Germany, which had long denied its role as a country of immigration (Constant et al., 2012), is today, after the US, the second most popular destination country among immigrants (McAuliffe & Triandafyllidou, 2021). Over the past decades, waves of immigration – to Germany in particular, and to Europe more broadly – have presented societies with numerous new challenges. These challenges exist both at the macro level in terms of social and educational policies to meet the needs of a pluralistic society, and at the micro level concerning how to live together in a culturally and linguistically diversified society (Malik, 2015; Vertovec, 2007b). The overlap between integration and education policies is large, and educational institutions are considered an influential context for immigrant families’ adjustment to the host country (OECD, 2017). In particular, the large achievement gaps between children based on their socioeconomic and immigrant backgrounds have highlighted the need for measures to address inequalities in children’s early years of life (Anders et al., 2012; Kluczniok & Mudiappa, 2019). Accordingly, in recent years, preschools and primary schools have become a greater focus of research and policy. However, it is questionable to what extent these institutions provide an inclusive environment and quality education to children who experience disadvantages due to their social and migration backgrounds. Immigrant parents can provide valuable insight into their children’s formal learning environment in the early years. However, there are limited studies that give immigrant parents a voice and portray their everyday realities. Despite the fact that immigrant parents have high educational aspirations for their children (B. Becker & Gresch, 2016), they experience acculturation stress in the host country, including their children’s schools, due to language and cultural barriers (Jäkel & Leyendecker, 2008; Norheim & Moser, 2020). Moreover, they have been observed to have a desire for their children to develop bicultural competencies in relation to both their heritage and their host countries (Uttal & Han, 2011). Accordingly, immigrant parents have particular identity-related concerns about their children, which affect their beliefs and practices in childrearing. However, we know little about how the characteristics of different contexts influence parents’ social identities and how their social identities shape those contexts. The educational sciences have only recently recognized the relevance of spatial theories in considering issues of identity and inequality (Ferrare & Apple, 2010; Gulson & Symes, 2007a), and there are few empirical studies that apply a socio-spatial theoretical framework. Further, research on immigrant families has not adequately illustrated the relationships between different contexts and usually focuses on only one particular context, such as the home learning environment and school. The study of socio-spatial relations has been mainly limited to the home–school relationship. The linkages between these and broader societal micro and macro contexts that may interact with immigrant parents’ social identities have not been adequately explored. Therefore, this dissertation focuses on this topic and addresses the Turkish-origin community in Germany, the largest immigrant group in the country (Statistisches Bundesamt, 2022). In particular, it examines how Turkish-origin parents of preschool- and primary school-aged children (re-)construct their social identities within home–school–society relational spaces. The dissertation consists of four sub-studies based on the qualitative and quantitative interview data collected within the framework of the Inclusive Education and Social Support to Tackle Inequalities in Society (ISOTIS) project. The quantitative data comprise survey responses from Turkish parents (n = 338) with children aged 3–6 (before primary school) or aged 8–12 (in primary school). The qualitative interview study subjects were drawn from a subsample of the quantitative survey respondents and consisted of 22 mothers. The qualitative data were analyzed utilizing content analysis and included in all four studies of this dissertation. Additionally, Study 4 used a mixed methods design, and content analysis of the qualitative data was used to provide possible explanations for the results of the quantitative data, which were analyzed using (multi-group) regression analysis. Study 1 examined how mothers perceive socio-spatial school and residential segregation and how they relate this issue to the quality of their children’s education. The results showed that mothers living in neighborhoods with high immigrant populations were largely dissatisfied with the quality of their children’s education. Respondents’ concerns about their children being marginalized in a native-dense environment, as well as concerns about their children’s ethnic identity in the context of their potential ‘Germanization,’ were cited as reasons for choosing an immigrant-dense or ethnically and socially diverse school and neighborhood. Despite the fact that some respondents complained about segregation tendencies on the part of the native population, the data showed that middle-class Turkish families, in particular, use similar strategies to raise their children in native-dense environments, even though they ascribe a high value to social diversity. The perceived high educational quality of schools in these neighborhoods was also identified as an influential factor. Moreover, the results indicated not only segregation between schools but also within schools, i.e., the creation of separate classroom groups in primary schools for children from native and/or middle-class families. Study 2 investigated mothers’ perceptions and experiences related to their language use at the intersection of their ethnocultural identities in home–school–society relational spaces. The results showed that the respondents’ linguistic competencies and the value they place on the German language, and their heritage language coincide extensively with their ethnocultural identities, which are mirrored in their ethnolinguistic upbringing beliefs and practices. Parents reported how language barriers affected their parenting (e.g., parental involvement, parent–child relationship) as well as their sense of belonging to the host country (e.g., everyday discrimination) and emphasized experiencing parental stress. Some parents also pointed out that while they did not face a language barrier, symbolic boundaries between them and the native population persisted (e.g., the misconception that women wearing headscarves have little knowledge of German). Regardless of their own German language skills, the parents placed great importance on their children’s German language development, which they saw as a source of success in the host country. Parents were particularly inclined to raise their children bilingually because they viewed their heritage language as an important resource for developing their children’s heritage ethnocultural identity and for enhancing the quality of parent–child interactions. Yet dynamics of inclusion and exclusion in school and society toward their heritage language, as well as the extent to which their linguistic support needs were recognized, appeared to be critical in influencing their social identities in the host country and thus their parenting within the home space. Study 3 addressed the ethnoreligious identities of immigrant mothers within home–school–society relational spaces. The findings showed that parents’ ethnoreligious identities make the home space religiously congruent with or separated from the school and societal space. Their desire to integrate into German society and to ensure that their children received high-quality education and were not marginalized in a non-family environment motivated parents to create congruent spaces (e.g., celebrating Christian festivals at home, parental involvement in Christian celebrations