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.

Global groundwater resources are under stress due to high extraction rates, pollution, landuse changes, and the impacts of climate change. In India, too, the decline in groundwater level is a growing issue for water supply. This is well investigated in northern India, but groundwater resources are also declining in parts of South India. While surface water historically supplied agriculture, it has been largely replaced by groundwater irrigation since the 1950s, resulting in the overexploitation of fragile aquifers. Population growth, urbanisation, and rising food demand are further intensifying water needs. Climate change adds uncertainty, with projections of higher temperatures, shifting rainfall patterns, and greater drought risks. The Sathaiyar basin, located in the South Indian state of Tamil Nadu, is marked by locally declining and rising groundwater levels, providing a unique case to study these dynamics. Half of the basin is covered by a cascade of irrigation tanks, which are small surface water bodies that store excess river water and rainwater. The primary objective of the present work is to assess the impact of i) natural groundwater recharge, as well as ii) indirect recharge from irrigation tanks on groundwater. The quantification of natural recharge was conducted using two approaches: the first involves simulating the infiltration of rainwater through the unsaturated zone, and the second evaluates the water level time series from an observation well. The local impact of tanks was assessed by modelling the saturated-unsaturated zone processes of two separate irrigation tanks. On the catchment scale, the effect of the tank cascade on groundwater was investigated using hydrochemical and stable isotope tracers. The natural groundwater recharge was simulated with three Hydrus 1D models. By calibrating the models with stable water isotopes from soil water at different depths, they provided reliable information on the quantity of recharge through different soils while considering the influence of varying vegetation. Using only the soil water content for model calibration would have resulted in a large range of recharge rates, which emphasises the importance of using multiple data sources to build a reliable model. At the site with the highest clay content of up to 80%, groundwater recharge is nearly negligible 0.01 cm from May to February, whereas at the site with only 20% clay, recharge amounts to 31 cm for the same period. The results are in the order of magnitude of the recharge estimated using the time series model Pastas, where the estimated annual recharge is up to 4.7 cm yr−1. Analysis of the data from rainfall stations in the catchment indicated a minor increasing trend for two stations, but no trend for the remaining locations. This suggests that natural recharge has only a small impact on groundwater level rise and is unlikely to increase substantially in the future. In contrast, the recharge from irrigation tanks is high: the spatio-temporal trend analysis of groundwater level time series shows that groundwater levels are mainly increasing below the tank cascade. Most likely, the increasing trends are caused by the iii infiltration capacity of the tanks. The results of the two tank models show a significant contribution of both tanks to groundwater recharge. As the tanks in the cascade are filled with water for most of the time throughout the year, recharge is mainly limited by low depth to groundwater and the resulting limited storage capacity of the aquifer. Model results suggest that regular desilting of the tank bed would increase infiltration rates. Another important parameter that strongly influences tank recharge efficiency is the hydraulic conductivity of the weathered hard rock. In the present study, it was constrained by calibration; future work could determine it directly using field experiments or tracer studies. The extent of the tanks’ impact was further investigated by using hydrochemical and isotope tracers 𝛿2𝐻 and 𝛿18𝑂 on the catchment scale. Samples from groundwater and tank water were taken before and after the monsoon season. The recharge effect of tanks could be demonstrated even in deep wells (up to 230m depth) by means of stable isotopes. An apparent difference was observed between the groundwater upstream of the tanks and the groundwater influenced by the tanks. Besides the benefit of enhanced groundwater quantity, a deterioration in its quality has been identified by hydrochemical analysis. Groundwater near tanks receiving sewage inputs showed evidence of anthropogenic pollutants, while agricultural activities additionally impacted the hydrochemical composition. In the present study, the influence of anthropogenic activities, such as sewage discharge and agrochemical application, could not be clearly distinguished from the natural processes that influence the chemical composition of groundwater. Employing tracers with higher specificity for human activities may enhance the resolution of future studies. The results of this work suggest that natural groundwater recharge is insufficient to balance current human extraction rates in the catchment during the study period. In contrast, the tank cascade provides sustained, indirect recharge and seems to be an effective tool for local water resources management. This benefit, however, is tempered by limited water quality, which emphasises the need to pair recharge management with upstream sanitation and water quality monitoring.

Object vision relies on neural computations across regions of the ventral visual pathway, mediated by feedforward and feedback connections. While anatomical studies have revealed a dissociation between these connections, the functional organization and roles of the associated information flows remain unclear, as feedforward and feedback processing operate in parallel with overlapping spatial and temporal profiles.

Leveraging the laminar specificity of feedforward and feedback projections in the visual cortex, I conducted two lamina-resolved functional magnetic resonance imaging (fMRI) studies to investigate the neural signatures of these two information flows in human object vision. In Study I, I examined the laminar organization of feedforward and feedback signals in high-level ventral visual cortex by contrasting visual perception and mental imagery. In Study II, I combined lamina-resolved fMRI with electroencephalography (EEG) to resolve the spatiotemporal dynamics of concurrent feedforward and feedback signals during object perception in early visual cortex (EVC) and the lateral occipital complex (LOC). Additionally, I characterized the representational format of these signals by comparing their neural representations to those derived from a deep neural network.

