In the context of drug development for the treatment of complex diseases such as cancer, it might be necessary to interfere with multiple targets. Inspired by the multiple functions of heparan sulfate proteoglycans (HSPGs) several compounds have been developed in the past. Here the fully synthetic dendritic polyglycerol sulfates dPGS and dPGTPS were evaluated with respect to their overall anti-tumorigenic properties. Primarily focused on the sonic hedgehog (Shh) pathway, which is upregulated in several aggressive tumors, it was found that both compounds reduce pathway activation. Shh binding was analyzed via SPR and gave the following KD values: 88.7 nM for dPGS and 37 nM for dPGTPS. The inhibition of the Shh-signaling pathway was further evaluated in two reporter cell-based systems: a luciferase reporter and an alkaline phosphatase (ALP) assay. While dPGTPS showed consistently strong pathway inhibitory activity (IC50 of 72 nM in the ALP and 111 nM in the luciferase assay), dPGS displayed a different behavior (IC50 of 81 nM in ALP and 6.5 µM in luciferase assay), which might be attributed to the different architecture of the polysulfates. Cancer cell line proliferation also mediated by the Shh pathway was further analyzed in 2D cultures and 3D spheroid-based assays. In monolayer 2D studies, dPGS did not show any influence, while dPGTPS at µM concentrations reduced cell proliferation. By contrast, in 3D spheroid-based cultures, both dPGS and dPGTPS, significantly arrested the growth of A549 spheroids, although the latter compound to a lower extent. At the molecular level growth factors mediate cell proliferation. Therefore, binding of FGF1, FGF2, and VEGF165 to the polysulfates was analyzed, again via SPR. All proteins bound tightly to the sulfated compounds (i.e., KD of 25 nM for FGF2-dPGS interaction). Further, the capacity of dPGS to hamper angiogenic processes was confirmed in case of inhibition of HUVECs proliferation. FGF2-induced HUVECs proliferation was reduced upon dPGS treatment (IC50=21 µM) and cell differentiation to initiate three-dimensional capillary-like tube formation dose-dependently blocked. Heparanase is an essential enzyme to initiate remodeling of the extracellular matrix (ECM) during tumorigenesis. The polysulfate dPGS displayed a remarkable affinity to the protein (KD of 3.11 nM) and blocked its enzymatic activity (IC50 = 2 nM). To conclude, these findings emphasize the potential of synthetic polysulfates and should inspire future studies to explore their anti-tumorigenic efficacy.

Carbohydrates from bacteria, in particular polysaccharides constituting bacterial capsules, have been used to develop vaccines against pathogens. Traditionally, these vaccines are made from polysaccharides isolated from natural sources. As an alternative, vaccines based on synthetic oligosaccharides offer the possibility of rationally designing new vaccines or improve the existing ones. Having access to amounts of highly-pure and well-characterized oligosaccharides is fundamental for performing studies aimed at understanding the structures of minimal sugar epitopes with immunogenic potential. The main objective of this work is the development of synthetic routes to obtain oligosaccharides representing sequences of capsular polysaccharides (CPSs) from pathogenic bacteria to elucidate minimal epitopes of antibodies. The aim was achieved via a combination of synthetic chemical methods and employed both solution-phase and automated solid-phase techniques. The ultimate goal was to design synthetic carbohydrate antigens useful for developing new semi-synthetic glycoconjugate vaccines for human or animal use. The first part of this dissertation describes the synthesis of five fragments related to the CPS of the pig pathogen Streptococcus suis serotype 2 using solution phase chemistry. Starting from the synthesis of seven monosaccharide building blocks bearing appropriate protecting groups, a series of chemical glycosylations and successive protecting group manipulations gave access to the target compounds. The obtained library was used to create glycan microarrays to evaluate binding specificities of antibodies contained in samples of sera from pigs infected with Streptococcus suis type 2. The second part describes the use of a combination of automated solid-phase synthesis and enzymatic glycosylations to synthesize three fragments related to the CPS of Streptococcus suis serotype 14. These glycans will be evaluated in glycan microarrays experiments as described above.

In recent years, the framework of network propagation has been adopted multiple times for the purpose of generating novel genotype-phenotype associations. However, existing methods usually rely on the standard degree-based formulation, which skews the results due to degree bias within protein-protein interaction networks. Furthermore, the network modules, which are identified post propagation by some of these methods, are rather dispersed and their genes are not well connected. In this thesis we present NetCore, a novel network propagation framework based on node core, for genotype-phenotype associations and module identification. NetCore explicitly addresses the node degree bias by incorporating node core in the random walk with restart formulation of network propagation. Additionally, NetCore applies a semi-supervised module identification procedure that allows us to connect between well characterized genes and novel candidate genes, which are significantly scored at the end of the propagation. We evaluate the performance of NetCore using gene sets from 11 different traits, which are based on previously established genome-wide associations. We show, using a cross-validation scheme, that our core-based approach improves the performance in comparison to the standard degree-based approach. Furthermore, we determine that our semi-supervised module identification procedure allows us to enhance the connectivity between the known phenotype-associated genes by introducing connections to novel candidate genes. The performance is assessed with respect to the choice of the different parameters in NetCore, along with assorted versions of the protein-protein interaction network, which was extracted from ConsensusPathDB. We demonstrate the application of NetCore to identify disease genes and modules for schizophrenia genome wide mutation data as well as for pan-cancer mutation data. We compare the results with existing network propagation methods and highlight the benefits of using NetCore in comparison to those. To illustrate the versatility of NetCore, we also apply it to gene expression levels measured upon anthracycline drug treatments, in order to elucidate the mechanisms of drug-induced toxicity. Altogether, this thesis provides a novel framework, with an easy-to-use implementation, which can be applied to various types of genomics data in order to obtain a re-ranking of genes and functionally relevant network modules. Our contributions improve the re-ranking after propagation, augment the experimental evidence towards candidate genes, and produce modules which connect well-characterized genes with novel predictions.

Peptides, as natural and highly specific and biocompatible substrates, fibers or active compounds, are developed since their first descriptions by Crick, Corey and Pauling in the 1950’s. Inside this diverse field, coiled-coil peptides have been increasingly investigated as suitable substrates due to their self-assembly properties, which enable multivalent ligand presentation. This thesis has the aim to develop various highly specific and stable coiled-coil peptides as possible 2D or 3D scaffolds for stem cell differentiation. Related to the up to date research in the field of cell culture materials for biological and “created by extracted own cells” implants for the human body, the goal is to direct the stem cell fate to the specific cell type needed e.g. as heart muscle tissue. Therefore, a library of different undecorated peptides was synthesized and their properties were compared to known standards. Furthermore, their impact on self-assembly and formation of stable hydrogels had to be evaluated as possible 2D or 3D scaffolds. With regard to the information, a hydrogelating fiber forming coiled-coil peptide (hFF03-bAcA) was chosen and functionalized by conjugation with biologically relevant ligands. Due to varying the density and ligands presented, the structural and mechanical properties could be adjusted. Combining all these parameters, two main applications for testing the designed peptide as suitable biomaterial were developed. On the one hand, hFF03-bAcA presenting biological relevant ligands was tested as a tailored artificial 3D material to mimic the so-called extracellular matrix (ECM). Therefore, the system was either functionalized with carbohydrates or peptide-epitopes as signal molecules and mixed with each other in different ratios. The aim was to create a suitable 3D scaffold, which presents the desired signal molecules in a multivalent fashion. Structural and rheological characterizations revealed that the coiled-coil systems build fibrous networks with viscoelastic properties. Moreover, embryonic mouse fibroblast populations showed excellent viability profiles, when cultured on these peptide hydrogels. On the other hand, peptide-carbohydrate conjugates were evaluated as potential inhibitors for Influenza A Virus. Therefore, sialic-acid was conjugated to fiber forming coiled-coil peptides and tested regarding density of ligands and suitability as substrates for virus inhibition. Hemagglutination-inhibition tests showed that sialic-acid conjugated coiled-coil peptides enable inhibition of Influenza A Virus in the micromolar range and are therefore promising substrates as diagnostic tool or anti-influenza drugs. In conclusion, the developed and established approaches represent a simple and efficient methodology to design 3D scaffolds based on coiled-coil peptide structures presenting in a defined and exactly adjustable density of biologically active ligands for specialized applications in the fields of tissue engineering, regenerative medicine and infectious diseases, like growing implants out of extracted steam cells.

