Elucidating neural circuit mechanisms that drive complex behavior and cognition requires a multidisciplinary approach combining neuroanatomy with neurophysiology and behavioral science. This integration of different disciplines works particularly well in the model organism Drosophila melanogaster, as it benefits from the rich arsenal of molecular and genetic tools that have been developed over the last century. A focus of research are the circuit elements that drive local computation in the optic lobes. However, considerably less is known about the pathways that leave the optic lobes and converge in the central complex, which is considered the navigation center in Drosophila. In this thesis I present the complete synaptic pathway connecting the optic lobes to the central complex. Starting from the terminals of inner photoreceptors in the medulla all the way to the dendrites of EPG neurons, the Drosophila counterpart of head-direction cells in mammals. Initially, by studying light microscopically the distribution of putative presynaptic sites of inner photoreceptors I turned to connectomic reconstructions as the first complete EM volume of an adult female brain (full adult fly brain FAFB) became available. First, I manually reconstructed a set of inner photoreceptors and all pre- and postsynaptic partners as well as annotated all synapses among them. In a second step, recent advances in automatic image segmentation of the FAFB volume allowed me to proofread the complete set of projection neurons connecting the photoreceptors to the central complex across multiple neurons and neuropils. I found that the neurons along the pathway fall into different subchannels that most likely carry information from qualitatively different visual modalities into the central complex. By mapping putative visual fields to the input neurons of EPG neurons I discovered a diverse mapping of visual space in the central complex. As a population the entirety of the fly’s visual field is covered, however the visual fields of individual neurons can differ drastically. Some neurons possess diffuse visual fields while others have discrete spot- or vertical bar-like visual fields supporting the idea of combinatorial integration of different visual modalities in the navigation center of Drosophila. These findings form the basis for analyzing the integration of visual modalities within the central complex, which could not only accelerate research in this area, but also underscore the crucial role of vision in spatial navigation.

Humans exhibit distinct phenotypic differences from other primates, despite sharing nearly identical protein-coding sequences. To understand these species-specific traits and adaptations, it is crucial to investigate changes in transcriptional regulation. In studying the evolution of the human brain, transcription factors like ZEB2 emerge as key players due to their roles in neurodevelopment and species-specific characteristics. Here, I investigated the functionally unique aspects of ZEB2 to better understand the molecular foundations of human brain development. To achieve this, I analyzed ZEB2 gene sequences, its potential regulatory partners, and conducted experiments using induced pluripotent stem cells (iPSCs). While the coding regions and DNA-binding domains of ZEB2 are largely conserved across primate species, I identified species-specific differences in its binding properties and functional roles across primates and different cell types. Notably, two distinct cellular mechanisms—neurogenesis and immune functions—were found to be closely connected through ZEB2’s regulatory influence. Additionally, ZEB2’s expression is strongly modulated by its non-coding regions, and many of its potential interaction partners were also non-coding genes, indicating that ZEB2 potentially recruits non-coding genes into its gene regulatory networks. Using iPSC-based models generated and established in this work, I further investigated how ZEB2 contributes to neurodevelopment in humans and primates. This work highlights ZEB2’s functional importance, emphasizing its splicing mechanisms, dynamic context-dependent regulation, and critical role in neurodevelopmental functions, providing new insights into human brain evolution.

Breast cancer is the most common malignancy and the leading cause of cancer deaths in women due to metastasis. Metastasis is a complex mechanism causing the distant dissemination of cancer cells, and the underlying mechanism is not fully understood. The bone morphogenetic protein (BMP) pathway is a key regulator of development and tissue homeostasis. Its aberrant activity has both inhibitory and promoting roles in malignancies. Increased level and nuclear translocation of β-CATENIN, the core mediator of the Wingless/Integrated (WNT)/β-CATENIN pathway, are observed in most malignancies, contributing to metastasis. However, current strategies targeting β-CATENIN are not as effective as desired. The WNT/β-CATENIN and BMP pathways crosstalk in the development and tissue homeostasis of different organs, either cooperating or balancing each other. This is most evident in colorectal cancer, where the BMP pathway inhibits WNT-driven tumorigenesis. However, it remains elusive whether a similar mechanism exists in breast cancer. In the first part, human breast cancer cell lines were stimulated with BMP2 or BMP6, which were significantly downregulated in the TCGA breast cancer datasets, to understand whether they have an effect on β-CATENIN. The data revealed that BMP simulation in MCF7 and T47D cells induces phosphorylation of β-CATENIN at residues that cause decrease in protein stability. This requires SMAD4 and the kinase activity of BMP type 1 receptors. In contrast, β-CATENIN protein level decreased exclusively in MCF7 cells, exerting a limited effect on the target gene expression. Intriguingly, BMP stimulation did not induce β-CATENIN phosphorylation in two other breast cancer cell lines, MDA MB 231 and MDA MB 468, independent of SMAD4 status, suggesting that regulation may occur in a cell line-specific manner. The second part investigated the physical interaction between cancer and endothelial cells. Mutations/inhibition of BMP type 2 receptor (BMPR2) expression in endothelial cells cause pulmonary arterial hypertension (PAH) by disrupting endothelial cell homeostasis in lung arteries and increasing the adhesion of monocytes to the endothelium. Tumor vasculature shares similarities with the endothelium driven by BMPR2 deficiency. However, no study has examined whether endothelial BMPR2 deficiency affects cancer cell adhesion. Therefore, BMPR2-deficient endothelial cell model was used to study the interaction of cancer cells using in vitro assays, such as transmigration and cell adhesion assays in different conditions. Similar to PAH, BMPR2 deficiency increased the junctional permeability of endothelial cells and increased the intravasation potential of MDA MB 231 breast cancer cells. However, it decreased cancer cell adhesion to the apical side of the endothelium, suggesting that endothelial BMPR2 could have opposing effects at early and late stages of metastasis. RNA-seq data showed that most of the cell adhesion and endothelial junction-related markers were reduced in BMPR2-deficient cells, whereas siRNA-mediated silencing of BMPR2 in wild-type endothelium reduced a limited number of adhesion molecules and did not affect cancer cell adhesion, suggesting that impaired cancer cell adhesion to endothelium could be due to a long-term change in adhesion markers downstream of BMPR2-mediated BMP pathway activity. Taken together, the findings highlight the importance of the BMP pathway in cancer progression and metastasis by focusing on two independent, yet related, aspects in the context of breast cancer.

Advances in sequencing technology have facilitated population-scale long-read analysis, in which one of the main challenges is arguably developing high-performance computational pipelines. Sequence alignment and assembly are two main long-read analysis methods. Alignment-based pipelines are commonly more efficient and require less read coverage than assembly-based ones, and thus are more applicable to population-scale analysis. However, alignment-based pipelines are less effective in reconstructing highly diverse structures in ultra-long reads such as intra-read SVs. Here, we propose a new filter-based pipeline that is designed to capture rearrangement signals at an earlier stage than conventional pipelines to improve long-read analysis performance. To this end, we investigated the feasibility and essential methods of the design and assessed the performance of the pipeline. Correspondingly, this work comprises three parts starting with data structure optimizations then module development and finally large-scale assessments. Assessments based on high-quality datasets suggest that filter-based pipelines are comparable to or outperform conventional pipelines in terms of detecting complex intra-read rearrangements and computational efficiency. Therefore, the newly proposed pipeline may further benefit population-scale long-read analysis.

