A remarkable discovery made in rodents three decades ago demonstrated that the brain reactivates previous experience during sleep and wakeful rest. This phenomenon, since known as replay, has been implicated in a variety of cognitive functions, ranging from spatial navigation and episodic memory consolidation to planning and decision-making. At the same time, research in machine learning (ML) has found that experience replay can substantially improve the performance of artificial agents. Together, these observations have spawned the idea that replay supports behavior by retrieving information from abstract internal representations of the environment. How the interplay between replay and internal task representations supports learning and decision-making in humans is still not well understood. In addition, investigating replay in humans is challenging because replay is fast, sequential, and occurs throughout the brain, but current non-invasive neuroimaging methods offer either sufficient temporal or spatial resolution, but not both. This dissertation consists of three publications that offer a theoretical and empirical perspective on the role of replay in learning and decision-making as well as methodological advances for the study of replay in humans using functional magnetic resonance imaging (fMRI). In Paper I, we provide a review of the recent computational and neuroscientific literature on replay and elucidate how replay can improve learning and decision-making in both biological and artificial agents. We identified five key computational functions of replay which include faster and data efficient learning, less forgetting, the reorganization and augmentation of experiences, planning, and generalization. We also discussed the benefits of reactivating abstract internal representations instead of recapitulating veridical experiences, and explored the idea that replay could be involved in learning which representation is useful for a given task. In Paper II, we developed and experimentally validated multivariate analysis methods for fMRI that allow studying the sequentiality and speed of fast-paced neural event sequences, like replay, with anatomical precision in humans. The results showed that probabilistic fMRI pattern classifiers make it possible to detect the sequential order of neural image representations at speeds of up to 32 milliseconds between sequence items. Finally, applying these methods to fMRI data from awake resting-state scans, we could differentiate fast from slow neural sequences that occurred at random time points and found evidence for sequential replay of task-related stimulus sequences during post-task rest. In Paper III, we investigated how humans form predictive internal representations of the statistical relationships between task stimuli and if the brain reactivates sequences from these internal representations during short pauses from ongoing behavior. The results showed that humans learned the higher-order relationships between consecutively presented images in the form of a predictive cognitive map that represents each item in terms of the subsequent items that follow from it. Applying the fMRI methods developed in Paper II to neural data during short pauses interleaved with task performance, we found that participants reactivated upcoming stimulus sequences that were most likely given this predictive internal representation. In summary, this dissertation makes three major contributions. First, linking findings about replay in the neuroscience and ML literature spurs new ideas how replay can support learning and decision-making in both biological and artificial agents. Second, novel methods to characterize the speed and sequentiality of replay with spatial specificity using fMRI have the potential to foster future insights into the role of replay in the human brain. Third, studying how replay interacts with internal representations opens avenues to further understand how the reactivation of experience supports adaptive behavior in machines and humans.

Magnetic resonance imaging (MRI) remains one of the most essential clinical tools for the early detection, diagnosis, and therapeutic management of multiple sclerosis (MS). Until now it has been important to detect and assess neuroinflammatory disease as well as to assess the response to prescribed disease modifying treatments (DMT). The gold standard to detect new relapses and new inflammatory episodes in MS is the detection of contrast-enhanced lesions with gadolinium-based contrast agents. Concerns regarding potential long-term deposition of these agents in the brain are advocating a paradigm shift towards new contrast-free MRI methods and biomarkers. Ultrahigh field (UHF) strengths have been instrumental to increase the level of detail and spatial resolution in brain MR images of MS patients and hence to uncover novel markers such as the central vein sign that are relevant to the MS pathology. An observation that we made in MS patients as well as in its animal model, the experimental autoimmune encephalomyelitis (EAE), is that brain ventricle size fluctuations play an important role early during the pathogenesis of the disease. Fluctuations in ventricle size appeared to follow the relapsing-remitting form of disease progression. In MS patients, we observed a high degree of cross-correlation between the timing of abnormal ventricle fluctuations and timing of changes in other clinical and MRI parameters. These cross-correlations seemed to be as strong as those achieved between contrast-enhanced MRI and the other parameters, indicating a similar level of diagnostic value between ventricle size and contrast-enhanced MRI in MS. MRI has also been instrumental to initiate treatment as early as possible in MS and to adjust treatment routines according to disease progression. Beyond this, MR methods may also be used to study the distribution of DMTs during pathology. Using MR spectroscopy (MRS) we recently detected teriflunomide in the brains of mice during EAE. Teriflunomide is used in relapsing-remitting MS patients as a DMT to prevent relapses. We used MRS to study teriflunomide levels during different disease stages of the EAE, compared MRS with an analytical method as reference and showed a correlation between both methods. Our results indicate that MRS could be used in the future to quantify drugs such as teriflunomide non-invasively in MS patients. Unfortunately, the significance of fluorine (19F) MRI to detect, follow and quantify DMTs in patients has not yet been sufficiently recognized nor has its need been appreciated, mostly because of its hurdles with respect to sensitivity barriers. While we used MRS to detect teriflunomide in the EAE in vivo, limits in signal sensitivity currently prohibit the detection of such drugs with MRI or single-voxel MRS. Novel methods and technologies that enhance sensitivity and signal-to-noise ratio (SNR) will be necessary to surmount this hurdle. Amongst the methods that we implement to increase SNR for 19F MRI, cryogenically cooled radio frequency (RF) coils significantly reduce thermal noise by the hardware, thereby increasing SNR by over an order of magnitude beyond that of a room temperature RF coil of similar size. While it is still debatable whether this technology can be used to improve SNR in the clinical setting, other methods of increasing SNR can certainly be valuable for implementation in the clinic. These include higher magnetic fields and methods to accelerate data acquisition such as compressed sensing. These will all be key to achieve the goal necessary to increase SNR and monitor drugs in vivo with MR methods. Future directions: Apart from increasing the sensitivity of the MR method, it will be necessary to focus on the signal source in the future while gauging MRI as a method to study the distribution of drug treatments. The design and synthesis of molecular labels and imaging probes will be an important domain in future MRI research. Incorporating MR reporter function to lead compounds should be a necessary added dimension when studying new compounds during drug discovery. Collaborations between academia and industry will be necessary to broaden this field of theranostics.

Rydberg atoms are the “giants” in the world of atomic physics. Their highly excited valence electron gives them remarkable properties, such as a long lifetime, large dipole moments and great sensitivity to external fields rendering them ideal tools for the study of quantum effects and quantum technology applications. Quantum technologies promise to outperform their classical counterparts in terms of speed, security, accuracy and performance while presenting us with new challenges. This thesis explores different applications of Rydberg atoms for quantum technologies from a quantum control perspective with a special focus on quantum measurements.

Many quantum technologies require the fast and accurate engineering of quantum states to achieve peak performance and avoid decoherence. I tackle this requirement by employing quantum optimal control theory (OCT) and demonstrate fast and accurate navigation in the high-dimensional Stark manifold of rubidium Rydberg atoms. This is illustrated by means of two examples: the circularisation of Rydberg atoms and the preparation of a Schrödinger-cat-like state which promises quantum sensing of electric fields at the fundamental limit using alkali atoms.

While Rydberg physics has focused for a long time on alkali atoms, it is worth to extend the study to alkaline-earth atoms, as their second valence electron promises new opportunities for quantum technology. However, modelling alkaline-earth atoms is challenging due to electronic interactions. I therefore develop an improved single-active-electron model and optimise the parameters to maximise the agreement with spectroscopic data. This enables OCT applications of strontium which require a precise model for the quantum system under consideration.

Fast protocols are an important tool to avoid decoherence. However, quantum technologies rely on accessing the system for information processing and read-out. The study of open quantum systems is thus crucial for realising quantum technology in presence of decoherence. I therefore propose a quantum simulator for open quantum systems which enables the systematic study of dissipation, memory effects and their interplay for quantum control. The simulator is based on frequent measurements of a system by a meter which can be realised, for instance, by a photonic mode of a cavity and a Rydberg atom, respectively.

The strong interaction of composite systems involving Rydberg atoms lends itself not only for quantum simulation but also for spectroscopy. Many standard detection methods for quantum objects are based on their destruction, e.g. by absorption or ionisation. Förster resonance energy transfer (FRET), on the other hand, is a popular spectroscopic tool and promising candidate for the non-destructive detection of polar molecules. The large size of Rydberg atoms, however, suggests a breakdown of the commonly employed dipole-dipole approximation. To enable the study of FRET, I simulate the collision between a Rydberg atom and a polar molecule considering dipole-dipole, -quadrupole and -octupole interactions. The computed scattering cross-sections allow for studying of the multipolar character of FRET and its spectroscopic potential.

