Inflammation is a biological response to tissue injury or infection, mediated by signalling cascades and triggered by endogenous and exogenous danger signals. The nuclear protein High Mobility Group Box 1 (HMGB1), when released extracellularly, activates inflammatory pathways (e.g., nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) pathway) via pattern recognition receptors (PRRs) such as the Receptor for Advanced Glycation Endproducts (RAGE). Its activity is shaped by the positively charged A- and B-boxes and negatively charged acidic C-terminal tail, influencing receptor binding. Here, the anti-inflammatory properties of dendritic polyglycerol sulfate (dPGS), a synthetic, Heparin-mimetic polyanion, were investigated. Surface plasmon resonance (SPR) revealed that commercial HMGB1 from mammalian cells binds dPGS with nanomolar affinity (KD = 94.3 ± 1.7 nM). Alongside, recombinant full-length HMGB1 and subdomains expressed in E. coli and purified by a two-step affinity chromatography, showed that the A-box (KD = 83.5 nM) and A-+B-box (KD = 82.3 nM) exhibited similar affinities, while full-length HMGB1 displayed biphasic kinetics. Fitting with the heterogenous ligand binding model resulted in KD1 = 5 nM and KD2 = 0.009 nM, while dPGS also bound soluble (s)RAGE (KD1 = 6 nM, KD2 = 0.006 nM). HMGB1 bound sRAGE with KD1 = 70 nM, KD2 = 52 nM. Competitive binding studies demonstrated that dPGS impaired the HMGB1/sRAGE complex (IC50 = 3.3 nM). At higher dPGS concentrations biophysical data indicated a ternary complex of HMGB1/sRAGE/dPGS. Further, imaging showed that dPGS reduced lipopolysaccharide (LPS)-induced HMGB1/RAGE complex formation by 18 % in RAW 264.7 macrophages and 24 % in human microglia. NF-κB nuclear translocation induced by either HMGB1 or LPS was reduced to approximately 13 % of the control. As a result, RT-PCR showed that TNF-α mRNA levels were lowered owing to dPGS by 91 % (HMGB1 stimulus) and 81% (LPS stimulus), IL-6 by 71 % and 26 %, and MCP-1 by 34 % and 48 %, respectively. Protein quantification via ELISA confirmed reduced secretion levels of TNF-α upon co-stimulation with HMGB1 (50 %) or LPS (25 %). To prove that dPGS is capable to act intracellularly, uptake studies were performed with a cyanine 5 (Cy5) fluorescent label. Flow cytometry analyses showed time-dependent dPGS-Cy5 uptake peaking at 16–24 h. HMGB1 and LPS reduced intracellular accumulation by up to 30-40 % from 6 h onwards. Summarising, these results show that dPGS inhibits HMGB1-mediated inflammation at multiple structural and signalling checkpoints, supporting its potential as a therapeutic agent.

Maternal smoking during pregnancy is the most important avoidable cause of gestational morbidity and mortality, exerting permanent impacts on fetal health. This behavior is causally associated with fetal growth restriction (FGR), fetal malformations, and an increased vulnerability to disease later in life. The placenta is the functional interface between mother and fetus during pregnancy and is essential for healthy fetal development. This transient organ controls nutrient and gas exchange in-utero and secretes pregnancy modulating hormones. Molecular mechanisms that disturb the early development and function of the placenta by smoking remain largely unknown. This thesis uses a multi-omics approach to elucidate the phenotype-specifc molecular effects of maternal smoking on the developmental phase of the early human placenta. To this end, I evaluate tissue gene expression via single nuclei RNA sequencing (n = 5 smokers, n = 6 controls) and tissue relative protein abundances using ultra-sensitive phenotype-specific proteomics (n = 3 smokers, n = 3 controls). Results are validated in an independent human cohort (n = 23 smokers, n = 15 non-smokers), and functionally by in-vitro cigarette smoke component exposure using a primary human trophoblast stem cell model. Smoking status stratification for all cohorts was done via maternal plasma cotinine levels, a stable metabolite of nicotine and clinical gold standard. Results demonstrate that the syncytiotrophoblast (STB), the functional barrier of the placenta in direct contact with maternal blood, is profoundly affected and constitutes the only phenotype with compositional differences between smokers and non-smokers. The molecular profiling of the STB at a high resolution has been seldom performed, as its syncytial multinucleated nature poses challenges for its isolation. Trophoblast differentiation modelling demonstrates a preferential differentiation towards the STB lineage in smokers, in agreement with STB nuclei abundance increases in smokers. There are increases in pro-angiogenic secreted placental growth factor (PGF) gene expression (p < 0.001) with systemic relevance, as PlGF protein is increased in the blood of maternal smokers (p = 0.03). Smoking affected genes and proteins associated with cellular signalling, transmembrane transport, cellular stress and extracellular matrix remodelling. Molecular mechanisms associated with dysregulated markers at the transcriptomic and proteomic levels include increases in oxidative stress, activation of the xenobiotic detoxification aryl-hydrocarbon receptor pathway and disturbed mitochondrial energy metabolism capacity. Significantly higher numbers of mitochondrion are present in the STBs of smokers, as evaluated by immunofluorescence staining. Identified pathways can deregulate biological processes important for placental development and function, consequently impacting fetal growth and development. Beyond smoking, these findings provide a framework for understanding modulators of placental dysfunction that contribute to FGR – a leading cause of neonatal mortality and fetal morbidity – early in pregnancy, before the onset of clinical symptoms. I anticipate this data to be instrumental towards advancing FGR diagnostics and therapies to enhance pregnancy outcomes.

Dass Lernenden im Chemieunterricht häufig die sprachlichen Mittel fehlen, um komplexe Inhalte zu erfassen und wiederzugeben, stellt eine Herausforderung heutiger Schulbildung dar. In der vorliegenden Arbeit wird der Disaggregate-Instruction-Ansatz empirisch untersucht. Ziel des Ansatzes ist es, fachbezogene Kompetenzen von Schüler:innen dadurch zu fördern, dass Fachinhalte und Fachsprache zunächst getrennt voneinander vermittelt werden.

In einer vergleichenden Interventionsstudie wurde anhand einer exemplarisch konzipierten Unterrichtsreihe mit N = 464 Lernenden aus 20 Klassen der Sekundarstufe I untersucht, wie sich der Disaggregate-Instruction-Ansatz auf den Erwerb von fachlichen und kommunikativen Kompetenzen auswirkt. Besondere Aufmerksamkeit galt dabei Schüler:innen, deren bildungssprachliche Kompetenzen verhältnismäßig niedrig sind.

