Carbon dots (CDs), nanoscale quasi-spherical carbon materials, have attracted considerable attention in recent years, owing to their unique properties such as superior photoluminescence (PL) properties as well as excellent chemical- and photo- stability. CDs could act as metal-free, green nano-catalysts and their tailorable surface groups such as hydroxyl, carboxylic acid and amino groups have been exploited for organic synthesis. Meanwhile, CDs have shown great potential as visible-light-absorbing photocatalysts due to their light-harvesting ability and electron-transfer efficiency. Still, their photcatalytic applications are limited to simple organic transformations. In this thesis, CDs were synthesized from abundant carbohydrate sources, following a microwave-based carbonization method. The use of different doping agents was explored to adjust the functional groups on the CD surface and tune the photophysical properties. The obtained CDs were implemented as nano-photocatalysts for complex organic transformations such as cross-coupling and isomerization reactions. In Chapter 2, CDs were immobilized on the surface of TiO2 to generate heterogeneous photocatalytic systems. The applicability of CD1/TiO2 nanocomposites as photocatalysts for nickel-catalyzed cross-couplings was demonstrated for a C-O arylation using visible-light. CD1/TiO2 nanocomposites also served as an active photocatalyst for the coupling of aryl halides with an alcohol, a thiol, a sodium sulfonate, and a sulfonamide. Next, the photostability and recyclability of the CD1/TiO2 nanocomposite were explored, showing superior performances in comparison to organic dyes. Having demonstrated the potential of CD1 as photosensitizer for dual photoredox/Ni catalysis, I assessed the effect of different carbon sources and doping agents on the photocatalytic reaction. In Chapter 3, CDs were used to construct a quasi-homogenous colloidal catalytic system in combination with a Ni complex. This approach bypassed the need of CD immobilization onto a semiconductor (TiO2) and expanded the scope of suitable Ni ligands. This quasi-homogeneous system was applied to catalyze a broad range of carbon–heteroatom cross-couplings. I further investigated the mechanism of a C-S cross-coupling, optimized the reaction conditions, and expanded the substrate scope. New CDs were synthesized and a series of characterizations were performed to explore their influence on the photocatalytic performance. In Chapter 4, CDs were tested as cheap and green visible-light-absorbing photocatalyst for E-to-Z isomerization, a reaction that follows an energy-transfer-based catalytic mechanism. The isomerization results of trans-stilbene proved the catalytic capabilities of CDs in energy-transfer reaction. Next, I showcased the potential of CDs for the photo-isomerization of ethyl (E)-3-(p-tolyl)but-2-enoate (4-3), an alkene exhibiting larger separation of the excited state energy with its Z-isomers. I further expanded the substrate scope of E-to-Z isomerization reactions and screened a collection of CDs as photocatalysts to shine light on the process of E-to-Z isomerization. Overall, I demonstrated that CDs could serve as valuable photocatalysts for complex organic transformations, enriching their applications in the field of photocatalytic organic synthesis. Their ease of preparation from abundant precursor, tunable PL properties, and superior photostability make CDs valuable alternatives for expensive metal-based photocatalysts.

Bats of the order Chiroptera are globally distributed mammals and known to be the reservoir of numerous human pathogenic viruses. The increasing emergence of infectious disease outbreaks in the past century has also enhanced the research on bats and their associated viruses. The underlying project of this thesis also aims to assess the prevalence of viruses in Sri Lanka and their possible impact on public health issues. The focus of this thesis was the virological study of bats inhabiting Wavul Galge cave (Koslanda, Sri Lanka). The bats of the species Miniopterus fuliginosus, Rousettus leschenaultii,Rhinolophus rouxii, Hipposideros speoris and Hipposideros lankadiva live in one of the largest sympatric colonies that are known in Sri Lanka. Three major aims were pursued in this work. First, three bat sampling sessions were conducted in Wavul Galge to collect different sample types from all bat species. In this context, the bat sampling was optimized for future studies to do structured and reasonable samplings by considering virological, microbial, zoological, ecological and further aspects. Second, a variety of molecular virus detection methods was applied to estimate the prevalence of different viruses in the collected bat samples. Coronaviruses and Paramyxoviruses were identified in the bat species M. fuliginosus and R. leschenaultii. Furthermore, a full genome sequence of an α-Coronavirus derived from M. fuliginosus was assembled from NGS data. Also, a virome analysis of M. fuliginosus bats was obtained from mNGS data revealing the presence of further viruses. With this, viral sequences related to Astroviridae, Coronaviridae, Iflaviridae, Paramyxoviridae, Picornaviridae and unclassified Riboviria were detected. Third, the obtained data were further used for in-depth sequence analysis, phylogenetic reconstruction and evaluation of the human pathogenic potential. Based on the available data, this human pathogenic potential was assessed to be rather low in all novel virus strains. Summarized, the presented results of this thesis represent the first evidence of different viruses in cave-dwelling bat species from Sri Lanka. Further bat studies in this cave and other locations will increase the knowledge of virus prevalence in different bat species from Sri Lanka.

This thesis introduces methods to efficiently generate and analyze time series data of many-body systems. While we have a strong focus on biomolecular processes, the presented methods can also be applied more generally. Due to limitations of microscope resolution in both space and time, biomolecular processes are especially hard to observe experimentally. Computer models offer an opportunity to work around these limitations. However, as these models are bound by computational effort, careful selection of the model as well as its efficient implementation play a fundamental role in their successful sampling and/or estimation.

Especially for high levels of resolution, computer simulations can produce vast amounts of high-dimensional data and in general it is not straightforward to visualize, let alone to identify the relevant features and processes. To this end, we cover tools for projecting time series data onto important processes, finding over time geometrically stable features in observable space, and identifying governing dynamics. We introduce the novel software library deeptime with two main goals: (1) making methods which were developed in different communities (such as molecular dynamics and fluid dynamics) accessible to a broad user base by implementing them in a general-purpose way, and (2) providing an easy to install, extend, and maintain library by employing a high degree of modularity and introducing as few hard dependencies as possible. We demonstrate and compare the capabilities of the provided methods based on numerical examples.

Subsequently, the particle-based reaction-diffusion simulation software package ReaDDy2 is introduced. It can simulate dynamics which are more complicated than what is usually analyzed with the methods available in deeptime. It is a significantly more efficient, feature-rich, flexible, and user-friendly version of its predecessor ReaDDy. As such, it enables---at the simulation model's resolution---the possibility to study larger systems and to cover longer timescales. In particular, ReaDDy2 is capable of modeling complex processes featuring particle crowding, space exclusion, association and dissociation events, dynamic formation and dissolution of particle geometries on a mesoscopic scale. The validity of the ReaDDy2 model is asserted by several numerical studies which are compared to analytically obtained results, simulations from other packages, or literature data.

Finally, we present reactive SINDy, a method that can detect reaction networks from concentration curves of chemical species. It extends the SINDy method---contained in deeptime---by introducing coupling terms over a system of ordinary differential equations in an ansatz reaction space. As such, it transforms an ordinary linear regression problem to a linear tensor regression. The method employs a sparsity-promoting regularization which leads to especially simple and interpretable models. We show in biologically motivated example systems that the method is indeed capable of detecting the correct underlying reaction dynamics and that the sparsity regularization plays a key role in pruning otherwise spuriously detected reactions.

