For the development of novel strategies for drug administrations, extensive knowledge over the delivery pathways, the physicochemical properties of the involved biological barriers, and the interactions with the drug are of paramount importance. In this thesis, I employed biophysical techniques like time-resolved fluorescence spectroscopy and microscopy in conjunction with advanced analytical tools to gain new insight into the structure of epithelial barriers as well as the biomolecular interactions of drugs and drug mimetics in the tissue. Fluorescent molecular rotors are fluorophores, which can be used to sense local nanoviscosity using their fluorescence lifetime. I applied these probes to artificial vesicles, in order to determine membrane viscosities and lipid phase transitions. In living cells of the gastrointestinal tract, they were used to map the 3D viscosity profile of the mucus layer lining the small intestine and characterize this diffusion barrier with unprecedented precision and spatial resolution. The extracted gradients and heterogeneities of the mucin network were compared based on culturing circumstances of the mucus producing epithelial cells, setting a framework for physiological cell growing conditions. In fluorescence lifetime imaging microscopy (FLIM), the target fluorescence of a molecular of interest can be discriminated from the autofluorescent background of the surrounding tissue based on the fluorescence lifetime. I used this advantage to generate background free penetration profiles of the drug mimetic Nile Red in human skin to extract biophysical properties of the outermost barrier of the body and compare unaided penetration with nanoparticle-assisted administration through various transdermal delivery routes. We finally developed a novel platform for labeling biomolecules with a fluorophore and a spin label. The multiplexed read-out of FLIM and EPR data facilitates the simultaneous determination of spatially resolved target molecule concentration and characterization of its immediate environment while avoiding analytical inconsistencies resulting from individual labeling. This thesis demonstrates the capabilities of time-resolved fluorescence techniques when paired with proper analytical strategies for the application in biophysical research and the development of new drug delivery systems.

This thesis studies the large scale behaviour of biological processes in a random en- vironment. We start by considering a system of branching random walks in which the branching rates are determined by a random spatial catalyst. In an appropriate setting we show that this process converges to a superBrownian motion in a space white noise potential. We study the asymptotic properties of this superprocess and prove that it survives with positive probability. We then consider scaling limits of a spatial Λ–Fleming–Viot model, relating it both to the process we just introduced and to a stochastic Fisher-KPP equation. Finally, we study the longtime behaviour of the Kardar–Parisi–Zhang equation on finite volume, proving asymptotic synchroniza- tion and a one force, one solution principle. Our analyses rely on techniques from singular stochastic partial differential equations for the parabolic Anderson model and the KPZ equation, and on the theory of superprocesses.

Objectives: Elba Island (Tuscan Archipelago, Italy) was one of the hotspots of Etrusco– Roman iron metallurgy. At least since the 6th century BCE, hematite ore was extracted from the deposits on the island. The run-of-mine was at first transported to the ‘industrial’ area of the major Etruscan city of Populonia. Iron smelting on the Island started most likely in the late 4th century BCE. Production increased after the Roman occupation in the mid-3rd century BCE, peaking around the mid- to late 2nd century BCE. Afterwards, the smelting activities on Elba decreased markedly. The time lack between the onset of mining and smelting on Elba, and rather the decline in production, are attributed to a lack of fuel on the island after deforestation. A ‘deforestation’ narrative developed at least since the mid-18th century and is continuously cited until recently. Most scholars rely on the decreases in archaeological material, an ancient observation by Strabo that iron was not processed on the island, and contemporary view on Elba’s landscape. Scientific evidence of a lack of fuel, deforestation, or environmental change during the smelting period is sparse. Besides the use of wood fuel for smelting, also legacy issues are an important aspect of historical human–environment interactions on Elba. The Greek name of Elba—Aitháleia, the fuming one—and historical observations point to the emission from furnaces. Some scholars believe that the luxurious villae maritimae were constructed on Elba only after the abandonment of most smelting sites, because soot emission would have made the island uninteresting for recreation. Additionally, marine sediments and recent data from the mines suggest that (subrecent) iron production had an environmental impact on Elba. Direct evidence for such an environmental impact caused by ancient smelting is, however, not propound. Approaches: In the thesis at hand I use (i) soil chemical data from the ancient smelting site in Magazzini; (ii) geochemical analysis of sediment sequences uncovered from the Campo coastal plain; (iii) a stochastic chronological model of sediment facies sediment accumulation using cumulative probability functions of cal-14C-ages and (iv) Monte-Carlo simulations on the woodlot requirements for iron smelting and the supply of the workforce to reconstruct human-landscape interactions on Elba during the mid- to late Holocene with a clear focus on the ancient smelting period (4th century BCE – 1st century CE). The body of the thesis comprises four case studies related to the four methodical strategies. The interpretation of the results is embedded in a characterization of the ‘metallurgical landscape’ on ancient Elba and a conceptual socio-ecological model of iron as a raw material that rests on the ideas of the Vienna School.

Results: The main outcomes of the reconstruction of human–environment interactions and the impact of smelting on the landscape balance are as follows. A specific signature of ancient iron smelting is still detectable for on-site geochemical data and terrestrial sediment sequences. Soil on the smelting site are increased in As, Fe, Cu, and Ca contents and organic and pyrogenic carbon, magnetic susceptibility, and pH. The spatial variability of these activity marker points to different processes of the smelting procedure; Ca is for instance related to ashes, whereas Cu points to the the deposition of metallurgical remains, and As to run-of-mine. As the data from the smelting site differs from other archives of metallurgy on and around Elba, our record gives a specific chemical impact of iron smelting. Sedimentological and chronological data suggest that during the ancient smelting period, geomorphic activity on Elba increased clearly. Sediment layers indicating soil erosion and high magnitude floods were deposited in valleys with smelting site in upstream areas; in different sediment archives distributed over several plains and valleys on Elba, sediment accumulation and geomorphic activity increased during Etruscan/Roman times. Sedimentological evidence also implies that the palaeolandscape—especially the accessibility of different land areas limited by the distribution of wetlands—was one location factor for smelting sites. Although the impact of smelting on the landscape balance is detectable in different archives using different proxies, Roman metallurgy on Elba did not necessarily cause a lack of fuel. Our Monte-Carlo experiments of the woodlot requirements reveal that it is (very) unlikely that not fuel wood was available during Roman times. This is especially clear when assuming that Elba was autarchic regarding the food supply for metalworkers. The model suggests that the non-technical requirements for smelting importantly contributed to the overall woodland availability on Elba.

Conclusions: Sediments and soils prove to be valuable archives of the ancient smelting period. In conclusion, iron smelting on Elba during the antiquity had a remarkable impact on the landscape balance, however, without necessarily causing a lack of fuel. We therefore consider that the ‘deforestation narrative’ developed under the historical–environmental conditions of the 18th to 21st century and other reasons than deforestation might have triggered the abandonment of smelting sites in the 1st century BCE. Smelting might also have continued after the turn of eras.

The synthesis of the first organonickelpentafluoro-orthotellurates is described. The obtained complexes [Ni(Hacac)2(OTeF5)2] and cis-[Ni(iPrIm)2(OTeF5)2] are characterized by NMR spec-troscopy, mass spectrometry and single crystal X-ray diffraction. The binuclear complex [{Ni(Hacac)(H2O)(OTeF5)(µ-OTeF5)}2] is characterized by single crystal X-ray diffraction, ex-tending the group of metals of which bridging pentafluoro-orthotellurato ligands are known. The facile one-pot synthesis of the strong methylation agent [Me2Cl][Al(OTeF5)4] is described. This reaction requires a Brønsted super acid. The dimethylchloronium salt is used to methyl-ated several weakly basic molecules like PF3, P(CF3)3 and cyanuric fluoride under formation of strongly Lewis acidic cations. Subsequent decomposition reactions of the formed salts are investigated. This leads to new insides on the electron withdrawing properties of the pen-tafluoro-orthotellurato group. When incorporated in a hypervalent 3-center-4-electron bond the pentafluoro-orthotellurato ligand is more electron withdrawing than the fluorido ligand. The de-composition reactions also leads to new insides on the stability of the weakly coordinating anion. The aluminate anion [Al(OTeF5)4]− is not the perfect anion for these organic cations, but it is the best available on a large scale. The role of the dimethylchloronium cation in the classical Friedel-Crafts-Methylation is evalu-ated by quantum chemical calculations. In similarity to the Friedel-Crafts-Methylation, the salt [Me2Cl][Al(OTeF5)4] is used to methylate electron deficient aromatic molecules like 1,2,3,4-tetrafluorobenzene.

