In both humans and animals, severe maternal stress and elevation of the stress hormone cortisol have been linked to reduced fertility. As a pivotal reproductive organ, the oviduct provides a suitable microenvironment for the maturation of gametes and early embryonic development. The early embryo is especially vulnerable to maternal health problems, including stress. Although many studies have demonstrated that reproductive function is impaired at multiple levels due to severe or prolonged maternal stress-activated HPA axis, the direct and local actions of the stress hormone cortisol on the oviduct epithelium are not yet fully understood. The aim of this study was to explore the potential effects of cortisol on the oviduct epithelium. First, porcine primary oviduct epithelial cells were cultured and differentiated using the ALI culture model to replicate the native oviduct epithelium in vivo. To investigate the effect of long-term stress on the oviduct epithelium, physiological levels of cortisol representing moderate and severe stress in pigs were administered basolaterally for long-term (21 d). The expression of GR pathway-related genes in POEC was activated in response to cortisol treatment. Even though long-term exposure to cortisol had no effect on the overall morphology of the oviduct epithelium, the barrier function and mRNA expression of genes regulating oviduct function and immune response were modified by cortisol. Additionally, the in vitro oviduct epithelium constantly metabolized cortisol to biologically inactive cortisone, suggesting that the oviduct epithelium is able to modulate the hormonal environment of the oviduct even under the condition of chronic repeated stress. Second, individual (cortisol, E2, P4) or combined (cortisol/E2, cortisol/P4) hormone stimulation was applied for 12 h and 72 h, and the morphological, bioelectrical, and transcriptional profile of the cultures were assessed to explore the specific effects of ovarian steroid hormones (i.e., E2 and P4) and the hormonal interactions between cortisol and ovarian steroid hormones. The results suggest that individual E2 and P4 have primary and complex effects on the function of the oviduct epithelium, and P4 is one of the driving force to regulate the morphological modification. In addition, E2 and P4 induced transcriptional regulation of genes involved in cortisol signaling (NR3C1, FKBP5, and TSC22D3), implying that ovarian steroid hormones affect cortisol action on oviduct epithelial cells. Cortisol, in turn, not only directly induces changes in the bioelectrical properties and gene expression of oviduct epithelial cells, but also appears to affect the response of cells to ovarian steroid hormones at the morphological, functional, and gene expression levels by altering the corresponding receptor-dependent signal transduction. In summary, the results of the present study in pigs suggest that the oviduct epithelium is capable of regulating the hormonal environment of the oviduct and limiting the luminal accumulation of stress hormone cortisol under stressed conditions. The cortisol exposure not only affected the function of the oviduct epithelium directly but also modified the E2- and P4-induced regulation of oviduct epithelium functions. This implies indirect effects on the dynamic control of the oviductal microenvironment, which is essential for proper gamete maturation and especially early embryonic development. Thus, perturbation of the fine-tuned interplay between cortisol and sex steroids in the regulation of oviduct epithelium functions may be one of the mechanism by which an elevated maternal cortisol level contributes to the stress-induced impairment of fertility in pigs.

Climate change and extreme resource conditions such as expanding droughts and increasing floods put vulnerable waterscapes and populations in constant danger. In the contemporary Iranian context, ongoing embargoes by foreign governments and the ‘Women Life Freedom’ movement within the current domestic political atmosphere highlight the challenging nature of life in Iran, especially for women. Discussing how female narratives and water resource mismanagement have been shaped historically, by applying a decolonial feminist political ecology lens, this study approaches two Iranian rural contexts in environments of extreme drought. Establishing a holistic contextual foundation, it interrogates correlations between interrelating global and domestic political and economic factors that influence the traditional Iranian qanat-based agricultural micro-structures. This work demonstrates how communities succeed in maintaining common-pool resources through autonomous collective work without control mechanisms and how female collective action thereby can function beneficial. Control over qanat irrigation structures represents power and independence due to their importance in shaping the quality of communal life. Long-established male hegemony and their legal and institutional reproduction by the Iranian theocratic state increase dogmatic gender perceptions in a context of rural familiarity, which legitimise power over resources in male hands and delegitimizes women’s freedom to entrench both their financial dependence and social disadvantage. Women, major actors and commodity producers, are more strongly impacted by structural and environmental transformations than men. Global and domestic politics have direct negative impacts on rural economies, which create multi-layered individual and collective resistances against social norms and theocratic law. Evolving understandings of the causes of marginalisation developed through local women’s research and their cognitive enhancement, reveals the significance of women’s collective resistance in support of social change. Findings show that local women’s collective management of the qanat is highly valuable and beneficial for the community. This study demonstrates how ultra-conservative rural contexts of extreme climatic conditions can be altered through feminist collective action and that thereby the involvement of the common resource can significantly benefit women’s success. Furthermore, it illustrates how despite challenges due to domestic politics in Iran, appropriate work by local NGOs, acting as intermediaries between the community and the provincial administration can be highly beneficial. Outcomes suggests that regarding women as a social group, the heterogeneity of the collective in its context must be considered with its multiplicity of experiences and resistances.

Precise control over complex quantum systems on scales out of reach of classical simulations hold promises for many scientific and technological applications. With the advent of these novel technologies comes the necessity for characterizing their functioning. The precise understanding of the inner-working of quantum devices is a particularly daunting task in the interesting regime of high complexity, easily exhausting time and memory of classical computers in the pre- and post-processing. In addition, inaccuracy in the implementation of the measurement apparatus reduces the achievable precision of characterization protocols. Our work introduces new semi-device-dependent quantum system identification protocols. These are protocols for identifying the abstract description of a quantum device, as being in a certain quantum state, implementing a quantum process or being governed by a specific Hamiltonian time-evolution. The protocols are designed to exhibit robustness against imperfections in the measurement apparatus and to efficiently exploit structural assumptions on the quantum system that reduce the resource requirements. In particular, we present results on the identification of a low-rank quantum state from measurements taken with a partially uncalibrated measurement device, the identification of a unitary quantum process from data that is robust against imperfections in the state preparation and measurement and the high-precision and robust identification of non-interacting Hamiltonians in an analogue quantum simulation. We report on rigorous mathematical guarantees for the protocols that delineate their realm of applicability in practice as well as numerical performance evaluations and experimental demonstrations. Occasionally, the development of technical methods will bring us to further applications and questions outside of the field of quantum characterization, such as the nature of the sign problem arising in the classical Monte-Carlo simulations of quantum systems.

Macrophages originate from the myeloid lineage and maintain tissue homeostasis, and repair as well as regulate the physiological inflammatory responses associat-ed with disease progression. Moreover, they are widely recognized for their adapt-able phenotypic changes in response to environmental as well as molecular cues which results in a broad phenotypic spectrum ranging from pro-inflammatory to immunosuppressive subtypes. Metabolic, hypoxic, and cytokine imbalance within the tissue microenvironment in response to cancer and atherosclerosis progres-sion, influences the phenotype of tissue-resident macrophages and infiltrating monocytes. Here, I generated and analyzed an in vitro model system to evaluate the effect of oleate-dependent polarization on macrophages. I identified that hu-man monocyte-derived macrophages when polarized in vitro in the presence of oleate, result in a novel macrophage phenotype. This is due to lipid accumulation, which harbors an active immunosuppressive transcriptional phenotype based on the expression of the transcription factors sXBP-1 and GATA3 transcription factors albeit downregulates the immunosuppressive scavenger receptors CD200R1, CD163. These macrophages do not modulate T-cell proliferation capacity indicat-ing an overall anergic immunosuppressive macrophage phenotype. These data emphasize the importance of increased lipid metabolism in macrophages and fur-ther identification of this phenotype in solid tumors and in atherosclerotic plaques. Herein I also reported that oleate-dependent murine bone marrow-derive macro-phages polarize into immunosuppressive TAM phenotype independent of IL-4 sig-naling. Additionally, I also generated a novel genetic mouse model to evaluate the role of DGAT1 & 2 enzymes in regulating myeloid cell phenotype. Initial investiga-tions based on oleate-dependent in vitro polarization of murine bone marrow-derived macrophages showed that the DGAT1 enzyme reduced lipid accumula-tion. Hence highlighting the importance of DGAT1 enzyme in regulating lipid drop-let formation associated with macrophage phenotype.