This work yielded three key findings. First, during perception, both feedforward and feedback signals are distributed across cortical layers in high-level ventral visual cortex, whereas during imagery, feedback signals are predominantly confined to the deep layers. Second, during perception, transient feedforward signals first emerge in the middle layers of EVC and LOC, followed by sustained feedback signals to the superficial layers of both regions and the deep layers of EVC. Third, feedforward signals to LOC convey mid-level feature information, while feedback increases representational complexity, aligning more closely with high-level visual representations.

Together, these findings provide novel insights into the laminar, temporal, and representational architecture of feedforward and feedback processing, shedding light on how these information streams shape human object vision.

This dissertation examines the contemporary epistemic crisis through the lens of counter-knowledge orders (CKOs). It argues that struggles over truth in the contemporary epistemic crisis extend beyond disagreements over facts or individual claims to contestations of the knowledge order itself. Whereas the established knowledge order is stabilized through institutionalized practices, CKOs reorganize these practices, redistribute epistemic authority, and challenge the hierarchies of knowers and knowledge. This conceptual framework is developed across three previously published papers and the present document, which synthesizes the papers’ findings. Paper I reconceptualizes the German COVID-19 protests as an emergent counter-knowledge order. Through structural topic modeling, as well as network and discourse analyses, Paper I demonstrates how protest actors constructed a parallel epistemic community, elevating false epistemic authorities and reinforcing group identity through conspiratorial imaginaries and superiority claims. Paper II investigates online monitoring activism (OMA) as a civic response to the mobilization identified in Paper I. The second paper conceptualizes OMA as a form of civic surveillance practice that both resists extremist mobilization and raises normative questions about citizens’ roles as the established order’s vigilante protectors. Paper III further theorizes on CKOs in the far-right context. The third paper situates CKOs among broader debates in communication science, social epistemology, and the sociology of knowledge, showing that far-right attacks on the established knowledge order must be understood as attempts to rule the entire knowledge process without resistance. Across the three previous papers and the present chapter, this dissertation advances the study of contemporary knowledge struggles in five ways. First, it develops the CKO concept as a heuristic for understanding conflicts concerning not only facts but also the knowledge order itself. Second, this research grounds this concept empirically by examining the COVID-19 protest movement, OMA, and far-right mobilization, showcasing its analytical value across diverse contexts. Third, the dissertation combines perspectives from communication science, social epistemology, and the sociology of knowledge, situating CKOs within broader discussions of epistemic authority, polarization, and democracy. Fourth, it introduces a new normative lens, considering epistemic justice as an alternative perspective on CKOs’ emergence and thus establishing a nuanced view of CKOs as both a danger to epistemic democracy and a possible response to the exclusion and misrecognition of knowers’ epistemic capacity. Finally, it demonstrates methodological breadth, combining computational, qualitative, and conceptual approaches to demonstrate the robustness and versatility of the framework.

The present work is a descriptive study of Ṭuroyo, an endangered Neo-Aramaic (Semitic) language that was originally spoken in the Tur Abdin region, part of what is now southeastern Turkey. Today, Ṭuroyo is preserved primarily in the diaspora, especially in large communities in Germany, Sweden, and the Netherlands. The focus of the study is on the constructions and forms associated with changes in diathesis and valency. The analysis follows a three-part structure: first, the verbal stems are examined; next, the relevant constructions; and finally, the interaction between the two. Based on corpus data and elicitation data from a hitherto little-studied Semitic language, the study addresses lexical and grammatical polysemy—a central problem both for language-internal description and for theoretical linguistics. In doing so, it draws on scholarly insights and methods from various linguistic approaches, including the Moscow School of Semantics and cognitive semantics.

Combinatorial optimization is intimately related to various scientific disciplines that originated from different historical roots, such as constraint programming and satisfiability. Despite their differences in origin, the methods developed within these fields exhibit many similarities while simultaneously offering complementary strengths and weaknesses, which suggests their integration for solving difficult optimization problems. This thesis addresses three real-world applications by integrating combinatorial optimization techniques with methods from adjacent disciplines, specifically constraint programming, satisfiability, and automata theory.

First, the logic-constrained shortest path problem (LCSPP) is studied. In this variant of the shortest path problem, only paths satisfying general logical constraints, expressed as propositional formulae on arcs, are admissible. A branch-and-bound method for the LCSPP is developed that incorporates domain reduction techniques from the satisfiability community. The practical relevance of the algorithm is demonstrated by solving a flight planning problem that takes traffic flow restrictions imposed by air traffic control into account. Compared to a mixed-integer programming solver, the hybrid approach achieves a run-time improvement of over two orders of magnitude.

Second, the first exact solver for price-optimal routing in public transit that is able to represent intricate real-world fare structures is presented. The solver is based on the notion of conditional fare networks, which are hybrids of language and resource constraints. Based on this model, the multi-objective RAPTOR algorithm is adapted for price-optimal route planning. This result is further generalized to a class of shortest path problems, in which paths are evaluated based on a general partial order.

Finally, this thesis examines a scheduling problem arising in cargo handling in hub airports. Here, logic-based Benders decomposition is employed to integrate mixed-integer programming and constraint programming, achieving computation times that are less than half of those required by a mixed-integer programming approach.

