Evidence-Based Veterinary Medicine (EBVM) is a relatively new field in veterinary curricula and veterinary practice. The aim of EBVM is to base clinical decisions regarding diagnostic procedures and treatments on recent, valid, clinically relevant research data. Veterinary practitioners and clinicians should use optimal diagnostics, interventions and medications to examine and to treat their patients. Therefore, they should assess the topicality of their procedures and therapies to treat their patients as best as possible. This means clinicians need skills in observation, manual dexterity, and also other skills such as communication and empathy for patients and owners. Specifically, the EBVM concepts should be incorporated into preclinical and clinical courses. For the realization of an evidence- based patient care, it is important to know core concepts of EBVM and to be skilled in five steps: formulation of a clinical question, searching for literature, assessing the validity and applicability, the implementation into practice and finally an assessment of whether the new findings have improved clinical practice. Rather than merely transferring information, veterinary education should stimulate and motivate students and let them think critically. Frontal teaching, however, is still applied frequently in veterinary education which only rarely stimulates student interaction, besides it does not support independent thinking and critical questioning. In addition to the concept of EBVM, the critical thinking, and also the rapid development of new communication technologies has influenced veterinary education already. One helpful tool to facilitate the access to research results and thereby the implementation of Evidence-Based Medicine (EBM) is a Critically Appraised Topic (CAT). A CAT is a standardized summary of research evidence evolved around a clinical question, generated from a specific patient situation or problem. The overall objective of the conducted studies was to survey possibilities to include EBVM concepts in veterinary education. For this purpose three studies were conducted: 1\. In the first study the research question was, if fourth-year students consider in-course discussion useful and if sufficient possibilities for discussion are provided and supported by their lecturers. The majority agreed or strongly agreed that clinical topics should be discussed during class time. Frequently stated reasons were improved learning and the opportunity to look at topics from different perspectives. In conclusion, a considerable absence of and request for discussion within veterinary education was found. In light of these findings, we emphasize the need for new teaching strategies that promote independent thinking and critical questioning. That suggested the implementation of more discussion opportunities in well considered and moderated settings in veterinary teaching. 2\. The research question of the second study was to determine adoption and use of mobile devices and online services of veterinary students. According to their answers the majority used a smartphone as mobile device. The data suggested, that most students are familiar with mobile devices and the use of social media, so that new learning strategies could be developed and applied that encompass mobile online learning. These strategies could help to better address different learning types, provide sufficient interactivity and feedback. However, despite promising results reporting a positive educational effect, these perceptions need to be validated in further research. 3\. The objective of the third study was the development, the use and an evaluation of a German language database for Critically Appraised Topics (CATs). Experts of the European Board of Veterinary Specialization were asked to appraise CATs written by students. A total of 153 veterinary medicine students in their fifth year developed 21 CATs. The majority of the students stated that writing CATs is a good exercise and that it is important to train the assessment of scientific information. Nine out of 13 CATs were graded as ´good`. In conclusion veterinary medicine should in general be more responsive to the integration of recent literature and to a critical approach of information. Specifically, the development of a CAT by students is a good approach to teach the concepts of EBVM. In consideration of new technologies, the CAT-database can be used by German veterinary students and in the future by practitioners.

Most people are not aware of the potential health risks associated with the ingredients of daily used polymeric consumer products. The application range is as diverse as the composition of the materials. Polymeric material is exemplarily used in tool handles, food contact materials and toys. It is thus even more important that the final product is harmless to health and ensures safe usage over the entire product life cycle. Analyzing the composition, intentionally added substances need to be distinguished from non-intentionally added substances. Unlike substances that were added for a defined purpose (e.g. plasticizers, antioxidants or processing aids), non-intentionally added substances are present as a result of material aging or inappropriate manufacturing processes (e.g. contaminants, decomposition or reaction products). In this thesis, the focus was on polymeric consumer products that are designated for skin contact. Besides the oral and inhalative route, the dermal path of exposure may pose a major route for xenobiotics to enter the organism. This is of special concern in case of toxicological relevant xenobiotics like polycyclic aromatic hydrocarbons (PAHs), aminobenzene- or cresol-derivatives. There is an EU-wide restriction on 8 PAHs that are classified as presumed to have carcinogenic potential to humans in toys and consumer products effective since 2015 (REACH EG No. 1907/2006, EU No. 1272/2013). Articles shall not be placed on the market if any of their rubber or plastic components that come into direct as well as prolonged or short-term repetitive contact with the human skin contain more than 0.5 mg/kg or 1 mg/kg respectively. The limits set refer to the PAHs content in the material and do not mirror the actual dermal exposure of consumers. Therefore, it is crucial to study the real dermal PAH load in order to generate data for a reliable assessment of potential health risks. In this thesis, dermal exposure to leachables of rubber and elastomers was investigated consequently using excised human skin in the Franz diffusion cell (FDC)-assay. Basing on this reference data, an alternative testing method was developed for dermal exposure assessment of PAHs. It uses a simulant suitable for the lipophilic PAHs and it realistically mirrors the combined permeation and migration of PAHs. Exposure data basing on this method was provided for the European Commission in order to review the limit values of PAHs in consumer products and toys. The skin permeation was visualized at the example of the procarcinogen N-phenyl-2-naphthylamine. Human skin was exposed ex vivo to a polyolefin entailing this antioxidant and a depth profile generated applying ATR-FTIR-microscopy. It was shown by this very graphic evaluation, that numerous polymer additives with in part toxicological relevance might migrate, overcome the skin barrier and ultimately lead to a potential health risk. A detailed characterization of the polymeric material was conducted using broad analytics. The development of multi-analyte-methods allowed quantification of 21 additives, 5 degradation products and 28 PAHs. The polymers were identified applying pyrolysis coupled online to gas chromatography and mass-spectrometric detection. Furthermore, additives were tested in different aging protocols to identify potential degradation products of toxicological relevance. It was shown, that cresol-derivatives are formed as a consequence of degradation of phenolic antioxidants and phthalates are formed by degradation of a phthalate substitute plasticizer. The results of this work can be useful to improve risk identification and to prioritize leachables of elastomers and rubber for risk assessment.

Photosynthesis is one of the most fundamental processes on Earth fuelling life by providing food and energy. Moreover, terrestrial vegetation is a key element in the climate system as it importantly affects exchange processes of carbon, water and energy between the land surface and the atmosphere. In times of a changing climate there is urgent need for detailed knowledge on the factors driving plant activity and for reliable observational systems of the terrestrial vegetation. Satellite remote sensing is the only means to obtain measurements with global coverage, including remote and inaccessible regions, in a spatially and temporally continuous manner. This thesis presents an assess- ment of our current observational capabilities of vegetation dynamics from space. Three complementary approaches of spaceborne ecosystem monitoring are inter-compared: 1) Spectral measurements of the land surface reflectance in the optical range give an indica- tion of the amount of green biomass (as an integrative signal of leaf quantity and quality) and hence of the potential to perform photosynthesis. 2) In the red and far-red spectral regions, satellite instruments register a very small additive signal to the reflected radiance which originates from photosynthetically active chlorophyll pigments, termed sun-induced chlorophyll fluorescence (SIF). 3) Carbon fluxes measured in-situ are upscaled to a global data set of model gross photosynthetic carbon uptake (known as GPP - gross primary production) using empirical relationships with remotely sensed land surface and environ- mental variables. Three case studies focus i) on the spring phenology in boreal forests, ii) on the peak growing season in circumpolar treeless regions, and iii) on phenological changes in ecosystems with varying abundances of trees globally in times of fluctuations in soil moisture availability. The results of all three case studies highlight the intrinsic differences between greenness on the one hand and photosynthetic activity on the other hand. Specifically – for the first time on synoptic scales – a decoupling of photosynthesis (as indicated by SIF and model GPP) and greenness (approximated by various indices derived from spectral reflectance measurements) could be observed in evergreen needleleaf forests during spring recovery. Similarly, a temporal mismatch occurs in northern hemi- sphere forests during the growing season. There, changes in incoming light co-vary with soil moisture and immediately affect photosynthetic performance but barely greenness. Moreover, it has emerged that the timing of peak photosynthesis and peak greenness are asynchronous in tundra areas, which is indicative of differing dynamics. Conversely, there is high consistency between the three approaches regarding the length of growing season in deciduous forests and moisture-related phenological shifts in non-forested ecosystems. The work in this thesis demonstrates that SIF represents an asset for the monitoring of the dynamics of photosynthesis and carbon uptake compared to greenness-based ap- proaches. There are further indications of SIF to track changes in photosynthetic yields. However, despite these promising results for the accurate tracking of photosynthesis from space, further research is required to provide higher resolution data sets with clearer sig- nals. Further, ground-based validation efforts are necessary to improve our mechanistic understanding of physiological and radiative transfer processes controlling the SIF signal.