In dieser Habilitationsschrift habe ich eine Übersicht über den Einsatz rechnergestützten Verfahren als Grundlage für die Analyse von genetischen Varianten gegeben und exemplarisch einige biomedizinische Ergebnisse dargestellt, die ohne den Einsatz maßgeschneiderter Programme nicht erreichbar gewesen wären. Die Quelltexte aller vorgestellten Methoden sind offen und stehen jeder Mensch unter freien Lizenzen über das Internet zu Verfügung.

Das Programmpaket SODAR ermöglicht die effiziente Verwaltung von Meta- und Massendaten für komplexe Studien, bei Anwendung mehrerer experimenteller Methoden und Erzeugung großer Datenmengen und/oder großer Anzahl von Dateien. Das Programm als Webanwendung auch für unerfahrene Anwender:innen einfach zu bedienen. Für Bioinformatiker:innen stellt es programmierbare Schnittstellen (APIs) bereit und ist auch von der Kommandozeile zu bedienen. Damit vereinfacht oder ermöglicht SODAR viele Forschungsvorhaben, die in der Core Unit Bioinformatik (CUBI) durchgeführt werden. Es wird aber mittlerweile auch unabhängig von CUBI an der Charité und anderen Instituten verwendet. Durch die Nutzung offener und freier Dateiformaten und Schnittstellen ermöglicht es SODAR, auch die Anforderungen der FAIR Grundprinzipien für Datenmanagement zu erfüllen.

Das Programm ClearCNV vereinfacht den Umgang von Sequenzdaten aus Anreicherungsverfahren und Bedingungen wie sie in der Praxis im Labor und Klinik oft anfallen. Solche Daten wurden meist über mehrere erzeugt, was unter anderem zu Verzerrungen (batch effect) führt. ClearCNV ermöglicht es dem Benutzer die für die gemeinsame Analyse homogenen und passenden Daten entsprechend auszuwählen und dann zuverlässig auch DNS Kopiezahlvarianten zu detektieren, die nur kleine Abschnitte des Genoms betreffen. Es stellt auch Module bereit, um die Ergebnisse grafisch darzustellen und die Qualität zu überprüfen. Wir konnten unter Verwendung realer Daten zeigen, dass die Güte der Ergebnisse mindestens vergleichbar mit vorherigen Methoden ist.

Die Anwendung VarFish stellt Anwendern in Klinik und Forschung eine grafischen Benutzeroberfläche für die Auswertung von DNS-Varianten bereit. Durch die enge Zusammenarbeit mit Nutzer:innen konnte sichergestellt werden, dass die Software einfach benutzbar ist. Die Soft-ware wird außerdem ständig weiterentwickelt und verbessert. Alle im Institut für Humangenetik der Charité prozessierten Exom- und Genomfälle werden mit VarFish bearbeitet, was den Erfolg des Ansatzes zeigt.

Durch die Anwendung einer verfeinerten Gene Burden Analyse im Kontext der dilativen Kardiomypathie konnte ich zusammen mit anderen Forscher:innen die Rolle von Varianten mit hoher Relevanz in diesem Krankheitsbild zeigen. Eine weitere Klärung des Sachverhaltes steht durch die Vergrößerung der Kohorte sowie der Exomsequenzierung statt der verwendeten Panelsequenzierung aus.

Durch die genaue Analyse genomweiter de novo Varianten konnte ich zusammen mit anderen Forscher:innen die zeigen, dass multisite de novo Varianten (MSDN) ein Marker für die Exposition des Vaters durch ionisierender Strahlung ist. Vorher nur im Mausmodell nachgewiesen, stellt unsere Studie den ersten Nachweis für die Relevanz des Markers im Menschen dar, nachdem die langjährige Lehrmeinung war, dass durch ionisierende Strahlung entstandene Schäden nicht vererbt werden. Die Rolle des Markers wird derzeit durch eine weitere Studie mit meinen Koautor:innen geklärt, das entsprechende Manuskript ist eingereicht.

Insgesamt zeigt meine Arbeit auf, wie der Einsatz der Bioinformatik unterschiedliche essenzielle Beiträge zur biomedizinischen Forschung im Zeitalter der Hochdurchsatzverfahren, insbesondere der Hochdurchsatzsequenzierung von DNS leistet.

As human development progresses rapidly, changes in land use become increasingly frequent, with deforestation emerging as a particularly rapid phenomenon since the industrial revolution. Consequently, understanding the ramifications of deforestation on climate change becomes paramount. While previous studies have predominantly examined the effects of deforestation on precipitation and temperature, the impacts of deforestation on drought, i.e. the interactions among precipitation, temperature, and other meteorological factors, remain understudied. This thesis aims to systematically analyze the influence of deforestation on drought across various temporal scales and geographical regions, drawing from a diverse range of data sources including observations and model outputs. The objective is to make significant contributions to the formulation of climate-focused land-use policies. Initially, historical forest and climate datasets spanning from 1992 to 2018 are employed alongside a series of linear models and analysis of variance methods to explore the impact of forest cover change, precipitation, and temperature on drought across diverse time scales and climate zones. Among these factors, precipitation emerges as the predominant driver of drought in equatorial, temperate, and snow regions, while temperature exerts control over drought occurrence in arid areas. Notably, precipitation moderates the influence of forest cover on long-term drought in arid regions, whereas temperature moderates the effects of forest cover changes on both short- and long-term drought in arid regions, as well as solely on long-term drought in temperate regions. Moreover, high forest cover fosters a combined effect of precipitation and temperature on long-term drought in arid and snow regions, whereas precipitation alone dominates under low forest cover conditions. Conversely, low forest cover triggers a robust combined effect of precipitation and temperature on drought in temperate regions. Subsequently, leveraging idealized deforestation experiment (deforest-global) and the pre-industrial control experiment (piControl) from the Land Use Model Intercomparison (LUMIP) project, deforestation accentuates dryness globally, particularly in equatorial regions, but enhancing moisture in dry zones. The impact on drought indices intensifies with longer time scales. Seasonally, deforestation amplifies short- term droughts in autumn and winter globally, notably impacting equatorial and northern polar regions. Snow zones witness significant seasonal shifts, becoming drier in winter and wetter in summer following global deforestation, while the northern dry regions experience heightened moisture, especially during autumn. Across Europe, forest alterations due to extensive land management policies are observed. Using idealized deforestation simulations (GRASS) and idealized forestation simulations (FOREST) from the Land Use and Climate Across Scales (LUCAS) project, an increase in drought severity is noted post-deforestation, particularly prominent in northern European regions and during prolonged drought periods. Additionally, significant monthly variability in the impact of deforestation on drought is evident, particularly in northern Europe (Scandinavia), where drought exacerbates during winter but tends to alleviate during summer months. Furthermore, an analysis of influencing factors in drought index calculation, namely precipitation and potential evapotranspiration, is conducted. In terms of climatic changes, alterations in precipitation closely correspond with changes in drought indices, whereas monthly fluctuations in potential evapotranspiration align with drought indices variations. These findings deepen our understanding of the intricate interplay between shifts in vegetation patterns and fluctuations in climate dynamics, thus serving as a cornerstone in advancing our ability to manage natural resources more effectively. Furthermore, they contribute significantly to our capacity to proactively mitigate the looming threats posed by climate change, paving the way for more sustainable and resilient ecosystems in the future.