In den letzten zwei Dekaden haben sich im Feld der Spondyloarthritiden wichtige Neuerungen ergeben. Vordergründig sind das Konzept der axialen Spondyloarthritis als Kontinuum mit zwei Untergruppen – der radiographischen axialen Spondyloarthritis und der nicht-röntgenologischen axialen Spondyloarthritis, die Diagnostik der Erkrankung unter Einbezug der MRT zur Erkennung der Frühformen der Erkrankung sowie direkten Visualisierung entzündlicher Prozesse im Bereich der Wirbelsäule sowie der SIG, die Implementation neuer Klassifikationskriterien sowie die Zulassung diverser hocheffektiver Therapien zu nennen. Nichtsdestotrotz bleiben weitere wichtige Fragen bestehen. So ist insbesondere die Ätiologie und Pathogenese der axSpA nicht ausreichend verstanden und somit stehen lediglich effektive Behandlungsansätze, jedoch weiterhin keine Heilungsmöglichkeiten dieser chronischen immunvermittelten Erkrankung zur Verfügung stehen. Ein wichtiger Schritt zu einem besseren Verständnis der Erkrankung könnte in der Entdeckung des Zusammenspiels des gastro-intestinalen Microbioms mit den Spondyloarthritiden bestehen. [135, 136] Dessen Einfluss auf Krankheitsentstehung und Krankheitsaktivität muss jedoch noch weiter erforscht werden, um hieraus möglichen Nutzen ziehen zu können. Auch konnte die Diagnoseverzögerung deutlich verkürzt werden, jedoch ist diese weiterhin mit durchschnittlich 5,7 Jahren in Deutschland [41] inakzeptabel lange und der Fokus zur Frühdiagnose muss beibehalten und nach neuen Möglichkeiten - auch unter Einbezug digitaler Ansätze – gesucht werden. Darüber hinaus erreichen trotz der Zulassung von bDMARDs als neue Therapieoptionen im klinischen Alltag weiterhin weniger als die Hälfte der axSpA Patienten den angestrebten Zustand einer inaktiven Erkrankung. [137, 138] Dies muss als ein klares Signal verstanden werden einerseits die zur Verfügung stehenden Therapien konsequenter einzusetzen und andererseits nach weiteren Therapieoptionen sowie komplementären Maßnahmen zu forschen. Da auf Grund der zum Teil erst kürzlich erfolgten Zulassungen diverser bDMARDs für das gesamte Spektrum der axSpA Langzeiterfahrungen zum Einsatz dieser Medikamente in der Patientengruppe mit axSpA fehlen, ist es von hoher Bedeutung Erfahrungen zu Sicherheit und Wirksamkeit dieser Therapien bei Patienten 84 mit axSpA im „echten Leben“ anhand von Registerdaten und Beobachtungsstudien zu sammeln. Um einen Leitfaden für die optimale Versorgung von axSpA Patienten zu haben stellen die kürzlich veröffentlichten Qualitätsstandards der ASAS [67] einen Meilenstein dar. Jedoch müssen Wege identifiziert werden, wie die hier empfohlenen Maßnahmen auch im Rahmen der klinischen Routine unter dem wirtschaftlichen Druck sowie in Anbetracht der aktuellen Versorgungssituation erreicht werden können. Im Rahmen dieser Habilitationsschrift wurde der aktuelle Stand zu den Themen der Diagnostik, Therapie und Verlaufsbeurteilung bei der axialen Spondyloarthritis erörtert, die eigenen Arbeiten zu dem Thema vorgestellt und deren möglicher Einfluss auf die Versorgungssituation von Betroffenen diskutiert. Darüber hinaus wurden weiterhin bestehende Fragen zur axialen Spondyloarthritis definiert, welche im Rahmen wissenschaftlicher Projekte in der Zukunft bearbeitet werden sollten.

This dissertation examines the introduction of the technologies of motion pictures and recorded sound in Argentina, Chile, and Uruguay and analyzes the changes they triggered in communication and cultural production. It reconstructs the lives and careers of a group of immigrant men who sold, distributed, and produced movies and records for the urban markets of these three countries, shaping the emergence of new media and the integration of the region into a global entertainment market. This dissertation poses the question of what impact the positions of Argentina, Chile, and Uruguay in the global economy had on the changes triggered by the introduction of motion picture and recorded sound technologies. It argues that cities in these three countries became part of a global entertainment market between the 1890s and 1920s in a particular way, which had important implications for cultural production and communication. Unlike in the United States and Europe, where production was the most dynamic sphere and producers the most powerful actors, the growth of the sphere of consumption drove the consolidation of distribution networks and the production of films and records in the case of the countries under examination in this study. Through advertisement and based on knowledge about the users’ expectations and demands, retailers shaped the appropriations of the new technologies. Entrepreneurs followed a strategy of vertical integration by moving from commercialization to distribution, establishing agreements with European and US based companies for the rights of their products in the region, further competing against each other for the bigger share. This had consequences for production and for the discourses that these media spread and contributed to shape alleged national cultural expressions, since producers favored certain genres and contents in which they could offer a distinctive feature based on local cultural references.

BHLHE40 ist ein Transkriptionsfaktor aus der Familie der basic helix-loop-helix Proteine, der hauptsächlich als Transkriptionsrepressor fungiert. Die repressive Wirkung wird meist via direkter DNA-Bindung oder indirekt, über Protein-Protein-Interaktion mit anderen Transkriptionsfaktoren, vermittelt. BHLHE40 ist involviert in die Steuerung der Adipogenese im Fettgewebe. Darüber hinaus lieferten Voruntersuchungen zu der vorliegenden Arbeit Hinweise darauf, dass BHLHE40, über die Beeinflussung von PPARα- und ChREBP-Zielgenen, an der Regulation des Energiestoffwechsels in der Leber beteiligt ist. Diese Arbeit sollte dazu beitragen, die Rolle von BHLHE40 während der Adipozytendifferenzierung noch besser zu verstehen, sowie potenzielle neue Funktionen von BHLHE40 im Energiemetabolismus der Leber aufzudecken. In diesem Zusammenhang wurde zusätzlich mittels Chromatin-Immunpräzipitation nach neuen genomischen BHLHE40-Bindungsstellen in der Leber gesucht. Zunächst konnten die Ergebnisse einer anderen Arbeitsgruppe bestätigt werden, dass eine Bhlhe40-Überexpression in 3T3-L1 Zellen zu einer Inhibition der Adipogenese führt. Diese hemmende Wirkung scheint allerdings nicht, wie vorgeschlagen, über eine direkte Repression der Pparγ2-Promotoraktivität vermittelt zu werden. Vielmehr deuten Ergebnisse dieser Arbeit darauf hin, dass BHLHE40 die Differenzierungskaskade upstream von PPAR2 hemmt. Weiterhin konnte gezeigt werden, dass ein Bhlhe40-Knockdown den gegenteiligen Effekt auf 3T3-L1 Zellen hat und die Adipozytendifferenzierung fördert. Anhand von Bhlhe40-Knockdown und -Überexpression in primären murinen Hepatozyten, konnte im zweiten Teil dieser Arbeit festgestellt werden, dass BHLHE40 die Expression bestimmter PPARα- und ChREBP-Zielgene fördert. Insbesondere die Expression von Hmgcs2, limitierendes Enzym in der Ketogenese, wird durch Bhlhe40-Knockdown und Bhlhe40-Überexpression signifikant reguliert. Zusammen mit der Tatsache, dass BHLHE40 unter Fütterung in der Leber hochreguliert wird, deutet dieses Ergebnis darauf hin, dass BHLHE40 an der Entstehung der diabetischen Ketose unter Hyperglykämie beteiligt ist. Zuletzt wurden mittels BHLHE40-spezifischer Chromatin-Immunpräzipitation in Leberproben von gefütterten, männlichen C57BL/6J Mäusen neue genomische BHLHE40-Bindungsstellen in der Nähe der Gene Klf10 und Dgat2 detektiert.

In dieser Studie wurde der Einfluss,den verschiedene Schweregrade von Geburtshilfen bei Kühen auf die folgende Laktation hatten betrachtet. Es wurden retrospektiv Daten zu 261 Geburten, an denen eine tierärztliche Geburtshilfe geleistet worden war, in drei Gruppen eingeteilt: mittlere Geburtshilfe (MG), schwere Geburtshilfe (SG) und Kaiserschnitt (KS). Zu jeder Schwergeburt wurde ein Kontrolltier ausgewählt, das ohne tierärztliche Hilfe im selben Zeitraum gekalbt hatte und im selben Alter, in derselben Laktation war und derselben Rasse angehörte. Studien und Kontrolltiere wurden hinsichtlich Milchleistung, Milchinhaltsstoffe, Fruchtbarkeit und Abgangsraten von Kuh und Kalb untersucht. MG hatte nur geringe Auswirkungen auf die Milchleistung, Fruchtbarkeit und die Abgangsrate der Kühe. Verglichen mit den Kontrolltieren gingen mehr SG (28.1 vs. 25.8%) und KS (30.3 vs. 15.8%) ab. Bis zum 200. Laktationstag waren weniger Tiere tragend in der SG Gruppe (48.3 vs. 61.8%) und in der KS Gruppe (48.7 vs. 69.7%). Der Unterschied war nur für die KS Tiere signifikant. Die SG zeigte keinen Einfluss auf die Milchleistung, während die KS tiere eine signifikant niedrigere Milchleistung in den ersten 5 Kontrollmonaten als ihre Kontrolltiere aufwiesen. Im Vergleich zu der Kontrolltieren steigen die Kosten mit der Schwere der Geburtshilfe an (MG 58.86, SG 130.51, KS 236.61 / Tier).