Parodontalerkrankungen zählen zu den häufigsten Erkrankungen in der Kleintierpraxis. Neben der hohen Prävalenz kann die Parodontopathie sowohl lokal als auch systemische Konsequenzen hervorrufen. Außerdem kann eine Periodontitis Halitosis verursachen. Aus diesem Grund spielt die Parodontalerkrankung eine große Rolle sowohl für die Tiergesundheit als auch die Tier-Mensch-Beziehung. Die Vitamin-D3-Konzentration im Blut korreliert beim Menschen mit einer Parodontalerkrankung; dies gilt in gleicher Weise für zahlreiche andere Erkrankungen im Bereich des Bewegungsapparates und anderer Organe. Die Korrelation zwischen der Vitamin-D3-Konzentration und organischen Erkrankungen wurde in der Tiermedizin ebenfalls nachgewiesen. Ein Zusammenhang zwischen Vitamin D3 und Periodontitis wurde beim Hund noch nicht untersucht. Bei Hunden kommen Parodontalerkrankungen vor, die einen ähnlichen pathohistologischen Mechanismus und eine ähnliche Zusammensetzung der Plaque wie beim Menschen aufweisen. Das Ziel dieser Studie war deshalb die Prüfung eines möglichen Zusammenhanges zwischen der Vitamin D3 Konzentration im Blut und dem Auftreten einer Periodontitis beim Hund. Des Weiteren wurde untersucht, ob ein Zusammenhang zwischen der Konsistenz des Futters und dem Parodontalstatus besteht. Insgesamt wurden 50 Hunde aus der Klein- und Heimtierklinik der Freien Universität Berlin zwischen 2016 und 2020 in die Studie eingeschlossen. Alle Hunde waren anhand der Anamnese, der Allgemeinuntersuchung und der Blutuntersuchung als klinisch gesund eingestuft worden. Serumreste wurden unter −80 °C bis zur Messung aufbewahrt. Die Messung von Vitamin D3 und dessen Metaboliten mittels LC-MS/MS wurde im Institut für Ernährungswissenschaft der Universität Potsdam durchgeführt. Der Parodontalstatus der Probanden wurde durch die dentale Untersuchung mithilfe der dentalen Indizes und dem klinischen Attachmentverlust in einem Parodontal-Score von 0 bis 3 ausgewertet. Anhand des Parodontal-Scores wurden die Hunde in 5 Gruppen (1. parodontal gesund, 2. Gingivitis, 3. ggr. Periodontitis, 4. mgr. Periodontitis und 5. hgr. Periodontitis) bzw. in 2 Gruppen (A ohne Periodontitis und B mit Periodontitis) eingeteilt. Vitamin D3, 25(OH)D3, 24,25(OH)2D3 und der 25(OH)D3-24,25(OH)2D3-Quotient wurden auf eine Korrelation mit dem Geschlecht, dem Alter und dem Körpergewicht geprüft und der Unterschied zwischen den 5 Gruppen bzw. den A und B Gruppen untersucht. Der Parodontal-Score wurde hinsichtlich der Korrelation mit dem Geschlecht, dem Alter und dem Körpergewicht untersucht und in Bezug auf den Unterschied zwischen den 3 Gruppen der Fütterungsart (Gruppe 1 Trockenfutter, Gruppe 2 Feuchtfutter und Gruppe 3 gemischtes Futter) analysiert. Die Serum-Konzentration von Vitamin D3 korrelierte signifikant negativ mit dem Alter. Kein signifikanter Unterschied wurde beim Vitamin D3 in der Untersuchung mit 5 bzw. der A und B Gruppen, zwischen beiden Geschlechtern sowie intakten und kastrierten Hunden, festgestellt. 25(OH)D3, 24,25(OH)2D3 und der 25(OH)D3-24,25(OH)2D3-Quotient korrelierten weder mit dem Alter noch mit dem Geschlecht der untersuchten Hunde. Weiterhin wurde kein signifikanter Unterschied bezüglich des Parodontal-Status, des Geschlechtes oder des Kastrationsstatus festgestellt. Die Hypothese, dass die parodontale Gesundheit mit einer erniedrigten Konzentration von Vitamin D3 und dessen Metaboliten assoziiert ist, konnte nicht bestätigt werden. Es wurde aber festgestellt, dass die Serum-Konzentration vom Vitamin D3 mit zunehmendem Alter sank. Der Parodontal-Score zeigte keine signifikante Korrelation mit dem Körpergewicht. Der Faktor Lebensalter hatte einen negativen Einfluss auf die parodontale Gesundheit. Dieses Ergebnis stimmte mit anderen Studien überein. Geschlecht und Kastrationsstatus hatten keinen signifikanten Effekt auf den Parodontalstatus. Mehrere Studien wiesen nach, dass Trockenfutter die parodontale Gesundheit positiv beeinflussen kann. Dieser Effekt konnte in der vorliegenden Untersuchung bestätigt werden. Der Zusammenhang zwischen einer erniedrigten Serum-Konzentration von Vitamin D3 und dessen Metaboliten beim Hund konnte in der vorliegenden Untersuchung nicht bestätigt werden. Als Ursache kommen mögliche Unterschiede im Metabolismus von Vitamin D3 oder in der Pathogenese der Parodontalerkrankung zwischen Menschen und Hunden infrage. Weitere Untersuchungen in Bezug auf den Metabolismus und die Messmethode von Vitamin D3 beim Hund sind zur Klärung dieser Frage notwendig. In der vorliegenden Arbeit wurde der Parodontal-Score zur Bewertung des Parodontalstatus des gesamten Gebisses verwendet. Die in anderen Studien beschriebene Assoziation zwischen Parodontalstatus und Alter sowie Trockenfutter deutet darauf hin, dass der Parodontal-Score beim Hund zur Bestimmung des Parodontalstatus herangezogen werden kann.