Ein zentrales Ziel des naturwissenschaftlichen Unterrichts ist die Förderung einer naturwissenschaftlichen Grundbildung (Scientific Literacy). Diese umfasst auch ein Verständnis über die Natur bzw. Kultur der Naturwissenschaften (Nature of Science, NOS). NOS beschreibt die Eigenschaften, Bedingungen und Grenzen naturwissenschaftlicher Erkenntnisprozesse. In der naturwissenschaftsdidaktischen Forschung wird intensiv diskutiert, welche NOS-Aspekte im Unterricht adressiert (inhaltliche Dimension) und wie diese dargestellt werden sollten (unterrichtsmethodische Dimension). Die Biologie, Chemie und Physik haben Gemeinsamkeiten, aber auch Unterschiede zueinander. Aus wissenschaftstheoretischer Perspektive lassen sich Besonderheiten biologischer Forschung auf spezifische Eigenschaften biologischer Forschungsobjekte zurückführen. Zudem hängt das NOS-Verständnis von Schüler:innen und Lehrkräften von der jeweils berücksichtigten Disziplin ab. Folglich sollten für eine differenzierte Analyse und Förderung des NOS-Verständnisses Unterschiede zwischen einzelnen naturwissenschaftlichen Disziplinen in einer Konzeptualisierung von NOS berücksichtigt werden. Mit dem Family Resemblance Approach (FRA) werden Naturwissenschaften wie Mitglieder einer Familie beschrieben, die Gemeinsamkeiten, aber auch Unterschiede zueinander aufweisen. Dadurch können neben disziplinübergreifenden auch disziplinspezifische NOS-Aspekte beschrieben werden. Ziel dieser Arbeit ist es, den FRA unter Berücksichtigung der Besonderheiten biologischer Forschung zu differenzieren und zu kontextualisieren, sowie aufzuzeigen, wie NOS-Aspekte in Unterrichtsmaterialien wie Schulbüchern dargestellt werden. Zudem soll anhand konkreter Lerngelegenheiten für den Biologieunterricht verdeutlicht werden, wie es gelingen kann, Besonderheiten der Biologie in die Unterrichtspraxis zu integrieren. Bezogen auf die inhaltliche Dimension wurden in einer Schulbuchstudie NOS-Aspekte, die im Biologie-Curriculum enthalten sind, beschrieben. Auf dieser Grundlage wurden in einer Interviewstudie mit Fachwissenschaftler:innen und Wissenschaftstheoretiker:innen biologiespezifische NOS-Konzepte entwickelt, mit denen Zusammenhänge zwischen den Eigenschaften biologischer Forschungsobjekte und Besonderheiten biologischer Forschung beschrieben werden. Bezogen auf die unterrichtsmethodische Dimension wurde untersucht, wie NOS in unterschiedlichen Kapiteln von Biologie-Schulbüchern dargestellt ist. Die Ergebnisse zeigen, dass NOS-Aspekte in den Einführungskapiteln signifikant häufiger explizit dargestellt sind als in fachlich kontextualisierten Kapiteln. Zudem wurde diskutiert, welche Möglichkeiten für eine Kontextualisierung von NOS in einer Lerngelegenheit für den Biologieunterricht bestehen. Auf Grundlage dieser Erkenntnisse wurden verschiedene Lerngelegenheiten in Form konkreter Vorschläge für die Praxis entwickelt, mit denen das NOS-Verständnis im Biologieunterricht gefördert werden kann. Insgesamt leistet diese Arbeit einen innovativen Beitrag in der fachdidaktischen NOS-Forschung, indem auf Grundlage des FRA empirisch gestützte biologiespezifische NOS-Konzepte aus curricularer, fachwissenschaftlicher und wissenschaftstheoretischer Perspektive entwickelt wurden. Zudem konnten anhand der empirischen Erkenntnisse konkrete Möglichkeiten für die Gestaltung von Unterrichtsmaterialien für den Biologieunterricht aufgezeigt werden.

Transposable elements (TEs) and their repressors, KRAB zinc finger proteins (KRAB-ZNF proteins), play pivotal roles in shaping regulatory innovation during vertebrate evolution, particularly in primates. This study introduces TEKRABber, a computational framework developed to enable systematic analysis and cross-species comparison of TE expression and KRAB-ZNF interactions. TEKRABber provides standardized normalization and differential expression analysis of TE subfamilies using outputs from various RNA-seq quantification tools, facilitating downstream exploration of TE–gene and TE–KRAB-ZNF relationships within and between species.

Application of TEKRABber to multiple RNA-seq datasets, including human cortical samples from healthy and Alzheimer’s disease patients as well as brain tissues from four primate species, revealed evolutionary patterns in KRAB-ZNF–TE regulatory networks. Bipartite network analysis identified an increased number of KRAB-ZNF–TE interactions in humans compared to other primates, particularly involving recently evolved TEs such as Alu elements. Notably, ZNF528 , a KRAB-ZNF gene under positive selection in the human lineage, showed numerous human-specific interactions. Negative correlations were primarily observed with Alu elements, consistent with transcriptional repression, while other TEs were more frequently associated with positive correlations. In Alzheimer’s disease samples, a regulatory subnetwork consisting of 21 Alu-associated interactions appeared reduced or absent, suggesting a potential link between TE dysregulation and neurodegeneration.

