The extracellular matrix (ECM) is a complex network of proteins and carbohydrates. Among others, it consists of structural proteins such as collagen, as well as proteoglycans (PGs), which have attached covalently bound and negatively charged carbohydrates called glycosaminoglycans (GAGs). GAGs play an important role in the development and maintenance of cellular functions and communication of cells. PGs, which carry the GAG keratan sulfate (KS), have important functions in the homeostasis, neuronal development, and regenerative processes. Changes in the structure and biochemical composition of KS, such as sulfation, are often associated with various pathologies. Therefore, the early detection of changes in GAG composition, expression, and distribution in the ECM is of great diagnostic interest. However, a reliable detection depends on the availability of specifically binding molecules such as carbohydrate-specific antibodies. In this work, the KS-binding monoclonal antibody (mAb) MZ15 was further characterized and established for imaging. Using commercially available hybridoma cells and protein A/G affinity chromatography, the mAb MZ15 could be produced in mg scale. Then, by utilizing synthetic and chemically defined oligomeric GAGs, the specificity of the mAb MZ15 for highly sulfated KS oligosaccharides was confirmed by glycan microarray assays. After the binding of the mAb MZ15 to KS was validated in a defined environment, binding was also demonstrated in a more complex environment of extracted PGs from rat cornea and salmon cupula by Western blotting. Enzymatic digestion using PNGase F and Niallia circulans keratanase II led to a strong reduction or complete loss of signal, confirming efficient enzymatic digestion of KS structures. Furthermore, the mAb MZ15 was used for the visualization of KS by immunofluorescence microscopy on tissue sections of rat, salmon, and human eyes. Thereby, KS was detected in the corneal stroma across all tested species. Additionally, it was shown that random fluorescent labeling of the mAb MZ15 has no influence on the visualization of KS. Binding of the mAb MZ15 towards KS was confirmed by enzymatic digestion of the tissue sections using keratanase II, resulting in abolished fluorescence in the stroma. Furthermore, visualization of KS was established using a second imaging technique, the laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). Therefore, first a site-directed introduction of a metal label into the mAb MZ15 was performed. The labeled antibody was then used on rat and human eyes. Element-specific measurement using LA-ICP-MS allowed for a detection of KS with high spatial resolution in the cornea of the eyes. After the suitability of the mAb MZ15 for imaging of KS was validated, a single-chain variable fragment (ScFv) based on the full-length antibody was developed. Accordingly, genes of the variable regions of the mAb MZ15 heavy and light chain were specifically amplified. After sequencing and bioinformatic analysis, the KS-binding paratope was identified. Then, the ScFv expression vector was generated and the ScFv was expressed and purified from E. coli. For KS imaging in rat eyes, the ScFv was equally suitable like the full-length antibody MZ15. Next, an apparent binding affinity (KDapp) of the mAb MZ15 to KS of 80 nM was determined by surface plasmon resonance spectroscopy. However, a binding affinity for the ScFv could not be determined. Moreover, various GAG-degrading enzymes were produced to be utilized in the Collaborative Research Center 1340 (CRC1340). To cover a wide range of processible GAGs, the enzymes heparinase I, heparinase II and heparinase III from Pedobacter heparinus, keratan sulfate endo-1,4-β-galactosidase from Sphingobacterium multivorum, keratanase II from Niallia circulans, and chondroitinase ABC from Proteus vulgaris were heterologously expressed in E. coli. Thereby, keratanase II and chondroitinase ABC were produced as 6xHis tagged proteins. Additionally, the enzymes heparinase I, heparinase II, heparinase III, and keratanase II were produced and purified as triple-tagged fusion proteins, where the tags consisted of maltose-binding protein, 6xHis tag, and Strep tag II, respectively. By photometric measurement, the following activities of the triple-tagged heparinases were determined: heparinase I: 0.6 U/mg, heparinase II (substrate: heparin): 38.5 U/mg and heparinase III: 31.7 U/mg. Furthermore, the analysis of heparinase digestion products by HPLC using the respective substrates heparin and heparan sulfate revealed expected substrate specificities for the produced heparinases.

Ein gutes klinisches Outcome zu erreichen ist das oberste Ziel in der Schlaganfallbehandlung. In dieser kumulativen Habilitationsschrift werden Ergebnisse klinischer Schlaganfallforschung vorgestellt, welche nur einen Teil des komplexen Mosaiks der Einflussfaktoren auf das klinische Outcome bei diesem Krankheitsbild darstellen. Die Nierenfunktion hat maßgeblichen Einfluss auf den ischämischen Schlaganfall. Mit einer retrospektiven Analyse eines prospektiv geführten Schlaganfallregisters, konnten wir verdeutlichen, dass Patienten mit einer schweren Nierenfunktionsstörung (eGFR < 30ml/min) zum Zeitpunkt des akuten ischämischen Schlaganfalls ein signifikant höheres Risiko für eine symptomatische intrazerebrale Blutung nach intravenöser Applikation von Alteplase haben was nicht dazu führen darf, dass per se diesen Patienten diese evidenzbasierte Therapie vorenthalten sollte. Vielmehr sollte die Nierenfunktionsstörung als entsprechenden Risikofaktor in der Risiko-Nutzen-Abwägung in Betracht gezogen werden. Zudem konnten wir anhand desselben Registers zeigen, dass Patienten mit einer Tandem-Okklusion der hirnversorgenden Gefäße (ipsilateraler Verschluss der A. carotis interna und dem Karotis T oder der A. cerebri media) signifikant häufiger eine relevante klinische Besserung (kurz- und langfristig) erleben, wenn sie zusätzlich zur intravenösen Applikation von Alteplase einer endovaskulären mechanischen Thrombektomie zugeführt wurden. Diese von uns damals erstmals publizierte Erkenntnisse konnte inzwischen mehrfach in bestätigt werden. In einer großen deutschlandweiten, prospektiv-randomsierten und multizentrischen Studie konnten wir nachweisen, dass die Detektionsrate fürs paroxysmale Vorhofflimmern mit einem standardisierten, verlängerten (bis zu 7 Tagen) und zentral ausgewerteten EKG-Monitorings im Vergleich zur Standarddiagnostik auf deutschen Stroke Units nach ischämischen Schlaganfall oder TIA signifikant höher ist und dieses additive kardiale Monitoring zur einer reduzierteren Mortalitätsrate innerhalb von 2 Jahren führt – dies war aber nicht verursacht durch eine höhere Rate an etablierter oraler Antikoagulantion oder einer reduzierten Rate an vaskulären Endpunkten erklärbar. Zudem gelang es uns anhand einer post-hoc Analyse dieser Daten zu zeigen, dass eine Abnahme der Nierenfunktion um 20% bei den Patienten mit einem ersten gemessenen eGFR-Wert von über 60ml/min (üblicherweise als eine Subgruppe angesehen, bei der kein relevanter Einfluss der Nierenfunktion auf das klinische Outcome beim Schlaganfall zu erwarten ist) signifikant mit dem häufigeren Auftreten von vaskulären Ereignissen / Komplikationen und einer höheren Rate an Mortalität assoziiert ist. Somit erscheint es zur Prognoseabschätzung sinnvoll, die Nierenfunktion bei Patienten mit einem akuten ischämischen Schlaganfall im Verlauf des stationären Aufenthaltes zu kontrollieren um diese Subgruppe zu identifizieren und so z.B. engmaschigeren klinischen Kontrollen zuzuführen. Patienten mit einem ischämischen Schlaganfall und einem Vorhofflimmern werden entsprechend internationaler Leitlinien mit oralen Antikoagulantien, vornehmlich mit DOACs zur medikamentösen Sekundärprophylaxe behandelt. Hierbei kommt es häufig zu einer fehlerhaften Unterdosierung, welche einen maßgeblichen Einfluss auf das klinische Outcome hat.33 Wir konnten anhand der Daten des Berliner Vorhofflimmer Registers zeigen, dass dies trotz Behandlung auf einer der Berliner Stroke Units bei etwa 10% der Patienten vorkommt und mit dem höheren Alter der Patienten und einem höheren Punktwert auf der HASBLED Skala assoziiert ist. Der Einfluss auf die erhaltene Selbständigkeit nach 3 Monaten war in unseren Daten nicht nachweisbar, bisher nicht veröffentliche Daten zeigen aber diesen Effekt nach 2 Jahren. Eine weitere in der Allgemeinbevölkerung häufig vorkommende Erkrankung mit Einfluss auf das Outcome von Patienten mit ischämischen Schlaganfall ist die Herzinsuffizienz. Mit einer retrospektiven post-hoc Analyse der TIM HF Studien zeigte sich eine geringe Rate an ischämischen Schlaganfall in dieser Herzinsuffizienzkohorte und war mit höheren Spiegeln an NT-pro-BNP sowie der vorhandenen Komorbidität pAVK assoziiert – zudem starben die Herzinsuffizienzpatienten mit einem inzidenten ischämischen Schlaganfall oder TIA innerhalb eines Jahres signifikant häufiger als die Herzinsuffizienzpatienten ohne ischämischen Schlaganfall oder TIA.