at school, enrolling their children in a church-run preschool). Conversely, some respondents chose contextually separate parenting approaches as a way to maintain their children’s strong religious affiliation. In addition, narratives showed that inclusive (e.g., teachers collaborating with minority parents on their religious celebrations, using interreligious pedagogical practices) and exclusive (e.g., teachers’ cultural prejudice, the perception that some preschools refused to enroll minority children) approaches in schools appeared to be closely linked to the societal space in terms of attitudes toward religious minorities. These spaces seemed to reproduce each other, influencing the ethnoreligious identities of the parents that were reflected in the home space. Thus, they also influenced parents’ beliefs and practices with regard to ethnoreligious upbringing. Finally, Study 4 was conducted to identify the relationship between Turkish immigrant parents’ perception of their children’s school climate and their life satisfaction in Germany. In addition, how this relationship varies depending on the immigrant generation of the parents (first vs. second generation) and the school level of their children (preschool vs. primary school) was investigated. Applying a mixed methods research in Study 4, an explanatory sequential design was used. Thereby, the qualitative interviews were used to further interpret the quantitative research findings. The results of the quantitative survey revealed that life satisfaction in Germany was predicted by the way parents perceived the children’s school climate. While the relationship was significant for both generations, it was stronger for second-generation parents. Further, the relationship was significant only for parents with children attending primary school. The qualitative research findings suggested that there was a high degree of overlap between perceived inequalities in school and in society. These included the sense of injustice (particularly in primary schools), the extent to which an inclusive school climate has been created, and the collaboration of schools with immigrant parents. In conjunction with the quantitative research findings on life satisfaction among Turkish families, this could potentially have implications for immigrant parents. Taken together, the present dissertation highlights the significance of socio-spatial relational theory approaches, which have been largely overlooked in educational sciences, and emphasizes such approaches’ power in portraying immigrant parents’ social identities. Accordingly, this dissertation seeks to contribute theoretical developments, as well as further concrete empirical research, for the exploration of the complex perceptions and experiences of immigrant families within and across various contexts. Moreover, it provides valuable insights for the inclusive pedagogical approaches in preschools and primary schools, as well as educational and social policies aiming to create inclusive environments in their societies.View less
Psoriasis ist eine chronisch-entzündliche Erkrankung, die außer der Haut und den Nägeln auch die Enthesen und die Gelenke betreffen kann. Durch die Fortschritte im Verständnis der Immunpathogenese der Psoriasis wurden neue hochwirksame gezielte Therapien entwickelt. Diese neuen Therapien ermöglichen individuelle Therapiekonzepte für die Betroffenen. Solche personalisierten Therapien garantieren die höchste Wirksamkeit mit den geringsten Nebenwirkungen. Die TNFα-Inhibitoren sind die ersten gezielten Therapien für Psoriasis. Darüber hinaus bietet die Entwicklung von Antikörpern gegenüber IL-12/IL-23, IL-17 und IL-23 mehr Therapiemöglichkeiten für Psoriasis. In dieser Arbeit wurde die Anwendung von den verschiedenen Klassen von Biologika (Adalimumab, Brodalumab und Ustekinumab) bei Psoriasispatienten:innen in besonderen Situationen untersucht. Das Ziel dieser Arbeit war die Unterstützung der Therapieentscheidung bei Psoriasispatienten:innen basierend auf einem klinischen Profiling.View less
Infections by gastrointestinal nematodes mandate an effective type 2 response for the parasite clearance. In line with the cross-regulatory nature of Th1 lineage specifying factors on the differentiation of Th2 cells seen at the molecular level, strong type 1 activity resulted by inflammation associated with senescence, specific genetic predisposition and co-infections with intracellular pathogens exacerbate the Th2 responses resulting in poor resistance in nematode infections. Despite reported cross-regulation, the Th1 and Th2 pathways are not mutually exclusive as polarization with IFN-g, IL-12 and IL-4 results in the generation of T-bet and GATA-3 co-expressing Th2/1 cells in vitro. Th2/1 cells are also induced naturally in nematode infections (Affinass et al., 2018; Bock et al., 2017; Peine et al., 2013). In the current study we demonstrate that the IFN-g competence progressively rises with the age of uninfected BALB/c mice displaying high resistance to nematode infection. The elevated type 1 bias in 5-10 months old compared to 2-3 months old mice resulted in poor parasite control manifested by higher female fecundity in the mature cohort infected with H. polygyrus. The poor resistance was accompanied by stronger generation and mucosal accumulation of Th2/1 hybrid cells and elevated proportions of parasite specific IFN-g producing cells. Substantiating the above findings, restriction of IFN-g availability in the priming phase of nematode infection led to improved resistance coinciding with sharp reduction in systemic and mucosal Th2/1 cells and a near complete absence of parasite specific IFN-g producing cells. Conversely, supplementation of early IFN-g availability led to impaired parasite control associated with robust expansion of Th2/1 cells and a significant rise in IFN-g producing cells in parasite specific T cell pool. Importantly, elevated IFN-g availability did not inhibit classical Th2 cells in the long run and rather promoted an accumulation of systemic GATA-3+ Teff cells in IFN-g treated BALB/c mice. The increased parasite egg production upon IFN-g treatment was traced back to the increased fitness of the L4 larvae maturating in the gut of IFN-g treated mice. In line with the findings in differently aged mice, C57BL/6 mice genetically predisposed to higher susceptibility in H. polygyrus infection more rapidly accumulate Th1 cells at steady state compared to resistant BALB/c mice. The elevated type 1 activity in C57BL/6 mice translated to greater accumulation of small intestinal Th2/1 cells post infection and poor resistance compared to BALB/c mice. However, the stark differences seen between the strains at younger age leveled out in older mice due to increased IFN-g competence and increased bias in favor of Th2/1 cells in mature BALB/c mice. Restricting IFN-g availability in C57BL/6 mice led to increased resistance thereby substantiating the significance of IFN-g in differential susceptibility across inbred lines. Overall, our findings report an age-dependent reduction in anti-nematode type 2 immunity resulted by steady state accumulation of IFN-g competent effector cells in the vertebrate host.View less