When investigating the evolution of language, scientists often approach one prominent question: What makes humans human? While researchers might share a common question that motivates them to investigate the origin of language, they do not share a common definition of that original term. The current dissertation hypothesises that definitions of language are ever-changing, temporary constructions which are implicitly informed by historical and social values. By utilising a mixed-methods approach, which combines socio-historical research with quantitative strategies, three examples are investigated: (i) Language defined as speech (oral norm); (ii) Language defined as highest evolutionary achievement (Scala Naturae); (iii) Language defined from its external structure (Behaviourism). The dissertation reveals and illustrates that each of the historical constructions has its problems. Regarding (i), a historical argument from analogy to the deaf discourse reveals prejudices towards nonverbal forms of communication. Addressing (ii), a quantitative text analysis on 915 articles from a time span of 10 years testifies the use of value-laden adjectives in some publications. Analysing (iii), a citation network on 653 articles, published over the time of 69 years, illustrates how the term intention enters a discourse that originates from a behaviouristic era and turned into a cognitive one. The quantitative evidence revealed by the dissertation demonstrates: Science is not, never was and likely never will be free from social and historical influences. That is not a problem. It is a problem, however, to neglect or ignore those influences. The current meta-analysis points to them in order to enable the reader to develop a critical standpoint in relation to the current and past language origin discourse. Hence, providing evidence by systematic investigation of these values is an active contribution to scientific self-correction.

Small rodents and their nests are fascinating and existential biotopes for numerous arthropod, helminth and protozoan animals. On the other side, some of the parasite species can cause disease in humans and companion animals and wild mice and voles are reservoir hosts for many tick-borne pathogens. Despite that, the biodiversity and quantitative occurrence of many wild rodent parasites and their zoonotic potential is largely unknown. Six rodent species from the genera Apodemus, Myodes and Microtus are presumably the most abundant non-commensal rodent species in Europe and also among the most important hosts for immature life stages of ticks in urban areas like Berlin. In the first instance, the present thesis therefore reviewed for the first time all the 460 invertebrate and 69 protozoan species which were reported from these six rodent species in Europe and gave a brief overview about the taxonomy, major morphological characteristics, life cycles and zoonotic potential of the macroparasites and intestinal Coccidia associated with these rodents. In a longitudinal field study, 257 rodents of these six species were trapped at four study sites in Berlin and examined for intestinal Coccidia, macroparasites and other invertebrates. The ectoparasites, as well as phoretic and non-parasitic arthropods detected in the fur and on the skin of the rodents were covered in manuscript 1, while helminths and intestinal Coccidia were addressed in manuscript 2. A high taxon richness of at least 84 species, comprising 63 arthropod, 20 helminth and one higher coccidian taxon was observed on/in the rodents in Berlin and no rodent individual was free of parasite infections. The tick Ixodes ricinus was the most frequent species with 56% prevalence and a mean intensity of 9.4 ticks per rodent host. Eight mite and one nematode species represent new records for the fauna of Germany. Rodent species, trapping location and season were clearly associated with the quantitative occurrence of most parasite groups. Mice were more often parasitised by digenean flukes, hymenlepidid tapeworms, the nematode Heterakis spumosa, lice and listrophorid mites but less often by anoplocephalid tapeworms, trombiculid and myocoptid mites than voles. In non-metric multidimensional scaling, host species even appeared to be more important than trapping location, since rodent individuals could mostly be allocated to one of three host taxon groups, only according to the parasite taxa they harboured. However, the different degrees of urbanisation between the trapping locations affected not only the presence and abundance of the rodent species, but also the species richness of rodent parasites. Compared to rural areas, mice and voles in Berlin carried less arthropod species with low host dependence and host specifity, such as fleas, trombiculid and non-parasitic gamasid mites. Furthermore, ecto- and endoparasites with lower host adaptation and high dependence on intermediate hosts or other external factors were decreasingly diverse, prevalent and/or numerous with increasing degree of urbanisation from periurban to urban sites. Endoparasites without host change (monoxenous) and stationary ectoparasites, in contrast, were more prevalent and/or numerous at urban sites. Apart from ticks, the parasites detected on the six peridomestic rodent species in Berlin only pose a minor zoonotic risk of infection for people, since species causing severe diseases, such as Echinococcus multilocularis were absent. In contrast, the role of these hosts in the urban life cycle of ticks is important and they most certainly participate in the maintenance of well-known and emerging tick-borne pathogens in Berlin. Hence, regression analyses were performed to assess the influence of co-infections on tick abundance on the rodent host. Considering several confounding factors, the abundance of I. ricinus larvae was negatively associated with the abundance of nematodes from the superfamily Heligmosomoidea and Syphacia sp., as well as of gamasid mite parasites from the family Laelapidae, while that of hymenolepidid tapeworms was positively associated. To verify a relationship of cause and effect, laboratory co-infection experiments were conducted and published in manuscript 3. Mice simultaneously infected with Heligmosomoides polygyrus nematodes as well as with larval or nymphal I. ricinus ticks exhibited substantially higher systemic type 2 T helper cell (Th2) responses, based on interleukin 13 and GATA 3 expression compared to single-infected mice. However, the development of partial immunity and the Th2 reactivity towards ticks were unaffected by the nematode infection during repeated larval tick infestations. Co-infections with H. polygyrus were also unable to affect the susceptibility for tick-transmitted Borrelia afzelii Lyme disease spirochetes and their replication, dissemination and induction of signs of pathology in the rodent host. The negative association between heligmosomoid nematodes and ticks in wild rodents could not be confirmed in laboratory mice. However, the observed negative effect of laelapid mites on tick abundance, which may be caused by predation, should be further investigated. These mites have the potential to affect feeding success of ticks and therefore the transmission of many tick-borne pathogens. The present field study constitutes a current basis for studies on parasite diversity, arthropod vector competence and natural co-infections.