Bei dieser rechtswissenschaftlichen Arbeit handelt es sich um eine Doktorarbeit, die im Jahr 2022 von der Freien Universität Berlin angenommen wurde. Sie beschäftigt sich mit dem Rechtsinstitut der Hinterlegung und dabei insbesondere mit der Grenzziehung zwischen der Hinterlegung als Erfüllungssurrogat und der Hinterlegung als Sicherheitsleistung. Aufbauend auf dieser Differenzierung wird untersucht, inwiefern die Hinterlegung im rechtlichen Bereich des Kontrahierungszwangs bereits angewendet wird und - mit Blick auf die Zukunft - angewendet werden könnte. Im Zentrum stehen dabei die Entscheidungen „Orange-Book-Standard“ des Bundesgerichtshofs aus 2011 und „Huawei/ZTE“ des Europäischen Gerichtshofs aus 2015.

North Korean defectors, who mostly go through China to reach South Korea, are treated as illegal economic migrants by the Chinese government. Due to their illegal status, they commonly face exploitation and are often repatriated to North Korea, where they face prosecution. This is frequently termed the ‘North Korean defector issue’ in the South Korean media. This thesis deals with the influence of ideology on the framing of the North Korean defector issue. It analyzes the South Korean media discourse on the North Korean defector issue in the context of the South-South conflict based on a type of critical discourse analysis, which combines a discourse-historical approach with a framing approach. The South Korean discourse on North Korean defectors is part of the larger discourse on how to deal with North Korea, including the North Korean human rights issue. This discourse is characterized by the division between South Korean conservatives and progressives, who have distinct conceptions of the South Korean identity. This thesis argues that the historical development of the 20th century is vital in explaining the ongoing South-South division. While progressives view the North primarily as a kin nation for future unification, conservatives perceive North Korea as an enemy. Progressives tend to emphasize humanitarianism in dealing with issues related to North Korea, whereas conservatives highlight human rights. Moreover, progressives construct North Korean defectors as people who fled for economic and/or political reasons. In contrast, conservatives frame them as refugees and human rights victims. Progressives view the North Korean defector issue as a matter of national sovereignty, diplomacy, human rights, and humanitarianism. Conservatives mainly perceive it as a matter of human rights and international law. Although the dispute between both ideological camps continues, the human rights frame has become dominant within South Korea and the international community. This thesis shows that the ideological affiliation of the Chosun Ilbo and the Hankyoreh has significantly influenced the framing of the North Korean defector issue, which indicates that they have been a key actor in reinforcing the South-South conflict. Moreover, the North Korean defector issue has been politicized by both camps. However, approaches advanced by both ideological camps have not solved the North Korean defector issue. Therefore, a new approach, which can be promoted by both ideological camps, should be explored. The hegemonic human rights frame should be critically approached and challenged.

Die vorliegende Studie widmet sich der Technik- und Sozialgeschichte im Nordpontus und geht der Frage nach, wie Innovationen im 4. Jt. v. Chr. gesellschaftlich wirksam werden. Im Besonderen erfolgt durch Auswerten von Wissenskomplexen um die Herstellung von Keramik, Metall und Textil eine Bezugnahme auf die Themen Standardisierung, Technik und Distinktion. Es zeigt sich, dass Vorformen der Institutionalisierung von Gesellschaften durch eine Typisierung und Habitualisierung von Herstellungstechniken und Produktionsweisen ausgeprägt werden und damit soziale Komplexität stimuliert wird. Eng ist damit ein veränderter Möglichkeitsrahmen für die Formierung politischer Systeme verbunden.

In psychological research on stereotypes, a seemingly paradox finding has demonstrated the complexity of their effects: Under specific circumstances, people judge members of negatively stereotyped groups more positively than others, and their communications with them can be overly positive (e.g., Biernat & Vescio, 2002; Crosby & Monin, 2007). Two central theoretical perspectives have been put forward to explain this finding, focusing on a cognitive-perceptual and motivational explanation for positive biases, respectively. The cognitive-perceptual perspective argues that positive biases emerge when members of a negatively stereotyped group are compared to a lower standard than others (shifting standards, e.g., Biernat & Manis, 1994). As a result, their work can more easily surpass the standard of a good performance, leading to more positive judgments. Alternatively, positive biases may result from a concern to be or appear to be prejudiced towards members of a negatively stereotyped group (e.g., Harber, 1998). The motivational perspective argues that this concern can lead to an overcorrection in one’s behavior so that it becomes overly positive in interactions with members of negatively stereotyped groups (positive feedback bias; Harber, 1998; failure-to-warn phenomenon; Crosby & Monin, 2007). The aim of the present dissertation is to focus on positive biases in the German school context and test whether (1) a positive bias in judgments and communications of teacher students exists towards students with Turkish names, and (2) whether either of two major theoretical perspectives could adequately predict under which conditions it occurs. To address these aims, four studies were conducted which focused on only one of the two perspective at a time (Studies 1 and 3) or compared the predictive power of the two perspectives in a single study design (Studies 2 and 4). As part of these studies, we tested for the presence of a positive bias in non-communicated judgments of as well as communications with students (advice, feedback) and required evaluations regarding various characteristics of students (academic track suitability, different aspects of writing skills, suitability of a proposed course load in upper secondary school). In Study 1, we used a behavioral checklist design to examine how many positive achievement-related behaviors n = 280 teacher students required in order to recommend a 4th grade student to the academic track. In a between-subjects design, we varied the origin (German vs. Turkish) and gender (male vs. female) of the student’s name. Moreover, the judgment standard was manipulated between subjects, that is, whether participants were asked to indicate when they would suspect (minimum) vs. be certain of (confirmatory) the student’s suitability for the academic track. Based on the Shifting Standards Model (Biernat & Manis, 1994), we expected that participants would require fewer behaviors for the student with a Turkish (vs. German) and male (vs. female) name when a minimum judgment standard was invoked (positive bias), but more behaviors when a confirmatory judgment standard was invoked (negative bias). In line with these predictions, we found that teacher students showed a positive bias towards students with a Turkish name under a minimum judgment standard and tended to show a negative bias under a confirmatory judgment standard. However, no effect of students’ gender was observed. Therefore, this study was the first to show that the judgment standard influences the bias in judgments made about Turkish-German students. In Study 2, we examined the evaluations of supposed student essays by n = 132 teacher students. In a 2 (evaluation condition: non-communicated judgments vs. feedback; between-subjects) x 2 (origin of name: Turkish vs. German; within subjects) design, teacher students read two target essays supposedly written by two male students and either provided feedback or a non-communicated judgment. In line with the predictions of the motivational perspective as well as prior research (e.g., Harber, 1998), teacher students showed a positive feedback bias towards students with a Turkish name when judging aspects of the essay that related to the quality of content, but not those that related to the mechanics of writing. Unexpectedly, the positive bias also extended to non-communicated judgments. This latter finding is more in line with the cognitive-perceptual perspective, though other patterns of results did not suggest this mechanism. Specifically, participants with higher self-esteem showed the positive bias to a lesser extent in their open-text responses. In sum, this study contributed to existing research by demonstrating a positive bias in feedback given to and judgments of Turkish-German adolescents by teacher students for the first time. Moreover, it demonstrates that further research is needed to understand which mechanism may drive such a positive bias. Study 3 represented a conceptual replication of two studies originally showing the failure-to-warn phenomenon based on the motivational perspective (Crosby & Monin, 2007). In it, we examined whether n = 174 teacher students would warn a student who proposed an overly ambitious course plan for upper secondary school to a lesser extent when the student had a Turkish vs. German name. In this situation, (rightfully) warning a student may signal low expectations and is therefore expected to be avoided by teacher students due to a concern about prejudice. However, our analyses showed that teacher students’ advice was equivalent for students with Turkish and German names, and this finding did not vary depending on participants’ self-esteem or contingency of self-esteem on other’s approval. Therefore, we did not replicate the failure-to-warn phenomenon in the German school context. Lastly, Study 4 again examined feedback given by n = 319 teacher students in a 2 (origin of students’ name: Turkish vs. German) x 2 (response scale format: objective vs. subjective) x 2 (cognitive load: yes vs. no) between-subjects design. Moreover, we examined both content- and mechanics-related feedback and measured participants’ self-esteem. By including multiple factors in the study design for which the two theoretical perspectives imply different predictions, this study was meant to provide a better understanding of the underlying mechanism. However, we did not find evidence of a positive bias in feedback given to students with a Turkish name in this study. Rather, participants’ feedback to students with a Turkish vs. German name did not differ, and the moderators included in the design did not change these results. Overall, Study 4 did not replicate the results from Study 2 and did not provide further indication as to the mechanism underlying positive biases when they do exist. Overall, the four studies paint an inconsistent picture of positive biases in Germany. Whereas we find support for both the cognitive-perceptual mechanism (Study 1) and the motivational mechanism (Study 2), the pattern of results is not firmly in support of one perspective across studies. Particularly the lack of positive biases in Studies 3 and 4 speak against both a motivational and a cognitive-perceptual mechanism. On the one hand, these inconsistent results could be explained by the absence of necessary, not yet articulated conditions for positive biases that are present in the U.S., but absent in Germany. Alternatively, differences in the mode and time of data collection may explain why the results diverge between the studies presented in this dissertation. Importantly, the inconsistency of the results highlights the usefulness of further specification of both theoretical perspectives, particularly with regards to the generalizability to sociocultural contexts outside the U.S. and the integration of different theoretical perspectives on the same phenomenon. While the work presented here cannot provide a conclusive answer to the question whether positive biases exist in Germany, its findings can contribute to a better understanding of boundary conditions of positive biases.

