This research reconstructs the historical process of the formation of local political power and the state in the department of Chocó, Colombia. Throughout the text, the idea of the state as a homogeneous and aseptic entity is challenged, and it is rather understood in terms of its ambiguous and contradictory features in its practices, which even become "illegitimate". The first chapter seeks to understand the process of state formation and local power in the late nineteenth and early twentieth centuries. The configuration of local power in those years represented a tense interaction between the minority 'white' political power in the territory and the majority black and indigenous population, but with limited access to the state apparatus and its institutions. In the midst of this, a relationship with Bogotá was established that positioned the territory as peripheral and abandoned throughout the twentieth century. This chapter examines the role of roads and rivers as instruments of power over the territory, since they were and are spaces through which the daily lives of the Chocoan people passed and through which the state made its way in the process of configuration. This was the perception of the local and regional powers, who had a desire to control them and to establish a particular domination over the territory. However, this attempt at domination did not go smoothly and the fires, as an apparent response of resistance to white power, show the level of confrontation and dispute that took place in the territory. Despite these disputes, at the beginning of the 20th century these conflictive relations began to change as the local political power, in its claim for autonomy from the tutelage of Bogotá, began to recognise the black population as fundamental to the development of local political life and a "better" relationship with the Andean power. In addition, the extractive processes, which involved confrontations between large mining companies, black people (artisanal miners) and local powers, highlighted the use of state instruments by the population to defend the forests and acquire mining titles. These conflicts were part of the beginning of the rapprochement between local traders, who were part of the local power, and the black mining population, as both groups were building the extractive and commercial economy from which they also benefited. Although the two sectors had different relationships with the state, this interaction is in itself evidence of the inhomogeneous and contradictory character that characterised the state-building process of those years. The second chapter shows the process of reconfiguration of political power in the territory between 1920 and 1950. These were the years of the rise of black power in the territory. The process of state 231 formation in those years was linked to the type of governance that emerged in Chocó as a result of the processes linked to the mining circuit and the department's position as the border of the recently separated Panamanian territory. This allowed for a certain capacity to negotiate with the power in Bogotá. The local power demanded autonomy, and although they obtained some, it was limited and under the watchful eye of Bogotá. This showed the capacity of the state to be present in the territory and linked the local powers to the national project. The participation of black people in mining gradually opened the way for them within the state and political power, and made concrete their intention to be part of the institutional game of the state, and the channel used was the political parties. These were central to local government. The presence of the parties led to a significant politicisation of the territory, as evidenced by the frequent electoral disputes. Thus, while the parties played a central role in access to the state and the national project, blacks who had made their fortunes in mining, trade and agriculture gradually entered popularly elected and appointed bureaucratic positions. The presence of black people and the role of commerce were central to the constitution of the territory as a liberal majority. Because access to the state was mediated through the role of political parties, the territory, like the rest of the nation, was caught up in the dynamics of partisan violence. This violence was also a manifestation of Chocó's connection to national dynamics. Meanwhile, the Catholic Church sided with the conservatives in an attempt to whip up sentiment against the liberals. However, the church's limited roots in a predominantly black area meant that its impact was limited. The rise of black power also transformed the church in the area. These changes and manifestations showed a shift in power relations within the territory. The emergence of workerism and the promotion of public education led to the definitive rise of black power in the political scenarios of the territory, coinciding with the revaluation of the black and the Chocoano, in contrast to the stereotypes coming from outside the territory. However, the rise of this new power was not without contradictions. Ethnic tensions intersected with class tensions. The rise of the blacks did not mean a break with white demands for traditional political power; on the contrary, many of them were taken up. Despite the denunciations of the state's dysfunctionality, its legitimacy does not seem to have been lost, but rather continually sought. The arrival of blacks in positions of power coincided with the rise of socialist discourse, which generated a discussion of the black question in local power circles. Moreover, this rise was indicative of a transformation that was taking place in the territory, leading to the departmentalisation of the territory. 232 The third chapter discusses the role of local power in Chocó during La Violencia and the Rojas Pinilla dictatorship between 1948 and 1957, and how different forms of social mobilisation emerged in response to political repression. Half a century of violence had a moderate impact compared to the dynamics of the Andean world. The characteristics of Chocó's liberals and conservatives showed an "affinity" to statehood in the years of the recently won departmentalisation, which in part would have distanced the possibility of confrontation with the state, although the discourse of La Violencia was used as a channel of communication with the national. Likewise, the socio-economic structure of the Chocó, with the absence of a hacienda model and the dominance of the Liberal Party, whose local militancy had no one to confront. However, the expansion of the conflict from the borders with Antioquia showed how the territory was linked to national dynamics. The violence served as a channel for the emergence of new forms of governance, in which the state of siege provoked the retreat of the Liberal Party, which capitulated to Bogotá and submitted to the temporary power of the military. Meanwhile, the conservatives were unable to capitalise on their electoral power, despite their dominance of the local state administration, because the absence of elections limited their ability to build a bureaucracy that could guarantee their permanence in local political power. Despite the low level of violence in Chocó, its existence affected the territory's relationship with the central government. The liberals were temporarily excluded from local power and the autonomy mechanisms achieved through departmentalisation were not implemented, while the imposition of military mayors was a sign of state control based on violence. Local political power was able to make traditional demands for infrastructure and state presence in the early years of the Rojas dictatorship. The figure of the governor and the Comité de Acción Chocoana were the intermediaries for these demands. Beyond the dictatorship, local power was able to consolidate its hold on the territory. The military also consolidated local political and state power in the area by attempting to dismember the department. The lack of services and infrastructure provoked a constant demand from the state, and local power, through the parties, continued to become the intermediary of this demand. In this way, Chocó was more than just a marginal territory; it had an important articulation with the process of state formation during this period. The fourth chapter focuses on the local impact of the National Front and the decentralising reforms of the Colombian state and the emergence of the violence of the armed conflict. During this period, 233 the territories were put on an equal footing in terms of their articulation with the political system. It shows that local administrations were put on an equal footing in terms of local governance and the implementation of the new regime. These changes were preceded by the death of one of the most important political leaders in Chocó and the departure of the traditional white families and the former Syrian-Lebanese traders due to the fire in Quibdó. One of the effects of the new regime was to equalise the bureaucracy, despite the fact that Chocó was a predominantly liberal area. The state thus homogenised the territories without taking into account local electoral dynamics, and the population and political power do not seem to have rebelled against such a situation. The new regime brought with it the expansion of the state and the arrival of new resources in the territory. The aim was to rehabilitate areas affected by violence and to accelerate the growth of areas lagging behind in order to prevent the outbreak of new violence. As a result of this expansion, the central, departmental and municipal governments grew, along with a decentralised parastatal bloc and the expansion of the legislative and judicial branches. This expansion brought with it the creation of new offices and bureaucracies for the territory and meant a local struggle for its control during the National Front and later years. As a result, ideological labels and party affiliations were lost in the search for access to the bureaucracy. Politics in the Chocó was reduced to the administration of elections, and it became increasingly clear that the parties were preventing social change, with the result that the support of the Chocoanos for elections, which had always been the mechanism for legitimising the political and party system and one of the main channels for linking the population to the institutions of the state, was declining. As in the rest of the country, the Chocó saw an increase in social protests, mainly demanding the extension or implementation of public services. Despite these popular demonstrations and denunciations of the absence of the state and of corruption, the leftist parties did not achieve major electoral successes, but the demands did provoke a response from the state that led to the search for a broadening of the political system. 234 The reaction of the traditional parties to the possibility of a democratic opening triggered the intensification of violence, which began to escalate in the 1980s. The "opening", however, did not mean any significant changes for the parties, for the local authorities or for the improvement of the administration of the state at the local level. Despite the denunciations of bad administration, political power continued to be shared amidst the traditional disputes within the party, which did not undergo any unfavourable changes in the eighties in terms of the electoral aspect. The point of arrival is the emergence of the violent reaction of local power and the state to the attempt to open up the state itself. It is part of the beginning of the violence of the armed conflict in Chocó.