The introduction of automation in carbohydrate synthesis has paved the way towards getting faster access to complex, immunologically relevant glycans. Automated assembly enables the synthesis of oligomers and polymers (as long as 50 mers) to be accomplished in weeks, compared to months or even years when performed via conventional solution phase synthesis. However, the optimization of the entire process still lies in its infancy, and standard protocols for the automated synthesis of oligosaccharides are not yet available. The work in this thesis aims to develop optimized protocols for the automated assembly of complex glycans using the Glyconeer synthesizer, which was accomplished by firstly, optimizing the synthesis of building blocks. Since building block synthesis is very often the most laborious and time consuming step in the entire process of automation, ready availability of standard protocols for procuring multi-gram quantities of these monomers further reduces the time required to synthesize complex glycans via automated synthesis. Thereafter, with multi-gram quantities of building blocks in hand, the automated synthesis of glycans using the Glyconeer synthesizer were streamlined. Optimized protocols for automated glycan assembly of complex glycans were established by streamlining the variables associated with the glycosylation reaction, namely, temperature, number of glycosylation cycles and concentration of donor (in this case building blocks). Therefore, the AGA of Lewisx epitope was optimized to establish optimal glycosylation conditions for the building blocks (Chapter 3) on a 0.0125 mmol scale. With these optimized protocols, the synthesis was then scaled up to a 0.025 mmol scale to procure milligram quantities of the Lex epitope. Secondly, in order to establish the reproducibility of these protocols, the optimized synthetic protocols were applied to procure a library of Lewis antigens, namely, Lewisa, Lewisy and Lewisb antigens (Chapter 4). The successful synthesis of these antigens further confirmed the reproducibility of the established synthetic protocols. Thereafter, these synthetic protocols were then validated for synthesizing longer structures, which was achieved by synthesizing a library of poly-N-acetyl glucosamine oligomers, such as, tetramer, pentamer and hexamer (Chapter 5). The oligomers synthesized were then used to determine the substrate specificity of the glucosamine hydrolase from xii Pseudomonas aeruginosa. Finally, the boundaries of AGA were further pushed by synthesizing one of the most difficult linkage, namely, the beta mannose linkage via automation (Chapter 6), which makes the synthesis of complex N-glycans possible by automated synthesis. In a nutshell, the work performed in this thesis aims to overcome the challenge of gaining quick access to pure oligosaccharides by establishing standard protocols for synthesizing immunologically relevant glycans via automated glycan assembly, thereby significantly reducing the time required to synthesize these glycans.

Animal life is largely characterized by movement and high levels of individual mobility. However, an endogenous system for egocentric and allocentric orientation is crucial if any movement is supposed to be goal-directed. Any goal can be reached by the help of more or less advanced navigational capacities. As part of this process, environmental cues are integrated by the available sensory organs. However, the more sensory organs are integrated, the more complex navigation will be due to the weighing of cues. Hierarchies of cues may be established for efficient navigation. Wild mammal navigation research is still in its infancy compared to its avian counterpart, in particular when it comes to long-range navigation and movements of long distances. Animal migration belongs to one of the most complex phenomena, we can observe in nature. To date, observation of long-distance moving mammal migrants is still technically limited, in particular if experimental manipulation of the moving individual is envisioned. Therefore, the navigational capacities and orientation mechanisms of wild species are virtually unknown. A promising example however, are bats. For non-migratory bat species, evidence of a magnetic sense has been provided (Holland et al. 2006, 2008). Further, we know that the calibration of a nocturnal compass system in bats happens at dusk. In this work I address the question of whether migratory bats have the potential for a mammalian model in navigation research. Assuming that non-migratory and migratory bats do not differ significantly in their navigational systems, two further questions can be deduced: Which directional reference or cue calibrates the compass system of bats at dusk? And further: Do migratory bats possess a magnetic sense which they could use for orientation and navigation? Among the migratory species, the Nathusius’ bat, Pipistrellus nathusii (Keyserling und Blasius, 1839), and its sister species the Soprano pipistrelle, Pipistrellus pygmaeus (Leach, 1825), make ideal models for experimental work, as they are relatively small and widely abundant in Europe. Every late summer, thousands of individuals from both species migrate along the Baltic Sea shore. Individuals ringed in the Baltics have been recovered in southern France (~2,000 km) which indicates that they might possess a well-advance navigation system. Here, I studied the orientation capacity of Nathusius’ bats and Soprano pipistrelles after translocation away from their coastal migration corridor. In chapter I, I investigated of polarized skylight calibrates the compass system in Nathusius’ bats. A recently published paper about non-migratory greater mouse-eared bats, Myotis myotis, revealed that these bats would use polarized light for exactly this purpose at dusk. Here, I used the exact same cages including polarization filter windows from that study and compared the departure flight directions of a control and a treatment group after translocation for 11 km. In contrast to the control, the experimental group watched the sky with any polarization cue 90° shifted due to the polarization filters. Animals were later fitter with VHF-tags, released and tracked until they vanished from tracking range. However, after translocation both groups continued flight in a southerly direction. Therefore a calibration based on the band of polarized light at dusk appears non-existent. In chapter II, I applied a self-made circular release box for bats based on eight exits to test whether takeoff orientation would be a reliable proxy for departure flight direction. Using advanced night vision scopes, I found that both Nathusius’ bats and Soprano pipistrelles depart in the same direction as they chose for takeoff. In chapter III, I conducted a mirror-experiment to test whether Soprano pipistrelles would use the solar azimuth (or a 180° deflection of it) at sunset to calibrate their compass system. However, I discriminated between naïve subadult migrants and experienced adult bats. For the measurement of takeoff at night, I built a novel version of the circular release box which enabled bats to take of in any direction. I found that adult Soprano pipistrelle takeoff orientation was dependent on the solar azimuth, with the experimental group departing in the opposite direction compared to the control group. However, naïve subadult migrants took off in random directions suggesting that calibration of a compass system using the solar azimuth bears a learning component. In chapter IV, I used Nathusius’ bats to investigate the hypothesis that the cornea could carry magnetic particles which could be part of a magnetic compass system (Wegner et al. 2006). If so, then bilateral topical anaesthesia using oxybuprocaine would impair magnetic compass-based navigation resulting in random departure flights of bats. In accordance with the predictions, animal with bilateral corneal anaesthesia departed in random directions while controls and unilateral treated animals vanished in seasonally appropriate southerly direction. In conclusion the data collected over the course of my dissertation demonstrate that migratory bats, i.e., P. nathusii and P. pygmaeus are highly suitable model species for studies of mammal navigation and sensory physiology. Both VHF tracking after translocation and release, and the application of the circular release box for bats are useful assays which also generate data that is reproducible. In contrast to findings from non-migratory M. myotis, the band of polarized skylight does not play a role for Nathusius’ bats’ compass calibration at dusk. However, in light of the data collected with Soprano pipistrelles, the solar azimuth appears to be the prevailing calibration reference. Yet, this could only be demonstrated in adult, experienced bats. Data from this thesis further support the assumption that the cornea plays an important role for the orientation capacity of Nathusius’ bats. Observed randomly directed departure flights in bats with bilateral corneal anaesthesia argue for a corneal sense contributing to orientation and navigation which could be a magnetic sense based on iron particles sensu Wegner et al. (2006).