Diese Dissertation analysiert die psychosoziale Betreuung und Rehabilitation unbegleiteter jüdischer Kinder durch die United Nations Relief and Rehabilitation Administration (UNRRA) in der US-amerikanischen Besatzungszone Deutschlands nach dem Zweiten Weltkrieg. Ausgehend von zentralen Quellen wie dem Bericht Psychological Problems of Displaced Persons zeigt die Studie, dass die UNRRA ein normativ geprägtes Repatriierungsmodell verfolgte, das familiäre Reintegration als universelles Ziel propagierte – ungeachtet der spezifischen Erfahrungen jüdischer Kinder, die häufig vollständig entwurzelt und tief traumatisiert waren.

Am Beispiel des DP Children’s Centers Kloster Indersdorf werden strukturelle Schwächen wie antisemitische Spannungen, standardisierte Betreuungskonzepte und mangelnde Traumakompetenz des Personals aufgezeigt. Zugleich identifiziert die Untersuchung individuelle Handlungsspielräume, etwa im Wirken der Sozialarbeiterin Greta Fischer, die versuchte, Lösungen jenseits starrer Vorgaben zu realisieren. Die wachsende Bedeutung zionistischer Jugendbewegungen ab 1945/46 verdeutlicht, dass alternative Rehabilitationskonzepte kollektive Identität, Zukunftsperspektiven und kulturelle Selbstbestimmung zu bieten vermochten – gerade dort, wo UNRRA-Strategien scheiterten.

Die Arbeit argumentiert, dass humanitäre Hilfe nicht als technokratisches Instrument, sondern als ethisch und politisch gerahmter Raum verstanden werden muss. Die Geschichte jüdischer DP-Kinder wird damit zum Spiegel für die normativen Begrenzungen und moralischen Prüfsteine internationaler Fürsorgesysteme in der Nachkriegszeit.

Synapses serve as critical information hubs in inter-neuronal communication. However, preserving their optimal capacity for information processing and storage exhibits a significant challenge in ensuring successful brain aging. Our previous research demonstrated that the protein scaffolds forming presynaptic release sites are subject to dynamic plastic remodeling with aging, a process we term “PreScale”. This remodeling plays a pivotal role in managing the delicate trade-offs among survival, sleep, and memory formation and mediating brain resilience during an early, malleable stage of drosophila brain aging. In this investigation, we disclose a reciprocal coupling between mitochondrial functional status and PreScale in the early aging brain of drosophila. The neuronal stimulation of PGC1 transcription co-activator protected the premature brain from aging-related mitochondrial dysfunction, as indicated by enhanced oxidative phosphorylation and increased ATP levels, and concurrently suppressed the aging associated PreScale. On the contrary, neuronal attenuation of ATP synthase subcomponent Ⅴsince adulthood deteriorated mitochondrial functionality during premature brain aging and simultaneously propelled PreScale. Neuron-specific fine tuning of mitochondrial metabolism by PGC1 significantly prolonged the lifelong time of individual drosophila, mitigated ROS accumulation and bolstered the organism's overall capacity to withstand oxidative stress in later stages. whereas, the elimination of blw (ATP5A) within neurons led to outcomes diametrically opposed to PGC1. Collectively, the salutary health-promoting effects resulting from brain rejuvenation of mitochondrial dysfunction via neuronal activation of PGC1 in the early phases of brain aging opens up a novel anti-ageing paradigm for the future. In our mechanistic exploration, ROS emerged as the molecular messenger for mitochondria in regulating the plastic change of age-dependent PreScale. Pharmacological administration of ROS agents acutely induced PreScale within 6 hours, while neuronal overexpression of antioxidants Cat and SOD2 relaxed the need to undergo age-driven PreScale. Therefore, it’s tempting to speculate that, contrary to its traditional damaging identity, ROS more likely serves as a signaling carrier, modulating age-associated PreScale in early-aging fly brain. Subsequently, in the following chapter, we progressed to confirm, comparably to autophagic impairment, MB-specific PGC1 overexpression and blw attenuation tuned in the metaplastic change of brain-wide PreScale. Furthermore, silencing ATP5A within MB neurons since adulthood led to a notable decrease in brain-wide short neuropeptide Y (sNPF) level. Given the significance of sNPF signaling in regulating PreScale, we suggest that sNPF might be the connector, linking mitochondrial functional status within MB to the spreading phenotype of PreScale throughout the entire brain. Conversely, we proceeded to explore mitochondrial plasticity in the context of genetically-engineered PreScale. artificially-installed PreScale suffices to transform the brain metabolic state into an energy-conserving mode, as evidenced by a decrease in both brain oxidative phosphorylation and ATP levels. Thus, PreScale, potentially via modifying mitochondrial performance, seemly acts as a precursor in regulating the brain's metabolic state. Subsequent analysis suggests that mitochondrial Ca2+ influx as feedback signals, might potentially modulate the adaptation of the mitochondrial state to align with the background of genetically installed PreScale.

