The present research was inspired by the chance encounter of an important dissonance between the Basic Principles and Guidelines on the Right to a Remedy and Reparation for Victims of Gross Violations of International Human Rights Law and Serious Violations of International Humanitarian Law and Uganda’s nascent transitional justice policy. The latter foresaw reparations for all victims of Uganda’s civil wars while the former stated that customary international law merely encouraged but did not oblige States to repair victims of non-State actors, the victims of others. Was Uganda’s policy gratuitous? Or has public international law evolved beyond the economy of the Basic Principles and Guidelines? It is the purpose of the present text to answer these questions. The thesis is divided into three substantive chapters that are preceded by an Introduction and tied together by a brief Conclusion.
The Introduction articulates the hypothesis and highlights that if correct, i.e., if there exists a rule of public international law obliging States to repair victims not their own, there exist two candidates for the content of that rule. The candidates are explored in Chapters 1 and 2. Before turning to them, the Introduction demonstrates that avenues typically proposed today are insufficient juxtaposed with the aim of making reparations a reality for victims of non-State actors. It thereby underlines that the hypothesis is not just thought-provoking but also of immense practical value.
Chapter 1 first investigates the nature of the States’ obligation to protect economic, social and cultural rights, and concludes that the existing consensus as it is contained in the Basic Principles and Guidelines is that the obligation is a qualified obligation of result. It then examines the historical origins of the rule, demonstrates why it is inappropriate to apply it to the situation at hand and proposes that the obligation to protect be understood as an unqualified obligation of result instead, meaning that the State would find itself in a position of wrongfulness at the exact moment a non-State actor committed a violation. This would ipso facto create the State’s secondary obligation to repair. Lacking a conventional articulation to that effect, such a rule would have to exist in the sphere of customary international law.
Chapter 2 takes under the magnifying glass the International Covenant on Economic, Social and Cultural Rights and explores the potential of the obligation of progressive realisation, the prohibition against discrimination and studies the work of the Committee on Economic, Social and Cultural Rights, substantiating the argument that the obligation to repair could be understood as a primary obligation.
What we do not yet know at this point in the thesis is whether either proposition corresponds to the States’ understanding of the law. Chapter 3 therefore examines a dozen countries that have experienced a non-international armed conflict in their more or less recent past. It looks at their practice in regard to reparations, paying particular attention to whether States discriminate between victims of the State and those not of the State. As far as it can be discerned, it also analyses their understanding of public international law.
The Conclusion suggests an affirmation of the hypothesis.
View lessRepresenting molecules in a computer-interpretable way plays a crucial role in enabling the application of computational method to the field of chemistry and pharmaceutical drug development in particular. Recently, there has been a surge of interest in using machine learning to predict molecular properties such as the binding affinity to protein targets of interest or to generate molecular structures with desirable properties. However, as chemical entities are challenging to represent in an expressive and computer-interpretable way, much work in the field of cheminformatics has concerned itself with defining clever feature extractors, which encode the chemical graph structure in a uniform, fixed-sized, numerical manner. Recently Deep Neural Networks have shown great success in learning to extract meaningful features directly from raw data representations, outperforming hand-crafted feature extraction protocols and revolutionizing fields such as image analysis or natural language processing. Deep Neural Networks have also been directly applied on raw data representations of molecules such as their structural graph. However, the capabilities of this method in pharmaceutical drug development are usually limited by the scarcity of labeled data as their collection usually involves running expensive wet lab experiments. Unsupervised Learning, on the other hand, is a powerful machine learning strategy that enables the training of Deep Neural Networks without the need of labeled training data. In this thesis we discuss how Unsupervised Learning can be used to train powerful feature extractors on unlabeled chemical structures. We propose for different input representations of molecules (such as line notations, graphs and point clouds) novel methods to extract expressive representations. We show how those representations can efficiently be used as input for downstream molecular property prediction models or to generate novel molecules with desirable properties. Moreover, we discuss how certain symmetries of molecular representations are crucial to respect (e.g. permutation invariance of molecular graphs or rotation and translation invariance of molecular conformations) and develop novel methods particularly designed to extract invariant representations.
View lessBacteria mostly prefer to live as biofilms on surfaces rather than in flowing environments. However, biofilms are mostly unwanted by humans and preventing possibilities besides biocides and antibiotics are urgently needed. One strategy is to prevent the bacteria directly from attaching to the substrate. This study aims to investigate the effect of nano- and microstructures on bacterial attachment and pursues two approaches whether such surfaces reduce bacterial attachment under flow conditions. The first approach involves ZnO nanorods to design surfaces with varying topographies in the nano- and micrometer range, while the second uses 3D printed microstructures to induce microflows that repel bacteria from the surface. The tailored substrates were integrated into a specially developed flow chamber and exposed to a flowing suspension of P. fluorescens under in-situ conditions. Additionally, the attached bacteria were subjected to higher shear forces by increased flow velocities. For evaluation, the attached bacteria were imaged using fluorescence microscopy and automated counted on a single-cell level. The cell counts were compared between different substrates and a control surface to assess the effectiveness of the surfaces in preventing bacterial attachment. Lower cell numbers indicated a surface that better prevented bacterial attachment. However, it was found that none of the investigated surfaces reduced the attachment of P. fluorescens. These findings and additionally made observations have the potential to alter the current perspective of the believed capability of nano and microstructures for preventing microbial attachment. Remarkably, it was found that although accompanying computational fluid dynamic simulations predicted uniform flows in the channels, anomalies in the flows occurred, resulting in uneven distribution of the bacteria. Furthermore, P. fluorescens revealed the ability to attach to any surface studied and rapidly establish irreversible attachment there. Thus, this study also suggests using those microorganism types that perform best in attachment for benchmarking surfaces that are intended to have a bacteria-repellent effect in the future. During the project, a method for a lipopolysaccharide encapsulated polystyrene (LPS-PS) microparticle system was developed as a further approach. The easy-to-use method was developed to mimic bacteria for attachment studies. A variety of analytical techniques were used to detect the LPS on the polystyrene microparticles. Among others, a procedure for labeling the particles for fluorescence microscopy is presented. The data from the analyses offers a reference for future applications of the LPS-PS microparticles, whose use goes far beyond bacterial attachment studies; they are attractive for vaccine research and serological tests.