Die vorliegende Arbeit untersuchte den Einfluss verschiedener Insektizid-Wirkstoffe auf das larvale Transkriptom und die Proteinbildung der Honigbiene Apis mellifera. Die Westliche Honigbiene gilt aufgrund ihrer Ökosystemdienstleistungen als eines der wichtigsten Nutztiere des Menschen. Durch die Bestäubung landwirtschaftlicher Nutzpflanzen und Blüten weltweit nimmt sie ökonomisch und ökologisch eine Schlüsselposition ein. Im Laufe der 2000er beobachtete man global einen starken Rückgang an Honigbienen, der zunächst nicht erklärt werden konnte. Mögliche Ursachen waren der Befall durch Pathogene oder verschiedene Virus-Erkrankungen der Bienen. Andere Erklärungen sahen den Hauptgrund in der landwirtschaftlichen Verwendung von Pestiziden oder dem Verlust an Lebensraum. Insbesondere der Einsatz von Insektiziden wurde aufgrund ihrer Wirkung auf Nicht-Zielorganismen kritisiert. Hierbei gerieten die Auswirkungen von subletalen Pestizid-Konzentrationen auf die Physiologie der Honigbiene in den Fokus. In Studien konnte gezeigt werden, dass geringe Konzentrationen eines Insektizids nicht zum Tod führen, allerdings negative Effekte auf das motorische Verhalten, die Flugfähigkeiten oder die Lern- und Gedächtnisleistungen zeigen. Im Rahmen der durchgeführten Versuche wurde der Einfluss subletaler Konzentrationen der neuen Wirkstoffe Flupyradifuron und Chlorantraniliprol untersucht. Im Vergleich kamen die etablierten Wirkstoffe Dimethoat und Fenoxycarb zum Einsatz. Gemäß den Vorgaben der OECD Richtlinie 239 erfolgte die Fütterung von Bienenlarven über acht Tage. Die Applikation der Wirkstoffe fand an vier aufeinanderfolgenden Tagen statt und an den Tagen vier, sechs und acht wurden Individuen für eine spätere Analyse eingefroren. Die Dosis an aufgenommenem Wirkstoff erhöhte sich bis zu einem maximalen Wert nach Tag 6. Die Analyse ausgewählter Transkripte erfolgte mittels eines RT-qPCR-Arrays (79 Kandidatengene). Die anschließende Proteinanalyse erfolgte durch eine 2D-Gelelektrophorese, um die Veränderungen im Transkriptom auch im Proteinmuster nachzuweisen. Die Ergebnisse der Transkriptomanalyse zeigten, dass vor allem Gene betroffen waren, die mit der Larvalentwicklung, Physiologie oder Immunantwort assoziiert waren. Dies betraf vor allem den Toll-Signalweg, die Ecdyson-induzierte Kaskade und die Autophagie-Signaltransduktion. In der Proteinanalyse waren Änderungen in Bezug auf das Immunsystem, den Metabolismus und die Entwicklung festzustellen (> 900 Proteinspots). Die beiden geringsten Dosen von Dimethoat (0,05 µg und 0,1 µg) wiesen keine signifikanten Unterschiede bei den identifizierten Proteinen auf. Es ließ sich feststellen, dass mit zunehmender Dosis an Wirkstoff auch die Anzahl an differenziell exprimierten Transkripten zunahm. Zudem zeigte Flupyradifuron in der Transkript- und Proteinanalyse die meisten Änderungen im Vergleich zur Kontrolle auf. Eine mögliche Erklärung hierfür ist, dass die applizierte Dosis an Flupyradifuron trotz subletaler Konzentration bei den durchgeführten Versuchen noch zu hoch angesetzt war. Nichtsdestotrotz wurden endogene Effekte nach Behandlung mit verschiedenen Wirkstoffen in subletalen Konzentrationen nachgewiesen. Weiterhin deutet sich an, dass der Fettkörper, die Mitochondrien oder auch die Hämozyten geschädigt werden. Zum einen führen die vorliegenden Ergebnisse zu der Folgerung, dass die Analyse der Genexpression und Proteinbiosynthese ein weiteres nützliches Werkzeug im Zuge einer holistischen Risikoabschätzung der Wirkung von Agrochemikalien auf Honigbienen darstellt. Zum anderen ist es wichtig, neben der Betrachtung der Transkripte ebenfalls die korrelierenden Proteine in die Auswertung mit einzubeziehen, um ein komplexeres Bild des zellulären Zustandes zu erhalten.