Die Ergebnisse zeigen, dass Lernende durch eine entkoppelte Vermittlung von Fachinhalten und korrespondierender Fachterminologie neue Konzepte vor allem dann besser erwerben, wenn sie über geringe bildungssprachliche Kompetenzen verfügen. Damit liefert die Dissertation Impulse für eine gerechtere und lernförderliche Gestaltung von Chemieunterricht in zunehmend heterogenen Klassenzimmern. So kann es in sprachlich schwächeren Lerngruppen sinnvoll sein, bei der Einführung naturwissenschaftlicher Konzepte neue Fachtermini zunächst auszuklammern.

This dissertation examines the mediatization and digitization of Islam, with a focus on Moroccan Muslims and mosque associations in Germany. Following a qualitative research design, it explores how digital technology and online media are used by Moroccan Muslim communities. It also examines how the construct of religious authority is perceived and embodied within this specific local context. By doing so, it aspires to identify the possible implications of digital media use on the dynamics of religious authority. Drawing on several case studies, hybrid ethnography, and semi-structured interviews with different actors within these Moroccan mosque associations, namely the associations’ administration, the imams (religious leaders), and the mosque community members, the research uncovers valuable insights regarding the digitization of Islam and Islamic authority in the local context. To do that, the study is guided by the mediatization and digitization of religion scholarship, which provides a framework for analyzing the interplay between the digitization processes and the dynamics of religious authority. The findings captured an increase in the use of digital media among the Moroccan Muslim associations under study, especially during the COVID-19 pandemic. Still, such development was unpredictable, inconsistent, and mostly dependent on offline circumstances. While the communities in focus tended to converge in resorting to the online sphere, they diverged in how they used digital technology and online media to achieve different purposes. The study also provided evidence for the contextual and dynamic nature of religious authority. By approaching the latter from a relational perspective, the interviews revealed that the imam can be considered the face of religious authority among Moroccan Muslim communities in the diasporic context. Such an authority draws mainly on the imam’s direct connection with the mosque community and his multi-dimensional role within the association’s setting. The interviews further suggested the importance and relevance of the construct of religious authority for Muslim communities, in terms of shaping religion-related decisions in this context. In addition to that, the study confirms that the digitization of religion has encouraged non-expert Muslim individuals to take their religiosity into their own hands and, therefore, actively engage in negotiating and constructing religious authority. Yet, it argues for the persistence of the traditional religious authority of the imam, given the nature of these local Muslim communities in the diasporic context. Thus, the study offers theoretical contributions by advancing our understanding of the mediatization and digitization of Islam in today’s digital age and by offering various insights into the concept of religious authority in this specific setting.

Die Einbindung von Frauen in den Arbeitsmarkt und die damit verbundene Erosion traditioneller Rollen- und Aufgabenverteilungen gehören zu den zentralen Merkmalen gegenwärtigen sozialen Wandels und verweisen ohne Zweifel auf neue Mechanismen der Verteilung von Lebenschancen. Die Tatsache, dass dem rasanten Anstieg weiblicher Erwerbsquoten eine Schlüsselrolle im Umbruch von Familie, Ökonomie und Wohlfahrtsstaat zukommt, ist dabei weniger umstritten als die sozialtheoretische Deutung der Entwicklung. Die vorliegende Arbeit folgt dem Ziel, die Auflösung ehemals separater Geschlechtersphären anhand der weiblichen Arbeitsmarktintegration in den USA historisch nachzuvollziehen und gesellschaftstheoretisch einzuordnen. Der Fall USA steht dabei für eine von Paradoxien und Ambivalenzen geprägte Entwicklung, die sich sowohl als Ausdruck eines individualistischen Liberalismus sowie als exemplarisch für eine allgemeine neoliberale Wende innerhalb moderner westlicher Wohlfahrtsstaaten verstehen lässt. Die übergeordnete Fragestellung lautet dabei, in welcher Weise sich die Strukturprinzipien gesellschaftlicher Ungleichheiten in den USA aufgrund der beschriebenen Verschiebungen im Geschlechterverhältnis verändert haben – und ob der Geschlechtszugehörigkeit überhaupt noch eine Bedeutung für die Verteilung von Lebenschancen zugeschrieben werden kann. Anhand einer empirischen Bestandsaufnahme (Teil I), der Gegenüberstellung und Evaluation zwei dominanter Deutungsmodelle (Teil II) sowie entlang der Revision gegenwärtiger Analyseinstrumentarien der feministischen Theorie (Teil III) kommt die Arbeit schließlich zu dem Schluss, dass sich gegenwärtige Geschlechterverhältnisse in den USA nur mit dem Blick auf ihre Verschränkung mit weiteren Ungleichheitslagen, vor allem der sozialen Klasse, analytisch nachvollziehen lassen.

The eastern section of the lower causeway and a small area of the south wall of the harbour area of the Bent Pyramid at Dahshur were archaeologically investigated between 2009 and 2018. A total of 424.6 kg of ceramic vessels was recovered, mostly in fragmentary condition and only rarely well-preserved or complete. The finds derived either from aeolian or fluvial sand layers, or from architectural contexts.

A fundamental aim of the present work was the creation of a fabric description system for the Dahshur pottery. At the outset of the study, the geomorphological conditions in the working area had to be examined in more detail. This knowledge formed the basis for the description system of the Dahshur pottery, modeled on the Vienna System. Another insight gained from the geology of the Dahshur region is the identification of a marl clay deposit at the mouth of the Sneferu Valley. In addition, it was established that both the Bent Pyramid and the Red Pyramid were founded on Pleistocene deposits (fluvial gravels and sands), which may have led to a different architectural layout of the two pyramids compared to the pyramids in Giza. In this regard, further important research remains to be carried out, as too little is yet known about the thickness of the Pleistocene sediments.

The core of the study consisted in the analysis of ceramic forms, particularly from a chronological perspective. Special attention was paid to vessel types whose dating has so far been difficult to fix in time, such as beer jars and miniature offering bowls. For the beer jars, a development from wide to narrow forms could be traced; for the miniature offering bowls, from large to small. For the latter ceramic type, the increased use of marl clay can be attested in the late Old Kingdom. In the study of beer jars, it was also observed that the Nile silt coatings required for this coarse ware resulted in a volume reduction of approximately 20%.

Another important topic of this work was dating the construction of the lower causeway and the harbour area, as well as their silting-up process. Both structures can be dated on the basis of the ceramic typology to the early to mid-4th Dynasty. Two later construction phases were identified at the lower causeway: a raising of the outer walls probably took place no later than in the reign of Niuserre (mid-5th Dynasty), and the insertion of a vault likely during the reign of Pepi I (6th Dynasty). The elevation of the outer walls of the lower causeway is associated with increasing landscape transformation, particularly heightened sand mobility. In the New Kingdom, with the decline of the Amarna period (ca. 1300 BCE), the cult at Sneferu’s valley temple ceased, and the dismantling of the temple — perhaps even of the entire pyramid complex — began.