Wann und wie ist eine Glasfassade durchsichtig? Kann auch eine Betonfassade transparent sein? Führen Düfte zu einer Transparenz in der Architektur? Die vorliegende Dissertation greift diese und weitere Fragen auf und entwickelt hierfür einen umfassenden konzeptionellen Rahmen, der die Transparenz über die klassische Betrachtung der gläsernen Durchsichtigkeit hinaus erfasst. Aufbauend auf der Theorie von Colin Rowe und Robert Slutzky werden die graduellen Abstufungen von Transparenz im Verhältnis zur Opazität beleuchtet. Ein zentrales Anliegen der Arbeit ist die Analyse der Transparenz in seiner Vielschichtigkeit und oft auch Janusköpfigkeit.

Die Dissertation ist in drei Teile gegliedert: Im ersten Teil werden die Transparenz-Diskurse nachgezeichnet, wobei zwischen einem architekturhistorischen und einem gesellschaftspolitischen Kontext zu unterscheiden ist. Im zweiten Teil wird das Konzept der Komplexitäten von Transparenz entwickelt: Einerseits wird Transparenz als Stilmittel in der Architektur analysiert; hierbei liegt der Fokus auf der Fassade und deren visuellen Eigenschaften. Transparenz kann in der zeitgenössischen Architektur - die sich über ihr Gegenteil, die Opazität, definiert - innerhalb dieses Kontinuums (1) durchschauen und durchdringen, (2) überlagern und vervielfältigen, (3) reflektieren und projizieren, (4) funkeln und glänzen, (5) spiegeln und verzerren, (6) verschleiern und verführen sowie (7) überblenden und verdunkeln. Die Erläuterung dieser sieben Komplexitäten erfolgt anhand von Gebäuden, die weltweit ab dem Jahr 2000 von renommierten Architekten – darunter Herzog & de Meuron, Jean Nouvel oder Sou Fujimoto und Toyo Ito – sowie weniger bekannten Architekten errichtet wurden.

Im weiteren Verlauf wird der Transparenz-Begriff auf die Raumerfahrung und die menschlichen Sinne übertragen und in einen gesellschaftspolitischen Kontext eingeordnet. In diesem Zusammenhang wird untersucht, wie Transparenz in der zeitgenössischen Architektur durch Wahrnehmungskanäle wie akustische Eindrücke, Geruch, Geschmack und Erlebnis oder Berührung geschaffen wird. Hierzu zählen Strategien der Kontrolle und Sichtbarmachung, der Erreichbarkeit und Niedrigschwelligkeit, der Grenzüberschreitung sowie der Vernetzung.

Im dritten Teil wird das Konzept der Komplexitäten von Transparenz unter Beweis gestellt. Zur Analyse werden Imagebauten der deutschen Automobilindustrie herangezogen, die innerhalb eines Jahrzehnts (2001–2009) entstanden sind. Konkret handelt es sich um das museum mobile der AUDI AG in Ingolstadt, die BMW-Welt in München, das Mercedes-Benz-Museum und das Porsche-Museum in Stuttgart sowie die Gläserne Manufaktur der Volkswagen AG in Dresden.

Die vorliegende Dissertation gelangt zu dem Schluss, dass erstens eine starke Betonung von Transparenz paradox wirken, ja, sogar das Gegenteil hervorrufen kann. Aus dieser Erkenntnis folgt die Dekonstruktion des klassischen Verständnisses von Transparenz: In der zeitgenössischen Architektur sollte Transparenz keineswegs auf die bloße Durchsichtigkeit oder Offenheit reduziert werden. Weiter wird zweitens in der Dissertation dargelegt, dass Transparenz nicht nur durch Sichtbarkeit definiert werden kann, sondern vielmehr als ein dynamisches Konzept verstanden werden muss, das je nach Perspektive variiert. Zudem wird Transparenz drittens als ein Konzept verstanden, das auch in verschiedenen Sinneserfahrungen und Wahrnehmungsstrategien zum Ausdruck kommt.

Die vorliegende Arbeit trägt somit zu einem erweiterten Verständnis von Transparenz in der Architektur bei und ermöglicht erstmals eine differenzierte und komplexe Betrachtung der verkürzten Gleichsetzung „Transparenz heisst Durchsichtigkeit“, die vorherrschend war.