The overall objective of the present work is the translation of advanced qMRI techniques from the research environment into the field of clinical neuroimaging. In this context, qMRI is defined as the application of absolute quantitative measures that are extracted from in vivo MRI data. These can be used to describe biophysical characteristics and processes and thereby enhance the diagnostic power of qualitative, “weighted” imaging that is primarily used in the clinical setting. The feasibility, usefulness, and limitations of five qMRI techniques were investigated in different CNS pathologies (brain tumours, ischaemic stroke, migraine, brain/skull malformations) and in the description of normal brain maturation in infants and young children. The translation of new imaging methods from “bench to bedside” involves several steps, and the presented studies are located at different stages in this process.

Studies 1 and 2 are examples of a relatively early stage. At the time of publication, pH-weighted APT imaging had been tested preclinically and in smaller cohorts of patients, but not in acute stroke, where anaerobic glycolysis and tissue acidosis is highly prevalent. In study 1, it was postulated that APT imaging could be a novel approach to demonstrate oligaemia in hyperacute stroke, allowing a more detailed description of tissue at risk. For acceleration purposes, sequence parameters were optimised by using computer simulations and subsequently validated in healthy subjects. Ten acute stroke patients were included (7 < 4 hours, 3 < 24 hours after symptom onset). As expected, the APT effect was significantly decreased in ischaemic regions compared to normal white matter (p=0.03) and APT values tended to be lower in the final infarct volume (p=0.10). In study 2, APT imaging was moved to a different pathology, also characterised by hypoperfusion, tissue hypoxia, and anaerobic glycolysis. Here, the metabolic changes during the migraine aura of a patient with FHM were investigated for the first time using APT imaging. The patient developed clear tissue acidosis and blood flow disturbances in the absence of ischaemia in the affected cerebral hemisphere, possibly caused by CSD, i.e. the state of neuronal inhibition that is supposed to be the pathophysiological basis of migraine aura. The studies were not designed to provide a statistical conclusion, but to identify technical strengths and weaknesses of this imaging technique.

Study 6 also represents an early phase of clinical translation. Here, a new postprocessing approach was developed to achieve absolute metrics for the measurement of dynamic processes on CINE MRI, a time-resolved method to visualise moving structures in vivo, e.g. in cardiac, bowel, or foetal imaging. Usually movement is evaluated qualitatively and to date objective quantitative approaches are missing. In this study, a measuring method (voxel intensity distribution method, VIDM) for subtle movements was developed and applied in 27 children with Chiari and other brain/skull malformations, where cerebellar tissue herniates dynamically through the foramen magnum following CSF pulsatility. The degree of movement was compared using VIDM and visually derived, clinically accepted linear measurements on CINE sequences. In 85% of the patients, VIDM showed significantly more cerebellar displacement (p=0.002) compared to simple visual assessments, although this did not correlate with the clinical outcome parameters (hydrocephalus or syringomyelia; Pearson’s correlation coefficient -0.28; p=0.16). It is suggested that VIDM might be a valuable tool to detect and measure subtle dynamic processes in the CNS, but extracranial applications are also very likely.

Study 3 and 7 represent validation studies of methods that have been presented in clinical data before. In study 3, 2HG MRS was used in 35 patients suspected for cerebral gliomas to determine the IDH mutational status that today is an integral part of the WHO brain tumour classification system. For this study, a dedicated MRS sequence was used and the routine imaging protocol was extended by only 6 min. The sensitivity/specificity for determining the IDH mutational status was 89.5% and 81.3%, respectively. It could be concluded that 2HG MRS is an easily applicable supplement to standard imaging protocols that allows presurgical diagnostics and opens up for more detailed assessment during treatment.

In study 7, T1 maps were generated from clinical MRI data using the MP2RAGE sequence, a technique extensively applied in neuroscience, but little in the clinical setting. The technical parameters were adapted to find a balance between short acquisition times, high signal-to-noise, and reliable T1 values to quantify myelin maturation in 94 children up to the age of 6 years. The assessment of adequate myelination is a central part of paediatric imaging diagnostics, but is to date done by evaluating images qualitatively. The aim was to validate the MP2RAGE-based T1 mapping technique for the assessment of normal myelination, and data were compared to those of children with various CNS pathologies. Additionally, the diagnostic power of the MP2RAGE was pointed out for the qualitative assessment of regular myelination and brain pathologies. The purpose of study 4 and 5 was to improve the diagnostic confidence of perfusion-weighted DCE maps. DCE is a well-established technique outside the CNS, but is used less in neuroimaging due to a number of technical issues. Here, postprocessing was addressed with the aim to reduce noise in the resultant parameter maps. Two curve-fitting methods, the Levenberg-Marquardt (LM) algorithm and a Baysian method (BM), were compared in digital phantoms and in 42 glioma patients applying two compartmental models (extended Toft’s, ETM, and 2-compartment- exchange model, 2CXM). The image quality was assessed with regard to tumour discrimination and overall impression of the images. Moreover, the diagnostic performance to differentiate high-grade from low-grade gliomas was investigated. The image quality of parameter maps generated by BM was significantly improved compared to LM (p<0.001), and the 2CXM- based maps were higher rated, regardless of the fitting method. The diagnostic performance to differentiate tumour grades was excellent for Ktrans and Vp (p<0.001). This was not affected by the fitting method for the leakage parameter Ktrans, whereas Vp was improved when using BM. These studies suggest that using BM to derive perfusion parameters from DCE data are superior to LM, hopefully leading to higher diagnostic confidence and acceptance in the clinical community. Clinical imaging diagnostics benefits without doubt from the integration of quantitative information gained by qMRI, thereby increasing reproducibility and reliability and enabling the objective comparison to normative and patient databases. Each step of the clinical translation process is essential to show opportunities, identify areas of optimisation, and to reveal challenges and limitations. After further development APT imaging is today available on standard MRI platforms, and BM-based curve fitting of perfusion data has been implemented in postprocessing software programmes. T1 maps of normal myelination in children are made publicly available and may be a first step towards an automated tool to detect myelination disorders more efficiently.

Located in the northwest of China and southeast of the Eurasian Steppe, Xinjiang has always been considered one vital meeting point that bridges East China, Central Asia, and Europe. The bridging road was then named the “Silk Road.” The earliest historical documents in the Han dynasty recorded the first official expansion carried out by Zhang Qian, a Chinese envoy, in 114 BC. This expedition put the previous communication between east and west into a formal connection. The languages and cultures of the Silk Road have exchanged various cultures from different regions, including the pre-Han time.

There were several independent small states in the Tianshan Mountain ranges before the Han government, like Yuezhi, Wusun, Xiongnu, etc. These states have displayed similar nomadic lifestyles with each other and other cultures from the north. Therefore, communication must have existed long before the Han Dynasty. The prehistoric Xinjiang must have several external/internal communication approaches that developed in many aspects.

This dissertation intends to organize the prehistoric Xinjiang materials, reconstruct the prehistoric Xinjiang framework, and provide new research to study subsistence patterns, economic strategy, social status, and state formation.

The whole dissertation is articulated as follows:

Part I. An introductive chapter provides the background and outlines of the research. Chapter 1 is devoted to the geographical and climate descriptions. The topography characteristic of Xinjiang can be summarized as “two basins sandwiched between three mountains” (Altai Mountain, Tianshan Mountain, Kunlunshan Mountain, Junggar Basin, and Tarim Basin). Its large scale contributes to variable climate differences from north to south: mountain-oasis-desert condition. Xinjiang is generally in the central continent and exhibits a typical continental arid climate. The dry weather has preserved the ancient relic remains in good condition.

Chapter 2 revived the research history concerning the Xinjiang prehistoric study, which can be divided into four phases: 1. 1900-1940s, 2. 1940-1970s, 3. 1970-1990s, 4. 2000-present. Even after more than 100 years of exploration, the comprehensive research on prehistoric Xinjiang is still limited due to the lack of excavation materials and little multidisciplinary cooperation.

Chapter 3 concerns the research problems, methodology, and related concepts during the research. After more than 100 years of research, it is evident that Xinjiang prehistoric cultures have been closely connected with other neighboring cultures, and this chapter mainly describes the possible related cultures in the nearby regions: Yamnaya culture, Afanasievo culture, Andronovo culture, Siba culture, and Kayue culture, etc.

Part II regards the prehistoric materials that have been published yet, which is the central part of this dissertation. In this part, Chapter 4 views the “Paleolithic Age” sites that are dated between 240,000-4,000 BP, while Chapter 5 is about the “Bronze Age”- “Iron Age” sites, according to the geographical order. Each site is described based on the smallest excavation unit, trying to provide the most detailed information for the reconstruction. Each section of this part follows the framework of 1. Location, 2. Research History, 3. Findings, 4. Age, 5. Interpretation.