Eps15 (epidermal growth factor receptor pathway substrate 15) homology domain containing proteins (EHDs) comprise a family of dynamin-related ATPases. The four mammalian members of this family (EHD1-4) are involved in various endocytic and membrane trafficking pathways. Structural studies revealed that EHDs assemble at the surface of membranes to form ring-like filaments. Assembly on membranes was shown to stimulate the ATPase activity. In case of EHD2, ring-like oligomers were proposed to stabilize the neck of caveolae, which in turn regulates cellular fatty acid uptake. The aim of this thesis was the identification of small molecule inhibitors that modulate EHD2 function and therefore cellular fatty acid uptake. Until now, there are no known inhibitors for EHD proteins. To this end, I optimized a malachite green-based ATPase assay to be robust and reproducible for a high-throughput setup. Drug screening was then employed to identify small molecules that inhibit the liposome-stimulated ATP hydrolysis of EHDs. Since EHD2 showed only a low ATPase activity, I initially screened for inhibitors against the closely related homologue EHD4. Validated hits were subsequently evaluated for inhibition against EHD2 in an HPLC-based setup. In this way, I identified chemical compounds that inhibited the ATPase activity of EHD4 and EHD2, and validated them in different biochemical assays. Interestingly, two of these small molecules were found to increase and decrease lipid droplet size in a cell-based assay. I also identified three inhibitors that were specific to EHD4 and did not interfere with the ATPase of EHD2 and the GTPase activity of Drp1, which was used as a control. Another exciting finding in this project were discovery of two compounds that accelerated the liposome-stimulated GTPase activity of Drp1. The identified inhibitors may have future applications to explore the function of EHDand Drp1-dependent cellular signaling pathways. Furthermore, they may be developed as therapeutic agents. Finally, my assay optimizations can be used to systematically and efficiently identify inhibitors for other dynamin superfamily membersView less
When we observe a scene in our daily lives, our brains seemingly effortlessly extract various aspects of that scene. This can be attributed to different aspects of the human visual system, including but not limited to (1) its tuning to natural regularities in scenes and (2) its ability to bring different parts of the visual environment into focus via eye movements. While eye movements are a ubiquitous and natural behavior, they are considered undesirable in many highly controlled visual experiments. Participants are often instructed to fixate but cannot always suppress involuntary eye movements, which can challenge the interpretation of neuroscientific data, in particular for magneto- and electroencephalography (M/EEG). This dissertation addressed how scene structure and involuntary eye movements influence the extraction of scene and object information from natural stimuli. First, we investigated when and where real-world scene structure affects scene-selective cortical responses. Second, we investigated whether spatial structure facilitates the temporal analysis of a scene’s categorical content. Third, we investigated whether the spatial content of a scene aids in extracting task-relevant object information. Fourth, we explored whether the choice of fixation cross influences eye movements and the classification of natural images from EEG and eye tracking. The first project showed that spatial scene structure impacts scene-selective neural responses in OPA and PPA, revealing genuine sensitivity to spatial scene structure starting from 255 ms, while scene-selective neural responses are less sensitive to categorical scene structure. The second project demonstrated that spatial scene structure facilitates the extraction of the scene’s categorical content within 200 ms of vision. The third project showed that coherent scene structure facilitates the extraction of object information if the object is task-relevant, suggesting a task-based modulation. The fourth project showed that choosing a centrally presented bullseye instead of a standard fixation cross reduces eye movements on the single image level and subtly removes systematic eye movement related activity in M/EEG data. Taken together, the results advanced our understanding of (1) the impact of real-world structure on scene perception as well as the extraction of object information and (2) the influence of eye movements on advanced analysis methods.View less
We begin this thesis with a discussion of problems from geometry and combinatorics, to which methods from equivariant algebraic topology have been successfully applied in the past.
The generalised Nandakumar & Ramana~Rao problem (due to Karasev, Hubard, & Aronov and Blagojević & Ziegler) asks whether given a full-dimensional compact convex body K in R^n, n-1 continuous real functions on the space of all full-dimensional compact convex bodies in R^n and a natural number m, one can always find a partition of K into m convex pieces of equal volume such that the value of each function is equal on all the pieces of the partition.
Inspired by this problem and recent parameterised generalisations of mass partition types by several groups of researchers, we formulate a parameterised version of the Nandakumar & Ramana~Rao problem, where we aim to equipart j>n-1 functions, but are allowed to choose a convex body K from some family parameterised by a vector bundle E over a CW-complex B.
After we make the notion of "parameterised by the vector bundle E'' precise in Chapter~II, we follow the strategy developed by Karasev, Hubard & Aronov to formulate a topological criterion for the existence of solutions to the parameterised Nandakumar & Ramana Rao problem. Due to the limitations of our topological methods, we restrict our attention to the case when m equals some prime p.
Chapter~III contains a brief overview of various standard algebraic topology results that we use extensively in the later chapters.
In Chapter~IV we extend the results of Jaworowski concerning Fadell-Husseini indices of sphere bundles, equipped with free fibrewise action of the cyclic group Z/Z_p, by considering the symmetric group S_p. Next, we compute the index of the fibrewise configuration space Fconf(p,E) of p distinct points with respect to S_p in the case of vector bundle E of an odd rank. In the case when E has an even rank, we provide bounds on the index, showing that the upper bound is tight in some cases. Then we change the group that acts on E, and compute the index of the space Fconf(p, E) with respect to cyclic group action in the special case when E admits two linearly independent nowhere zero sections.
In Chapter~V we use these computations to find a partial solution to the parameterised Nandakumar & Ramana~Rao problem. For any pair of a vector bundle E and a prime p, we describe a range of j such that the parameterised Nandakumar & Ramana~Rao has a solution for the family of convex bodies parameterised by E, the desired number p of pieces in partition and a choice of j appropriately defined continuous functions. Finally, we apply these computations to the case of tautological bundles over the Grassmannians.View less
The function of non-coding RNA sequences is largely determined by their spatial conformation. This is the secondary structure of the molecule, which is formed by Watson–Crick interactions between nucleotides. Hence, modern RNA alignment algorithms routinely take structural information into account. Essential tasks for discovering yet unknown RNA families and inferring their possible functions are the structural alignment of RNAs and the subsequent search of the derived structural motifs. These tasks demand a lot of computational resources, especially for aligning many long sequences, and it therefore requires efficient algorithms that utilize modern hardware when available. A subset of the secondary structures contains pseudoknots, which are overlapping interactions that add additional complexity to the analysis and are often ignored in available software.
In this thesis, I present LaRA 2 and MaRs, two SeqAn-based software tools that implement algorithms for finding sequence-structure motifs in genomic sequences. In contrast to other programs, my tools can handle arbitrary pseudoknots. They use multithreading for parallel execution and are implemented in modern C++ code for maximal longevity and performance.
LaRA2 is significantly faster than comparable software for accurate pairwise and multiple alignments of structured RNA sequences. It uses a new heuristic for computing a lower boundary to the solution and employs vectorization techniques for speeding up the time-critical parts of the algorithm.