Vaccination confers protection against pathogens that is built up via active or passive immunization. This thesis is divided into two projects presenting novel approaches for passive and active vaccination. Passive immunization aims at providing instant support to the human immune system that is not able to curtail and clear infections. Past and current strategies, such as serum therapy and monoclonal antibodies, however, lack memory formation and thus require regular administration. Newer approaches of cellular vaccines, such as engineering of B cells, aim at replacing native B cell receptor sequences ex vivo with those of known neutralizing antibodies. Upon reinjection, modified B cells differentiate into long-lasting plasma cells expressing these protective antibodies. It needs to be considered, however, that amino acid changes in immunodominant epitopes of viral antigens - the main target of neutralizing antibodies - allow viruses to evade the immune system. The discovery of LAIR1-containing antibodies that bind broadly to various malaria-causing Plasmodium falciparum isolates has prompted us to establish a new type of passive vaccination, which integrates key virus-binding domains of cell entry receptors into antibodies. Antibodies containing pathogen receptor domains are expected to be difficult to be evaded by the pathogen and therefore would diminish viral immune escape. In addition, LAIR1-receptor antibodies were generated via a cell-intrinsic mechanism, likely involving the activity of activation-induced cytidine deaminase (AID). AID contributes to antibody diversity via induction of double-strand breaks in the antibody gene. In my thesis I show that CD40L plus IL-4 stimulation is the strongest inducer of AID mRNA transcripts and further enabled the successful in vitro engineering of LAIR1 insert-containing B cells, albeit at low frequency. To optimize insert modality for its subsequent integration and to quantify insertion efficiency, a flow-cytometry-based GFP-reporter assay was performed. Engineered B cells maintained 0.1 to 1% GFP expression with a diverse set of DNA substrates. Single-stranded DNA containing homology arms represented the most promising substrate design. Speaking of other pathogens than malaria, HIV concurrently lacks a working vaccine and SARS-CoV-2 appeared during my doctoral thesis as a highly relevant target. Therefore, I aimed at applying the obtained knowledge from LAIR1, integrated into antibodies, to key entry receptor domains for HIV-1 and SARS-CoV-2. While LAIR1-antibodies were designed by nature, insert-containing antibodies against HIV and SARS-CoV-2 still need to be developed. To this end, I recombinantly expressed antibodies containing pivotal cell entry receptor or nanobody domains and was able to obtain insert-mediated specific binding. Hence, such knowledge can serve as a template for functional protein domain insertions into antibodies of primary human B cells in the future. Taken together, this first project has laid the base for AID-stimulated B cell engineering. Primary human B cells can be endowed with key sites of viral entry receptors, such as immunoglobulin-like receptor domains from LAIR1, and may contribute a new strategy of passive vaccination. Active immunization involves the direct contact with pathogens that mounts adaptive immune cell responses, thereby eradicating infection and inducing long-term memory. The outbreak of COVID-19 and its impact around the globe has illustrated the need for safe and effective vaccines. Hitherto, conventional vaccine designs have not considered interactions of immunogens with the host cell receptor as a potential drawback of vaccine efficacy. We hypothesized that high-affinity binding of the SARS-CoV-2 spike to the ubiquitously expressed ACE2 receptor may on the one hand exert masking and on the other hand promote displacement of the vaccine antigen, thereby limiting immunogen availability and hampering the generation of neutralizing antibodies. Hence, we aimed for an active vaccine design strategy that by abrogation of entry receptor binding diminishes antigen displacement and preserves immunogenicity as well as accessibility to all epitopes of the receptor binding domain (RBD) of the viral spike. We therefore developed a bioinformatically residue scoring in collaboration with Prof. Dr. Simon Olsson, which was based on available data from high throughput cell receptor binding and antibody escape studies. We were able to stratify amino acids of the SARS-CoV-2 RBD into different groups based on their contribution to ACE2 receptor binding, their involvement in recognition by neutralizing antibodies as well as their respective expressibility. We identified a high scoring candidate, G502E, which displayed similar binding of neutralizing antibodies compared to WT, but lost association with ACE2. My in vitro studies confirmed higher adsorption as well as increased internalization of the SARS CoV-2 spike or RBD WT proteins compared to G502E by ACE2-expressing cells. Immunization of rabbits with the G502E spike induced higher anti-RBD antibody titers, indicating that receptor binding abrogation can focus the response towards the RBD. Furthermore, a G502E RBD mutant induced superior antibody titers and neutralization compared to WT. Taken together, this project merges information of the immunogenic nature and ACE2 binding features of amino acids of the RBD from the SARS-CoV-2 spike to design an improved protein vaccine candidate by abrogating interaction with the viral entry receptor. In future, this methodology may be applied to other vaccine platforms and to pathogens that engage cell entry receptors with high affinity and lack vaccines that elicit protective antibody responses.

In der vorliegenden Arbeit wird die Auswirkung des Persönlichkeitsmerkmals Neigung zum intensiven Nachdenken (NFC) (Cacioppo & Petty, 1982) auf die Entwicklung einer wissenschaftlichen Grundhaltung bei Grundschullehramtsstudierenden untersucht. NFC bildet als stabiles Persönlichkeitsmerkmal ab, wie sich Individuen bezüglich ihres Engagements und ihrer Freude bei aufwändiger gedanklicher Aktivität wie Argumentieren, Informationsaneignung und komplexem Problemlösen unterscheiden (Bless et al., 1994). Mit der Untersuchung eines Persönlichkeitsmerkmals auf die Professionalisierung von Lehrkräften schließt die Arbeit an den Persönlichkeitsansatz der Lehrer:innenbildung an (Mayr, 2016; Rothland, 2021). In einem Mixed-Methods Design aus quantitativer Vor- und qualitativer Nacherhebung nahmen zunächst 294 Grundschullehramtsstudierende einer deutschen Universität an einem bereits validierten Persönlichkeitsfragebogentest zum NFC teil (Preckel, 2014). Zusätzlich zum NFC wurde eine im Rahmen der vorliegenden Arbeit entwickelte Skala zum wissenschaftlichen Interesse im Lehramtsstudium (WIL), weitere etablierte Persönlichkeitsmaße wie die Big-5 (McRae & Costa, 2008), die Selbstwirksamkeitserwartung (Jerusalem & Schwarzer, 1999) und die Abiturnote als etablierter Prädiktor für den Studienerfolg (Haase et al., 2022) erhoben, um den Einfluss des NFCs auf das wissenschaftliche Interesse im Lehramtsstudium (WIL) differenzierend beurteilen zu können.

Die Ergebnisse der Auswertung der Daten der quantitativen Erhebung belegen, dass das Persönlichkeitsmerkmal NFC das wissenschaftliche Interesse im Lehramtsstudium (WIL) besser vorhersagen kann als die anderen verwendeten Prädiktoren.

Um Erkenntnisse zum Einfluss des NFC auf die Entwicklung einer wissenschaftlichen Grundhaltung – im Sinne eines reflexiv-forschungsorientierten Habitus (Fichten, 2017; Helsper, 2021) – bei den Studierenden zu gewinnen, wurden acht Studierende, die sich durch extrem hohe oder niedrige Werte auf der NFC-Skala auszeichnen, zu narrativ-biographischen Interviews eingeladen. Für die Interviews wurden als wesentliche Kategorien das familiäre Aufwachsen, die Bildungsbiographie und – für die Forschungsfrage der vorliegenden Arbeit besonders relevant – das Erleben wissenschaftlicher Anforderungen an der Universität operationalisiert. Die Auswertung der Interviews mit der qualitativen Inhaltsanalyse (Kuckartz, 2018) führte zu einer Typologie mit zwei Haupttypen: Typ 1: Offenheit gegenüber der Entwicklung einer wissenschaftlichen Grundhaltung und Typ 2: Ablehnung gegenüber der Entwicklung einer wissenschaftlichen Grundhaltung. Die Ergebnisse der qualitativen Auswertung zeigen, dass bei den untersuchten Fällen die Ausprägung des NFC deutlich die Bildungsbiographie und das Erleben wissenschaftlicher Lernsettings an der Universität beeinflusst. Mit der Ausnahme von zwei Grenzfällen konnten Personen mit hohem NFC eindeutig dem Typ 1: Offenheit gegenüber der Entwicklung einer wissenschaftlichen Grundhaltung und Personen mit niedrigem NFC dem Typ 2: Ablehnung gegenüber der Entwicklung einer wissenschaftlichen Grundhaltung, zugeordnet werden.

Die Ergebnisse der vorliegenden Arbeit belegen die Relevanz individueller Persönlichkeitsfaktoren für eine erfolgreiche Professionalisierung im Lehramtsstudium. Die Auswertung der quantitativen und qualitativen Daten spricht deutlich dafür, dass das Persönlichkeitsmerkmal Neigung zum intensiven Nachdenken (NFC) wesentlichen Einfluss auf die erfolgreiche Bewältigung wissenschaftlicher Anforderungen im Studium und damit auf die Entwicklung einer wissenschaftlichen Grundhaltung bei Grundschullehramtsstudierenden hat.