Die vorliegende Habilitationsschrift untersucht den Einsatz von 3D-gedruckten, nicht-invasiven Restaurationen zur Behandlung nicht kariesbedingter Verluste der Zahnhartsubstanz. Im Fokus stehen Ätiologie und klinische Herausforderungen solcher Defekte sowie die Eignung additiv gefertigter Hybridmaterialien. Anhand präklinischer und klinischer Studien wird das Potenzial der 3D-Drucktechnologie als innovative Behandlungsoption evaluiert und mit. Die Ergebnisse zeigen vielversprechende Ansätze für eine individualisierte, nicht-invasive und langzeitprovisorische Versorgung in der restaurativen Zahnmedizin.

Extreme precipitation is one of the main meteorological hazards in Central Europe that causes high numbers of casualties and financial losses. Therefore, the interplay of intensity and frequency of heavy precipitation events is of importance when building safety structures like dikes and flood control mechanisms as well as hydrological infrastructure such as sewerage systems. Additionally, the variations of those precipitation characteristics due to climate change are an important subject of investigation.

In this thesis, a statistical model is used to find a relation between intensity and frequency. Therefore, we model the distribution of block maxima. To do so, we use the method of Extreme Value Statistics (EVS). Since extreme precipitation events occur over different durations and have varying consequences, we use a duration-dependent formulation for the distribution parameters. This procedure prevents inconsistencies such as quantile crossing. Including different durations in the model has two further advantages: (1) With the duration-dependent model, we are able to estimate return periods and associated return levels for different durations. (2) Data is now used more efficiently because high-temporal-resolution data can be aggregated to provide information on different durations which would not be available otherwise. This increases the amount of usable data. An efficient use of data is crucial in modeling extreme events since data is by definition rare. An important tool to analyze the main characteristics of extreme precipitation, are Intensity-Duration-Frequency (IDF) curves. They describe the relation between quantile (intensity), time scale (duration) and probability (frequency) of heavy precipitation events and provide a concise visual representation of these characteristics. A variety of methods can be used to estimate the statistics that define IDF curves and so, their shape and potential for a meaningful estimation depends strongly on the choice of method. In this thesis, a new and more flexible approach is presented that enables the model to capture effects resulting from seasonality of precipitation, although only annual maxima are required as input data. The flexible model comprises different features that control a duration offset, multiscaling and an intensity offset. According to our findings, incorporating multiscaling or a duration offset in the model is beneficial only for very short or long durations. Moreover, implementing an intensity offset in the model results in an overall improvement for the medium duration range of one hour to one day.

In most studies about statistics of extreme precipitation, potential changes of the climate system are neglected. However, extreme precipitation shows inter-annual changes and should be modeled accordingly. In this thesis, large-scale parameters are included in the statistical model as covariates for the distribution parameters. This approach further enables the estimation of extreme precipitation in different large-scale settings and adds another dimension to the intensity-duration-frequency relationship. The results indicate that the probability of severe precipitation has been increasing since 1950 in every season. The occurrence of extreme precipitation is strongly linked with atmospheric blocking situations during summer and temperature during winter, resulting in higher probabilities of extremes with a fixed intensity.

El primer dato de la geografía centroamericana es una imponente cadena de volcanes que se extiende por más de mil kilómetros a lo largo del istmo. Denominada por los vulcanólogos como Arco Volcánico Centroamericano, esa cadena contiene alrededor de cincuenta volcanes activos que presentan una gran variedad de formas. Entre las que destacan los estratovolcanes, con conos altos y esbeltos, como el volcán de Agua en Guatemala, de 3760 metros de altura, y los volcanes complejos, que se levantan como grandes montañas extendidas, como el volcán Irazú en Costa Rica, de 3432 metros de altura. Con la excepción de Honduras, todos los estados centroamericanos tienen volcanes activos, a los pies de los cuales, se extienden las ciudades y los valles donde se ha concentrado históricamente la población en la región. A pesar de la presencia reiterada de estas eminencias en el paisaje, existen pocos estudios que hayan abordado la pregunta por la influencia de los volcanes en los procesos de construcción de estado-nación y modernidad en la región. Enfocándose en el período 1880s-1940s, un período clave para la formación del estado-nación y la comprensión moderna de los volcanes en Centroamérica y el mundo, esta tesis va tras esa pregunta. Basándose en una variedad de fuentes producidas por observadores volcánicos centroamericanos y foráneos, y contra una arraigada tendencia en la historia intelectual de las montañas a mirar estos hitos como espacios desconectados de la historia y la temporalidad humanas, el trabajo plantea que los volcanes, con su presencia eminente en el paisaje, influyeron en la forma en que los centroamericanos se pensaron a sí mismos y al lugar de Centroamérica en el mundo, y fueron incorporados en los proyectos de modernidad de la región como un recurso valioso para aspectos medulares de los procesos de construcción de estado-nación, tales como la escritura y las conmemoraciones históricas, la exploración y producción de conocimiento y el ensayo de nuevas actividades económicas típicamente modernas, como el turismo.

This dissertation focuses on the development and application of polyglycerol (PG)-based polymers for the modulation of type 2 inflammation as well as their use as innovative materials for biosensor analysis using surface plasmon resonance (SPR) spectroscopy. Dysregulated type 2 inflammation forms the pathophysiological basis of atopic diseases such as atopic dermatitis or allergic asthma. Among other factors, disease progression is influenced by increased levels of cytokines such as thymic stromal lymphopoietin (TSLP) and extracellular matrix proteins such as fibronectin (FN). Both molecules exhibit cationic regions on their surface and therefore offer potential for electrostatic interactions with polyanions. In the first part of this work, linear and dendritic PGs were carboxylated and sulfated and subsequently analyzed via SPR with regard to their interactions with FN and TSLP. Highly sulfated polymers showed high-affinity binding to both target molecules. The most promising polymer candidates were further investigated to assess the extent to which they can modulate or suppress the inflammatory effects mediated by TSLP and FN. Even at low concentrations (10 ng/mL), TSLP-neutralizing effects were observed with respect to the proinflammatory type 2 polarization of T cells. In contrast, significantly higher concentrations were required for FN-neutralizing effects in inflamed bronchial epithelium tissue models. As these biochemical investigations require highly sensitive and selective analytical methods, the second part of the work focused on the development of innovative SPR biosensors based on a PG-polyethylene glycol (PEG) hydrogel. The main requirements were high ligand loading capacity and minimal nonspecific binding. Heparin-binding proteins such as the described FN or lectins often lead to nonspecific interactions with the carboxymethyldextran (CMD) matrix of conventional SPR biosensors, which complicates analysis. In contrast, the newly developed PG-PEG SPR biosensors exhibited significantly reduced nonspecific binding while maintaining high loading capacity. Furthermore, they were validated for the analysis of both small (222 Da) and large (150 kDa) biomolecules by comparing the determined binding constants with those obtained using CMD-based biosensors.