MaRs can be applied in a workflow right after LaRA2 and derives sequence-structure motifs from the structural alignments. The motifs are descriptors of the RNA sequences’ properties and drive the search for homologs in genomic sequences. MaRs employs a bidirectional index on the genomic sequences and an optimized multithreaded search strategy for finding the matches really fast. The use of a thread pool, effective pruning strategies, and a low memory footprint ensure that MaRs is capable of processing extremely large data sets.View less
Climate change, antibiotic resistances and environmental pollution are growing threats. Therefore, finding alternatives for fossil resources and discovery of new pharmaceuticals grows more important every day. Natural compounds and their in vivo production pathways proved to be a possible solution to overcome those problems. Optimized microbial hosts can serve as sustainable production platforms for various compounds as it is done for penicillin since many years. The first research topic of this thesis are borneol dehydrogenases, enzymes which convert borneol to camphor. Enantiomerically pure camphor has numerous applications in cosmetic, pharmaceutical, and chemical industry. Thus, enantioselective borneol dehydrogenases would be an attractive candidate to achieve enantiomerically pure camphor. To better understand the differences of enantioselective and unselective borneol dehydrogenases we solved the structures of two selective borneol dehydrogenases from Salvia rosmarinus and Salvia officinalis using X-ray crystallography and cryo-electron microscopy. The obtained structures were compared to the previously solved structure of the unselective borneol dehydrogenase of Pseudomonas sp. TCUHL1. The second focus of this thesis are terpene synthases, a class of enzymes responsible for the cyclization of linear terpene precursors. The products of terpene synthases are interesting candidates for the chemical and pharmaceutical industry due to their diverse characteristics and properties. Latest advances in genome sequencing enabled the discovery of many new and diverse terpene synthases from various organisms. We report on the discovery of two terpene synthases from Coniophora. puteana, Copu5 and Copu9, that not only have identical product profiles, but also show high yields in an optimized Escherichia coli strain. Main product of both enzymes is (+)-δ-cadinol that has been shown to have cytotoxic effect on MCF7 cells and could be used as a new and sustainable anti-tumor drug. To investigate their properties and gain deeper understanding into their function, we attempted to crystallize and biochemically characterize Copu5 and Copu9.View less
One of the great societal challenges of today is the fight against diseases which reduce life expectancy and lead to high economic losses. Both the understanding and the addressing of these diseases need research activities at all levels. One aspect of this is the discovery and development of tool compounds and drugs. Tool compounds support disease research and the development of drugs. For about 20 years, the discovery of new compounds has been attempted by screening small organic molecules by high-throughput methods. More recently, X-ray crystallography has emerged as the most promising method to conduct such screening. Crystallographic fragment-screening (CFS) generates binding information as well as 3D-structural information of the target protein in complex with the bound fragment. This doctoral research project is focused primarily on the optimization of the crystallographic fragment screening workflow. Investigated were the requirements for more successful screening campaigns with respect to the crystal system studied, the fragment libraries, the handling of the crystalline samples, as well as the handling of the data associated with a screening campaign. The improved CFS workflow was presented as a detailed protocol and as an accompanying video to train future CFS users in a streamlined and accessible way. Together, these improvements make CFS campaigns a more high-throughput method, offering the ability to screen larger fragment libraries and allowing higher numbers of campaigns performed per year. The protein targets throughout the project were two enzymes and a spliceosomal protein-protein complex. The enzymes comprised the aspartic protease Endothiapepsin and the SARS-Cov-2 main protease. The protein-protein complex was the RNaseH-like domain of Prp8, a vital structural protein in the spliceosome, together with its nuclear shuttling factor Aar2. By performing the CFS campaigns against disease-relevant targets, the resulting fragment hits could be used directly to develop tool compounds or drugs. The first steps of optimization of fragment hits into higher affinity binders were also investigated for improvements. In summary, a plethora of novel starting points for tool compound and drug development was identified.View less
The aim of this dissertation is to better understand Roman grand strategy by analyzing imperial policy in a single province, Lower Germany, and during a particular time period, from the reign of Augustus to that of Hadrian. Despite the local—and, hence, limited— approach, this method lends itself to broader conclusions. On the one hand, examining closely the development and defense of this area— the edge of the Roman Empire’s military territory on the European continent’s northwest— helps to compare and contrast policies carried out in other frontier provinces. Hence, one can scrutinize, confirm, or modify broad, general theses of imperial defense and grand strategy, such as that of Edward Luttwak. On the other hand, Germania Inferior, despite the small extension of its territory, had an outsized military and strategic importance. Emperors often visited the province, and its troops played crucial roles in the conquest and upkeep of Britain and in the later reinforcement of the Danube garrisons. As such, an analysis of Lower German defense—and of troop movements in and out of the province— is inevitably linked with the broader study of Roman grand strategy proper.
Since Roman Lower Germany was heavily militarized, the purely military component of grand strategy, which included constant campaigns of limited scope beyond the Rhine, became intertwined with a political component. The Rhine armies and its commanders became essential players in the dangerous game of imperial politics. The diplomatic component played a role insofar as there were alliances—often shifting, sometimes broken— with tribes and kingdoms beyond the empire’s borders. And, as Lower Germany became further integrated into the Roman imperial structure over time, the area’s economy developed considerably, even if it remained mostly a peripheral province.