The quantitative analysis of vessel types from excavation trench 1 showed that, in the aeolian sand layers of the 5th Dynasty, beer jars, miniature offering vessels, and, to a lesser extent, bread molds are predominant. This pottery was located primarily north of the lower causeway and, due to its association with hearths, faience beads, and intentionally broken vessels interpreted as ritual acts, can be understood as an element of a cult site. For various reasons, it can be assumed that this cult shows parallels to the sun temples at Abusir and is connected to the agricultural calendar of Ancient Egypt, which was primarily influenced by the Nile inundation occurring in summer. The deposition of cult ceramics during the 5th Dynasty at the lower causeway is therefore most plausibly interpreted in the context of festivals celebrated during the annual flooding of the Nile and during the harvest months.

The examination of landscape change at the end of the Holocene humid phase revealed that the present climatic state had not yet been reached in the first half of the 3rd millennium BCE. A shift towards a hyperarid climate comparable to today’s landscape very likely began at the transition from the 4th to the 5th Dynasty. The particular interest in a Sneferu cult throughout the 5th Dynasty can be well explained against the background of advancing aridification and Sneferu’s self-presentation — already in his lifetime — as a guarantor of sufficiently high Nile inundations and the resulting abundant harvests.

Diese Arbeit untersucht die Verbreitung von römischem Glas im kontinentalen barbaricum von der Zeitenwende bis zum Beginn der Völkerwanderungszeit unter Verwendung eines neuen Werkzeugs zur wissenschaftlichen Analyse umfangreicher Datenbanken, dem Digital Atlas of Innovations. Durch die Zusammenstellung einer gesamten Fundgattung auf (barbarisch-) europäischer Ebene wurde deutlich, dass es sich nicht um einen einheitlichen, linearen Entwicklungsprozess handelte, und es wurde nach Möglichkeiten gesucht, die unterschiedlichen Phänomene in einen sinnvollen Zusammenhang einzuordnen. Es wird argumentiert, dass der erste größere Niederschlag von Hohlgläsern im Fundgut des barbarischen Mittel- und Nordeuropas zwischen Rhein und Weser in die erste Hälfte des 1. Jahrhundert n. Chr., im Zuge der sogenannten „Okkupationszeit“, datiert, jedoch keinen besonderen Einfluss auf die Entwicklung der Glasproduktion im barbaricum genommen habe. Eine etwaige Entwicklung und Innovation im Bereich der Glasherstellung und -verarbeitung kann nur anhand von mehreren „Verständnisebenen“ stichpunktartig festgestellt werden. Drüber hinaus wurden zwei weitere Schwerpunktverschiebungen festgestellt, zum einen vom Rhein hin zur Donau im Zuge der „Markomannenkriege“ (166–180 n. Chr.) und zum anderen im 3. Jahrhundert n. Chr., sowohl von der Donau in den pontischen Raum, wo vor allem Becher mit eingeschliffenen Facetten über die großen osteuropäischen Flusssysteme bis in den skandinavischen Raum gelangten und so enge Kontakte über den Limes hinweg belegen, als auch eine Rückverschiebung in die ober- und niedergermanischen Provinzen sowie nach Raetien. Erst im aufkommenden frühen Mittelalter sind verschiedene Orte im ehemaligen barbaricum als regionale Zentren der Glasherstellung und -verarbeitung sicher ansprechbar.

The present study investigates the protein-polyelectrolyte complex formation and folding of proteins with a primary focus on how external factors such as temperature, salt concentrations, types of salt ions, reducing agents and pH affect the thermodynamic parameters. Using an array of biophysical techniques, including ITC, nanoDSF, DLS, DSC, CD and pressure-dependent FT-IR, this study provides a comprehensive thermodynamic perspective on protein stability and protein interactions with polyelectrolytes. To further quantify these protein-polyelectrolyte interactions and characterize protein behaviour under varying conditions, theoretical models based on the experimental data were validated and applied. The first part of this thesis contributes to the understanding of how ion-specific effects influence the thermodynamics of protein-polyelectrolyte interactions. The interaction of heparin and lysozyme in the presence of KGlu under varying salt concentrations was measured by ITC. The free energy of binding ΔGb depends strongly on salt concentration cs, with counterion release identified as the primary driving force for the interaction. In this investigation, a model for the free energy of binding ΔGb as the function of the two decisive variables temperature T and salt concentration cs was applied. This model highlights the significant role of hydration in the binding process. It was shown that temperature T, salt concentration cs and the type of ions present in the solution influence the free energy of binding ΔGb. In the second part, a critical comparison of Differential Scanning Fluorimetry nanoDSF and Differential Scanning Calorimetry DSC based on the thermal unfolding of lysozyme is presented. The unfolding of proteins is a well-understood problem, widely studied by thermal analysis such as Differential Scanning Calorimetry DSC, which needs high amounts of protein together with large protein concentrations. On the other hand, Differential Scanning Fluorimetry nanoDSF offers the advantage of requiring only small quantities and volumes of protein. For the first time, this study presents an evaluation model of the degree of unfolding α obtained from the nanoDSF fluorescence signal in order to determine the thermodynamic parameters. The thermal unfolding of the model protein lysozyme was measured at varying ranges of pH values and compared with the literature. Subsequently, the evaluation protocol of the nanoDSF fluorescence signal was applied to study the thermal stability of HMGB1, a redox-sensitive protein involved in numerous biological functions. NanoDSF enabled the determination of thermodynamic parameters with minimal protein sample requirements. Here, the impact of the disulfide bridge between Cys23 and Cys45 on the stability of the HMGB1 protein was explored. Several methods, like Differential Scanning Fluorimetry nanoDSF, fluorescence spectroscopy FT-IR, circular dichroism CD, and high-pressure FT-IR, were employed to quantify the unfolding and folding transitions. To understand its possible contribution to the stability and flexibility of HMGB1. The variants of the HMGB1 protein A-Box, B-Box, (A+B)-Box and a full-length HMGB1 were analysed. Moreover, the stability and flexibility of HMGB1 for the different redox states of A-Box and full-length HMGB1 were proved. Those different thermodynamic fingerprints of HMGB1 appear to have biological consequences, defining its function, as the redox state is closely connected to it and depends on the surrounding environment of the protein. Depending on its redox state, the HMGB1 protein changes the conformation and has distinct roles in the organism.

Soft tissue sarcomas represent a rare and highly heterogeneous group of tumors that pose complex challenges in both diagnosis and therapy. These difficulties range from limited awareness and delayed detection to potential misdiagnoses and the selection of appropriate, subtype-specific therapeutic modalities. Although established treatment concepts exist, many are still based on older and less differentiated approaches. Insights and resources derived from more common tumor entities will be of great value in advancing the goal of personalized oncology within sarcoma management.