Borderline Personality Disorder (BPD) is a severe mental disorder characterized by a disturbed relational style, emotional dysregulation, and impulsive behaviors. Individuals with BPD often engage in aggressive or dismissive behaviors in relationships. These difficulties are driven by a pervasive fear of abandonment and a constant expectation of rejection. They are likely linked to deficits in social cognition, which is the accurate interpretation and response to social signals, including facial emotion recognition (FER), empathy, and prosocial behavior. Studies on social cognition in BPD yield inconsistent results ranging from impaired to enhanced capabilities. One promising factor that may account for heterogeneous results is stress. Stress, especially in social contexts like exclusion, exacerbates many BPD symptoms, contributing to interpersonal dysfunction and emotional instability. However, research on how stress affects social cognition in BPD is limited, and results are mixed. This dissertation aims to address this gap by examining the effects of social stress on social cognition in female patients with BPD, particularly on FER, empathy, and prosocial behavior. Given previous conflicting findings, the first specific aim of this dissertation is to examine whether FER in individuals with BPD remains intact under social stress. Moreover, previous research suggests that healthy individuals react to psychosocial stress with a prosocial reaction, including elevated empathy and prosocial behavior, which can be interpreted as a “tend-and-befriend” reaction to stress. Women with BPD, on the other hand, reacted to psychosocial stress with reduced emotional empathy, possibly suggesting an aggressive or less prosocial “fight-or-flight” reaction to psychosocial stress. The second aim of this dissertation is to explore whether social exclusion, a particularly stressful experience for individuals with BPD and a key component of psychosocial stress, might explain this reaction previously seen in women with BPD. Lastly, the role of testosterone, which has been linked to aggressive and competitive behaviors, will be examined, as its relationship with prosocial behavior after social exclusion in BPD remains understudied. These aims resulted in the following three research questions: 1. Does psychosocial stress impair FER in individuals with BPD? (Study 1) 2. Does (perceived) social exclusion result in lower emotional empathy in women with BPD? (Study 2) 3. Will social exclusion result in less prosocial behavior in women with BPD compared to healthy controls (HC), and will this correspond with changes in salivary testosterone levels? (Study 3) In Study 1, we tested FER after psychosocial stress induced with the Trier Social Stress Test. In Studies 2 and 3, we examined whether social exclusion compared to overinclusion induced with the virtual ball game Cyberball affected empathy (Study 2), prosocial behavior (Study 3), and salivary testosterone levels (Study 3). The main findings of Study 1 were that women with BPD did not differ from healthy women in FER performance and that this was not influenced by psychosocial stress. Study 2 revealed that women with BPD showed less emotional empathy for positive emotions than HC but not for negative emotions after both social exclusion and overinclusion. This effect was most pronounced after social exclusion. Furthermore, women with BPD did not differ from HC in cognitive empathy, which was unaltered by the social stressor of social exclusion. The BPD group reported more negative feelings and higher threatened psychological needs and felt more excluded than HC in both conditions. In Study 3, women with BPD showed higher prosocial behavior than HC in terms of sharing more money but did not differ in their punishment behavior in economic exchange games. Both sharing and punishment behaviors were unaffected by social overinclusion or exclusion. Moreover, women with BPD displayed higher testosterone levels than HC, which did not change in response to the Cyberball manipulation. Contrary to our expectations, the results of this dissertation suggest that women with BPD do not significantly differ from HC across various facets of social cognition following different forms of social stress. Cognitive aspects of social cognition, such as FER and cognitive empathy, appear resilient to stress. Emotional responses, on the other hand, particularly empathy for positive emotions, appear to be more vulnerable to social stress in general and to social exclusion in particular. Findings of greater prosocial behavior in women with BPD than in HC challenge the hypothesis that women with BPD respond to social stress with an aggressive or antisocial “fight-or-flight” reaction. Individuals with BPD, who are highly sensitive to exclusion, may display outward prosocial behavior as a strategy to avoid further rejection and to maintain the relationship. In clinical practice, the findings of this dissertation may be applied in therapeutic interventions for training interpersonal and stress-tolerance skills. The observed elevated baseline testosterone levels observed in women with BPD may influence social behaviors, potentially contributing to the overall BPD pathology. To possibly establish causality, future research should further elucidate this association using methods such as ecological momentary assessment in longitudinal study designs. Overall, the findings of this dissertation contribute to closing a gap in the literature toward a more nuanced understanding of social cognition after social stress in patients with BPD.  