Imaging of the rupture process of an earthquake produces valuable insights on the kinematics of earthquakes. In earthquake seismology rupture propagation imaging has been applied impressively to many megathrust events to visualize the rupture process and path. This can help to comprehend the cascade of processes within an ongoing earthquake and consequently it may help to improve hazard mitigation measures. As the coverage of seismic stations and the quality of the instruments has been increasing rapidly in the last years, there is a growing potential to apply similar imaging approaches to medium-sized and small earthquakes, too. In this thesis, I implement and apply three different rupture imaging techniques to infer rupture properties from events at local and at microseismic scales covering magnitudes of 1 ≤ M ≤ 8: the back projection imaging, the empirical Green’s function analysis, and the P wave polarization stacking. I examine two different data sets: the fluid-induced microseismicity from the enhanced geothermal system in Basel, 2006, and the natural occurring seismicity in the vicinity of the rupture area of the 2014 MW 8.1 Iquique earthquake in northern Chile. In a first study, I carefully adjust, numerically test, and apply the back projection technique in the microseismic reservoir at the Basel EGS. The results demonstrate for the first time that back projection imaging is capable of illuminating the rupture process at scales where events have rupture lengths of only a few hundred meters. To complement this study, I perform a second study based on empirical Green’s function analysis in combination with directivity measurements for the smaller magnitude events at this site to estimate corresponding rupture orientations and directions. Based on the combination of the two imaging approaches, I find valuable results for a larger amount of events which cover a broader spectrum of magnitudes compared to a single method approach. The combined results indicate that the rupture behavior at the Basel reservoir appears to be magnitude-dependent and it is strongly influenced by the induced pressure-field from the injection. At the northern Chilean subduction zone, numerous foreshocks and aftershocks of the 2014 MW 8.1 Iquique event were recorded by the Integrated Plate boundary Observatory Chile, which I use to perform P wave polarization stacking to find rupture orientations of 5 ≤ M ≤ 8 events. Although applied to huge teleseismic events before, this is the first successful application of this technique at local scale. My estimated directions are in good agreement with independent back projection studies for the Iquique event itself and its largest foreshock and aftershock. In a second study, I apply empirical Green’s function analysis at the same site for events with 2.6 ≤ M ≤ 5.3. Again, the combination of the results of the two methods yields important findings: the distribution of orientations of rupture directions shows a preferred direction towards east, which is the down-dip direction. It is less sharp for the larger magnitude events and it led to the hypothesis that a bimaterial effect at the plate interface could be responsible for the observed preferred rupture direction. The effect appears to be stronger pronounced for smaller events which are not capable to overcome the barriers of the asperity of their nucleation. In this thesis, three rupture propagation imaging approaches were adjusted in a way that it became possible to analyze events of significantly smaller scale than previously feasi- ble. This thesis shows that the integration of multiple imaging approaches can produce enhanced results for the same data set and how to achieve them. For the further study of the physics of earthquake rupture processes, we need more comprehensive data on the rupture behavior.

Epidermal Dendritic cells, termed Langerhans cells (LC), together with dermal Dendritic cells (DDC), represent the most outer immunological sentinels of the human skin. Acting as specific cutaneous antigen-presenting cells, skin resident DC subtypes perform key roles in mediating the adaptive T cell-triggered immune response. Gained present insights of their functional specializations are largely derived from mouse models. Our understanding of human skin DC is comparatively limited, relying on the use of excised skin and ex vivo differentiated DC derived from peripheral blood monocytes. Hence, this thesis aimed to evaluate monocyte-derived Langerhans-like cells (MoLC) and monocyte-derived dendritic cells MoDC as in vitro test systems to study the complex immune regulatory functions of epidermal LC and DDC. Specific focus was placed on pathologically inflamed skin as found in conditions such as psoriasis and allergic contact dermatitis (ACD). In accordance to the distinct Toll-like receptor (TLR) expression patterns of their in vivo counterparts, MoDC stimulated with bacterial pathogen-associated molecular patterns (PAMP) increased the expression of surface maturation markers CD83/CD86, enhanced the secretion of pro-inflammatory cytokines driving Th1 and Th17 responses. CCR7 was also upregulated, in turn promoting increased MoDC migratory capacity towards CCL21 gradients. Conversely, MoLC displayed relatively little response following exposure to microbial antigens. This immunological inactivity underlines the tolerogenic function of human LC towards bacteria which is important to consider with regard to the maintenance of skin-associated commensals. Invading microbes that infiltrate down to the dermis, on the other hand will instigate a DDC- triggered immune response. Activation of MoLC by a synthetic analog of viral PAMP strongly provoked maturation and Th1-related IL-12p70 release. This same treatment left the MoDC relatively unaffected. This data is in line with existing literature demonstrating that human LC render direct anti-viral activity as they are ideally located at the most outer part of the skin. Interestingly, the results revealed distinct differences in the reactivity of MoLC and MoDC towards bacterial and viral PAMP under sterile-inflammatory conditions induced by TNF and IL-1β. TNF and IL-1b are primarily secreted by skin-resident cells due to inflammatory stimuli, thereby affecting surrounding DC. MoLC activated by TNF and IL-1β increased Th1 and Th17 cytokine Summary Summary secretion and induced the development of IFN-g-producing Th1 cells when co- stimulated with TLR agonists whereas MoDC amplified cytokine release, but without modulating the cytokine pattern. When applied in addition to TNF and IL-1b, a synthetic TLR3 ligand mimicking viral infection led to an increased release of Th1 and Th17 cytokines from MoLC and induced IL-6 secretion in MoDC. The findings imply an immune regulatory function for TNF- and IL-1b-mediated inflammatory environment, where susceptibility towards pathogens and modulation of immune regulatory properties of MoLC and MoDC are rendered. Hence, the complex cross- talk between specific DC subsets is shaped by the local inflammatory setting established by skin-resident cells, which is important to consider with regard to emergence chronic inflammatory skin disorders. Very recent findings have highlighted ontogenetic, phenotypic, and functional similarities between monocyte derived LC or DC and inflammatory DC subsets detected in lesional skin in autoimmune skin diseases. Accordingly, ex vivo generated epidermal LC and DDC might resemble inflammatory DC subsets and could be utilized for the investigation of pathological inflammatory skin conditions. Several drugs, including the anti-malarial chloroquine and the beta-adrenoceptor antagonist (beta-blocker) propranolol, are known to induce and/or exacerbate psoriasis-like skin inflammation. However, the specific pathomechanism remains unknown. Interestingly, chloroquine and propranolol share common physico-chemical properties that lead to their accumulation within lysosomes, a property termed lysosomotropism. Since a key determinant in the pathogenesis of psoriasis revolves around the IL-23/Th17 axis, MoLC and MoDC were used to investigate the lysosomotropism-induced modulation of inflammatory responses in dendritic cells. Chloroquine and propranolol raised the pH within native acidic cell compartments, confirming a lysosomotropic character. Interestingly, lysosomotropism strongly induced IL-23 release in IL-1b-activated MoLC and subsequently elevated the release of IL-17A by CD4+ T cells. IL-1R-mediated NF-kB signaling and p38 MAPK activation were necessary for lysosomotropism-triggered IL-23 secretion. Furthermore, p38 enhanced the binding of the NF-kB transcription factor RelB to IL23A promoter regions. Autophagy has been associated with the secretion of IL-1 family cytokines that are upregulated in chronic inflammatory disorders such as psoriasis. Both, chloroquine and propranolol elevated the expression levels of p62 and the conversion of LC3-I to LC3-II, both markers of active autophagy. Moreover, 143 144 propranolol specifically increased expression of PINK1, a protein that plays a key role in mitophagy, and mitochondrial DNA levels, indicating a late stage block in autophagy. Concomitantly, propranolol provoked mitochondria-derived ROS formation. Notably, scavenging of ROS fully abolished IL-23 secretion. The data highlight an interference with autolysosomal maturation triggered by lysosomotropic compounds, as underscored by the increased abundance of autophagy-related substrates and ROS-producing mitochondria. These results provide insight into a potentially pivotal immune regulatory mechanism stimulating IL-23 release from cutaneous dendritic cells, thereby contributing to Th17-mediated psoriasis-like skin inflammation. The induction of ACD by xenobiotics and haptens follows several essential steps such as percutaneous penetration, subsequent haptenization, and the provocation of epidermal/dermal inflammation and cutaneous DC activation. To emulate ACD and investigate crucial molecular events driving early responses to skin sensitization and the disease’s initially pathogenesis study this, reconstructed human skin (RHS) with integrated epidermal DC was developed. This consisted of a dermal compartment composed of human fibroblasts and collagen, layered underneath an epidermal compartment consisting of human keratinocytes and Langerhans-like cells; MoLC or MUTZ-LC. Firstly, the RHS was demonstrated to sufficiently resemble human skin in its stratification and LC allocation, LC quantity and LC maturation of prominent dendrites. Next, MoLC-RHS and MUTZ-LC-RHS were topically treated with the extreme skin sensitizer 2, 4-dinitrochlorobenzene (DNCB), which provoked an enhanced release of IL-6 and CXCL8/IL-8. It also increased transcriptional activity of LC activation markers CD83, PDL1, and CXCR4 in the dermis, as well as induced an elevated mobility of LC-like cells towards the dermal compartment. Summarily, RHS incorporating MoLC or MUTZ-LC display the fundamental early immune events seen in vivo induced by extreme skin sensitizers. As such, they allow for the investigation of immunological response by LC in the pathogenesis of ACD. This advanced research tool may help to unravel how skin-resident keratinocytes, fibroblasts and LC co-operatively initiate ACD, as well as contributing to the search for valid predictive read-out markers in hazard assessment of potential skin sensitizers.