Current (pre-)clinical and translational research demonstrates a clear trend toward subtype-specific and individualized therapeutic strategies. Innovations such as the integration of immunotherapies, TCR-T cell technologies, and the identification of predictive biomarkers are expected to enable increasingly refined treatment approaches tailored to the unique tumor profile and clinical context of each patient.

A paradigm shift is also emerging in radiation oncology: hypofractionation aims to shorten treatment duration and improve patient satisfaction. At the same time, multimodal treatment concepts and recognition of subtype-specific radiosensitivity are expected to allow for individualized dose adjustments, thus overcoming the current “one-size-fits-all” approach. In the future, patient-derived 3D tumor models may serve as “avatars” to test personalized therapeutic strategies and directly translate experimental findings into clinical care.

Furthermore, radiation oncology research will play a key role in implementing stereotactic body radiotherapy (SBRT)—already established as an effective local-ablative alternative to surgical resection in other tumor entities—for the management of soft tissue sarcoma metastases.

Collectively, these developments are paving the way toward increasingly differentiated and personalized care for patients with soft tissue sarcomas, with the overarching goal of sustainably improving therapeutic outcomes.

The field of nanophotonics studies the interaction of light and matter at microscopic scales. It plays an important role in many modern technologies, such as efficient solar cells, fast and secure quantum communication devices, and many other applications. The development of these technologies in a primarily experimental environment is challenging. As such, nanophotonics is a computationally heavily involved discipline. It often involves numerical simulations, optimization algorithms, as well as advanced modeling techniques, that all complement each other.

This cumulative dissertation explores the application of a particular kind of machine learning surrogate model, Gaussian processes, to certain optimization and modeling problems that appear in nanophotonics. Gaussian processes---in the context of nanophotonics---are trained on results of numerical simulations and can afterwards be used to approximate these simulations. They can help reduce the computational impact because approximate solutions obtained using Gaussian processes are much cheaper than results from numerical simulations. In addition to an approximation of the training inputs, the predictions of a Gaussian process are also associated with a measure of the confidence in the approximation. We develop methods and approaches that rely on these properties, implement them as (typically) Python code, investigate their performance and properties, and finally also apply them to solve two particular problems that appear in nanophotonics.

First, we employ Gaussian processes to accelerate parameter reconstruction tasks in optical nanometrology that involve computationally expensive model functions. In addition to aiding in the reconstruction of the model parameters that best explain some experimental measurement, trained Gaussian processes are then further used to determine the confidence bounds of the found model parameters. We present the methodology and perform extensive benchmarks, measuring its performance with respect to other methods that have been used to perform parameter reconstructions. We additionally apply it to give insights into the impact of properly or improperly chosen numerical accuracy parameters during a parameter reconstruction effort.

Second, we employ Gaussian processes for the quantification and optimization of the robustness of nanophotonic devices under an assumed manufacturing uncertainty. Gaussian processes are well suited for this task due to their intrinsic ability to model uncertainties. We present approaches that use Monte Carlo methods to assess the robustness of design candidates using Gaussian processes. We apply these approaches to assess the manufacturability of a novel cavity design, as well as to optimize certain optical resonators in a way that incorporates manufacturing uncertainties, first on a comparatively small domain using a multi-objective function, and second on a much larger domain.

The methods we present here are developed and applied in the context of nanophotonics. Their applicability, however, is not limited to this field.

Stress is a fundamental biological and psychological process that can have profound effects on brain structure and function. In the face of stress, a complex neuroendocrinological cascade is activated, enabling the individual to respond rapidly and adaptively to the stressor. Unfortunately, chronic activation of this adaptive stress response can lead to permanent brain changes that increase an individual's vulnerability to a variety of mental and somatic health problems. The present dissertation project aims to elucidate how different forms of stress influence structural and functional brain correlates. The dissertation consists of three studies, each addressing different aspects of stress-related brain changes. The first two studies focus on structural brain changes associated with childhood trauma (CT) and CT-related psychopathologies. Specifically, these studies sought to disentangle the effects of CT and adult CT-related psychopathologies – post-traumatic stress disorder (PTSD) and borderline personality disorder (BPD) on brain volume and cortical thickness. The underlying idea is to identify CT-related structural brain changes that may be initially adaptive but increase the risk of adult psychopathology, and psychopathology-specific structural brain changes that may explain disorder-specific symptom clusters. The third study investigates the neuroendocrinological basis of stress-related brain function by examining the effects of norepinephrine and cortisol on resting-state functional connectivity (RSFC) of the hippocampus and amygdala. Study one assessed hippocampal, amygdala and total brain volumes in three groups of women exposed to CT: (1) healthy women with CT, (2) women with CT and PTSD, and (3) women with CT and BPD. The study aimed to determine whether CT alone or in combination with PTSD or BPD was associated with volumetric reductions in limbic regions commonly implicated in stress responses. Contrary to expectations, there were no significant differences in hippocampal, amygdala or total brain volume between the groups. However, self-reported severity of CT was negatively associated with total brain volume, and self-reported depressive symptoms correlated with hippocampal volume reduction. The results suggest that reduced total brain volume may serve as a transdiagnostic vulnerability factor associated with CT, whereas reduced hippocampal volume may be associated with a CT-related depressive phenotype. The lack of significant group differences suggests that volumetric brain changes are not disorder specific but rather reflect underlying aetiological (CT) and symptomatic processes. Study two examined whole-brain cortical thickness in the same cohort to investigate whether cortical integrity was affected by CT and whether specific reductions in cortical thickness might indicate a latent vulnerability for the development of psychopathology. Results showed that both healthy women with CT and women with CT and BPD had reduced cortical thickness in the right lingual gyrus compared to healthy controls. In addition, healthy women with CT had reduced cortical thickness in the left lateral occipital lobe. Women with BPD showed further reductions in frontal and cingulate cortical thickness, consistent with the hypothesis that these regions are involved in emotion regulation deficits in BPD. Women with PTSD did not show significant differences in cortical thickness compared to healthy controls. The results of the second study suggest that reductions in cortical thickness in visual brain regions are associated with the experience of CT and may contribute to an increased risk of adult psychopathology. In addition, reductions in cortical thickness in cingulate and frontal brain areas appear to be specifically associated with individuals with CT-related BPD. Results from the first two studies suggest that CT is associated with reductions in total brain volume and cortical thickness in the lateral occipital lobe and lingual gyrus. While reduced cortical thickness in the lateral occipital lobe may function as an adaptive response that reduces trauma-related visual memory and reduces the risk of psychopathology, reductions in total brain volume and lingual gyrus thickness are likely to serve as vulnerability factors that increase susceptibility to mental disorders. In addition, disorder-specific structural changes were identified, with reductions in hippocampal volume associated with depressive symptoms and cortical thinning in frontal and cingulate regions appearing specific to BPD. Structural brain changes may represent both risk and resilience factors, with their role in psychopathology depending on the brain regions involved and their functional consequences. Study three focused on neuroendocrinological mechanisms linking stress and brain function in healthy male participants. This study used a pharmacological manipulation approach to investigate the independent and combined effects of norepinephrine and cortisol on hippocampal and amygdala RSFC in healthy young men. While no significant effects of either norepinephrine or cortisol alone on RSFC were observed, simultaneous elevation of both hormones led to increased connectivity between the hippocampus, amygdala, and cerebellum. This finding suggests that stress-related neuroendocrine responses may influence functional interactions between limbic structures and the cerebellum, possibly activating a functional network that is crucial for emotional memory processes. This dissertation offers valuable new insights into the relationship between stress and brain structure and function. Future research should build on these findings by enhancing generalizability, utilizing transdiagnostic and symptom-based approaches, empirically testing the relationship between brain changes and behavioral correlates, and further exploring the role of the cerebellum in stress and trauma.