Eine Veränderung von Struktur und Funktionalität des kardiovaskulären Systems ist im Alter generell zu beobachten. Hierbei spielt der Symptomkomplex des Metabolischen Syndroms eine herausragende Rolle. Die Mechanismen hinter der Assoziation zwischen geriatrischen Syndromen wie Frailty oder Sarkopenie mit kardiovaskulären Erkrankungen gilt es weiterhin besser zu verstehen. Basierend auf eigenen wissenschaftlichen Analysen wird der in dieser Arbeit der Zusammenhang zwischen dem Metabolischen Syndrom mit Inflammationsprozessen, Sarkopenie, Frailty, Vitamin D-Status und Lp(a) dargestellt und diskutiert.

By means of a theoretical introduction and fourteen case studies, this dissertation formulates and validates its overarching thesis: that religious thought in the pre-modern world of Islam has at its core a trans-denominational disposition and therefore requires a historiographical approach that systematically and methodically transcends the boundaries of individual religious communities. Irrespective of the religious community, religious thought is the result of a constant and open-ended effort to understand, organize, and explain the manifold and changing manifestations of one’s own religion. The present dissertation understands these endeavours as an intellectual practice that has an irreducibly trans-denominational and transcultural complexion, as it is in constant exchange with other intellectual practices and decisively shaped by these transactions. In a first step (I.), the introductory essay presents various reasons why historical accounts of religious thought tend to remain within the confines of a particular religion or denomination, thus conveying the deceptive impression that religions are self-referential and self-contained entities. This tendency towards navel-gazing has been bolstered by the formation of disciplinary segmentation in Western academia, which has assigned a separate specialist discipline to each of the major religious traditions. At best, these disciplines engage in scattered exchanges with disciplines assigned to other religious traditions and occasionally resort to a comparative approach. In a second step, the basic components of trans-denominational religious thought are presented based on action-theoretical models that have been adopted from transcultural theories. Following the lead of transcultural theories, religious thought is understood as an aggregate of intentional and unintentional transactions that are marked by the characteristics of agents (II.1.), the constitution of commodities (II.2.), places and contexts (II.3.), and the type and mode of the (trans-)action (II.4.). The third part of the introductory essay (III.) presents the fourteen case studies included in this dissertation with reference to the aforementioned components of trans-denominational religious thought by clarifying which of them is relevant to each case study. The fourth part (IV.) traces precursors for the emergence of a trans-denominational approach to the history of religious thought within the humanities at European universities and outlines processes of disciplinarisation that hampered this development. Until well into the nineteenth century, ‘oriental’ religions were primarily studied from the vantage point of Christian theology and closely linked to the study of ‘oriental’ languages, each of which was assigned to a specific religious tradition, while at the same time being subordinate and auxiliary to the study of the biblical languages. The gradual abolition of admission restrictions for Jewish university teachers over the course of the nineteenth century generated a necessary condition that furthered the emergence of rudimentary trans-denominational approaches to religious thought. Such developments were dealt a heavy blow prior to World War II, not least because of the employment ban imposed on Jewish government employees. In recent decades, efforts to promote a trans-denominational approach to the history of religions and religious thought have again gathered pace thanks to the adoption of new methodological approaches from the historical sciences, the social sciences, and anthropology, which put an emphasis on transcultural relationality, entanglement, interconnectedness, and interaction. The final section of the introductory essay outlines the basic points of a heuristic framework that structures the trans-denominational approach to the history of religious thought. The fourteen case studies that follow the introductory essay are divided into three thematic clusters in accordance with their thematic thrust. The nine studies in the first cluster deal with various aspects of the Jewish Muʿtazila. The Muʿtazila was a dominant strand of speculative thought during the ʿAbbāsid period that has typically been presented as an Islamic school of thought. Jewish Muʿtazilism is not only a reflection of the fact that Jewish religious thought was at the time decisively shaped by the socio-cultural milieu of the Islamic world, but also makes plain that Jewish champions of Muʿtazilī thought actively contributed to advancing the intellectual profile of this school of speculative thought. Their works therefore constitute an invaluable source for drawing a more nuanced picture of Muʿtazilī thought. The second thematic cluster comprises four case studies that demonstrate the trans-denominational character of religious thought during the heyday of Copto-Arabic literature in the thirteenth and fourteenth centuries. During this period, the transformation of religious thought was driven by Coptic clerics and intellectuals whose family members held key positions in the Ayyubid state administration and thus enjoyed privileged access to the canon of knowledge of the educated elite. Based on the reception of the works of Maimonides and Fakhr al-Dīn al-Rāzī in major works by Coptic authors, the studies in this cluster exemplify that the renewal of religious thought in Coptic Christianity was largely negotiated through terms and concepts fleshed out in non-Christian literature. The third thematic cluster explores cross-connections between the thought of major representatives of kalām and Galenic literature during the ʿAbbāsid period. Generally, these two knowledge traditions have been associated with two sharply separated epistemic communities that functioned independently from each other and in mutual ignorance of one another. In stark contrast to this assumption, my study points to social and intellectual contexts that provided recurring opportunities for the exchange of ideas between two discrete bodies of knowledge. In addition, the relationship between kalām and the Galenic tradition is reassessed and resituated in the light of late antique points of contact between patristic and Galenic literature. Using the example of the concepts of ‘desire’/‘aversion’ and ‘pleasure’/‘pain’ in Muʿtazilī literature, the second part of the case study seeks to demonstrate that specific views of the eminent physician Abū Bakr Muḥammad bin Zakariyyāʾ al-Rāzī prompted intra-Muʿtazilī debates. The emphasis on the trans-denominational condition of religious thought, which constitutes the common thread of the fourteen case studies included in this dissertation, is grounded in the methodological hypothesis that the dynamic history of religious thought is best explored and understood in light of a trans-denominational approach, as it reveals important facets of religious thought that remain hidden to a self-referential, mono-denominational historiography.

