhD thesis.

This thesis explores the dynamics of faulting, vertical deformation, and stress within the Hellenic Subduction System (HSS) forearc, focusing on the islands of Kythira, Antikythira, Kassos, Karpathos, and Rhodes. Using techniques such as field mapping, analysis of high-resolution Digital Elevation Models (DEMs), seabed bathymetry, stress inversion and dating methods like radiocarbon and Sr-isotope dating, the study uncovers the geological processes that contribute to shaping the region's landscape over several different time-scales during the Quaternary.

The investigation of normal faults in Kythira and Antikythira unveils their unique characteristics. These faults, which accommodate NE-SW extension, exhibit a wide range of variations in terms of length and cumulative displacement (over short and long-term term scales). The study also reveals a significant increase in fault activity on some faults since the Last Glacial Maximum, indicating periods of intense earthquake activity. Notably, while shorter faults demonstrate more variability in their displacement rates, the overall network of faults displays a more stable net cumulative extension due to fault interactions.

On Karpathos Island, the research undertakes a comprehensive mapping and dating of marine terraces and sediments to unravel the intricate vertical motion of the island's landmass over time. The findings bring to light the complex nature of this motion, with uplift rates showing a much faster pace over short time scales compared to longer periods. The vertical motion of Karpathos is influenced by a multitude of factors, including sediment underplating, which adds material to the base of the upper plate, large earthquakes at the plate boundaries, and smaller earthquakes caused by horizontal stretching of the Aegean crust. Thus, several processes interact across time-scales to deform the island.

This thesis also examines the stress state of the Hellenic subduction forearc by analyzing 43 active faults along the forearc along all islands *(including Crete). It identifies the obliquity of the convergence as critical factors shaping fault kinematics and geometry. In the western part of the margin, where the obliquity is low, faults run parallel to the trench. In the eastern region, where the obliquity is high, faults accommodate extension oblique to the margin, leading to different patterns of crustal deformation.

This thesis provides a comprehensive look at the tectonic processes (over a range of time scales) shaping the Hellenic Subduction System. Bridging time scales is crucial to improving our understanding of the phenomena that interact to shape the earth. Hence, the studies presented in the following chapters have used datasets on various time scales.

Seit der Humboldt’schen Bildungsreform um 1810 gilt an deutschen Universitäten das Ideal der Einheit von Forschung und Lehre. Diese Prämisse prägte die Lehre über die Jahrhunderte hinweg als wissenschaftlich orientiert. Die Bologna-Reform, die 1999 unterzeichnet wurde und praktische sowie berufsvorbereitende Ausbildungselemente in die Curricula integrierte, veränderte dieses Grundverständnis zunächst nur geringfügig. Allerdings leitete sie einen grundlegenden Veränderungsprozess an den Hochschulen ein. Ab 2010 verstärkte das Bundeswirtschaftsministerium mit der Förderlinie „EXIST Gründungskultur“ diesen Praxisbezug weiter, indem es die wirtschaftliche Ausgründung wissenschaftlicher Erkenntnisse förderte. Ziel dieser Initiative war der Aufbau einer hochschulweiten Gründungskultur an den geförderten Einrichtungen. Hochschulen, die sich um diese Förderung bewarben, mussten in ihrer Lehre Wissenschaft, Praxis und Gründungskultur miteinander verbinden. Doch wie lässt sich die Lehre zwischen dem Humboldt’schen Ideal und einer praxisnahen Ausbildung gestalten? Wie stark nehmen Lehrende diese scheinbar widersprüchlichen Anforderungen wahr, und welche Konsequenzen ergeben sich daraus für die Gestaltung der Lehre? Die vorliegende Dissertation untersucht die Implementierung von Gründungskultur an deutschen Universitäten, die traditionell vom Humboldt’schen Bildungsideal geprägt sind, unter besonderer Berücksichtigung der damit verbundenen institutionellen Spannungen und deren Einfluss auf die Lehre. Die Arbeit stützt sich theoretisch auf die Annahme, dass das Vorhandensein unterschiedlicher institutioneller Logiken zu Spannungen führt, die auf Makro-, Meso- und Mikroebene sichtbar werden. Im Rahmen einer qualitativen, eingebetteten Einzelfallstudie wird das Förderprogramm EXIST IV analysiert, das darauf abzielt, unternehmerisches Denken und Handeln an Universitäten zu fördern. Die Ergebnisse zeigen, wie Lehrende in einem Spannungsfeld zwischen Wissenschaft und Praxis agieren und welche Strategien sie entwickeln, um den widersprüchlichen Anforderungen gerecht zu werden. Auf Grundlage dieser Erkenntnisse wird ein erweitertes theoretisches Framework vorgestellt, das die Auswahl geeigneter Strategien in Situationen institutioneller Spannungen unterstützt. Die Arbeit leistet sowohl praxisrelevante Implikationen für Hochschulpolitik und Universitätsmanagement als auch konzeptionelle Beiträge zur Organisationstheorie.