This thesis is about the design and synthesis of redox-active mechanically interlocked molecules. The work combines a designer approach towards the form and structure of these molecules with scientific method in endeavours of preparing these molecules.

The general field of the work is in supramolecular chemistry and concerns thinking on how parts of a molecule work together in the whole structure.

The work may be interesting for scientists working with mechanically interlocked molecules, systems chemistry, systems biology as well as researchers in organic chemistry, as this is the chemistry that was used in the synthetic procedures.

To summarise, the work explores how parts of mechanically interlocked molecules relate with each other, how they move and rearrange. Synthetic strategies toward making these molecules are explored and presented in five project-based chapters.

Several Enterobacteriaceae are capable of producing phosphoethaolamine (pEtN) celluloses as part of the protective biofilms they construct in challenging environment. The composite of proteins (e.g. curli) and pEtN cellulose promotes biofilms with enhanced elasticity and generates hallmark macrocolonies with wrinkling and ridging phenotype. Genetic analysis revealed that approximately half of glycosyl units in celluloses are functionalized with pEtN at C-6 position. Yet, no systematic insights into the modification pattern of cellulose and its impact on biofilm formation exist, since the complete structural information is altered during isolation and purification from the microbial matrix. Synthetic pEtN oligosaccharides are therefore ideal references to deepen the chemical characterization of Escherichia coli (E. coli) biofilm. The ultimate goal of this thesis is to establish a structure-property correlation in bacterial biofilms and produce pEtN-cellulose based material with tunable properties. To achieve this goal, a collection of well-defined pEtN oligosaccharides are prepared using automated glycan assembly (AGA) along with post-AGA manipulations, and used to shed light on how the substitution pattern modulates structure and biological and materials properties. In chapter 2, I developed a general on-resin method to access zwitterionic pEtN oligosaccharides. After obtaining the glycan backbone by AGA, I addressed several issues related to synthesis of pEtN oligosaccharides on solid support including the phosphorylation, deprotection and purification steps. On-resin phosphorylation was performed using H-phosphonate or phosphoramidite reagents. The utilization of H-phosphonate resulted in higher isolated yields compared to the operation with phosphoramidite. Treatment with sodium methoxide led to a short deprotection step. Final global deprotection and purification guaranteed a repertoire of pEtN oligosaccharides with different amounts and patterns of pEtN oligosaccharides in a quick fashion. In chapter 3, three systems with different levels of complexity were introduced to understand biofilm formation. All systems were based on synthetic pEtN oligosaccharides with different lengths, amounts and patterns of substitutions. Nanocomposites consisting of amyloidogenic peptide R5 co-assembled with pEtN celluloses revealed that the pEtN pattern affected the peptide fiber growth rate and modulated the adhesion of the matrices. The co-assembly of amyloidogenic protein CsgA and some pEtN hexasaccharide showed structural changes in the amide III band, indicating that the glycans affected the conformation of CsgA. Lastly, I applied synthetic pEtN celluloses to specific E. coli biofilms to study the changes in biofilm organization. Addition of different pEtN glycans onto bacteria resulted in less biofilm matrix production and granular patterns when treated with longer pEtN glycan chains with free-reducing end, suggesting that the natural zwitterionic glycopolymers were capable of disrupting E. coli biofilm production. In chapter 4, I employed pEtN celluloses to reveal the importance of pEtN substitution patterns in protein-glycan interactions. The biosynthesis of pEtN cellulose in bacteria requires multiple enzymes. BcsZ hydrolyzes internal β-1,4-glycosidic bond in cellulose during biosynthesis. Different constructs of catalytically inactive BcsZ and pEtN hexasaccharide complex demonstrated that certain pEtN patterns were decisive for BcsZ recognition and activity. Other protein-pEtN cellulose interactions were identified using the glycan array technology. Linker-coupled pEtN oligosaccharides were printed onto glass slides and incubated with various lectins. Binding to humoral lectins suggested that the interactions were specific and seemed to be related to the amount and pattern of pEtN substitution. Combined, the synthetic pEtN oligosaccharides prepared and investigated in this thesis served as starting point to drive the development of novel pEtN cellulose-based materials.