First-principles methods provide unmatched accuracy and robustness for the computational simulation of materials. However, the computational cost of first-principles methods scales unfavorably with the problem size N, with commonly used density functional theory (DFT) and wavefunction theory (WFT) methods typically exhibiting at least O(N^3) scaling. Consequently, first-principles methods are routinely restricted to system sizes of a few to a few hundred atoms. Beyond this, large-scale material simulations or the creation of extensive reference datasets, e.g. for training machine learning models, often become computationally prohibitive. As a result, cost-efficient alternatives that offer the same high accuracy and broad applicability as first-principles methods are highly sought after. Consequently, this thesis focuses on the development of low-cost electronic structure methods based on cost-efficient first-principles baselines, enhanced by (semi-)empirical and physics-inspired corrections. Potential cost-reducing measures were rigorously analyzed to assess their computational advantages relative to potential losses in accuracy or precision from systematic and stochastic errors. Based on this analysis, guidelines were established for designing robust and reliable baselines and corresponding corrections. A key outcome of this work is the development and implementation of the PBE/min+s/LPC method in the FHI-aims code. PBE/min+s/LPC allows for the cost-efficient calculation of structural properties of inorganic solids. The baseline, PBE/min+s, uses a compact and computationally inexpensive min+s basis set. To address the systematic overestimation of bond lengths caused by basis set incompleteness, a linear pairwise correction (LPC) was developed. LPC's minimally invasive form as well as requiring only one fitting parameter per elemental species, ensures the method's generalizability. PBE/min+s/LPC demonstrates reliable results for structural properties, enabling large-scale geometry optimizations and molecular dynamics simulations. Additionally, PBE/min+s/LPC has been successfully employed to relax the structure of a complex supramolecular architecture on Ag(111), a task for which conventional first-principles methods are prohibitively expensive. In a second project, the applicability of the Bayesian error estimation functional (BEEF-vdW) was extended to electronic structure codes without efficient fast fourier transform algorithms by employing cost-efficient atom-pairwise and many-body dispersion corrections. The results indicate that atom-pairwise methods, such as the Tkatchenko-Scheffler (TS) van der Waals correction and, particularly, the exchange-dipole model (XDM) method, provide a well-rounded description of molecules, solids and chemisorption processes. In a third project, a Bayesian linear regression approach was used to obtain robust and transferable parameterizations as well as uncertainty estimates for spin-component-scaled second-order Møller–Plesset perturbation theory (SCS-MP2), termed BSCS-MP2. The obtained BSCS-MP2 uncertainty estimates are shown to effectively reflect changes in data quality and model complexity as well as being robust for out-of-sample inference.

This dissertation examines the development of Digital Government Service Platform (DGSP) in China. This exploratory research centers around three core questions: to what extent do DGSPs differ in local China? What factors and how do they influence the imbalanced development of DGSPs and digital service integration at local level? What factors influence citizens’ DGSP use, and how does DGSP influence citizens? By employing a mix-method research design, this dissertation explores DGSP’s evolution, local practices, and the implications for government-citizen relations. This research presents four stages of DGSP development in China and identifies the disparities of local DGSPs. Meanwhile, this study finds that the change in power and resource distribution among actors and contextual characteristics are jointly influencing local DGSP development. Moreover, this study has identified variables correlated to individuals’ DGSP use. Citizens’ satisfactions on DGSP and the government-citizen communication tools are both potential to decrease traditional preference on personal connection, enhance government performance, improve perceived government transparency, and promote social equity. Overall, developing DGSP is a process of strengthening top-down digital supervision, promoting cross- government collaboration, improving government-citizen relations, and centralizing data. This dissertation contributes to understand the interactions of actors and institutions in complex dynamics of digital government transformation and generates empirical knowledge of digital government studies in non-democracies.

Lahmheit stellt weltweit eine der größten Herausforderungen in der Milchkuhhaltung dar, sowohl aus tierschutzrechtlicher, als auch ökonomischer Sicht. Ziel dieser Arbeit war es, die aktuelle Prävalenz lahmer Kühe anhand einer umfangreichen Stichprobe zu ermitteln. Weiterhin sollte der Einfluss von Weidezugang und potenziellen Risikofaktoren auf die Lahmheitsprävalenz in verschiedenen Laufstall-Haltungssystemen untersucht werden. Die für diese Untersuchung verwendeten Daten waren Teil einer groß angelegten Beobachtungsstudie in 3 Regionen Deutschlands: Nord (Schleswig-Holstein und Niedersachen), Ost (Mecklenburg-Vorpommern, Brandenburg, Sachsen-Anhalt und Thüringen) und Süd (Bayern). Die Datenerhebung erfolgte von Dezember 2016 bis August 2019. In jedem der 659 Betriebe wurde der Status praesens bei einem einmaligen Betriebsbesuch durch Interviews, Frage- und Erhebungsbögen, Probensammlungen und Scorings management- und tierbezogene Daten erhoben. Zur visuellen Beurteilung des Gangbildes wurde eine 5-Punkte-Skala (modifiziert nach Sprecher) angewandt, wobei Tiere mit einem Sprecher-Score von ≥3 als lahm und Tiere mit einem Sprecher-Score von ≥4 als schwer lahm eingestuft wurden. Die mittlere Lahmheitsprävalenz auf Betriebsebene betrug 29,4% und 8,2% für schwer lahme Kühe. Bezüglich des Weidezugangs verdeutlichen die Ergebnisse dieser Studie einen positiven Einfluss auf die Lahmheitsprävalenz. Mit zunehmender Weidedauer (bis etwa 10 Stunden pro Kuh und Tag) nahm die Lahmheitsprävalenz in den besuchten Herden kontinuierlich ab. Bereits kurze Perioden des Weidezugangs von mindestens 2 Stunden pro Kuh und Tag durchschnittlich im Jahr, haben sich positiv auf das Gangbild ausgewirkt. Hinsichtlich der Risikofaktoren in Laufstallhaltungen zeigten die Ergebnisse, dass die Gestaltung der Liegeboxen und die Art der Fütterung mit der Lahmheitsprävalenz assoziiert sind. Kühe aus Betrieben mit Hoch-Tiefboxen oder Tiefboxen zeigten ein geringeres Risiko eine Lahmheit zu entwickeln als Kühe in Betrieben mit Hochboxen. Durch die Verwendung von Einstreu kann das Risiko für eine Lahmheit in Hochboxen gesenkt werden, erreicht aber nicht die Werte von Hoch-Tiefboxen oder Tiefboxen. Weiterhin konnte gezeigt werden, dass mit steigender Liegeboxenbreite das Risiko für Lahmheit abnimmt. In Betrieben, die eine TMR (Total-Mischration) verfüttern, war das Lahmheitsrisiko geringer als in Betrieben, die eine AMR (Teil-TMR mit individueller Kraftfutterzuteilung) oder eine Einzelkomponentenfütterung durchführten. Speziell für die Erstlaktierenden konnte gezeigt werden, dass die Art und Weise der Lahmheitsbeobachtung den Anteil lahmer Tiere beeinflusst. Die tägliche Lahmheitsbeurteilung (im Vergleich zu seltener als täglich) und Lahmheitsbeurteilung zusammen mit anderen Routinetätigkeiten (im Vergleich zur Lahmheitsbeobachtung als separater Arbeitsschritt) waren mit einem geringeren Lahmheitsrisiko verbunden. Dies zeigt, dass durch die frühzeitige Erkennung bei gleichzeitig zeitnaher und angemessener Behandlung lahmer Kühe in der ersten Laktation, chronische Lahmheitsfälle sowohl bei primiparen als auch bei multiparen Kühen verhindert werden können. Die vorliegende Studie liefert Belege für entscheidende Zusammenhänge zwischen managementbedingten Risikofaktoren und der Höhe der Lahmheitsprävalenz auf Betriebsebene, insbesondere der Kuhkomfort und der Weidezugang sind hier hervorzuheben. Zukünftige Studien sollten die festgestellten Assoziationen in Longitudinalstudien validieren und daraus geeignete Maßnahmen ableiten. In weiteren Interventionsstudien könnten diese Maßnahmen auf ihre Wirksamkeit überprüft werden. Anhand der besten Betriebe aus dieser Studie können Richtwerte für andere Betriebe mit ähnlichen Betriebscharakteristika abgeleitet werden. Insgesamt muss durch kontinuierliche und evidenzbasierte Beratung der Betriebe mit nachfolgend konsequenter Umsetzung der Maßnahmen, die zu hohe Lahmheitsprävalenz deutscher Milchkühe verringert werden.