View lessAprès l’énonciation en 1993 de conditions d’adhésion à l’Union européenne (UE), la politique d’élargissement à l’Est a été qualifiée d’asymétrique et unilatérale. A la suite de la réforme de 1997, la littérature a identifié l’introduction d’un nouveau mode de gouvernance. Qu’en est-il exactement ? Les éléments empiriques réunis entre 2000 et 2004 nous ont permis de formuler l’hypothèse selon laquelle l’UE a transféré une méthode de gouvernance interne fondée sur l’interaction – la méthode ouverte de coordination (MOC) – pour résoudre les difficultés rencontrées au niveau externe. Lors des élargissements précédents, la Communauté européenne s’est toujours inspirée des modes d’intégration interne – intergouvernementalisme, régulation économique, méthode communautaire – pour dépasser ses contradictions. Ainsi, dans quelle mesure la conditionnalité de l’adhésion à l’UE a-t-elle représenté à partir de 1997 un cadre d’apprentissages et de socialisation mutuelle entre acteurs de l’élargissement ? L’approche constructiviste par les cadres normatif et d’action nous a permis de déconstruire trois vertus de la gouvernance par les connaissances : la cohérence et la légitimité interne de la politique d’élargissement sont restées inaccomplies ; dans les pays candidats, la mise en oeuvre des réformes est restée limitée par les héritages du passé ; enfin, les mécanismes d’apprentissages et de socialisation mutuelle ont certes ouvert des possibilités de définition communes des cadres cognitif et d’action des politiques internes et externes à l’UE. Néanmoins, la convergence sur des valeurs partagées n’empêche pas l’existence de tensions internes relatives au sens à donner à l’Europe à Vingt-Cinq.
View lessPredicting the behavior of foldamer assemblies with all-α-peptides in higher-ordered arrangements remains a challenge. However, there is a strong interest and need to develop a deeper and more thorough knowledge to access foldamer designs that undergo interactions with natural peptide motifs. In this dissertation, the endeavors of investigating higher-ordered interactions between foldamers and all-α-peptides were continued in a well-defined tetrameric coiled-coil model system. First, two Cys/Phe-motifs identified in previous work as complementary binding partners of an α/β/γ-chimera were compared using CD-spectroscopy and cryogenic transmission electron microscopy (cryo-TEM). Systematic substitutions were performed on cysteine and analyzed by CD-spectroscopy to determine differences between the two different Cys/Phe-motif-containing complementary sequences in the formation of helical bundles with the α/β/γ-chimeric sequence. High-resolution structural data were obtained using a variety of analytical methods to investigate the favored side chain packing in the higher-ordered helical fold. The analytical techniques applied are NMR spectroscopy, vibrational sum-frequency generation (SFG) spectroscopy, Fourier-transform infrared (FT-IR) spectroscopy, and X-ray crystallography. In the course of this thesis, the thiol region was examined for the first time by vibrational SFG-spectroscopy at the air/water interface for shifts due to H-bonding. In addition, the first crystal structure of a heterotypic coiled-coil assembly of an α/β/γ-chimera with an all-α-peptide was generated, providing the first high-resolution packing information of the heterotypic helical bundle in a solid state. Another part of this work deals with the construction of a library of chimeric peptides with iterative substitutions that increase the number of β/γ-modules. These chimeras were then evaluated for stability when complemented with corresponding all- α-peptide sequences involving the Cys/Phe-motifs. This investigation revealed a restriction of intermolecular interactions sensitive to a variation in the number of backbone residues. Finally, a β/γ-peptide consisting of five β/γ-modules was analyzed for structural features by CD-spectroscopy.
View lessIn the arid and semi-arid region in northern Namibia, there are three main catchment areas the Kunene, the Kavango, and the Cuvelai-Etosha Basin (CEB). The Kunene and the Kavango Rivers are perennial and provide the northwestern and northeastern regions with water. In central northern Namibia, the transboundary CEB consists of an ephemeral and endorheic drainage system with channels and depressions, known as the Iishana system. High temperatures, high evaporation rates, and low rainfall increase the risk of polluting these waters. Groundwater resources near the surface are heavily salinized and can hardly serve as an adequate water source. Deeper groundwater reservoirs are difficult to access. The high population density in the Iishana system area increases the demand upon the surface waters. The geomorphology and surface hydrology of the Iishana system favors very slow surface runoff and low infiltration rates. An extreme change in dry and rainy seasons results in an erratic freshwater supply, which can decrease water quantity and water quality and is thus a major challenge. Since there were no data on the quality of the surface waters in this area, the state of the ecosystem and the health risk for the population are completely unclear; therefore, the regional surface waters were examined to determine their suitability as potable water. The aim is to better understand the hydrological systems in northern Namibia. In four field campaigns between 2017 and 2021, the surface waters, suspended solids, and sediments of the three systems (Kunene, Kavango, and CEB) and the local water supply system, the Calueque-Oshakati Canal, were sampled at more than 30 sites. Relevant hydrochemical parameters were analyzed, microplastics were investigated, and bioassays were conducted to gain insights into the status of aquatic ecosystems and the ecological impacts of pollutants. Spatial differences in the water quality relative to the decreasing precipitation gradient from east to west were noticed. Furthermore, metals such as aluminum and iron accumulate around the densely populated region in the eastern part of the study area. These waters were more polluted during the drought events in 2018 and 2019 than in 2017. Microplastics were found in different quantities, in particular PE and PP fragments. Three different trophic levels (algae, daphnia, and zebrafish embryos) were tested for acute toxicity. Mechanism-specific effects, such as estrogenicity (YES), cytochrome potential (micro-EROD), and mutagenicity (AMES) were investigated using in vitro assays. Acute toxicity could be detected for all three systems; in particular, the fish embryos showed several effects. Estrogenic and mutagenic effects were identified for several sampling sites. The different methodological approaches facilitate a holistic monitoring. This work is the first study to provide a comprehensive statement on water quality. The ecosystems of the Iishana, the Kunene, and Kavango Rivers are severely stressed and differ significantly. They show several signs of anthropogenic pollution that can affect human health. The use of water as potable water is not possible without prior treatment. Further investigation of the exact influencing factors, such as pesticides, is necessary to find suitable treatment measures for water use.