This dissertation presents recent contributions to Ehrhart theory and its applications in Combinatorics. It investigates the enumeration and structure of integer points subject to linear inequalities from a geometric perspective.

We give an introduction in Chapter 1 and background on polyhedral geometry and combinatorial structures used in this work in Chapter 2.

In Chapter 3 we use Ehrhart polynomials to count combinatorial and geometric data in generalized permutahedra and hypergraphs. Generalized permutahedra are a class of polytopes with many interesting combinatorial subclasses. We introduce pruned inside-out polytopes, a generalization of inside-out polytopes introduced by Beck–Zaslavsky (2006), which have many applications such as recovering the famous reciprocity result for graph colorings by Stanley. We study the integer point count of pruned inside-out polytopes by applying classical Ehrhart polynomials and Ehrhart–Macdonald reciprocity. This yields a geometric perspective on and a generalization of a combinatorial reciprocity theorem for generalized permutahedra by Aguiar–Ardila (2023), Billera–Jia–Reiner (2009), and Karaboghossian (2022). Applying this reciprocity theorem to hypergraphic polytopes allows us to give a geometric proof of a combinatorial reciprocity theorem for hypergraph colorings by Aval–Karaboghossian–Tanasa (2020). Aside from the reciprocity for generalized permutahedra, this proof relies only on elementary geometric and combinatorial properties of hypergraphs and their associated polytopes.

In Chapter 4, which is joint work with Eleonore Bach and Matthias Beck, we investigate the coefficients of the Ehrhart polynomial for special classes of zonotopes associated with signed graphs. There is a well-established dictionary between zonotopes, hyperplane arrangements, and (oriented) matroids. Arguably one of the most famous examples is the class of graphical zonotopes, also called acyclotopes, which encode subzonotopes of the type-A root polytope, the permutahedron. Stanley gave a general interpretation of the coefficients of the Ehrhart polynomial (integer-point counting function for a polytope) of a zonotope via linearly independent subsets of its generators. Applying this to the graphical case shows that Ehrhart coefficients count (labeled) forests of the graph of fixed sizes. Our first goal is to extend and popularize this story to other root systems, which on the combinatorial side is encoded by signed graphs analogously to the work by Greene–Zaslavsky (1983). We compute the Ehrhart polynomial of the acyclotope in the signed case, and we give a matroid-dual construction. This gives rise to tocyclotopes and we compute their Ehrhart polynomials. Applying the same duality construction to a general integral matrix leads to a lattice Gale zonotope, whose face structure was studied by McMullen (1971). We describe the Ehrhart polynomials of lattice Gale zonotopes in terms of the given matrix.

Chapter 5 is joint work with Matthias Beck and Sophia Elia. Here, we extend Ehrhart theory to consider rational dilates of polytopes. The Ehrhart quasipolynomial of a rational polytope P encodes fundamental arithmetic data of P, namthe number of integer lattice points in positive integral dilates of P. The enumerative theory of lattice points in rational (equivalently, real) dilates of rational polytopes is much younger, starting with work by Linke (2011), Baldoni–Berline–Köppe–Vergne (2013), and Stapledon (2017). We introduce a generating-function ansatz for rational Ehrhart quasipolynomials, which unifies several known results in classical and rational Ehrhart theory. In particular, we define γ-rational Gorenstein polytopes, which extend the classical notion to the rational setting and encompass the generalized reflexive polytopes studied by Fiset–Kasprzyk (2008) and Kasprzyk–Nill (2012).

In Chapter 6, which is joint work with Alexander E. Black and Raman Sanyal we study poset permutahedra, an interesting class of polytopes arising as monotone path polytopes of order polytopes. Poset permutahedra are an amalgamation of order polytopes and permutahedra. We show that poset permutahedra give a unifying perspective on several recent classes of polytopes that occurred, for example, in connection with colorful subdivisions of polygons and Hessenberg varieties. As with order polytopes, the geometry and the combinatorics of poset permutahedra can be completely described in terms of the underlying poset. As applications of our results, we give a combinatorial description of the h-vectors of the partitioned permutahedra of Horiguchi–Masuda–Shareshian–Song (2024) and poset generalizations of Landau’s score sequences of tournaments. To prove our results, we show that poset permutahedra arise from order polytopes via the fiber polytope construction of Billera–Sturmfels (1992).