Type I Interferons are an early key defence mechanism against viral infections. The extent to which this system is active in peripheral neurons is not known, although these neurons can fall victim to viral infection. In recent years, a growing body of evidence has challenged the view that neurons were passive entities within immunological processes, showing that they can employ their own immune defence mechanisms. This study looks at the characteristics and importance of the type I IFN system in immunity in peripheral sensory neurons through the help of an in vitro infection model.

IFNAR1, one of two proteins that form the type I Interferon receptor, was found to be expressed in DRG neurons. CGRP+, NF200+ and IB4-binding DRG neurons demonstrated similar levels of IFNAR1 expression, showing that type I Interferon receptor expression was not restricted to a specific neuronal subtype. In vitro experiments on cultures of peripheral sensory neurons showed that they have the ability to detect IFN- and react through upregulation of IFN-stimulated genes. IFN-stimulated genes were seen to be expressed basally and upregulated upon presentation with Poly I:C.

This study introduces a new conditional KO mouse model, where a Snap25Cre-driver was bred with Ifnar1-floxed mice, resulting in a neuron-specific deletion of Ifnar1. This Snap25Cre/+ Ifnar1flox/flox model was shown to be efficient. In in vitro infection with AAV-2/9, significantly increased apoptosis was observed in the DRG neurons lacking IFNAR1 compared to the wildtype DRG neurons. This shows that type I IFN signalling is active in peripheral sensory neurons. This signalling serves as an inherent protection mechanism for the DRG neurons against viral infection. More knowledge on this will prove important in combating viruses that are able to use the PNS as an entryway, as well as in the development of virus-based therapy strategies.

This thesis investigates all-optical switching and domain wall (DW) dynamics in GdFe ferrimagnetic alloys following femtosecond laser excitation. Advanced magnetic imaging techniques, including photoemission electron microscopy (PEEM) and Kerr microscopy, are used to capture the magnetic behavior of the sample. The study examines single-pulse all-optical toggle switching, where the magnetization of the films is reversed by a single p-polarized laser pulse, independent of the initial magnetization direction. Specifically, we investigate the mechanisms behind deviations from deterministic toggle switching, especially near magnetic domain walls. The study reveals that non-deterministic switching arises from intrinsic factors, such as domain wall elasticity and laser-induced motion related to the sample itself, as well as extrinsic factors, like laser pulse variations, which depend on the setup. Further, double pulse excitation experiments probe the fastest toggle-switching frequency, where two laser pulses with an adjustable time delay between them excite the sample. By using different fluence ratios of the pulses as a function of the time delay, the experiments explore the role of fluence in re-switching. It was found that re-switching occurs within a time delay between 4 and 40 ps after the first pulse, with optimal conditions when the first pulse is just above the single-pulse switching threshold and the fluence of the second pulse is 0.5–0.7 times that of the first pulse. Atomistic spin dynamic simulations support these findings, offering insights into cooling dynamics where re-switching requires that electron and lattice temperatures equilibrate. We also investigated the behavior of the sample at time delays of 2 ps or less between pulses, following double-pulse switching at two temperatures, one below (70K) and one above (room temperature) the magnetic compensation temperature. Findings indicate that the threshold fluence required to induce multi-domain formation or demagnetization varies with the sample’s initial temperature, with more deterministic toggle switching observed at the lower temperature of 70K. Notably, the switching probability rises drastically at these short time delays, where the second pulse significantly amplifies the effect of the first, even if one or both pulses are below the threshold fluence of single pulse switching. Additionally, we examine DW motion in GdFe thin films with an in-plane easy axis under laser excitation. Depending on the DW’s position relative to the laser spot, either entropic torque or magnon spin transfer torque may dominate the motion. Although we did not identify a single, consistent direction of DW movement, it is evident that for DW motion, the DWmust be located within the (σx) region of the laser spot. Together, these findings advance our understanding of high-speed, energy-efficient magnetic switching and DW control, with promising implications for ultrafast magnetic storage technologies.

The increasing need to reduce atmospheric CO₂ emissions has driven interest in the electrochemical CO₂ reduction reaction (CO₂RR) as a sustainable approach for converting CO₂ into valuable chemicals. However, the development of efficient electrocatalysts for CO2RR to target products remains challenging due to the high overpotential and low selectivity. This thesis explores the design and performance of copper (Cu)-based foam electrocatalysts, with an emphasis on their potential to enhance the electrochemical conversion of CO₂ into multi-carbon products, such as ethanol and ethylene. In addition to developing robust electrocatalysts for efficient CO2RR, the goal was to follow the composition and structural transformations of the catalysts and reaction intermediates under operating conditions using operando spectroscopies, complemented by ex-situ methods. Operando X-ray absorption spectroscopy (XAS) revealed that bulk oxidation state transitions in oxide-derived Cu (OD-Cu) catalysts occur over tens of minutes, with kinetic trapping of subsurface oxygen species. In contrast, surface-enhanced Raman spectroscopy (SERS) indicated rapid oxide-to-metal transitions on the catalyst surface within seconds. Surface adsorbed hydroxides and carbon-containing intermediates were identified, suggesting their role in facilitating *CO adsorption and enhancing multi-carbon selectivity. A morphology-control strategy was implemented to optimize alcohol selectivity. Introducing NaCl during electrodeposition altered the OD-Cu structure, significantly improving faradaic efficiency for alcohol production. Enhanced electrochemical surface area per Cu atom promoted co-adsorption of *OH and *CO, favoring ethanol formation. The foam catalyst design was extended to bimetallic Cu-In and Cu-Sn systems to further modulate CO₂RR selectivity. Depending on the Cu-to-M (In or Sn) ratio, these catalysts preferentially produced CO or formate. XAS and SERS analyses revealed that Cu-In and CuSn catalysts undergo dynamic structural transformations, with surface copper oxides converting into mixed hydroxides and carbonates before reduction. Despite differences in composition, specific Cu-M ratios resulted in similar CO₂RR selectivity, highlighting the role of secondary metals in tuning catalytic performance. In conclusion, a combination of bulk- and surface sensitive operando spectro-electrochemical techniques have been employed to investigate and compare the changes in oxidation state and surface species of different Cu-based foam catalysts via electrochemical operation. This thesis provides valuable insights into reaction mechanisms and suggests potential strategies for further enhancing the electrochemical performance of Cu-based catalysts.

This dissertation examines the variations in bidding strategies and outcomes among different types of bidders in public takeovers, with a focus on private equity firms, public strategic buyers, and private strategic buyers. Drawing on a dataset of European public takeovers from 2005 to 2022, the study analyzes key deal characteristics, including toeholds, premium payments, irrevocable commitments, competition, hedge fund activism, and deal success rates.