Auch im Jahr 2020, fünf Jahre nach der so genannten Flüchtlingskrise, steht das deutsche psychiatrisch-psychotherapeutische Gesundheitssystem vor der Herausforderung, immer mehr Menschen aus verschiedenen Ländern mit unterschiedlichen Sprachen angemessen zu behandeln. Obwohl das Thema in den letzten Jahren zunehmend an Relevanz in Forschung und Praxis gewonnen hat, mangelt es an aktuellen empirischen Daten zur Versorgungslage von Patienten mit Migrationshintergrund. Die wenigen Untersuchungen deuten auf eine Fehlversorgung von Patienten1 mit Migrationshintergrund in der psychiatrischpsychotherapeutischen Versorgung hin. Dabei ist allerdings bislang wenig darüber bekannt, wie Patienten mit Migrationshintergrund einerseits und Behandler in der psychosozialen Versorgung andererseits, die Behandlung einschätzen und welchen Bedarf und welche Lösungsvorschläge sie sehen. Bislang werden transkulturellen Kompetenzen von Mitarbeitern eine zentrale Rolle für eine Verbesserung der Versorgungsbedingungen zugeschrieben. Dabei ist nach wie vor nicht geklärt, was transkulturell kompetentes Handeln für den Bereich der psychiatrischpsychotherapeutischen Versorgung genau beinhalten könnte. Entsprechend widmet sich die vorliegende Arbeit zunächst der Einführung zentraler Begriffe. Es gilt zu klären, wer eigentlich gemeint ist, wenn von „Menschen mit Migrationshintergrund“ gesprochen wird. Auch die Begriffe „Kultur“ und „Transkulturelle Kompetenz“ werden ausführlich dargestellt. Weiterhin wird der aktuelle Stand der psychosozialen Versorgung von Patienten mit Migrationshintergrund in Deutschland wiedergegeben. Dabei liegt ein Fokus auf möglichen Gründen für die bestehende Fehlversorgung sowie den bislang diskutierten Lösungsvorschlägen. Es folgt die Darstellung über den Stand der Aus- und Weiterbildung von Behandlern in transkulturellen Kompetenzen. Der Abschnitt schließt mit einem Überblick über den aktuellen Forschungsstand zur Perspektive von Patienten mit Migrationshintergrund und Behandlern auf die transkulturelle Behandlung. In der vorgelegten kumulativen Dissertation werden qualitative Daten aus fünf Untersuchungen zusammengeführt. Bei den Daten handelt es sich zum einen um Textpassagen und Definitionen von transkultureller Kompetenz aus deutsch- und englischsprachigen Fachartikeln, zum anderen um Daten aus insgesamt 41 Interviews mit Patienten mit Migrationshintergrund sowie mit Behandlern. Als qualitative Auswertungsmethoden kamen die Grounded Theory sowie die inhaltlich-strukturierende qualitative Inhaltsanalyse zum Einsatz. Im Rahmen eines Literaturreviews (Publikation 1) wurden Textpassagen und Definitionen von transkultureller Kompetenz aus 130 deutsch- und englischsprachigen Artikeln auf die Frage hin untersucht, welche Konzeptionen von transkultureller Kompetenz es in Psychologie, Medizin und angrenzenden Fachdisziplinen gibt und welche für die psychosoziale Versorgung relevant sein könnten. Die Analyse ergab drei Ansätze von transkultureller Kompetenz, den technologischen Ansatz, den Komponentenansatz sowie den Haltungs-und Einstellungsansatz. Es werden verschiedene Kriterien aufgezeigt, die bei der Einschätzung von Vorschlägen zur Umsetzung von transkultureller Kompetenz in der Praxis helfen können. An die Frage, was unter transkultureller Kompetenz in der psychiatrischpsychotherapeutischen Versorgung zu verstehen ist, schließt die Überlegung an, inwiefern es sich bei der Kompetenz um eine „Spezialkompetenz“ handelt oder ob anzunehmen ist, dass die Qualifikation für transkulturell kompetentes Handeln bereits in den allgemeinen Kernkompetenzen psychiatrisch-psychotherapeutischen Arbeitens aufgeht. Dieser Frage wurde in Publikation 4 nachgegangen. Behandler und Patienten mit Migrationshintergrund wurden nach ihren Vorstellungen von transkultureller Kompetenz gefragt. Es zeigte sich, dass sich nach Ansicht der Befragten, transkulturelle Kompetenzen in allgemeinen psychotherapeutischen Kernkompetenzen abbilden. Eine zentrale Schlüsselqualifikation für transkulturell kompetentes Handeln scheint die Fähigkeit zum individualisierten Vorgehen in der Behandlung zu sein. In einer weiteren Untersuchung wurden die aus den Interviews mit Behandlern erhobenen Daten hinsichtlich der Frage untersucht, wie sie die Arbeit mit Patienten mit Migrationshintergrund erleben (Publikation 2). Es zeigte sich, dass die Arbeit mit dieser Klientel für die befragten Behandler als sehr herausfordernd und häufig verunsichernd empfunden wird. Auch wurde deutlich, dass das professionelle Selbstkonzept der Behandler Einfluss auf das Erleben in der Behandlung zu haben scheint. Ein professionelles Selbstkonzept als „lebenslang Lernender“, der die im Rahmen der transkulturellen Behandlung offenbar häufiger auftretenden Unsicherheiten bezogen auf die Symptomatik oder die adäquate Behandlung als immanenten Bestandteil der Behandlung ansieht, scheint mit mehr Offenheit einherzugehen, die Klientel überhaupt in die Behandlung aufzunehmen (Publikation 3). Daraus lassen sich Implikationen für die Aus- und Weiterbildung von psychiatrisch-psychotherapeutischen Behandlern ableiten. Den Erfahrungen von Behandlern wurden in einer weiteren Studie die Erfahrungen von Patienten mit Migrationshintergrund gegenüber gestellt und geschaut, wie diese die bestehenden Versorgungsangebote bewerten. Ein Schwerpunkt bildete dabei die Frage, wie sie den Zugang zum psychosozialen Versorgungsystem einschätzen (Publikation 5). Es zeigte sich auch hier, dass die befragten Patienten jedes „technologische“ Vorgehen in der Behandlung ablehnten und sich besonders von Behandlern angesprochen fühlten, die individuell auf ihre Anliegen eingehen konnten. Demgegenüber schätzten sie „kulturspezifisches“ Expertenwissen als unwichtig für eine gelungene Behandlung ein. Spezialangebote bewerteten die Befragten aus Angst vor weiterer Stigmatisierung und Ausgrenzung als problematisch und wünschten sich eher Unterstützung und Aufklärung – auch auf verschiedenen Sprachen – beim Zugang zum deutschen Versorgungssystem. Das übergeordnete Ziel der Arbeit ist die Verbesserung der Versorgungsbedingungen von Patienten mit Migrationshintergrund. Die vorgelegte Arbeit bietet neben der ausführlichen Darstellung der einzelnen Studien eine Zusammenführung der Ergebnisse und gibt Hinweise auf 1. Ursachen für bestehende Fehlversorgung von Patienten mit Migrationshintergrund in der psychiatrisch-psychotherapeutischen Versorgung 2. Möglichkeiten zum Abbau von Engpässen in der psychiatrisch-psychotherapeutischen Versorgung von Patienten mit Migrationshintergrund 3. den Nutzen präventiver Maßnahmen in der Versorgung von Patienten mit Migrationshintergrund 4. die Konzeption von transkultureller Kompetenz für die psychiatrischpsychotherapeutische Versorgung 5. die Aus- und Weiterbildung von psychiatrisch-psychotherapeutischem Fachpersonal

Fußnote 1 Aus Gründen der Lesbarkeit wird in der vorliegenden Arbeit auf die gleichzeitige Verwendung männlicher und weiblicher Sprachformen verzichtet, wenn es sich um Beschreibungen beider Geschlechter handelt. Es sei jedoch ausdrücklich darauf hingewiesen, dass die männliche Form in diesen Fällen explizit als geschlechtsunspezifisch zu verstehen ist.

This dissertation consists of four empirical chapters in migration economics. The first chapter analyzes the effect of a recently introduced policy reform on participation in integration courses and refugees' language proficiency levels in Germany. The reform restricts initial residence for refugees with a permanent residence permit. Given that treatment intensity varies distinctly across states, I use this quasi-experiment and apply a difference-in-differences approach based on representative survey data of refugees in Germany. Despite policy makers' intention to improve access to integration measures, I find that residence restrictions have no impact on the probability to participate in integration courses and refugees' language proficiency levels. This result is robust to several robustness checks as well as the participation in any language course. Overall, the evidence suggests that refugees were being misallocated to counties with insufficient supply of integration courses. Chapter 2 studies the causal effect of local labor market conditions and attitudes towards immigrants at the time of arrival on refugees' multi-dimensional integration outcomes (economic, linguistic, navigational, political, psychological, and social). Using a unique dataset on refugees, we leverage a centralized allocation policy in Germany where refugees were exogenously assigned to live in specific counties. We find that high initial local unemployment negatively affects refugees' economic and social integration: they are less likely to be in education or employment and they earn less. We also show that favorable attitudes towards immigrants promote refugees' economic and social integration. The results suggest that attitudes toward immigrants are as important as local unemployment rates in shaping refugees' integration outcomes. Using a machine learning classifier algorithm, we find that our results are driven by older people and those with secondary or tertiary education. Against a background of increasing violence against non-natives, Chapter 3 estimates the effect of hate crime on refugees' mental health in Germany. For this purpose, we combine two datasets: administrative records on xenophobic crime against refugee shelters by the Federal Criminal Office and the IAB-BAMF-SOEP Survey of Refugees. We apply a regression-discontinuity-design-in-time to estimate the effect of interest. Our results indicate that hate crime has a substantial negative effect on several mental health indicators, including the Mental Component Summary score and the Patient Health Questionnaire-4 score. The effects are stronger for refugees with closer geographic proximity to the focal hate crime and refugees with low country-specific human capital. While the estimated effect is only transitory, we argue that negative mental health shocks during the critical period after arrival have important long-term consequences. The fourth chapter focuses on political effects of emigration. Emigrants are less likely to participate in elections in their home country. They are also self-selected in terms of education, gender, age, and political preferences, changing the structure of the origin population. High emigration rates can therefore have a systematic influence on election results. Using administrative migration and voting data, we show that high emigration from Poland following the accession to the European Union in 2004 has caused an increase in vote shares for right-wing parties. To account for endogenous migration patterns, we construct an innovative instrument that measures the distance to the closest EU border and adds time variation by exploiting the gradual opening of different EU labor markets. Our results further highlight that emigration increases voting for parties with pro-European positions, but has no effect on incumbent parties.

Tunneling across superconducting junctions is associated with a variety of different processes that transfer single electrons, Cooper pairs, or even larger amounts of electrons by multiple Andreev reflections. Resonances inside the superconducting energy gap, like e.g. induced by magnetic adatoms, add resonant Andreev reflections to the variety of tunneling processes. We have successfully established two spectroscopic methods to study the nature of tunneling processes in superconductors. In the first approach, we complement the capabilities of a scanning tunneling microscope by introducing high-frequencies (HF) up to 40 GHz into the tunnel junction. The charge carriers involved in the tunneling process can exchange energy with the radiated HF field which leads to photon-assisted tunneling. Based on the theory of Tien und Gordon it is predicted that the sideband spacing in the bias voltage is a direct fingerprint of the number of electrons transferred in a single tunneling event.