The three chapters of this dissertation provide new insights in modeling and estimating dynamic discrete choice models. Building on previous identification results, several new strategies are presented to estimate important aspects of dynamic decision processes. A focus lies on hyperbolic discounting and biased expectations, two elements that the vast majority of the literature on female labor supply ignores. Furthermore, the empirical analyses demonstrate that the proposed models describe behavior better than the models dominantly used in the literature. Estimations show that these elements have an economic meaning, as they increase the costs of child-related career breaks. The first chapter provides new exclusion restrictions for identifying the exponential discount factor in dynamic discrete choice models. It demonstrates how exogenous changes in restriction probabilities can be used to recover time preferences from choice data. The second chapter further extends this strategy and analytically shows the identification of hyperbolic discounting parameters within a three-period model of dynamic discrete choice. Furthermore, the chapter discusses how the identification carries over to models with more than three periods. Focusing on women's child-related career breaks, a dynamic discrete choice model of female labor supply, human capital accumulation and labor market frictions is developed. Data from the German Socio-Economic Panel is used to estimate the model, finding a present-bias of 0.77 that significantly deviates from an exponential discounting model. Interestingly, the yearly discount factor for two subsequent future periods is close to values usually assumed for exponential discounters in the literature, with a value of 0.92. This result implies that women do not tend to be myopic per se since even utilities 20 years away receive an overall weight of 0.14 in the lifetime utility. Instead, it is that instantaneous utility is valued much more than any future utility, thus providing evidence that women postpone their re-entry into the labor market, by overvaluing current leisure over future career advancements. The third chapter concentrates on another crucial aspect of dynamic choice, expectations about future states of the world. It represents one of the first analyses in the literature on female labor supply that deviates from the rational expectations hypothesis. This hypothesis assumes that individuals, on average, correctly predict future events. After presenting some suggestive evidence that economic agents systematically mispredict their future employment opportunities, I develop a structural life-cycle model of labor supply, human capital accumulation, and labor market frictions. Nesting the rational expectations framework, the model allows job offer expectations to deviate from their real probability. In this chapter, I develop an identification strategy to recover expectations within the model that allows estimating the key parameters from observed labor supply choices. Estimations provide evidence that mothers strongly overestimate their chances on the labor market since they expect the half-yearly job arrival rate to be 66% higher than the actual rate. The structural framework allows for quantifying the costs stemming from these biased beliefs. The results are striking. Overestimating future employment opportunities prolongs career breaks on average between five and eight months, depending on the length of employment protection. In total, the bias causes a reduction of lifetime earnings from employment, as measured at the first birth of a child, between 12% and 18%. Various benefits and the earnings of a potential husband mitigate some of these losses, causing consumption losses to only range from 3.1 % to 4.1 %.

Ziel: Das übergeordnete Ziel der vorliegenden Arbeit ist die Analyse der Dynamiken zwischen psychiatrischer Praxis und bildender Kunst in Brasilien von 1920 bis 1980 und die in dieser Zeit entstandenen Institutionen in ihrer Neuheit einzuordnen. Die spezifischen Ziele waren (I) zu beschreiben, mit Hilfe welcher ProtagonistInnen die Kunst als klinische Anwendung Eingang in die Psychiatrie fand, (II) aufzuzeigen, unter welchen Umständen und an welchen Orten die PatientInnen arbeiten konnten, (III) zu zeigen, wie die Kunstanwendungen in der Psychiatrie als Aspekt der Behandlung von PatientInnen dokumentiert und rezipiert wurden, (IV) gegenüberzustellen, mit welchen medizinischen, gesellschaftlichen und politischen Vorbedingungen sich die MedizinerInnen und KünstlerInnen konfrontiert sahen und (V) zu erforschen, zu welcher Institutionalisierung und Institutionskritik die neuen Dynamiken an der Grenze von Kunst und Psychiatrie geführt haben. Folgende Methoden wurden angewandt: (I) Systematische Literaturrecherche, (II) ExpertInnenbefragung und Interviews, (III) Analyse von filmischem Material. Ergebnisse: (I) drei medizinische ProtagonistInnen wurden identifiziert: Osório César, Nise da Silveira und Lula Wanderley (II) sowie drei KünstlerInnen: Alice Brill, Almir Mavignier und Lygia Clark. Nur aufgrund des gemeinsamen unberirrten Strebens der zwei Gruppen, die sich auch gegen die Repressionen der Diktatur ab den 1950er Jahren zur Wehr setzten, wurden Kunstateliers (César), Museen (Silveira) und neue Freiheiten (Wanderley) institutionalisiert. (III) Es konnten drei Dynamiken festgestellt werden, die zur Etablierung der Kunst in den Kliniken geführt haben: die Ankunft der Psychoanalyse in Brasilien, die Rezeption der Antropofagia in der Kunst und Psychiatrie und die Institutionalisierungsbestrebungen bzw. Institutionskritik. Schlussfolgerungen: Mithilfe der drei beschriebenen Dynamiken wird gezeigt, dass die entwickelten Therapiemethoden erst durch das Verwischen der Fachgrenzen zwischen MedizinerInnen und KünstlerInnen zustande kommen konnte. Die gesellschaftlichen und politischen Umbrüche in Brasilien im Laufe des 20. Jahrhunderts schufen eine neue Situation, die es – im Gegensatz zu Europa – ermöglichte, alternative Behandlungsmethoden wie die Therapie mit Kunstanwendung bereits ab 1920 zu institutionalisieren.