The results demonstrate clear distinctions between bidder types. Strategic bidders exhibit a structural advantage over private equity bidders, as they are more likely to secure toeholds, offer higher premiums driven by synergies, and encounter less competition and hedge fund activism. Despite these advantages for strategic bidders, private equity firms achieve comparable success rates due to their extensive deal-making expertise, which allows them to negotiate effectively during the pre-offer phase.

While the differences between public and private strategic bidders are more nuanced, meaningful distinctions exist. Public strategic companies are considerably more likely to acquire toeholds before a deal announcement. In contrast, private strategic companies offset this disadvantage by offering higher premiums; however, in the absence of toeholds, the premium disparity diminishes. Notably, private strategic companies demonstrate slightly higher success rates in completing takeover attempts.

Netzwerke der Zugehörigkeit knüpfen. Konzeptionen nachbarschaftlichen Lebens in ausgewählten Stadtvierteln in Khartum und Omdurman Diese Arbeit befasst sich mit Konzeptionen von Nachbarschaft in städtischen Gebieten in Khartum und Omdurman, Sudan. Das gemeinschaftsbildende Potenzial in diesen Vierteln, ein starker Glaube an gemeinsames Handeln und die Anerkennung von und Erfahrungen mit Unterschiedlichkeit durch die Menschen, wurden während der Feldforschung zu zentralen Themen. Ziel der empirischen Studie war es, das eigene Verständnis und die Vorstellungen der Menschen von „Gemeinsamkeit" und „Zugehörigkeit" zu untersuchen. Zu diesem Zweck wurden sowohl gesellschaftliche Normen, historische Bezüge sowie kulturell-religiöse Bindungen erfasst. Aus der Vielfalt der Perspektiven ergibt sich ein Konzept der sudanesischen Nachbarschaft. Meine theoretische Auseinandersetzung mit den Begriffen Zugehörigkeit, Lokalität, Raum und Nachbarschaft stützt sich auf die Migrations-, Stadtforschungs- und Erinnerungsforschung. Die Grundannahme ist, dass sowohl der Ort als auch die sozialen Beziehungen für eine Nachbarschaft gleichermaßen wichtig sind. Die auf der Grundlage der Grounded Theory gewonnenen empirischen Ergebnisse zeigen, dass Zugehörigkeit durch soziale Prozesse entsteht, die durch lokale Praktiken gestärkt und stabilisiert werden: Gegenseitige Hilfe, Teilen, Respekt, Gleichheit und Gegenseitigkeit sind in den untersuchten Nachbarschaften besonders relevante Normen. Diese nachbarschaftlichen Praktiken haben eine starke integrative Wirkung auf dieses sozioökonomische Netzwerk mit ausgeprägten traditionellen Strukturen. Die Arbeit dokumentiert eine Reihe solcher Praktiken und beschreibt ihre Wirkung auf das Individuum. In „Sandugs" erhalten Frauen Zugang zu Kapital und damit zu unabhängiger wirtschaftlicher Tätigkeit, während gleichzeitig ein Raum für gegenseitige Beteiligung und Einflussnahme geschaffen wird. Die Prozesse der „Judiya" ermöglichen es, Familien- und Nachbarschaftskonflikte konstruktiv und schlichtend zu bearbeiten, wobei die Unabhängigkeit der Akteure betont wird. Beides ist Teil einer Identitätskonstruktion, in der Lokalität und Zugehörigkeit auf der Grundlage von Konzepten des „Sudaneseness" ausgehandelt werden. Die Menschen stellen ihr Handeln, um Stabilität und Schutz für ihre Nachbarschaft zu schaffen, in den Kontext kultureller Ideale, sie verstehen und beschreiben ihr nachbarschaftliches Verhalten als inhärent „sudanesisch". Diese traditionellen Konzeptionen von gegenseitiger nachbarschaftlicher Unterstützung und Zusammensein bilden eine starke lokale Struktur in den Nachbarschaften. Eine andere lokale Struktur ergibt sich durch die „lokalen Komitees". Sie stellen die untere Verwaltungsebene des Staates dar. Seit 2011 versuchte das Regime von Al Bashir, seine Macht und die Kontrolle über die politischen Unruhen zu erhalten, indem es die Überwachungsmaßnahmen massiv ausbaute. Dazu bediente es sich auch dieser "lokalen Ausschüsse". Seit den Aufständen von 2013 wurden jedoch parallel klandestine „Widerstandskomitees" in den Stadtvierteln gebildet, um diejenigen zu schützen, die an den Protesten teilnahmen. In den folgenden Jahren übernahmen diese Widerstandskomitees immer mehr Versorgungs- und Betreuungsaufgaben. Ihr Motto „Wir passen auf, wir kümmern uns, wir leisten Widerstand" (We watch, we care, we resist) spiegelte den sudanesischen Nachbarschaftsgeist wider, den ich während meiner zweijährigen Feldforschung von 2014-2016 beobachtet und dokumentiert habe. Während der Revolution 2019 spielten diese Nachbarschaftsnetzwerke erneut eine wichtige Rolle bei der Unterstützung des zivilen Widerstands. Im Jahr 2023 gaben sie den Anstoß zur „Revolutionären Charta zur Errichtung der Volksmacht". Schlüsselwörter: Nachbarschaft, Zugehörigkeit, Lokalität, Widerstand, Sudaneseness