Here we have used photon-assisted tunneling to study superconducting tunnel junctions that exhibit Yu-Shiba-Rusinov states (YSR) induced by magnetic Mn adatoms on Pb(111). By exploiting the tunability of the junction conductivity we could specifically obtain insights into the contributions of single-electron tunneling and resonant Andreev processes to the YSR states. While the simple Tien-Gordon description is sufficient to describe single-electron tunneling and Cooper pair tunneling into the pure substrate, we show that the description breaks down for resonant Andreev reflections. We developed an improved theoretical model based on rate equations and the ac modulation of the bias voltage. Our model is in excellent agreement with our data.

In a second spectroscopic approach, we investigate Cooper pair tunneling in current-biased Josephson junctions. We show that the critical current is strongly reduced by magnetic impurities, which reflects a reduced superconducting order parameter in the vicinity of the magnetic adatom.

Our results of photon-assisted tunneling and Josephson spectroscopy show that we have established two powerful methods for the investigation of superconducting tunneling processes at the atomic scale. These methods could be particularly informative for the investigation of unconventional and topological superconductors.

Molecular imaging has revolutionized the practice of medicine and patient healthcare. The use of targeted imaging tools have enabled the non-invasive and selective interrogation of biological processes triggering pathology. This approach includes a variety of complementary techniques such as PET, MRI, and optical imaging. In particular, fluorescent probes allow for the synergistic evaluation of the drug, the target, and treatment response in real-time and excellent spatiotemporal resolution. Generally, three main components should be considered for the design of a fluorescent probe: (i) a recognition element (ligand or pharmacophore) that tolerates further chemical functionalization while preserving its affinity and selectivity towards the protein-target, (ii) an appropriate reporter unit (fluorophore), and (iii) a linker that combines these two functionalities. Each of these constituents poses unique challenges for the successful design of a molecular probe as their selection will strongly depend on the imaging technique the probe will be applied to (Chapter 1.). The presented thesis displays a case in which the design, synthesis, and pharmacological characterization of highly specific imaging probes led to the labeling of two relevant drug targets. In both projects, a modular synthesis strategy enabled the assembly of ligand and fluorophore units tailored for specific optical imaging applications. The first part of this thesis described the development of fluorescent ligands to trace the cannabinoid type 2 receptor (CB2R) (Chapter 2.). This receptor is known to be strongly up-regulated in pathological conditions correlated with the onset of inflammation and, thus, represents an important protein-target for both therapeutic and diagnostic purposes. Exploiting a preclinical CB2R agonist drug as recognition element, investigations on suitable linker length, composition, and placement were conducted. Of particular interest was to avoid detrimental interactions of the linker-reporter construct with the CB2R, while providing a linker trajectory that reaches the extracellular space, i.e., outside the receptor binding pocket. This strategy resulted in the generation of a robust platform where binding affinity and selectivity were largely independent of fluorophore attachment. The second part of this thesis aimed at the synthesis of imaging ligands containing multiple targeting moieties, i.e., multivalent for applications in the early detection of pancreatic cancer (PDAC) (Chapter 3.). Here, probe design was based on the fourfold derivatization of the cyclen scaffold to develop a “clickable” platform encompassing three terminal maleimides and one alkyne. This cyclen-based platform enabled the one-pot assembly of PDAC-targeted agents which were labeled with two different cyanine fluorophores. These fluorescent compounds displayed high specificity for the detection of PDAC in cell-based assays in comparison to their respective non-targeted controls.

The rumen epithelium (RE) functions as an absorbing layer for short-chain fatty acids (SCFA) and at the same time as a protective interface between the blood circulation and the ruminal environment. These functions are strongly interconnected by the epithelial barrier (EB). A failure of this barrier compromises both absorbing and protective abilities and may lead to sickness of the animal and economic loss for the farmer. One of the main causes of EB failure is nutritional oversupply of easily fermentable carbohydrates, which leads to acute or subacute ruminal acidosis. Under these conditions, several changes occur in the rumen environment. One of these changes is the increase of SCFA, which is associated with a decrease of pH. In a previous study, it was demonstrated that the combination of low pH and high SCFA is necessary for impairing the EB of the RE and low pH alone did not impair the EB. In this study the three main SCFA were tested all together in a mix. The present study investigated whether the effect of individual SCFA at physiological and low pH lead to different changes of the EB of the RE. Rumen epithelia for Ussing chamber experiments were obtained from seven sheep. Epithelia were incubated 7 h with 30 mM of either acetate, propionate, or butyrate on the mucosal side at mucosal pH of 6.1 or at pH 5.1. Some extra epithelia were incubated with 100 mM acetate and tested under both pH conditions. Electrophysiological parameters and fluorescein flux rates were monitored during the incubation. Following incubation, mRNA and protein abundance of the TJ proteins claudin-1, -4, -7, and occludin were investigated, and TJ proteins were visualized using immunofluorescence staining. The results showed that SCFA incubation at physiological mucosal pH did not functionally affect the epithelial barrier. However, the results showed increased mRNA expression of some TJ proteins suggesting some protective effects of SCFA on the EB, but also a reduction of claudin-7 at protein level after incubation with 100 mM acetate and 30 mM butyrate. At pH of 5.1 all individual SCFA impaired to a comparable degree the EB and downregulated the TJ proteins. The group of epithelia incubated with 100 mM acetate caused more intense barrier failure. Epithelia incubated without SCFA at pH 5.1 showed no signs or very little evidence of barrier failure. This data suggests that the RE is extremely resistant to low pH environment. However, the combination of low pH with SCFA impairs the EB. Each SCFA caused a similar detrimental effect on the EB if incubated at the same concentration, while increasing their concentration augmented the harmful effect on the EB. The second study focused on molecules that may potentially strengthen the EB. According to literature, GLP-1, -2, and EGF usually improve the EB of other different epithelia. Therefore, their effects on RE were studied in ex vivo experiments. RE were obtained from six sheep and incubated with two different concentrations of GLP-1, GLP-2, and EGF in Ussing chambers. GLP-1 and GLP-2 were incubated on the serosal side. EGF was tested at a higher concentration on the serosal side and on the mucosal side, while a lower concentration of EGF was also tested on the mucosal side. The results of this second study did not show functional effects on the EB from any of the molecules tested. However, some potentially beneficial effects were seen at the mRNA level after incubation with high concentration of GLP-2 and high concentration of EGF on the serosal side. An interesting result was also the downregulation of claudin-7 at mRNA level in all epithelial treated with GLP-1, -2, and EGF. The result suggests that GLP-1 may have no, or a minor, role in EB regulation of RE, while EGF and GLP-2 may potentially regulate and protect the EB of the RE. Further studies in vivo are needed to confirm these results.