To investigate the molecular basis of these interactions, multi-omic integration of KAP1 ChIP-seq and RNA-seq data from B-lymphoblastoid cells (B cells) of humans, chimpanzees, and orangutans was performed. Thousands of species-specific KAP1-binding sites were identified, the majority of which overlapped with TEs located in intronic or intergenic regions. Genes proximal to KAP1 peaks in non-human primates were enriched for neuronal development functions and more frequently downregulated than in humans. Locus-specific TE expression profiles were incorporated into downstream analyses with TEKRABber, enabling detailed comparisons of transcriptional activity across species. These analyses revealed that KAP1-bound TE loci are generally transcriptionally repressed. By combining motif analysis, gene expression, and binding profiles, species-specific regulatory networks were reconstructed, linking differentially expressed KRAB-ZNF genes to their putative targets. These findings underscore the utility of TEKRABber in integrating multi-modal data and support the hypothesis that the evolving interplay between KRAB-ZNFs and TEs contributes to lineage-specific gene regulation and primate brain evolution.

Storing energy from renewable but intermittent energy sources such as wind and solar into chemical bonds is one of the most promising strategies we have for transiting from fossil fuel-based technologies and addressing the environmental challenges we currently face. A vital part of this strategy is the production of hydrogen through electrochemical water splitting, where the oxygen evolution reaction (OER) is still a fundamental bottleneck and the rate-limiting part of the reaction. Recent efforts have focused on developing efficient electrocatalysts for alkaline electrolysis using earth-abundant materials such as 3d transition metal oxides and hydroxides based on Ni and Co. Notably, it has been found in previous work that cationic species in the electrolyte can strongly influence the properties of these materials. The exact impact of these species and how they alter the catalyst morphology under reaction conditions, however, remain poorly understood due to lack of in situ and operando microscopy investigations that reveal such changes at the nanoscale. Among the impurities relevant to OER, iron (Fe) is particularly influential. It has been widely reported that incorporating Fe into Ni or Co-based OER catalysts, whether intentionally or unintentionally, significantly enhances their OER activity. However, obtaining direct insight into how Fe alters the structure of Ni and Co (hydro)oxides during the reaction remains a challenge, which in turn limits our understanding of the mechanisms behind its role. A major part of my thesis focuses on revealing the effect of Fe impurities in the electrolyte on catalyst morphology using state-of-the-art operando microscopy and spectroscopy methods, especially with electrochemical liquid-cell transmission electron microscopy (EC-TEM). In the latter part of the thesis, I will discuss the impact of a more innocuous but common cationic impurity, Na, on the long-term evolution of Ni hydroxides reacted in potassium hydroxide. In Chapter 3, I first describe the specific changes that occur in NiO when Fe is added into the electrolyte. To track the chemical changes arising from Fe impurities, I extended our EC-TEM study to incorporate time-resolved energy-dispersive X-ray spectroscopy (EDS) mapping of the samples under reaction conditions. These results together with supporting evidence from additional operando spectroscopy measurements on the same pre-catalysts revealed that when Fe is present in the electrolyte during OER, it transforms the NiO surface into a superficial layer of NiFe layered double hydroxide. This continuous transformation of the surface can be correlated with the beneficial shift in onset potential for water oxidation. The superficial layer, however, does not grow with further reaction time in the presence of Fe. Instead, Fe aggregates start to form once the NiO surface becomes saturated and these aggregates poison the surface, leading to a decrease in the anodic currents for OER. Building on the findings from Chapter 3, I extended our investigation to the incorporation of Fe into Co and Ni hydroxides (Chapter 4). Specifically, I studied the behavior of Co(OH)2 nanosheets and investigated their chemical and structural changes during OER, with and without Fe impurities, through correlated operando microscopy and spectroscopy. Here, operando scanning transmission X-ray microscopy measurements were performed to provide spatially resolved information about the catalyst oxidation state. The results revealed that Co(OH)2 underwent significant restructuring in Fe-free electrolytes by forming amorphous CoOxHy, which was accompanied by catalyst dissolution-redeposition where Co were redeposited as Co3+ or Co3+δ (hydr)oxide nanoparticles. In the presence of Fe, I saw significantly less redeposition and the formation of a stable Co(Fe)OOH phase on the surface, which I attributed to the reduced morphological changes. The lower average oxidation state of Co observed in our system is a direct consequence of this reduced dissolution-redeposition cycle, highlighting how the balance of restructuring, dissolution and redeposition alters the performance of Co-based catalysts and leads to a revised interpretation of the function of Fe versus that of the Co host during catalytic processes. In Chapter 5, this thesis broadens its scope to examine the influence of Na+ and K+ ions in a KOH electrolyte. Here, we compared the evolution of well-defined Ni(OH)2 nanoplates in NaOH, KOH and KOH with trace amounts but defined impurity concentration of Na+. Through both electrochemical and (operando) structural characterization, I show that even trace-amounts of Na+ ions in a KOH electrolyte accelerates the β- to γ-NiOOH phase transition of the catalyst, resulting in lower long-term OER activity. This is driven by the different intercalation behaviors of metal cations. Specifically, the β-NiOOH phase tends to overcharge into the γ-NiOOH phase upon intercalation of K+. The presence of Na+ ions, with their larger hydrated radius, further facilitates this overcharging in mixed electrolytes by expanding the interlayer structure. This work provides valuable new insights into the relationship between cation intercalation and surface restructuring in nickel-based catalysts. It also emphasizes the importance of controlling cation composition in the electrolyte to optimize OER performance. In summary, the work described in this thesis reveals the structural changes induced by cationic impurities in model Ni and Co-based pre-catalysts for OER. Scientifically, it highlights how we must consider the impact of the catalyst structural evolution under applied potential to obtain a more comprehensive understanding of these impurities and their associated effects. Another aspect of the work encompasses the advancement of multi-modal operando microscopy approaches, particularly with the incorporation of concurrent time-resolved EDS mapping and correlative operando investigations combining both electron and X-ray microscopy insights, which will inspire the use of similar approaches towards the study of functional materials under working conditions.