For both emperors and legates, ruling Lower Germany involved the complex issue of incorporating the allied, native Batavians into the Roman imperial structure. The extraordinary status of this remarkable, warrior people— at once fiercely loyal to the emperor as the core of his personal bodyguard and partially independent from Rome in their distant domains—sheds light on the Romans’ practice of grand strategy. This applies especially in terms of the simultaneous use of both direct and indirect rule, even within a single province.View less
It is incumbent on scholars of Arabic studies and Islamic studies who deal with manuscripts to understand pre-modern Arabic scribal practices. This thesis aims to improve our understanding of two aspects of Arabic scribal practices from the third/ninth-fourth/tenth centuries: the paratexts of manuscripts and the elements that help establish clarity and correctness. The study of the paratexts includes the title page, the introductory section, and the colophon. Regarding elements that help establish clarity and correctness, this thesis pays attention to the use of diacritical points and vowels, the cancellation of dittographies, the insertion of omissions, and the methods of preventing and correcting text mistakes. This thesis also analyzes the collation process and how it is marked in the manuscripts. The methodology of this study is to synthesize the normative sources that discuss these elements of scribal practice and then use the findings of this analysis on a selection of manuscripts.View less
Radicals play a pivotal role in nature and are involved in many biochemical processes. However, until the late 20th century only minor attention was given to single electron processes in synthetic organic chemistry, due to the persistent notion of being difficult to control. With the development of new synthetic approaches to access such reactive open-shell intermediates in a practical fashion, radical chemistry has gained renewed interest. Photoredox catalysis (PRC) has emerged as the cornerstone in accessing these reactive open-shell intermediates under mild conditions. Key to the success of these strategies is the ability of chromophores to harvest visible light and reach long-lived excited states. Subsequently, the excited photocatalytic species can activate intermediates or reagents via single electron transfer (SET), energy transfer (ET), or hydrogen atom transfer (HAT) to yield radicals and enable chemical transformations. The mechanism of such photocatalytic systems often includes multiple catalytic species and reagents, which are actively involved in the catalytic cycle and render mechanistic investigations complicated. State-of-the-art methodologies to investigate photocatalytic systems mainly focus on the properties of the excited state species and consecutive quenching interaction with reagents, catalysts or intermediates. A more holistic picture of the overall process can be acquired via in situ monitoring techniques (Chapter 4). The value of real-time monitoring for gaining mechanistic insights was demonstrated during the development of a photocatalytic benzyl ether cleavage (Chapter 9). Due to their high stability, benzyl ethers are commonly used protecting groups in carbohydrate and natural product syntheses, though commonly utilized harsh deprotection strategies with poor functional group tolerance render them typically unattractive for multistep organic synthesis. Upon visible light irradiation, 2,3-dichlor-5,6-dicyano-1,4-benzoquinone (DDQ) reaches a highly oxidizing, long-lived excited triplet state (DDQ*), capable of oxidative cleavage of benzyl ethers.
A combination of DDQ and tert-butyl nitrite (TBN) cleaved benzyl groups from monosaccharides under ambient atmosphere and visible light irradiation with high functional group tolerance. Real-time monitoring using LED-NMR spectroscopy gave insights in the crucial role of TBN and light. The scale-up of light promoted reactions is typically detrimental to the efficiency of photocatalytic reactions, due to poor light penetration. Careful optimization of the reaction conditions for photooxidative debenzylations was required to access a deprotection methodology applicable on the gram scale (Chapter 6). The facile access to reactive open-shell intermediates enabled by photocatalysis has led to a myriad of new synthetic approaches, including photoredox catalyzed cross-coupling reactions. This is achieved using a combination of nickel and noble metal photocatalysts (PC). A more sustainable alternative to commonly used expensive and homogeneous iridium- and ruthenium polypyridyl complexes was found in graphitic carbon nitrides (gCN). The ability of CN-OA-m in combination with a nickel complex was showcased in an etherification and extended to the coupling of aryl iodides with thiols (Chapter 8). In situ IR-monitoring was applied for detailed kinetic analysis of the developed semi-heterogeneous system and the state-of-the-art photocatalyst tris(2-phenylpyridine)iridium(III) on a model O-arylation reaction. This indicated that different photocatalysts can result in different mechanistic scenarios, that result in the same product (Chapter 7). Incorporating fluorine into organic scaffolds increases the compounds physicochemical properties, such as lipophilicity and metabolic stability, resulting in improved active pharmaceutical ingredients and agrochemicals. Hence, the development of new safe and simple fluorination methodologies is of interest. A divergent benzylic radical fluorination reaction, initiated via a charge transfer complex that does not require visible-light activation, selectively yielded either benzyl fluorides or α-fluorophenylacetic acids depending on the conditions (Chapter 5). Charge transfer complex mediated in situ generation of a highly reactive radical species enabled hydrogen atom transfer (HAT) as well as single electron transfer (SET), solely depending on the pKa of the phenylacetic acid starting material.View less
Der Dissertation liegt die übergreifende Frage zugrunde, unter welchen Bedingun-gen sich Lehrkräfte auf offene Lernsettings wie das Freie Explorieren und Experimentieren (FEE) einlassen. Im Rahmen einer Interventionsstudie wurde untersucht, inwiefern schulische Rahmenbedingungen und persönliche Faktoren von Lehrkräften die Implementation innovativer, geöffneter Lehr-Lernformen beeinflussen. Den theoretischen Rahmen für die Untersuchung bilden (u.a.) das Konzept des FEEs, die Persönlichkeits-System-Interaktionen Theorie (PSI) und die Selbstbestimmungs-theorie (SDT). Die qualitative Erhebung umfasste eine Stichprobe von neun Grundschullehrkräften und wurde in einem PRE-INTER-POST-Design durchgeführt. Die Auswertung der Daten erfolgte mit der inhaltlich strukturierenden qualitativen Inhaltsanalyse. Die Ergebnisse der Untersuchung zeigen, dass es im Wesentlichen persönliche Fak-toren der Lehrkräfte sind, die die Einführung und Umsetzung der geöffneten Unter-richtsform FEE beeinflussen. So erweisen sich individuelle Selbstkompetenzen, motivationale Orientierungen und die Selbststeuerungsfähigkeit der Lehrkräfte als zentrale Schaltstellen für den Umgang mit der Herausforderung, den eigenen Unterricht zu öffnen. Es zeigt sich, dass ein hohes Professionswissen, die Fähigkeit zum Selbstwachstum und eine klare Autonomieorientierung bedeutsame Gelingensbe-dingungen für die Öffnung des Unterrichts darstellen. Die Ergebnisse der Studie zeigen auch, dass sich ein der Situation angemessenes professionelles pädagogisches Handeln mit der Zeit entwickeln und verändern kann.View less
The respiratory system is composed of different tissues with their respective cell types that together work in concert to perform air conductance and gas exchange. With the advent of single-cell RNA-sequencing (scRNA-seq), it is now possible to comprehensively interrogate the function of each individual cell in homeostatic and diseased states. In this dissertation, various roles of epithelial, mesenchymal, and immune cell types of the respiratory system in idiopathic pulmonary fibrosis (IPF) and corona virus disease 2019 (COVID-19) were investigated with scRNA-seq.