The dissertation addresses the lack of in-depth research that thoroughly compares the thoughts of Heidegger and Benjamin. Existing literature is dominated by anecdotal juxtapositions. While Heidegger’s and Benjamin’s works offer numerous potential points of comparison, it has yet to be clarified how these parallels align with Benjamin’s well-known critique of Heidegger. In what follows, I compare Heidegger’s deconstruction with Benjamin’s translation. The research hypothesis posits that both concepts are rooted in phenomenology, particularly in Husserl’s method of phenomenological reduction. While Heidegger’s connection to phenomenology is extensively documented, Benjamin’s affinity with it has largely gone unnoticed. Accordingly, this thesis provides the first comprehensive account of the phenomenological aspects of Benjamin’s early thought. My central argument is that while both Heidegger and Benjamin employ phenomenological reduction in their early work, they do so from profoundly different metaphysical perspectives. As a result, the sense and trajectory of their phenomenological reductions diverge significantly: Benjamin’s approach remains closely aligned with Husserl’s original intent, whereas Heidegger’s, as Husserl himself rightly observed, does not.

Bacterial infections are one of the leading causes of death, which have become a major threat to human health. Many infections are attributable to Gram-negative bacteria like Neisseria meningitidis or Acinetobacter baumannii. The number of infections has drastically increased due to treatment limitations and the rise of antimicrobial resistance. Unfortunately, as traditional antibiotics are no longer effective, alternative strategies are needed to fight bacteria and the associated diseases. Monoclonal antibodies (mAbs) and vaccination are two approaches which confer protection and prevention with a much lower probability of resistance emergence. Some commercial glycoconjugate vaccines using native capsular polysaccharides (CPSs) are available, but the isolation of CPS is complex and may lead to impurities. To address this, synthetic and pure oligosaccharides that mimic native CPS and are conjugated to a carrier protein can be used to ultimately promote specific immune responses. In the first part of my thesis, I demonstrated that using a fluorinated synthetic glycan conjugated to carrier proteins induced a strong immune response. The fluorinated glycan mimicked the epitope of N. meningitidis serotype C, which was conjugated to two carrier proteins, CRM197 or Porin A (PorA), respectively. After immunization, I showed that the raised antibodies recognized the fluorinated glycan as well as the native epitope of serotype C. Moreover, as PorA is expressed by serotype B, employing this carrier protein led to the creation of a bivalent glycoconjugate targeting both serotypes. I also proved the protective effect of the glycoconjugates since the pathogens were successfully cleared in vitro by the action of the complement and phagocytic cells, induced by the generated antibodies. Consequently, this strategy presents as a novel platform for developing glycoconjugate vaccine leads. In the second part of my thesis, I worked on the development of mAb candidates and vaccine leads against A. baumannii. On one hand, I produced three mAbs against the K1 capsule of A. baumannii. The mAbs recognized specifically both the synthetic glycan and the native CPS K1. The protective effects of the mAbs were studied in vitro, demonstrating their activity in reducing the bacterial load of A. baumannii. On the other hand, I also developed glycoconjugate vaccine leads containing synthetic oligosaccharides mimicking CPS types K1 and K3 of A. baumannii. The immunized mice produced a robust and long-lasting immune response, generating different subclasses of IgGs that are linked to a higher protective potential. The semi-synthetic glycoconjugates induced the production of antibodies with higher or similar binding to native CPS compared to those generated by the traditional CPS-based glycoconjugates, which were also evaluated in mice. Moreover, the protective activity in vitro induced by the semi-synthetic glycoconjugates was superior. An in vivo study with a mouse model of A. baumannii infection revealed that immunization with the semi-synthetic glycoconjugate candidates led to the reduction of bacterial burden in organs and alleviated disease symptoms, especially against the strain with K1 capsule. However, the results obtained with the K3 CPS strain showed a moderate efficacy, likely due to its higher virulence or the higher inoculum dose. In summary, my work during this thesis demonstrates that the utilization of synthetic oligosaccharides is a great alternative for the generation of effective glycoconjugate vaccine leads and mAbs against N. meningitidis and A. baumannii. Therefore, making them promising approaches for the treatment and/or prevention of infections, especially in high-risk or immunocompromised patients.