The rapid development of nanotechnology and its application in all areas of life not only provides many chances, but also poses potential risks for users and their environment. Modern health-based risk assessment strategies for nanomaterials include three major pillars: analytical data about surface chemistry, composition and size distribution patterns of manufactured nanomaterials (NMs), toxicological data from in vitro experiments and lastly also from in vivo experiments. This thesis provides scientific advancements for each of the three pillars, in order to enhance a holistic health based risk assessment approach for nanomaterials. The chemical characterization, quantification and the determination of size distributions is a key issue in defining a NM and predicting its interactions. In the context of the research work of this dissertation, a further development of the single particle inductively coupled plasma mass spectrometry (sp-ICP-MS) technique is presented. With the help of this method the fast and reliable size distribution characterization of metal containing NMs is now possible. The new approach is based on the application of a dual sample introduction system using both, a pneumatic nebulizer and a micro droplet generator. The design of the system allows a comprehensive size characterization of NMs within 20 minutes. The obtained data is evaluated using three approaches presented in the thesis. Each of these approaches is based on a unique calibration principle. Thus, this work contributes to an independent and precise analytical characterization of NMs. Furthermore, in order to gain insights into the solubility behavior of NMs after oral uptake a in vivo toxicological assessment was carried out. Aluminum-containing NMs (Al2O3 and Al0) were administered to rats via oral gavage for three-days and the aluminum organ burden was determined. The comparatively low exposure level in combination with the ubiquitous aluminum background posed a challenge for conventional analytical techniques. We solved this problem in the present study by means of a matrix calibration and the application of a daily response factor, which enabled us not only to reliably determine the applied materials in organic matrices, but also to obtain information on the uptake and distribution of the two NMs. A special focus was laid on the differences in the uptake of the NMs and the subsequent distribution of the materials in the intestinal and systemic organs (liver, kidney, spleen). Our work has shown that the materials behave significantly different, irrespective of similar size and composition. Especially shape and surface properties of the NM could be identified as decisive factors for these differences. Moreover, in vitro experiments with the two aluminum containing NMs in human keratinocytes were carried out to further investigate the cellular uptake and intracellular distribution as well as the resulting metabolic changes within the cell. In order to make the exposure scenario more realistic and mimic ingredients of cosmetic products, the influence of the two bioactive vitamins A and D3 was tested in addition to the two NMs. The ICP-MS results showed significant differences between the uptake of the two NMs after addition of the vitamins. Time of Flight secondary ion mass spectrometry (ToF-SIMS) was then used to further investigate metabolic changes in the cell. It was found that the increased uptake of Al0 NMs after vitamin D3 addition was due to a loss of cell membrane integrity. The combination of Al2O3 NM and vitamin D3 led to an increase in membrane stability. However, the exact difference could not be conclusively clarified in the study. Our results indicate the need for further research to identify which properties of a NM are decisive for the observed different interactions. In summary, this work contributes to a more precise characterization and detection of NMs and to a better explanation of their interactions with biological systems. The pillar based methodology can be used for future research and thus contributes to a safer and more reliable application of nanotechnology without major health risks.

The typical prenatal male or female development of the somatic sex is a complex differentiation process affected by multiple genes, enzymes and hormones. Conditions in which the development of the somatic sex is atypical are medically summarised under the umbrella term “Disorders of Sex Development“ (DSD). Although new clinical guidelines emphasize the importance of psychosocial care, there is a research gap, since most research studies focus on medical aspects rather than on psychological or social aspects. The aim of the present cumulative thesis is to close this research gap with a quantitative study design based on patient reported outcomes. The three studies in this thesis were part of two large quantitative cross-sectional outcome studies, network DSD and dsd-LIFE. So far, these two studies have the largest cohorts in DSD research. Furthermore, network DSD and dsd-LIFE included a diversity of psycho-social outcomes, which was rare in DSD research when the studies were designed. It was therefore possible to evaluate the views of individuals by diagnostic group and add more detailed empirical data to the current scientific knowledge. The first evaluation focused on the term Disorders of Sex Development (DSD) invented in 2005 by the „Chicago Consensus Group on management of intersex conditions“ - an international congress of experts. The DSD terminology is controversial, as dissatisfaction about it was expressed by researchers, clinicians and support groups. It is stated that it should therefore be avoided. The European research group dsd-LIFE evaluated opinions on the terminology from 1040 individuals with conditions labelled as Disorders of Sex Development. Overall, a large majority of participants (69%) reported that the term Disorders of Sex Development applies to their condition or that they feel neutral about it. Overall, the data does not support the view that, in general, the term Disorders of Sex Development is insensitive to concerns of affected persons and that it should therefore be abandoned. In the second study, health related Quality of life (HRQoL) and psychological wellbeing of individuals with DSD were evaluated as indicators of successful psychosocial adaptation to the conditions. 110 adults with DSD from the multicentre clinical evaluation study of the German network DSD were included. A trend towards a lower mental HRQoL and a significantly higher physical HRQoL of the participants compared to a norm was found. Participants reported significant higher psychological distress compared to the norm. Forty- seven participants (43%) reported distress in a clinically relevant range. This outcome supports the demand for psychological support in DSD care. In the third study the subjective need for psychological support in parents of children and adolescents with DSD was analysed. 329 parents of children with DSD who took part in the multicentre clinical evaluation study of the German network DSD were included. 40% of the parents indicated to have a need for psychological support, only 50% of this group received it adequately. In particular, parents of children with XY-DSD with androgen effects other than hypospadias expressed a high need for psychological support. Psychological support therefore should be improved and should be an integral part of DSD care with families with children and adolescents with DSD. Although network DSD and dsd-LIFE helped to objectify the discourse about the DSD terminology and support the demand of psychosocial support in DSD care there were significant methodical problems. In summary, the results of the studies presented can only be generalised to a limited extent. Together with DSD research in all psychosocial areas, the three studies of this thesis showed, that there is a great diversity in the needs of individuals with DSD. Empirical research alone cannot establish an evidence-based gold standard for DSD care, therefore guidelines depend on clinical expertise and current ethical considerations. In summary, training of mental health professionals is needed and training should cover clinically relevant topics such as traumatisation, infertility, gender, partnership, sexuality and education on DSD.

Quantum thermodynamics is a blossoming research program that uses tools and ideas from quantum information theory to extend the laws of thermodynamics to the domain of systems to which the laws of quantum mechanics apply and the thermodynamic limit does not necessarily apply. The contributions of this program are both foundational, in providing an approach to constructively derive the laws of phenomenological thermodynamics from the postulates of unitary quantum mechanics in a rigorous and bottom-up fashion, but also prac- tical, in providing the theory for an increasing number of experiments that attempt to build thermodynamic machines at scales that were previously inaccessible. One key mathematical tool used in quantum thermodynamics is the framework of resource theories, specifically the resource theory of thermal operations, in which the thermodynamic interaction of a system with a heat bath and various additional components such as work batteries, clocks or catalysts are modeled. In this cumulative thesis, various extensions and modifications of this framework are studied in order to derive novel results and insights about the possible thermodynamic evolution of quantum systems. In particular, following a system- atic exposition of the resource theory of thermal operations from first principles, I develop answers to the following questions: i) What is the smallest heat bath required to provide the necessary randomness for a system to undergo a given stochastic or thermodynamical evolution? ii) Does this size differ depending on whether the interaction between bath and system is quantum or classical? iii) How can quantum systems thermodynamically evolve in the presence of catalytic bystander systems and how can this be put to use? iv) What are the thermodynamic state transitions that an agent can operationally affect when she only has access to partial information about the underlying states of system and bath? v) How can we understand the emergence of the canonical ensemble in statistical thermodynamics from quantum mechanics? These questions cover a wide ground, but it will become clear that they can in fact all be discussed using the same formal tools. As such, the answers to the above questions provided in this thesis are both interesting in their own right — showing for example that there exists a gap in how efficiently randomness can be exploited quantumly as compared to classically or that catalytic bystander systems can be used to extract finite amounts of work per particle from macroscopic systems with non-vanishing probability — as well as illustrate the power of quantum thermodynamics as a set of tools to connect quantum mechanics and the theory of thermodynamics more generally.

Technokratie und Demokratie sind die Pole des Spannungsfeldes, welches sich um die Frage wölbt, ob gesellschaftliche Entscheidungen rational oder demokratisch getroffen werden. In unserer heutigen Wissens- und Informationsgesellschaft, die sich durch einen hohen Grad an Spezialisierung auszeichnet, spricht das Gebot der Rationalität dafür, hochspezialisierte Experten in Entscheidungsprozesse einzubinden, um - in der Terminologie Fritz Scharpfs - die "Output-Legitimation" zu erhöhen. Auf der anderen Seite besteht die Sorge, dass demokratische Freiheit und Gleichheit eingebüßt werden zugunsten einer alles kontrollierenden, aber unkontrollierten Elite aus Wissenschaft, Wirtschaft und Bürokratie, die - ebenfalls in der Terminologie Fritz Scharpfs - nicht über die nötige "Input-Legitimation" verfügt.

Die vorliegende Arbeit untersucht in dem aufgeworfenen Spannungsfeld den Bereich der Risikoregulierung aus einer rechtsvergleichenden Perspektive. Risikoregulierung ist per definitionem von einem hohen Maß an Ungewissheit über den Regulierungsgegenstand gekennzeichnet. Aufbauend auf den Arbeiten Fritz Scharpfs wird dementsprechend die These aufgestellt, dass politische Legitimität (allein) durch Output-Legitimation in diesem Bereich aufgrund der großen wissenschaftlichen Ungewissheit nicht zu erreichen ist, sondern dass es einer besonders starken demokratischen Input-Legitimation bedarf.