Pickering emulsions—emulsions stabilized by nanoparticles—are well-known for their pronounced stability. They are promising candidates for pharmaceutical applications aimed at improving drug loading efficiency, facilitating drug penetration in topical delivery, and protecting sensitive drugs in oral delivery. Among colloidal stabilizers, nanogels, as soft nanoparticles, can spontaneously adsorb to interfaces and facilitate emulsification, exhibiting distinct interfacial behavior compared to their solid nanoparticle counterparts. Importantly, a thorough understanding of the types of emulsions is crucial for designing new pharmaceutical formulations for specific applications. However, emulsions involving nanogels are predominantly of the oil-in-water (O/W) type, due to the hydrophilic nature of most nanogels studied. In contrast, reports of water-in-oil (W/O) emulsions with more hydrophobic nanogels are less common and tend to be case-specific. Currently, a comprehensive understanding of the correlation between nanogel hydrophobicity and emulsion types is still lacking. To bridge this knowledge gap, a series of nanogels with tailored and varied hydrophobicity were synthesized and used to create both O/W and W/O emulsions with oils of differing polarity. Importantly, the types of emulsions were correlated with nanogels’ swellability in the solvents and their differential affinity for oil and water. This correlation was visualized through atomic force microscopy studies on nanogels immobilized on solidified oil-water interfaces. Quantitatively, the differences of Flory-Huggins interaction parameters between nanogels with water and oil (χwater − χoil) serve as a numerical approach to describe such affinity differences. Moreover, it was found that more deformable nanogels at the oil-water interfaces exhibit faster adsorption kinetics and demonstrate greater efficiency for emulsification. These hydrophobicity-dependent emulsification properties were also found to be temperature-sensitive. At elevated emulsification temperatures, W/O emulsions are favored, suggesting a temperature-induced preference for nanogel interaction with the oil phase. The stability of these emulsions upon cooling to room temperature underscores the strong adhesion of nanogels at the interfaces, effectively locking the nanogels in place. In the first part of this study, as described above, competitive affinity of nanogels for water and oil was identified as the underlying principle for emulsion type determination. To further understand the influences of nanogel hydrophobicity on their interfacial behavior, studies were conducted on nanogels at air-water interfaces. These interfaces served as simplified model systems to isolate the interaction of nanogels with the water phase by excluding influences of the oil phase. It was observed that at the air-water interfaces, nanogels deform less and tend to form aggregates with enhanced hydrophobicity. These findings provide potentially valuable insights for understanding the corresponding foams and emulsions from the interfacial nanogel films. Overall, nanogels with tailored hydrophobicity serve as a versatile platform for the development of Pickering emulsions with adjustable properties. The critical insights gained in stabilization mechanisms hold significant promise for the tailored design of advanced Pickering emulsions, applicable in fields ranging from pharmacy and biomedicine, to interfacial catalysis and beyond.