Diese Arbeit behandelt erstmals Pietro Angeli da Bargas neulateinisches Epos Syrias (vollständig erstmals 1591 gedruckt) über den Ersten Kreuzzug in monographischer Ausführlichkeit. Nach einführenden Bemerkungen zu Autor, Werk und insbesondere dem im Zentrum stehenden Text werden drei wesentliche Aspekte in den Blick genommen: (1) Der Einfluss des ideologischen Kontexts der Zeit, die insbesondere von der Gegenreformation und dem poetischen Aristotelismus geprägt war (Kapitel 3). (2) Der politische Kontext. Die Syrias wurde in 1580er Jahren in enger Abstimmung mit und wohl auch auf Anregung von Kardinal bzw. ab 1587 Großherzog Ferdinando de’ Medici geschrieben und für dessen persönliche Agenda instrumentalisiert. Neben einer allgemeinen kreuzzugsparänetischen Werksintention wurde mit der Syrias als Mittel einer Ferdinandeischen Paralleldiplomatie während Ferdinandos Kardinalats eine philofranzösische Politik propagiert, die der offiziellen hispanophilen Ausrichtung des mediceischen Großherzogtums unter Francesco de’ Medici zuwiderlief. Ferdinando lockerte als Großherzog die starke Abhängigkeit Florenz‘ von den Habsburgern, indem er die Verbindungen zu Frankreich stärkte. Ausdruck dieser Neuausrichtung der mediceischen Außenpolitik war die Hochzeit Ferdinandos mit der französischen Prinzessin Christiane von Lothringen im Jahr 1589. Die von Pietro Angeli mitgestalteten Hochzeitsfeierlichkeiten griffen auch in der Syrias entwickelte philofranzösische Motive und Narrative der politischen Repräsentation auf. (3) In der bisherigen Forschung wurde die Syrias nahezu ausschließlich als ‚Zwilling‘ von Tassos Gerusalemme-Dichtungen besprochen. Die um die vorletzte Jahrhundertwende intensiver diskutierte Frage der relativen Chronologie wird in dieser Arbeit dahingehend beantwortet, dass die Syrias in ihrer gesamten Genese unter dem Eindruck der Gerusalemme Liberata stand und von ihr allgemein beeinflusst wurde, während Tasso für die Überarbeitung der Gerusalemme Liberata zur Gerusalemme Conquistata einige Ratschläge aus der sog. Revisione Romana (1575/1576), an der Pietro Angeli da Barga beteiligt war, umsetzte und sich stärker an solchen poetischen Grundsätzen (Historizität, Fiktionsskepsis, meraviglioso cristiano) orientierte, die auch Angeli in der Syrias befolgte. Eine konkrete punktuelle Bezugnahme des späten Tassos konnte an einigen wenigen Stellen zumindest plausibel gemacht werden.

Long-term maintenance of positive health-related behaviors is key in the prevention, management, and rehabilitation of chronic conditions, such as cardiovascular diseases, diabetes and cancer. Habits, i.e., context-response associations where the context automatically triggers a behavioral impulse, are proposed to facilitate behavioral maintenance by guiding behavior despite low intentions (de Bruijn & Rhodes, 2011). However, findings on the interplay between habit and intention strength remain inconclusive due to methodological limitations, and little is understood about how habit interacts with volitional processes, such as spontaneous action planning. Supporting successful habit formation requires an understanding of determinants that facilitate learning of context-response links. Habits are assumed to form more quickly if the behavior is intrinsically rewarding (de Wit & Dickinson, 2009), but study designs that are able to capture reward in the critical moment are lacking. Aside from intrinsic reward, few theoretical determinants have been tested that may be linked to habit strength beyond behavioral repetition. Moreover, unwanted habits present a barrier for behavior change (Gardner et al., 2021) and opposing assumptions exist on whether old habits persist or decay, when substituted with a new habitual response (Mercuur, 2021). These propositions warrant investigation in real-life settings where participants are supported to substitute unwanted habits with healthier alternatives. The present thesis examined the role of habit in complex health behaviors and its determinants in real life settings. Specifically, the following research questions were addressed: RQ 1: How do reflective processes (i.e., intention strength and spontaneous action planning) and habit interact when guiding complex health behavior? (Study 1). RQ 2: How do habits form over time and what factors facilitate habit formation in real-life settings? (Study 2 and 3). RQ 3: How do habits decay over time and what factors facilitate habit decay in real-life settings? (Study 3). The empirical findings of this thesis are based on three data sets. The first study is a secondary analysis of data from 225 participants in a planning intervention that targeted increase of daily physical activity. The participants self-reported their intention strength, spontaneous action planning, and habit strength at five measurement follow-ups over a one-year period. The second study is a secondary analysis of data from 135 participants in an online planning intervention that aimed at forming a healthy nutrition habit. The participants reported habit strength and theoretical determinants daily over 12 weeks. The third study is a primary analysis of data from 42 participants in an online planning intervention that targeted substitution of an old with a new, more active commuting habit. The participants provided multiple daily assessments during a baseline week and five post-intervention weeks, spanning 14 weeks. Participants reported daily habit strength, experienced reward and regret, and weekly plan enactment for both new and old commuting behaviors. In all studies multilevel models were fit. Based on the empirical findings of this thesis, the research questions 1-3 can be answered as follows: RQ 1) Strong habits seem to compensate lowered intention strength when guiding complex health behavior. However, spontaneous action planning remains an important reflective process for behavioral engagement independent of habit strength. RQ 2) In the context of habit formation and substitution, habit strength increases more quickly in earlier phases whereas the increase is less pronounced in later phases. Every opportunity to engage in the new behavior seems important when substituting habits. Moreover, experienced reward upon behavioral performance, captured through momentary assessments, is associated with higher habit strength, whereas more distal affective judgments may not reflect the reward directly linked to habit strength. Additionally, the findings suggest that higher than usual alignment between reflective processes and habit is associated with more automatic behavioral performance on a given day and a certain degree of average alignment of reflective processes and habit seems to be a pre-requisite for healthy habits to form. RQ 3) When substituted with a healthier alternative, old habit strength decays linearly but only in part. The decay of old habit strength is associated with consistently performing the new, desired behavior in the old context. Moreover, immediate negative experiences of the old behavior seem to be associated with habit decay. Future research is needed to further examine how determinants of habit change can be manipulated in habit interventions to facilitate habit formation and habit decay.