Im Rechtsvergleich zwischen der Europäischen Union und den Vereinigten Staaten von Amerika wird dementsprechend untersucht, wie demokratisch das institutionelle Gefüge und die Entscheidungsprozesse im Bereich der Risikoregulierung gestaltet sind und wie groß der inhaltliche demokratische Handlungsspielraum ist. Dabei spielen die Organe und deren Handlungsformen ebenso eine Rolle wie Grundrechte und Verfassungsprinzipien wie z.B. das Vorsorgeprinzip, die den Handlungsspielraum dieser Organe beschränken oder erweitern.

Im Rechtsvergleich werden Unterschiede in den untersuchten Rechtsräumen hinsichtlich der demokratischen Absicherung der Entscheidungen im Bereich der Risikoregulierung herausgearbeitet und Verbesserungsvorschläge unterbreitet.

This dissertation analyzes what has framed and conditioned the Chinese State’s perception of international monetary order, which is so far of problematic interpretation. Market economic reforms can be seen as what indicates its views on the matter. However, the unfulfilled promise to open the capital account since 2007 and the concurrent crisis in the international monetary system constitute what has perplexed the interpretation of its perception. It is problematic not only to the US imagination of China but also to China’s imagination of itself. So, this research will conduct a critical analysis of several issues in what regards the postwar international monetary system, neo-liberalism, the being of the Chinese State, and its perception. Thus, the research is situated within a broad, ongoing debate concerning the rise of China and the future of the liberal international order. The first issue concerns the State’s general being and its perception that will be addressed through an in-depth inquiry into the metaphysical foundation, which underlies neo-liberalism, the modern conception of the State, and the relationship between knowledge and perception. The second issue concerns the “nature” of the postwar international monetary system that will be addressed through the analytics of American IR knowledge and discourse to show how the international monetary system has been conceptualized differently and how the dominant power/rising power relationship has been framed accordingly. This analysis will analyze each paradigm’s narrative ground that renders possible the quasi-perception of the other’s perception and the “scientific” determination of China’s identity, interest, and power relationship with the United States. The analysis will revisit two critical junctures – i.e., the collapse of the Bretton Woods system and the US subprime mortgage crisis – and compare France and China’s characters in two stories. The mismatch between the theoretical expectation and China’s actual behavior necessitates a new approach. The third issue concerns China’s being that remains “enigmatic” to conventional IR knowledge due to the lack of in-depth theorization of the Chinese State. All three IR paradigms look for a continuous, coherent representation of unity. To address this issue, this dissertation adopts a Foucauldian inspired perspective that allows observers to see discontinuity and inconsistency. The research will recontextualize the post-1978 economic reforms, especially the 2007 financial reform, against a backdrop of growing regional heterogeneity in China since the 1950s. This analysis will point to the acute interregional confrontations since the 1980s and the subsequent formation of a triadic political economy (Beijing-Shanghai-Shenzhen). This dissertation argues that the derailment of the 2007 capital account reform has little to do with the concurrent global financial crisis, which only plays a reinforcing role, nor with the resentment at the dollar’s hegemony. Quite the contrary, the Wen Jiabao government supports the international dollar standard by cooperating with the United States. The derailment of the reform momentum is just a matter of more complex struggle within China and has everything to do with the triad-based interests. The reason is closely related to the political economy of interregional relations, and the established fiscal, exchange rate, and capital account regimes. An analysis of the identities of Tientsin, Beijing, Shanghai, and Shenzhen will show the different impacts of their identities on China’s politics. This dissertation thus helps formulate an alternative theory that can explicate what has affected China’s perception of the international monetary order. In the end, this dissertation raises attention to the rise of the Beijing-centric economic geography and the ideological lineage between Beijing’s own urban project (i.e., “Big Beijing” since the early 2000s) and the “One Belt One Road” (since 2013).

This thesis addresses the steroid metabolism and its role in the detection of steroids. The results were achieved by performing metabolic studies in combination with different analytical techniques. Three main outcomes were achieved. First, the generation of reference material for a long-term metabolite of the synthetic steroid Oral-Turinabol (OT) was presented. The obtained results enhance unambiguous detection and quantification of this metabolite and hence help to uncover the prohibited OT administration in sports doping. Second, structural requirements and tolerated functionalities for substrates of the enzyme Cytochrome P450 subtype 21A2 (CYP21A2) were evaluated. These insights help to extrapolate known metabolic reactions to new and potentially unknown compounds. Third, investigations on steroid profile changes caused by the intake of non-steroidal anti-inflammatory drugs were described. These findings provide knowledge on substances influencing steroid metabolism, which is of high relevance for accurate steroid determination and hence the correct interpretation of analytical results. All results were obtained using mainly three models to study steroid metabolism and its influenceability. First, incubations with Schizosaccharomyces pombe strains recombinantly expressing human CYPs were used to generate reference material in small amounts and to evaluate metabolic reactions. Second, incubations with isolated recombinantly expressed human enzymes were used to examine metabolic reactions and their influenceability by other drugs. Third, in vivo drug administration was used to study steroid metabolism in humans and to investigate whether the intake of non-steroidal anti-inflammatory drugs leads to changes in steroid concentrations and concentration ratios. To subsequently evaluate the samples generated by the methods described above different analytical techniques were utilized. High-resolution mass spectrometry (HRMS) was used for quantification and tentative structure identification. Liquid chromatography and gas chromatography were both combined with HRMS. Additionally, gas chromatography coupled to single or triple quadrupole mass spectrometry was employed to identify and accurately quantify compounds where reference material was already available. Finally, fluorometric measurements carried out in real time were used to determine kinetic characteristics of enzymatic reactions. The results presented in this thesis build a solid base for the refinement of steroid detection. It was shown that combinations of in vitro and in vivo metabolic studies and investigations on metabolic reactions together with adequate analytical techniques are of high relevance for the improvement of steroid detection methods. Furthermore, the results are of relevance to enhance methods for generation of reference compounds, to identify potentially new drugs and to re-evaluate the risk potential of drugs. Further areas that can benefit from the results of this work include clinical and toxicological analysis, analysis of environmental and biological samples and endocrinology. Finally, the results are of high importance for anti-doping analysis. This field shall be mentioned separately as the results presented particularly contribute to tackle challenges relevant in this research area.