En esta investigación me ocupo de analizar la transición a la vida civil de los excombatientes músicos de las FARC-EP (Fuerzas Armadas Revolucionarias de Colombia – Ejército del Pueblo) tras la firma del acuerdo de paz en la Habana en 2016. Este análisis lo hago a la luz de sus experiencias socio-digitales, de sus prácticas musicales y de la disputa mediática visible en la construcción de la esfera pública. Por medio de un acercamiento metodológico basado en la etnografía digital, le hago un seguimiento a las biografías y a las experiencias socio-digitales de los músicos de las FARC en la etapa temprana de implementación del acuerdo de paz. El foco teórico con el que abordo mi pregunta de investigación se fundamenta en un diálogo entre la antropología digital y la antropología de la música. Este lente le da un marco al análisis de las experiencias socio-digitales de los/las firmantes de paz, con cuyas expresiones los músicos exguerrilleros habitan los espacios onlife en este periodo de transición. Explorar las formas en las que se habitan estos espacios implicaron un diálogo teórico con la definición de espacio en términos de creación de relaciones locales y transnacionales, con la resignificación de la memoria a partir de la creación archivos digitales y con la construcción de identidades y afectos. Concluyo que sus experiencias socio-digitales se han resignificado para darle voz a individualidades imperceptibles bajo el marco de la colectividad fariana y, por otro lado, que las experiencias adquiridas durante la guerra también han tenido un carácter constructivo, dinámico y creativo reflejadas en el ámbito de las producciones culturales y en las estrategias comunicativas ligadas a ellas. En ese sentido, estas experiencias han sido re-instrumentalizadas por los/las exguerrilleros/as para figurar en la esfera pública con un perfil que dista del talante guerrerista y que se orienta hacia la construcción de paz.

Biological cells interact with their environment through molecular processes in the cell membrane. By this means, the interplay between the lipid membrane and specialized membrane proteins determines cell morphology and controls a variety of specific cellular functions. For modelling these interactions on relevant time and length scales, so-called hybrid models are widely-used and established. Thereby the proteins are modelled as dicrete particles, while the lipid membrane is seen as a two-dimensional elastic continuum, whose energy is given by a Canham-Helfrich-like functional. Particularly focusing on the accessibility for efficient numerical methods and numerical analysis, this thesis investigates the somehow most detailed hybrid model. Thereby, the particles are described as discrete rigid objects with finite size, which, according to their particular properties and geometry, induce local constraints along the membrane-particle-contour. First of all, the variational formulation of the membrane-particle hybrid model problem is provided, along with a suitable solution space, particularly incorporating the particle-induced constraints and their degrees of freedom. Furthermore, existence and uniqueness of the corresponding weak solution is proven, followed by the main part of this work - the derivation of a suitable discretization and the provision of an appropriate a priori error estimate. For discretization, the non-conforming Morley finite element is chosen. Due to its simple structure and its few degrees of freedom, it is particularly attractive. However, as Morley's element does not even provide C⁰-continuity, estimating the discretization error is not straightforward, even not for simple model problems with homogenous boundary data on convex, polygonal domains. For the membrane-particle problem, which constitutes the basis of this work, the curved boundaries, the non-homogeneous boundary conditions - particularly depending on the particles' degrees of freedom - and the lacking convexity of the domain are additionally aggravating factors.