Dickens Undone seeks to reframe what is commonly construed as the periphery of Victorian novels as an expansive, fertile area of ‘undone science.’ The introduction argues that the characters populating this ‘periphery’—often referred to as ‘minor characters’—are the tip of an iceberg of ‘negative knowledge’ in Victorian Studies: knowledge that is systematically presented as not worth gaining. This disciplinary closure, I suggest, is embedded in a centripetal aesthetics that is racialising and heteronormative, and shapes the knowledge that we do produce on a fundamental level. The readings of Martin Chuzzlewit, Dombey and Son, David Copperfield and Little Dorrit that follow seek to generate and trial analytical tools that can help readers appreciate ex-centric elements, in other words, tools that can help ‘get the science done.’ To break with the racialising heteronormative categories of ‘main’ and ‘minor,’ ‘central’ and ‘peripheral’ characters that continue to order our thinking, I propose a critical practice that aims to read lovingly, in Agamben’s interpretation of the term: a critical practice that seeks to ‘want’ a text ‘with all of its predicates,’ including aspects and characters that have been previously dismissed as ‘minor’ or ‘mere details.’ The first two readings look for ways of appreciating two particular qualities in characters that tend to put critics off: lack of structural relevance and what E. M. Forster called ‘flatness,’ respectively. Chapters three and four use these interpretative tools to zoom in on individual characters that have been considered peripheral to David Copperfield and Little Dorrit. Both readings uncover previously overlooked facets of key thematic concerns of these texts—autobiography and imprisonment, respectively—demonstrating how a more loving, less lopsided reading practice can considerably deepen and subtilise critical understanding of a text as a whole. To illustrate the extent to which our centripetal aesthetics have distorted our knowledge of Dickens’s writing, the readings in Dickens Undone pay special attention to one particular group of characters whose systematic marginalisation by the Academy is unusually well-documented: working- and lower-class women and women of (some) economic independence. These characters’ exclusion from the conversation, I argue, has been refigured as a critical fiction: that femininity in Dickens is strictly middle-class. The working-class and working women characters I discuss are (like many others) presented by their texts as explicitly feminine. They point toward a femininity that is much more accommodating when it comes to class and age—a femininity, I suggest, which in this inclusivity and in the face of the absence of women of colour in Dickens’s fiction must be examined as a technology of whiteness.

Three aspects of group 7 isocyanide chemistry were considered in this thesis. First, the reactivity of electron-poor isocyanides with facial tricarbonyl starting materials was investigated. As expected, the reactions with technetium were significantly faster than with rhenium and carbonyl ligands of fac-[Tc(CO)3(CNR)2Cl] (R = tBu, nBu) could be exchanged under thermal conditions forming the key intermediate mer-[Tc(CNp-FArDArF2)3(CNR)2Cl]. The chlorido ligand in this compound can be abstracted using a halide scavenger and replaced by a sixth isocyanide ligand leading to the first defined heteroleptic hexakis(isocyanide)technetium(I) complex : [Tc(CNp-FArDArF2)3(CNnBu)2(CNtBu)][PF6]. CNPhpF was then used to assess the reactivity of electron-poor isocyanides without the sterical strain caused by the flanking rings of the m,m´-terphenyl isocyanide CNp-FArDArF2. The reaction kinetics were even faster once the sterical strain was removed. In both cases, the combination of 99Tc and 19F NMR spectroscopy proved invaluable to monitor the progress of the reaction in solution. The use of 19F NMR was even more important for reaction involving rhenium as the metal center cannot be observed by NMR. The slower reaction rates of the rhenium compounds allowed the facile isolation of intermediate compounds such as fac-[Re(CO)3(CNPhpF)2Br] or trans-[Re(CO)(CNPhpF)4Br], which could both only be spectroscopically observed for technetium. In a second part of the thesis, the reactivity of isocyanides with high-valent phenylimido starting materials was studied. Both electronic and steric factors play a role in the outcomes of the reactions. The electron-deficient CNPhpF was able to cleave the technetium-nitrogen bond and replaced the entire coordination sphere to form a hexakis(isocyanide)technetium(I) complex. Such a high substitution degree was not observed for rhenium and only a [Re(NPhF)(PPh3)(CNPhpF)Cl3] complex could be obtained. On the other hand, the electron-rich m,m´-terphenyl isocyanides CNArDipp2 and CNArTripp2 were able to form bis(isocyanide) complexes with both metals. The reactions with [Re(NPhF)Cl3(PPh3)2] also show, which role fluorine-substitution may have in the coordination chemistry. The non-fluorinated starting material [Re(NPh)Cl3(PPh3)2] is too little soluble for reactions with delicate isocyanides and the introduction of a fluorine atom on the phenylimido ring increases the solubility. Furthermore, this fluorine atom shows small, but significant shifts in 19F NMR resonances, which were used to monitor the progress of such reactions. Moreover, the electron deficient and highly fluorinated CNp-FArDArF2only forms [M(NPhR)Cl3(PPh3)(CNp-FArDArF2)], even though the sterical hinderance of the ligand does not preclude a higher substitution. Remarkably, the IR stretches of all used isocyanides show hypsochromic shift upon coordination on Re(V) and Tc(V) centers. This means, they act exclusively as σ-donors. In the last part of this thesis, the gained knowledge on the influence of steric and electronic parameters on the reactivity of isocyanide ligands was applied to synthesize a functionalizable isocyano ligand. Surface-Averaged Donor−Acceptor Potential (SADAP) parameters showed that the alkyne functionalized isocyanide CNPhpC≡CH should have a similar reactivity to the CNPhpF ligand, which replaces carbonyl ligands under thermal conditions. Indeed, the reaction of (NBu4)[Tc2(µ-Cl)3(CO)6] with CNPhpC≡CH lead to the (hexakis)isocyanide complex [Tc(CNPhpC≡CH)6]+. The latter complex could be “clicked” with benzyl azide using an appropriate copper catalyst. The reaction conditions to form the (hexakis)isocyanide complex were harsh and required an inert atmosphere which precluded equivalent reactions with aqueous 99mTc. The Cu(I) complex [Cu(CNPhpC≡CH)4](BF4) could be readily synthesized and “clicked” under milder conditions. The resulting [Cu(CNPhazole)4]+ can be used as a transmetalation reagent for the synthesis of the hexakis(isocyanide)technetium(I) complex, which is the preferable approach for the synthesis of the technetium complex with the short-lived isotope 99mTc. Alternatively, the uncoordinated ‘Click’ product can be obtained by cleaving the [Cu(CNPhazole)4](BF4) complex with aqueous NaCN. It readily reacts with mer-[Tc(CO)3(tht)(PPh3)2](BF4) (tht = tetrahydrothiophene) under the exchange of the thioether ligand.