IPF is a chronic interstitial lung disease characterized by the progressive scarring of the lung parenchyma. Previous studies that surveyed the cellular landscape of IPF lungs utilized explant lungs that reflect end-stage fibrosis. To uncover disease mechanisms of airway cell types in early-stage fibrosis, air-liquid interface (ALI) cultures of primary cells taken from newly diagnosed IPF patients were used. This identified proinflammatory epithelial cells, profibrotic basal cells, and primed fibroblasts as early-stage drivers of IPF. Treatment with antifibrotic compounds nintedanib, pirfenidone, and saracatinib fail to completely ameliorate the identified signatures.
With the emergence of the COVID-19 pandemic and its extensive public health burden, it was imperative to understand the molecular mechanisms of viral entry and disease pathology to identify potential risk factors and therapeutic targets. In the early stages of the pandemic, viral entry factors ACE2, TMPRSS2, and FURIN were found to be expressed by a transient secretory cell type (differentiating from secretory to ciliated cell) of the airway mucosa and by alveolar type 2 cells of the alveolar epithelium. With further investigation of severe COVID-19, the early-stage of COVID-19 infection characterized itself with a hyperactivated immune response mediated by proinflammatory macrophages. On the other hand, late-stage COVID-19, especially those with acute respiratory distress syndrome (ARDS), was characterized by an accumulation of profibrotic macrophages and activated myofibroblasts that drove pulmonary scarring and fibrosis.
Although IPF and COVID-19 are different diseases by their own right, they share a commonality in aberrant wound healing responses. Both diseases are characterized by tissue inflammation that is followed by a profibrotic phase. Unlike in IPF where the tissue remodeling is progressive and chronic, COVID-19 ARDS-associated fibrosis undergoes a resolution phase. Future studies comparing the cellular and transcriptional landscape of both conditions in early and late stages of disease will uncover pathogenic mechanisms and therapeutic targets of lung fibrosis.
The application of high-resolution transcriptomic profiling techniques such as scRNA-seq permits the interrogation of individual cell types and their direct contribution to the development of diseases. Moreover, it allows the comparison and transfer of identified pathomechanisms across different pulmonary diseases and, in doing so, provides deeper and generalizable insights. As this field continues to evolve, it will undoubtedly continue to provide a deeper understanding of respiratory diseases.View less
Biopolymers self-assemble generating dynamic and complex functional materials that carry out sophisticated tasks. Nature has been a source of inspiration for chemists to create artificial analogs that mimic biopolymer self-assembly. In contrast to peptides and DNAs, carbohydrates are less understood at the molecular level and therefore have rarely been employed as scaffolds to construct self-assembling materials using bottom-up approaches. To date, carbohydrates’ potential in supramolecular chemistry remains mostly untapped. In this thesis, I established structure-property correlations for oligosaccharides and then translated this knowledge into design principles to access self-assembling carbohydrate materials. The use of non-natural monosaccharides and bottom-up approaches were central to deeply understand and design synthetic carbohydrate materials. In Chapter 2, I developed synthetic routes to fluorinated monosaccharide building blocks (BBs) and employed these BBs to assemble a broad collection of complex fluorinated glycans using Automated Glycan Assembly (AGA). Fluorination was exploited as a method to manipulate the hydrogen bonds of cellulose, a polysaccharide with high propensity to crystallize. The subtle role of the substitution pattern and position of the fluorine atom was investigated using X-ray diffraction analysis (XRD). In the second part of Chapter 2, I explored the use of fluorinated glycans as NMR probes. First, 19F-labelled glycans served for structural analysis via NMR revealing the tendency of some oligosaccharides to adopt helical conformations. Last, 19F-labelled Lewis antigens, a class of biologically relevant glycans, were employed to study their binding to proteins and to monitor in real-time enzymatic reactions. In Chapter 3, I developed a bottom-up approach to study the self-assembly and the chirality of supramolecular carbohydrate materials. In the first part, I employed a simple disaccharide that self-assembles into helical fibers to study the transfer of chirality across scales. Site-specific modifications identified key non-covalent interactions stabilizing the assembly. In the second part, I translated the bottom-up approach to a more complex natural polysaccharide and used synthetic oligomers to understand chirality transfer across scales in cellulose. Synthetic D- and L-cellulose oligomers were found to assemble into platelets with controlled dimensions that further aggregate into bundles, displaying chiral features directly connected to their monosaccharide composition. The insertion of L-Glc units in the sequence of D-Glc cellulose oligomers drastically impacted macroscopic properties such as solubility, crystallinity, and chirality of bundles. In Chapter 4, I presented the rational design and synthesis of a glycan adopting a stable secondary structure, challenging the common belief that glycans are not capable of folding due to their flexibility. By combining natural glycan motifs, stabilized by a non-conventional hydrogen bond and hydrophobic interactions, I designed a glycan hairpin, a secondary structure not present in nature. AGA enabled rapid access to synthetic analogs, including site-specific 13C-labelled ones, for NMR conformational analysis. Structural analysis via NMR unequivocally confirmed the folded conformation of the synthetic glycan hairpin. This work demonstrates that it is possible to program glycans to adopt defined conformations in aqueous solution. Overall, the bottom-up approaches used in this doctoral thesis allowed for a deeper understanding of the principles dictating carbohydrate self-assembly. The work presented here opens the way to future explorations of glycans as scaffolds for self-assembly or to perform complex functions as catalysis.View less
Videogames have always depicted representations of American culture, but how exactly they feed back into this culture is less obvious. Advocating an action-based understanding of both videogames and culture, this book delineates how aspects of American culture are reproduced transnationally through popular open-world videogames. Playing American proposes an analytic focus on open-world videogames' "ambient operations" and traces practices of "playing American" through the stages of videogame development, gameplay, and reception. Three case studies – concentrating on the Grand Theft Auto, Watch Dogs, and Red Dead Redemption franchises, respectively – highlight different figurations of "playing American." Thematic foci range from public discourses on systemic racism and neoliberal capitalism to the justification of real-world surveillance practices and to the reconfiguration of the Western in the digital age. Playing American provides those interested in either videogames or American culture with a fresh angle and new concepts regarding its subject matters. It demonstrates that videogames are agents of cultural reproduction that do distinct cultural work for American culture in the twenty-first century.View less