Pneumolysin (PLY) is a cholesterol-dependent cytolysin secreted by Streptococcus pneumoniae and a major virulence factor in invasive pneumococcal diseases, including pneumonia, meningitis, otitis media, and myocarditis. Importantly, PLY remains active even after bacterial lysis, and the increasing prevalence of antibiotic resistance highlights the urgent need for adjunct antivirulence therapies capable of directly neutralizing this toxin. This thesis focuses on the development and optimization of small-molecule PLY inhibitors, building upon the previously identified lead compound Pathoblocker 3 (PB.3). Although PB.3 exhibits potent PLY inhibition (IC₅₀ = 3.2 µM), its limited aqueous solubility and susceptibility to hydrolysis in phosphate-buffered saline constrain its therapeutic potential. The primary objective of this work was to improve the stability and solubility of PB.3-derived compounds while retaining or enhancing inhibitory activity. Using a scaffold-hopping approach, PB.3 was divided into three structural regions (A, B, and C) to enable systematic modification. A focused library of derivatives was synthesized using Knoevenagel, Henry, and Vilsmeier–Haack reactions, while Meerwein, CuAAC, and Suzuki reactions provided key intermediates. The resulting compounds were evaluated for aqueous stability and solubility, followed by assessment of PLY inhibition in a collaboratively performed hemolysis assay. Structure–activity relationship analysis identified thiophene as a superior replacement for the original furan ring, yielding compounds with complete aqueous stability and enhanced potency. Thiophene-containing derivatives, including compounds 9, 14, 23, and 40, displayed strong PLY inhibition with IC₅₀ values in the low micromolar range (~2–5 µM) and high stability. In contrast, pyrrole- and triazole-based modifications negatively affected stability. Alternative warheads, such as nitrovinyl and olefinic hydroxyl groups, improved stability but resulted in reduced inhibitory activity. Thiobarbituric acid derivatives exhibited excellent potency but showed impaired stability. Overall, this work identifies stable and potent PLY inhibitors and supports their further development as adjunct therapeutics to complement antibiotic treatment of pneumococcal infections.

The twenty-first century is the century of displacement. An unprecedented 125 million individu-als are currently displaced globally, with 40 million of them being internationally displaced and crossing international borders. The majority of these displaced individuals gravitate toward urban areas in search of asylum, protection, and sanctuary. However, within cities, internationally dis-placed migrants encounter formidable challenges arising from increasingly restrictive, violent, and market-driven migration regimes, rendering them vulnerable to social, economic, political, and legal insecurity. These challenges are compounded by a pervasive housing crisis and the proliferation of urban displacement phenomena, such as evictions and homelessness. These multifaceted processes and conditions continue to further displace those already displaced in-ternationally; and they multiply displacement processes and experiences. In this dissertation, I examine the enduring coercion and dispossession experienced by inter-nationally displaced migrants, demonstrating that such experiences persist and intensify long after migrants’ arrival in urban centers. The core objective of this thesis is to understand the ex-tent to which the urban governance of internationally displaced migrants in cities is embedded in wider structures of neoliberal and austerity urbanism, and (re)produces global structures and processes of displacement. Overall, this cumulative thesis explains that the combination of the precarious legal status of people produced in response to international displacement and through violent migration governance, and exclusionary and racialized urban migration and hous-ing policies, produce what I call multiplied displacement. Multiplied displacement describes the intersecting, overlapping, and mutually reinforcing forms, processes, experiences, and factors relevant for the (re)production of displacement against the backdrop of international displace-ment, and urban processes of marginalization, exclusion, and unhousing in cities of arrival. This thesis includes eight scholarly articles, in which I employ various perspectives and case studies to elucidate the complexities inherent in these issues across different geographical and urban contexts. Specifically, my work scrutinizes urban governance structures and their implica-tions through case studies in Europe and the United States. Central to my investigation is the revelation of the economic imperatives driving displacement, whereby multiple urban stake-holders profit from the perpetual relocation of migrants. This includes exploring the racialization processes that underpin displacement, as well as the emergence of neoliberal forms of sanctu-ary and support for displaced populations. By conceptualizing cities as both recipients and pro-ducers of displacement, this dissertation encompasses the creation of systematic knowledge about the way displacement shapes contemporary cities, how it relates to urban housing mar-kets and governance processes, and its embeddedness in wider structures of racial exclusion and marginalization in cities.