Polycomb Repressive Complex 2 (PRC2) is a major epigenetic regulator in animals and plants which represses transcription of genomic loci by trimethylation on lysine 27 of histone H3 (H3K27me3), concerning genes and repetitive elements. This molecular activity was linked to several pivotal developmental processes, including maintenance of tissue identities as well as induction of flowering in response to environmental cues. While the function of PRC2 has been extensively studied in higher organisms, its importance in lower eukaryotes, such as unicellular photoautotrophic eukaryotes, remains largely undescribed. To extend this knowledge, the present study aims to determine the role of PRC2 in the single celled, photosynthetic active red alga Cyanidioschyzon merolae. For this, the PRC2 loss-of-function mutant ∆E(z) was employed, which is deficient in H3K27me3, caused by deletion of CMQ156C encoding the PRC2 catalytic subunit ortholog Enhancer of zeste E(z). To evaluate whether H3K27me3 is involved in protecting the genome integrity via repetitive element (RE) silencing, the transcriptome of ∆E(z) was compared to 10D wild type (WT) cells. As a result, H3K27me3 absence lead to increased transcription of subtelomeric regions predominantly constituted of REs. Next, I hypothesized, that PRC2 relevance might evolve in stress situations and, moreover, memory thereof. In the context of testing this assumption, a heat stress memory protocol was established, that in fact demonstrated the alga’s ability to generate a heat stress memory (termed thermomemory). More specifically, cells pre-exposed to a priming heat stimulus were largely resistant to a subsequent lethal heat exposure. Furthermore, transcriptome analysis revealed a set of genes showing revised transcriptional responses (termed trainability) upon sequential heat exposure. Interestingly, a trainable genomic heat shock locus spanning five genes could be identified. Furthermore, the chloroplast (CP) genome exhibited substantial trainability, which was most pronounced for genes encoding vast parts of the CP genetic system machinery. Finally, a substantial contribution of PRC2 to thermomemory was detected by including ∆E(z) in the memory protocol, reflected in aberrant physiological and transcriptional responses. In summary, PRC2 in C. merolae serves the function of maintaining genome integrity via RE silencing and moreover it contributes to heat stress responses, and memory thereof. A putative link between both functions may be found in the lasting, partially H3K27me3-dependent RE repression detected in response to heat. The presented results contribute to our understanding of how PRC2 function has developed during the course of evolution. As in C. merolae PRC2 combines its importance in genome protection, found predominantly in unicellular organisms, with control of memory processes described mainly in multicellular species, this situation may represent a gradual shift in PRC2 function and reflect the phylogenetic position of C. merolae situated at the border between plants and lower eukaryotes.

For evidence-based policy-making, reliable information on socio-economic indicators are essential. Sample surveys have a long tradition of providing cost-efficient information on these indicators. Mostly, there is a demand for the quantity of interest not only at the level of the total population, but especially at the level of sub-populations (geographic areas or sociodemographic groups) called areas or domains. To gain insights into these sub-populations, disaggregated direct estimators can be used, which are calculated solely on area-specific survey data. An area is regarded as ’large’ if the sample size is large enough to enable reliable direct estimates. If the precision of the direct estimates is not sufficient or the sample size is even zero, the area is considered as ’small’. This is particularly common at high spatial or socio-demographic resolutions. Small area estimation (SAE) is promising to overcome this problem without the need for larger and thus more costly surveys. The essence of SAE techniques is that they ’borrow strength’ from other areas to improve their predictions. For this purpose, a model is built on survey data that links additional auxiliary data and exploits area-specific structures. Suitable auxiliary data sources are administrative and register data, such as the census. In many countries, such data are strictly protected by confidentiality agreements and access to population micro-data is a challenge even for gatekeeper organisations. Thus, users have an increased interest in SAE estimators that do not require population micro-data to serve as auxiliary data. In this thesis, new methods in the absence of population micro-data are presented and applications on socio-economic highly relevant indicators are demonstrated.

Since different SAE models impose different data requirements, Part I bundles research combining unit-level survey data and limited auxiliary data, e.g., aggregated data such as means, which is a common data situation for users. To account for the unit-level survey information the use of the well-known nested error regression (NER) model is targeted. This model is a special case of a linear mixed model based on several assumptions. But how can users proceed if the model assumptions are not fulfilled? In Part I, this thesis provides two new approaches to deal with this issue. One promising approach is to transform the response. Since several socio-economically relevant variables, such as income, have a skewed distribution, the log-transformation of the response is an established way to meet the assumptions. However, the data-driven log-shift transformation is even more promising because it extends the log by an additional parameter and achieves more flexibility. Chapter 1 introduces both transformations in the absence of population micro-data. A particular challenge is the transformation of the small area means back to the original scale. Hence, the proposed approach introduces aggregate statistics (means and covariances) and kernel density estimation to resolve the issue of lacking population micro-data. Uncertainty estimation is developed, and all methods are evaluated in design- and model-based settings. The proposed method is applied to estimate regional income in Germany using the Socio-Economic Panel and census data. It achieves a clear improvement in reliability, and thus demonstrates the importance of the method. To conveniently enable further applications, this new methodology is implementedin the R package saeTrafo. Chapter 2 describes the various functionalities of the package using publicly available income data. To increase user-friendliness, established unit-level models under transformations and their uncertainty estimations are implemented and the most suitable method is automatically selected. For some applications, however, it is challenging to find a suitable transformation or, more generally, to specify a model, particularly in the presence of complex interactions. For this case, machine learning methods are valuable as a transformation is not necessarily required nor a model needs to be explicitly specified. The semi-parametric framework of mixed effects random forest (MERF) combines the advantages of random forests (robustness against outliers and implicit model-selection) with the ability to model hierarchical dependencies as present in SAE approaches. Chapter 3 introduces MERFs in the absence of population micro-data. As existing random forest algorithm require unit-level auxiliary population data, an alternative strategy is introduced. It adaptively incorporates aggregated auxiliary information through calibration-weights to circumvent unit-level auxiliary data. Applying the proposed method on opportunity costs of care work for Germany using the Socio-Economic Panel and census data demonstrates the gain in accuracy in comparison to both direct estimates and the classical NER model.