In ferroelectric materials, the properties such as Curie temperature, polarization switching and ferroelectric domain patterns, are very sensitive to the electrical, mechanical and chemical boundary conditions. This is particularly true at the nanoscale where minimization of the depolarization field drives the formation of new polarization patterns, including whirling ones. In this work, we explore the ferroelectric properties of epitaxial BaTiO3 nanostructures on silicon, with the objective to understand the effect of lateral scaling (< 500 nm) on ferroelectricity and to define routes to stabilize polar textures. The research begins with the investigation of He and Ne focused ion beam milling to fabricate BaTiO3 nanopillars with sub-500 nm diameters from single-crystalline BaTiO3. While He ion irradiation induces surface swelling and blistering due to He nanobubble formation, Ne ion milling proves to be a highly effective method to fabricate BaTiO3 nanopillars. They consist of a defect-free single-crystalline core surrounded on the top and lateral sidewalls by a defect-rich crystalline region and an outer Ne-implanted amorphous shell. We demonstrate that the geometry and beam-induced damage of the nanopillars can be precisely controlled via patterning parameters, establishing Ne ion milling as a useful technique for the rapid prototyping of crystalline nanostructures. Second, we investigate ferroelectricity in 20 nm-thick single-crystalline BaTiO3 nanodisks with diameters ranging from 400 nm down to 100 nm, fabricated using Ne ion milling from a 20 nm-thick epitaxial BaTiO3 film grown on SrTiO3-buffered silicon. The nanodisks are ferroelectric, with a Curie temperature ranging between 230 and 270 °C. Decreasing the diameter leads to an increased amount of Pup polarization relatively to Pdown. Signatures of polar textures emerge in the 100 nm nanodisks in both the lateral and vertical directions. Three distinct configurations are observed for the out-of-plane polarization patterns, consistent with existing theoretical predictions. The up-oriented polarization component can be progressively switched to a down-oriented state using electrical pulses. Third, we present the realization of chiral topological polar states in BaTiO3 nanostructures on silicon. The single crystalline nanoislands, grown by molecular beam epitaxy, are embedded in a continuous 20 nm-thick BaTiO3 layer on SrTiO3-buffered silicon and have a trapezoidal shape with lateral dimensions as small as 30-60 nm. They exhibit a center down-convergent polarization pattern with a swirling lateral component, which confers chirality. The center down-convergent pattern can be electrically switched to a center up-divergent one, occasionally passing through metastable states as experimentally observed and predicted in theoretical simulation. Engineering the shape of nanostructures (a trapezoidal shape similar to a narrowing funnel) is an original and highly promising route to design chiral polar textures. Finally, we investigate optical switching and domain modification in epitaxial BaTiO3 thin films on silicon. The as-grown films contains both a-domains (with in-plane polarization) and c-domains (with out-of-plane polarization). Upon UV laser irradiation (325 nm), ferroelastic and ferroelectric switchings occur leading to a mostly Pup single polarization orientation. Major structural changes are observed, which involve defect motions and full strain relaxation to bulk c-axis BaTiO3. We propose that this structural transformation and the resulting Pup domain configuration are triggered by high strain/stress fields resulting from internal electric fields created by the spatial separation of the photoexcited carriers and by internal heating. Our findings advance the understanding of nanoscale ferroelectrics on silicon, particularly in epitaxial BaTiO3 nanostructures and brings new perspectives particularly for the realization of chiral polar textures. By investigating the effects of lateral miniaturization on ferroelectricity and exploring both electrical and optical stimuli for domain control, this thesis highlights the potential of BaTiO3-based nanostructures for nanoelectronic applications in CMOS technology.

This dissertation explores novel mechanisms underlying ion channel function and regulation by examining three proteins with distinct external stimuli: the mechanosensitive channel of large conductance from Escherichia coli, EcMscL, the voltage-gated proton channel from Karlodinium veneficum, KvHv1, and the cation channel channelrhodopsin-1 from Chlamydomonas augustae, CaChR1. Initially, we tested the force-from-lipid gating model for EcMscL by incorporating a photoswitchable lipid into artificial membrane. This strategy enabled modulation of channel activity through light-driven manipulation and therefore providing us with support for the lipid-based gating hypothesis while presenting a novel technique for light-controlled ion channel activation. Additionally, chemical activation of the protein provided information about activation in the absence of mechanical stimuli and the gating model of the system. Furthermore, the structural simplicity of KvHv1, suggests it as a model protein for biophysical studies. Its functional properties and ion selectivity region offers fundamental insights into activation and regulation of voltage-gated proton channels. Mutation studies as well as spectroscopical investigation (in collaborations), shade light to the selectivity filter and its dynamics. Notably, inhibitory studies with the trivalent cation La3+ are suggesting a new model of activation. Finally, this work also presents for the first time the structural characterization of CaChR1 ground state obtained via CryoEM providing further support to previous spectroscopic results with detailed structural analysis. Comparative studies with a structurally homologous channelrhodopsin provided extra information over key amino acid residues governing its photocycle. Collectively, the investigation of EcMscL, KvHv1, and CaChR1 presented here enrich our understanding of ion channel’s function and manipulation, while offering substantial groundwork for future studies aimed at elucidating complex molecular mechanisms of channel activation and regulation.

The perfluorinated Cp* anion [C5(CF3)5]− is the extremely electron deficient counterpart of the well-studied Cp* ligand [C5(CH3)5]−. Although its first synthesis took place as early as 1980, the perfluorinated Cp* remained a synthetic dead end for decades, due to its low reactivity. Here, the preparation and full characterization of its first coordination complex [Rh(COD)(C5(CF3)5)] (COD = 1,5-cyclooctadiene) is presented. This allowed for extraordinary insights on the bonding situation between a metal and an electron-poor Cp ligand and revealed [C5(CF3)5]− as the weakest bound Cp ligand known.

The weakly bonding character of the perfluorinated Cp* is demonstrated by the quantitative and even reversible substitution by toluene to the cationic [Rh(COD)(PhMe)][C5(CF3)5] complex. Also the metallocenes [M(C5H5)(C5(CF3)5)] (M = Fe, Ru) are studied with respect to an unprecedented substitution lability of the perfluorinated Cp* ligand. Their photolysis in MeCN not only yields [M(C5H5)(MeCN)3][C5(CF3)5], but also reveals a unique photo/thermoswitchability by the back-reaction to the corresponding ruthenocene.

The low nucleophilicity and high oxidative resistance of [C5(CF3)5]− is further demonstrated by the coexistence with electrophilic and oxidizing cations and its introduction into the group of weakly coordinating carbanions (WCCAs). The prepared salts comprise hydride-accepting [(C6H5)3C]+, valuable Ag(I) reagents, oxidizing [Fe(C5H5)2]+ or [N(p-C6H4Br)3]+ and Brønsted acidic [H(m,m-NC5H3F2)2]+.

The preparation of the first complete series of coinage metal Cp coordination compounds with [M(C5(CF3)5)(PtBu3)] (M = Cu, Ag, Au) demonstrates the ability of the perfluorinated Cp* to stabilize metal centers by its extreme oxidative resistance. The binding modes between metal and ligand range from η3 to η1 and illustrate the coordinative versatility of [C5(CF3)5]−.

The impact of the perfluorinated Cp* ligand on the redox chemistry of metal complexes is demonstrated by the synthesis of the extremely electron deficient ferrocene [Fe(C5H5)(C5(CF3)5)]. Oxidation potentials of E1/2 = +1.35 V (vs. Fc/Fc+) represent the highest reported values obtained for any ferrocene. The corresponding stable and storable ferrocenium [Fe(C5H5)(C5(CF3)5)][AsF6] is the strongest organometallic oxidant to date and even capable of C-H activation.

Finally, the rhodocenium salt [Rh(C5(CH3)5)(C5(CF3)5)][BF4] is prepared. The surprisingly high reduction potentials E1/2 = −0.90 and −1.46 V (vs. Fc/Fc+) combined with the coordinative flexibility of [C5(CF3)5]− allow for the twofold reduction by decamethylcobaltocene [Co(C5(CH3)5)2]. The reported [Co(C5(CH3)5)2][Rh(C5(CH3)5)(C5(CF3)5)] not only represents the first structurally characterized 4d metallocene anion, but also shows an unprecedented coexistence with a metallocene cation.