Part III is the discussion part, in which it first establishes the prehistoric chronological sequence and then divides the whole prehistoric Xinjiang into 11 cultural zones: (A). Southern Hami Zone, (B). Eastern Hami Zone, (C). Balikun region Zone, (D). Turfan Basin Zone, (E). Altai Mountain Zone, (F). Western Junggar Zone, (G). Mid-northern Tianshan Mountain Zone, (H). Mid-southern Tianshan Mountain Zone, (I). Lop Nur Zone Southern, (J). Tarim Zone, (K). Pamir Plateau Zone. According to the chronological framework and the separate cultural zones, this chapter proposes the possible cultural communication route in prehistoric Xinjiang.

The conclusive part, Chapter 7, summarizes the prehistoric material and the cultural zones and provides a general picture of prehistoric Xinjiang before Han Dynasty.

The prehistoric Xinjiang started around 300,000 BP in the Altun Mountains region, when two spots exhibit the earliest lithic percussion assemblage. Several Paleolithic sites were distributed in the Altai Mountain, Hami Basin, and Tarim Basin until 4,000 BP, respectively; however, these lithic traditions did not transform into the Neolithic technologies in the following centuries. The arrival of Bronze Age cultures from central Asia leads the Paleolithic Xinjiang into the Bronze Age around 2,500 BC. The outside Bronze Age culture from the west and east contribute to the unique Xinjiang native cultures, with the coexistence of painted pottery wares and bronze items. The continuous communication helped the development of metallurgy; at the beginning of the first millennium BC, iron came into use in Xinjiang prehistoric sites. The transmission of tool production and continuously external/internal cultural communication contributed to the revolution on subsistence strategy. The rise of horse nomadism with metal harnesses and weapons has led to frequent conflicts and expansion of local territory. The adoption of agricultural practice assured a relatively stable sedentary life.

In general, this thesis intends to first build a fundamental database for prehistoric Xinjiang research, and this database will be enriched with more discoveries and research results. Only by collecting all the published data can we have a basic knowledge for the further study. In addition, this thesis also provids a new general chronological sequence of Xinjiang prehistory, and discussed the possible cultural interaction route according to the cultural comparisons.

Parental self-efficacy is an essential predictor of beneficial parenting practices, parenting skills, and positive child development (Albanese et al., 2019; Ardelt & Eccles, 2001; P. K. Coleman & Karraker, 2000; T. L. Jones & Prinz, 2005; Schuengel & Oosterman, 2019; Stievenart & Martinez Perez, 2020; Verhage et al., 2013; Wilson et al., 2014; Wittkowski et al., 2017). It describes the parents’ belief in their efficaciousness in influencing the child and its environment in such a way that it supports child development (Ardelt & Eccles, 2001). Parental self-efficacy as a parental belief (Sigel & McGillicuddy–De Lisi, 2002) is part of the home learning environment. The home learning environment has proven to be an important factor for beneficial child development and later school performance (Kluczniok et al., 2013; Lehrl et al., 2012; Sammons et al., 2015; Tamis- LeMonda et al., 2017). Studies indicate that the home learning environment can be structured into structural family characteristics (e.g., socio-economic background or family language), beliefs (e.g., parental self-efficacy), and processes or process quality (e.g., parent-child activities), whereby the processes have a direct effect on child development (Anders et al., 2011; Kluczniok et al., 2013; NICHD Early Child Care Research Network, 2003). This thesis follows the structure of the home learning environment, called the home learning environment model, and presents its component’s interrelationships. In the first study, the construct of parental self-efficacy is investigated in more detail. The construct of parental self-efficacy and, in particular, its content-specificity is not well understood: Parental self-efficacy can either refer to parents’ general perception of how well they judge themselves in their role as parents or refer to a specific parental task. To investigate this, it was tested whether (a) general and task-related parental self-efficacy could be assessed separately or (b) be mapped in a hierarchical model. Results indicate that general and task-related parental self-efficacy are separate dimensions. Furthermore, general and task-related parental self-efficacy were tested for differences in family characteristics. Results suggested that parents with a non-German family language experienced lower general parental self-efficacy and perceived themselves to be less self-efficacious in caring for a sick child. Parents with a university degree felt more efficacious in communicating a responsible media use but less efficacious in caring for a sick child than parents who did not have a university degree. The second study investigated the relationship of parental self-efficacy with family characteristics and home learning activities of native-born German parents and parents with a Turkish immigration background. Little is known (a) about the relationships between structural characteristics, parental self-efficacy, and home learning activities, especially for Turkish immigrant families with average educational levels and income, and (b) whether parental self-efficacy and home learning activities and their relationship are affected by the parents’ immigration background. Results showed that parental self-efficacy and the educational level but not the immigration background were significant predictors of home learning activities. The immigration background was related to the number of home learning activities via parental self-efficacy. However, there was no direct relationship between the immigration background and the home learning activities. This indicates the importance of parental self-efficacy for home learning activities regardless of the immigration background. Surprisingly, parents with a Turkish immigration background felt significantly more self-efficacious than native-born German parents. The third study investigated the relationship of parental self-efficacy and home learning activities with child outcomes at the children’s transition from preschool to elementary school. The interplay between parental self-efficacy, home learning activities, and preschool children’s socio-emotional and language skills has not yet been investigated. By linking these variables, this study went beyond previous research that concentrated on relationships between two factors. Findings indicate that the more self-efficacious parents felt, the more home learning activities they offered, and the higher they rated their children’s language skills at age 5. Moreover, parents who felt more efficacious in supporting their children’s language skills also described their children as having fewer socio-emotional problems. Also, parents whose children were about to transition from preschool to elementary school did not significantly undertake more school-preparatory home learning activities than parents of children who were not to enter elementary school. This thesis contributes to better understand the structure of parental self-efficacy in terms of the relationship between different levels of measurement. Furthermore, this thesis was able to show that parents with an immigration background do not generally perceive themselves as less self-efficacious in parenting their children, but that other family characteristics and the context are also decisive for this relationship. Finally, parental self-efficacy emerged as a significant predictor of the number of home learning activities, emphasizing the importance of parental self-efficacy for improving the home learning environment.

The experience of prolonged stress at the workplace is associated with a variety of adverse health outcomes among employees. If job demands are high and job-related stress is chronic, employees are at risk of developing physical and mental health problems. A common health problem among working populations is burnout, a syndrome that results from prolonged exposure to job demands that exceed the individual’s abilities to cope. An occupational group that is especially vulnerable to develop burnout are police officers, who are exposed to high job demands and serious stressors on a daily basis. The aim of this thesis is to identify factors that protect against work-related strain in policing, with a special focus on the beneficial role of leadership for workplace health promotion. Results of study 1 indicated that job demands, operationalized by high workload and assaults by citizens, were associated with higher levels of depression and anxiety levels among police officers, mediated through emotional exhaustion, the core dimension of burnout. On the other hand, social support by colleagues, shared values and positive leadership climate constituted job resources that were negatively associated with the experience of depression and anxiety. Furthermore, job resources buffered the effect of job demands on emotional exhaustion, indicating that the more resources are available in the work context, the lower is the negative impact of job demands on police officers’ mental health. In study 2 the concept of health-oriented leadership was applied to the context of police work. The results confirmed the beneficial impact of health-oriented leadership on police officers’ health. It was associated with more well-being and lower levels of burnout, depression and musculoskeletal problems. Moreover, health-oriented leadership was positively associated with work-related health behaviors (self-care) of subordinate police officers. Thus, health-oriented leaders promoted police officers’ self-care, which was associated with higher levels of well-being in turn. This implicates that police leaders do not solely affect officer health and well-being by creating favorable working conditions but also by promoting officers’ own health-related behaviors. According to the well-established effort-reward imbalance (ERI) model, job rewards in terms of money, esteem, and career opportunities counterbalance the health-impairing impact of job demands. Leadership plays only a minor role in the operationalization of the reward dimension in the ERI model. The aim of study 3 was thus to enhance the ERI model by adding the concept of health-oriented leadership and to apply it to the context of police work. The results showed that high work effort was associated with higher levels of burnout among police officers. Furthermore, both job rewards and health-oriented leadership were associated with lower levels of burnout. However, only health-oriented leadership, but not job rewards, buffered the health impairing effects of high work effort on burnout levels. In summary, the results of all three studies point to the crucial role of leadership for the prevention of psychological strain and the promotion of health in policing. Police officers especially seem to benefit from leaders who adopt a leadership style that is not only characterized by health-promoting behavior, but also by a heightened awareness for specific health issues at the work and a sense of responsibility for health concerns. The findings of this thesis provide valuable directions for future research and practical interventions for promoting healthy working conditions in the challenging and demanding job of police officers.