In contrast to methods using a unit-level sample survey, Part II focuses on the well-known class of area-level SAE models requiring direct estimates from a survey while using (once again) only aggregated population auxiliary data. This thesis presents two particularly relevant applications of this model class. Chapter 4 examines regional consumer price indices (CPIs) in the United Kingdom (UK), contributing to the great interest in monitoring inflation at the spatial level. The SAE challenge is to construct model-based expenditure weights to generate the regional basket of goods and services for the twelve regions of the UK. They are estimated and constructed from the living cost and food survey. Furthermore, available price data are linked to the SAE estimated baskets to produce regional CPIs. The resulting CPI series are closely examined, and smoothing techniques are applied. As a result, the reliability improves, but the CPI series are still too volatile for policy use. However, our research serves as a valuable framework for the creation of a regional CPI in the future. The second application also explores the reliability of the disaggregated estimation of a politically and economically highly relevant indicator, in this case the unemployment rate. The regional target level are the functional urban areas in the German federal state North Rhine-Westphalia. In Chapter 5, two types of unemployment rates - the traditional one and an alternative definition taking commuting into account - are estimated and compared. Direct estimates from the labour force survey are linked with SAE methods to passively collected mobile network data. This alternative data source is real-time available, offers spatial flexible resolutions, and is dynamic. In compliance with data protection rules, we obtain aggregated auxiliary mobile network information from the data provider. The SAE methods improve the reliability, and the resulting predictions show that alternative unemployment rates in German city cores are lower than traditional estimated official unemployment rates indicate.

Die postnatale Kälbergesundheit wird aufgrund des unvollständig ausgebildeten Immunsystems zum Zeitpunkt der Geburt in hohem Maße von der Kolostrumversorgung bestimmt. In zahlreichen Studien konnte gezeigt werden, dass Kälber mit einem Serum-IgG-Gehalt von unter 10 g/l in den ersten 24 bis 48 Lebensstunden eine höhere Morbiditäts- und Mortalitätsrate, geringere Tageszunahmen und schlechtere Leistungen aufweisen als gut versorgte Kälber. Diese unzureichende Versorgung wird auch als „failure of passive transfer“ (FPT) bezeichnet. Trotz dieser Erkenntnis zeigen aktuelle Untersuchungen, dass viele Kälber nicht adäquat versorgt sind. Eine regelmäßige Überprüfung des Kolostrummanagements empfiehlt sich somit für jeden Betrieb. Hierbei sollte nicht nur die Kolostrumqualität, sondern auch der IgG- bzw. der Gesamteiweißgehalt im Serum der Kälber geprüft werden. Ein Gesamteiweißgehalt von über 55 g/l in den ersten Lebenstagen kann hierfür als Richtwert herangezogen werden. In der vorliegenden Studie sollte die Immunokritmethode als mögliches Verfahren zur Prüfung der Kolostrumversorgung bei Kälbern validiert werden. Dazu wurden im Zeitraum vom 06.08.2018 bis zum 21.02.2019 bei 500 Kälbern aus 50 Betrieben im Raum Niedersachen und Nordrhein-Westfalen der Immunokrit und als Referenzwert die Gesamtproteinkonzentration im Blutserum mittels Biuretreaktion im Labor bestimmt. Die erhobenen Daten weisen eine sehr hohe Korrelation zueinander auf (r = 0,89). Somit werden vorherige Studien bestätigt, in denen die Immunokritmethode bereits bei anderen Tierarten als geeignetes Verfahren zur Prüfung der Kolostrumversorgung beschrieben wird. Der hohe Arbeitsaufwand und ein fehlender Mehrwert machen dieses Verfahren für den praktischen Gebrauch jedoch wenig sinnvoll. Als signifikante Einflussfaktoren auf den Immunokrit haben sich in dieser Studie die aufgenommene Kolostrummenge innerhalb der ersten 24 Lebensstunden, die Tränketechnik, die Milchleistung, die Eisenversorgung der Kälber und die Mutterschutzimpfung der Kühe erwiesen. Ebenfalls konnte beobachtet werden, dass die Überlebensrate bei Kälbern mit einem hohen Immunokrit höher ist als bei Kälbern mit einem niedrigen Immunokrit. Die vorliegende Studie zeigt, dass die Kolostrumversorgung neugeborener Kälber von größter Bedeutung für deren Gesunderhaltung und spätere Lebensleistung ist. Es konnten signifkante Einflussfkatoren auf den Immunokrit ermittelt werden. Betriebe mit erhöhter Kälbermorbidität und -mortalität sollten diese Einflussfaktoren prüfen und so die eigene Kälberaufzucht optimieren.

Im Rahmen einer Online-Umfrage bei Dozierenden der fünf veterinärmedizinischen Bildungsstätten in Deutschland wurde der Stand der Digitalisierung in der Lehre insbesondere in den Phasen vor, während und (perspektivisch) nach Ende der COVID-19-Pandemie erfasst. Zusätzlich wurden die Dozierenden zu ihrer Bewertung von E-Learning-Ansätzen befragt. Infektionsschutzrechtliche Vorgaben während der COVID-19-Pandemie führten an vielen Hochschulen ab dem Frühjahr 2020 zu einer teilweisen bis vollständigen Umstellung von Präsenzlehre auf digitale Lehre (Marinoni et al. 2020); so auch an den veterinärmedizinischen Standorten in Deutschland. Vor dem Sommersemester 2020 hatten die Dozierenden wenig Erfahrung mit digitaler Lehre und verwendeten nahezu keine digitalen Lehrinhalte in ihren Lehrveranstaltungen. Ab dem Sommersemester 2020 kam es zu einem starken Anstieg im Einsatz digitaler Lehrmaterialien, -ansätze und -konzepte. Besonders online Live-Veranstaltungen, in denen sich Lehrinhalte schnell digitalisieren ließen, wurden umfangreich verwendet. Darüber hinaus motivierten die Erfahrungen während der COVID-19-Pandemie die Dozierenden langfristig, wenn alle COVID-19-bedingten Einschränkungen im Hochschulbetrieb wieder aufgehoben sind, vermehrt auf digitale Lehre zu setzen. Ziel ist eine vielfältige Gestaltung der digitalen Lehrstunden mit synchronen und asynchronen Lehrinhalten. Im Vergleich zum Zeitraum vor dem Sommersemester 2020 planen die Dozierenden, mehr Lehrstunden digital umzusetzen, häufiger digitale Lehrmaterialien und -ansätze einzusetzen und ihre Lehrveranstaltungen vermehrt in Blended Learning-Konzepten zu gestalten. Damit hat die COVID-19-Pandemie die digitale Lehre in der Veterinärmedizin wirksam gefördert und den Digitalisierungsprozess beschleunigt. Gleichzeitig werden die Grenzen der Digitalisierung in der veterinärmedizinischen Lehre deutlich. Es herrscht Konsens unter den Dozierenden, dass sich nicht alle Lehrinhalte in der Veterinärmedizin digitalisieren lassen. Dies betrifft insbesondere die in der TAppV verankerte praktische Ausbildung. Die fehlende Vermittlung praktischer Fertigkeiten sowie die verminderte soziale und kommunikative Interaktion mit und zwischen Studierenden stellen zentrale Schwächen digitaler Lehre dar. Dementsprechend eignen sich praktische Übungen schlechter für den Einsatz digitaler Lehre als Seminare und Vorlesungen; sie wurden während der COVID-19-Pandemie und werden voraussichtlich in der Zukunft geringer digital gestaltet. Auch wenn ein gewisses Maß an Präsenzlehre in der Veterinärmedizin als unerlässlich angesehen wird, können digitale Lehrmaterialien und -ansätze die Lehrqualität und den Lernerfolg bei den Studierenden verbessern. Zusätzlich wird die erhöhte Flexibilität für Dozierende und Studierende mit der einhergehenden größeren Reichweite, Möglichkeit zur Kooperation und Individualisierung der Lehre wertgeschätzt. Der Fokus der Digitalisierung der veterinärmedizinischen Lehre liegt daher auf der optimalen Kombination aus Präsenz- und digitaler Lehre, dem Blended Learning. Folglich werden klassische Präsenzveranstaltungen und Blended Learning langfristig die überwiegenden Lehrkonzepte darstellen. Vollständig digitale Lehrveranstaltungen, wie sie während der COVID-19-Pandemie aufgrund rechtlicher Vorgaben notwendig waren, werden zukünftig nur eine untergeordnete Rolle spielen. Neben den in der Veterinärmedizin spezifischen Herausforderungen, die durch die praktischen Ausbildungsinhalte bedingt sind, hemmen externe Rahmenbedingungen den Digitalisierungsprozess der veterinärmedizinischen Lehre. Die fehlende Gleichstellung von digitaler Lehre und klassischer Präsenzlehre in Bezug auf das Lehrdeputats- und Kapazitätsrecht sowie urheberrechtliche und datenschutzrechtliche Fragestellungen stellten die größten Hemmnisse für die Dozierenden dar. Mangelnde digitale Kompetenzen und eine negative Einstellung gegenüber digitaler Lehre konnten während der COVID-19-Pandemie vermutlich überwunden werden, externe Herausforderungen bestehen aber weiterhin. Die Dozierenden wünschen sich daher eine stärkere Unterstützung der Gesetzgebung. Die Bundes- und Landesregierungen stehen in der Verantwortung, entsprechende Verordnungen anzupassen und übergeordnete Regelungen zur digitalen Lehre festzulegen. Des Weiteren stellt die Erhöhung des Stellenwerts der Lehrleistung in der Hochschulkarriere einen notwendigen Faktor dar, um den Digitalisierungsprozess voranzutreiben. Diese Ergebnisse verdeutlichen den Handlungsbedarf der Regierung und Hochschulen im Digitalisierungsprozess der Lehre. Auch wenn die Dozierenden nach dem Ende COVID-19-bedingter Einschränkungen einem verstärkten Einsatz digitaler Lehre positiv gegenüberstehen, müssen langfristige Lösungen für bestehende Herausforderungen und Hemmnisse gefunden werden.