Diese Habilitationsschrift vereint klinische und experimentelle Studien mit dem Ziel, diagnostische und therapeutische Verfahren in der Neurochirurgie zu optimieren und die Versorgung von Patient:innen mit Hirntumoren und vaskulären Erkrankungen des ZNS zu verbessern. Ein Schwerpunkt liegt auf der Weiterentwicklung der intraoperativen Tumorvisualisierung, der Etablierung molekularer und bildgebender Marker zur Charakterisierung von Gliomen sowie der Untersuchung biologischer Mechanismen, die Progression, Rezidivgeschehen und Therapieresistenz bestimmen.

In einer klinischen Phase-I-Studie wurde der Einsatz des Notch-Inhibitors RO4929097 in Kombination mit Temozolomid und Radiotherapie bei neu diagnostizierten malignen Gliomen untersucht. Die Behandlung erwies sich als sicher und gut verträglich und zeigte vielversprechende synergistische Effekte. Pharmakokinetische Analysen bestätigten das Eindringen des Wirkstoffs in das Parenchym, während Gewebestudien die Rolle des Notch-Signalwegs bei Gliomstammzellen und Angiogenese verdeutlichten. Gleichzeitig zeigte sich, dass Tumoren unter Therapie auf alternative angiogene Mechanismen ausweichen können, was die Notwendigkeit kombinierter Strategien unterstreicht.

Darüber hinaus wurde Fluorescein als optische Sonde für die Visualisierung von ZNS-Tumoren charakterisiert. Spektroskopische Untersuchungen belegten eine bathochrome Verschiebung und emissionsbandenabhängige Verbreiterung im Tumorgewebe, beeinflusst durch pH-Sensitivität und Konzentrationseffekte. Klinisch konnte gezeigt werden, dass fluoresceingestützte stereotaktische Biopsien die diagnostische Ausbeute erhöhen, die Anzahl notwendiger Biopsien um bis zu 50 % reduzieren und auch bei niedriggradigen Gliomen ohne Kontrastmittelanreicherung wertvolle Informationen liefern.

Weitere Arbeiten befassten sich mit der Pathophysiologie der Subarachnoidalblutung (SAB). Untersuchungen in Mausmodellen und an Patientenproben zeigten eine zeitlich-räumliche Akkumulation von neutrophilen extrazellulären Fallen (NETs). Die intravenöse Gabe von RNase A hob diese Ablagerungen auf und deutet auf eine mögliche Rolle von RNase in der angeborenen Immunantwort hin. Zur Standardisierung präklinischer SAB-Modelle wurde zudem ein MRT-gestützter Score zur Graduierung der Blutungsgröße etabliert. Insgesamt zeigen diese Arbeiten, dass die Kombination experimenteller und klinischer Ansätze Anknüpfungspunkte für die Weiterentwicklung diagnostischer und therapeutischer Verfahren in der Neurochirurgie bietet.

Eukaryotic precursor mRNAs contain noncoding regions or introns that must be removed, and the coding sequences or exons are ligated together to generate the mature mRNA. The spliceosome, an elaborate and dynamic multi-megadalton ribonucleoprotein complex, achieves RNA splicing. Alternative splicing enhances the genomes’ coding capacity and allows a quicker response to cellular stimuli via transcriptome-wide adjustments independent of de novo transcription. These transient responses, which are implemented immediately after cellular stimulation via changes in alternative splicing programs, are referred to as immediate early splicing switches. The role of immediate early splicing in controlling switches in gene expression in cell-type specific responses to stimuli has been underexplored. A transient alternative splicing switch upon T-cell activation is implemented via heterogenous ribonucleoprotein C (hnRNPC2 isoform) through transient phosphorylation. This study validated a possible mechanism for the hnRNPC2-phosphorylation-mediated alternative splicing switch in vitro using recombinantly produced hnRNPC WT and its phosphomimetic variant. The primary focus of this study was tool development to gain a deeper understanding of the splicing switches modulated by core spliceosomal components. Multiple highly conserved RNP remodeling enzymes guide and control the compositional and conformational rearrangements of the spliceosome that accompany each splicing event. Among these enzymes, the U5 snRNP-associated human BRR2 (SNRNP200) RNA helicase profoundly remodels the pre-catalytic spliceosome by unwinding U4/U6 di-snRNA to facilitate the transition to the activated spliceosome and therefore was targeted using small-molecule inhibitors. This dual cassette RNA helicase is tightly regulated to ensure splicing fidelity. Cryogenic electron microscopy (cryo-EM), in combination with single-particle analysis of these allosteric inhibitors, bound human BRR2, revealed large, global conformational changes in BRR2, altering the relative position of the helicase cassettes. Our findings underscore the utility of single-particle cryo-EM in uncovering ligand-induced conformational rearrangements that may be obscured in crystal structures and have implications for optimizing compounds that target the dynamic molecular machinery of the spliceosome. The mechanistic understanding of the small-molecule allosteric inhibition supported by high-resolution structures provided the basis for the rational design of next-generation compounds that could be utilized in studying splicing switches.

Carboxylic acids and organotrifluoroborate salts have been extensively explored as radical precursors for organic synthesis using photocatalysis or electrochemistry. Both approaches suffer from limitations in terms of price and sustainability due to the requirement of rare metals or complex setups. My doctoral thesis aimed to expand the applicability of these bench-stable precursors by exploring alternative approaches that do not require photocatalysts or electrochemical tools. In Chapter 2, I describe the development of a method for benzylic fluorination of phenylacetic acids that was realized by forming a charge-transfer complex between the fluorinating reagent Selectfluor and the organic base DMAP. This strategy is metal-free and does not require light irradiation to form C-centered radicals. The method described is two-fold, thanks to a solvent-dependent selectivity switch that allows selectively forming the decarboxylated product in aqueous conditions, or the α-fluoro-α-arylacetic acids in anhydrous conditions. In Chapter 3, I outlined the step-by-step development of a new paradigm for light-driven cross-couplings enabled by photoactive nickel complexes that can be activated through intramolecular charge transfer (ILCT) upon blue light irradiation. I studied donor-acceptor ligands formed by installing carbazole (Cz) units and bipyridine (bpy) motifs. These ligands accessed cross-coupling reactivity without adding exogenous photocatalysts, thus bypassing the use of rare metals. The first-generation ligand design (5,5'-Czbpy) enabled C(sp2)–heteroatom using aryl iodide starting materials. By synthesizing a small library of derivatives, I identified an improved ligand design (4,4'-Czbpy) that expanded the scope to aryl bromides. Moreover, this ligand facilitated light-mediated nickel-catalyzed C(sp2)–C(sp3) cross-couplings between aryl bromides and benzyl organotrifluoroborate salts. Thanks to extensive mechanistic studies, I could provide strong evidence for a new C(sp2)–C(sp3) cross-coupling mechanism. The key finding was that this ligand enabled the unprecedented transmetalation between a nickel intermediate and the organoboron starting material. This allowed me to propose a unified mechanistic paradigm for all cross-couplings enabled by Ni(Czbpy)X2-type catalysts, featuring a light-driven activation to access the key Ni(I) intermediate, followed by “dark” nickel cycles that proceed independently of light irradiation.