Frustrated magnetic systems are characterized by competing interactions that in some cases prevent conventional magnetic ordering, leading to unconventional ground states such as quantum and classical spin liquids. These states exhibit strong entanglement, fractional- ized excitations, and emergent topological phenomena. Such systems are of interest not only from a theoretical perspective, due to their rich and unconventional physics, but also from a materials standpoint, as they offer promising platforms for realizing exotic phases in real compounds. The theoretical study of magnetic models using numerical methods plays a crucial role in advancing our understanding of the magnetic properties of materials. It helps interpret experimental results, predicts properties not yet explored experimentally, and enhances the interpretation of data through the development of new numerical tools. In this thesis, we address these aspects through three main investigations. First, we study classical spin models on the distorted windmill lattice, which is relevant to the spin-liquid candidate PbCuTe2O6. Through this study, we determine the origin of frustration in this compound and examine the thermodynamic behavior and the magnetic excitations of the associated classical model. Additionally, by mapping out the classical phase diagram, we identify a novel type of classical spin liquid. Next, we investigate the dynamical signatures of soft modes, focusing on quartic spin oscillations in isotropic systems with spiral magnetic order. We show that these modes exhibit a gap that decreases with temperature, a feature observable in real materials through inelastic neutron scattering experiments. Finally, we introduce a machine learning–based approach to infer the underlying magnetic Hamilto- nian. Specifically, we train a neural network on synthetic spectra generated using linear spin-wave theory and apply the trained model to analyze experimental inelastic neutron scattering spectra.

Polymodal faulting, which comprises three or more coeval fault sets, has been documented from centimeter to kilometer scale in nature. Differing from previously well-known conjugate, or bimodal, fault patterns under biaxial or plane strain, the polymodal faulting phenomenon is considered to represent triaxial deformation or strain (e.g., constriction and flattening strain). Triaxial tectonic regimes can take place variably in obliquely divergent, transcurrent, and convergent settings, allowing the coeval existence of different tectonic regimes (e.g., thrust, strike-slip, and normal faulting). The classical and widely accepted Mohr-Coulomb failure criterion can predict the orientation of conjugate fault planes parallel to (i.e., contain) the direction of the intermediate stress under plane strain, whereas polymodal fault patterns forming under triaxial deformation cannot be explained with fault orientations oblique to the direction of the intermediate principal stress (σ2). Aiming to understand the evolution, geometry, and kinematics of polymodal faults, I use 3D scaled analogue and numerical modelling to generate triaxial strain fields under variable initial and boundary conditions to decode the mechanisms and mechanics of triaxial deformation. In the first step, I primarily investigate how rheology and strain rate control deformation localization, faulting regime, and pattern in brittle‐viscous crustal‐scale models under constriction strain. I perform triaxial analog experiments by varying strain rates (or extension velocity), where distributed longitudinal extension resulting in crustal thinning is accompanied by lateral shortening. I found the structural style of faults and the degree of localization as a function of strain rate. As strain rate (ė) decreases, (1) fault patterns change from conjugate sets of strike‐slip faults (ė > 3 × 10⁻⁴ s⁻¹) to sets of parallel oblique normal faults (ė = 0.3–3 × 10⁻⁴ s⁻¹) to horst‐and‐ graben system (ė < 0.3 × 10⁻⁴ s⁻¹); (2) The strain localization increases systematically and gradually. The former change in fault pattern is interpreted to be affected by the strain rate dependency of vertical coupling between the model upper crust and upper mantle, which controls spontaneous switching of principal stress axes. The latter change in strain localization is controlled by mechanical coupling between the upper and lower crust. Furthermore, many extensional systems often experience multiple phases of deformation; however, the spatial and temporal evolution of fault networks during triaxial and biaxial strain is still poorly understood. Benefiting from the first part of the work, which identifies the change in strain conditions from constriction to plane strain over strain rate, I also use a scaled analogue model to investigate fault geometry and activity across multiple phases of triaxial (constrictional) and biaxial (plane) strain by changing extension velocity to obtain time-dependent kinematic strain conditions. Our modelling results show that (1) when shifting from plane to constrictional strain, earlier developed normal faults are completely reactivated and new conjugate sets of oblique-slip faults form during the constrictional phase; (2) when shifting from constrictional to plane strain, conjugate sets of oblique-slip faults forming during constrictional strain are randomly abandoned or reactivated. New normal faults developed during plane strain cut across and link up earlier-phase faults. Kinematic interactions of fault networks between multiphase strains are identified by observing how perturbations in stress/strain domains control the geometry of new faults and mechanical obstacles hinder fault propagation. I further explore the relationship between principal stresses and polymodal fault orientation by means of 3D scaled numerical modelling. Our models demonstrate that triaxial deformation can be accommodated by the simultaneous development of faults with different trends and partitioned into one more faulting regime. Additionally, our models can explain fault distribution with respect to the principal stress. The modelling results show good similarity with the natural prototypes at various backgrounds. In regions under a constrictional deformation field, for example, Tibet, Anatolia, and the Friulian-Venetian basin, as well as in regions under a flattening strain, for example, northern Tibet and the Barents Sea, our modelling results provide new implications for fault geometry, fault kinematics, and stress distribution. Moreover, our models with multiphase triaxial and biaxial strain can re-interpret tectonic evolution in the Aegean and Barents Seas.