Die orthotope Lebertransplantation ist das Standardtherapieverfahren bei terminalem Leberversagen. Auf Grund von anhaltendem Spenderorganmangel, dem Risiko von Abstoßungsreaktionen und dem Nebenwirkungsprofil der notwendigen Immunsuppression besteht der dringende Bedarf nach Optimierung des Transplantationsverfahrens und Alternativen wie der Leberzelltransplantation. Das übergeordnete Ziel des Projektes in dessen Rahmen diese Arbeit entstand, ist es, orthotope allogene Transplantate mit autologen Hepatozyten und Vorläuferzellen zu besiedeln und somit eine sogenannte neohybride Leber zu schaffen. Das Ziel der vorliegenden Arbeit ist es, den Einfluss der Zellquelle auf die Neohybridisierung der Mausleber zu vergleichen. Hierzu werden, wie bereits in Vorarbeiten der Arbeitsgruppe untersucht, die Rekolonisierungseigenschaften der Hepatozyten und Vorläuferzellen von Patienten ohne chronische Lebererkrankung (bei denen eine Leberteilresektion zur Entfernung einer Neoplasie in der Leber vorgenommen wurde) und Zellen aus erkrankten, zirrhotischen Lebern isoliert und deren unterschiedliche Rekolonisierung im Empfängertier evaluiert. Zudem soll geprüft werden, ob eine Verlängerung des Tierversuches auf 30 Tage ohne Abnahme der Überlebensrate der Versuchstiere möglich ist. Hepatozyten und Vorläuferzellen wurden isoliert, mittels Dichtegradientenzentrifugation aufgereinigt und bis zur Transplantation über 12 bis 24 Stunden kühl gelagert. Viabilität, Zellzahl und Verhalten in Zellkultur wurden verglichen. Parallel zur Zellisolation wurden für jede Probe je 12 FOX CHASE SCID / beige® Mäuse mit dem Pyrrolizidinalkaloid Monocrotalin (200mg / kg intraperitoneal) vorbehandelt, um eine Leberschädigung zu initiieren. 12 bis 24 Stunden später wurden die Mäuse einer 50 % igen Hepatektomie unterzogen und jeweils 1 Mio Hepatozyten und Vorläuferzellen über die Milz transplantiert. Nach 7, 15 und 30 Tagen wurden jeweils 3 Mäuse euthanasiert und die Leber entnommen. Der Rekolonisierungsnachweis wurde mittels immunhistochemischer Färbung (anti-human-Albumin) geführt. Zusätzlich erfolgte die Detektion der humanen Hepatozyten in der Mausleber mittels real time PCR (Humanalbumin, B2M und ACTN4). Die Isolierung von Hepatozyten und Vorläuferzellen gelang sowohl aus Resektaten als auch Explantaten in hoher Zellzahl und Viabilität, allerdings war die Viabilität bei den Resektaten signifikant höher. Die anschließende Kühllagerung der Zellen für 12 bis 24 Stunden konnte mit akzeptablen Verlusten der Zellviabilität durchgeführt werden. Hier schienen die Explantatzellen deutlich stabiler, so dass die Viabilität und Zellzahl beider Zellgruppen nach Kühllagerung in etwa identisch war. Auch in Zellkultur waren beide Zellquellen gleichermaßen stabil. Das etablierte Mausmodell konnte mit einer Überlebensrate von 86 % der Tiere als erfolgreich gewertet werden, wobei in der Resektatgruppe weniger Tierverluste zu verzeichnen waren, als bei den Explantaten. Der immunhistochemische Rekolonisierungsnachweis zeigte mittels Detektion von Humanalbumin bei 92 % der Tiere ein Engraftment von humanen Hepatozyten in der Mausleber in den ersten 15 Tagen in gleichem Maße in Resektat- und Explantatgruppe, an Tag 30 dann in deutlich höherer Menge bei den Explantaten. Eine Bestätigung der immunhistochemischen Ergebnisse mittels Real Time PCR gelang nur bedingt. Die Ergebnisse der vorliegenden Arbeit zeigen, dass eine erfolgreiche Zellisolation, Kühllagerung und Transplantation sowohl von Hepatozyten und Vorläuferzellen aus gesundem Lebergewebe, als auch aus erkrankten, zirrhotischen Lebern möglich ist. Zudem gibt es Hinweise dafür, dass die Explantatzellen bei Kühllagerung den Resektatzellen überlegen sind und sie auch bei der Rekolonisierung über längere Zeiträume den Resektatzellen überlegen sind. Um beide Zelltypen weiter auf ihre repopulativen Eigenschaften zu untersuchen, eignet sich das in dieser Arbeit verwendete Mausmodell, zur weiteren Untersuchung der Rekolonisierung sollte und kann die Versuchsdauer für zukünftige Studien verlängert werden.

'Opposing Desires' delves deeply into the contentious practices of the South Korean anti-LGBT movement, investigating its roots, framing strategies, transnational ties, and political endeavors. In times of right-wing populists gaining traction worldwide, this case study offers new insights into the cunning ways conservative Christians engage in both continuous and dynamic action forms to gain societal and political hegemony. Sociologists, political scientists and practitioners alike will discover how this dynamic continuity runs like a thread through anti-LGBT politics in Korea, displaying not just another far-right success story, but unveiling also contradictions and internal conflicts.

This thesis examines the role of Community Supported Agriculture (CSA) as spaces of resistance and transformation of the hegemonic food system in Berlin and Brandenburg, Germany. Embedded in critical debates about food movements and social innovations as dynamics that can counter intersectional food inequalities in processes of socio ecological transformation of the food and agrarian system (Motta 2021a, 2021b) this study combines the diverse economies approach (Gibson-Graham 1996, 2006) with Foucault's concept of heterotopias (2005) as sites of resistance. It aims to contribute both theoretically and empirically to understanding how CSA can create food heterotopias, influencing the (re)production of new subjectivities. Positioned at the intersection of food studies, social movement studies, and diverse economies studies, this research employs a multi-method qualitative approach in a case study of a CSA cooperative. This includes ethnography, interviews, content and discourse analysis, conducted during fieldwork between 2020-2023. The fieldwork involved participant and online observations, participation in various cooperative events, and a working stay on the farm. The findings highlight the significance of creating alternative spaces where food practices are guided by principles of solidarity, cooperation, care, social justice, and diversity, to transform food system based on conventional forms of enterprise, labor, and transactions. Furthermore, this research underscores the necessity of adopting feminist perspectives in research to address the intersections of social categories such as race, nationality/ethnicity, gender, sexual orientation in food and interspecies relations.