Bei der primär immunbedingten Polyarthritis (IPA-I) des Hundes handelt es sich um eine entzündliche Gelenkerkrankung nicht-infektiöser Ätiologie, gekennzeichnet durch eine Synovitis mit oftmals systemischen Krankheitszeichen wie Lethargie, Arthralgie und Fieber. Akute Phase Proteine werden zur Diagnose, Prognose und zur Überwachung des Therapieerfolges bei verschiedensten Erkrankungen eingesetzt. Zur Verwendung als Biomarker bei IPA-I des Hundes gibt es bisher nur wenige Daten. Das Ziel dieser prospektiven Studie war es, das C-reaktive Protein (CRP), Haptoglobin und Albumin im Verlauf bei Hunden mit IPA-I zu messen, mit dem klinischen Verlauf unter Therapie zu vergleichen und ihren Nutzen bezüglich Diagnostik, Monitoring und Prognose zu evaluieren. Dazu wurden von Oktober 2014 bis Dezember 2019 an der Klinik für kleine Haustiere der Freien Universität Berlin 21 Hunde mit IPA-I, bei denen eine vollständige diagnostische Abklärung inkl. Gelenkpunktion, Synoviaanalyse, Blutbild, Blutchemie, Tests auf Infektionserkrankungen, Röntgen, Sonografie und regelmäßige Verlaufskontrollen möglich waren, eingeschlossen. Bei jedem Kontrolltermin wurden klinische und Laborkontrollen durchgeführt und die CRP-, Haptoglobin-, und Albumin- Konzentrationen im Serum gemessen. Alle Patienten wurden bei Erstvorstellung (T0) beprobt. Weitere Seren wurden bei jeweils 20/21 Hunden (95,2 %) an Tag 2-7 (T1) und Tag 8-14 (T2) gesammelt. Bei 19/21 Hunden (90,5 %) wurden weitere Kontrollen in den Wochen 3–4 (T3) und bei 16/21 (76,2 %) Hunden in Woche 5-8 (T4) durchgeführt. Bei 12/21Tieren (57,1 %) erfolgten Kontrollen über die genannten Zeitpunkte hinaus. Die erhobenen Daten wurden mittels Shapiro-Wilk-Test auf Normalverteilung überprüft und deskriptiv ausgewertet. Bei nicht normalverteilten Daten wurden nicht-parametrische Tests (Wilcoxon-Test, Friedman-Test), bei normalverteilten Daten parametrische Tests (T-Test, ANOVA) angewendet. Das Signifikanzniveau wurde auf α ≤0,05 festgesetzt. Die klinischen Symptome (Dauer 1-300 Tage) bei Erstvorstellung umfassten Fieber (20/21; 95,2 %), gestörtes Allgemeinbefinden (19/20; 90,5 %), Lahmheit (14/21; 66,6 %), vermehrte Gelenkfüllung (12/21; 57,1 %), Gelenkbiegeschmerz (13/21; 61,9 %), vermehrt erwärmte Gelenke (10/21; 47,6 %), Halsbiegeschmerz/Dolenz der Wirbelsäule (4/21; 19 %). Die Röntgenaufnahmen ergaben bei 13/21 Hunden (61,9 %) einen vermehrten Kapsel-/Weichteilschatten an mindestens einem Gelenk. Zu den entzündlich veränderten Gelenken gehörten: Karpus (28/31 punktierten Karpalgelenken; 90,3 %), Knie (35/39, 89,7 %), Tarsus (24/30; 80 %), Ellenbogen (18/23; 78,2 %), Schulter (2/2). Nach Diagnosestellung erfolgte eine immunsuppressive Therapie mit Prednisolon bei allen Hunden. Zusätzlich erhielten zehn Hunde Leflunomid, drei Ciclosporin und einer Mycophenolat-mofetil. Es besserten sich daraufhin alle Hunde klinisch. Alle Hunde wurden an T0, 20/21 (95,2 %) an T1 und T2, 19/21 (90,5 %) an T3 und 16/21 (76,2 %) an T4 nachuntersucht. Bei allen Hunden war CRP an T0 erhöht (16–169 mg/l, median [m] 97,1; Leukozytenzahl [WBC] 6,7-64,7 G/l [m 15,5]; Albumin [Alb] 26,1 g/l [SD±3,4]). Im Verlauf fiel bei allen Hunden die CRP-Konzentration von T0 zu T4 ab (p<0,0001), bei der Leukozytenzahl ergab sich keine signifikante Konzentrationsänderung, während Albumin zu Beginn bei 13/21 (62 %) erniedrigt war und im Verlauf anstieg (T1: CRP 3,5-149,9 mg/l [m 26,6]; WBC 9,1-62,2 G/l [m 20,8]; Alb 28,2 g/l [SD±3,3 g/l]; T2: CRP 0,3-88,6 mg/l [m 7,4]; WBC 6,7-73,4 G/l [m 19,3]; Alb 29,3 g/l [SD±2,6]); T3: CRP 0,2-100,1 mg/l [m 3,0]; WBC 8,1-53,9 G/l [m 17,0], Alb 30,9 g/l [SD±2,4]). An T4 lag CRP bei 19/21 Hunden im Referenzbereich (0,5-38,5 mg/l [m 1,8]; WBC 7,0-37,5 G/l [m 12,8]; Alb 30,7 g/l [SD±1,8 g/l]). Bei 8/21 Hunden (38,1 %) kam es zum Rezidiv. Das CRP stieg signifikant an (19,9-159,4 mg/l [m 66,3]) und fiel nach erfolgreicher Therapie erneut ab. Die Konzentrationsänderungen der Leukozytenzahl, Albumin waren nicht signifikant. Keiner der Hunde zeigte einen erhöhten Haptoglobin-Wert an T0. Die Differenzen des Haptoglobins zwischen T0 zu T4 waren statistisch nicht signifikant (p= 0,93) und auch im Verlauf konnte kein signifikanter Unterschied des Haptoglobins an den verschiedenen Zeitpunkten festgestellt werden. Limitationen der Studie sind die relativ kleine Studienpopulation, die unterschiedlichen Zeitpunkte der Probenentnahme und die Anzahl der Proben je Tier. Basierend auf den Daten der vorliegenden klinischen Studie wurde deutlich, dass CRP bei an IPA-I erkrankten Hunden als Biomarker hinsichtlich Diagnostik und Monitoring Verwendung finden kann. Der schnelle Konzentrationsanstieg des CRPs während der Verlaufsmessungen spiegelt die ablaufende Akute-Phase-Reaktion und somit die Krankheitsaktivität der IPA-I, insbesondere im Vergleich zur Leukozytenzahl und Albumin, am besten wider. Es zeigt schnell und präzise das Ansprechen auf die Therapie und das Auftreten von Rezidiven an und wird nicht durch die Glukokortikoidtherapie beeinflusst. Der Nutzen von Hp bei der IPA-I konnte nicht nachgewiesen werden.