View lessCarbohydrates represent the most diverse and prevalent class of biomolecules in nature and are essential in a wide variety of biological processes. Antigenic glycans at the surface of microbes have the potential to be developed into glycoconjugate vaccines. The Automated Glycan Assembly (AGA) approach can provide those glycans rapidly in a solid-supported synthesis. Challenges in the synthesis of glycans by AGA arise from their complex structures, which require both strict regio- and stereocontrol, but also from technical limitations of the current AGA synthesizer. The goal of my research was to expand capabilities of AGA by introducing new orthogonal protecting groups and developing new strategies for 1,2-cis stereoselective glycosylations to give access to materials for research on infectious diseases. The first part of this dissertation focuses on orthogonality and the expansion of the protecting group portfolio in AGA (Chapter 3). The introduction of microwave-assistance to the AGA synthesizer enabled a larger temperature range (-40 to 100 °C) and the development of a mannose building block with four orthogonal protecting groups. When utilized in the microwave-assisted platform, this building block allowed 1) on-resin global deprotection and 2) the synthesis of glycan structures with up to four branches. In parallel, photo-labile 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) protecting groups were developed. A BODIPY protecting group bearing a boron difluoride unit provided the optimal compromise between glycosylation-stability and photo-lability by green light irradiation. This protecting group enabled a solution-phase consecutive glycan assembly without intermediate purification up to a trisaccharide. The second part of this dissertation describes studies on factors that influence the stereoselectivity for 1,2-cis glycosylations (Chapter 4). The influence of positional and electronic effects in acyl and ether groups on the efficacy for remote participation were investigated. An array of uniquely substituted building blocks was synthesized followed by the evaluation in model glycosylations and cold-ion IR spectroscopy. The obtained mechanistic insights helped to design building blocks for the formation of α-(1→3)-galactosidic linkages. In Chapter 5, the new knowledge and developed methods were utilized to synthesize a conjugation-ready glycan library of the Porphorymonas gingivalis lipopolysaccharide (LPS). P. gingivalis has an immense social and medical impact as it is the major cause of chronical periodontitis and is associated with several systemic diseases. The improvement of our basic understanding of interactions between human immune system and LPS may allow for treatment and prevention strategies. Twelve LPS fragments of P. gingivalis were screened for IgG and IgA binding in human saliva and serum using glycan microarray studies, which enabled the identification of 5-amino-pentyl α-D-Galp-(1→6)-α-D-Glcp-(1→4)-α-L-Rhap-(1→3)-2-β-D-GalNAc as a potential glycoconjugate vaccine candidate against P. gingivalis.
View lessThe project’s objective is to gain knowledge about the interconnection between cell growth and metabolism in the colon cancer cells HCT116 and RKO that rely on glutamine’s nitrogen. The non-cancerous HEK293 cells were tested in parallel to understand the specific metabolic settings and differences in glutamine-independent proliferation. A proteome analysis via liquid chromatography coupled to mass spectrometry (MS) was performed and revealed compartment specific protein expression in HCT116 and RKO cells. Interestingly, the enzyme glutamine synthetase (GLUL) was highly expressed in HEK293 cells under normal growth conditions. We wanted to know if HCT116 and RKO cells can grow independently from glutamine and starved the cells upon glutamine for a longer period. Surprisingly, HCT116 cells survived and persisted, while RKO cells did not. We suspected small molecules or residual glutamine in the growth medium and replaced the cell culture medium composition by dialyzed fetal bovine serum (FBS). Interestingly, in this case neither HCT116 nor HEK293 cells were able to proliferate when glutamine was deprived. Thus, glutamine was also essential for these cells when using dialyzed FBS. Based on these results, we assumed that HCT116 and HEK293 cells synthesize glutamine in the absence of external glutamine. Therefore, a supplementation growth experiment with substrates of the glutamine-centric metabolic network was performed. HCT116 and HEK293 cells showed highest proliferation rates in Glu + NH4 +, while RKO cells revealed an irreplaceable dependence on glutamine supplemented medium. Treatment with a competitive inhibitor of glutamine synthetase, methionine sulfoximine (MSO), blocked proliferation. Thus, glutamine synthetase was confirmed to be the survival factor in glutamine-depleted conditions, if substrates are provided. In order to examine the metabolic fate of glutamine, newly synthesized via GLUL, we have developed an isotope tracing technique using ultra high resolution MS, which allows us to distinguish between simultaneous labeling of carbon- 13 and nitrogen-15 isotopic patterns and that allows new insights into biological reactions in glutamine-deprived HCT116, RKO and HEK293 cells. With this new technique we were able to observe 13C and 15N incorporation in purine nucleotides. Additionally, we investigated the glutamine-analogue 6-Diazo-5-oxo-l-norleucine (DON) as it inhibits all glutamine-utilizing enzymes with focus on amidotransferases. An inital DON-inhibition experiment was performed to examine the interconnection of nucleotide synthesis and glutamine. We revealed an accumulation of nucleotide intermediates in HCT116 and HEK293 cells. To gain a clearer understanding, we traced glutamine‘s nitrogen flow in de novo nucleotide biosynthesis and where it is interfered by DON. Therefore, in the Kempa laboratory a new technique and method based on direct-infusion MS was developed that facilitates dynamic tracing of nitrogen with applied drugs on nucleotide substrates (Rayman (2022)). Finally, we observed decreased nitrogen incorporation into FGAR and the nucleotides of the purine pathway upon DON treatment in HCT116 cells. In conclusion, we demonstrated the inability of RKO cells to synthesize glutamine or to compensate glutamine-deficiency perhaps because of missing functionality of the enzyme GLUL. However, HCT116 and HEK293 cells have proven survivability. Furthermore, we were able to show DON targets in the purine nucleotide biosynthesis.