Arcobacter (A.) spp. was regarded as an emerging pathogen associated with enteritis, diarrhea and occasionally bacteremia in human. It has been widely isolated from animals, foods and water environment. In the recent ten years, more than half of the newly described species of this genus were recovered from aquatic environments and water-borne animals. Therefore, the occurrence of Arcobacter in seafood has raised increasing interest for food safety concern. Consuming undercooked or preparing raw seafood was regarded as a potential risk of human transmission. Despite the frequent reports of this genus from food, the knowledge of its pathogenicity and the cold stress response is still scarce. This work aimed to evaluate the prevalence of Arcobacter spp. in retail seafood in Berlin, and to characterize all isolates by the genetic diversity and the distribution of 10 putative virulence genes. In addition, the growth of A. butzleri isolates from different origins was tested at chilling temperature. The presence and transcriptional expression profile of 13 cold-related genes homologues in E. coli were preliminarily reported in A. butzleri. Chapter 1 introduces a comprehensive literature review on the taxonomy, occurrence, current isolation and typing methods of Arcobacter spp. The information about virulence determinants, cold adaptation of A. butzleri as well as cold-related genes in E. coli is also provided. In the first study (Chapter 2), the overall prevalence of Arcobacter in retail seafood was 17.6%. For each food matrix, cephalopod was found to have the highest prevalence (27.4%) and species diversity (6 species) followed by bivalves (17% and 5 species) and shrimp (8.5% and 4 species). High genetic heterogeneity was observed both at inter- and intra-species level. A. butzleri was found to carry most putative virulence genes and the gene ciaB was 100% detected in all Arcobacter isolates. No correlation between the ERIC-PCR pattern/virulence gene distribution and the source of the isolates can be deduced. The cold adaptation of A. butzleri was further investigated in Chapter 3. The growth of eight A. butzleri isolates from human, mussel and chicken was tested at 8°C under aerobic condition to mimic natural environment for food storage at chilling temperatures. One A. butzleri strain (H2) showed growing capability at this temperature while most of others (6/8) were not culturable after 28 days under these culture conditions. No correlation between the growth and / or survival behavior and the source of A. butzleri isolates was observed, and the growth of A. butzleri at 8°C under aerobic circumstance in our study seemed to be strain-dependent. The transcriptional expression pattern of 13 cold-related genes in E. coli was also investigated in three A. butzleri strains with different growth mode after a temperature downshift to 8°C by RT-qPCR. Several similarities in the cold-related genes expression pattern of A. butzleri with E. coli were determined. For elucidating whether similar functions of these genes in A. butzleri at cold were utilized, further investigation was needed. To summarize, our research provide more information to estimate whether consumption/handling of seafood have a potential risk for human health and help to better understanding the survival strategy of A. butzleri encountering to cold stress.

Eine wiederkehrende Konjunktivitis und/oder Keratitis, hervorgerufen durch eine Infektion mit dem Caninen Herpesvirus-1 (CaHV-1), stellt für die betroffenen Hunde eine deutliche Einschränkung ihres Wohlbefindens dar. Die Manifestation von einer primären oder wiederkehrenden CaHV-1 Infektion am Auge wird beeinflusst durch das Alter und den Immunstatus des Hundes. Die Konjunktivitis ist das häufigste benannte Symptom im Zusammenhang mit einer CaHV-1 Infektion. Sie kann einzeln auftreten oder mit anderen Symptomatiken oder Hornhautläsionen einhergehen (Ledbetter et al., 2006, Ledbetter et al., 2009b, Ledbetter et al., 2009c, Malone et al., 2010). Es können sowohl ulzerative, als auch nicht ulzerative Keratitiden auftreten (Ledbetter et al., 2006, Ledbetter et al., 2009c, Ledbetter et al., 2009d, Malone et al., 2010). Durch CaHV-1 verursachte korneale Ulzera betreffen die Oberfläche der Kornea, sie sind lokal in einer Gruppe begrenzt oder linear angeordnet (Ledbetter et al., 2009c) und können punktförmig, dendritisch oder geografisch aussehen (Ledbetter et al., 2006, Ledbetter et al., 2009c, Malone et al., 2010). In dieser prospektiven Multizenterstudie wurden gesunde Hunde, Hunde mit Konjunktivitis und Hunde mit Keratitis deutschlandweit ophthalmologisch untersucht, beprobt und auf das Vorhandensein von dem Caninen Herpesvirus-1 getestet. Ziel der Studie war es, möglichst viele vom Signalement unterschiedliche Hunde deutschlandweit auf das Vorhandensein von CaHV-1 zu testen, um damit Rückschlüsse auf die Bedeutung in Deutschland ziehen zu können. Es wurden Daten zum Alter, dem Geschlecht, dem Gewicht, der Rasse, der Herkunft und dem Sozialleben gesammelt. Zwischen April und November 2018 wurden 133 Hunde für die Studie ophthalmologisch untersucht und anschließend in die Gruppen augengesunde Hunde (n=43), Hunde mit Konjunktivitis (n=46) und Hunde mit Keratitis (n=44) unterteilt. Es wurde mittels Cytobrush Proben aus dem Konjunktivalsack für die PCR gewonnen. Die virologische Untersuchung auf das CaHV-1 war in allen Fällen negativ. In der Studie waren 133 Hunde von 47 unterschiedlichen Hunderassen, mit verschiedenem Signalement und unterschiedlichen sozialen Kontakten vertreten. Insgesamt ist die Infektion mit CaHV-1 als Verursacher von Konjunktivitiden und Keratitiden in Deutschland von geringerer Bedeutung als angenommen.

Traditionally, philosophy uses the discrimination of self and non-self to define individuality with the immune system performing this discrimination. In the evolutionary field of biology this distinction is not that simple. Nowadays it is becoming more and more apparent that individuals can no longer be considered as ‘lone isolated islands’ in the ‘environmental sea’. All kinds of eukaryotic taxa harbour their own microbiota consisting of bacteria, archaea, fungi, protozoa and viruses and they are tolerated by the host’s immune system because of their manifold beneficial functions on, for example, host nutrition, detoxification, development, fecundity or pathogen protection. However, not only the beneficial microbiome, but also the host’s nutrition can strongly affect its physiology and its ability to combat pathogen infections. Microbiome and host form a unit – the holobiome. Notably, even though we gained insights on either the function of the microbiome or of the nutrition on host immune defence in diverse separate studies we still poorly understand how they act together in particular organisms. An insect model system to study these interactions are cockroaches. This is because, 1) they are omnivorous generalists, which makes them easily accessible for nutritional studies; 2) they harbour a diverse microbiota which can be manipulated through sterilization methods; and 3) they feature effective strategies to combat pathogens since they are frequently exposed to a rich antigenic environment due to their lifestyle. First, in Chapter I I investigated the nutritional dependencies of immunity in the cockroach system by performing food choice experiments using the cockroach species Blatta orientalis upon exposure to the opportunistic Gram-negative bacterial insect pathogen Pseudomonas entomophila. I could show that depending on the strength of infection B. orientalis males reduce their overall nutrient intake and increase the protein to carbohydrate ratio being consumed. Interestingly, these behavioural shifts do not boost the insect’s immunity as indicated by the examination of the hemolymph’s antimicrobial activity, the abundance of immune proteins in the hemolypmph or the general host survival. This lack of benefits for the host highlights a possible decoupling of dietary macronutrient regulation from immunity in these invasive animals with the possibility that anorexia, in general, might be a more powerful tool if diet quality is highly unpredictable for generalist species. In Chapter II I evaluated two different approaches for the development of a germ-free Blatella germanica cockroach breeding system which forms the basis of any study dealing with the function of the cockroach microbiome. While one of these methods uses peracetic acid, the other one uses a combination of peracetic acid and sodium hypochlorite to surface-sterilize cockroach oothecas to deprive the hatchlings from their natural microbiota. These treatments should leave them only with their obligate symbiont Blattabacterium sp., which supplies essential vitamins and is required for the development into fecundant adults. I tested the success of those techniques by plating adult individuals on Lysogeny-broth-agar and by using state of art 16S metabarcoding. It turned out that both methods performed quite poorly leading to individuals which can be considered as germ-free in 40 % of all cases. I therefore developed our own method by combining sequential ootheca surface sterilizations with peracetic acid and sodium hypochlorite followed by a treatment of freshly hatched nymphs with the antibiotics rifampicin and gentamicin which significantly improved its effectiveness resulting in germ-free adult cockroaches to 99 % of all cases. In addition, I used our germ-free cockroach system for an early study on the impact of the absence of an intact microbiome on developmental time. I could show that B. germanica cockroaches deprived of their natural microbiota needed approximately 35 days longer from the day of hatching to the day molting into adults than their conventional counterparts, which already grants a small glimpse on the strong impacts of the microbiome on the host physiology and its overall performance. In Chapter III I analysed the transcriptome of germ-free and conventional B. germanica males and followed their survival upon P. entomophila systemic infection to gain further insights on the influence of the cockroach microbiome on host traits. The basis of our gene identification were two published genomes either the one by Harrison et al. (2018) or the one by He (2018). Depending on the reference genome used for the analyses small differences existed. When the Harrison et al. genome was used 25451 putative genes were identified and 184 of those including 19 immune-related genes were significantly different expressed between conventional and germ-free cockroaches. When the He genome was used 111778 putative genes were identified and 1082 of those including 30 immune-related genes were significantly different expressed between conventional and germ-free cockroaches. Immune-related genes which were significantly expressed between germ-free and conventional cockroaches identified with both reference genomes included hemolymph lps-binding protein related genes which were mostly upregulated in germ-free individuals because of their role in trapping the Blattabacterium sp. endosymbiont and tenecin-1 genes, a transferrin, a caspase-1, a alpha-1-macroglobulin, a lysozym c-1 as well as a catalase found to be upregulated in conventional individuals. All the latter ones contribute to the recognition and the suppression of microbial life to maintain a stable host microbiota. This regulation of gene expression by the microbiome might also assist the host in combating infections as indicated by the significantly higher survival of conventional cockroaches infected with P. entomophila. In conclusion I was able to show, that host biology is heavily shaped by microbial life. Those microbes can be either invading pathogens or commensal or beneficial microbiota. In all cases they radically alter host behaviour, development and/or physiology. While pathogens only harm their hosts, the microbiome promotes host phenotypes like development or immune competence. Therefore, pathogens do not only interact with their hosts but also with its microbiota. Since this fact became only apparent within the last few years more research is needed to reveal all its aspects. A stable foundation for such future work is paved by my recently established germ-free B. germanica breeding system. In this framework it will be particularly important and likewise exciting to perform refaunation experiments with single microbial taxa followed by infections with different pathogens and further transcriptomic analyses to uncover their special tasks in this broad network of interactions.