Die Messung der Herzfrequenzvariabilität (HRV) stellt eine nicht-invasive Technik dar, mit der die Funktionsweise des autonomen Nervensystems am Herzen sichtbar gemacht werden kann (von Borell et al. 2007). Die HRV-Analyse kommt neben vielerlei anderer klinischen Anwendungen in Human- und Veterinärmedizin auch im Bereich der Schmerzforschung und Anästhesiologie zum Einsatz. So verändert sich der das sympathovagale Gleichgewicht beschreibende Parameter LF/HF bei Schweinen nach Schwanzbeißen (Zupan et al. 2012). Ebenso wirken sich chirurgische Manipulationen unter Allgemeinanästhesie auf frequenzbezogene HRV-Parameter bei Schweinen aus (Martin Cancho et al. 2006). Die HRV-Messung bei Schweinen erfolgte bisher neben invasiven Messmethoden auch mittels nicht-invasiven telemetrischen Messmethoden, um auch Messungen am nicht-fixierten Schwein vorzunehmen. Telemetrische Messmethoden sind bei Schweinen einerseits mittels telemetrischen EKG-Geräten (Suzuki et al. 1998, Kuwahara et al. 1999, Kuwahara et al. 2004, Olmstead et al. 2005) oder mittels primär für den Menschen konzipierten Brustgurtsystemen möglich (Marchant-Forde and Marchant-Forde 2004, Marchant-Forde et al. 2004, Düpjan et al. 2011, Zupan et al. 2012, Mahnhardt et al. 2014, Leliveld et al. 2016). Der in der Studie verwendete Brustgurt BioHarnessTM 3 (Zephyr Technology, Medtronic, Annapolis, USA; im Folgenden: BioHarness-Brustgurt) wurde bisher am Schwein noch nicht eingesetzt. Ziele der Studie waren, den BioHarness-Brustgurt auf seine Messgenauigkeit mit einem etablierten, telemetrischen EKG-Gerät (Televet® 100, Engel Engineering GmbH, Heusenstamm, Deutschland; im Folgenden: Televet 100) zu evaluieren und nach Feststellung der Eignung des BioHarness-Brustgurts zu untersuchen, ob die HRV-Analyse ein valides Analgesiemonitoring im Kastrationsmodell ermöglicht. Dafür wurden die HRV-Parameter bei intraoperativen, schmerzspezifischen Abwehrreaktionen anhand eines Scorings mit prä- und postoperativen Ruhewerten verglichen. Für die Evaluierung des BioHarness-Brustgurts in der Voruntersuchung wurde bei fünf männlichen Aufzuchtschweinen (Deutsche Landrasse/Deutsches Edelschwein x Piétrain/Duroc; 28 – 58 kg) unter Betäubung zeitgleich Messungen mit dem BioHarness-Brustgurt und dem Televet 100 durchgeführt. Für die HRV-Analyse mit dem BioHarness-Brustgurt der Hauptuntersuchung wurden insgesamt 30 männliche Aufzuchtschweine (Rasse s. o., 36 – 48 kg) zum Zwecke der weiteren Mastnutzung und Schlachtverwertung kastriert. Die Schweine wurden in vorübergehender Einzelhaltung im Wachzustand einen Tag vor der geplanten Kastration mit dem BioHarness-Brustgurt in liegender Ruheposition gemessen. Die Kastration in der Regio pubis erfolgte unter der praxisüblichen Ketamin-Azaperon-Allgemeinanästhesie. Alle intraoperativen Schritte (Messungen à 3 Minuten) wurden mittels eines Schmerzscorings beurteilt, wobei Score 0 keinerlei Abwehrreaktion (chirurgische Toleranz), Score 1 und höher Vorhandensein und Intensität von Abwehrreaktionen beschreiben. 24 Stunden nach der Operation erfolgte nochmals wie am Tag vor der Operation eine HRV-Messung und eine Untersuchung auf klinisch manifeste postoperative Schmerzanzeichen. Ergebnisse der Evaluierung des BioHarness-Brustgurts in der Voruntersuchung waren eine vergleichbare Messgenauigkeit mit dem Televet 100-EKG-Gerät. Ergebnisse der HRV-Analyse mit dem BioHarness-Brustgurt in der Hauptuntersuchung waren, bezogen auf die intraoperativen Schritte bzw. Zeitpunkte, ein Anstieg des Parameters meanRR im Vergleich zum Ruhewert vor den Operationen bzw. ein Abfall der Parameter SDNN und RMSSD über alle intraoperativen Zeitpunkte Es kam zu einem Anstieg der für die sympathische Aktivität sprechende Parameter LF (n.u.) und LF/HF bei den Zeitpunkten Inzision in die Haut, Inzision in den Processus vaginalis sowie Zug am Samenstrang. Der hauptsächlich durch vagale Einflüsse dominierte Parameter HF (n.u.) fiel bei den Zeitpunkten Inzision in die Haut und Inzision in den Processus vaginalis ab. Bezogen auf das Schmerzscoring kam es zum signifikanten Anstieg von LF (n.u.) bei Score 1 bis 3 im Vergleich zur chirurgischen Toleranz (Score 0). Die Parameter HF (n.u.) und LF/HF verfehlten das Signifikanzniveau (p < 0,05) knapp. Postoperativ kam es nur bei zwei Tieren zu möglichen Schmerzsymptomen (Fieber, bzw. Wundirritation), weshalb hier keine Aussage getroffen werden konnte. Die Schweine tolerierten den Brustgurt allgemein sehr gut, es gab keinen Einfluss auf das arttypische Fress-, Liege- und Aktivitätsverhalten. Erkennbar ist in dieser Studie ein mit schmerzspezifischen Abwehrreaktionen positiv korrelierender LF-Wert, welcher auch in der Literatur einerseits bei intraoperativen Schmerzstimuli, aber auch mit anderen schmerzhaften Zuständen beim Schwein beschrieben wird (s. o.). Sowohl die somatische (hier Inzision in die Haut) als auch die viszerale Schmerzkomponente (hier Inzision in den Processus vaginalis und Zug am Samenstrang) führen zu einer Beeinflussung der Parameter LF (n.u.), HF (n.u.) und LF/HF. In Bezug auf ein effektives, prädiktives Analgesiemanagement müsste in weiterführenden Studien an einer größeren Tierzahl bzw. Zahl an Messdaten ein Grenzwert für LF (n.u.) und ggf. weitere Parameter etabliert werden, welcher Schmerz bei nachlassender Anästhesie noch vor Auftreten einer Abwehrreaktion anzeigt. Ausblickend könnten mit dem BioHarness-Brustgurt auch Tierwohlbeeinträchtigungen bei Schweinen in anderen klinischen Fragestellungen untersucht oder auch bei zootechnischen Eingriffen überprüft werden.

Die chronisch-entzündlichen Enteropathien des Hundes sind multifaktorielle Erkrankungen, deren Ätiopathogenese bisher nicht vollständig aufgeklärt werden konnte. Durch das Ansprechen auf eine bestimmte Therapie wird eine Unterscheidung in Futter-responsive Enteropathie (FRE), Antibiotika-responsive Enteropathie (ARE) und Inflammatory Bowel Disease (IBD) möglich. Diese Erkrankungsformen lassen sich klinisch teilweise schwer voneinander unterscheiden. Daher ist es das Ziel verschiedener Studien, Biomarker zu etablieren, deren Bestimmung die Aussagekraft bezüglich der Diagnostik und Prognostik der Erkrankung frühzeitig erhöht. Diese prospektive, unizentrische Studie sollte untersuchen, ob eine gleichzeitige Messung der Biomarker S100A12, Calprotectin, C-reaktives Protein (CRP) und N-Methylhistamin (NMH) in Serum und/ oder Kot das Monitoring der chronisch-entzündlichen Enteropathien des Hundes verbessern kann. Es sollten jene Marker identifiziert werden, die allein oder in Kombination von diagnostischem und/oder prognostischem Nutzen sein könnten. Dazu wurden von März 2015 bis März 2018 an der Klinik für kleine Haustiere der Freien Universität Berlin 32 Hunde mit chronisch intermittierenden oder persistierenden gastrointestinalen Symptomen in die Studie eingeschlossen. Daten zu Anamnese, Signalement, der klinischen Aktivität der Erkrankung (Canine Inflammatory Bowel Disease Activity Index (CIBDAI)), Laborparametern sowie bildgebender Diagnostik und Endoskopie wurden ausgewertet. An Hand des Ansprechens auf eine bestimmte Therapie wurden die Tiere in die Gruppen FRE (n= 11), ARE (n= 9) und IBD (n= 12) eingeteilt. Die Messung der Biomarker erfolgte wenn möglich zum Zeitpunkt der Erstvorstellung, im Verlauf und bei Letztvorstellung. Das Ansprechen auf die Therapie bzw. die Besserung der klinischen Anzeichen wurde eingeteilt in klinische Remission, partielle Remission oder keine Remission. Die Daten der drei Diagnosegruppen wurden miteinander verglichen. Es zeigten sich keine signifikanten Unterschiede zwischen den Diagnosegruppen hinsichtlich der Anamnese, des Signalements oder der Klinik. Der CIBDAI war zum Zeitpunkt der Erstuntersuchung bei Hunden mit IBD gegenüber Hunden mit FRE oder ARE deutlich erhöht (p= 0,015). Hunde der IBD- Gruppe erreichten seltener eine vollständige klinische Remission (p= 0,046). Auch für das im Serum gemessene Calprotectin zeigte sich ein signifikanter Unterschied zwischen den Erkrankungsgruppen (p= 0,048). Hunde mit IBD wiesen deutlich höhere Calprotectinkonzentrationen im Serum auf als Hunde mit FRE oder ARE. Auf Grund der stark positiven Korrelation zwischen S100A12 und Calprotectin im Serum (rs = 0,810; p <0,0001) scheint eine alleinige Messung von Calprotectin im Serum ausreichend. Die fäkalen Marker S100A12 und Calprotectin zeigten bei Erstvorstellung die höchsten Konzentrationen in der FRE-Gruppe. Im Verlauf erreichten beide Marker die höchsten Konzentrationen in der IBD-Gruppe. Somit könnte eine Verlaufsmessung dieser Marker hinweisend für die Aktivität der Erkrankung sein. Da beide Marker auch im Kot sehr stark miteinander korrelierten (rs = 0,934; p <0,0001), scheint die Messung eines der beiden Marker, Calprotectin oder S100A12, im Kot ausreichend. Das im Serum gemessene NMH scheint zudem eine prognostische Aussage hinsichtlich des Therapieansprechens bei Erstuntersuchung zu ermöglichen. Hunde mit partieller oder ausbleibender klinischer Remission zeigten deutlich höhere Serum NMH-Konzentrationen (p= 0,007) als Hunde mit kompletter Remission. Hunde mit IBD wiesen zudem sowohl bei Erstvorstellung als auch im Verlauf höhere NMH-Werte im Kot als Hunde mit FRE oder ARE auf. Basierend auf den Ergebnissen dieser Studie scheinen NMH in Serum und Kot sowie Serum Calprotectin nützlich in der Diagnostik der chronisch- entzündlichen Enteropathie des Hundes zu sein. Kotmarker scheinen hinweisend für eine erneute klinische Verschlechterung zu sein. Daher eignen sich die Biomarker im Kot vor allem für Verlaufsuntersuchungen, während die Biomarker im Serum eine Aussage bezüglich der Diagnose und Prognose bei Erstuntersuchung ermöglichen sowie die klinische Aktivität im Verlauf anzeigen können. Die kleine Studienpopulation stellt die größte Limitation dieser Studie dar. Größere prospektive Studien sollten sich anschließen, um die hier festgestellten Zusammenhänge zu verifizieren.