View lessHigh-alpine landscapes are exposed to pronounced temperature rise due to climate change. In particular, glacial and periglacial dynamics such as glacier retreat and permafrost thaw are accelerating, affecting the stability of rockwalls and posing hazards to the alpine environment. With recent deglaciation, rockfall activity and the production of debris are observed to increase. As the erosion of so-called headwalls above glaciers and associated debris deposition onto the ice surface increase, a thick supraglacial debris cover can form, modifying glacial mass balance and potentially delaying glacier retreat. Yet, debris supply rates and their changes vary spatially. To predict the evolution of glacial landscapes with climate change therefore requires to temporally and spatially examine rockwall erosion and potential temperature-related patterns. However, in situ measurements of rockwall erosion rates, specifically at headwalls, are rare as they are potentially dangerous in the difficult-to-access terrain, and the few existing records are often based on short-term monitoring from the last few decades. This thesis examines spatiotemporal records of headwall erosion in the Swiss Alps on longer terms to study glacial landscape dynamics with climate change. Headwall erosion rates were quantified by concentrations of the in situ-produced cosmogenic nuclide 10Be in medial moraine debris, obtained by interval-sampling along longitudinal moraine profiles. In a first small-scale case study, the archive function of medial moraines and temporal evolution of headwall erosion are studied in detail. Two medial moraine records were combined with a simple glacier transport model to account for the additional accumulation of 10Be during post-depositional downglacier debris transport and to assess the time of headwall erosion. Systematically varying 10Be concentrations over approximately the last 200 years indicate an increase in headwall erosion from the end of the Little Ice Age towards the following deglaciation period. This trend is reflected by different debris grain size fractions, implying that the records are unaffected by episodic large-scale erosion. In a follow-up study on a small mountain massif, temporal and spatial patterns of rockwall erosion are examined for five nearby glaciers and in relation to spatially distinct rockwall morphology. As an extension of the first study, ice cover changes across each debris source area were quantified to assess the potential contribution of recently deglaciated bedrock of possibly low 10Be concentrations, which seems to be low at most sites. Compared to the data from the first study, temporally constant 10Be concentrations over the last 100 years imply more stable rockwall erosion throughout the deglaciation period. At the same time, rockwall erosion rates are higher at steeper north faces in the massif. In a final, still ongoing study on a large-scale glacier catchment, two high-resolution medial moraine records are combined for the first time with paired in situ 14C/10Be analysis to resolve erosional landscape transience in more detail. Preliminary analyses suggest that conditions that caused an apparent pulse in erosion in one of two major debris source areas may be minor in the other due to differing headwall deglaciation histories. Yet, such rapid changes in transient landscapes, debris supply from long-time exposed or recently deglaciated surfaces, and post-depositional 10Be accumulation pose methodological challenges to derive rockwall erosion rates directly from measured medial moraine 10Be concentrations and require debris particle tracing in glacial landscapes and future research. Eventually, the studies of this thesis demonstrate that 10Be concentrations along medial moraines provide systematic results in landscapes that typically erode stochastically. Headwall erosion seems to be controlled by slope and temperature, and to accelerate at the transition of the Little Ice Age to deglaciation before stabilizing again - both observations that ultimately highlight the climate sensitivity of glacial landscapes.
View lessIn response to the climate crisis, there is a need for technological innovations to reduce the escalating CO2 emissions. Two promising semiconductor technologies in this regard, perovskite-based solar cells and memristive devices based on two-dimensional layered transition metal dichalcogenide (TMDC), can potentially contribute to the expansion of renewable energy sources and the development of energy-efficient computing hardware.
Within perovskite and TMDC materials, ions dislocate from their ideal position in the semiconductor crystal and leave void spaces. So far, the precise influence of these vacancies and their dynamics on device performance remain underexplored. Therefore, this thesis is dedicated to comprehensively examining the impact of vacancy-assisted charge transport in innovative semiconductor devices through a theoretical approach by modeling and simulating systems of partial differential equations. We start by deriving drift-diffusion equations using thermodynamic principles, including Maxwell-Stefan diffusion and the grand canonical ensemble of an ideal lattice gas. Particular attention is directed towards accurately limiting vacancy accumulation. Furthermore, we formulate drift-diffusion models to describe charge transport in perovskite solar cells and TMDC memristors. We discretize the transport equations via the finite volume method and establish the existence of discrete solutions using the entropy method. Our study concludes with simulations conducted with ChargeTransport.jl, an open source software tool developed in the programming language Julia. These simulations investigate the large time behavior of discrete solutions for both transport models. Additionally, we explore the influence of volume exclusion effects on charge transport in perovskite solar cells and compare our simulation results with experimental measurements found in literature for TMDC-based memristive devices.