Die Verkehrswende, der Umbau des Verkehrssystems hin zu einer ökologisch nachhaltigen Mobili-tät, ist ein komplexer gesellschaftlicher Transformationsprozess. Der Wandel erfordert, neben der Schaffung entsprechender politischer Rahmenbedingungen und dem Einsatz neuer Technologien, tiefgreifende Änderungen von Einstellungen und Verhaltensweisen sowie kulturell geprägter Deu-tungsmuster in der Gesellschaft. Unter welchen Bedingungen sich derartige Veränderungen auf der Ebene des Individuums und auf der Ebene sozialer Strukturen ergeben können und wie diese Ebe-nen miteinander wechselwirken, ist jedoch nicht ausreichend erforscht. Ziel dieser kumulativen Dissertation ist es, auf theoretischer sowie empirischer Basis ein agentenbasiertes Modell der Ein-stellungs- und Entscheidungsänderungen der Verkehrsmittelwahl zu schaffen. Ich beziehe mich dabei auf die kognitionswissenschaftliche Forschung zur Rolle von Emotionen bei der Informati-onsverarbeitung und Entscheidungsfindung, auf Forschungsarbeiten zu der Wirkung sozialer Ein-flüsse aus den Bereichen der Sozialpsychologie und Soziologie sowie auf die umweltpsychologische Forschung zur Segmentierung von Zielgruppen. In Studie 1 wurde anhand eines Vignettenexperiments und eines kognitiv-affektiven Modells dyadischer Kommunikation untersucht, welchen Einfluss die Verwendung emotionaler Sprache im Zuge persuasiver Kommunikation auf die Informationsverarbeitung von Menschen hat. Die Ergeb-nisse zeigen, dass die Tendenz zur motivierten Informationsverarbeitung (motivierte Kognition) durch die Valenz und den Grad der Emotionalität in der Kommunikation beeinflusst wird. Mithilfe des Modells können die beobachteten Effekte durch den Mechanismus der emotionalen Kohärenz erklärt und in ihrer Wirkung auf mentale Strukturen geschätzt werden. In Studie 2 wurden die Einstellungen und affektiven Bedeutungen einer breiten Palette von konventionellen und neueren Verkehrsmitteln untersucht. Auf Basis der affektiven Wahrnehmun-gen konnten unterschiedliche Mobilitätstypen identifiziert werden. Darüber hinaus zeigt die Studie, dass die typspezifischen affektiven Bedeutungsmuster die Bereitschaft, emissionsarme Verkehrsmit-tel zu nutzen, im hohen Maße bestimmen. In Studie 3 wurden die theoretischen und empirischen Ergebnisse aus den vorangegangenen Studien in dem agentenbasierten Modell InnoMind (Innovation diffusion driven by changing Minds) zusammengeführt. Die Simulationsszenarien zu unterschiedlichen Fördermaßnahmen von Elektromobilität verdeutlichen, dass die Wirksamkeit der Instrumente durch die zielgruppenspezifi-schen Einstellungsmuster und sozialen Interaktionen der Verkehrsteilnehmerinnen und Verkehrs-teilnehmer beeinflusst werden. In Studie 4 wurde das Modell InnoMind genutzt, um die einstellungsverändernden Effekte von Informationskampagnen zur Nutzung von Carsharing zu untersuchen. Das Vorgehen verdeutlicht die Flexibilität und Adaptivität des Simulationsansatzes. Darüber hinaus zeigt die Studie, dass die veränderte Darstellung der Mobilitätsoptionen in den Kampagnen deren Wirkung in bedeutsamen Maß beeinflussen kann. Insgesamt unterstreichen die Ergebnisse die Bedeutung affektiv-emotionaler Prozesse für die Einstellungsbildung und -änderung. Die Verarbeitung von (sozialen) Informationen unterliegt Ver-zerrungen, die zu einer Konstruktion einer konsistenten Repräsentation bestehender Überzeugun-gen und Emotionen führen. Diese auf individueller Ebene wirkenden Mechanismen haben in Wechselwirkung mit sozialen Kommunikationsprozessen und Informationsflüssen einen entschei-denden Einfluss auf die Dynamiken im Zuge gesellschaftlicher Transformationen. Das in dieser Arbeit entwickelte agentenbasierte Modell ermöglicht es, derartige komplexe In-teraktionsprozesse und Dynamiken zu analysieren. Auf der Grundlage kognitionswissenschaftlicher, sozialpsychologischer und soziologischer Theorien sowie umfassender Empirie erweitert es die bis-herige Forschung zu Meinungsdynamiken und sozialen Einflüssen mithilfe sozialer Simulationen. Zudem vermittelt das Modell handlungsrelevantes Wissen, um die Akzeptanz der Verkehrswende in der Gesellschaft zu fördern.

Die KMK hat diagnostische Kompetenzen als eine der vier zentralen professionsbezogenen Kompetenzen von Lehrkräften herausgestellt, die es bereits im Studium vorzubereiten gilt. Bislang ist das Angebot an evaluierten Interventionen zur Förderung, vor allem in der universitären Ausbildungsphase, allerdings überschaubar. Dabei kann professionelles diagnostisches Vorgehen bereits im Lehramtsstudium vorbereitet werden, indem neben deklarativem Wissen auch prozedurales diagnostisches Wissen gefördert wird (diagnostische Expertise). Die Förderung prozeduralen Wissens ist jedoch mit Herausforderungen verbunden, weil dabei praktische Erfahrungen essentiell sind. In der vorliegenden Arbeit wird die Entwicklung, Erprobung und Evaluation einer fallbasierten Lerngelegenheit vorgestellt, die den Aufbau prozeduralen Wissens von Lehramtsstudierenden unterstützt. Im Rahmen komplexitätsreduzierter, realistischer Fallvignetten wird damit auf einen Diagnoseanlass vorbereitet, der weitreichende Konsequenzen hat: die Feststellung von Lernbesonderheiten. Dieser Diagnoseanlass erfordert sogenannte formelle Diagnosen, die im Rahmen eines regelgeleiteten diagnostischen Prozesses unter Anwendung standardisierter diagnostischer Testverfahren erstellt werden. Zur Vorbereitung auf diese anspruchsvolle Aufgabe üben die Studierenden im Fallinventar die Vergabe von Diagnosevermutungen sowie die Ableitung von pädagogischen Anschlusshandlungen ein. Bei der Bearbeitung des Fallinventars zeigte sich, dass den Studierenden die Ableitung von Anschlusshandlungen noch schwerer fällt als die Vergabe von Diagnosevermutungen. Diese Schwierigkeit konnte dadurch erklärt werden, dass die Studierenden formelle diagnostische Informationen noch nicht systematisch genug nutzten und dass sie ihre Empfehlungen nicht auf Grundlage der Diagnosen vergaben. Die Fähigkeit zur Vergabe von Empfehlungen konnte erfreulicherweise durch die Arbeit mit dem Fallinventar verbessert werden, indem prozedurales Wissen trainiert wurde. In Kombination mit einer aufgabenbasierten Übung konnte andererseits deklaratives Wissen gefördert werden, das die Trefferquoten bei Diagnosevermutungen erhöhte. Außerdem konnten erste affektiv-motivationale Voraussetzungen geschaffen werden, die die Wahrscheinlichkeit diagnostisch kompetenten Verhaltens in der späteren Berufspraxis erhöhen. Um diese Voraussetzungen zu stabilisieren und weiter auszubauen, bedarf es allerdings weiterer Lerngelegenheiten, die eine schrittweise Praxisannäherung im Lehramtsstudium ermöglichen. Die Ergebnisse erweitern die Befundlage zur Förderung diagnostischer Kompetenzen im Lehramtsstudium und haben Implikationen für die Modellierung diagnostischer Kompetenzen, die bislang die Qualität der Anschlusshandlungen unzureichend berücksichtigt.

Phänomene der Immersion gehen häufig mit dem Wirkungsversprechen einher, Rezipierende möglichst komplett in eine Umgebung, Fiktion oder Parallelwelt einzutauchen. Insbesondere der Topos einer ‚totalen‘ Immersion suggeriert, dass Rezipierende physisch, psychisch oder emotional derart eingenommen werden, dass sie nicht nur das Vermögen verlieren, zwischen Realität und Fiktion zu unterscheiden, sondern auch, dass ihr Reflexionsvermögen zugunsten eines unmittelbaren, intensiven Erlebens eingeschränkt werde. Die vorliegende Studie zeigt am Beispiel immersiven Theaters jedoch, dass es gerade die emotionale Involvierung ist, die Prozesse der Reflexion auslöst – und eine solche, den Diskurs prägende, binäre Denkfigur die Komplexität zahlreicher Immersionsphänomene deshalb nicht angemessen erfassen kann. Vor dem Hintergrund der transdisziplinären Immersionsforschung differenziert die Studie zunächst zwischen immersiven Aufführungsdispositiven und immersivem Theater im engeren Sinn. Letzteres zeichnet sich dadurch aus, dass Zuschauer:innen nicht nur in einen multisensorischen Erfahrungsraum, sondern zugleich in eine geschlossene, gestaltete Weltversion eingelassen werden. Für die Analyse der Publikumsinvolvierung im immersiven Theater wird eine polyperspektivische Szenen- und Situationsanalyse vorgeschlagen. Diese fokussiert anhand ausgewählter Sequenzen die Relation von Aufführungsdispositiv und Zuschauer:innen im Hinblick auf konstellierte Selbst-/Weltverhältnisse. Ausgehend von der These, dass die verschiedenen Modi der Involvierung (räumlich, haptisch-taktil, olfaktorisch, figurenperspektivisch oder handlungsbezogen etc.) wirkungsästhetisch auf Vereinnahmung zielen, zeigen die Analysen, wie Zuschauer:innen z.B. von Geruchs- oder Soundwahrnehmungen derart affiziert werden können, dass es sie situativ zu einer bestimmten Re-Aktion drängt. Prozesse der Vereinnahmung werden dabei nicht nur konstitutiv reziprok gedacht, sondern in ihren vielschichtigen, hochgradig ambivalenten Wirkungen beschrieben. Über das Konzept der Vereinnahmung und die Analyse vereinnahmender Publikumsinvolvierung wird eine affekttheoretische Perspektive auf immersives Theater plausibilisiert. Die Studie nimmt damit nicht nur eine wichtige, korpusgebundene Präzisierung des umbrella-Phänomens immersive theatre vor. Sie leistet nicht zuletzt über die Integration von Zuschauer:innen-Interviews zudem eine methodische Erweiterung etablierter Strategien der Aufführungs- und Inszenierungsanalyse und zielt mit dem Konzept der Vereinnahmung auf eine Theoriebildung für Prozesse der Publikumsinvolvierung im Gegenwartstheater.