SARS-CoV-2 und ZIKV sind zwei neu auftretende Krankheitserreger. Ein wesentliches Werkzeug für die Charakterisierung des viralen Lebenszyklus sind Antikörper. Monoklonale Antikörper (MAbs) sind ein immunologisches Instrument mit vielfältigen Anwendungen in Forschung, Diagnose und Therapie. Die konventionelle Herstellung von MAbs ist jedoch zeitaufwändig, kostspielig und erfordert die Verwendung vieler Tiere und geht außerdem mit einer Belastung der Versuchstiere einher. Alle tierexperimentell arbeitenden Wissenschaftler sind sich der großen Verantwortung bewusst, die sie für das Wohlergehen der Versuchstiere tragen. Obwohl Tierversuche in der Forschung unerlässlich sind, besteht Einigkeit darüber, sie auf ein notwendiges Minimum zu beschränken. Als Richtlinie gilt dabei das ethische Prinzip der „3R“: Replace (Vermeiden), Reduce (Verringern) und Refine (Verbessern). Nach dem 3R-Prinzip zielte dieses Projekt darauf ab, SARS-CoV-2 und ZIKV-spezifische monoklonale Antikörper durch In-Vitro Immunisierung zu erzeugen. In diesem Projekt wurden zellpermeable Carrier-Capside benutzt, die einerseits das Zellpermeabilität vermittelnde TLM-Peptid beinhalten und im Bereich des Spike tips einen insertierten Strep-tag aufweisen. Dies ermöglicht die flexible Beladung mit Antigenen, die an Streptavidin fusioniert sind, so dass zellpermeable VLPs entstehen, die an ihrer Oberfläche mit Antigen beladen sind. Durch die Verwendung dieser Plattformtechnologie, die einen effizienteren Antigentransfer und eine robustere Immunantwort induziert als eine konventionelle Immunisierung mit dem freien Antigen, soll die geringere Effizienz der In-Vitro Immunisierung kompensiert werden. Rekombinante Antigene und VLPs konnten in E. coli hergestellt und durch Affinitätschromatographie gereinigt werden. Dichtegradientenzentrifugation und Elektronenmikroskopie zeigten den Aufbau der vlps und die Beladung mit den Antigenen. Diese Antigen-beladenen Partikel wurden zur In-Vitro Immunisierung von Milz-abgeleiteten Lymphozyten verwendet. Bei der In-Vvitro Immunisierung erfolgt die Immunisierung nicht im Tier, sondern in Kultur. Nach 4 Tagen war die Immunisierung abgeschlossen und die Zellen bereit für die Fusion mit Myeloma Zellen, um Hybridoma herzustellen. Wir haben ein Elektrofusionsprotokoll zur Fusion von B-Zellen mit Myelomzellen erstellt. B-Zellen und Myelomzellen werden über Komplexe aus Biotin- und Streptavidin–gekoppeltem Antigen verknüpft. Dazu wurde eine Biotinylierung von Oberflächenproteinen der Sp2/0-Ag14 Zellen durchgeführt. Fusionsproteine bestehend aus monomerem Streptavidin und ZIKV.E oder spike RBD können an das Biotin auf der Zelloberfläche binden. Auf der anderen Seite kann das Antigen an Oberflächen von B-Zellen binden. Nach Inkubation der B-Zellen mit Myeloma Zellen entstehen Verbindungen zwischen beiden Zellen, was zu einer effizienten Fusion führt. Anschließend erfolgt die Elektrofusion der Zellsuspension in einem Puffer niedriger Ionenstärke. Die monoklonalen Antikörper werden von den Zellen an das Medium abgegeben und können daraus in großen Mengen in vitro gewonnen werden. Durch diesen Ansatz wurden SARS-CoV2-Spike-RBD- und ZIKV.E-spezifische Antikörper-Mabs in vitro erhalten. Die Antikörperbindung wurde durch die Oberflächenplasmonresonanz auf einem Biacore-System charakterisiert. Somit können diese Antikörper zum Nachweis von SARS-CoV2-Spike bzw. ZIKV.E durch Western-Blot- oder Immunfluoreszenzmikroskopie und zur Quantifizierung von SARS-CoV2 S oder ZIKV.E durch spezifische ELISAs verwendet werden. In Übereinstimmung mit dem 3R-Prinzip haben wir ein Protokoll zur In-Vitro Immunisierung und Erzeugung monoklonaler Antikörper entwickelt. Es wurden hochspezifische Antikörper zum Nachweis und zur Quantifizierung von entweder SARS-CoV2-Spike oder ZIKV-Hüllprotein erhalten.

Amphiphilic peptide-based biomaterials are of great interest for pharmaceutical and biomedical applications and mainly associated with pronounced biocompatibility and biodegradability. In fact, introducing fluorine-containing amino acids into peptides & proteins offers an unique opportunity to enhance their biophysical properties such as membrane permeability. Through its influence on hydrophobicity and polarity, the degree of fluorination dictates the extent of fluorine-specific interactions on peptide folding and stability, intermolecular interactions, and biological activity. The first study of this doctoral thesis describes the folding, self-assembly, and hydrogelation of single-strand amphipathic peptides with different degrees of fluorination on the amino acid side chains by the iterative incorporation of monofluoroethylglycine (MfeGly), difluoroethylglycine (DfeGly), and trifluoroethylglycine (TfeGly). A combination of experimental and theoretical approaches proved a higher degree of side chain fluorination to promote β-sheet formation and the rheological stability of peptide-based hydrogels in physiological conditions, whereas secondary structure formation was inhibited at a low fluorine content due to fluorine-induced polarity. In a follow-up study, the selective modification of antimicrobial peptides (AMPs) by fluorinated amino acids was investigated. A β-hairpin-forming peptide motif, whose amphipathic structure enables the targeted disruption of bacterial cell membranes, was therefore examined. Extensive MIC screening with Gram-negative and Gram-positive bacteria confirmed highly fluorinated amino acids such as trifluoroethylglycine (TfeGly) or pentafluoropropylglycine (PfpGly) to strengthen the bioactivity of the AMPs through enhanced intrinsic hydrophobicity without causing a simultaneous increase in toxic & hemolytic properties. Numerous studies on the singular incorporation of fluorinated amino acids have been published to date, whereas synthetic peptides with larger or exclusive amounts of these building blocks remained unexplored. That drove the motivation for the herein-described development and characterization of so-called "fluoropeptides". In brief, β-sheet to α-helix or fluorine-induced PPII-helix transitions were observed in SDS-supplemented buffer (pH 7.4). In situ SEIRAS experiments with POPC:POPG-based membrane models functioned to investigate the fluoropeptide’s lipid insertion and (re)folding. Thus, the highest α-helical secondary structure content was found for the nonfluorinated homooligopeptide and decreased in the order of tri-, di-, and mono-fluorination of the side chains. An important focus of this doctoral thesis was the evaluation of biodegradability for especially higher polyfluorinated sequences. In fact, all peptides prepared in this work could be hydrolyzed by various proteases regardless of the fluorine content. In cooperation with the University College Dublin, first data on the microbial digestion of fluorinated peptides and individual amino acids could be generated. The enzyme-catalyzed cleavage of the C-F bond on the side chain for both kind of substrates was, for instance, proven by detection of released fluoride ions in solution. The results of this work will contribute to the rational design and potential application of polyfluorinated peptides, whose enzymatic degradability is going to be of great interest for the future development of fluorinated biomaterials.