View lessEinleitung Das Zervixkarzinom tritt mit hoher Inzidenz auf, wobei das mittlere Alter der Erstdiagnose stetig sinkt. Durch die Standardtherapie, die radikale Hysterektomie, wird die Familienplanung vieler Frauen beeinträchtigt. Die radikale vaginale Tachelektomie ermöglicht es, das Zervixkarzinom bis zum Stadium FIGO Ib2 stadiengerecht und zugleich fertilitätserhaltend zu therapieren. Unser Ziel war es, die Effekte der prophylaktischen, quadrivalenten HPV-Impfung bei Applikation post-Trachelektomie zu quantifizieren und die Stimulation einer Immunreaktion nachzuweisen. Methoden Den 75 zwischen 2002 und 2008 in unserer Klinik trachelektomierten Frauen wurde die quadrivalente HPV-Impfung empfohlen. 19 Patientinnen lehnten die Studienteilnahme ab, 37 entschieden sich für, 16 gegen die Impfung (Kontrollgruppe). Um die Titerentwicklung der Impf- und Kontrollgruppe beurteilen zu können, wurden die Antikörpertiter (L1-, E6- und E7-Antikörper der HPV-Typen 6, 11, 16, 18, 31 und 45) im Plasma der Patientinnen vor und gegebenenfalls nach Impfung an mehreren, longitudinal verteilten Zeitpunkten, durch GST-Luminex bestimmt (Anzahl der Messungen pro Patientin: 1-13, Median=5). Die Titer wurden deskriptiv dargestellt und zwischen den Messzeitpunkten durch den Wilcoxon-Vorzeichen-Rang-Test verglichen. Unter Miteinbeziehung der Daten zum HPV-Typ im Primärtumor und dem Blutabnahmezeitpunkt bildeten wir gemischte lineare Modelle zur Testung der Titerveränderungen nach Impfung bzw. in der Kontrollgruppe. Ergebnisse Wir konnten nachweisen, dass die L1-Antikörper aller geimpfter HPV-Typen sowie der Typen 31 und 45 als Folge der Impfung stark anstiegen. Der aggregierte Median der Titer der gegen die im Impfstoff enthaltenen L1-Antigene gerichte-ten Antikörper stieg von 162,3 MFI vor der ersten Impfung auf 3218 MFI nach mindestens einer Impfung (p<0,001). Auf die serologische Antwort gegen die jeweils untersuchten HPV-Typen hatte die zweite Impfung den stärksten Effekt (Range: 3,3- [HPV 18] bis 9,6-fach [HPV 11] des L1- Baseline-Titers) (Tab. 13-24). Die dritte Impfung hatte einen schwächeren Effekt (Range 1,8 [HPV 45] – 8,1-fach [HPV 11] im Vergleich zu vor der Impfung), gefolgt von der ersten Impfung (Range 1,4 [HPV 45] – 6,6-fach [HPV 11] im Vergleich zu vor der Impfung). Dieser Effekt konnte, wenngleich deutlich schwächer, auch für die E6- und E7-Antikörper der HPV-Typen 6, 11, 18 und 45 sowie die E6-Antikörper des HPV-Typ 31 nachgewiesen werden. Ebenso zeigten wir, dass der Effekt der Impfung auf den Titeranstieg bei Patientinnen, bei denen HPV-16, -18 oder -31 im Primärtumor nachgewiesen werden konnte, schwächer war als bei Probandinnen mit anderen HPV-Typen im Primärtumor. Begründet ist dies durch den vorhergehenden Antigenkontakt – und die dadurch bereits erhöhten Baseline- Antikörpertiter. Die L1-Antikörpertiter stiegen im Verlauf auf ein letztendlich hohes Niveau. Diskussion Wir konnten einen zuverlässig starken Anstieg der L1-Antikörpertiter der HPV-Typen 6,11,16,18,31 und 45 um mehr als das 10-Fache im Vergleich zu den Werten vor der Impfung signifikant nachweisen. Dieser Effekt ist der Impfung zuzuschreiben, in der Kontrollgruppe war er nicht nachweisbar. Dieser Nachweis wurde hier erstmalig bei Patientinnen nach Behandlung eines Karzinoms erbracht. Die Immunogenität der Impfung post-Trachelektomie ist gegeben. Ein leichter, aber dennoch signifikanter Anstieg der E6- und E7-Antikörper der HPV-Typen 18, 45, 6 und 11 sowie den E6-Antikörper des HPV-Typs 31 konnte ebenso nachgewiesen werden, die Bedeutung dieser indirekt stimulierten Reaktion, insbesondere der Langzeitauswirkungen, bedarf weiterer Forschung.
View lessThe process of bone fracture healing relies on a tight regulation of cellular and molecular events. However, obesity can disrupt the healing cascade, leading to defective repair. A heightened inflammatory state, primarily regulated by the adaptive immunity, is believed to contribute to the pathophysiology of obesity linked to bone healing defects. Despite the high obesity prevalence, limited research has explored this relationship. Herein, the underlying hypothesis of this work is that increased pro-inflammation associated with obesity may be causative for delayed bone repair. The specific aims were to understand the impact of different degrees of obesity, as encountered in clinical settings, on the modulation of immunity and its effects on bone fracture healing. To investigate this, a high-fat diet (HFD)-induced obesity model was used in conjunction with femoral osteotomy. Based on metabolic measurements, two obese subtypes were included in this study: a group with low glucose intolerance and a group with high glucose intolerance that indicates a possible developing type 2 diabetes mellitus (T2DM). The findings provided evidence that the early onset of obesity induced by a short-term HFD resulted in a pro-inflammatory state that caused impaired healing of femoral fractures with an altered microarchitecture in both obese groups. Remarkably, obese mice with high glucose intolerance showed signs of adapting to the metabolic conditions in terms of pro-inflammatory responses and bone healing capacity. Consistently, a long-term HFD resulted in reduced pro-inflammation in both groups. Surprisingly, along with increased weight gain, callus adiposity and bone mineralization, the previously observed healing defects associated with obesity were repealed regarding the mineralization process. However, abnormal extracellular matrix (ECM) remodeling and formation were observed during initial bone fracture healing, with more pronounced effects seen in mice with high glucose intolerance, hinting at a T2DM manifestation. This finding poses a potential risk for the development of fibrosis. Neutralization of potentially detrimental CD8+ T cells during the early healing phase reversed the disturbance in the formation of ECM in the obese group with high glucose intolerance. This finding highlights the critical role of CD8+ T cells in regeneration and offers a potential therapeutic approach to improve bone formation in specific patients. The microbiome's role in obesity and its connection to adaptive immunity and metabolic inflammation is well established. The analysis of feces and cecal samples revealed that long-term obesity altered the gut microbiome structure, while bacterial diversity remained unchanged. Interestingly, obese mice with high glucose intolerance exhibited a distinct microbial signature associated with metabolic rather than immunological alterations. Importantly, these obesity-related changes were partially reversible through the neutralization of CD8+ T cells. Overall, this work emphasizes that aberrant bone formation occurs early in the progression of obesity, before the development of obesity-associated T2DM. The activation of the immune system is even enhanced at the onset of obesity, leading to impaired bone formation. Although the skeletal system adapts to the immunological and metabolic imbalance associated with persistent obesity, this still results in an altered ECM. The data increase our comprehension and awareness of obesity progression in clinical contexts, providing potential therapeutic avenues. Addressing obesity becomes crucial to making right and timely decisions for susceptible fracture patients.