The process underlying vocal communication acquisition in humans, the most complex form of vocal communication, has been aptly named “Vocal Production Learning”. While human language remains unrivaled in complexity, a multitude of species have evolved individual hallmark features to approximate its intricacies and allow them to be ranked on a heterogenic spectrum. The zebra finch (Taeniopygia guttata) has been studied extensively and serves as an ideal model organism to investigate some of the characteristic features of vocal production learning: The auditory processing and integration of conspecific vocalizations and the potential for temporal and spectral adjustments of vocalizations during the critical developmental period. While behavioral approaches have provided insights into song learning, the neuronal mechanisms underlying this process remain poorly understood. The cortical vocal premotor nucleus HVC (proper name) is an integral part of the song system. In addition to receiving input from multiple upstream auditory nuclei, HVC innervates the downstream motor pathway, triggering song production, and sends efference copies of the motor program to the anterior forebrain pathway. To understand how representation of prominent temporal and spectral song features develops in the neuronal activity patterns of excitatory glutaminergic HVCRA/X projection- and local inhibitory GABAergic interneurons, I investigated their membrane potential during singing and listening to song, employing intracellular single- and extracellular multiunit recordings in awake juvenile and adult birds. During playback experiments, excitatory projection neurons of adult animals did not respond with consistent action potentials to either intact bird’s own song or to a pitch shifted or syllable swapped version thereof. In juvenile birds, however, precisely timed, highly robust response patterns temporally locked to individual syllables were elicited. These patterns occurred independent of the syllables position in the song. Furthermore, firing rates were altered in response to spectral shifts. Inhibitory interneurons in both adult and juvenile animals exhibited activity patterns precisely locked to the temporal aspects of the song while spectral song alterations only seemed to elicit limited responses in juvenile birds. In an additional set of experiments, I was able to provide evidence for a less efficient, less sparse representation of the premotor output program responsible for the elicitation of song production during singing in juvenile birds. These results indicate that the neuronal network in HVC undergoes a complex refinement process during song learning and maturation. The development of the inhibitory network is hypothesized to be responsible for the suppression of excitatory activity and ultimately the protection of the already learned temporal and spectral song features.

Background: Despite the control efforts, ascariasis remains a major public health concern. The introduction of regular preventive chemotherapy (PC) in endemic regions has led to a shift from high- to low-intensity Ascaris infections. These infections cannot be reliably detected by the standard diagnostic methods and thus act as reservoirs for sustained transmission. Furthermore, although the detrimental impacts of high-intensity Ascaris infections on nutrition, immunity, growth, and intellectual capacity are well established, both the short- and long-term impacts of low-intensity infections remain unknown. Additionally, Ascaris coexist in a dynamic interplay with the gut bacteria which are also linked to immune function and host metabolism. These interactions highlight the need to comprehensively examine Ascaris infections beyond their direct pathological effects, considering their broader impact on nutrition, microbiome and immune homeostasis. To address these gaps, we aimed to investigate the integrated effects of low-intensity Ascaris infections on nutrition, immunity and microbiome in schoolchildren living in an endemic setting. Additionally, by using the domestic pig as a human-relevant animal model, we aimed to gain preliminary insights into the natural killer (NK) cells functional disruptions triggered by a low-dose Ascaris infection and its potential to alter host susceptibility to Salmonella. Specifically, we aimed to: 1. Assess the diagnostic performance of copromicroscopy, multiplex-qPCR, and serology in the detection of low-intensity Ascaris infections. 2. Investigate the immune alterations associated with low-intensity Ascaris infections. 3. Determine the nutritional consequences of low-intensity Ascaris infections. 4. Analyze the gut microbiota composition and its associations with low-intensity Ascaris infection, immune responses, and nutritional status. 5. Evaluate how low-dose Ascaris infection modulates NK cell function in domestic pigs as a human-relevant model, to inform mechanisms relevant to human health outcomes during common coinfections in Ascaris-endemic human populations. Results: To precisely detect low-intensity Ascaris infections, we developed and optimized a multiplex-qPCR assay, which exhibited superior sensitivity compared to conventional microscopic techniques. Additionally, we identified IgG1 and IgG4 antibodies against adult Ascaris excretory-secretory products as potential accurate serological markers for current Ascaris infections and exposure, owing to their high accuracy and sensitivity, respectively. We observed a high prevalence of low-intensity Ascaris infections among schoolchildren four months following the administration of STH PC. The children's diet was predominantly carbohydrate-based with a low intake of protein-rich foods. Notably, we identified a relatively high prevalence of protein-energy malnutrition, reflected in low albumin levels, stunting and thinness, particularly among boys. Low-intensity Ascaris infections were negatively associated with zbfa (thinness) and zhfa (stunting) as well as ferritin levels. We show that Ascaris infection is associated with systemic memory CD4 responses, characterised by enhanced gut-homing capacity and a mixed Th1/Th2/Th17 cytokine profile and a mixed IgM/IgG/IgA/IgE antibody response. Notably, Ascaris-specific mucosal IgA1 responses correlated with Oscillospiraceae, Dorea formicigenerans, and Prevotella species which are all short-chain fatty acid-producing gut bacteria taxa known for their immunomodulatory properties. These microbial taxa were also linked to ferritin levels. Furthermore, we demonstrate that a low-dose Ascaris infection significantly impairs NK cells cytokine production and cytotoxicity both in the lungs and in the systemic circulation by altering transcription factors balance and upregulating inhibitory receptors. Conclusion: This study highlights the adverse effects of low-intensity Ascaris infections on nutrition, growth, and immunity. Low-intensity Ascaris infections may also modulate the gut microbiome indirectly by altering ferritin levels and mucosal immunity to foster specific microbial shifts. The profound suppression of NK cell functions by a low-dose Ascaris infection and during Ascaris-Salmonella coinfection indicate that Ascaris infection increases host susceptibility to coinfections and potentially influences disease outcomes. Our findings underscore the urgent need for highly sensitive diagnostic tools such as qPCR and serological markers to accurately ascertain the true burden of Ascaris infections. Future research should prioritize longitudinal human and parallel pig studies to understand the long-term impacts of low-intensity Ascaris infections and their broader implications for coinfections and disease outcomes in children to inform evidence-based interventions.