Das Ziel dieser Arbeit war es, die nahe verwandten Spezies V. cholerae und V. mimicus mittels MALDI-TOF MS und den zur Verfügung stehenden Standard-Softwares (flexAnalysis, MALDI Biotyper OC) und deren Tools schnell und sicher zu differenzieren. Später war es möglich, eine weitere Software (ClinPro Tools) und eine zusätzliche Vibrio-spezifische Datenbank (VibrioBase) zu erhalten und diese in die Untersuchungen einzubinden. Zunächst wurden von 62 Vibrio-Isolaten 20 (zehn je Spezies) ausgewählt, um sie auf potentiell speziesdiskriminierende Peaks in der Software flexAnalysis zu untersuchen. Hier war eine interne Kalibrierung der Spektren auf einen gattungsgemeinsamen Peak (4279 Da) vorteilhaft, da sie einheitlich darauf ausgerichtet und Streuungen minimiert wurden. Auffällige Peaks mussten Auswahlkriterien standhalten, um als potentiell speziesdiskriminierend gewertet zu werden. Anschließend wurden diese Peaks anhand der bisherigen 20 und weiterer 42 Isolate validiert. Dabei ergab sich für V. cholerae eine Sensitivität von 97% und eine Spezifität von 100%, für V. mimicus waren es 93% und 97%. Mit den Anwendungen der Software MALDI Biotyper OC konnten keine diskriminierenden Peaks ermittelt werden. Allerdings konnten die Spezies mit der Dendrogramm- und PCA-Funktion gut voneinander unterschieden werden, sofern Kontrollisolate mitgeführt wurden. Parallel wurden von den 42 o.g. Isolaten sowohl Spektren mittels Direkttransfer (BRUKER DALTONIK GmbH, 2013b) als auch mit der Ameisensäure-Extraktion (BRUKER DALTONIK GmbH, 2013a) erstellt und verglichen. Dabei machte sich schnell bemerkbar, dass der Direkttransfer eine erhebliche Einsparung von Arbeitsaufwand, -mitteln und -zeit erbringt. Später wurde mit der Software ClinPro Tools festgestellt, dass sich die bisher gefundenen diskriminierenden Peaks hiermit sehr viel schneller ermitteln ließen. Besonders mit der Funktion, eigene Modelle zu generieren, ergäbe sich künftig mit dem Direkttransfer die Möglichkeit, ein Ergebnis für ein V. cholerae-mimicus-fragliches Isolat (von der Agarplatte bis zum Resultat) innerhalb von etwa 15 min zu erhalten. Allerdings hatte ClinPro Tools die Einschränkung, dass Spektren gleicher Isolate oder von sehr nahe verwandten Spezies, wie z.B. V. metoecus, nicht auffallen und nicht differenziert werden konnten. Bei dieser Problematik stellte sich flexAnalysis zwar als zeitintensiv, aber durch die sehr genaue Spektrenauswertung als geeigneter heraus. Zu einem nochmals späteren Zeitpunkt wurden weitere elf Isolate vom BfR zur Verfügung gestellt, bei denen in vorherigen Untersuchungen widersprüchliche Speziesergebnisse auftraten. Diese Isolate wurden in gleicher Weise, wie die Bisherigen untersucht. In allen drei verwendeten Softwares und deren Anwendungen erhielten sie das Ergebnis V. mimicus. Dies wurde später vom BfR über Genom-Sequenzanalysen bestätigt und es unterstützt die Anwendbarkeit der in dieser Arbeit untersuchten Differenzierungsmöglichkeiten nahe verwandter Bakterienspezies mittels MALDI-TOF MS. Zuletzt wurde die Datenbank VibrioBase in MALDI Biotyper OC hinzugefügt. Es sollte geprüft werden, ob sich mit ihr die untersuchten Spezies besser differenzieren ließen als mit den bisher verfügbaren Datenbanken (BDAL und SR). V. cholerae-Isolate wurden sowohl mit der VibrioBase (+ SR) als auch mit der Bruker BDAL-Datenbank (+SR) zu 100% richtig identifiziert. Die V. mimicus-Isolate wurden zu 89% richtig identifiziert und zu 11% falsch als V. cholerae oder nicht sicher. Wohingegen die BDAL-Datenbank (+SR) nur etwa 20% der V. mimicus-Isolate korrekt differenzieren konnte. Die in dieser Arbeit zufällig gefundenen Isolate der Spezies V. metoecus erhielten immer das falsche Ergebnis V. mimicus, da diese Spezies in den Datenbanken nicht hinterlegt war. Um künftig Routineisolate zügig zu differenzieren, wird empfohlen, V. cholerae-mimicus-fragliche Isolate zunächst per Direkttransfer aufzuarbeiten und mit Vibrio-spezifischen Datenbanken z.B. VibrioBase abzugleichen. Hat der Anwender keine solcher Datenbanken zur Verfügung, kann er eigene Modelle in ClinPro Tools mit den Peaks bei 4025 Da, 7969 Da und 9122 Da für V. cholerae und 7958 Da, 9141 Da, 9477 Da und 9981 Da für V. mimicus erstellen und die Isolate in kurzer Zeit klassifizieren. Andernfalls können diese Peaks selbst in flexAnalysis aufgesucht werden, nachdem die Spektren intern auf den Peak bei 4279 Da kalibriert wurden. Die Spezies V. metoecus konnte nicht differenziert werden, da nur zwei Isolate vorlagen. Allerdings kann ein erfahrener Anwender u.U. die Andersartigkeit dieser Spektren im Vergleich zu V. cholerae- und V. mimicus-Spektren erkennen. Um künftig bei weiteren Spezies mit sehr ähnlichen Spektren, z.B. V. metoecus, spezifische Peaks selbst zu ermitteln, wird empfohlen, die zu untersuchenden Isolate unter standardisierten Bedingungen anzuzüchten und mit der Ameisensäure-Extraktion aufzuarbeiten. Die Suche nach spezifischen Peaks sollte zunächst in ClinPro Tools erfolgen z.B. mit dem Total Average Spektrum, der Gelview Funktion, der ROC Analyse oder einer Kombination daraus. Anschließend können entsprechende Modelle generiert werden. Eine kurze Überprüfung in flexAnalysis sollte trotzdem erfolgen, um auffällige Isolate zu erkennen. Steht ClinPro Tools nicht zur Verfügung, ist ein visueller Abgleich in flexAnalysis auf alleinstehende Peaks oder Peakshifts möglich. Dabei sollte eine interne Kalibrierung aller Spektren z.B. auf einen gattungsspezifischen Peak erfolgen.