In deutschsprachigen Schulsystemen treffen aktuell die Reformansätze der Inklusion und der Bildungsstandards aufeinander, wodurch ein vielschichtiger bildungswissenschaftlicher Diskurs um deren Vereinbarkeit ausgelöst wurde. Jedoch liegt kaum Evidenz dazu vor, ob und inwiefern Lehrkräfte mit diesen aktuell bedeutsamen Reformen unterschiedliche oder gar gegensätzliche Anforderungen verbinden. Im Rahmen der vorliegenden Arbeit wurde unter Rückgriff auf sozialpsychologische und erziehungswissenschaftliche Theorien empirisch untersucht, wie sich in der Literatur diskutierte potentielle Gegensätze zwischen Inklusion und Bildungsstandards aus der Sicht von Lehrkräften darstellen. Dabei wurden Aspekte der Unterrichtsgestaltung (Studie 1) ebenso betrachtet wie Aspekte der Leistungsbeurteilung (Studie 1 und Studie 2) und Konsequenzen, die mit der Hervorhebung unterschiedlicher Beurteilungsmaßstäbe im Kontext beider Reformen für die Leistungsbeurteilung bestimmter Schülergruppen verbunden sein können (Studie 3). Die experimentell angelegte Studie 1 untersuchte auf Basis der theoretischen Unterscheidung von Sicht- und Tiefenstrukturen des Unterrichts (Oser & Baeriswyl, 2001) und der Theorie der Bezugsnormorientierung (BNO, Rheinberg, 1980) an einer Stichprobe von N = 135 Lehrkräften im Vorbereitungsdienst, inwiefern diese mit Inklusion und Bildungsstandards eine jeweils andere Unterrichtsgestaltung und Leistungsbeurteilung verbinden. Dabei wurden zwei Perspektiven der Unterrichtsbeschreibung (Selbst- und Fremdeinschätzung) kontrastiert. Die Ergebnisse zeigten, dass sich aus Lehrersicht inklusiver Unterricht von standardorientiertem Unterricht hinsichtlich der Umsetzung zentraler Merkmale von Unterrichtsqualität und hinsichtlich der darin auftretenden BNO bei der Leistungsbeurteilung unterscheidet. Berichtete Unterschiede waren zum Teil auf Einstellungen zu und Erfahrungen mit beiden Reformen sowie diesbezügliche Selbstwirksamkeitserwartungen seitens der Lehrkräfte zurückzuführen und variierten mit der Perspektive, aus der Unterricht beschrieben wurde. Davon ausgehend, dass Inklusion und Bildungsstandards unterschiedliche Bezugsnormen bei der Leistungsbeurteilung (Rheinberg, 1980) implizieren, untersuchte die experimentell angelegte Studie 2 anhand einer Stichprobe von N = 57 Lehrkräften im Vorbereitungsdienst, inwiefern eine Auseinandersetzung mit Bildungsstandards oder Inklusion in Abhängigkeit von den Einstellungen zu diesen Reformen zur Anwendung unterschiedlicher Bezugsnormen führt. Die Auseinandersetzung mit Bildungsstandards zog bei Lehrkräften mit einer positiven Einstellung zu diesen eine schwächer ausgeprägte individuelle BNO sowie tendenziell eine stärker ausgeprägte soziale BNO nach sich, während diese bei Personen mit einer negativen Einstellung zu Bildungsstandards zu einer stärker ausgeprägten individuellen BNO und tendenziell zu einer schwächer ausgeprägten sozialen BNO führte. Die Auseinandersetzung mit Inklusion beeinflusste die BNO hingegen nicht, weder bei positiver noch bei negativer Einstellung zu Inklusion. Da im Kontext beider Reformen unterschiedliche Maßstäbe der Leistungsbeurteilung hervorgehoben werden, untersuchte Studie 3 mögliche Konsequenzen der Anwendung subjektiver und objektiver Beurteilungsskalen für die Leistungsbeurteilung stereotypisierter Schülergruppen, wobei die sozialpsychologische Shifting-Standards-Theorie (z.B. Biernat, Manis & Nelson, 1991) zugrunde gelegt wurde. Die Studie gliederte sich in zwei experimentelle Vignettenstudien, wobei Teilstudie 1 (N = 115 Lehramtsstudierende) negative Stereotype gegenüber Mädchen in Mathematik fokussierte und Teilstudie 2 (N = 265 Lehramtsstudierende) negative Stereotype gegenüber türkischstämmigen Schülern in Deutsch. In beiden Teilstudien wurde jeweils das Mitglied der stereotypisierten Schülergruppe bei gleicher Leistung auf der objektiven Beurteilungsskala negativer eingeschätzt als das Mitglied der nicht stereotypisierten Schülergruppe, während sich auf der subjektiven Beurteilungsskala kein Unterschied in der Einschätzung beider Schülergruppen zeigte. Die Ergebnisse der drei Studien weisen auf bedeutsame Aspekte hin, hinsichtlich derer aus der Sicht von Lehrkräften unterschiedliche Anforderungen mit Inklusion und Bildungsstandards verbunden sein können, und tragen somit Erkenntnisse zur wahrgenommenen Vereinbarkeit beider Reformen in Bezug auf Unterrichtsgestaltung und Leistungsbeurteilung bei. Abschließend werden aus den Ergebnissen Vorschläge für die pädagogische Praxis sowie weitere Fragestellungen für die zukünftige Forschung abgeleitet.

Die Pythaïs-Prozession ist ein athenisches Fest mit einigen Besonderheiten: Im Gegensatz zu den meisten anderen griechischen Prozessionen fand sie nicht periodisch statt, sondern wurde in unregelmäßigen Abständen und insgesamt betrachtet auch relativ selten durchgeführt. Dennoch besaß sie eine große politische Bedeutung, da sie die Führungsposition Athens und die Verbindung zwischen Athen und dem panhellenischen Heiligtum in Delphi hervorheben sollte. In diesem Band werden sämtliche zur Verfügung stehenden epigraphischen, literarischen und archäologischen Quellen zusammengeführt und neu ausgewertet, insbesondere das außergewöhnlich reiche Inschriftenmaterial aus der hellenistischen Epoche und der römischen Kaiserzeit, das hier erstmals in kompletter Übersetzung vorgelegt wird. Neben der Analyse und dem Vergleich der sich verändernden Teilnehmergruppen insbesondere in der hellenistischen Zeit steht die Rekonstruktion des für eine Prozession ungewöhnlich langen Weges von Athen nach Delphi im Mittelpunkt. Damit bietet der Band eine umfassende Rekonstruktion des Pythaïs-Rituals von der klassischen Epoche bis in die römische Kaiserzeit.

Human genome has been expanded to approximately 8% by multiple waves of retroviral invasions, followed by lateral expansion, mainly in germ cells. Recent advancements provide substantial evidence that few families of Human Endogenous Retro-Viruses (HERVs) are co-opted to regulate cell-type specific physiological networks. Following up, we show that diverse modes of HERV-H activity have played a pivotal role in the evolution and development of human- specific embryogenesis including pluripotency. HERV-H provides binding sites for pluripotency transcription factors and serves as a major source for ncRNAs and chimeric transcripts in hPSCs. The interplay of host kruepel box proteins with HERV- H transcription determines the stability of human pluripotency. We updated the transcriptomic and transposcriptomic atlas of Human Preimplantation Embryogenesis (HPE) that re-define the progression of HPE at single-cell resolution. We characterize an unattended cell population in HPE that did not commit to any of the known lineages to form a stable preimplantation blastocyst. ICM being considered as reference frame for the purity of hESCs in naive/primed state conflict, we redefine ICM which adds another layer to the understanding of basic and regenerative biology. Committed and non-committed cells are distinguished by the reactivation of full-length HERVs and mutagenic retrotransposons respectively. We show that HERV-H transcripts control younger mutagenic elements with the mechanisms not known to us yet. Additionally, we also show that HERV-H expression is also prominent during fertilization and early stage of embryogenesis. We find the contrasting pattern of distinct loci of HERV-H during HPE, few of them driving the stage-specific markers that might determine the commitment of host cells to pluripotent lineages. Upon comparing the embryonic lineages and pluripotent states between primates, we decipher the probable mechanisms shaping the human-specific nature of embryogenesis. Much divergence within primate early development is owed to de-novo genes and chimeric transcripts that were remodeled by HERV-H. Moreover, HERV-H orchestrates the human-specific role in stabilizing self-renewal/pluripotency during HPE as inferred from transcriptome-wide cross-species comparison of primate pluripotent cells. Nevertheless, the HERV-H-derived regulatory network has been incorporated, and appears to be an essential feature of human pluripotency in native state. I show that HERV-H derived genes distinguishes the different pluripotent states in human embryos which plays pivotal role in the self-renewal during embryonic development and somatic reprogramming too. I show that the human pluripotency is required to maintain human-specificity in vitro to concur the native biological states with high fidelity. Finally, we show that HERV-H displays human-specific cross-talk with host-factors in distinct developmental lineages, including in-vivo and in vitro human pluripotent states. Finally our check-list of markers would be advantageous in order to sort in vitro pluripotent cells resembling in-vivo cells.