Abdominale Aortenaneurysmen (AAA) zählen zu den kardiovaskulären Erkrankungen mit potentiell lebensgefährlichen Folgen. Obwohl die Ruptur von AAAs die dritthäufigste Ursache für ein plötzliches Versterben darstellt, hinter Herzinfarkten und Schlaganfällen, sind sowohl die genauen Ursachen als auch die pathologischen Mechanismen der Entwicklung von Aneurysmen noch weitetestgehend ungeklärt. Da die Zahl an Patienten mit dieser irreversiblen Erweiterung der infrarenalen Aorta in den letzten Jahren konstant zugenommen hat, werden neue Ansätze in der Diagnostik und Behandlung von AAAs dringend benötigt. Derzeit stehen in der klinischen Praxis verschiedene bildgebende Verfahren zur Diagnose von abdominalen Aortenaneurysmen zur Verfügung, darunter Ultraschall, Computertomographie und Magnetresonanztomographie. Bisher erfolgt die Diagnosestellung durch das Vermessen des Aortendurchmessers. Seit mehrere Studien gezeigt haben, dass sich der Durchmesser der Aorta diagnostisch und vor allem prognostisch für die weitere Entwicklung des Aneurysmas als sehr begrenzt erweist, hat die molekulare Bildgebung - die es ermöglicht, Veränderungen innerhalb der Aortenwand auf molekularer Ebene zu beurteilen - an Bedeutung gewonnen. Das Ziel unserer Studien war es daher, die Anwendbarkeit der molekularen MRT Bildgebung für die Visualisierung und Charakterisierung von AAAs in einem Mausmodell mit verschiedenen molekularen Sonden zu untersuchen. Einerseits konnten durch den Einsatz einer Gadolinium-basierten Sonde, welche spezifisch an elastische Fasern bindet, die pathologischen Veränderungen der extrazellulären Matrix dargestellt und darüber hinaus quantifiziert werden. Andererseits konnten durch die gleichzeitige Verabreichung von Eisenoxidpartikeln, die Entzündungsprozesse während der AAA-Entwicklung zeitgleich in derselben MRT Untersuchung evaluiert werden. Darüber hinaus konnte eine zukünftige Ruptur der Gefäßwand anhand der kombinierten Informationen beider molekularer Sonden zuverlässig vorhergesagt werden. Die molekulare MRT Bildgebung hat das Potenzial, nicht nur die Diagnostik und Risikostratifizierung von AAAs zu verbessern, sondern auch die Beurteilung des Ansprechens auf Therapien. Daher war das Ziel unserer zweiten Studie, die molekulare MRT Bildgebung zur Beurteilung der therapeutischen Wirkung eines Interleukin-1β (IL-1β) Antikörpers auf die Bildung von AAAs zu untersuchen. Durch den Einsatz der Elastin-spezifischen Sonde, konnten die entzündungshemmenden Effekte des IL-1β Antikörpers innerhalb der Aortenwand bereits frühzeitig visualisiert und quantifiziert werden. Die Hemmung des proinflammatorischen Zytokins IL-1β schien die Bildung der AAA im Mausmodell zu verhindern und bietet daher möglicherweise einen neuen therapeutischen Ansatz in der Behandlung von Aortenaneurysmen. Da das derzeitige Management von abdominalen Aortenaneurysmen lediglich eine regelmäßige Überwachung bzw. eine operative Behandlung großer AAAs beinhaltet, würde eine entzündungshemmende pharmakologische Behandlung von AAAs eine wesentliche Verbesserung für die Patienten darstellen. Die Studien zeigen, dass molekulares MRT eine neuartige Bildgebungstechnik mit großem Potenzial zur Verbesserung der Diagnose, Charakterisierung, Risikobewertung und die Beurteilung des Ansprechens auf Therapien von abdominalen Aortenaneurysmen darstellt. Durch die Kombination zweier bildgebender Sonden konnten die beiden Schlüsselprozesse der AAA-Entwicklung, Entzündung und Abbau extrazellulärer Matrixproteine, zuverlässig bewertet werden. Diese neuen bildgebenden Parameter können die bereits etablierten morphologischen Parameter, wie den Aortendurchmesser, ergänzen und somit insbesondere die Vorhersage des Rupturrisikos der Gefäßwand verbessern. Dennoch müssen verschiedene Hindernisse überwunden werden, wie hohe regulatorische Hürden und Kosten sowie die Bewertung der Sicherheitsprofile dieser neuartigen Sonden, um eine zukünftige Umsetzung in die klinische Praxis zu realisieren.