In der vorliegenden Arbeit werden experimentelle Untersuchungen im Rahmen eines Mausmodells und eines translationalen Ansatzes, sowie klinische Forschungsergebnisse bezüglich der Behandlung und Prognose von Subarachnoidalblutungen (SAB) dargestellt. In der experimentellen Studie wurde die Beteiligung von Neutrophil Extracellular Traps (NETs) an SAB assoziierten Immunreaktionen identifiziert. Die Ergebnisse zeigten erstmalig eine räumliche und zeitliche Dynamik der Bildung von NETs nach der Ruptur eines intrakraniellen Aneurysmas und liefern somit die Basis für weitere grundlagenwissenschaftliche Studien. Der verzögerte Höhepunkt der NET-Belastung sowohl im Mausmodell als auch in humanen Proben deutet auf ein potenzielles therapeutisches Zeitfenster nach dem Blutungsereignis hin, um inflammationsgetriebene sekundäre Hirnschäden nach einer SAB abzumildern. Eine Therapie mit RNase A konnte unter Laborbedingungen die Belastung an NETs sowohl in basalen, kortikalen wie auch periventrikulären Bereichen reduzieren. Dies deutet auf eine Rolle im Auf- und Abbau von NETs und somit in der Modulation der Reaktionen des angeboren Immunsystems auf eine SAB hin. Ein Einsatz als Therapeutikum ist grundsätzlich vorstellbar, jedoch sind hierfür weitere umfangreiche Forschungsarbeiten notwendig. Im klinischen Teil der vorliegenden Arbeit konnte gezeigt werden, dass interventionsbedingte Komplikationen bei der Versorgung von Patient:innen häufig auftreten und einen negativen Einfluss auf das neurologische Outcome der Patient:innen haben. Als unabhängige Risikofaktoren für das Erleiden einer Komplikation bei der Behandlung eines rupturierten Aneurysmas konnten die Lokalisation des Aneurysmas, ein erneutes Blutungsereignis vor der Intervention, der Tag der Behandlung, sowie die Anzahl an eingeschlossenen Studienpatient:innen je Zentrum ermittelt werden. Interventionsbedingte Komplikationen traten dabei unabhängig von der Behandlungsmodalität auf. Im Rahmen der Studie wurden 51,2% der Patient:innen mittels Coiling und 48,8% durch mikrochirurgisches Clipping behandelt. Da die Entscheidung der Behandlungsmodalität der/dem Behandler:in überlassen wurde, unterstreichen die Daten, dass beide Techniken im klinischen Alltag weiterhin eine wichtige Rolle spielen. Sowohl für das Clipping, als auch das Coiling, sind somit stetige Verbesserung der Interventionstechniken wichtige zukünftige Forschungsfelder. Die weiteren Arbeiten zeigten, dass sich das Gesamtliquordrainagevolumen zwischen Patient:innen mit gutem und schlechtem neurologischen Outcome nach einer SAB nicht unterscheidet. Bei der Betrachtung der einzelnen Kompartimente zeigte sich jedoch ein hohes Volumen und ein hoher Anteil an lumbal drainiertem Liquor mit positiven Outcome assoziiert, während sich hohe Drainagemengen aus einer externen Ventrikeldrainage (EVD) negativ auswirkten. Die Daten deuteten dabei auf einen möglichen potenziell mengenabhängigen Schutzeffekt durch eine lumbale Drainage hin. Des Weiteren zeigte sich eine Assoziation zwischen den ermittelten Hirndruck (ICP) Höchstwerten und dem Auftreten von schlechtem neurologischen Outcome. Es könnte somit therapeutisch sinnvoll sein nach einer SAB zur Detektion von ICP-Spitzen eine kontinuierliche ICP-Messung durchzuführen und das lumbale Drainagevolumen auszuweiten. Der Einsatz von lumbalen Drainagen wird im klinischen Alltag jedoch häufig restriktiv gehandhabt, da beim Vorliegen einer intrakranialen Pathologie eine konsekutive infratentorielle Herniation gefürchtet wird. In einer prospektiven Pilotstudie wurde hierfür der ICP nicht, wie in der klinischen Praxis gewohnt, lediglich als Absolutwert analysiert, sondern seine Eigenschaften als wellenförmige Druckkurve ebenso mitberücksichtigt. Es zeigte sich, dass Oszillationsanalysen auf Basis der arteriellen Blutdruck (ABP)-, ICP- und Lumbaldruck (LP)- Kurve potenziell sichere Phasen einer Lumbaldrainage mit geringem Risiko einer infratentorielle Einklemmung anzeigen können. Des Weiteren konnte beobachtet werden, dass das Vorliegen von ICP-Werten im Normbereich < 20 mmHg keine Sicherheit vor einer möglichen Einklemmung beim Einsatz einer Lumbaldrainage bietet. Die Arbeit lieferte somit eine wichtige Grundlage um mit Hilfe einer Echtzeit-Schwingungsanalyse am Patient:innenbett eine weniger invasive Hirndrucküberwachung durch eine alleinige lumbale Drainage zu ermöglichen und um Lumbaldrainagen potentiell ausgiebiger bedienen zu können. Vor einem klinischen Einsatz sind hierzu jedoch weitere umfangreiche Forschungsarbeiten notwendig. In der abschließenden Arbeit konnte gezeigt werden, dass moderne ML-Modelle zu einer Verbesserung der Vorhersage eines shuntpflichtigen Hydrocephalus nach einer SAB beitragen können, indem sie auf Basis von früh im Krankheitsverlauf vorliegenden Daten gute Vorhersagergebnisse erzielen können. Die beste Performance erreichten Mehrschichtige Perzeptronen Modelle, sowie Tree-Boosting-Algorithmen. Die Arbeit legte, durch den Vergleich mit traditionellen Scores und der Berechnung von Wichtungen einzelner Faktoren für das jeweilige Modell, einen Schwerpunkt auf eine Nachvollziehbarkeit der Ergebnisse. Die Studie liefert somit eine Grundlage für die weitere Entwicklung von Machine LearningAnwendungen, die nachvollziehbar im klinischen Alltag Behandler:innen unterstützen können.