The number of refugees worldwide has been rising for years. In resettlement countries, interpreters play a central role in caring for and supporting refugees due to language barriers. In particular, qualitative studies have shown that many interpreters find themselves in a complex and precarious work situation. For example, many refugees report traumatic events they have experienced, and interpreters often translate this traumatic content in the first person. Nevertheless, unlike other professional groups, they often have no supervision or opportunities for support. In the triad of practitioners, interpreters and refugee clients, interpreters are also often confronted with different and high expectations of their role, although many have not received professional interpreter training themselves. There is little reliable research on how these difficult working conditions affect the well-being of interpreters. The present dissertation therefore comprises four studies which examine the psychological distress of interpreters as well as potential work-related risk and protective factors. Study 1 is a systematic literature review, which summarises findings from qualitative and quantitative studies on the mental health of interpreters and their work experiences in mental health settings. The majority of the studies are qualitative and were conducted in non-German-speaking countries. Based on a thematic analysis of these studies, positive and negative emotional reactions as well as stressful working conditions and difficulties within the triadic work emerged as the main themes. The quantitative studies were mainly conducted in Germany and focused predominantly on the investigation of secondary traumatic stress or work-related distress. Moreover, there are first indications of significantly higher stress and anxiety symptoms among interpreters compared to representative samples. Studies 2, 3 and 4 were conducted as part of an online survey of interpreters working with refugee clients. Throughout Germany, paid interpreters for spoken languages were invited to participate. The online survey consisted of two measurement points nine months apart and included various standardised questionnaires, for example regarding psychological distress, work-related exhaustion and job satisfaction. Participants were also asked to choose a main work setting of four (psychotherapy, counselling, medical setting and authorities) in which they were mostly working at the time of the study, and to answer questions about working conditions regarding this main work settings. The aim of study 2 was to investigate psychological distress and work-related exhaustion in interpreting when working with refugees and to identify possible work-related correlates for psychological distress and work-related exhaustion. A total of 164 interpreters from the first measurement point of the online survey were included in the analyses. The participants had significantly higher psychological distress compared to a representative sample from Germany, and about 7% showed indications of a post-traumatic stress disorder. An exploratory regression analysis showed an association between younger age and psychological distress. In addition, dissatisfaction with pay and a higher amount of traumatic content interpreted were associated with work-related exhaustion, while a link between dissatisfaction with recognition and client-related exhaustion was identified. Study 3 focused on the different work settings of interpreters. The aim of this study was to compare the work-related variables and possible changes in the well-being of interpreters between the four main work settings. A total of 158 interpreters were included in the cross-sectional analyses and 63 of them in the longitudinal analyses. The results showed that significantly more traumatic content was interpreted in counselling sessions and psychotherapy than in medical settings and authorities. The highest proportion of interpreters with a degree in interpreting worked for authorities. The results regarding the cross-sectional data showed that interpreters in counselling settings indicated significantly higher levels of psychological distress and work-related exhaustion than interpreters in authorities or in the medical setting. With regard to compassion satisfaction, there were no significant differences between work settings. Study 4 presented the development and evaluation of a questionnaire on role conflicts between interpreters and challenging aspects within the triad. The exploratory factor analysis for categorical variables resulted in 23 items over four subscales (lack of emotional boundaries between interpreter and client, devaluation by practitioners, perceived formal framework of the interpreter role, emotional distress due to the role within the triad). All subscales showed good or excellent reliability and correlational analyses gave first indications of convergent validity with psychological distress, work-related exhaustion and secondary traumatic stress. The final questionnaire (RoCo) therefore showed good psychometric properties and can help to better understand emotional stress due to role conflicts among interpreters. Overall, the results indicate an increased level of distress of interpreters working with refugee clients. In addition, there are first indications that interpreters’ distress is associated with certain working conditions. Furthermore, associations between role conflicts and psychological distress as well as work-related exhaustion and secondary traumatic stress could be identified for the first time. In summary, this points to the need for an improved work-related support structure for interpreters. In addition, the results show that collaboration between interpreters and practitioners should be strengthened in order to enable transparent communication in the triad and thus create an adequate working environment for interpreters.View less
Metal cations are essential to life. About one-third of all proteins require metal cofactors to accurately fold or to function. Computer simulations using empirical parameters and classical molecular mechanics models (force fields) are the standard tool to investigate proteins’ structural dynamics and functions in silico. Despite many successes, the accuracy of force fields is limited when cations are involved. The focus of this thesis is the development of tools and strategies to create system-specific force field parameters to accurately describe cation-protein interactions. The accuracy of a force field mainly relies on (i) the parameters derived from increasingly large quantum chemistry or experimental data and (ii) the physics behind the energy formula. The first part of this thesis presents a large and comprehensive quantum chemistry data set on a consistent computational footing that can be used for force field parameterization and benchmarking. The data set covers dipeptides of the 20 proteinogenic amino acids with different possible side chain protonation states, 3 divalent cations (Ca2+, Mg2+, and Ba2+), and a wide relative energy range. Crucial properties related to force field development, such as partial charges, interaction energies, etc., are also provided. To make the data available, the data set was uploaded to the NOMAD repository and its data structure was formalized in an ontology. Besides a proper data basis for parameterization, the physics covered by the terms of the additive force field formulation model impacts its applicability. The second part of this thesis benchmarks three popular non-polarizable force fields and the polarizable Drude model against a quantum chemistry data set. After some adjustments, the Drude model was found to reproduce the reference interaction energy substantially better than the non-polarizable force fields, which showed the importance of explicitly addressing polarization