Soil plays a central role in the functioning of terrestrial ecosystems and is essential for the production of food for the world population. Yet, soil is a fragile resource whose health is increasingly endangered by unsustainable land-use practices, growing population and global warming. Acquiring knowledge on the processes controlling the natural formation of soils and their associated ecosystems through studies of primary successions is crucial to develop sustainable land-use strategies and predict the adaptation of soil ecosystems to global warming. Chapter #1 of this thesis discusses these issues. While most studies on ecological successions focus on relatively well-developed ecosystems, our understanding of initial development of ecosystems, soils in particular, is comparatively scarce. Glacier forefields provide ideal setting to study the earliest stages of soil development and primary successions. Glacier forefield successions are most commonly studied using a chronosequence approach in which distance from the ice front of a retreating glacier (‘time since deglaciation’) is used as a proxy from ‘terrain age’. The development of pioneer microbial communities in glacier forefields is limited by the scarcity of nutrients. Chemical weathering, which can be enhanced by microbial activity, is often considered to be the dominant mechanism controlling the initial build-up of nutrients in these environments. However, the linkages between microbial communities, nutrient contents and weathering are still poorly understood. A major goal of my thesis was to study the changes in physical, chemical, mineralogical and microbiological parameters and their linkages using a chronosequence approach to gain insights into the processes controlling the initial autogenic development of soil ecosystems in glacier forefields. Interestingly, these tight relationships between chemical weathering and microbial communities indicate that microbial weathering is a strong driver of the build-up of a labile nutrient pool in early successional stages. The chronosequence approach is based on the two core assumptions that (1) all sites of the succession were characterized by homogeneous initial conditions and (2) all sites followed the same sequence of change after the original disturbance that is glacier erosion. The work presented in this thesis shows that these assumptions about chronosequences are not always valid because abiotic initial environmental conditions and geomorphological disturbances can affect successional behavior in a temporally and spatially heterogeneous manner. The second major goal of my thesis was to investigate how allogenic factors (initial site conditions and geomorphological disturbances) can affect successional patterns in glacier forefields in a heterogeneous . In Chapters #2 and #3, I present published studies in which I investigated the physical, geochemical and microbial successions leading to soil development in glacier forefields in Svalbard and in Iceland. With increasing terrain age, my data shows a build-up of nutrient contents, a progression of chemical and physical weathering and an increase in microbial diversity and abundance. My dataset also highlights the strong correlations between nutrient cycling, weathering and microbial community structures. Altogether, these trends evidence an increasing degree of soil ecosystem development along the chronosequence. I emphasize that patterns of successional change related to time since deglaciation are also strongly influenced by geomorphological disturbances and heterogeneous initial environmental conditions. Specifically, in Chapters #2 (Longyearbreen proglacial area, Svalbard) and 3 (Fláajökull glacier forefield, Iceland) I show that areas affected by hillslope and glacio-fluvial erosion disturbances depict considerably delayed succession rates. In Chapter #4, I investigated how the supply of dry (dust) vs. wet (snow /rain) aeolian deposition has contributed to the build-up of phosphorus in the forefield of Vernagt glacier (Austrian Alps). I assessed if this P supply enhanced the ecosystem succession rates in this glacier forefield. Importantly, I also investigated the effects of seasonal variability on biogeochemical processes in this glacier forefield by monitoring the year-round variability of aeolian phosphorus, as well as soil nutrient contents. Finally, Chapter #5 is a review, where I present a comprehensive overview of how initial site conditions (substrate characteristics, microclimatic conditions and resources availability) and geomorphological disturbances (hillslope, glacio-fluvial, periglacial and aeolian processes) may affect the rate and/or trajectory in a spatially heterogeneous manner. I end this last chapter with a discussion on the changes in the relative importance of autogenic, allogenic and stochastic processes over the course of successions in glacier forefields.

In future electronics, quantum effects in integrated circuits containing coupled nanostructures will play a key role. In this framework, the coupling between distant on-chip components could be realized by the exchange of ballistic electrons. The present thesis aims at optimizing the exchange of ballistic electrons between quantum point contacts (QPCs), fundamental building blocks of quantum circuits. To couple distant QPCs, we use the concept of ballistic electron optics.

In the first experimental part of this thesis, we study the actual electrostatic potential shape of a gate-defined single QPC by measuring its one-dimensional subband spacings. The potential shape is central for the emission process of ballistic electrons as well as interaction effects. Comparing the measured subband spacings of the QPC to models of lateral parabolic versus hard-wall confinement, we find that it is compatible with the parabolic saddle-point scenario near pinch-off. However, as we increase the number of populated subbands, Coulomb screening flattens the potential bottom and a description in terms of a hard-wall potential becomes more realistic.

In the second experiment, we consider the ballistic and laterally coherent electron transport through two distant QPCs in series in a three terminal configuration. We study the emission and detection properties of the QPCs in detail via magnetic deflection of ballistic electrons in a perpendicular magnetic field. Additionally, we enhance the serial transmission by using a field effect electron lens. Comparing our measurements with quantum mechanical and classical calculations we discuss generic features of the quantum circuit and demonstrate how the coherent and ballistic dynamics depend on the details of the QPC confinement potentials.

In a third experiment, we consider an open ballistic electronic cavity formed by four QPCs. Performing bias voltage spectroscopy measurements, we characterize coherent Fabry-Pérot-like resonances. Furthermore, we find fingerprints of a transition from chaotic to integrable cavity dynamics in magnetotransport measurements, as we decrease the size of the cavity.

Finally, in a fourth experiment, we investigate a parabolic, open and ballistic electronic cavity. Working at a higher temperature, where the QPCs are better described as classical pinholes without coherent mode structure, we demonstrate how the serial transmission through the two pinholes can be enhanced by the cavity.

Since its development in the 1980s the second-order nonlinear optical technique of vibrational sum frequency generation spectroscopy (SFG) evolved into a versatile tool to detect and characterize molecules at interfaces. To obtain complete information on the molecules’ absolute orientation and to disentangle the interference of a possible non-resonant substrate’s response which distorts the spectral line shape, however, phase-resolved measurements need to be applied. In such heterodyned SFG experiments the signal pulse which is generated by the nonlinear interaction between two incoming short pulses and a sample subsequently interferes with a so called local oscillator (LO) pulse. To yield accurate results, relative phase stability between the signal and LO as well as a precise control of their individual timings must be warranted. The simultaneous fulfillment of this two requirements so far have restricted heterodyned SFG experiments to the study of solid/air and liquid/air interfaces. This thesis presents a way to overcome these limitations by integrating a timing control scheme into a collinear high accuracy phase-resolved SFG spectrometer. The versatility of this approach is tested at the solid/liquid interface and extended to potential dependent measurements since among others understanding of electrochemical processes at the electrode/electrolyte interface will be critical in the development of more efficient batteries and fuel cells to tackle the challenges presented by the climate crisis. The obtained heterodyned SFG spectra allow an insight into the parameters that influence the non-resonant substrate’s response, such as an applied potential bias and the presence of specifically and non-specifically adsorbed ions and molecules. In addition a method is presented how to use phase-resolved SFG spectra to determine the phase of the local field Fresnel factors, which so far had to be modeled. The heterodyned spectra are compared to their homodyned analogs to discuss which new information in fact can be obtained and what limits still need to be overcome.

Understanding the electronic structure and the chemical composition of a catalyst is of interest, not only for scientific reasons but also for the technological development of catalysts for the (photo) electrochemical production of hydrogen from water, in order to solve the world's steadily growing problems, such as the global warming through CO2 accumulation in the atmosphere, the increasing energy demand of mankind and environmental pollution. Manganese oxide (MnOx) catalysts are promising candidates taking advantage of being abundant, non-toxic, and inexpensive for an economically competitive future technology. This thesis reports two aspects of MnOx: One is to use it as an electrocatalyst, and the other as a cocatalyst, deposited on a semiconducting photoanode. The first topic of the thesis addresses studies of the electronic structure of MnOx as an electrocatalyst for water oxidation reaction using absorption spectroscopy and resonant inelastic scattering of soft X-rays at the manganese L2,3-edge and the oxygen-K-edge. Two main questions in the first topic were addressed: First, what is the origin of catalytic activity changes in MnOx films prepared under different pH conditions? The answer is found in the X-ray absorption spectra of seven samples, prepared from highly acidic to (near-)neutral to highly basic electrolytes. The spectra showed a remarkable change in the electronic structure of the pH-dependent MnOx catalysts. All investigated catalysts include mixtures of Mn2O3, Mn3O4, and birnessite in different proportions. The highest catalytic active catalyst, prepared under neutral conditions, is composed of birnessite and Mn2O3. In contrast, other films are composed predominantly of only one of these phases with a low content of Mn3O4. It reveals that the interplay of MnIII and MnIV species can drastically enhance the catalytic activity, but not a single contribution of any of them alone. This study led to the second significant question of what are the electronic states of MnOx catalysts during the water oxidation reaction and whether a charge transfer occurs between Mn-metal and O-ligand? Are the Mn valence states increase continuously with increasing the oxidizing potential? The answer has been found after conducting an in situ XAS/ RIXS spectroscopic study tracking the electronic state changes happening in the electrodeposited MnOx catalyst under real reaction conditions (0.75-2.25 VRHE). The in situ XAS reveals a full transformation of the MnOx film into a birnessite state at ca. 1.45 VRHE (just before the water oxidation). However, the in situ RIXS analysis showed continuous changes in the electronic state of MnOx up to a potential of ca. 1.75 VRHE. More precisely, the Mn 3d - O 2p hybridization degree increases by applying a more positive potential to the MnOx films up to 1.75 VRHE. Furthermore, the water oxidation catalysis by MnOx is facilitated by an O-to-Mn charge transfer, achieved at ca 1.75 VRHE, which is believed to be of crucial importance for efficient electrocatalytic water oxidation. The second topic of the thesis discusses how the MnOx can enhance the water-oxidation activity of a tantalum-oxynitride (TaON) photoanode when it is coupled as an overlaying co-catalyst to the photoanode. The chemical composition and electronic structure changes at the MnOx/TaON interface as a function of the thickness of the MnO overlayer (2, 5, 7, and 26 nm) were addressed and studied with hard X-rays photoemission spectroscopy. By depositing ultrathin MnO layers on the TaON photoabsorber, the photocurrent enhances ca. 5 times, whereas the amount of Ta2O5 at the MnOx/TaON interface was reduced with increasing MnO overlayer thickness. It implies that the MnOx co-catalyst reduces the unfavorable Ta2O5 at the MnOx/TaON interface, which in turn facilitates the hole transfer from photoanode to MnOx surface for water oxidation reaction to occur. Simultaneously, MnO at the interface is oxidized to Mn2O3 and birnessite. Our interpretation suggests that MnIIO at the interface consumes oxygen from Ta2O5, leading to a reduction of this oxide and oxidation of MnII to MnIII and MnIV. A quantitative analysis using SESSA simulations supports the experimental results. In the present dissertation, manganese oxide characteristics as a (co)catalyst for oxygen evolution from water are highlighted. The results are of interest for artificial photosynthesis devices and elucidate some of the missing pieces of the puzzle of the challenging water oxidation reaction.