Die chirurgische Frakturversorgung mit resorbierbaren Osteosynthesematerialien auf Magnesiumbasis hat sich in der Vergangenheit für manche Indikationen als vorteilhaft gegenüber nichtresorbierbarem Osteosynthesematerial wie Titan oder resorbierbaren Osteosynthesematerialien auf Polymerbasis erwiesen. Die Limitation für den routinemäßigen Einsatz ist das bei der Degradation frei werdende Wasserstoffgas, was in vorangegangenen Studien zu subkutanen und intraossären Gasansammlungen um das Implantat führte. Um einen stabilen Knochen-Implantat-Kontakt während der Frakturheilung zu gewährleisten und im späteren Verlauf der Degradation keine nachteiligen Effekte im Knochen um das Implantat zu erhalten, wurde mittels Legierung und Beschichtung von magnesiumbasierten Implantaten versucht, die Degradation zu verlangsamen. Ziel der Dissertation war es somit, erstmals im Großtierversuch das Degradationsverhalten sowie die Reaktion des umgebenden Knochens auf ZX00-Implantate mit und ohne PEO-Oberflächenmodifikation nach 6, 12 und 18 Monaten Implantationszeit zu untersuchen und gegenüberzustellen. Dafür wurden die Implantate in das Os frontale von Minipigs eingebracht und nach der jeweiligen Standzeit nach Explantation der Implantate mit umliegenden Knochen radiologisch und histomorphometrisch analysiert. Das Residualvolumen konnte in der Micro-CT-Untersuchung aufgrund der Dichte des Materials berechnet werden (SV/TV). In der histomorphometrischen Untersuchung wurde ebenfalls der noch nicht resorbierte Anteil an Implantationsmaterial mittels der Fläche des Implantatquerschnitts (SA/TA) berechnet. Die Ergebnisse beider Untersuchungsmethoden zeigen, dass das Residualvolumen der PEOoberflächenbeschichteten Implantate zu jedem Zeitpunkt höher ist und somit die Beschichtung erfolgreich die Degradation verlangsamt. Signifikante Unterschiede zeigten sich in der radiologischen Auswertung nach 12 und 18 Monaten Implantationszeit (p < 0,001), in der histomorphometrischen Untersuchung nach 12 Monaten (p < 0,001). Im Vergleich des Residualvolumens (SV/TV) zeigte sich nach 18 Monaten ein signifikant (p < 0,001) niedrigerer Wert als nach 6 Monaten bei den unbeschichteten Implantaten. Bei den beschichteten Implantaten war durch die verlangsamte Degradation der Unterschied nicht signifikant (p = 0,25). Durch die verlangsamte Degradation der PEO-Oberflächenbeschichtung und der daraus resultierenden langsameren Freisetzung von Gas sollte die Bildung von Hohlräumen im Knochen reduziert und somit die Osseointegration verbessert werden. Radiologisch und histomorphometrisch wurden jeweils zwei Bereiche von der ursprünglichen Implantatgrenze bis 0,5 mm und bis 1,5 mm auf den Anteil an mineralisiertem Knochen innerhalb der Auswertungsbereiche (BV/TV in der radiologischen, BA/TA in der histomorphometrischen Untersuchung) untersucht. Die radiologischen Ergebnisse zeigen einen signifikant höheren BV/TV (p < 0,001) in beiden Bereichen nach 18 Monaten Implantationszeit bei den PEObeschichteten Implantaten. Histomorphometrisch ergaben sich die gleichen Tendenzen. Im Vergleich des Volumenanteils an mineralisiertem Knochen (BV/TV) um die Implantate nach 6 und 18 Monaten Implantationszeit zeigten sich in beiden Untersuchungsbereichen die gleichen Tendenzen. Zwischen ursprünglicher Implantatgrenze und 0,5 mm Umgebung zeigt sich ein signifikant höherer mineralisierter Knochenanteil (p = 0,035) nach 18 Monaten beim beschichteten Implantat. Der BV/TV-Anteil nimmt hingegen bei den unbeschichteten Implantaten im Untersuchungsbereich bis 1,5 mm zur ursprünglichen Implantatgrenze im gleichen Untersuchungszeitraum signifikant ab (p = 0,034). Weshalb der Unterschied des Knochenvolumens erst zum letzten Untersuchungszeitpunkt auftritt, bleibt unklar. Ausgehend von den Ergebnissen dieser Studie wird vermutet, dass die PEO-Oberflächenbeschichtung im Untersuchungszeitaum bis 18 Monate post implantationem die Osseointegration durch verminderte Bildung von Hohlräumen verbessern kann.

A new CT generation with a detector coverage of 16 cm and a rotation speed of 0.32 seconds / rotation makes it possible to obtain high quality images of equine cervical articular process joint C4/5 in motion. This work further confirms that dynamic CT imaging has the potential to provide new insight into the movement pattern of articular motion segments, which may be of value for the examination of APJ and other joint conditions. The study provides a first step in the investigation of the potential of dynamic 3D CT in veterinary medicine, a technique that has only begun to be explored and leaves much room for refinement prior to its introduction in routine practice. Additionally, the ex-vivo study did not show any significant association between fusion of a cervical motion segment and change in range of motion of the adjacent vertebral segments. However, apart from adjacent segment disease due to an increase in range of motion of adjacent vertebral segments, adjacent degenerative disc disease is commonly diagnosed in other species after vertebral fusion. Increased pressure acting on the intervertebral joint after adjacent vertebral fusion may also affect the intervertebral disc in the equine patient. Further research investigating the implications of vertebral fusion on the intervertebral pressure in the equine cervical spine is indicated. For the first time, a surgical approach to stabilize complete luxation of the atlantoaxial articulatiom in an American quarter horse yearling has been successfully performed. A complete atlantoaxial luxation has historically been associated with a very poor prognosis for athletic function or even survival, especially in cases in which attempts of manual reduction were unsuccessful or caused damage to the spinal cord (Fürst 2019; Vaughan et al. 1973; Guffy et al. 1969). Nine months postoperatively, bony fusion between C1 and C2 was radiographically evident, the horse did not show any neurological deficits or apparent reduction in cervical range of motion. More cases are required to evaluate the surgical technique and the long-term outcome. A small case series revealed that arthroscopic removal of osteochondral fragments in the equine cervical APJs can be performed safely, with a good prognosis for return to athletic function in 3 horses with low-grade lameness and mild neurologic deficits. Arthroscopic removal of APJ fragments may be considered as an approach to treat these lesions, but a clear link between clinical signs and the fragments has not yet been proven. Surgical treatment of a larger number of horses will help to further establish the clinical significance of these osteochondral fragments in the cervical articular process joints.