Fung Asseng (馮亞星, 1792–?) und Fung Ahok (馮亞學, 1798–1877), zwei einigermaßen gebildete Matrosen aus der chinesischen Provinz Guǎngdōng oder Canton (廣東), waren die ersten Chinesen, die sich nachweislich in Deutschland aufhielten. In den 1820er Jahren fertigten sie in Halle und Potsdam umfangreiche zweisprachige Handschriften christlichen Inhalts an, in denen sie ihre frühkantonesischen Aussprachen zahlreicher chinesischer Schriftzeichen in das lateinische Alphabet transkribierten. Gleichzeitig berichteten auch einige deutsche Autoren über ihre Sprache. Diese Schriften, die von Asseng und Ahok selbst oder ihren deutschen Mitmenschen produziert wurden und summarisch als die „deutschen Quellen“ bezeichnet werden können, gelten als aufschlussreiche Materialien für die Erforschung der frühkantonesischen Sprache. Sie werden in der vorliegenden Arbeit zum ersten Mal systematisch untersucht, und zwar aus der Perspektive der chinesischen Dialektologie, der Missionarslinguistik sowie der (deutschen) Graphematik. Dadurch können nicht nur zwei historische Varianten des Frühkantonesischen phonetisch und phonologisch rekonstruiert, sondern auch die Transkriptionsregeln herausgearbeitet werden, die im Wesentlichen unter dem Einfluss der neuhochdeutschen Orthographie entstanden sind.

The morphogen sonic hedgehog (SHH) regulates central patterning processes along the dorsoventral axis of the emerging forebrain. Secreted from the prechordal plate (PrCP), SHH targets neuroepithelial cells of the overlying forebrain organizer region in the rostral diencephalon ventral midline (RDVM), to establish and further specify ventral identity of the forebrain. Defects in this pathway result in severe developmental forebrain defects including holoprosencephaly (HPE). Besides the canonical SHH receptor patched 1 (PTCH1), several additional cell surface proteins have been identified as being essential for SHH signaling in the neuroepithelium. Jointly, they are referred to as the SHH receptorsome and include LRP2 and GAS1. Mutations in these co-receptors are the cause of familial forms of HPE and related phenotypes, such as in Donnai-Barrow syndrome (DBS), corroborating their importance for SHH-dependent forebrain development in humans. Intriguingly, the structure of SHH coreceptors is highly diverse and they show spatial and temporal differences in expression pattern, arguing for distinct functions of each receptor in SHH-dependent developmental processes. In this thesis, I used human induced pluripotent stem cell (iPSC)-based cell models to recapitulate early steps in neuroepithelial patterning and to elucidate unique roles for LRP2 and GAS1 in these processes. In the first project, I studied a unique missense mutation in LRP2 in two siblings with DBS. To do so, I differentiated patient-derived iPSCs into neural progenitor cells (NPCs) and studied the impact of this mutation on receptor handling of SHH. I demonstrated that the mutant receptor was unable to discharge its ligand SHH, leading to enhanced lysosomal degradation of the mutant receptor bound to its ligand. These studies showed that ligand-induced decay of LRP2 is responsible for the disease phenotype in this family with DBS. Additionally, the results of this study verified the molecular function of LRP2 as SHH co-receptor as it mediates endocytosis and trafficking of the morphogen in forebrain neuroepithelial cells, a process essential for SHH signal reception in this cell type. In the second project, I uncovered a novel function for GAS1 in integrating SHH and NOTCH signaling during early forebrain development. Performing comparative analyses in GAS1- deficient mice and genetically engineered GAS1 knockout (KO) iPSC-derived NPCs, I showed that loss of GAS1 impairs NOTCH-dependent facilitation of SHH signaling and results in a failure to maintain the SHH activity domain in the rostral ventral neuroepithelium. Thus, besides its known function as SHH co-receptor, GAS1 also acts as co-receptor for NOTCH1, enhancing pathway activation which, in turn, promotes maintenance of SHH signaling in the rostral ventral neuroepithelium during forebrain development.

In the context of the euro crisis, several member states of the Eurozone were forced to implement so-called Economic Adjustment Programmes. The implementation of these programmes was supervised by a troika consisting of the European Commission, the European Central Bank, and the International Monetary Fund. Fiscal adjustment was one cornerstone of the adjustment programmes. The objective of the programmes was to reduce previously soaring public deficits and to stabilise and reduce public debt in the long term. All programmes primarily aimed at cutting government spending. Increasing government revenues was to play only a secondary role. However, a look at the adjustment programmes for Ireland and Portugal shows a striking difference in the fiscal adjustment strategies. Different Irish governments pursued an adjustment strategy with a strong focus on expenditure cuts. By contrast, Portugal's adjustment strategy changed over the course of the programme and was increasingly driven by increases in revenues. How can we explain these differences? To answer this question, my dissertation provides two in-depth case studies of the adjustment programmes for Ireland and Portugal. I argue that fiscal adjustment strategies are determined by the activity of coalitions of different economic actor groups at the domestic level. These actor groups have different fiscal policy preferences. On the one hand, they differ in terms of their preferred level of redistribution and the economic risks to which they are exposed. On the other hand, sectoral actor groups have different preferences based on their prioritisation of international competitiveness and domestic demand. Actor groups with similar preferences form coalitions to influence the government’s policy-choice. Two logics determine which coalitions ultimately prevail. On the one hand, some coalitions are involved in policy-making through social pacts and other institutional arrangements. On the other hand, sectoral coalitions are influential due to their importance for economic growth. Although national coalitions have decisive influence, governments in a globalised world are constrained in their actions by international financial market actors. In Ireland, coalitions that favoured an adjustment strategy with a focus on spending cuts were more assertive. This is mainly due to the Irish growth model, which has been based on exports and foreign direct investment for more than two decades. Trade unions, which would have preferred an alternative adjustment strategy, were not able to prevail against the influential coalition of export-oriented actor groups and high-skilled workers. In Portugal, such a coalition was feasible. Here, trade unions and actor groups exposed to high economic risks were successful in preventing several attempts to cut public spending. In the face of this resistance, the government increasingly decided to resort to revenue increases. These results show, on the one hand, that domestic political processes were crucial for fiscal adjustment during the euro crisis. On the other hand, it shows that these processes differ greatly due to different national growth models and different economic dynamics.

A K_r-factor in a graph G is a collection of vertex-disjoint copies of K_r covering the vertex set of G. In this thesis, we investigate these fundamental objects in three settings that lie at the intersection of extremal and probabilistic combinatorics.

Firstly, we explore pseudorandom graphs. An n-vertex graph is said to be (p,β)-bijumbled if for any vertex sets A, B ⊆ V (G), we have e( A, B) = p| A||B| ± β√|A||B|. We prove that for any 3 ≤ r ∈ N and c > 0 there exists an ε > 0 such that any n-vertex (p, β)-bijumbled graph with n ∈ rN, δ(G) ≥ c p n and β ≤ ε p^{r −1} n, contains a K_r -factor. This implies a corresponding result for the stronger pseudorandom notion of (n, d, λ)-graphs. For the case of K_3-factors, this result resolves a conjecture of Krivelevich, Sudakov and Szabó from 2004 and it is tight due to a pseudorandom triangle-free construction of Alon. In fact, in this case even more is true: as a corollary to this result, we can conclude that the same condition of β = o( p^2n) actually guarantees that a (p, β)-bijumbled graph G contains every graph on n vertices with maximum degree at most 2.

Secondly, we explore the notion of robustness for K_3-factors. For a graph G and p ∈ [0, 1], we denote by G_p the random sparsification of G obtained by keeping each edge of G independently, with probability p. We show that there exists a C > 0 such that if p ≥ C (log n)^{1/3}n^{−2/3} and G is an n-vertex graph with n ∈ 3N and δ(G) ≥ 2n/3 , then with high probability G_p contains a K_3-factor. Both the minimum degree condition and the probability condition, up to the choice of C, are tight. Our result can be viewed as a common strengthening of the classical extremal theorem of Corrádi and Hajnal, corresponding to p = 1 in our result, and the famous probabilistic theorem of Johansson, Kahn and Vu establishing the threshold for the appearance of K_3-factors (and indeed all K_r -factors) in G (n, p), corresponding to G = K_n in our result. It also implies a first lower bound on the number of K_3-factors in graphs with minimum degree at least 2n/3, which gets close to the truth.