The last two decades have seen the zoonotic emergence of three highly pathogenic coronaviruses (CoVs): MERS-, SARS- and SARS-CoV-2. Their epidemic and pandemic spread, respectively, underlines the importance of monitoring emerging CoVs and of developing a deeper understanding of the molecular mechanisms that contribute to their emergence and pathogenicity. CoV are highly diverse in their animal reservoirs, yet how this diversity translates to phenotypical traits that may account for the zoonotic and pandemic potential of these viruses remains elusive. In the first part, several generated clinical Middle East respiratory syndrome coronavirus (MERS-CoV) isolates pertaining to different phylogenetic clades were analyzed for their in-vitro and ex-vivo infection phenotypes. Importantly, the isolate diversity used here reflects phylogenetic lineages sampled before and after the year 2015, when a novel phylogenetic lineage emerged by a recombination event (MERS-CoV lineage 5) and superseded other, hitherto co-circulating viral lineages from circulation, as well as causing large nosocomial outbreaks in Saudi Arabia and South Korea. The present studies demonstrate that MERS-CoV recombinant lineage 5 isolates have increased replicative capacity in the human lung, in correlation with increased interferon resilience and signaling antagonism. These phenotypic differences might explain the dominance of lineage 5 on the Arabian Peninsula and suggests an increased pandemic potential of the currently circulating MERS-CoV lineage 5. The second part comprises a phenotypical comparison of severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2, focusing on potential differences in their capacity to antagonize the innate immune response. Both viruses share a completely homologous repertoire of open reading frames (ORFs) and pertain to the same phylogenetic clade of SARS-related CoV, yet display differences in their transmission efficiencies and pathogenic traits. The data presented here show that SARS-CoV-2 is more sensitive to the antiviral activity of interferons and that SARS-CoV-2 is less efficient in antagonizing cytokine induction and interferon signaling. SARS-CoV-2 protein 6 expressed in the context of a fully replicating SARS-CoV backbone had reduced functionality in suppressing interferon signaling induction, suggesting that the overall reduced antagonism of SARS-CoV-2 might therefore by a function of reduced antagonistic capacity of protein 6.

Host defence and parasite pathogenicity interactions determine infection outcomes. Antimicrobial peptides (AMPs) are conserved components of immune defences of multicellular organisms. In this thesis, the fitness costs of the evolution of resistance toward the host’s own AMPs were investigated. In chapter 1, the experiment focused on the in vivo fitness cost of evolving AMP resistance. The mealworm beetle, Tenebrio molitor, was used as a host. The opportunistic pathogen Staphylococcus aureus selected against one or two of the beetle abundant AMPs was injected into T. molitor. The AMPresistant parasite persistence and virulence were investigated. The infection dynamics of an array of AMPs-selected bacteria versus sensitive unselected control strains were monitored. Our laboratory, previously, showed that the AMP-selected strains harboured a mutation in either nsa or pmt operons. To measure the genetic costs of evolving resistance to these immunological stressors, the bacterial loads, were reanalyzed based on the resistance driving mutation. The induced host mortality rate inferred the virulence of the AMP-resistant pathogen. The findings in chapter 1 showed that, unexpectedly, a pathogen resistant to one or two of the host’s own AMPs neither had increased bacterial load nor affected the host’s survival rate. Costs of resisting AMP were presumably high, suggesting that intrinsic costs might constrain natural AMP resistance. As AMP-resistant pathogen showed limited infection success, this might explain the hampered AMP resistance evolution observed in environmental bacteria. Despite being resistant to one or two of the host’s own AMPs, S. aureus did not perform well in the beetle. The thesis investigated reasons that might cause such unexpected limited pathogenicity. The study, herein, hypothesized that an AMP-resistant pathogen might be more susceptible to eradication by host’s other immune effectors. However, in chapter 1, all AMP-resistant pathogens were shown to be phagocytosis resistance except those harbouring mutation in both nsa and rpo operons. In chapter 2, RNA interference-based knockdown study was performed to investigate the collateral sensitivity of AMP-resistant pathogen towards the host’s other immune effectors. The results highlighted that AMP-selected S. aureus strains are cross-sensitive towards phenoloxidase dependent immune responses, except the nsa-rpo mutants, which were, uniquely, resistant to phenoloxidase activity. Furthermore, collateral sensitivity to other AMPs of the in vivo defence cocktail was investigated. Strains harbouring mutations in pmt or both nsa and rpo operons showed cross-sensitivity to one or more component of the in vivo AMP defence cocktail. In conclusion, resistance against AMPs and phagocytosis neither influenced the host’s morbidity nor mortality because it is balanced by collateral sensitivity to other immune effectors. Despite being essential for infection success in vertebrates, AMP resistance does not provide a survival advantage to S. aureus in a host environment that is dominated by AMPs because of collateral sensitivity to other immune effectors. It was interesting to investigate whether bacterial evolution of AMP resistance triggers fitness-adaptive modifications to their growth parameters and pharmacodynamic parameters in vitro. In chapter 1, the defensin- (tenecin 1) selected S. aureus showed an extended lag phase compared to the sensitive unselected control. However, the maximum velocity of bacterial multiplication was not affected by AMP resistance evolution. In chapter 3, a four-parameter pharmacodynamic model was used to analyze time-kill curves of AMP-resistant S. aureus strains. The comparative analysis of pharmacodynamic curves of pexiganan, melittin and tenecin-resistant S. aureus demonstrated that the Hill coefficient, kappa, describing the steepness of the pharmacodynamic curve evolves. Kappa was usually ignored or set to a constant value in most pharmacodynamic models. Such a finding is crucial, as it was shown, previously, that the kappa relates to the probability of resistance evolution against AMPs. Medical practitioners routinely perform pharmacodynamic analysis for various drugs. However, the results in chapter 3 clarified that pathogens showed different pharmacodynamics evolution patterns, which should be considered, for example, when optimizing the choice of a new drug candidate in cycling therapy. Moreover, this finding could be extended to all kind of host-pathogen relationship. Pharmacodynamic parameters evolution should not be over-simplified to minimum inhibition concentration (MIC) when studying co-evolution to host’s AMP defence cocktail or other antimicrobials; this might enrich our perception of drug resistance evolutionary dynamics. Collectively, the thesis revealed that AMP resistance displayed, mostly, high fitness costs both in vivo and in vitro. This impaired pathogen fitness plays a decisive role in supporting AMPs as therapeutics. Some AMP-resistant mutants showed increased infection success than others. Therefore, for any AMPsbased therapy, a survey of fitness costs of possible evolving resistant pathogen mutants should be evaluated. Weighing the pros and cons of AMPs as therapeutics and avoiding unintentional evolution of felicitous AMP-resistant superbugs are tremendously important.