Die vorliegende Arbeit untersucht die Auswirkungen ausgewählter Reformen der Steuerbemessungsgrundlage im Bereich der Unternehmensbesteuerung. Drei Studien analysieren und evaluieren die Steuerwirkungen in Form von Belastungs-, Verteilungs- und Aufkommenswirkungen der (potentiellen) Steuerrechtsänderungen. In den Untersuchungen wird die Methode der (statischen) Mikrosimulation unter Verwendung von handelsrechtlichen Jahresabschlussdaten eingesetzt. Die erste Studie widmet sich dem implementierten EBITDA-Vortrag im Rahmen der Zinsschrankenregelung und analysiert die Steuerbelastungswirkungen auf Unternehmensebene. Die Ergebnisse zeigen, dass aus fiskalischer Sicht der EBITDA-Vortrag eine Entlastung für die Unternehmen bietet (gemessen an den Prognosen des Haushaltsausschusses). Auch aus unternehmensindividueller Sichtweise entlastet der EBITDA-Vortrag überwiegend zielgenau nach abgeleiteten Kriterien aus der Gesetzesbegründung. Unter Verwendung eines Maßstabs zur Berechnung der Steuerersparnis durch Zinsabzug (tax shield) wird allerdings deutlich, dass weitgehend die „falschen“ Unternehmen von der aktuell geltenden Zinsschranke getroffen werden. Der EBITDA-Vortrag hingegen entlastet tendenziell die „Richtigen“, kann jedoch entstandene Kollateralschäden nicht kompensieren. Die zweite Studie widmet sich zwei Reformkonzepten der zinsbereinigten Besteuerung auf Kapitalgesellschaftsebene in Deutschland unter besonderer Berücksichtigung der Verlustverrechnung und analysiert die potentiellen Steueraufkommenswirkungen. Die Ergebnisse zeigen, dass beide Ausgestaltungsalternativen zu deutlich geringeren Aufkommensverlusten führen, als bisher vom Gesetzgeber angenommen wurde, und dass vor allem auch kleine Unternehmen profitieren würden. Nahezu Aufkommensgleichheit wäre bei Grundkapitalverzinsung und Beibehaltung der Mindestbesteuerung zu erreichen. Da mit Zinsbereinigung die Verlustvortragsbestände leicht ansteigen würden, würde eine Verlustkappung die aktuelle Lage der hohen Bestände von Kapitalgesellschaften entschärfen und diese um knapp die Hälfte gegenüber dem Referenzrechtsstand reduzieren. Die dritte Studie widmet sich der Aufteilungsformel des Richtlinienvorschlags über eine gemeinsame konsolidierte Körperschaftsteuer-Bemessungsgrundlage (CCCTB) in der EU und analysiert die potentiellen Verteilungswirkungen auf Unternehmensebene. Die Studie untersucht, wie gut die CCCTB-Aufteilungsformel den „wahren“ Gewinn auf Unternehmensebene approximiert. Die Ergebnisse zeigen sehr hohe Gewinnfehlverteilungen unter dem vorgeschlagenen System des Formula Apportionment (FA). In der Hauptanalyse wird eine durchschnittliche negative (positive) Gewinnabweichung von -4,2% (6,2%) der Bilanzsumme festgestellt. Gegenüber dem durchschnittlichen Return on Assets der Stichprobe ergibt sich ein durchschnittlicher Fehler von -49,5% bzw. +74,1%. Die Analyse zeigt, dass die durch FA verursachte Abweichung nicht zufällig, sondern systematisch ist. Eine zusätzliche Analyse zeigt, dass insbesondere Verlustunternehmen unter zusätzlichen Steuerzahlungen durch FA leiden würden. Im Ergebnis schneidet die CCCTB-Aufteilungsformel im Rahmen der Studie bemerkenswert schlecht ab.

Pre-exposure prophylaxis (PrEP) has recently been identified as one of the five pillars by UNAIDS to achieve the goal of reducing the new infections to approximately 500,000 by 2020. Truvada is the only medication that is approved for PrEP. Although PrEP with Truvada is beneficial, there are a number of limitations. There are a number of novel compounds and treatment-approved antivirals that might overcome these limitations. The challenge is to screen for potential candidates and to design roll-out strategies. Pre-clinical experiments are very insightful but owning to a number of limitations they do not readily guide the candidate-screening and the designing deployment strategies. Although clinical trials provide these answers, they are ethically problematic and prohibitively costly. This highlights that tools are urgently needed that can determine the prophylactic utility of antivirals in order to prioritize candidates and to design the deployment strategies. To this end, we built a mathematical framework (pipeline) to serve as a tool to predict the prophylactic utility of antivirals. Building such a framework for PrEP is a challenging task, which requires solving modelling and simulation problems owing to the various complex processes occurring at different scales (multiscale). We presented the multiscale systems pharmacology framework that integrates processes occurring at various scales including; 1) microscale interactions of active moiety of NRTIs with viral DNA polymerization; 2) meso- and macroscale processes, such as the drug pharmacokinetics, viral replication dynamics; and 3) population scale processes, such as viral exposure and long-term infection probabilities after repeated virus exposures, similar to a clinical trial. The main algorithmic challenge considered in the work is the task of quantifying the infection probability after a viral challenge within a host under the influence of antiviral pharmacokinetics. Time-invariant reaction propensities are valid for constant target-site antiviral concentrations. We employed the theory of branching processes to derive extinction and infection probabilities for time-invariant reaction propensities. However, for time-varying antiviral concentrations at the target-site, the reaction propensities are time-variant. For time-variant reaction propensities, we introduced the reduced-state chemical master equation as an approximation. Furthermore, we adapted the recently developed rejection-based stochastic simulation algorithm. We tackled the challenge of the classification of stochastic trajectories as infection or extinction events which improves the run-time of the algorithm and at the same time guarantees that the misclassification error is below the user-defined threshold. In this work, we derived drug-class specific concentration-prophylactic efficacy (dose-response) curves. The framework allows for the translation of in vitro and ex vivo parameters into the measure of in vivo potency/efficacy. We analyzed all the treatment-approved antivirals for PrEP using the framework. We quantified the role of TDF and FTC and emphasized their complementary roles in the Truvada combination for PrEP. Furthermore, we suggested cost-effective alternatives, such as lamivudine, efavirenz, nevirapine etc. Using the pharmacokinetic model of DTG, we analyzed various roll-out scheme and found that it is non-inferior to truvada.