Lastly, we consider the setting of randomly perturbed graphs; a model introduced by Bohman, Frieze and Martin, where one starts with a dense graph and then adds random edges to it. Specifically, given any fixed 0 < α < 1 − 1/r we determine how many random edges one must add to an n-vertex graph G with δ(G) ≥ α n to ensure that, with high probability, the resulting graph contains a K_r -factor. As one increases α we demonstrate that the number of random edges required ‘jumps’ at regular intervals, and within these intervals our result is best-possible. This work therefore bridges the gap between the seminal work of Johansson, Kahn and Vu mentioned above, which resolves the purely random case, i.e., α = 0, and that of Hajnal and Szemerédi (and Corrádi and Hajnal for r = 3) showing that when α ≥ 1 − 1/r the initial graph already hosts the desired K_r -factor.

This habilitation thesis summarizes the results of 10 scientific publications (references: paper1-10) addressing the topic "Emergence of antimicrobial resistant bacteria in and beyond companion animal medicine”. The first chapter’s intention is to introduce my research area to the reader by providing basic information on the occurrence of antimicrobial resistance (AMR) in bacteria, including general resistance mechanisms, distribution and spread in different ecological environments and the commonly applied clinical classifications relevant for the veterinary medicine field. The following section characterizes the nature of health care associated infections (HAIs) in human and veterinary medicine, including baseline similarities and differences. Subsequently, bacterial pathogens exhibiting particular antibiotic resistances are introduced. Here, a strong focus is set on AMR bacteria frequently associated with HAIs in human and veterinary medicine, which are therefore also considered as “indicator pathogens”. Since β-lactams such as penicillins and cephalosporins are known for their excellent pharmacokinetic properties which is commonly accompanied by a low toxicity for mammals, this group of active substances is of particular importance for antimicrobial treatment of bacterial infectious diseases in both humans and animals. Infections with indicator pathogens harboring resistance towards β-lactams such as Staphylococcus aureus [methicillin resistant S. aureus, (MRSA)] and Escherichia coli [Extended-Spectrum β-Lactamase (ESBL)-producing E. coli (ESBL-E. coli)] are therefore often accompanied by treatment failure. Since antibiotics belonging to this group are among the “first choices” for empirical treatment of infectious diseases, including life-threatening scenarios such as septicemia, collaborative efforts to limit spread of β-lactam resistance are currently an important goal in human- and veterinary medicine. Additional resistances towards further classes of antibiotic substances are frequently associated with MRSA and ESBL-E. coli, leading to a further reduction of therapeutic possibilities in case of infection. In the second chapter, the publications’ results are summarized into four distinct sections. First, the importance of HAI in small animal and equine medicine is illustrated by a literature review considering outbreak events reported so far. A brief historical sketch reveals that problems due to HAI in animal clinics, including cases of zoonotic transmission, have been known since at least 1961. While there have been numerous reports in the past highlighting the technical and scientific developments during the last decades in companion-animal medicine, other important fields such as hygiene management, infection control and occupational safety of employees still lack comparable achievements. The current challenges faced by companion animal clinics are described by studies evaluating the introduction rates for multi drug resistant (MDR) indicator pathogens via colonized horses in a large German university clinic. Overall, n = 341 horses representing distinct medical indications (i.e. 233 horses with "colic symptoms" and 108 with "open wounds") were sampled immediately upon hospital admission. The overall screening results showed that MRSA was detected in 3.5% of the nasal swabs and ESBL-Enterobacteriaceae in 10.3% (mainly ESBL-E. coli) of the fecal samples. Subsequent molecular typing of the isolates showed that all MRSA belonged to sequence type (ST) 398, the currently predominating MRSA lineage identified in clinical samples of horse origin in Europe. In contrast, ESBL-E. coli showed a broad heterogeneity in genomic backgrounds associated with the β-lactam resistance. However, isolates belonging to ST complexes (STC) 1250 (31.7%) and STC10 (19.5%) clearly dominated the collection. Notably, all MRSA and ESBL- E. coli isolates isolated in these studies showed additional antimicrobial resistances to a minimum of three further classes of antibiotics. For assessment of a particular AMR situation in certain bacterial pathogens and/or environments, e.g. if surveillance of AMR in a pathogen causing HAI is needed, an unambiguous species identification is mandatory. Species identification is essential for sound interpretation of antimicrobial sensitivity testing (AST) results and therefore a prerequisite to classify the resistance phenotype of the pathogen correctly. Moreover, species identification is also needed for precise interpretation of additional results gained by other molecular biological methods. A combination of bacterial genome analysis with matrix-assisted laser desorption ionization - time of flight mass spectrometry (MALDI-TOF MS) allowed us to differentiate between the species Staphylococcus intermedius, S. delphini and S. pseudintermedius, which was previously a time-consuming and uncertain approach. Since methicillin resistant S. pseudintermedius (MRSP) are often associated with resistances towards several other antimicrobials, a rapid and reliable species identification using MALDI-TOF MS promotes early and targeted antimicrobial therapy in cases of infection and, if necessary, the initiation of additional hygiene measures to prevent its spread. The following results demonstrate the overwhelming importance of constant adjustments of microbiological diagnostic screening methods for identification of MDR: In 2011, a novel variant of the methicillin resistance gene (later: mecC) was described for MRSA of cattle and human origin. A study we immediately initiated identified mecC-MRSA in clinical samples from horses, dogs, cats, wild animals and rodents. Here, the “weak” expression of the resistance phenotype, now known to be a common feature of mecC-MRSA, was a challenge to classify an isolate as MRS, which was achieved after diagnostic adjustments. As described above, methicillin resistance is often associated with other resistances, e.g. towards tetracyclines, zinc and arsenic compounds. Our detailed analysis of the integration site for the methicillin resistance-mediating mobile genetic element in staphylococci was identified as a "hot spot" for recombination events: We discovered a mosaic-like genomic structure which is prone to integration of mobile resistance-mediating elements of different types. The combination of up-to-date microbiological diagnostics with classical principles of infection epidemiology allowed us to answer important questions concerning possible transmission scenarios for MDR pathogens in companion animal clinics and identify risk factors for MRSA infections in these animals. In 2012, the ability of MRSA to cause HAI in companion animals and its importance as an indicator pathogen for veterinary medicine was already known. At that time however, similar information was not available for ESBL- E. coli. To address this deficit, we retrospectively investigated several cases of serious infections caused by ESBL-E. coli in hospitalized horses in a veterinary clinic. Comparative analysis of molecular typing results obtained for 13 ESBL-E. coli together with the horses’ clinical data revealed a putative spatio-temporal relationship of the isolates, which probably reflected several transmission events between these patients. In another case-control study, we have examined the possible risk factors for wound infections caused by MRSA in horses, dogs and cats. Multivariable logistic regression identified the following variables as risk factors for MRSA infection compared to methicillin susceptible infection: (i) the number of employees working at the veterinary setting (n>10; p<0.001), (ii) antibiotic treatment prior to sampling (systemic: p=0.002; local: p=0.049, both: p=0.011) and (iii), surgical site infection (p<0.001). Spa typing revealed clonal complexes (CC) previously known for hospital-associated lineages spreading in human health-care settings in Germany (i.e. CC5 and CC22) as the dominating lineages among isolates of dog and cat origin. Equine MRSA belonged nearly exclusively to CC398, a CC previously described as a nosocomial pathogen in equine clinical settings. While performing the studies mentioned above, we considered whether transmission of relevant AMR bacteria between pets and their owners (e.g. MRS) occur outside the typical hospital environment, and further, which circumstances and human behavioral patterns might influence such events. Therefore, we investigated different aspects of the human-to-dog relationship together with MRS carriage at a dog show in 2009. We introduced a questionnaire accompanied by a screening program of the nasal swabs of dog owners (108) and their dogs (108) with respect to staphylococci. S. aureus was identified in swabs obtained from 20 (18.5%) humans and two dogs (1.8%), respectively. 15 dogs (13.9%) and six owners (5.6%) harbored S. pseudintermedius, including one MRSP. Interestingly, 68.5% of the dog owners allowed their dog(s) to rest on the sofa, 39.8% allowed their dog(s) to lay on their bed, 93.5% let them lick their hands, and 52.8% let them lick their face. A bivariate analysis of putative risk factors showed that dog owners who kept more than two dogs were significantly more likely to become colonized with S. pseudintermedius than those who kept only one or two dogs (p<0.05). The results section closes with the most recent results, which demonstrated the continuing adaptation of MDR bacteria to the companion animal hospital environment. We showed that equine MRSA-ST398 have acquired different mobile genetic elements (i.e. pathogenicity islands, phages) harboring immune-modulating factors which impede the activation of the complement system, which is among the most important defense measures of the innate immune system towards invasive S. aureus infections. The equine MRSA harbored genes encoding variants of the staphylococcal complement inhibitor protein (SKIN), known for its function in subverting the complement system in plasma of humans, cattle, pigs and horses. These results clearly demonstrated the existence of extended host (EHSG) lineages and their characteristic flexibility with respect to niche- and host-adaptation. Chapter 3’s discussion section presents the general concepts of surveillance of antibiotic consumption, HAI and antibiotic resistance in human medicine, and expands the context with respect to the results of this habilitation thesis. The importance of HAI and MDR pathogens in companion animals for human health is pointed out and current developments in this area are discussed. With regard to integrated surveillance for antibiotic resistance, antibiotic consumption and HAI, a "best practice" model featuring the One Health concept is outlined. This is followed by a discussion of prospects for small animal and horse medicine, taking into account realistic human and financial resources to establish fundamental surveillance structures. The following section summarizes the key factors for HAI prevention in veterinary clinics. In particular, technical progress (i.e. genomics/bioinformatics) in the field of molecular epidemiology has contributed to these findings, a development which is reflected in the publications presented. Finally, possible reasons for the occurrence of MDR pathogens in animal clinics are given, using horse clinics as an example. The occurrence of ESBL-E. coli and MRSA belonging to EHSG-lineages explain why further research on these MDR pathogens is necessary, especially with respect to further host- and niche-adaptation. In summary, the publications presented make it clear that research on EHSG pathogens and their importance has only just begun. New methods of molecular epidemiology currently (2020) offer completely new opportunities to study adaptive changes in bacterial genomes in large, representative studies. However, care is needed with respect to establishment of a suitable, representative isolate collection, which is of crucial importance for the validity of the studies. Integrated One Health surveillance, as outlined in this document, could reflect the current importance of MDR EHSG pathogens for human and veterinary medicine. An integrated approach would lead to a better understanding of the bacterial adaptation processes to ecological niches as a whole and reveal new, epidemiologically significant developments in a timely manner, whereas currently we can often only trace these types of developments in retrospect.