Dass die mechanische Umgebung (Stabilisationssteifigkeit) entscheiden für den Heilungserfolg einer Fraktur ist, wurde mehrfach demonstiert (Histings et al., 2010; Bartnikowski et al., 2017; Claes, 2017; Glatt et al., 2017). Unter welchen biomechanischen Bedingungen eine möglichst schnelle und effiziente Frakturheilung erreichbar wäre, ist seit geraumer Zeit Gegenstand intensiver Forschung (Claes, 2017). In diversen Studien ist zudem der postitive Effekt von BMP-2 auf die Knochenheilung belegt worden (Nauth et al., 2011; Wildemann et al., 2011). Weitgreifendere Erkenntnisse über die Wirkung der Dosierung des Wachstumsfaktors und inwieweit seine Interaktion mit mechanischer Belastung die Effizienz der Knochenregeneration beeinflusst, eröffnen mögliche Zukunftsstrategien in Fällen wo knöcherne Überbrückung bisher unerreichbar war (Schmidt-Bleek & Willie et al., 2016). Aufgrund dessen untersuchte die vorliegende Arbeit den Einfluss kombinierter biologischer und mechanischer Stimulation auf die Defektheilung im Pseudarthrosemodell der Ratte. Es sollte untersucht werden, welchen Effekt die variierenden Steifigkeiten eines externen Fixateurs auf die BMP-2-stimulierte Knochendefektheilung ausübte. Ziel der vorliegenden Arbeit war es, auf Grundlage von mikrocomputertomographischen Untersuchungen und biomechanischer in vitro Testung, den Heilungsverlauf eines kritischen Defekts unter semi-rigider Fixation gegenüber rigider und flexibler Steifigkeit aufzuzeigen. 32 weibliche Sprague-Dawley Ratten in einem Alter von 12 Wochen wurden randomisiert in vier Gruppen von je acht Tieren eingeteilt. Die experimentellen Versuchsgruppen erhielten einen standardisierten kritischen 5 mm Defekt (CSD), eine intraoperative Einbringung von 5μg rhBMP-2 mittels absorbierbaren Kollagenschwamms und wurden mittels variierenden Verbindungsbalken des externen Fixateurs (flexibel, semi-rigide, rigide) stabilisiert, während die Kontrollgruppe eine 1mm Osteotomie ohne rhBMP-2-Applikation erhielt und als positive Kontrolle bezüglich einer physiologischen Knochenheilung diente. Alle Versuchstiere durchliefen am 10., 21. und 42. postoperativen Tag eine in vivo-Mikrocomputertomographuntersuchung. An Tag 42 wurden die Tiere euthanasiert und der linke osteotomierte Femur (inklusive des Fixateurs externe) entnommen. Randomisiert wurden sieben Tieren zusätzlich der intakte rechte Femur entnommen. Sämtliche Proben wurden biomechanisch hinsichtlich Steifigkeit und maximalen Drehmoments getestet. Die Initialheilung der Steifigkeitsgruppen stellte sich im deskriptiven Mikro-CT mit einer vergleichbaren Gewebezusammensetzung dar. Im Defektspalt war moderat periostale Knochenneubildung erkennbar, die in keiner Defektüberbrückung resultierte. Dennoch ließ die semi-rigide Gruppe tendenziell den höchsten Grad an Mineralisation erkennen, welches mit den größten nicht signifikanten TV-, BV- und TMC-Werten im Vergleich zu den anderen Versuchsgruppen korrelierte, während die flexible Gruppe den kleinsten TV-Wert zeigte. An Tag 21 stellten sich alle Versuchsgruppen knöchern überbrückt dar. Als Ausdruck der beginnenden Reifung ließen sich im Mikro-CT Resorptionsvorgänge darstellen. Die flexible Gruppe zeigte eine verzögert einsetzende Heilung gegenüber den beiden steiferen Gruppen sowie einen mit verkalktem und mineralisierten Kallusgewebe ausgefüllten Defektspalt. An Tag 42 zeigte die flexible Gruppe signifikant größere Werte für TV, BV, BV/TV und TMC, während die semi-rigide Gruppe diesbezüglich die kleinsten Werte aufwies. Dies machte sich durch einen mit mineralisiertem Knochengewebe gefüllten Defekt in der flexiblen Gruppe deutlich, während die beiden steiferen Gruppen bereits Resorptionsvorgänge mit Wiederherstellung der Markhöhle erkennen ließen. Bezüglich TMD zeigte die semi-rigide Gruppe den größten Wert und die flexible Gruppe den kleinsten Wert, jedoch ohne Signifikanz. Die rigide Gruppe zeigte wie die semi-rigide Gruppe eine Abnahme des Gesamtkallusvolumens (TV) sowie geringere BV- und TMC-Werte als die flexible Gruppe, jedoch auch einen kleineren TMD-Wert als die semi-rigide Gruppe, weshalb hier ein verzögerter Reifungsprozess vermutet wurde. Mittels biomechanischer in vitro Testung zeigte die semi-rigide Gruppe annähernd gleichwertige Ergebnisse bezüglich der Steifigkeit und des maximalen Drehmoments wie die rigide und flexible Gruppe. Die Arbeit hat gezeigt, dass die BMP-2- stimulierte Defektheilung mechano-senitiv ist. Zwar zeigten sich in den biomechanischen und mikrocomputertomographischen Ergebnissen kaum statistisch signifikante Unterschiede, jedoch konnte deskriptiv eine beschleunigte Heilung der semi-rigiden und rigiden Versuchsgruppe gegenüber der flexiblen Fixation demonstriert werden, die in einer verzögerten Knochenheilung resultierte, während die steiferen Gruppen eine Re-Kanalisation der Markhöhle zeigten. Dies führte zu der Erkenntnis, dass die Modulation der mechanischen Umgebung des kritischen Defekts, trotz BMP-2-Anwesenheit, einen Einfluss auf den Heilungsverlauf ausübt.

This thesis seeks to contribute to the understanding of European labor organization by focusing on two guiding questions: (1) How can a framework integrating (competing) logics explain the current form of European trade union organization? and (2) Which critical junctures explain the formation and stabilization of the present form of European trade union organization? The practical implications of the findings highlight the importance of political incentives for non-governmental cooperation on the European level as well as the role of cross-national community building, lobbying activities and clear coordination strategies with global partners for European trade unions. A longitudinal single case study of the European Federation of Building and Woodworkers from the 1950s to ca. 2015 was selected as an extreme case since pressure for European coordination in this industry is particularly high while competitive pressures among workers are also especially intense. European associations are explained by an interplay of the multilevel logics of influence, membership, and administration (Schmitter and Streeck 1999 [1981], Child et. al. 1973; Donaldson and Warner 1974). These diverse logics entail conflicting rationalities leading to potentially constraining conflicts. The current form of Europeanization in the construction sector was established in the mid-1980s to 1990s when critical developments in all three logics set the federation in its current organizational form with the role of coordinating non-binding standards: Commission funding and Posted Workers legislation triggered increased joint activities coordinated by the European federation (influence), a highly motivated administration had the will and energy to create European organizational structures (administration) and a growing and more diverse membership needed a European federation to provide information and conduct lobbying activities (membership). The conclusions indicate that although unions in the construction sector have expanded their organizational activities across national boundaries, two self-reinforcing processes partly seem to explain the stabilization of the current form: resource dependence and adaptive expectations. The first result suggests a pattern whereby organizational development adjusts to external project funding, potentially overshadowing alternative forms of action. This is enhanced by a diminishing resource base from the membership, while at the same time the diversity and number of affiliates have risen. As the coordination needs of the members increase, the administration needs to secure external funds to implement the federation’s goals. Over time, the expectation of the members to implement their goals with contentious politics seemed to conflict with a logic of goal implementation which focuses on cooperation. And within the federation, democratic goal formation among the members started to conflict with flexible and autonomous goal implementation by the administration. The second outcome implies that the orientation toward project funding has been underpinned by the EFBWW’s logic of membership, which is defined by both the “shadow of the past” of the traditional division of labor between the international federation BWI and the EFBWW and the legacy of the European trade union movement’s political and religious division. Over time, adaptive expectations might have led to a stabilization of the division of labor and resources between the two federations.