effects. Tweaking of the Drude model involved Boltzmann-weighted fitting to optimize Thole factors and Lennard-Jones parameters. The obtained parameters were validated by (i) their ability to reproduce reference interaction energies and (ii) molecular dynamics simulations of the N-lobe of calmodulin. This work facilitates the improvement of polarizable force fields for cation-protein interactions by quantum chemistry-driven parameterization combined with molecular dynamics simulations in the condensed phase. While the Drude model exhibits its potential simulating cation-protein interactions, it lacks description of charge transfer effects, which are significant between cation and protein. The CTPOL model extends the classical force field formulation by charge transfer (CT) and polarization (POL). Since the CTPOL model is not readily available in any of the popular molecular-dynamics packages, it was implemented in OpenMM. Furthermore, an open-source parameterization tool, called FFAFFURR, was implemented that enables the (system specific) parameterization of OPLS-AA and CTPOL models. Following the method established in the previous part, the performance of FFAFFURR was evaluated by its ability to reproduce quantum chemistry energies and molecular dynamics simulations of the zinc finger protein. In conclusion, this thesis steps towards the development of next-generation force fields to accurately describe cation-protein interactions by providing (i) reference data, (ii) a force field model that includes charge transfer and polarization, and (iii) a freely-available parameterization tool.View less
Auf Grundlage der vorliegenden Habilitationsschrift kann der Begriff des motorisch- und Sprach-eloquenten Hirntumors nunmehr objektiviert und genauer charakterisiert werden. Bei Patientinnen und Patienten mit bislang als inoperabel eingeschätzten Hirntumoren kann unter Einsatz der nTMS und der nTMS-basierten DTI-Traktografie eine differenziertere Abwägung zwischen Operationsrisiko und möglichem onkologischem Benefit einer Hirntumorresektion erfolgen. Die Standardisierung der Pyramidenbahn-Traktografie im Rahmen der ersten Studie verbesserte mit Integration der funktionellen nTMS-Daten die Traktografie-Qualität und zeichnete sich zudem durch eine ausgezeichnete Interrater-Reliabilität aus. Eine beeinträchtigte Integrität der peritumoralen Pyramidenbahn kann durch die Diffusionsparameter FA und ADC charakterisiert werden und war mit einem erhöhten Risiko für ein neues postoperatives motorisches Defizit assoziiert. Die Erkenntnisse der ersten Arbeit wurden mit Analysen zuvor publizierter Arbeiten genutzt, um in der zweiten Studie die nTMS-basierte Risikostratifizierung bizentrisch zu validieren. Neben der topografischen Analyse (Infiltration des Motorkortex und Bestimmung der Tumor- Trakt-Distanz) erwiesen sich die FA und der RMT, welche die Faserbahnintegrität bzw. die Exzitabilität des motorischen System repräsentieren, als entscheidende Parameter zur V orhersage des Operationsrisikos. So konnte ein verbessertes, auf einer Regressionsbaumanalyse basierendes Risikomodell zur Vorhersage des kurz- und langfristigen motorischen Outcomes entwickelt werden. Im Rahmen der dritten Studie konnte gezeigt werden, dass die präoperative Risikoanalyse die Durchführung des IOMs unterstützen kann, indem subkortikale Stimulationsintensitäten angepasst und unspezifische Phänomene wie transiente/partielle MEP- Amplitudenminderungen differenzierter interpretiert werden können. Somit kann eine hoch individualisierte Behandlungsstrategie für Patientinnen und Patienten mit motorisch- eloquenten Hirntumoren gewährleistet werden. Für die Beurteilung Sprach-eloquenter Hirntumoren kommen sowohl das kortikale rTMS- Sprachmapping (als Negativmapping) sowie die DTI-basierte Traktografie des Sprachnetzwerks zum Einsatz. In der vierten Arbeit offenbarte der Vergleich aller bisher publizierten Algorithmen, dass die Platzierung anatomischer ROIs die besten Traktografie- Ergebnisse hinsichtlich der Darstellbarkeit und Plausibilität der Trakte offenbarte. Dieser Algorithmus wurde von internationalen Experten auch zur Operationsplanung und für das Risiko-Assessment bevorzugt. Die Integration funktioneller rTMS-basierter ROIs ermöglichte die zusätzliche Darstellung von kortiko-subkortikalen Fasern, deren Relevanz für das Sprachoutcome es in weiteren Studien zu untersuchen gilt. Die Cluster-Analyse der fünften Studie identifizierte zwei Hochrisikoareale, die mit dem Auftreten eines neuen postoperativen Sprachdefizits assoziiert waren: 1. die temporo-parieto- occipitale Übergangszone und 2. der Temporalstamm der periinsulären weißen Substanz. Der AF als V ertreter des dorsalen Systems zeigte sich als wichtigste Faserbahn für die Sprachfunktion, deren Verletzung mit dem höchsten Risiko für eine postoperative Sprachstörung assoziiert war. Eine Schädigung des ventralen Faserbahnsystems spielte vor allem dann für das postoperative Sprachoutcome eine Rolle, wenn sowohl die direkte Bahn (IFOF) als auch der indirekte Kreislauf (UF und ILF) betroffen waren. Die hier dargelegten Technologien der nTMS und DTI-Traktografie ermöglichen für motorisch- und Sprach-eloquente Hirntumoren eine differenzierte und individuelle Operationsplanung. Ziel zukünftiger Arbeiten wird es sein, diese Technologien weiter zu optimieren, um Hirntumoroperationen sicherer zu gestalten und damit die individuelle Patientenbehandlung zu verbessern.View less
Due to the circulation of infectious diseases and the emergence of new pathogens, fundamental research, as well as the development of vaccines are of utmost importance. Peptide microarrays (PMAs) can facilitate the investigation of an immune response to an antigen by detecting linear B cell epitopes. They consist of a miniaturized spot pattern containing different peptide sequences. These reproduce all potential linear epitopes of a protein, usually as a map of overlapping peptides. Therefore, PMAs allow for high-throughput screening in a fast manner. To show their versatility, PMAs were applied for the detection of linear B cell epitopes elicited by infectious pathogens or a vaccine-delivered antigen. First, PMAs of the Ebola virus spike glycoprotein were used to analyze the development of antibodies, recognizing linear peptide epitopes, in vaccine recipients and an Ebola virus disease survivor. Second, PMAs covering the SARS-CoV-2 coronavirus proteome were used to identify epitopes. The antibodies elicited by patients with COVID-19 disease were studied during the course of the disease. Today, commercially available PMAs do either lack peptide sequence flexibility and/or a high peptide density. Thus, the price per analyzed sample is high and therefore, reducing the usage of PMAs. Hence, the combinatorial laser-induced forward transfer (cLIFT) technology was developed for the fabrication of high-density PMAs. Thereby, a polymer and an amino acid are transferred via laser irradiation from a donor to an acceptor in a spot pattern. Together with intermittent chemical processing, this laser based technique can be used to in situ synthesize microarrays. With the implementation of an automated synthesizer and optimal synthesis parameters, it was possible to produce up to 20-residue peptides with controlled spot size. Finally, a full combinatorial synthesis of overlapping 15-mer peptides containing the Ebola virus proteome with 4444 and 10 000 spots per cm2 was performed. The antibody binding was compared to a commercial peptide microarray containing the same peptides of the spike glycoprotein. The results revealed an excellent quality up to a density of 4444 spots per cm2. Moreover, the flexibility of this method allows the exchange of building blocks and thus, enables the synthesis of other molecules.View less