The thesis combines four papers that introduce a coherent framework based on MERFs for the estimation of spatially disaggregated economic and inequality indicators and associated uncertainties. Chapter 1 focusses on flexible domain prediction using MERFs. We discuss characteristics of semi-parametric point and uncertainty estimates for domain-specific means. Extensive model- and design-based simulations highlight advantages of MERFs in comparison to 'traditional' LMM-based SAE methods. Chapter 2 introduces the use of MERFs under limited covariate information. The access to population-level micro-data for auxiliary information imposes barriers for researchers and practitioners. We introduce an approach that adaptively incorporates aggregated auxiliary information using calibration-weights in the absence of unit-level auxiliary data. We apply the proposed method to German survey data and use aggregated covariate census information from the same year to estimate the average opportunity cost of care work for 96 planning regions in Germany. In Chapter 3, we discuss the estimation of non-linear poverty and inequality indicators. Our proposed method allows to estimate domain-specific cumulative distribution functions from which desired (non-linear) poverty estimators can be obtained. We evaluate proposed point and uncertainty estimators in a design-based simulation and focus on a case study uncovering spatial patterns of poverty for the Mexican state of Veracruz. Additionally, Chapter 3 informs a methodological discussion on differences and advantages between the use of predictive algorithms and (linear) statistical models in the context of SAE. The final Chapter 4 complements the previous research by implementing discussed methods for point and uncertainty estimates in the open-source R package SAEforest. The package facilitates the use of discussed methods and accessibly adds MERFs to the existing toolbox for SAE and official statistics.

Overall, this work aims to synergize aspects from two statistical spheres (e.g. 'traditional' parametric models and nonparametric predictive algorithms) by critically discussing and adapting tree-based methods for applications in SAE. In this perspective, the thesis contributes to the existing literature along three dimensions: 1) The methodological development of alternative semi-parametric methods for the estimation of non-linear domain-specific indicators and means under unit-level and aggregated auxiliary covariates. 2) The proposition of a general framework that enables further discussions between 'traditional' and algorithmic approaches for SAE as well as an extensive comparison between LMM-based methods and MERFs in applications and several model and design-based simulations. 3) The provision of an open-source software package to facilitate the usability of methods and thus making MERFs and general SAE methodology accessible for tailored research applications of statistical, institutional and political practitioners.

Welche Anforderungen stellten Militär, Medizin, Politik und Gesellschaft an die nervliche Belastbarkeit von Offizieren im Krieg in Deutschland zwischen 1890 und 1939? Wie gingen sie mit psychisch erkrankten Offizieren um? Wie nahmen die Betroffenen selbst ihre Erkrankungen wahr? Und welche Auswirkungen hatten diese auf ihr Selbstbild und ihre Lebensläufe? Gundula Gahlen untersucht diese Fragen vom Kaiserreich über die Weimarer Republik bis zur NS-Zeit. Ihre Studie füllt eine Lücke, da sich die bisherige Forschung zu kriegsbedingten psychischen Erkrankungen vor allem mit Mannschaftssoldaten beschäftigte, obwohl das Offizierskorps zu Beginn des 20. Jahrhunderts in Deutschland eine herausgehobene Herrschafts- und Werteelite war und zeitgenössische Leitvorstellungen von Willensstärke und Männlichkeit verkörperte.

Arbuscular mycorrhizal (AM) fungi have gained immense research interest due to their symbiotic relation with roots of most terrestrial land plants. Diverse positive effects on plant health and fitness, as well as a high ecological relevance for many other below-and aboveground processes have been recognized. Despite growing research ambitions, sufficient knowledge on drivers and their relative impacts on AM fungal communities at varying scales and ecosystems is lacking. Very little attention has been paid to the interrelation of the spatial structure of AM host plants (here meaning the small- scale distribution of host plant individuals or populations) and AM fungal community dynamics, although deeper insights could move forward the development of theoretical community frameworks applicable to these important endosymbionts. The work presented in this thesis aimed to study the effects of host plant spatial structure for the establishment of mycorrhizal symbiosis as well as for AM fungal diversity and community composition. To do so, controlled experiments mimicking micro- landscapes of AM fungal habitats were conducted and compared with observational data from temperate forests in Germany. In the experiments, we used meta-community designs to test the responses of root colonization, AM fungal diversity and community composition to levels of habitat connectance or habitat heterogeneity. We assayed rates of root colonization across forests sites differing in AM-associating plant cover. For assessing the importance of further spatio-temporal parameters and host-specificity we surveyed AM fungal communities within one of the forest sites over two years. As expected, we observed a consistent pattern of higher rates of root colonization at a higher proximity of host plants, which in the case of the field study was a higher cover of AM- associating woody plants and in the case of the experiment treatments a higher connectance of host plant patches. There were generally no clear effects of habitat structure on AM fungal diversity and community composition in both the field and the experimental study. In the field, the main finding was that spatial parameters, followed by host identity, more strongly affected AM fungal assemblages than temporal parameters. In the experiments, we observed within-experimental-unit differences of beta-diversity between pairs of long- and short-distance patches as well as between pairs of different habitat quality, which rendered those communities less predictable. In conclusion, we present empirical evidence for a co-variation of AM plant host structure and AM fungal abundance. These findings are of importance for the restoration or management of natural forest habitats, as well as for sustainable agriculture. Furthermore, this work supports previous findings of high stochasticity in AM fungal communities, highlighting the need for further research into spatial scale-specific drivers of this important organism group.