Due to their ubiquitous presence throughout the universe, one may scarcely even dare to count the sheer number of collisions between atoms and molecules occurring at any given moment in time. Even so, the laws of nature governing the interaction between such vanishingly small particles have eluded observers for all but a tiny fraction of the history of science. The work presented in this thesis is motivated by the quest to gain an enhanced understanding of collisions governed by quantum mechanics, which might ultimately lead to useful applications such as the control of chemical reactions. To this end, we have leveraged the power of a general and flexible theoretical de- scription of scattering, which, specialised to the case of atoms colliding with diatomic molecules, can be translated into a feasible numerical simulation which is compared and contrasted with ground-breaking experiments, opening avenues for in-depth analysis of quantum effects. At the forefront of these effects are Feshbach resonances, a phenomenon leading to the short-lived formation of ‘quasi-bound’ states between colliding particles due to the resonant coupling between scattering and bound states. Simulations of cold col- lisions between either helium or neon and dihydrogen or hydrogen-deuterium molecules have been carried out, allowing us, for instance, to gain insight into the role of the nuclear spins of diatomic molecules and its connections to the symmetry of the collision complex. Interestingly, we can show that despite being highly anisotropic, the systems studied here still demonstrate a noteworthy sensitivity to various factors influencing the outcome of the collision. Further, we have turned our attention towards the electronic structure of interacting atoms and molecules, designing, implementing and applying an algorithm to improve ab-initio potential energy surfaces used for cold collisions between helium and dihydrogen molecules by incorporating measured data derived from Feshbach resonance experiments. Obtaining a potential energy surface in this way is in the spirit of machine learning - a widespread and useful tool in the context of electronic structure calculations. Along the way, we have discovered the viability and limitations of adopting different approaches to modifying potential energy surfaces and gleaned a better understanding of their connection to Feshbach resonances. Finally, we have repurposed the simulated data in order to reveal some of the dynami- cal details of the collision process. Specifically, by regarding the wavepacket of the system as a superposition of the scattering states at many different collision energies, we are not only able to reconstruct the wavepacket at different times during the interaction but also see how some interesting observables change as a function of time. This approach is of interest, for example, in evaluating the trajectory of the interacting particles or to judge whether certain states the system may end up in are populated directly or through intermediate states.

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.