Loneliness is defined as the feeling that one’s social relationships are deficient in some important way, either quantitatively or qualitatively. Results from previous research suggest that loneliness is both a consequence and an antecedent of social relationships and relationship goals. It is still an open question, however, to what extent the experience of loneliness remains stable as people grow older. The aim of the present dissertation is to combine previous research on loneliness and adult development by examining how the average level, social antecedents and social consequences of loneliness change with increasing age. Specifically, I address three major research questions in this dissertation (1) Does the average level of loneliness change between midlife and old age?; (2) Do the social antecedents of loneliness change with age?; and (3) Do the socio-motivational consequences of loneliness change with age? To answer research questions 1 and 2 I used data from the German Ageing Survey (DEAS), a cohort-sequential and nationally representative study of community-dwelling adults in the second half of life (40 years and older) living in Germany. To analyze the socio-motivational consequences of loneliness (research question 3) I used data from a diary study and two experimental studies with young, middle-aged and older adults in Germany. The results of this dissertation show that the average level of loneliness remains relatively stable between midlife and old age. Moreover, the findings suggest that age-related changes in emotional qualities of the social network include both gains (e.g. a reduced number of distressing relationships) and losses (e.g. a reduced satisfaction with friendships). While poor emotional quality of social relationships was equally predictive of loneliness between midlife and old age, the absence of a romantic partner appeared to be less straining and less relevant as an antecedent of loneliness as people grew older. The results regarding the socio-motivational consequences of loneliness indicate that a temporarily heightened level of loneliness may amplify people’s motivation to avoid negative social experiences. There was no indication that the immediate socio-motivational consequences of loneliness differ between young, middle-aged and older adults. Taken together, the findings of this dissertation suggest that age-related stability in loneliness from midlife into old age may reflect changed relationship goals rather than improved relationship quality. Moreover, the results provide first evidence suggesting that the immediate socio-motivational consequences of loneliness may be relatively stable across the adult life span. Further studies are needed to understand how both stable inter-individual differences and intra-individual changes in a person’s relationship goals contribute to the development of loneliness across the adult life span. Specifically, it is an important open question to what extent a flexible adaption of relationship goals may be both beneficial and damaging to a person’s social well-being. It can be concluded that both researchers and practitioners dealing with loneliness should pay greater attention to the opportunity that factors in the emergence and maintenance of loneliness may vary over persons and time.

The major aims of this thesis were to describe how arbuscular mycorrhizal (AM) fungal communities vary with depth in agricultural land, and to gain insights into AM fungal community assemblage processes in subsoil. In chapter 1 I introduce basic aspects of AM fungal biology, review existing literature on the topic of this thesis and introduce the molecular methodology used in my studies. Chapter 2 and its appendices provide highthroughput sequencing evidence for the differences in AM fungal community composition in top- and subsoil, such as for the existence of phylotypes exclusively found in subsoil. As compared to topsoil, studied subsoil communities are less species rich, less even and have higher community turnover. However, they are not just a subset of topsoil communities and harbor unique taxa. In chapter 3 a top- subsoil mixing event is studied to trace the fate of subsoil phylotypes in topsoil. Here we observe the inability of these subsoil phylotypes to persist in topsoil, and interpret this as evidence for subsoil specialization in certain AM fungal taxa. Chapter 4 discusses the potential roles of subsoil AM fungi in agriculture, with a focus on sustainability and climate smart approaches. The major potential roles identified concern the access to greater nutrient and water pools, the resistance of the system to unfavorable conditions in topsoil, and the avoidance of nutrient leaching and greenhouse gas emissions. We also point out future research needs in this field. Chapter 5 puts the results of this thesis in the broader context of the literature, summarizing the conclusions 97 of previous chapters. In this chapter I also introduce ideas on AM fungal growth strategies and implications of subsoil AM fungi for the understanding of AM fungal biogeography.

The current study focused on the development of an ex vivo human skin model to investigate the added value of nanoparticle-based drug delivery systems on skin penetration and drug-mediated efficacy compared to conventional drug formulations for the topical therapy of inflammatory skin diseases. In order to induce different types and intensities of skin barrier disruption, physical and chemical means were applied on human skin explants obtained from plastic surgery. Comparative studies on structural integrity, biophysical parameters and cytokine levels were performed three times within 48 hours in two culture systems of skin. Cultures of skin maintained in tissue media preserved key skin barrier parameters and viability better than medium-free cultures in humidified chambers. The standardization of 50-times tape stripping and 4-hour sodium lauryl sulfate (5% w/v) pretreatment was reliable: transepidermal water loss values and interleukin-6 /-8 levels as examples of a wide range of affected inflammatory mediators were increased reproducibly compared to intact skin. Different structural and biological changes were induced, which are usually associated with pathological changes in diseased skin. Transepidermal water loss measurements provide a noninvasive screening tool to control and standardize skin barrier disruption ex vivo. Based on these results, time- and tissue-sparing protocols and methods for further investigations were adapted to a short-term skin culture system. Intradermal microdialysis in one experimental setup including up to nine sets for up to 24 hours enabled comparison of intact versus physically and chemically barrier-disrupted skin on the skin of one donor as well as three dexamethasone formulations (ethyl cellulose nanocarriers, nanocrystals and a conventional cream) in parallel. The application of highly sensitive detection methods, such as liquid-chromatography-tandem-mass spectrometry and Luminex R multiplex technology, provided a complex set of data on skin penetration and biological effects. The model successfully demonstrated that skin barrier disruption and the characteristic properties of the dexamethasone formulations affected drug penetration differently. Penetration rates in chemically treated skin were lower compared to tape-stripped skin. Nanocrystals quickly and effectively penetrated intact and barrier-disrupted skin. Thus, significantly higher dermal drug concentrations were achieved within six hours compared to the other formulations. The benefit of encapsulation in ethyl cellulose nanocarriers was more pronounced in intact skin. The results were largely in line with the prediction made based on in vitro release kinetics and Franz diffusion cell studies. High local cytokine levels indicated a trauma induced by probe insertion, which restricted the estimation of drug-mediated efficacy over time. Nevertheless, evidence was found that the application of nanocrystals was associated with high dermal cytokine levels, although significantly higher amounts of the anti-inflammatory drug penetrated the skin. This could point toward an irritative potential of the nanocrystals. In summary, conclusion can be drawn about drug penetration and local biological effects in intact versus barrier-disrupted skin after the application of up to three different drug formulations. Such a complex screening tool can help to characterize the added value of each individual nanoparticle-based drug delivery systems compared to conventional formulations for different pathological skin changes in order to determine the most appropriate for a particular clinical indication. To answer the questions as to whether and to which extent nanoparticles are capable of translocating across an intact skin barrier, an in situ imaging mode based on wide-field two-photon microscopy was implemented. The analysis of full-thickness samples allowed sample preparation steps to be reduced to a minimum, which mainly avoids the production of artifacts. Moreover, both interfollicular and follicular penetration were investigated in histomorphological correlation. Proof-of-concept work on fluorescently tagged nanoparticles revealed that the vast majority of nanoparticles remained in the upper Stratum corneum. However, rare events of deeper penetration were also observed in intact skin close to regions with high focal nanoparticle aggregations in the Stratum corneum and in the infundibulum of hair follicles. Total internal reflection fluorescence microscopy confirmed barrier crossing with high sensitivity. Individual nanoparticles as well as clusters of nanoparticles were detected in the Stratum corneum and within the epidermal layer directly beneath the Stratum corneum. The combination of both technologies provides highly important insights into penetration processes and pathways as well as into the barrier function of the skin, which are crucial for the development of nanoparticle-based drug delivery systems for improved topical application of drugs for inflammatory skin diseases.