References paper1 Walther, B., K. Tedin, and A. Lübke-Becker, Multidrug-resistant opportunistic pathogens challenging veterinary infection control. Vet Microbiol, 2017. 200: p. 71-78. paper2 Walther, B., Klein, K.S., Barton, A.K., Semmler, T., Huber, C., Wolf, S.A., Tedin, K., Merle, R., Mitrach, F., Guenther, S., Lübke-Becker, A., Gehlen, H., 2018. Extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli and Acinetobacter baumannii among horses entering a veterinary teaching hospital: The contemporary "Trojan Horse". PLoS One 13, e0191873. paper3 Murugaiyan, J., Walther, B., Stamm, I., Abou-Elnaga, Y., Brüggemann-Schwarze, S., Vincze, S., Wieler, L.H., Lübke-Becker, A., Semmler, T., Roesler, U., 2014. Species differentiation within the Staphylococcus intermedius group (SIG) using a refined MALDI-TOF MS database. Species differentiation within the Staphylococcus intermedius group using a refined MALDI-TOF MS database. Clin Microbiol Infect 20(10): 1007-1015. paper4 Walther, B., Wieler, L.H., Vincze, Sz., Antão, E.-M., Brandenburg, A., Stamm, I., Kopp, P.A., Kohn, B., Semmler, T., Lübke-Becker, A., 2012b. MRSA variant in companion animals. Emerg Infect Dis 18, 2017-2020. paper5 Semmler, T., Harrison, E.M., Lübke-Becker, A., Ulrich, R. G., Wieler, L. H., Guenther, S., Stamm, I., Hanssen, A. M., Holmes, M. A., Vincze, Sz., Walther, B. 2016. A Look into the Melting Pot: The mecC-Harboring Region Is a Recombination Hot Spot in Staphylococcus stepanovicii." PLoS One 11(1): e0147150. paper6 Walther B, Lübke-Becker A, Stamm I, Gehlen H, Barton AK, Janssen T, Wieler LH, Guenther S. Suspected nosocomial infections with multidrug resistant E. coli, including extended-spectrum beta-lactamase (ESBL)-producing strains, in an equine clinic. Berl Muench Tieraerztl Wochenschr. 2014, 127(11-12):421-427. paper7 Vincze S., Brandenburg, A.G., Espelage W., Stamm I., Wieler L. H., Kopp P. A., Lübke-Becker A., Walther B., 2014. Risk factors for MRSA infection in companion animals: Results from a case-control study within Germany. Intl J Medical Microbiol 10/2014; DOI: 10.1016/j.ijmm.2014.07.007 paper8 Walther, B., Hermes, J., Cuny, C., Wieler, L.H., Vincze, S., Abou Elnaga, Y., Stamm, I., Kopp, P.A., Kohn, B., Witte, W., Jansen, A., Conraths, F.J., Semmler, T., Eckmanns, T., Lübke-Becker, A., 2012a. Sharing more than friendship--nasal colonization with coagulase-positive staphylococci (CPS) and co-habitation aspects of dogs and their owners. PLoS One 7, e35197 paper9 Walther, B., Monecke, S., Ruscher, C., Friedrich, A.W., Ehricht, R., Slickers, P., Soba, A., Wleklinski, C.G., Wieler, L.H., Lübke-Becker, A., 2009a. Comparative molecular analysis substantiates a zoonotic potential of equine Methicillin- resistant Staphylococcus aureus (MRSA). J Clin Microbiol. 47, 704-710. paper10 Walther B., Klein K.S., Barton A.K., Semmler T., Huber C., Merle R., Tedin K., Mitrach F., Lübke-Becker A., Gehlen H. Equine Methicillin-Resistant Sequence Type 398 Staphylococcus aureus (MRSA) Harbor Mobile Genetic Elements Promoting Host Adaptation. Front Microbiol 2018, 9:2516.

Hypertension prevalence is still growing worldwide as well as the number of drug-therapy non-responsive patients. Therefore, improving the current and developing new therapies to control blood pressure (BP) is warranted. Growing literature points to the sympathetic nerve system as the major system controlling long-term BP homeostasis, and human hypertension is often accompanied by increased sympathetic nerve activity (SNA). The renin angiotensin system (RAS) is involved in cardiovascular control and beyond due to the broad actions of the powerful hormone angiotensin II (Ang II) produced in the circulation or within organs. The project aimed to further characterize the modulatory effects of the RAS on SNA and its impact on cardiovascular control and erythropoiesis, particularly focusing on the role of brain-borne Ang II. These questions were experimentally addressed with RAS gain and loss of function mouse models in the FVB/N background strain, and complementary experiments were performed with rats and mixed background mice. A transgenic line with brain-specific angiotensinogen (Agt) expression was validated (Agt-Tg) and used to demonstrate in vivo local brain Ang II formation. FVB/N mice cardiovascular regulation revealed predicted and surprising phenotypes. As expected FVB/N mice lacking the major Ang II receptor (AT1a-KO) presented reduced BP, and Agt-Tg displayed increased BP accompanied by increased SNA. Surprisingly, adult FVB/N mice lacking Agt (Agt-KO) were normotensive contrasting previous findings in other strains. Paradoxically, the genetic brain-rescue of Agt in Agt-KO (Agt-KO-Tg) strongly reduced BP. Using integrative physiology, we identified that the normotension in Agt-KO is driven by increased vascular tone due to exaggerated sympathetic outflow and impaired nitric oxide production which is reversed by brain Ang II in Agt-KO-Tg contrasting Agt-Tg. Agt-KO-Tg also presented better renal function compared to Agt-KO despite similar renal morphological damage. In addition, brain Ang II strongly activated renal SNA in Agt-KO-Tg, and renal denervation had minimal effect on Agt-KO and Agt-KO-Tg baseline BP. A genome-wide-association-study was employed to uncover the genetic alteration causing FVB/N Agt-KO to fail in reducing BP. For this, a mixed background (FVB/N x C57BL/6N) F2 Agt-KO line was generated. Strikingly, the phenotyping data of the F2 Agt-KO strongly indicates a single recessive allele responsible for the BP phenotype in FVB/N Agt-KO once the BP in the F2 presented a clear bimodal distribution with most mice being hypotensive. However, the association analyses demonstrated that several loci likely contribute to the phenotype in FVB/N Agt-KO. Finally, we identified one central and one peripheral mechanism of erythropoiesis regulation modulated by the RAS. In the brain, Ang II favors erythropoiesis via SNA. Agt-Tg with elevated brain Ang II displayed increased erythropoiesis that was reverted by peripheral sympathectomy, and rats with depleted brain Agt presented decreased baseline erythropoiesis. In the periphery, the experiments revealed that the RAS influences the iron homeostasis because Agt-KO mice presented microcytic anemia accompanied by reduced levels of circulating and tissue-stored iron. Altogether, the data set generated within the frame of my doctoral thesis supports local formation and function of brain Ang II. Furthermore, we provided evidence that brain Ang II is involved in differential SNA regulation to different organs impacting BP homeostasis. Finally, two unprecedented mechanisms of erythropoiesis control modulated by the RAS via SNA and iron homeostasis were revealed.