Ziel dieser Arbeit war es, im in vivo-Teil den immunmodulatorischen Effekt nanopartikulärgebundener CpG-ODN an zehn an Sommerekzem erkrankten Pferden zu untersuchen. Dazu wurden die Tiere im Zeitraum Juni bis Dezember 2020 zweimal innerhalb von fünf Wochen in einem Abstand von jeweils zwei Tagen mit CpG-GNP behandelt. Die intrakutane Applikation erfolgte an den beiden Prädilektionsstellen Mähnenkamm und Schweifrübe. Im in vitro-Teil wurde untersucht, ob sich durch die Behandlung mit CpG-GNP immunmodulatorische Effekte nachweisen ließen. Bei jedem der fünf Untersuchungszeitpunkte wurden die Pferde und Ponys allgemein untersucht. Der allgemeinen Untersuchung schloss sich die dermatologische Untersuchung mit der Ermittlung der Ekzemerscores an. Weiterhin wurden den Pferden Serumproben entnommen, um aus ihnen IgE-Antikörper-Titer und die Sekretion des Zytokins IL-4 zu bestimmen. Zusätzlich wurde EDTA-Blut gewonnen, um die daraus isolierten PBMC in drei Ansätzen mit CpG-GNP, CpG-ODN und GNP zu inkubieren und anhand ihrer Proliferationsraten und Zytokinprofile (eIL-4, eIL-10, eIFN-ỿ) die immunstimulatorische Wirkung zu untersuchen. Des Weiteren wurde bei den Tieren der Sommerekzemgruppe bei der Erst- und Abschlussuntersuchung ein Intradermaltest mit fünf Allergenen durchgeführt. Mit dem in der vorliegenden Studie angewandten Behandlungsschema der CpG-GNP konnte über den gesamten Studienverlauf ein signifikant positiver Effekt auf die klinischen Symptome des Sommerekzems der behandelten Pferde und Ponys nachgewiesen werden. Zwischen den einzelnen Untersuchungsterminen in den Heimatställen wurden die Symptome und Ekzemerscores durch die Besitzer ermittelt. In weiterführenden Studien sollte eine zeitgleiche Einbestellung aller Probanden stattfinden, um unter gleichen Witterungsbedingungen eine optimale Vergleichbarkeit der symptomatischen Besserungen zu gewährleisten. Um die Wetterverhältnisse und die Vergleichbarkeit der SE-Symptome auch während der Betreuung in den Heimatställen sicherzustellen, sollten sich die Ställe aus logistischen Gründen in einer Region befinden. Weiterhin sollte die Expression von IL-4 vergleichend sowohl in Serumproben als auch in Hautbiopsien aus Läsionen bestimmt werden. Dabei wäre zu überprüfen, ob die Messung in Hautbiopsien betroffener Pferde die aussagekräftigere diagnostische Methode für das Krankheitsbild des Sommerekzems darstellt. Weiterhin ist auch die Bestimmung zusätzlicher bzw. anderer Zytokine zu bedenken, um die Modulation der Immunreaktionen von SE-Patienten zu überprüfen und zuverlässig nachzuweisen. Im in vitro-Teil der Studie konnte für die Zellproliferation und für die Expression der bestimmten Zytokine aufgrund der unerwarteten Beobachtungen und unplausiblen Ergebnisse keine sichere Aussage zur immunmodulatorischen Wirkung der CpG-GNP gemacht werden. So stiegen die Konzentrationen von eIL-4, eIL-10 und eIFN-γ nach der Behandlung der Sommerekzempatienten statistisch signifikant an- abhängig von der jeweiligen Konzentration der CpG-GNP, der CpG-ODN und der GNP. Auch die PBMC wiesen nach Inkubation konzentrationsabhängig sowohl durch CpG-ODN, CpG-GNP als auch durch GNP eine Stimulation auf. Gelatinenanopartikel werden als immunologisch inertes Transportsystem verwendet. Ein immunmodulatorischer Einfluss von GNP wurde bisher nicht beschrieben. Anhand der Beobachtungen und Ergebnisse wurden zwei Annahmen in Hinsicht auf die Ursachen getroffen. Die erste Annahme beinhaltete eine fehlende Sterilität als Ursache für den immunmodulatorischen Einfluss der GNP, während die zweite Annahme die Ursache in den Eigenschaften der verwendeten A-Gelatine vermutete. Weiterführende Studien sind sinnvoll, um diese Annahmen und den potenziell immunmodulatorische Einfluss von Gelatine bzw. Gelatinenanopartikel unter Verwendung verschiedener Gelatine-Typen zu untersuchen.