Racism is a structural force that organizes daily life, shapes access to resources and opportunity, and produces cumulative impacts on health across the life course. Health disparities between racially privileged and racially marginalized groups are not due to innate genetic differences; they emerge through processes that are both chronic and systematic, rooted in long-standing structures of marginalization. Despite growing recognition of racism’s health impacts, research often treats race as a static covariate and fails to interrogate racism as a dynamic, cumulative, and upstream driver of unequal health outcomes—particularly in childhood and adolescence. Few studies examine racism as a structural force that shapes mental health trajectories over time. Even fewer integrate children’s lived experiences of racialization with epigenetic data. These gaps are especially stark in Germany, where historical legacies limit the direct study of racism’s impact on development and health. This cumulative dissertation addresses these gaps by advancing and applying a race-critical biosocial framework. While biosocial approaches are well suited to explore how social conditions shape health, they have often fallen short in addressing the structural dimensions of racism. A race-critical biosocial framework offers tools to trace how racism operates and becomes embodied, shaping children’s and adolescents’ mental health. Three peer-reviewed papers structure and guide this inquiry. Paper 1 advances a race-critical biosocial framework that integrates critical race theory, developmental science, and sociogenomics, with particular attention to Germany’s scientific and sociopolitical context. Paper 2 applies this framework in the German context through communities-based qualitative research with 29 Black families. Focus group findings highlight racism as a chronic, multisite stressor that shapes family health, children’s mental health, identity development, and coping strategies. Paper 3 extends the race-critical biosocial framework to U.S. longitudinal data (N = 4,898; DNA methylation data N = 2,039), operationalizing racism through self-identified race/ethnicity, neighborhood segregation, and skin tone. Findings show that racially marginalized children exhibit higher baseline levels of internalizing and externalizing behaviors in childhood, as well as accelerated epigenetic biological aging during adolescence, with mental health and biological aging progressing in parallel. Together, the three papers provide conceptual, qualitative, and quantitative evidence that racism is a biosocial health risk. It structures children’s environments from birth, becomes embodied through stress-related mechanisms, and contributes to early mental health disparities. The dissertation highlights the urgent need for child-centered, intersectional, and longitudinal measures of racialization in both Germany and the U.S., and calls for co-designed, communities-led biosocial research. By showing how racism “gets under the skin,” it advances a race-critical biosocial agenda for public health and developmental science.

Progeroid syndromes are a heterogeneous group of rare genetic diseases characterized by a prematurely aged appearance. They are caused by pathogenic variants in various genes, including those encoding DNA repair enzymes and components of the extracellular matrix (ECM). Additionally, alterations in gene expression can also contribute to the development of these syndromes. Within the scope of this dissertation, two progeroid syndromes were characterized. First, pathogenic variants in SUPT7L were identified as the genetic cause of a new progeroid syndrome. Second, further insights into the pathomechanism of ARCL2A were obtained. One complex regulating gene expression is the transcriptional coactivator complex STAGA. Loss-of-function variants in SUPT7L, encoding a subunit of STAGA, cause a so far undescribed clinical syndrome with a progeroid appearance, developmental delay, intellectual disability and a generalized lipodystrophy. Loss of SUPT7L presumably leads to reduced stability of the entire complex, decreased expression of c-MYC- and p53-dependent genes. It also results in reduced DNA repair and subsequent accumulation of DNA damage in primary dermal fibroblasts and genome-edited HeLa cells. Moreover, evidence suggests changes of the ECM, a common feature in other progeroid syndromes such as autosomal recessive cutis laxa type 2A (ARCL2A). ARCL2A is a congenital disorder of glycosylation (CDG) characterized by connective tissue weakness and brain abnormalities. Its molecular basis are loss-of-function variants in ATP6V0A2, encoding the V0a2 subunit of the vacuolar (v)-ATPase. This subunit determines the subcellular localization of the multiprotein complex and forms the proton channel. To analyze the underlying mechanisms of ARCL2A, two mouse models were generated. A knockout (Atp6v0a2-/-) leading to absence of Atpv0a2 and a knock-in (Atp6v0a2RQ/RQ) model, carrying the p.R755Q variant, which selectively blocks proton transport. These mouse models exhibited structural aberrations of the dermis, reduced secretion of ECM proteins and altered glycosylation. However, the O-glycosylation defects appeared to be more relevant for the ARCL2A pathomechanism. Reduced O-mannosylation of ɑ-dystroglycan impairs cell-matrix interaction, leading to a secondary dystroglycanopathy involving abnormal migration of cortical neurons. Furthermore, enhanced core fucosylation in skin and murine embryonic fibroblasts (MEF) correlated with an elevated trans-Golgi pH and a delay in the intracellular vesicle transport. In both mouse models, impaired Golgi-derived acrosome formation and altered O-glycosylation lead to a globozoospermia, a previously undescribed symptom of ARCL2A. Thus, the pathomechanism of ARC2A is determined by an interplay between an elevated Golgi pH and alterations in intracellular vesicle trafficking.