Eine forschungsrelevante Schwierigkeit hinsichtlich der objektivierten Vergleichbarkeit von klinischen Studien stellen die multimodalen Therapien in der Intensivmedizin dar. Die Variabilität von einzelnen Therapiebestandteilen wie Beatmungsmanagement, Nierenersatzverfahren und Infusionsmanagement ist sowohl im eingeschlossenen Patientengut als auch generell zwischen Kliniken sehr hoch. Bislang wurde darauf jedoch nicht näher eingegangen. Auch die Azidämie im klinisch tolerierten Bereich (bis zu einem arteriellen pH-Wert von 7,2) stellt, als ein potentiell maßgeblich einflussnehmender Parameter für Organversagen und Mortalität, einen noch unzureichend erforschten Aspekt dar. In der hier vorgestellten tierexperimentellen Studie an Schweinen (n=29) zeigten sich in allen Tieren bereits nach wenigen Expositionsstunden prägnante Auffälligkeiten der Lebern mit Leberzellschädigungen in Form histologischer Pathologien und veränderter serumspezifischer Werte. Durch die Unterteilung der möglichen, verschiedenen Interventionskombinationen konnte folgendes untersucht werden: 1. der unter Azidäme potentiell unterschiedliche Einfluss von 6% Hydroxyethylstärke 130 kDa/0,4 (HES) und 4% Gelatine (GEL), 2. die durch die Azidämie potentiell veränderte Biokompatibilitätsreaktion auf eine venovenöse Hämofiltration 3. der Einfluss einer bisweilen zusätzlich zur Azidämie tolerierten Hypoxämie im Rahmen der lungenprotektiven Beatmung Es zeigte sich, dass die Wahl der Infusionslösung einen relevanten Einfluss auf die Lebermorphologie hat. So ließen sich bei der ersten Interventionskombination (Interventionskombination Azidämie und Kolloidtyp HES versus GEL) in der HES-Tierversuchsgruppe zentrolobulär vermehrt Vakuolen und in der GEL-Tierversuchsgruppe, unabhängig von der hepatischen Zonierung, eine signifikant stärkere Ödematisierung feststellen. Die bei mit Gelatine infundierten Tieren auffallende, signifikant stärkere Ödematisierung als 1. Grad der hydrophischen Degeneration, lenkt bei der GEL-Tierversuchsgruppe die Interpretation der Gesamtdaten eher in Richtung einer unzureichenden O2-Versorgung für die unter Azidämie benötigte gesteigerte Stoffwechselleistung um den Erhalt der Säuren-Basen-Homöostase zu ermöglichen. Diese Interpretation wäre deckend mit dem Befund des signifikant geringeren Sauerstoffangebotes mit der Anwendung einer GEL-Infusion (Esche et al., 2008). Die 4. Interventionskombination (Azidämie mit versus ohne Hypoxämie) zeigte ergänzend zu der ersten Interventionskombination, dass mit einem geringeren Energieumsatz (absolut weniger Glucose bei der GEL-Tierversuchsgruppe und/oder absolut weniger O2 bei der Hypoxämie-Tierversuchsgruppe) ein reduzierter Stoffwechsel der Leberzelle einhergeht und somit zu vermuten ist, dass eine hepatozelluläre Schädigung durch die reduzierte Stoffwechsellage verlangsamt wurde. Im Vergleich zwischen keiner, kurzer (4,5-stündiger) und längerer (6,5-stündiger) Azidämieexposition [2. Interventionskombination (Hämofiltration und Azidämie (pH 7,2 versus pH 7,4)) und 3. Interventionskombination (alleinige Azidämie, pH-Wert 7,2 (mit versus ohne continuous venovenous hemofiltration))] zeigten die Tierversuchsgruppen ohne und mit kurzer (4,5-stündiger) Azidämieexposition nur wenig Vakuolen bei gleichzeitig starker Ödematisierung. Die Tierversuchsgruppe, die der längsten (6,5-stündigen) Azidämieexposition ausgesetzt wurde, wies hingegen eine signifikant stärkere Vakuolisierung bei gleichzeitig geringerer Ödematisierung auf. Unter Berücksichtigung der histologischen sowie der serumspezifischen Ergebnisse (insbesondere der zum Versuchende fallenden Kreatinin- und Harnstoffwerte in den hämofiltrierten Tierversuchsgruppen), zeigten die Ergebnisse dieser tierexperimentellen Studie, dass allein die Azidämie zu ersten hepatozellulären Degenerationserscheinungen führen kann. Es zeichnet sich damit ab, dass die Azidämie nicht nur Konsequenz komplexer pathophysiologischer Reaktionen und damit Parallelereignis ist, sondern dass sie selbst Kausalität einer Zustandsverschlechterung und gesteigerten Mortalität sein kann. Den aufgeführten Gefahren einer Organschädigung steht gegenüber, dass bei einer multimodalen Therapie mit lungenprotektiver Beatmungssituation die Notwendigkeit der permissiven Hyperkapnie und tolerierte Azidämie akzeptiert werden, solange die hämodynamische Situation des Patienten stabil ist. Um die nachweislich die Mortalitätsrate senkende, lungenprotektive Beatmung (Network, 2000) nicht aufgeben zu müssen, wären alternative Methoden zur risikoarmen Wiederherstellung der pH-Homöostase erstrebenswert. Bei der Interpretation der Ergebnisse dieser Arbeit ist zu berücksichtigen, dass Schweine im Vergleich zum Menschen eine deutlich höhere Stoffwechselrate aufweisen. Die Veränderungen der stoffwechselrelevanten Parameter in dieser tierexperimentellen Studie sind daher vom Schwein nicht direkt auf den Menschen übertragbar. Es zeigten sich beim Schwein allerdings bereits nach 4,5 Stunden Azidämieexposition erste hepatozelluläre Degenerationserscheinungen, die darauf schließen lassen, dass auch bei einem Menschen bereits nach kurzer Zeit diese Art von Degenerationserscheinungen zu erwarten sind. Unsere tierexperimentellen Befunde und Schlussfolgerungen decken sich mit der neusten Studienlage. In letzter Zeit häufen sich retrospektive Studien und Metaanalysen, die belegen, dass eine Azidämie mit einer erhöhten Rate an Organversagen und Mortalität einhergeht (Curley & Laffey, 2014; Nin et al., 2017). In diesem Sinne erscheint es sinnvoll, zukünftig Studien zum Einfluss eines frühzeitig einsteigenden Regimes zur Korrektur der Azidämie unter dem Aspekt der Organprotektion durchzuführen.

Genetic diversity in animal hybrids can affect each physiological system differently. If reproduction usually suffers from breakdown of coadapted complexes, resistance to parasite could benefit from the novelty brought by recombination. The question of hybrid relative resistance or susceptibility to parasites in the European house mouse hybrid zone has been discussed for the past thirty years, leading to contradictory conclusions on relative hybrid fitness. But drawing conclusions on hybrid host fitness in relation to parasites requires first to investigate the link between resistance and host health. Resistance (the host’s capacity to reduce parasite burden) and tolerance (the host’s capacity to reduce impact on host health of a given parasite burden) manifest two different lines of immune defences. Trade-offs arise, as resistance limits infection load and thereby the scope of possible tolerance, and both resistance and tolerance can be costly in terms of resource allocation. During this PhD project, we assessed infections by intracellular protozoans, Eimeria spp., using field sampling and laboratory infection of wild and wild-derived mice from a hybrid zone between \textit{Mus musculus domesticus} and \textit{Mus musculus musculus}. We asked (1) whether hybrid mice are more or less resistant than their parents and (2) how resistance and tolerance are correlated, this correlation potentially differing between Eimeria species. We found lower intensities in hybrid hosts than in parental mice and no evidence of lowered probability of infection or increased mortality in the centre of the hybrid zone. This challenges the longstanding impression that hybrid mice are more highly parasitised than parentals. Upon experimental infection, we found a trade-off between resistance and tolerance in E. falciformis, but not in E. ferrisi. Building on previous research showing that resistance and tolerance should be studied jointly, our results show that assumptions on coupling of the two can not be transferred across even closely related parasite taxa. We showed that the impact of parasitism on hybrid fitness is a complex matter that needs to be investigated for each parasite beyond the measurement of hybrid vigour on resistance, taking into account possible trade-offs between resistance and tolerance.