View lessIn the last years many foodborne outbreaks in Germany were caused by Campylobacter spp. in raw milk that had not been properly heat treated prior to consumption. Feces from Campylobacter-colonized cows pose a risk for cross-contamination of teats, which can transfer the Campylobacter spp. contamination into raw milk during the milking process. The aim was to identify and fill data gaps regarding Campylobacter spp. transfer along the supply chain of raw milk and to investigate its survival in raw milk. Finally, possible intervention strategies to minimize the risk from raw milk consumption were outlined. A systematic review and meta-analysis was performed to summarize previous research on Campylobacter spp. in feces of dairy cows worldwide. The prevalence varied widely from 0-100%. Only limited quantitative data on Campylobacter spp. in the feces of dairy cows were available. The reported Campylobacter mean concentrations ranged between 2.1 and 4.17 log CFU/g feces. A longitudinal study was performed to investigate the transmission of Campylobacter spp. along the raw milk supply chain. The investigated samples comprised rectal feces, boot socks, teat skin swabs, milking cluster swabs, raw milk and milk filters. Samples were analyzed for the presence and concentration of Campylobacter spp., E. coli, total aerobic colony count (TACC) and for Pseudomonas spp. In total, Campylobacter spp. were detected in 77.1% of the fecal samples with an average concentration of 2.43 ± 0.9 log CFU/g. Of the boot sock samples 29.2% were tested positive with a mean concentration of 3.01 ± 1.05 log CFU/two socks. Among the teat swabs, 12.2% tested positive for Campylobacter spp. None of the milking clusters were positive. Only one raw milk sample and the milk filter tested positive on the same day. In addition, on this day nine teat swab samples were tested positive for Campylobacter spp. The results showed that contamination of raw milk, albeit rare, can occur. The survival of C. jejuni was investigated by two different methods, culturally according to ISO 10272-2 and in addition using a quantitative polymerase chain reaction specifically detecting viable Campylobacter spp. in raw milk (v-qPCR). The experiment was performed at three temperatures (5°C, 8°C, and 12°C). While only colony-forming units (CFU) can be detected according to ISO 10272-2, the newly developed v-qPCR (Wulsten et al., 2020) allows detection of intact and potentially infectious units (IPIU), which includes CFU and viable but non-culturable units (VBNC). According to Wulsten et al. (2020) who performed their experiments at 5°C, the survival was also underestimated in our study by CFU for the strains and temperature tested. To date, the infectious potential of Campylobacter spp. in VBNC status is unknown. Wulsten et al. (2020) demonstrated that C. jejuni VBNCs developed upon incubation in raw milk at 5°C were recovered into a cultivable state (recovery) within a certain time period (at least 90 h), using a specific gas mixture with a lower oxygen level for 72 h. Here, the recovery was investigated at 8°C and 12°C. The recovery time periods for both strains were longer at 8°C (up to 80 h) compared to 12°C (at least up to 48 h). Hence, the recovery period shortened with increasing temperature. Predictive models providing a rapid response for predicting microbial behavior in the food environment were developed on the two generated data sets. Three tertiary models consisting of one for all IPIU data and two for the CFU data, were provided to predict the survival of C. jejuni in raw milk between 5°C and 12°C. Finally, a quantitative microbial risk assessment (QMRA) model was developed. Through various uncertainty analyses, parameters with the greatest impact on the risk for consumers for drinking Campylobacter spp. contaminated raw milk were identified. In addition to the initial concentration of Campylobacter spp. in cow feces, the prevalence of contaminated teats had a major impact on the risk of consuming Campylobacter-contaminated raw milk. In summary, transmission of Campylobacter spp. can occur due to cross-contamination of teats by cow feces into the raw milk. However, this is a rare event. Clean udders are therefore of crucial importance. It was shown that survival of C. jejuni is underestimated based on CFU data compared to VBNC data at different temperatures in raw milk. The overall data are valuable to support risk managers in controlling Campylobacter spp. More CFU and IPIU data are needed to improve the developed predictive models. The significance of the finding on underestimated survival should be determined through studies, e.g., in animal models, on the infectivity of Campylobacter spp. in VBNC status, within and beyond the time window in which VBNC can be recovered to CFU.
View lessJoint homeostasis is maintained by loading, synovial lubrication, and a plethora of resident and migrating immune cells, cytokines, and signaling molecules. If this balance is disrupted by either local or systemic factors, the body responds with articular inflammation. Persisting inflammation, like in the case of rheumatoid arthritis and osteoarthritis, causes progressive joint destruction which often results in debilitating pain and reduced quality of life. This thesis outlines cellular and molecular pathways relevant in inflammatory and degenerative joint pathologies that contribute to disease progression, and which may be exploitable in the development of future therapeutics.
View lessFlooding events are one of the most dangerous hazards for society. Central Europe was regularly affected by high-impact river floods within the last few decades, causing high socioeconomic losses. In order to improve flood protection, a detailed understanding of the underlying processes and precise return value estimates of the associated extreme precipitation is from importance, especially when these characteristics change in a warmer climate. For process analysis, past studies have either analysed individual events or systematically studied events with smaller return periods on the order of one year, due to the limited length of observational time series. The main objective of this thesis is, hence, to perform such a systematic analysis of 100-year precipitation events.