Mechanosensation is a process by which nerves encode physical stimuli such as cotton swab or pinprick into electrical signals that can be understood by the nervous system. In this way, organisms can gain crucial information about the environment by means of touch sensation and avoid harmful influences thanks to nociceptive pain. But what is the molecular basis of mechanosensation, allowing this process to occur? And what happens if its functioning is disrupted? I tackle those questions in my doctoral thesis, investigating a role of newly described mechanosensitive channel and discussing tactile phenotypes in autism spectrum disorders (ASDs). This work is mostly an electrophysiological study of cutaneous mechanoreceptors, studied with the use of ex vivo mouse skin-nerve preparation. Focus is on c-fibers, small diameter unmyelinated sensory neurons, involved in relying nociceptive cues. In the first part of my doctoral project I investigate the role of Elkin1 (TMEM87a) channel in the nociceptor physiology. Results show that Elkin1-/- knockout mice exhibit lowered mechanical sensitivity when tested in behavioral assays using a hindpaw stimulation. Electron microscopy showed no structural changes in the somatosensory system of mutant animals, albeit there are changes in the physiology of sensory afferents. Extracellular recordings from single nerve fibers, made during simultaneous mechanical stimulation of receptors located in the skin, showed a changed pattern of activity in response to mechanical stimulation with faster adaptation in fibers from Elkin1-/- animals, but only when a specific protocol of stimulation was used. Furthermore, I explore the relationship of Elkin1 with Piezo2 mechanosensitive channel by studying double knockout animals. Effect of deleting both protein seem to have greater effect on dampening response to mechanical stimuli than removing any one of them separately. On the other hand, introducing human point mutation into mouse genome slightly strengthen the response. Overall, Elkin1 is a novel mechanosensory protein presumably required mostly for light touch, as changes in functioning of c-fibres point toward minor involvement in nociception. Sense of touch is also critically important for proper development. It constitutes the most primal form of communication between an infant and a parent, building foundation for more advanced social skills. Tactile-related impairments observed in toddlers pose a strong predictor of core autistic symptoms later in life and sensory processing disturbances belong to the most replicable symptoms emerging early in the diagnosis of ASDs. Modified touch perception phenotype observed in human subjects is replicated in animal models. Global knockout of 4E-BP1, the downstream effector of mTOR signalling pathway affected in some ASDs forms, was shown to be a source of mechanical hypersensitivity with enhanced nociception in mice. However, my results on the specific involvement of this phenomenon in the peripheral sensory neurons did not show any positive results. My findings, both of electrophysiological study and behavioral assessment, indicate that mechanical hypersensitivity observed in the model of 4E-BP1 deletion ca not be explained by differences in the physiology of cutaneous nociceptors.

Two-dimensional (2D) materials exhibit unique physical and chemical properties that make them promising candidates for electronic, optoelectronic, and energy-related applications. However, the limited tunability of pristine 2D materials restricts their broader practical use. This work presents a series of computational studies focused on tailoring the structural, electronic, optical, magnetic, and catalytic properties of 2D materials through functionalization and engineering strategies, including defect engineering, doping, heterostructure formation, molecular modification, and strain or pressure. The results demonstrate that these approaches effectively modulate key material properties such as band structure, charge transfer, excitonic behavior, magnetic ordering, and catalytic performance. Overall, this study provides theoretical insight and design guidelines for the rational tuning of 2D materials toward advanced device and energy applications.

This thesis focuses on the exploration of the metabolomics approach as a guided tool in the field of anti-doping by defining a workflow based on the synergy between High-Resolution Mass Spectrometry and chemometric tools.

First, the optimization of a low-energy electron ionization source to maximize the formation of molecular ion and minimize the fragmentation degree of steroid pathways, preserving the specific fragmentation pathway of the steroids considered and increasing the m/z coverage range. To this end, the effects of electron energy, emission current and source temperature on steroid fragmentation pathways were studied by performing full factorial experimental designs, using steroid reference materials chosen to cover the entire urinary steroid profile.

Second, the development and validation of systematic metabolomics workflows to reduce the time and resources required to identify direct drug metabolites for GCHRMS. To do so, the administration of 7-keto-DHEA was studied as a Proof-of-Concept to highlight the strong synergy between high-resolution mass spectrometry and chemometric tools for early detection of drug metabolites in anti-doping. A comparison of the most significant features with the spectra library validated the proposed metabolomics approach, further supported by existing data in the literature.

Third, extension of the previously proposed workflow on GCHRMS data to LCHRMS data, development and validation. The primary differences between the two workflows lie in the method validation, sample analysis processes, including preparation and acquisition, as well as in the raw data preprocessing steps. This knowledge gives the opportunity to gain insight into all possible metabolic changes, regardless of whether it is the formation of new compounds or the reduction of compounds. In contrast, the metabolite-focused approach generally reduces the scope of investigation to the formation of metabolites from the parent molecule, thus losing the response that other endogenous compounds might have as a result of its intake.

Fourth, application of the developed workflow for the investigation of the physiological and post training effects of ecdisteroid supplementation on the human serum metabolome. These outcomes elucidates the effectiveness of a metabolomics-based approach in detecting specific trends related to the intake of performance-enhancing substances that would otherwise remain undetected through traditional analytical methods or be masked by physiological changes.

The results presented in this thesis are of relevance for a more depth understanding of the complex relationships between different steroids, which may not be apparent when examining individual steroids in isolation, and in the identification of patterns or combinations of steroids that may discover new biomarkers for disease diagnosis, prognosis, or monitoring. This is a step forward in the metabolic characterization of different physio-pathological conditions that allow for the personalization of treatment strategies and optimization of individual performance outcomes. This personalized treatment enhances the value of the proposed metabolomics approach, making it beneficial not only for improving sports performance, but also in the clinical setting, where targeted supplementation can promote better health and recovery.