This doctoral work focuses on the epidemiology and public health implications of non-malarial febrile illnesses (NMFIs) in endemic regions. The research delivers a comprehensive investigation of leading causes of NMFIs in febrile patients in Africa and is the first to present them in proportional morbidity rates, an important health metric that shows the relative importance of clinically relevant aetiological agents. While there was a paucity of relevant data across the continent, a remarkable diversity of bacterial, viral, fungal and parasitic infectious agents was found, with most being observed from blood and/or serum samples using both direct and indirect methods. Bacterial agents were the most prominent causes of non-malarial fevers, with viruses following closely. The first meta-analytic summary estimates of selected agents in African patients were also estimated from the work, with Streptococcus being detected using direct methods in 3.2% of the 241,499 patients investigated. A need for more fever studies to even out the regional disparities observed on the continent is discussed, with harmonised protocols for patient selection and diagnosis being needful to lower the high study heterogeneity seen for various agents. An in-depth investigation of febrile patients from Garissa County of Kenya, an arid and semiarid region of Kenya revealed further understanding of NMFIs in an endemic region. A high presence of Brucella was observed (only B. melitensis was found) in the patients examined (19.4% by PCR), much higher than the African average meta-analytic estimates of 3.1% for pathogenic brucellae. Additionally, 1.7% of patients were PCR positive to P1 subclade (formerly termed pathogenic) Leptospira and none (<1%) to C. burnetii which are leading zoonoses prioritised by the country’s health authorities for control. Younger patients (5-17 years old) were at higher odds of being seropositive to leptospires and C. burnetii than adults, showing the urgent need for surveillance and prevention measures to protect vulnerable populations. A metagenomic shotgun sequencing of serum from selected patients also revealed Streptococcus and Moraxella to be possible bloodstream infections, showing the need for the country to expand its surveillance efforts for common but under-investigated bacterial agents using untargeted sequencing or multiplex detection assays. Additional longitudinal follow-up of small ruminants in neighbouring Tana River County presented the country’s first incidence rate estimates for these infectious diseases in animal hosts. A high incidence of Leptospira and C. burnetii was observed in the animal hosts as indicated by seroconversions, and none were observed for Brucella spp. The country lacks a systematic prioritisation of animal diseases which suggests that zoonoses that have a high public Health impact may be overlooked, thereby leading to exposure of vulnerable human populations. There is a need for the adoption of prevention strategies such as vaccinations of humans and animals alike, the use of personal protective equipment and biosecurity measures to Prevent occupational exposures, and treating foods to prevent ingestion of contaminated animalsource foods. Additionally, avoiding contaminated water sources and protecting food stores from reservoir animals such as rodents is vital to prevent exposure.

Human herpesviruses 6A and 6B are two closely related betaherpesviruses with the ability to integrate their genomes into the host chromosomes, establish a latent infection and persist in the host for life. These viruses can also infect germ cells and be inherited by the offspring, resulting in individuals who harbor the integrated virus in every cell of their body. This condition is termed inherited chromosomally integrated HHV-6A/B (iciHHV-6A/B). However, Integration must not be seen as a dead end for the virus, as it can be released from the chromosome and start a new lytic infection, resulting in different clinical manifestations. The currently available pharmacological treatments can only partially reduce the viral replication and counteract the clinical symptoms. Unfortunately, until now we have neither a way to prevent the viral reactivation nor get rid of the integrated virus. Here we provide the first proof-of-concept that integrated HHV-6A genomes can be successfully removed in vitro from the host chromosomes using CRISPR/Cas9 system and specific guide RNAs targeting the direct repeats of the viral genome. The successful genome removal was achieved in latently infected cells generated in vitro, as well as in iciHHV-6A patient cells, and confirmed using three different techniques: flow cytometry, quantitative PCR (qPCR), and fluorescence in situ hybridization (FISH) analyses. Our results open the road to possible future clinical applications and provide an additional research tool to further investigate different aspects of HHV-6A biology in vitro. As for many other aspects of HHV-6A/B, the integration process still needs to be fully understood and many questions remain unanswered. HHV-6A/B does not randomly integrate into the host chromosomes, but specifically into the telomeres. We know that the viral telomeric repeats play an essential role, and this aspect raises the question whether the host telomeres length also plays a role in this process. With this question in mind, we developed a method to measure the telomere length by quantitative fluorescence in situ hybridization, confocal microscopy, and computational processing. Our findings suggest that the integration can occur regardless of the telomere length and the integration process itself seems not to have a Major short-term effect on the telomere length. The data generated in the two works presented in this thesis, collectively represent a further step towards a better understanding of HHV-6A/B biology.