Germany, which had long denied its role as a country of immigration (Constant et al., 2012), is today, after the US, the second most popular destination country among immigrants (McAuliffe & Triandafyllidou, 2021). Over the past decades, waves of immigration – to Germany in particular, and to Europe more broadly – have presented societies with numerous new challenges. These challenges exist both at the macro level in terms of social and educational policies to meet the needs of a pluralistic society, and at the micro level concerning how to live together in a culturally and linguistically diversified society (Malik, 2015; Vertovec, 2007b). The overlap between integration and education policies is large, and educational institutions are considered an influential context for immigrant families’ adjustment to the host country (OECD, 2017). In particular, the large achievement gaps between children based on their socioeconomic and immigrant backgrounds have highlighted the need for measures to address inequalities in children’s early years of life (Anders et al., 2012; Kluczniok & Mudiappa, 2019). Accordingly, in recent years, preschools and primary schools have become a greater focus of research and policy. However, it is questionable to what extent these institutions provide an inclusive environment and quality education to children who experience disadvantages due to their social and migration backgrounds. Immigrant parents can provide valuable insight into their children’s formal learning environment in the early years. However, there are limited studies that give immigrant parents a voice and portray their everyday realities. Despite the fact that immigrant parents have high educational aspirations for their children (B. Becker & Gresch, 2016), they experience acculturation stress in the host country, including their children’s schools, due to language and cultural barriers (Jäkel & Leyendecker, 2008; Norheim & Moser, 2020). Moreover, they have been observed to have a desire for their children to develop bicultural competencies in relation to both their heritage and their host countries (Uttal & Han, 2011). Accordingly, immigrant parents have particular identity-related concerns about their children, which affect their beliefs and practices in childrearing. However, we know little about how the characteristics of different contexts influence parents’ social identities and how their social identities shape those contexts. The educational sciences have only recently recognized the relevance of spatial theories in considering issues of identity and inequality (Ferrare & Apple, 2010; Gulson & Symes, 2007a), and there are few empirical studies that apply a socio-spatial theoretical framework. Further, research on immigrant families has not adequately illustrated the relationships between different contexts and usually focuses on only one particular context, such as the home learning environment and school. The study of socio-spatial relations has been mainly limited to the home–school relationship. The linkages between these and broader societal micro and macro contexts that may interact with immigrant parents’ social identities have not been adequately explored. Therefore, this dissertation focuses on this topic and addresses the Turkish-origin community in Germany, the largest immigrant group in the country (Statistisches Bundesamt, 2022). In particular, it examines how Turkish-origin parents of preschool- and primary school-aged children (re-)construct their social identities within home–school–society relational spaces. The dissertation consists of four sub-studies based on the qualitative and quantitative interview data collected within the framework of the Inclusive Education and Social Support to Tackle Inequalities in Society (ISOTIS) project. The quantitative data comprise survey responses from Turkish parents (n = 338) with children aged 3–6 (before primary school) or aged 8–12 (in primary school). The qualitative interview study subjects were drawn from a subsample of the quantitative survey respondents and consisted of 22 mothers. The qualitative data were analyzed utilizing content analysis and included in all four studies of this dissertation. Additionally, Study 4 used a mixed methods design, and content analysis of the qualitative data was used to provide possible explanations for the results of the quantitative data, which were analyzed using (multi-group) regression analysis. Study 1 examined how mothers perceive socio-spatial school and residential segregation and how they relate this issue to the quality of their children’s education. The results showed that mothers living in neighborhoods with high immigrant populations were largely dissatisfied with the quality of their children’s education. Respondents’ concerns about their children being marginalized in a native-dense environment, as well as concerns about their children’s ethnic identity in the context of their potential ‘Germanization,’ were cited as reasons for choosing an immigrant-dense or ethnically and socially diverse school and neighborhood. Despite the fact that some respondents complained about segregation tendencies on the part of the native population, the data showed that middle-class Turkish families, in particular, use similar strategies to raise their children in native-dense environments, even though they ascribe a high value to social diversity. The perceived high educational quality of schools in these neighborhoods was also identified as an influential factor. Moreover, the results indicated not only segregation between schools but also within schools, i.e., the creation of separate classroom groups in primary schools for children from native and/or middle-class families. Study 2 investigated mothers’ perceptions and experiences related to their language use at the intersection of their ethnocultural identities in home–school–society relational spaces. The results showed that the respondents’ linguistic competencies and the value they place on the German language, and their heritage language coincide extensively with their ethnocultural identities, which are mirrored in their ethnolinguistic upbringing beliefs and practices. Parents reported how language barriers affected their parenting (e.g., parental involvement, parent–child relationship) as well as their sense of belonging to the host country (e.g., everyday discrimination) and emphasized experiencing parental stress. Some parents also pointed out that while they did not face a language barrier, symbolic boundaries between them and the native population persisted (e.g., the misconception that women wearing headscarves have little knowledge of German). Regardless of their own German language skills, the parents placed great importance on their children’s German language development, which they saw as a source of success in the host country. Parents were particularly inclined to raise their children bilingually because they viewed their heritage language as an important resource for developing their children’s heritage ethnocultural identity and for enhancing the quality of parent–child interactions. Yet dynamics of inclusion and exclusion in school and society toward their heritage language, as well as the extent to which their linguistic support needs were recognized, appeared to be critical in influencing their social identities in the host country and thus their parenting within the home space. Study 3 addressed the ethnoreligious identities of immigrant mothers within home–school–society relational spaces. The findings showed that parents’ ethnoreligious identities make the home space religiously congruent with or separated from the school and societal space. Their desire to integrate into German society and to ensure that their children received high-quality education and were not marginalized in a non-family environment motivated parents to create congruent spaces (e.g., celebrating Christian festivals at home, parental involvement in Christian celebrations at school, enrolling their children in a church-run preschool). Conversely, some respondents chose contextually separate parenting approaches as a way to maintain their children’s strong religious affiliation. In addition, narratives showed that inclusive (e.g., teachers collaborating with minority parents on their religious celebrations, using interreligious pedagogical practices) and exclusive (e.g., teachers’ cultural prejudice, the perception that some preschools refused to enroll minority children) approaches in schools appeared to be closely linked to the societal space in terms of attitudes toward religious minorities. These spaces seemed to reproduce each other, influencing the ethnoreligious identities of the parents that were reflected in the home space. Thus, they also influenced parents’ beliefs and practices with regard to ethnoreligious upbringing. Finally, Study 4 was conducted to identify the relationship between Turkish immigrant parents’ perception of their children’s school climate and their life satisfaction in Germany. In addition, how this relationship varies depending on the immigrant generation of the parents (first vs. second generation) and the school level of their children (preschool vs. primary school) was investigated. Applying a mixed methods research in Study 4, an explanatory sequential design was used. Thereby, the qualitative interviews were used to further interpret the quantitative research findings. The results of the quantitative survey revealed that life satisfaction in Germany was predicted by the way parents perceived the children’s school climate. While the relationship was significant for both generations, it was stronger for second-generation parents. Further, the relationship was significant only for parents with children attending primary school. The qualitative research findings suggested that there was a high degree of overlap between perceived inequalities in school and in society. These included the sense of injustice (particularly in primary schools), the extent to which an inclusive school climate has been created, and the collaboration of schools with immigrant parents. In conjunction with the quantitative research findings on life satisfaction among Turkish families, this could potentially have implications for immigrant parents. Taken together, the present dissertation highlights the significance of socio-spatial relational theory approaches, which have been largely overlooked in educational sciences, and emphasizes such approaches’ power in portraying immigrant parents’ social identities. Accordingly, this dissertation seeks to contribute theoretical developments, as well as further concrete empirical research, for the exploration of the complex perceptions and experiences of immigrant families within and across various contexts. Moreover, it provides valuable insights for the inclusive pedagogical approaches in preschools and primary schools, as well as educational and social policies aiming to create inclusive environments in their societies.

Psoriasis ist eine chronisch-entzündliche Erkrankung, die außer der Haut und den Nägeln auch die Enthesen und die Gelenke betreffen kann. Durch die Fortschritte im Verständnis der Immunpathogenese der Psoriasis wurden neue hochwirksame gezielte Therapien entwickelt. Diese neuen Therapien ermöglichen individuelle Therapiekonzepte für die Betroffenen. Solche personalisierten Therapien garantieren die höchste Wirksamkeit mit den geringsten Nebenwirkungen. Die TNFα-Inhibitoren sind die ersten gezielten Therapien für Psoriasis. Darüber hinaus bietet die Entwicklung von Antikörpern gegenüber IL-12/IL-23, IL-17 und IL-23 mehr Therapiemöglichkeiten für Psoriasis. In dieser Arbeit wurde die Anwendung von den verschiedenen Klassen von Biologika (Adalimumab, Brodalumab und Ustekinumab) bei Psoriasispatienten:innen in besonderen Situationen untersucht. Das Ziel dieser Arbeit war die Unterstützung der Therapieentscheidung bei Psoriasispatienten:innen basierend auf einem klinischen Profiling.