Redox biomolecules play vital roles in many biological processes, where their level relates to the occurrence and progression of various diseases. Inorganic fluorescent nanoprobes have been widely used for biomedical studies in the last decades due to their tunable optical properties and outstanding photostability. Furthermore, recent advances show their diagnostic potential for in vitro quantification or in vivo imaging of redox biomolecules, which can provide essential information to guide treatment. However, there are two recognized bottlenecks in this research field. On the one hand, many nanoprobes lack robustness in biologically relevant environments due to their sensitivity to temperature, humidity, or oxygen, which is unfavorable for their production and especially their application. On the other hand, all current research on nanoprobe-guided treatment remains at the stage of evaluating therapeutic efficiency, overlooking the impact of individual differences, such as tumor depth and microenvironment, which leads to significant under- and over-treatment. In this thesis, the robustness of inorganic fluorescent nanoprobes has been improved by designing a thermostable recognition group or developing a novel confined flash (conFlash) synthesis method. In addition, a customized phototherapeutic strategy has been devised to minimize the individual differences of for example tumor environment during treatment. In Chapter 2, I applied engineered enzymes to replace the traditional natural enzymes as recognition groups on inorganic fluorescent nanoprobes, which allows their storage at an elevated temperature of 37 °C for 10 days and maintains a serodiagnostic accuracy of >95% within this period. Moreover, I established the conFlash method to prepare stable nanofilm of perovskite quantum dots (PQD) under ambient conditions, combining perovskite synthesis, crystallization, and polymer protection in a single step within milliseconds. By marrying with thermostable engineered enzymes, for the first time, I could realize serodiagnosis by using PQD nanofilms. Next, in Chapter 3, aiming at the individual difference of intratumoral glutathione (GSH) level, I proposed a customized phototherapeutic strategy by using lanthanide-doped nanoprobes with multiple fluorescence channels. The orthogonal fluorescence channels indicate the distribution, intratumoral GSH level, and eigen temperature (E.T.) of the nanoprobe, respectively. This provides sufficient information to predict the photothermal heat generation by the nanoprobes, which accumulated in the tumors, under different laser prescriptions. By using customized laser prescriptions, the temperature could be precisely controlled in an efficacious range (42 – 45 °C), allowing photothermal-based therapy with both high efficiency and reduced risk of over-therapy. Finally, I expanded this customization strategy to regulate the tumor sensitivity to hyperthermia in Chapter 4. A specificially functionalized nanoprobe can load more hydrophilic heat shock protein (HSP) 90 inhibitor (~389.8 μg mg-1) than the traditional ones (~88.9 μg mg-1) by forming a hydrogen bond network with the surrounding environment through an encapsulated heteropolymetalate guest. With the assessment of tumor depth by fluorescence, an irradiation prescription can be customized to release sufficient HSP90 inhibitor and generate heat for sensitized photothermal treatment of tumors, which not only ensured therapeutic efficacy but also minimized damage to the surrounding tissues. In conclusion, the strategies proposed in this thesis provide practical solutions to the current challenges in robustness of nanoprobes and precise theranostics of diseases. Furthermore, the presented approaches will also guide future sustainable development of inorganic fluorescent nanoprobes for diagnostics and treatment.

Volatile cycles are crucial feedback processes balancing Earth´s chemical and physical systems. The outgassing of volatiles such as H-C-O (hydrogen, carbon, and oxygen) is an essential source for the formation of the atmosphere and hydro- sphere. These reservoirs significantly shaped the Earth´s surface and transformed our planet into a habitable environment. Especially on early Earth, hot mantle temperatures led to vigorous convection, resulting in enhanced volcanism and volatile outgassing. However, hydrous conditions in the mantle are proposed to be required to develop the continental crust, another major player in shaping the Earth´s surface and determining its evolution. This renders the recycling of volatiles a critical sink, rehydrating the mantle. Volatile cycles stabilize the global climate (by maintaining clement conditions) and influence physical and chemical mantle properties (e.g., oxygen fugacity, solidus temperature, viscosity, and den- sity). All these processes and feedback mechanisms render investigating volatile cycles essential for geology and natural sciences in general. In this thesis, I focus on three research questions regarding H-C-O cycling from an observational, theoretical, and modeling point of view: • How did the mantle redox state affect volatile outgassing on early Earth and vice versa? • What are the relative amounts of H2O and CO2 that can be released from an intrusive system on (early) Earth? • Which parameters influence the deep recycling of water, the melt generation, and the water-melt ascent? The Earth´s redox state (considered crucial for the emergence of life) is significantly influenced by volatile cycles and conversely. To answer the first research question of this thesis, I review the accretion and partitioning of volatiles on early Earth. Additionally, I investigate the H-C-O contribution to the early atmosphere. Here, I consider intrusive and extrusive volatile release, including the redox state of the melt, by combining my newly developed RICH (Release of Intrusive CO2 and H2O) code with the volatile speciation code of Caroline Brachmann. The results reveal that the proportions of outgassed volatiles can vary considerably for intrusive versus extrusive systems and for distinct oxygen fugacities. Finally, I discuss the mechanisms that have led to a delayed accumulation of free oxygen in Earth´s atmosphere (e.g., subaerial outgassing of oxidized or burial of reduced species). The primary source of Earth´s atmosphere is volatile outgassing (intrusive and extrusive). As previous publications have already investigated extrusive out- gassing, the second study of this thesis focuses in detail on intrusive volatile release and its potential contribution to the (early) atmosphere. For this purpose, I developed the RICH code that calculates the solubility, accumulation (due to fractional crystallization), and release of H2O and CO2 from an intrusive melt. Furthermore, this study considers the buoyancy of the melt and the uptake of OH via the formation of hydrous phases. I found that about 0 - 85 % of H2O and 100 % of CO2 can be released from intrusive systems depending on the initial volatile content, the buoyancy of the melt, and the formation of hydrous minerals. These results indicate that the total outgassing on Earth is likely underestimated if intrusive volatile release (including fractional crystallization and repartitioning of volatiles in the system) is neglected. Therefore, the process of fractional crystallization and the resulting release of volatiles from intrusions are crucial in estimating outgassing fluxes on rocky planets, including Earth. Closing the volatile cycle, recycling is the essential volatile sink process, returning volatiles to the Earth´s interior. To investigate the depth to which water can be recycled and water outgassing during subduction, I enhanced a 2D numerical convection code, simulating a subduction process. The innovative features of this third study are the coupling of the dehydration calculation with that of the melt generation and the introduction of a saturation efficiency factor. This factor controls the proportion of excess water reacting with the surrounding rock. One result of this study is that the saturation efficiency factor significantly influences the extent of the (water-saturated) melt ascent. If the water that reacts with the surrounding rock exceeds 40 %, the water-saturated melt does not reach the surface (within the maximum simulation time of 50 Myr). Furthermore, the ascent of the water-saturated melt is facilitated by comparatively high initial water contents, high dip angles, and low plate velocities. In contrast, the deep recycling of water is favored by low dip angles, high plate velocities, and comparatively low initial upper mantle temperatures. In summary, this thesis contributes to an enhanced understanding of volatile cycles by investigating the sources (outgassing) and sinks (recycling). Specifically, it reveals the importance of intrusive volatile release and the redox state for total outgassing on early Earth. Regarding volatile recycling, the thesis highlights the significance of the water-melt ascent as an essential process forming arc volcanism.

Die Körperhaftigkeit der Werkzeichnungen (1963-1974) von Franz Erhard Walther und ihre Bedeutung für das Gesamtwerk des Künstlers wurde vielfach unterschätzt.