Die Sammlung französischer Skulpturen des 18. Jahrhunderts im Bestand der Stiftung Preußische Schlösser und Gärten Berlin-Brandenburg (SPSG) zählt aufgrund ihrer Quantität wie auch ihrer zum Teil überragenden Qualität zu den bedeutendsten derartigen Sammlungen in Deutschland. Entstehung und Gewichtung sind wesentlich dem Sammelinteresse Friedrichs II. von Preußen (reg. 1740-1786) zu verdanken, der den Künsten eine maßgebliche Rolle im Gefüge herrschaftlicher Selbstinszenierung zuwies. 1747 etablierte er in Berlin ein königliches Bildhaueratelier, dessen jeweilige Leitung er mit François Gaspard Adam (1710-1761), Sigisbert François Michel (1728-1811) und Jean Pierre Antoine Tassaert (1727-1788) ausschließlich französischen bzw. lange Zeit in Frankreich tätigen Bildhauern anvertraute. Wesentliche Aufgabe dieses Ateliers war es, den erhöhten Bedarf an lebensgroßen Marmorskulpturen für die Ausschmückung der ab 1744 bei Potsdam entstehenden königlichen Sommerresidenz Sanssouci zu decken. Neben der Vergabe von Aufträgen an das großzügig finanzierte Berliner Atelier gelang es Friedrich II. aber auch, durch Ankauf in Paris, diplomatischen Geschenkaustausch oder Auftragsvergabe an Pariser Bildhauer eine Reihe erstrangiger französischer Skulpturen in seinen Besitz zu bringen. Die vorliegende Promotionsarbeit rekonstruiert durch Erschließung neuer Quellen die Entstehungs- und Sammlungsgeschichte der aus Paris beschafften großen Marmorwerke des friderizianischen Skulpturenbestandes. Dabei rückt sie mit Friedrich Rudolph Graf von Rothenburg (1710-1751), Guy Louis Henri marquis de Valory (1692-1774) und Dodo Heinrich Freiherrn von Inn- und Knyphausen (1729-1789) Akteure aus dem Umkreis Friedrichs II. in den Blick, deren Anteil an der Vermittlung dieser Skulpturen (Werke von Lambert Sigisbert Adam, Jean-Baptiste Pigalle, Guillaume II Coustou, Louis Claude Vassé und Jean-Baptiste II Lemoyne) bisher unbekannt geblieben ist. Sie deckt Kommunikationswege auf, klärt zeitliche Abläufe und verdeutlicht Handlungsmotivationen. Sie bezeugt die aktive Rolle des Königs, stellt zugleich aber auch die Bedeutung der Diplomatie für den kulturellen Transfer heraus. Im Licht der Quellen interpretiert sie die Beschaffung der Pariser Skulpturen und ihre Aufstellung an zentralen Orten der Lustschlossanlage (Großes Bassin im Schlossparterre und Galerieraum der Bildergalerie) als eine Facette des Bemühens des Königs, nach den schlesischen Kriegen auch in Sanssouci den Status- und Prestigegewinn zu demonstrieren, der ihm aus den militärischen Erfolgen dieser Kriege erwachsen war. Sie bestätigt für das Medium der Skulptur, dass der König vorrangig für die Ausstattung seiner Schlossanlagen sammelte und in begrenzten Phasen auch Ausgaben im obersten Preissegment nicht scheute.

Innate lymphoid cells (ILCs) are rare immune cells that are mainly tissue-resident but are able to quickly adapt their feature- and cytokine profile in the presence of specific stimuli in their microenvironment. The spatial analysis of ILCs is challenging as many markers are required for the identification of ILCs. Additionally, ILCs possess many similarities with T helper (Th) subsets, although ILCs do not express T cell receptors. Concurrently, spatial analysis and characterization of ILCs is highly desirable in order to be able to understand how the microenvironment shapes their phenotype and function and vice versa. Here, mulit epitope ligand cartography (MELC), a spatial multiplexing technology on histological sections, was used and combined with an IL-33 systemic type 2 inflammation model to study ILC subtypes and locations, as well as their phenotypical and spatial alterations in murine lung and small intestine (SI). For this, antibody panels of 40 to 50 markers were established in both murine lung and SI. MELC data was acquired in both organs from GATA3eGFP reporter mice under healthy conditions and at early time points after IL-33 application, mimicking acute type 2 inflammatory conditions. The existing image analysis pipeline was adapted and optimized by using open-source analysis software so that single cell information with spatial coordinates of 64,914 cells in the lung with 33 features, and 73,268 cells from the SI with 26 features were extracted and analyzed. Subsequently, dimensionality reduction, as well as cluster and spatial analysis was performed. This approach enabled the identification of major and rare cell types that were annotated based on their respective feature profiles. Multiple ILC subtypes were resolved and annotated as EOMES+/- TBET+/- NK cells/ILC1s, GATA3eGFP+ ILC2s and RORγt+ ILC3s in the lung data, as well as GATA3eGFP+ ILC2s and a mixed cluster of EOMES+/- TBET+/- RORγt+/- NK cells/ILC1s/ILC3s in the SI. Analyzing the feature profiles of ILC subtypes revealed immediate phenotypical adaptations in both organs, lung and SI. Quantitative analysis confirmed an early expansion of immune cells after one dose of IL-33 in the SI, combined with a shift of the ILC compartment towards proliferating ILC2s, while the lung immune compartment increased only after day 3 of IL-33 application, showing a strong significantly increase of ILC2s. Spatial analysis of identified ILC subtypes revealed ILC2s to accumulate in perilymphatic niches in both lung and SI. Besides lymphatic vessels and fibroblasts, ILC2s share their niche with myeloid cells. At the same time, this data showed that identified NK cells/ILC1s in the lung and NK cells/ILC1s/ILC3s in the SI were spatially associated with the blood vessel endothelium, marked by EMCN- and/or CD31-expression, and with this, revealed a perivascular localization. Under steady state conditions, localization of NK cells/ILC1s/ILC3 with epithelial cells of the basal area of villi and crypts was observed in SI villi tissue regions, while already after one dose of IL-33, partial migration towards the central and luminal LP of the villi was visible. This study successfully applied the multi-parameter analysis MELC in a murine model of type 2 inflammation, confirming the ability of ILCs to rapidly adapt their profiles and consequently their niches to suit the present threat. Linking the spatial dimension to the cellular function might shine light onto complex pathologies where a deeper understanding of local and global processes is required to develop novel targets for therapeutical interventions.

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.