Infections by gastrointestinal nematodes mandate an effective type 2 response for the parasite clearance. In line with the cross-regulatory nature of Th1 lineage specifying factors on the differentiation of Th2 cells seen at the molecular level, strong type 1 activity resulted by inflammation associated with senescence, specific genetic predisposition and co-infections with intracellular pathogens exacerbate the Th2 responses resulting in poor resistance in nematode infections. Despite reported cross-regulation, the Th1 and Th2 pathways are not mutually exclusive as polarization with IFN-g, IL-12 and IL-4 results in the generation of T-bet and GATA-3 co-expressing Th2/1 cells in vitro. Th2/1 cells are also induced naturally in nematode infections (Affinass et al., 2018; Bock et al., 2017; Peine et al., 2013). In the current study we demonstrate that the IFN-g competence progressively rises with the age of uninfected BALB/c mice displaying high resistance to nematode infection. The elevated type 1 bias in 5-10 months old compared to 2-3 months old mice resulted in poor parasite control manifested by higher female fecundity in the mature cohort infected with H. polygyrus. The poor resistance was accompanied by stronger generation and mucosal accumulation of Th2/1 hybrid cells and elevated proportions of parasite specific IFN-g producing cells. Substantiating the above findings, restriction of IFN-g availability in the priming phase of nematode infection led to improved resistance coinciding with sharp reduction in systemic and mucosal Th2/1 cells and a near complete absence of parasite specific IFN-g producing cells. Conversely, supplementation of early IFN-g availability led to impaired parasite control associated with robust expansion of Th2/1 cells and a significant rise in IFN-g producing cells in parasite specific T cell pool. Importantly, elevated IFN-g availability did not inhibit classical Th2 cells in the long run and rather promoted an accumulation of systemic GATA-3+ Teff cells in IFN-g treated BALB/c mice. The increased parasite egg production upon IFN-g treatment was traced back to the increased fitness of the L4 larvae maturating in the gut of IFN-g treated mice. In line with the findings in differently aged mice, C57BL/6 mice genetically predisposed to higher susceptibility in H. polygyrus infection more rapidly accumulate Th1 cells at steady state compared to resistant BALB/c mice. The elevated type 1 activity in C57BL/6 mice translated to greater accumulation of small intestinal Th2/1 cells post infection and poor resistance compared to BALB/c mice. However, the stark differences seen between the strains at younger age leveled out in older mice due to increased IFN-g competence and increased bias in favor of Th2/1 cells in mature BALB/c mice. Restricting IFN-g availability in C57BL/6 mice led to increased resistance thereby substantiating the significance of IFN-g in differential susceptibility across inbred lines. Overall, our findings report an age-dependent reduction in anti-nematode type 2 immunity resulted by steady state accumulation of IFN-g competent effector cells in the vertebrate host.

Eps15 (epidermal growth factor receptor pathway substrate 15) homology domain containing proteins (EHDs) comprise a family of dynamin-related ATPases. The four mammalian members of this family (EHD1-4) are involved in various endocytic and membrane trafficking pathways. Structural studies revealed that EHDs assemble at the surface of membranes to form ring-like filaments. Assembly on membranes was shown to stimulate the ATPase activity. In case of EHD2, ring-like oligomers were proposed to stabilize the neck of caveolae, which in turn regulates cellular fatty acid uptake. The aim of this thesis was the identification of small molecule inhibitors that modulate EHD2 function and therefore cellular fatty acid uptake. Until now, there are no known inhibitors for EHD proteins. To this end, I optimized a malachite green-based ATPase assay to be robust and reproducible for a high-throughput setup. Drug screening was then employed to identify small molecules that inhibit the liposome-stimulated ATP hydrolysis of EHDs. Since EHD2 showed only a low ATPase activity, I initially screened for inhibitors against the closely related homologue EHD4. Validated hits were subsequently evaluated for inhibition against EHD2 in an HPLC-based setup. In this way, I identified chemical compounds that inhibited the ATPase activity of EHD4 and EHD2, and validated them in different biochemical assays. Interestingly, two of these small molecules were found to increase and decrease lipid droplet size in a cell-based assay. I also identified three inhibitors that were specific to EHD4 and did not interfere with the ATPase of EHD2 and the GTPase activity of Drp1, which was used as a control. Another exciting finding in this project were discovery of two compounds that accelerated the liposome-stimulated GTPase activity of Drp1. The identified inhibitors may have future applications to explore the function of EHDand Drp1-dependent cellular signaling pathways. Furthermore, they may be developed as therapeutic agents. Finally, my assay optimizations can be used to systematically and efficiently identify inhibitors for other dynamin superfamily members

When we observe a scene in our daily lives, our brains seemingly effortlessly extract various aspects of that scene. This can be attributed to different aspects of the human visual system, including but not limited to (1) its tuning to natural regularities in scenes and (2) its ability to bring different parts of the visual environment into focus via eye movements. While eye movements are a ubiquitous and natural behavior, they are considered undesirable in many highly controlled visual experiments. Participants are often instructed to fixate but cannot always suppress involuntary eye movements, which can challenge the interpretation of neuroscientific data, in particular for magneto- and electroencephalography (M/EEG). This dissertation addressed how scene structure and involuntary eye movements influence the extraction of scene and object information from natural stimuli. First, we investigated when and where real-world scene structure affects scene-selective cortical responses. Second, we investigated whether spatial structure facilitates the temporal analysis of a scene’s categorical content. Third, we investigated whether the spatial content of a scene aids in extracting task-relevant object information. Fourth, we explored whether the choice of fixation cross influences eye movements and the classification of natural images from EEG and eye tracking. The first project showed that spatial scene structure impacts scene-selective neural responses in OPA and PPA, revealing genuine sensitivity to spatial scene structure starting from 255 ms, while scene-selective neural responses are less sensitive to categorical scene structure. The second project demonstrated that spatial scene structure facilitates the extraction of the scene’s categorical content within 200 ms of vision. The third project showed that coherent scene structure facilitates the extraction of object information if the object is task-relevant, suggesting a task-based modulation. The fourth project showed that choosing a centrally presented bullseye instead of a standard fixation cross reduces eye movements on the single image level and subtly removes systematic eye movement related activity in M/EEG data. Taken together, the results advanced our understanding of (1) the impact of real-world structure on scene perception as well as the extraction of object information and (2) the influence of eye movements on advanced analysis methods.

We begin this thesis with a discussion of problems from geometry and combinatorics, to which methods from equivariant algebraic topology have been successfully applied in the past.

The generalised Nandakumar & Ramana~Rao problem (due to Karasev, Hubard, & Aronov and Blagojević & Ziegler) asks whether given a full-dimensional compact convex body K in R^n, n-1 continuous real functions on the space of all full-dimensional compact convex bodies in R^n and a natural number m, one can always find a partition of K into m convex pieces of equal volume such that the value of each function is equal on all the pieces of the partition.

Inspired by this problem and recent parameterised generalisations of mass partition types by several groups of researchers, we formulate a parameterised version of the Nandakumar & Ramana~Rao problem, where we aim to equipart j>n-1 functions, but are allowed to choose a convex body K from some family parameterised by a vector bundle E over a CW-complex B.

After we make the notion of "parameterised by the vector bundle E'' precise in Chapter~II, we follow the strategy developed by Karasev, Hubard & Aronov to formulate a topological criterion for the existence of solutions to the parameterised Nandakumar & Ramana Rao problem. Due to the limitations of our topological methods, we restrict our attention to the case when m equals some prime p.

Chapter~III contains a brief overview of various standard algebraic topology results that we use extensively in the later chapters.

In Chapter~IV we extend the results of Jaworowski concerning Fadell-Husseini indices of sphere bundles, equipped with free fibrewise action of the cyclic group Z/Z_p, by considering the symmetric group S_p. Next, we compute the index of the fibrewise configuration space Fconf(p,E) of p distinct points with respect to S_p in the case of vector bundle E of an odd rank. In the case when E has an even rank, we provide bounds on the index, showing that the upper bound is tight in some cases. Then we change the group that acts on E, and compute the index of the space Fconf(p, E) with respect to cyclic group action in the special case when E admits two linearly independent nowhere zero sections.