The dissertation was part of the project “Women’s Action towards Climate Resilience for Urban Poor in South Asia” under the lead of the Indian NGO Mahila Housing SEWA Trust. The pro-ject took place in the frame of the Global Resilience Partnership funded by Rockefeller Founda-tion, USAID and SIDA for a two-year period (2016-2018). The Hydrogeology Group from Freie Universität Berlin focused on Jaipur, the capital of Rajasthan in Northwest India, and was respon-sible for socio-hydrogeological investigations. Two low-income communities in the peri-urban fringe of Jaipur without sufficient water supply both in quality and quantity were selected as pilot areas for socio-hydrogeological studies. They represent two different typical geological settings in Jaipur and their water problems are representative of many low-income areas throughout the country. They also differ significantly from each other in terms of social aspects being a Hindu community on the one hand (Khara Kuaa) and a Muslim community on the other hand (Nai Ki Thari). The main research question was how to establish participatory groundwater management in these areas together with local women groups. The research was therefore structured into two parts. Next to the participatory work, which was executed with women from both communities, the hy-drogeology of the two study areas was investigated to understand the groundwater-related prob-lems occurring in peri-urban poor areas in detail and to develop scientific sound solution strate-gies adapted to local conditions. The two main aquifers of the area, the overlying Quaternary alluvium (up to 100 m thick) and the deeper Proterozoic fractured hard rock aquifer show both anthropogenic and geogenic impacts which decrease groundwater quality and quantity. In general, the groundwater of both aquifers is not potable, due to high TDS values above the permissible limit of 500 mg/L given in the Indian Standard for drinking water and/or high nitrate values above the permissible limit of 45 mg/L. Declining water tables due to over abstraction put further stress on the intensively used ground-water resource. Significant differences exist between Khara Kuaa and Nai Ki Thari in terms of water supply. In Khara Kuaa, about two thirds depend on the municipal water line (surface water mixed with groundwater) followed by >25 % ordering private tanker (groundwater), while in Nai Ki Thari the main supply source is private tanker (groundwater) followed by 30 % using wells (groundwa-ter). In general, the water supply infrastructure is characterized by a large number of privately organized legal and illegal components which poses a challenge both for consumers and responsi-ble authorities. The poorer the household, the higher the cost of drinking water and the more time it takes to fetch it, while wealthier households can draw water freely and “unlimited” or are con-nected to public water supply. Preparatory social investigations revealed that a lack of knowledge and expertise in the communi-ties leads to many water-related problems, such as wastage of water, illegal pipeline connections, practicing open defecation up-gradient of drinking water production wells and thinking in limited ways (temporal and spatial). A lack of capacity in terms of time, media access and confidence of the slum dwellers requires a solution, which is tailored to their needs and capabilities. A participatory approach including three main steps – awareness raising and basic knowledge transfer, capacity development and active involvement, evaluation and upscaling – were developed and applied during a 1.5-year field stay in Jaipur. While this study showed that it is definitely pos-sible to teach non-experts how to map their area, to take a water sample by themselves and to make a first basic assessment of the groundwater situation of their area, the concrete outcomes in terms of an improvement of the current situation were not satisfying. Reasons for this lie in mis-communications, a lack of time, a missing detailed stakeholder analysis and the fact that the branch office of the NGO in Jaipur is not yet as established within the city institutions as the head office in Ahmedabad. Furthermore, the concept of time consuming research work necessary to establish sustainable solutions is not widely known among the target group of the project. Nevertheless, sustainable outcomes were achieved by developing a media portfolio which was handed over to the Indian NGO. It consists of various formats and is adapted to the target group of local NGOs and, in large parts, uneducated poor women. Components of the portfolio are the “water workshops”, a physical groundwater model, the training manual, which is based on the experiences gained during the project, as well as the filmic documentation and the educational short film which emerged out of the transdisciplinary cooperation with a filmmaker. The results of this study add new knowledge to the expanding field of participatory and socio-hydrogeological research in groundwater management and show that this approach can contribute to a raising awareness of groundwater among local population as well as NGOs working in the field of water management.

The George Fisher deposit is located in the northern Australian Carpentaria province, which is host to several of the world’s largest Zn and Pb mineral deposits. The annual metal production from George Fisher is crucial in order to meet the global demand for Zn and Pb. The main ore minerals at George Fisher are sphalerite (ZnS) and galena (PbS), which occur in stratabound, and in discordant, massive sulphide ore bodies together with pyrite (FeS2) and pyrrhotite (FeS). These massive sulphide ore bodies are hosted within carbonaceous, pyritic, calcareous, dolomitic siltstones and mudstones of the Paleoproterozoic Urquhart Shale Formation (ca. 1654 Ma), which is also host to two other world class base metal deposits (Mount Isa and Hilton). All three deposits are highly deformed, the textural relationships are complex, and there is a lack of indicator minerals to constrain the metamorphic grade of the Urquhart Shale. As a result, there has been considerable debate over (1) the processes that led to the accumulation of such huge amounts of base metal sulphides in the deposits of the area, and (2) the alteration footprint these processes have produced beyond the massive sulphide zones. In this project, petrographic observations across several scales (drill core logging down to backscatter-electron microscopy) were combined with whole rock, and in situ, mineralogical, geochemical, and isotopic analyses of representative samples from (1) four drill holes that intersected the main ore bodies at George Fisher, and also from (2) a drill hole that intersected the barren Urquhart Shale Formation. These data were collected in order to constrain the background heterogeneity that is inherent to rocks of the Urquhart Shale Formation (e.g., from background diagenetic processes). Using this framework, the nature of some of the hydrothermal processes responsible for ore formation were constrained. Particular emphasis was put on constraining (1) the accumulation processes of reduced sulphur, (2) the ore forming processes, and (3) the mineralogical and geochemical alteration footprint of the George Fisher deposit. In brief, the data from this study suggest that the Urquhart Shale Formation in the location we studied has not undergone regional greenschist metamorphism. The mineralogy and the paleoredox proxies (S-isotope data, Mo concentrations, rare earth elements in carbonate minerals) from the barren Urquhart Shale sequence can, therefore, be interpreted in a sedimentary and diagenetic context; and those data concur with deposition of the Urquhart Shale Formation in a ferruginous, marine environment, which is consistent with the current understanding for the Paleoproterozoic oceans. Using this background composition as base line the petrographic, mineralogical, geochemical, and isotopic data from George Fisher suggest that (1) ore formation occurred in multiple events during diagenesis and later deformation, that (2) reduced sulphur in the deposit was likely derived via thermochemical sulphate reduction and the recycling of sulphur from pre-ore diagenetic pyrite, and that (3) fluid-rock interaction of hot (>200-250 °C), saline (Cl-rich), metal-bearing hydrothermal fluids with the Urquhart Shale Formation led to the dolomitization and replacement of pre-ore carbonate and the precipitation of base metal sulphides. Besides ore formation at George Fisher, these hydrothermal processes have resulted in mineralogical and bulk geochemical changes that include (1) albite, chlorite, and calcite depletion, (2) dolomite, phyllosilicate, and sulphide formation, (3) Na and Sr depletion, and (4) Tl and Mn enrichment relative to the barren host rocks. Furthermore, the fluid-rock interaction has led to light rare earth element (LREE) depletion in hydrothermal and hydrothermally altered carbonate minerals relative to whole rock and pre-ore carbonate LREE compositions. Overall, this project has provided new constraints on background diagenetic and hydrothermal processes, and footprints, in the Urquhart Shale Formation at George Fisher. Moreover, the findings from this study can help to further refine exploration models for Zn-Pb deposits in one of the world’s most important base metal provinces.