Microbial communities developing on glacier and ice sheet surfaces decrease snow and ice albedo and enhance melting. The associated loss of global ice masses changes the proglacial landscapes worldwide and contribute to global sea-level rise. This is very pronounced in the Arctic, where the temperature increases four time faster than the global average. The loss of snow and ice also corresponds to an increased presence of pigmented microbial communities that bloom annually. The drivers of these blooms and the ecological relationships between the microbes inhabiting these environments, the pigmented microalgae and other microorganisms, remain misunderstood. Furthermore, snow and ice have been under-investigated as habitats supporting life, particularly regarding the ecological niches they offer through the seasonal shifts experienced in glacier ecosystems. These shifts include daily to seasonal freeze-thaw cycles, extreme light or darkness, nutrient limitations, dry conditions in winter or the abundance of liquid water in the summer. The overall diversity of such pigmented microbes and the habitat specific processes has been studied over the past decades. However, prior to my Ph.D., only sparse information was available about the ecological dynamics in supraglacial microbial communities, and their potential effects on the evolution of glacier and ice sheet surfaces under climate change are still unknown. Gaining such knowledge is crucial for the development of global models to help predict the evolution of glaciers and ice sheet biomes, and better understand their environmental implications. Additionally, quantifying changes in snow and ice habitat structure and assessing the interactions between microbial species are vital for understanding the survival strategies of microorganisms in these extreme conditions. Such knowledge can ultimately be used for astrobiological purposes, as glaciers are considered terrestrial analog systems for extraterrestrial life on cold planets and moons. To address some of the above set out questions, I combined genomic and visualization techniques and investigated the ecology of supraglacial microbial communities in the presented thesis. My work spans from the global scale, in which I assessed the biogeographical drivers shaping supraglacial microbial communities’ composition worldwide, to the single cell or mineral particle microscopic scale, where I assessed the 2D and 3D architecture of microbes and minerals on and in the ice. Specifically, in the first part, I utilized 16S, 18S and ITS rRNA gene amplicon sequencing of my own samples collected in Greenland, Iceland and Svalbard, and integrated these with data available in public repositories or shared by collaborators to create a dataset covering the Arctic, Antarctica, as well as continental glaciers worldwide. I unveiled a first global biogeographical pattern, and explored large-scale and local drivers that affect the composition and dynamics of supraglacial microbial communities. Diving deeper into the local and environmental influences, I then further investigated the specific ecological shifts in community composition, dynamics, and complexity across the snowline on the Greenland Ice Sheet by combining the genomic data from 19 supraglacial sub-habitats with their associated nutrient, ionic and carbon contents. My research revealed the existence of a global glacier core microbiome composed of both generalist and cold-specialized taxa such as Hymenobacter, Acidiphilium, Polaromonas, and Parafrigoribacterium. I showed that large-scale factors such as latitude and distance-decay partly explained microbial variability on glaciers worldwide. However, it also became clear that these were less important in defining the composition and diversity of glacier microbial communities, compared to local parameters, including sampling site, habitat, and sub-habitat. Clear ecological transitions were observed across the ever-moving snowline during the melt season on the Greenland Ice Sheet. These were characterized by an increase in bacterial diversity, dissolved organic carbon content, and a shift in community dynamics. Above and at the snowline, co-occurrence networks in white snow, red snow, and white ice showed that communities were predominantly driven by stochastic processes. In contrast, the sub-habitats below the snowline such as dark ice and black cryoconite holes exhibited more complex interactions and negative relationships, their dynamics responding to deterministic processes. A second trust of my work was focused on microscopic and tomographic analyses. I investigated the spatial and structural variations in ice core samples and assessed the influences of the ice architecture on the ecology of microbial communities. For this purpose, I studied the surface features of summer ice samples using a workflow that I developed spanning different scales of cryogenic microscopic approaches. Ice surfaces and their particulates were imaged in the field itself using a hand-held microscope. Ice patches displaying glacier ice algae were subsequently sampled, those samples preserved and transported frozen to the home-laboratory, where they were imaged with a stereoscopic microscope in a climate chamber, and a high-resolution cryo-scanning electron microscope (cryo-SEM). In addition, I employed conventional and synchrotron based cryo-computed tomography to evaluate the 3D distribution of mineral-biological aggregates and the pore structure in ice cores, collected either from below a 1.4 m snow cover or from the top bare surface ice, or weathering crust, in summer. The detailed analysis of these ice cores revealed substantial seasonal variations in ecological niches, with only a minor fraction of biological-mineral aggregates, considered as hotspots of biodiversity, having access to atmospheric inputs through the percolating channels in the winter ice. This underscores the necessity for supraglacial microorganisms to adapt to the harsh and arid conditions of the Arctic winter. This study presents a preliminary explanation for the dominance of taxa like Hymenobacter and Acidiphilium, capable of degrading organic matter under anoxic conditions, in glacier environments all over the world. Moreover, the cryo-SEM imaging highlighted the adaptive strategies of glacier ice algae communities. I could document the tendency of Ancylonema sp glacier ice algae to form chains loosely attached to ice crystal edges, an observation that suggests an evolutionary advantage for wind dispersion or enhanced photosynthetic drive. Importantly, my research highlights the existing biases in our understanding of glacier ecosystems, particularly emphasizing the disproportionate focus on the "Three Poles", while noting that continental glaciers, especially those in South America, remain significantly understudied. This discrepancy extends to the sampling of glacier habitats, where cryoconite holes have been investigated much more compared to the other sub-habitats. My thesis addresses this gap by contributing 221 new samples representing various sub-habitats from the glaciers of Svalbard and the Greenland ice sheet, thereby enriching the global sampling database. Moreover, my data underscore the critical role of sample collection and processing methods as variables that will affect amplicon sequencing outcomes, further stressing the imperative need for more standardized protocols that would facilitate better comparisons between studies and across glacier microbiomes. Overall, my work provides a new understanding about the ecology of supraglacial microbial communities, elucidating their drivers, their adaptation to the extreme conditions they thrive in, and the potential ecological shifts worldwide as glaciers melt and the bare ice area on ice sheet margins will more and more extend inland due to climate change.

To achieve membrane homeostasis, eukaryotic cells employ a complex protein machinery that orchestrates cargo flow between the Golgi apparatus, the plasma membrane and different classes of endosomes. Adaptor proteins facilitate selection, enrichment, and transport of various secretory and endocytic cargoes. Post-Golgi adaptor protein complexes (APs) as well as Golgi-localized, gamma-ear containing, ADP-ribosylation factor binding proteins (GGAs) are recruited to membranes by the small GTPase ARF1. Once on the membrane they bind cargoes and accessory factors, and according to classical models, drive the formation of small clathrin-coated vesicular transport intermediates to promote bidirectional transport between the Golgi and endosomes. The recent discovery of tubular, ARF1-positve transport intermediates decorated by clathrin, made us rethink the classical long-range vesicular model and brought us to investigate the function of these compartments in post-Golgi trafficking. In this work, I re-evaluated the localization and the function of different post-Golgi adaptor proteins in the context of tubular ARF1-transport intermediates. By combining CRISPR-Cas9 gene editing with interactome mapping and advanced imaging techniques, including live-cell confocal and stimulated emission depletion (STED) microscopy as well as correlative lightelectron microscopy, I discovered that ARF1 compartments are a novel class of tubulovesicular endosomal compartments. Importantly, the majority of non-endocytic clathrin and different adaptors including AP-1, AP-3 and GGAs localize to segregated nanodomains on ARF1 compartments. Settling a debate in the field, I observed that clathrin is only recruited to AP-1- but not AP-3-nanodomains. AP-1-nanodomains are found at the interface of ARF1 compartments and recycling endosomes and AP-1 knock-out (KO) causes the formation of long aberrant tubules possessing the identity of both compartments and disrupts cargo flow. These findings suggest that AP-1 mediates short-range transport from ARF1 compartments to recycling endosomes, possibly via a kiss-and-run mechanism rather than promoting longrange vesicular transport. Furthermore, I observe transient interaction of AP-1- and GGAnanodomains on ARF1 compartments and interactome analysis shows that AP-1 binds most of its cargoes only in the absence of GGAs. Thus, GGAs could act as switch in AP-1-mediated cargo sorting by regulating cargo-AP-1 interaction. Taken together, in this work I re-envision the mechanisms of adaptor-mediated cargo-transport and expand our understanding of how proteins are transferred between organelles. AP-1mediated cargo hand-over from newly described ARF1 compartments to recycling endosomes, redefines the role for AP-1 in post-Golgi transport. My data and recent literature suggest that post-Golgi communication occurs via transient interactions between compartments of a tubulovesicular endosomal network. In addition, I present an alternative model for the role of GGAs in AP-1-mediated protein sorting, where GGAs control which cargoes are sorted by AP-1.