In Chapter~V we use these computations to find a partial solution to the parameterised Nandakumar & Ramana~Rao problem. For any pair of a vector bundle E and a prime p, we describe a range of j such that the parameterised Nandakumar & Ramana~Rao has a solution for the family of convex bodies parameterised by E, the desired number p of pieces in partition and a choice of j appropriately defined continuous functions. Finally, we apply these computations to the case of tautological bundles over the Grassmannians.

The function of non-coding RNA sequences is largely determined by their spatial conformation. This is the secondary structure of the molecule, which is formed by Watson–Crick interactions between nucleotides. Hence, modern RNA alignment algorithms routinely take structural information into account. Essential tasks for discovering yet unknown RNA families and inferring their possible functions are the structural alignment of RNAs and the subsequent search of the derived structural motifs. These tasks demand a lot of computational resources, especially for aligning many long sequences, and it therefore requires efficient algorithms that utilize modern hardware when available. A subset of the secondary structures contains pseudoknots, which are overlapping interactions that add additional complexity to the analysis and are often ignored in available software.

In this thesis, I present LaRA 2 and MaRs, two SeqAn-based software tools that implement algorithms for finding sequence-structure motifs in genomic sequences. In contrast to other programs, my tools can handle arbitrary pseudoknots. They use multithreading for parallel execution and are implemented in modern C++ code for maximal longevity and performance.

LaRA2 is significantly faster than comparable software for accurate pairwise and multiple alignments of structured RNA sequences. It uses a new heuristic for computing a lower boundary to the solution and employs vectorization techniques for speeding up the time-critical parts of the algorithm.

MaRs can be applied in a workflow right after LaRA2 and derives sequence-structure motifs from the structural alignments. The motifs are descriptors of the RNA sequences’ properties and drive the search for homologs in genomic sequences. MaRs employs a bidirectional index on the genomic sequences and an optimized multithreaded search strategy for finding the matches really fast. The use of a thread pool, effective pruning strategies, and a low memory footprint ensure that MaRs is capable of processing extremely large data sets.

Climate change, antibiotic resistances and environmental pollution are growing threats. Therefore, finding alternatives for fossil resources and discovery of new pharmaceuticals grows more important every day. Natural compounds and their in vivo production pathways proved to be a possible solution to overcome those problems. Optimized microbial hosts can serve as sustainable production platforms for various compounds as it is done for penicillin since many years. The first research topic of this thesis are borneol dehydrogenases, enzymes which convert borneol to camphor. Enantiomerically pure camphor has numerous applications in cosmetic, pharmaceutical, and chemical industry. Thus, enantioselective borneol dehydrogenases would be an attractive candidate to achieve enantiomerically pure camphor. To better understand the differences of enantioselective and unselective borneol dehydrogenases we solved the structures of two selective borneol dehydrogenases from Salvia rosmarinus and Salvia officinalis using X-ray crystallography and cryo-electron microscopy. The obtained structures were compared to the previously solved structure of the unselective borneol dehydrogenase of Pseudomonas sp. TCUHL1. The second focus of this thesis are terpene synthases, a class of enzymes responsible for the cyclization of linear terpene precursors. The products of terpene synthases are interesting candidates for the chemical and pharmaceutical industry due to their diverse characteristics and properties. Latest advances in genome sequencing enabled the discovery of many new and diverse terpene synthases from various organisms. We report on the discovery of two terpene synthases from Coniophora. puteana, Copu5 and Copu9, that not only have identical product profiles, but also show high yields in an optimized Escherichia coli strain. Main product of both enzymes is (+)-δ-cadinol that has been shown to have cytotoxic effect on MCF7 cells and could be used as a new and sustainable anti-tumor drug. To investigate their properties and gain deeper understanding into their function, we attempted to crystallize and biochemically characterize Copu5 and Copu9.

One of the great societal challenges of today is the fight against diseases which reduce life expectancy and lead to high economic losses. Both the understanding and the addressing of these diseases need research activities at all levels. One aspect of this is the discovery and development of tool compounds and drugs. Tool compounds support disease research and the development of drugs. For about 20 years, the discovery of new compounds has been attempted by screening small organic molecules by high-throughput methods. More recently, X-ray crystallography has emerged as the most promising method to conduct such screening. Crystallographic fragment-screening (CFS) generates binding information as well as 3D-structural information of the target protein in complex with the bound fragment. This doctoral research project is focused primarily on the optimization of the crystallographic fragment screening workflow. Investigated were the requirements for more successful screening campaigns with respect to the crystal system studied, the fragment libraries, the handling of the crystalline samples, as well as the handling of the data associated with a screening campaign. The improved CFS workflow was presented as a detailed protocol and as an accompanying video to train future CFS users in a streamlined and accessible way. Together, these improvements make CFS campaigns a more high-throughput method, offering the ability to screen larger fragment libraries and allowing higher numbers of campaigns performed per year. The protein targets throughout the project were two enzymes and a spliceosomal protein-protein complex. The enzymes comprised the aspartic protease Endothiapepsin and the SARS-Cov-2 main protease. The protein-protein complex was the RNaseH-like domain of Prp8, a vital structural protein in the spliceosome, together with its nuclear shuttling factor Aar2. By performing the CFS campaigns against disease-relevant targets, the resulting fragment hits could be used directly to develop tool compounds or drugs. The first steps of optimization of fragment hits into higher affinity binders were also investigated for improvements. In summary, a plethora of novel starting points for tool compound and drug development was identified.

The aim of this dissertation is to better understand Roman grand strategy by analyzing imperial policy in a single province, Lower Germany, and during a particular time period, from the reign of Augustus to that of Hadrian. Despite the local—and, hence, limited— approach, this method lends itself to broader conclusions. On the one hand, examining closely the development and defense of this area— the edge of the Roman Empire’s military territory on the European continent’s northwest— helps to compare and contrast policies carried out in other frontier provinces. Hence, one can scrutinize, confirm, or modify broad, general theses of imperial defense and grand strategy, such as that of Edward Luttwak. On the other hand, Germania Inferior, despite the small extension of its territory, had an outsized military and strategic importance. Emperors often visited the province, and its troops played crucial roles in the conquest and upkeep of Britain and in the later reinforcement of the Danube garrisons. As such, an analysis of Lower German defense—and of troop movements in and out of the province— is inevitably linked with the broader study of Roman grand strategy proper.

Since Roman Lower Germany was heavily militarized, the purely military component of grand strategy, which included constant campaigns of limited scope beyond the Rhine, became intertwined with a political component. The Rhine armies and its commanders became essential players in the dangerous game of imperial politics. The diplomatic component played a role insofar as there were alliances—often shifting, sometimes broken— with tribes and kingdoms beyond the empire’s borders. And, as Lower Germany became further integrated into the Roman imperial structure over time, the area’s economy developed considerably, even if it remained mostly a peripheral province.

For both emperors and legates, ruling Lower Germany involved the complex issue of incorporating the allied, native Batavians into the Roman imperial structure. The extraordinary status of this remarkable, warrior people— at once fiercely loyal to the emperor as the core of his personal bodyguard and partially independent from Rome in their distant domains—sheds light on the Romans’ practice of grand strategy. This applies especially in terms of the simultaneous use of both direct and indirect rule, even within a single province.