The relevance of mental health problems has accumulated over the last few years in light of the potential detrimental effects of the worldwide pandemic. The burden of mental ill-health with its various negative long-term consequences for children, family and the high indirect and direct costs for society raises the essentiality to make mental health promotion a central issue. General scientific research on mental health problems among children and adolescence has largely relied on variable-centred methodology (e.g., multiple regression, factor analysis, cumulative risk index) by focusing mainly on explaining relationships between variables (i.e., linear association and single relationship). However, this method assumes homogeneity of mental health problems and risk factors for mental ill-health within a population, however there is likelihood for diversity of individual patterns for types of problems and exposure to multiple risk factors. The current dissertation uses a person-centred approach, a complementary and promising method to identify subpopulations with heterogenous patterns of mental health problems and to investigate different risk subgroups. The aims of the present work include the exploration and modelling of patterns and transitions of mental health problems with a focus on the importance of parental factors, the examination of multiple risks and the manifestation of mental disorders. In Study I, the central question was: “How do mental health problems differ across individuals and time”. Based on a sample of almost 1,300 children and adolescents (age range 8 – 26), a three-class solution identified a normative class, an emotional problem class, and a multiple problem class. The findings confirm the stability of mental health problems as common rather than atypical. According to Latent transition analysis, the majority of the sample (91.6%) did not change latent class membership over time, while 14.7% of individuals showed a persistent pattern of mental health problems across time. Co-occurring internalizing and externalizing problems (i.e., multiple problem class) were found in 11.3% of the sample and diagnoses of mental disorders were more likely to be reported by individuals in the emotional problem or multiple problem class. Taken together, implications for prevention can be formulated based on the findings including the importance of early, continuous, and gender-sensitive preventive interventions to ameliorate the mental health burden for the young and their family. In Study II, the mediating role of parenting dimensions between parental personality and adolescent mental health problems was investigated with a cross-sectional sample of 4,258 German adolescents (48.7% male, 11–17 years). The results underline and extend previous indications of direct associations between parental personality and their children’s mental health problems by highlighting the adverse role of neuroticism with increased externalizing and internalizing problems. Furthermore, results confirmed a positive effect of parental warmth and behavioural control on externalizing and internalizing problems and a negative effect of psychological control on both problems. An important finding includes the mediating role of parenting. Results showed negative associations between parental neuroticism as well as psychological control and adolescent mental health and highlighted their mutually reinforcing negative effect. To summarise, a good entry point for effective preventive intervention to ameliorate mental health problems during adolescence could include early screening of personality traits that may result in maladaptive parenting practises and therefore could be a guidance towards a better preparation for parenthood. In Study III, a longitudinal survey data of 10,853 German children, adolescents and young adults was used to examine 27 robust risk and protective factors for mental health across multiple domains (i.e. individual, family, social) to identify four subgroups of individuals with different risk profiles: a basic-risk (51.4%), high-risk (23.4%), parental-risk (11.8%) and social-risk class (13.4%). Results confirmed the crucial role of family-specific risk factors across the extracted classes and point towards parents as a key target to develop effective interventions to promote children’s health. Risk classes are associated with negative mental health outcomes (e.g., mental health problems, depression, ADHD). Gender differences were found. In conclusion, results contribute to previous research by stressing the effect of multiple risk factor on youth mental health. Future approaches to ameliorate mental health problems should include a combination of strengthening protective factors, involving parents and targeting schools. The findings of the present dissertation which include the importance of co-occurring mental health problems (Study I) and the examination of multiple risk factors (Study III) as well as the central role of parents (Study II), highlight the necessity to intervene early, continuous and on different levels of society. Implications and future research directions are discussed, focusing on the societies responsibility to guarantee that the most vulnerable and most important members have a chance for a healthy development. While important steps have been taken toward mental health prevention, there is still a lot of potential for research and practise.

Anaplastic lymphoma kinase (ALK) is a driving oncogene in neuroblastoma and mutated in 8% - 10% of neuroblastoma cases. Despite high-risk neuroblastoma patients being treated with an intensive multimodal therapy, up to 60% of these patients relapse and the 10-year overall survival rate for high-risk cases is less than 40%. Therefore, targeted therapies are under investigation for paediatric use and might be considered as first-line therapy. Many cases of acquired therapy resistance to targeted therapies have been reported, including cases during paediatric clinical trials of ALK inhibitors. Hence a deeper understanding of resistance development is required and investigated within this thesis. The first part of this thesis focused on the identification of genes associated with ALK inhibitor (ALKi) resistance using in vitro neuroblastoma systems. A CRISPR/Cas9 knockout screen in the ALK-mutated neuroblastoma cell line SH-SY5Y identified the tumour suppressor gene NF1 to be associated with resistance to the ALK inhibitors ceritinib and lorlatinib. The hypothesis, whether a loss of NF1 can confer ALKi resistance in ALK-mutated neuroblastoma was investigated by generating isogenic NF1 knockout (KO) models using the CRISPR/Cas9 system in respective neuroblastoma cell lines. It was observed, that an NF1 KO leads to an ALKi-resistant phenotype as well as increased RAS/MAPK pathway signalling.

Moreover, gene alterations were also investigated in tumour and liquid biopsy samples of patients with relapsed, ALK-driven neuroblastoma, who have been treated with ALK inhibitors in paediatric clinical trials. These patients had initially responded well to the treatment but eventually relapsed and de novo inactivating mutations of NF1 were detected in these relapse tumour samples using sequencing approaches. Thus, genes which were found associated with ALKi resistance in neuroblastoma cell lines were also observed in relapse samples of patients with ALK-driven neuroblastoma treated with ALK inhibitors.

The second part of this thesis focused on the role of NF1 loss in ALKi resistance, its effect on ALK downstream signalling and new collateral sensitivities. This role was investigated by perturbation experiments and subsequent ELISA assays to quantify protein phosphorylation, and thus pathway activity. NF1 knockout cell line models showed increased downstream signalling of the RAS/MAPK pathway. The perturbation data was used with a prior known signalling network topology to model the downstream signalling response in NF1-deficient neuroblastoma cells. The model indicated an absent ERK-RAF feedback loop and implied a possible MEK inhibitor sensitivity. When NF1-deficient neuroblastoma cells were exposed to the MEK or RAF inhibitors, increased inhibitor sensitivities were observed.

Overall, this thesis employed phenotypic screens as well as isogenic cell lines as suitable models to investigate and elucidate clinical observations. Hence, it was successful in demonstrating an association of genetic NF1 alterations with ALKi resistance in cell line models, in the same manner as in a functional experimental recapitulation of observed NF1 alterations in clinical cases of ALKi resistant ALK-driven neuroblastoma. This thesis underlined how modelling of signalling pathways can be used to reveal new collateral sensitivities and gives some mechanistic insights as well as new potential therapy options, which may potentially impact clinical practice and clinical trial design. The identified collateral sensitivities represent promising therapy options for patients with relapsed ALK-mutated and ALK-inhibitor resistant neuroblastoma harbouring loss of NF1 mutations, which are worth being investigated in clinical trials, that cover sequential treatment as well as a pre-emptive combination therapy with ALK and MEK inhibitors.

Hydrogen bonds (H-bonds) are an essential interaction in membrane proteins. Embedded in complex hydrated lipid bilayers, intramolecular interactions through the means of hydrogen bonding networks are often crucial for the function of the protein. Internal water molecules that occupy stable sites inside the protein, or water molecules that visit transiently from the bulk, can play an important role in shaping local conformational dynamics forming complex networks that bridge regions of the protein via water-mediated hydrogen bonds that can function as wires for the transferring of protons as a part of the protein’s function. For example, the membrane-embedded channelrhodopsins which are found in archaea are proteins that couple light induced isomerization of a retinal chromophore with proton transfer reactions and passive flow of cations through their pore. I contributed to the development of a new algorithm package that features a unique approach to H-bond analyses. I performed analyses of long Molecular Dynamics (MD) trajectories of channelrhodopsin variants embedded in hydrated lipid membranes and large data sets of static structures, to detect and dissect dynamic hydrogen-bond networks. The photocycle of channelrhodopsins begins with absorption and isomerization of the retinal from an all-trans state to a 13-cis state and followed by the deprotonation of the Schiff base. Thus, the retinal is found in the epicenter of the analyses. Through the use of 2-dimensional graphs of the protein H-bond networks I identified protein groups potentially important for the proton transfer activity. Local dynamics are highly affected by point mutations of amino acids important for function. The interior of channelrhodopsin C1C2 hosts extensive networks of protein and H-bonded-water molecules, and a never reported before, network that can bridge transiently the two retinal chromophores in channelrhodopsin dimers. In a recently identified inward proton pump, AntR, I applied centrality measures on MD trajectories of the homology model I generated, to assess the communication of the amino acid residues within the networks. I detected a frequently sampled long water chain that connects the retinal with a candidate proton acceptor, as well as a conserved serine in the vicinity of the retinal chromophore plays a significant role in the connectivity and communication of the H-bond networks upon isomerization. A similar water bridge is sampled in independent simulations of ChR2, where a participant for the proton donor group connects to the 13-cis,15-anti retinal. Proton transfer reactions often take place through certain amino acids, forming patterns. I analyzed H-bond patterns or motifs in large hand-curated datasets of static structures of α-transmembrane helix proteins, organized according to the superfamilies they belong, their function and an alternative classification method. The presence of motifs in TM proteins is tightly related to their families/superfamilies of the host protein and their position along the membrane normal.