In order to improve the understanding of atmospheric processes during extreme precipitation, robust process analyses are performed in this thesis. For this, ensemble simulations are used to generate a large set of daily precipitation events. With this approach, time series can be obtained that are considerably longer than observational time series, resulting in a more systematic assessment of processes (beyond individual events) and in reduced uncertainties of return value estimates. Firstly, ensemble weather prediction (EPS) data from the ECMWF are used to investigate atmospheric processes of realistic 100-year events over central European river catchments and their differences to less extreme events. 100-year events are generally associated with an upper-level cut-off low over central Europe in combination with a surface cyclone southeast of the specific catchment. Differences to less extreme events vary between the catchments, indicating that either dynamic processes (intensified upper-level cut-off low and surface cyclone) or thermodynamic mechanisms (higher lower-tropospheric moisture content) are more relevant. Secondly, 100-year return values of daily precipitation are estimated on a global scale from the EPS data, substantially reducing the uncertainty compared to observational estimates. Despite a general agreement of spatial patterns, the model-generated data set leads to systematically and significantly higher return values in several regions (e.g. the Amazon, western Africa, the Arabian Peninsula). This may point to an underestimation of very extreme precipitation events in observations. Finally, changes of daily 10-year precipitation events (due to the too small sample size for a robust analysis of 100-year events) over central European river catchments are analysed from ensemble climate simulations between the historical and a projected warmer climate. Precipitation extremes are projected to intensify and occur more frequently in spring and autumn. Dynamical changes of these events are often associated with a slight westward shift of the upper-level cut-off low, an intensified ridge over eastern Europe and less pronounced changes near the surface. Thermodynamic changes such as an increased horizontal temperature gradient and higher lower-tropospheric moisture content play an important role as well.
View lessDie Arbeit untersucht im ersten Teil, welche unionsrechtlichen Vorgaben eine Umsetzung des gerechten Ausgleichs nach der InfoSoc-Richtlinie für Vervielfältigungen zum privaten und sonstigen eigenen Gebrauch erfüllen muss. Dabei wird insbesondere die Rechtsprechung des EuGH miteinbezogen. Der zweite Teil der Arbeit behandelt die Frage, inwieweit das System der angemessenen Vergütung aus §§ 54 ff. UrhG, das gesetzliche Vergütungsansprüche und ihre Durchsetzung für Vervielfältigungen nach § 53 Abs. 1 und 2 UrhG sowie nach §§ 60 a – 60 f. UrhG regelt, diesen Anforderungen genügen kann.
View lessDie vorliegende Dissertation betrachtet die Entwicklung von Parteiidentifikationen (PI) mit der SPD in verschiedenen sozialen Gruppen sowie von Einstellungen zur SPD im Hinblick auf die Wahlentscheidung über den Zeitraum von 1984 bis 2017. Die Entwicklung der Partei wird aus zwei Perspektiven der Wahlforschung betrachtet: Zum einen aus der makrosoziologischen Perspektive („Cleavage-Modell“), zum anderen aus der sozialpsychologischen Perspektive („Michigan-Modell“). Das erste zentrale Ergebnis ist, dass die soziostrukturelle Prägung der SPD-Anhängerschaft durch formal Niedriggebildete und Arbeiter über den Beobachtungszeitraum praktisch vollständig aufgelöst wurde. Während in den 1980ern SPD-Bindungen bei Arbeitern und Niedriggebildeten noch deutlich häufiger vorkamen als in anderen Gruppen, ist das am Ende der Beobachtungsreihe im Jahr 2017 nicht mehr der Fall. Der zweite Ergebnisteil beschäftigt sich mit der Rolle von Einstellungen zur SPD bei der Wahlentscheidung bei den Bundestagswahlen von 1994 bis 2017. Je nach Wahljahr erhöhte eine SPD-Bindung die Wahrscheinlichkeit für eine entsprechende Wahl um 60 bis 80 Prozentpunkte. Die Verluste, die die Partei im Vergleich zu den 1990ern erlebte, können also teilweise durch den Rückgang an Parteibindungen an die SPD erklärt werden. Dies konnte noch für einige Wahlen durch starke Kandidateneffekte, kombiniert mit einem populären Amtsinhaber kompensiert werden, ab 2009 fielen solche kurzfristig wirksamen Effekte allerdings weg.
View lessIn the frame of this thesis, the effects of a suddenly occurring prolongation of the light period leading to photoperiod stress in Arabidopsis thaliana were investigated. In particular, the photoperiod stress response is characterised through three approaches. First, the response of plants to a prolonged light (PL) period of 0.5 h to 8 h is investigated in sensitivity experiments. Second, the effects of a photoperiod stress stimulus on plant responses to a subsequently occurring similar photoperiod stress are examined in cis-priming experiments. Third, the impact of photoperiod stress on plant responses to infections by pathogens are studied in trans-priming experiments. Transcriptome analysis by RNA-seq showed that a prolongation of the light period by one hour is sufficient to alter the expression level of 22 genes at the end of the following night in four-week-old short day-grown plants. The expression of the photoperiod stress marker genes ZINC FINGER OF ARABIDOPSIS THALIANA12 (ZAT12) and BON ASSOCIATION PROTEIN1 (BAP1) was not significantly affected by PL periods up to 2.5 h. An extension of the PL period by 2.5 h, 4 h or 8 h is associated with an increase in the number of genes regulated at the end of the night that follows a PL period. Three genes regulated independent of the duration of the PL period were identified: PHYTOCHROME INTERACTING FACTOR4, BES1-INTERACTING MYC-LIKE1, and COLD REGULATED 314 INNER MEMBRANE1. The cis-priming experiments revealed that photoperiod stress induced by a 4 h-prolonged light period (priming stimulus) causes in wild-type plants a different response to a second photoperiod stress (triggering stimulus). The first photoperiod stress induces the expression of ZAT12 and BAP1, an accumulation of peroxides, and a decrease in catalase activity. These responses are suppressed in response to a second photoperiod stress. The suppression to a second photoperiod stress lasts for several days over a stress-free lag phase indicating the existence of a memory. Transcriptome analysis by RNA-seq revealed different kinds of memory genes for photoperiod stress showing a sustained, altered, or sensitized expression when exposed to a 4 h-PL period after a first similar PL period. A prolongation of the light period up to 2 h results only in a weak photoperiod stress response in wild-type plants and is not sufficient to prime (induce) the plants’ resistance suggesting that the first stimulus needs to induce a substantial response to be memorized. The responsiveness of Arabidopsis wild-type plants to photoperiod stress and their ability to become primed by a photoperiod stress depends on their developmental phase. Analysis of plants of different age exposed to a 4 h-PL period showed that only three- to five-week-old plants responded to and were primed by the PL period indicated by induction of ZAT12 and BAP1 or by accumulation of peroxides and suppression of these responses, respectively. The memory of photoperiod stress-sensitive mutants arabidopsis histidine kinase2 (ahk2) ahk3 and circadian clock associated1 (cca1) long elongated hypocotyl (lhy) is shorter than the memory of wild- type plants indicating that a functional cytokinin signalling and circadian clock are required for maintaining memory. Trans-priming experiments revealed that photoperiod stress induced by an 8 h-PL period improves resistance of wild-type plants against infections with the bacterium Pseudomonas syringae pv. tomato DC3000 and the fungus Botrytis cinerea. Photoperiod stress-induced resistance against P. syringae and B. cinerea requires salicylic acid- and jasmonic acid-related responses as revealed by analysing mutants defective in salicylic acid or jasmonic acid biosynthesis/signalling. NONEXPRESSOR OF PATHOGENESIS RELATED GENES1 (NPR1) is crucial for the oxidative burst-like response of photoperiod stress, since npr1 mutants do not accumulate peroxides during photoperiod stress and several genes were differently regulated in these mutants. Further investigation is necessary to fully understand the molecular mechanisms involved in photoperiod stress-induced resistance against pathogens.