Lucia Schreyer nimmt sich dieser beidseitigen Blätter an, in denen Sprache und Bild ineinandergreifen und die auf Erlebnissen und Vorstellungen bei der Handlung mit den 58 Werkstücken des 1. Werksatzes (1963-1969) beruhen. Dabei zeichnet sie ihre spannungsreiche Entwicklungsgeschichte zwischen Zensur und Emanzipation im ideologischen Zeitgeist der Konzeptkunst nach und stellt fest: Ihre Ambivalenz und Resistenz gegenüber tradierten Kunstformen steht für eine autonome künstlerische Sprache, in der die dialektische Verbindung von Gegensätzen gedacht wird.

The accessibility of chromatin is a prerequisite for regulatory elements in a cell to carry out their role in gene regulation in a dynamic and cell type-specific manner. Various methods have been developed to investigate the accessibility of chromatin. Initially, techniques were developed for an entirety of cells (“bulk”), but with technological progress, methods were also developed to determine the accessibility of chromatin at the single-cell level. One of the popular techniques to measure chromatin accessibility at single-cell resolution is scATAC-seq. While the resulting data holds promising insights for unraveling the heterogeneity that bulk measurements cannot capture, annotating cell types in scATAC-seq data remains a challenging task. Current methods typically translate the accessibility of a gene to its expression levels and rely on methods developed for scRNA-seq data for cell-type annotation. Given that gene expression is regulated in a highly complex manner, this assumption may not always hold true and does not fully exploit the unique characteristics of the scATAC-seq modality. In this thesis, we developed a novel method for cell-type annotation in scATAC-seq datasets that we call scATAcat. Our method leverages a large number of characterized bulk ATAC-seq data to annotate scATAC-seq data without relying on biological assumptions. When compared to existing methods across various datasets, scATAcat demonstrates better or comparable performance. Although the main focus of this thesis is on cell-type annotation in scATAC-seq data, we also discuss and provide a comprehensive guide to other challenges in scATAC-seq data analysis.

The present volume is the systematic analysis of the chronostratigraphic occupational sequence and spatial organization of the Lower Town South excavation sample of the third millennium BCE at Tell Leilan, northeastern Syria. Tell Leilan is located along the wadi Jarrah on the Khabur Plains where 440 mm annual precipitation can generate extensive cereal agricultural surpluses. The deployment of these surpluses assisted Leilan’s swift growth from a fifteen hectare town to a ninety hectare city at ca 2700 BCE, when the city was known as Shekhna, and its subsequent reorganization as the regional capital, Shubat Enlil, at the post-collapse Amorite resettlement of the region in the early 19th century BCE. Tell Leilan was investigated between 1978 and 2008 by the Yale University Tell Leilan Project with seven seasons of excavation designed to sample the topographically distinct Acropolis and Lower Town, and four seasons of the Leilan Region Survey across 1650 square kilometers, north to south from the Turkish to the Iraqi frontiers. The Tell Leilan occupational sequence spanned the mid-fifth millennium to the 19th century BCE, while the Leilan Region Survey quantified settlement from the early Neolithic to the Islamic periods. The Lower Town South excavation exposed six hundred square meters of third millennium residential occupation on each side of a planned street. The general stratigraphic sequence and organization of the area was published in Weiss 1990, with 15 radiocarbon dates in Weiss et al. 1993, and a schematic doctoral dissertation in Senior 1998. The present doctoral thesis refines and finalizes the chronostratigraphic history of the Leilan Lower Town South: 1) the analysis and description of the stratigraphy and architecture of the 600 m2 area based on the excavation field notes, stratigraphic sections, topographic plans, and the excavation’s photographic record; 2) the generation of 24 new cereal grain radiocarbon dates, flotation-retrieved during the 1989 excavations, with OxCal calibration and modelling, using a total of 38 Lower Town South radiocarbon dates; 3) the analysis of the stratigraphically retrieved ceramic assemblages, ca. 2100 diagnostic sherds and profiles, to produce a new typology and a quantified ceramic chronology. The resulting relative and absolute sequence spans 500 years, from ca. 2700 to 2200/2150 cal. BCE, and provides detailed correlations with the contemporary occupations on the Leilan Acropolis and the northern City Gate, with their ceramic assemblage sequences and their radiocarbon dates. The Tell Leilan Lower Town radiocarbon-dated occupations, LTS/domestic-workshop, Acropolis/public-official and City Gate/administrative, show that different ceramic types’ distributions are not always chronological but can also be functional/social. The chronology of occupational transformations at Tell Leilan during the 3rd millennium, from initial occupation to terminal abandonment, defined here in six stages, is reflected in Khabur Plains regional settlement history that is now enhanced in detail.

Freshwater ecosystems are highly biodiverse and provide essential ecosystem services, yet they are highly endangered, with approximately one in three freshwater species at risk of extinction due to human activity. Among other taxa, aquatic insects are a significant component of freshwater biodiversity. Their immense intrinsic value derives from their status as the most diverse taxonomic group of animals, encompassing high richness of species and traits and occupying numerous positions within food webs. Because of their different sensitivities to water pollution, they are widely used as bioindicators of ecosystem health. However, delineating the global distributions of aquatic insects has been hindered by the limited availability of species occurrence data and the lack of scalable hydrographic data processing tools that would allow assessing their environmental preferences and mapping their populations. This thesis suggests a novel, open-science approach to assess and map global freshwater biod- iversity at a high spatial resolution, with an emphasis on aquatic insects. My research aims were threefold: i) to create a comprehensive, standardised global dataset of aquatic insect occurrences, ii) to develop intuitive tools for complex hydrographic data processing and provide reproducible workflow examples, and iii) to explore the spatial patterns of ecological niche breadths of aquatic insects at the global scale. Therefore, the thesis is divided into three parts. First, I compiled the Global EPTO Database by standardising 50 datasets of Ephemeroptera, Plecoptera, Trichoptera and Odonata georeferenced occurrences at the genus level and attributing them with additional environmental and topographic information. I mapped the global distributions of aquatic insect genera, revealing biodiversity hotspots and knowledge gaps across the different regions of the world. Second, I co-lead the development of the ’hydrographr’ R-package, a tool that enables large-scale freshwater-specific longitudinal connectivity and network analyses, as well as the processing of numerous types of spatial data. Further, I created reproducible workflows of case studies that involve species distribution modelling and network distance and connectivity ana- lyses, aiming to facilitate the use of the package by freshwater ecologists. Third, I explored the large-scale spatial patterns in the ecological niche breadth of aquatic insects using worldwide occurrence records from the Global EPTO Database. The study showed that spatial patterns of assemblage niche breadth are likely shaped by evolutionary origins and dispersal history of EPTO, challenging the common assumption that niches are consistently narrower in species-rich tropical regions. Overall, this thesis represents a valuable contribution to spatial freshwater biodiversity science by providing the first comprehensive and standardised global dataset of aquatic insect occurrences, intuitive tools for complex hydrographic data processing, and novel insights into the spatial patterns of ecological niche breadth of aquatic insects at the global scale. All three outcomes are of high importance in freshwater ecological research, not only by tackling knowledge gaps on global aquatic insect biodiversity distributions, but also by suggesting an integrative approach that can be applied to other freshwater taxa.