View lessJoining the field of New Economic Criticism, this dissertation examines a strand of recent American fiction expressing a yearning for intimacy while simultaneously reflecting on the various material circumstances that frustrate its satisfaction. Through what this study calls the “aesthetics and economics of intimacy,” a range of contemporary authors distinguish themselves from postmodernism’s playful detachment from the world by deliberating questions of subjectivity, interiority and the difficulty of interpersonal reciprocity with renewed urgency. The selection of David Foster Wallace’s The Pale King, Jennifer Egan’s A Visit From the Goon Squad, Tao Lin’s Taipei and Barbara Browning’s The Gift is cautiously optimistic about intersubjectivity, it evinces an ethical commitment to earnest exchanges within, and via its readers, through literature. As self-aware fiction ‘after postmodernism,’ these texts negotiate irony (distance) and sincerity (intimacy). They seek to form genuine relations in a post-Fordist society that mandates disintegration and connectivity at once and thus illuminate the contradiction of concealment and disclosure at the heart of reflexive intimacy that, unlike its forerunner romance, demands perpetual attention.
By shedding light on how material relations can exacerbate such dilemmas, the examined primary literature brings attention to intimacy’s frequently overlooked economic context. This study employs the analytical tools of New Economic Criticism to contextualize the cultural turn to intimacy—epitomized in literary studies by postcritique—as both symptomatic of reflexive modernization (Beck) and a reaction against economic challenges for literature and literary studies. Given the tangible affinity between the concerned texts’ explicit communicative impetus and sociological discourses on a contemporary capitalistic rhetoric of care, this dissertation analyzes the re-emergence of sincerity both against the backdrop of post-Fordism’s communicative emphasis and intimacy’s discursive history.
Contemporary fiction negotiates intimacy in an open-ended manner. On the one hand, the literary craving for intimacy participates in the antimodernist tradition by seeking individual mitigation from the social burdens that induce such escapism in the first place. On the other hand some fiction can, through meditation on the estranging state of social relations, encourage in its readers’ the very reflection on sociality that antimodernist thought eschews. Devoting a full chapter to each of the four selected primary texts, this dissertation heeds the insight that the turn to intimacy’s cultural work produces ambivalent artistic results that ought to be studied individually.
View lessThe Taiwan Island is located at the convergence of the Eurasian and Philippine Sea plates. Dynamic orogeny caused the rapid uplift of the Neogene mountain ranges. The sediments yielded from these Neogene mountain ranges were deposited in the foreland basins, and subsequently uplifted, eroded, and redeposited, progressively toward the west. The sedimentation-uplift-erosion-redeposition cycles resulted in the formation of sedimentary terraces there, which are locally called “tablelands”. Due to methodological restrictions in early studies, the chronological control and corresponding Quaternary environmental change factors are still open for debate. This study focuses on the Miaoli Tableland, where is highly accessible for observing numerous outcrops of the tableland segments. A synthesis of the Miaoli Tableland morphology is proposed based on the analyses of high precision 3D geomorphological mapping, particle size analysis, borehole data interpolation, and OSL dating for depositional ages. The mapping results reveal that the palaeo-topography of alluvial fan(s) covered throughout the Miaoli Tableland area. A new numeral classification of the tableland segments is carried out, with subdivisions based on geometrical properties as Sedimentary Highlands (SH-I/II), and Sedimentary Terraces (ST). Spatial distributions of parallel / dendritic fluvial network developments and corresponding fluvial valley shapes (V-shaped / box-shaped) are identified, roughly bounded at ca. 150m asl. Three sub-types of sedimentary successions are summarized based on the existence and varying thickness of the gravel and cobble bed(s). Spatial distributions of these sub-types correspond to the morphological states of tableland segments. The geometry and morphological state of tableland segment surfaces, the corresponding sub-types of sedimentary successions, and their locations are combined into a 3D model. This 3D model shows that tectonic uplift and successive fluvial dissection caused redepositions of gravels and cobbles from the SH-I through the SH-II and ST to the coastal areas. The cross sections interpolated from the borehole data reveals a spatial pattern of the movement of the gravels and cobbles that corroborates this 3D model. The depositional age estimations provided by OSL dating of the coastal, fluvial and aeolian sediments show that the depositions of gravels and cobbles in the SH-I started during the marine isotope stage (MIS) 5a (approximately 90ka). Those gravels and cobbles were successively redeposited towards the west and north (proximal areas of the SH-II/ST) approximately from the MIS5a to the MIS3. The successive redepositions of gravels and cobbles reached the distal areas by the coast approximately during the MIS2. These depositional phases are correlated with low base level and relative dry climate periods, which are affected by loosened vegetation that provide less protection to the tableland segments during intensive erosion events (e.g. typhoons). The deposition ages among the tablelands surface depositions in western Taiwan shows a pattern that the formation of tablelands in the central to north, including the Miaoli Tableland, are younger than the tablelands in the central to south. A revision of the lithostratigraphy nomenclatures is proposed based on the international stratigraphic guidelines, which reintroduces the original Japanese time stratigraphical terms.
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