Mastzellen (MZ) gehören neben basophilen Granulozyten zu wichtigen Effektorzellen bei IgE-vermittelten allergischen Reaktionen (z.B. allergisches Asthma) und sind als Zellen des angeborenen und des erworbenen Immunsystems auch bei der Abwehr von Pathogenen und in der Pathogenese von Autoimmunerkrankungen (z.B. Urtikaria) involviert. MZ sind weiterhin in der Pathogenese von Mastozytose bedeutsam. MZ stammen, wie alle hämatopoetischen Zellen, aus dem Knochenmark, zirkulieren als Mastzellprogenitoren (MZP) im peripheren Blut und reifen im Gewebe (Haut, Schleimhäute und Lungengewebe) vollständig aus. Die nähere Charakterisierung dieser Vorläuferzellen im peripheren Blut ist bislang nur unzureichend möglich. Die Entwicklung der MZ aus hämatopoetischen Stammzellen (HSZ) wird unter Anderem durch das Zusammenspiel von Transkriptionsfaktoren (TF) maßgeblich bestimmt. Im Mausmodell konnten in den letzten Jahren, auf der Suche nach den Entwicklungsstufen der MZ, einige bedeutsame TF identifiziert werden. Für das humane System sind bisher nur wenige relevante TF identifiziert und bestätigt. Die bisher unzureichende Charakterisierung der MZ-Vorläuferzellen erschwert experimentelle Studien darüber, welche TF in den einzelnen Entwicklungsstufen der MZ bedeutsam und aktiv sind. Die genetische Modifikation von humanen HSZ durch beispielsweise lentivirale Vektoren ist eine Methode, die nähere Aussagen über die Differenzierung der MZ aus HSZ ermöglicht. Die vorliegende Austestung relevanter TF mit zwei Gruppen lentiviraler Viren konnte die TF GATA-3 und HMOX1 identifizieren, um aus humanen HSZ MZ zu generieren. Diese Ergebnisse bestätigen den bereits bekannten Einfluss des GATA-3 auf die MZ Entwicklung. Das HMOX1 Protein konnte bereits in neoplastischen MZ von Mastozytose Patienten nachgewiesen werden und kann durch die vorliegenden Ergebnisse auch genutzt werden, MZ-Vorläuferzellen in der Pathogenese der Mastozytose näher zu charakterisieren.

Vanadium redox flow batteries (VRFBs) are amongst the most promising energy storage systems for storing renewable energies on a large scale. However, the system still has some challenges which limit its widespread application in industry. For instance, the unsatisfactory activity together with insufficient long-term stability of the state-of-the-art commercial activated carbon electrode (i.e., carbon felts) are the most known issues referenced in literature. This thesis introduces two novel solutions for the aforementioned problems: (i) fabrication of non-woven carbon nanofiber networks as alternative, efficient and stable electrodes and (ii) improving the performance of the commercial carbon felt electrodes via coating their surfaces with metal oxide nanostructures. Additionally, the hydrogen evolution reaction, a parasitic side reaction, which is believed to have detrimental impact on the performance of VRFBs, will be investigated at different operating temperatures. Non-woven polyacrylonitrile-based carbon nanofiber networks with a very high electrochemically active surface area were first produced by the scalable electrospinning approach and then directly used as an electrode in a vanadium redox flow battery. Using five sheets of polyacrylonitrile-based electrospun nanofibers achieved ~10% increase in the energy efficiency compared to the commercial carbon felt at current densities of 15 mAcm-2. Furthermore, low-cost highly active carbon-carbon composite freestanding nanofibers were produced by electrospinning a mixture of polyacrylonitrile and carbon black powder using poly acrylic acid (PAA) as binder. PAA enables the loading with higher amounts of the relatively cheap carbon black material. This results in an increase of the productivity of the electrospun carbon nanofibers at lower cost together with simultaneously enhancing the performance of the battery. Battery test results demonstrated a promising performance for the newly designed electrospun carbon fibers as negative and positive electrodes of vanadium redox flow batteries at current densities below 60 mAcm-2. The damaging role of the parasitic hydrogen evolution reaction (HER) in the negative half-cell of the vanadium redox flow battery on the performance of the commercial carbon felt electrodes was studied at different temperatures. Increasing the temperature resulted in a better catalytic performance for both the positive and negative half-cell reactions. Nevertheless, higher temperature significantly enhanced also the undesired HER at the negative side. This led to a decrease in the coulombic efficiency attributed to the higher amount of generated hydrogen causing faster fading of the overall VRFBs performance. Due II to rapid degradation of the commercial carbon felts resulting from the corrosion of their fibers. To minimize the degradation of the commercial carbon felt electrodes and therefore extend the lifetime of the battery, neodymium oxide (Nd2O3) nanoparticles were chemically deposited onto the fibers of the carbon felt by a precipitation method in non-aqueous solution. Nd2O3 modified carbon felts showed 4 times higher stability compared to the unmodified thermally activated carbon felt after 50 consecutive charge/discharge cycles. Moreover, Nd2O3 modified felts retained their original performance after exchanging the electrolyte, indicating less degradation occurred. Additionally, they could maintain their oxygen donating functionalities compared to the thermally activated commercial carbon felt.

Infektionen der unteren Atemwege zählen zu den häufigsten Todesursachen weltweit und betreffen jährlich mehr als 3 Millionen Menschen. Davon ist ein Großteil jünger als 5 oder älter als 65 Jahre alt. Der häufigste Erreger ist mit 1,5-2 Mio. Todesfällen pro Jahr S. pneumoniae. Ein grampositives, kokkoides Bakterium, das zwar allgemein gut antibiotisch behandelbar, jedoch schon lange für seine Resistenzen gegenüber u. a. β-Lactam- und Makrolidantibiotika bekannt ist. In gesunden Individuen mit einem intakten und potenten Immunsystem, die nicht ins Krankenhaus eingeliefert werden müssen, ist die Sterblichkeit mit ca. 0,1% relativ gering. Das Immunsystem verfügt offensichtlich über effektive Abwehrmechanismen. Des Weiteren sorgen kommensale Mikrobiota durch verschiedene Mechanismen dafür, dass es Pathogenen schwerfällt, sich im Wirt zu etablieren. Dies kann u. a. durch Konkurrenz um Nährstoffe, Belegung der Körpernischen oder durch die Ausschüttung von immunmodulatorischen und antibakteriellen Metaboliten geschehen. Körpereigene Immun-Abwehrproteine können durch direkte antibakterielle oder indirekte immunmodulatorische Wirkungen gegen eindringende Pathogene wirken und sorgen ebenso für ein sogenanntes gesundes Mikrobiom [67,68]. Diese Funktionen sind ebenfalls für die PGLYRP bekannt. Bislang sind jedoch keine Studien zur Wirksamkeit der PGLYRP gegenüber S. pneumoniae veröffentlicht. Um diese Lücke zu schließen wurde in dieser Arbeit der Einfluss der Proteine PGLYRP2 und PGLYRP4 auf eine S. pneumoniae-induzierte Pneumonie untersucht. Hierfür wurden WT und PGLYRP KO Mäusen transnasal infiziert und Auswirkungen auf das angeborene Immunsystem und das Mikrobiom analysiert.

PGLYRP2 KO Mäuse zeigten gegenüber den WT Mäusen eine Verschlechterung des klinischen Verlaufs der Pneumokokken-induzierten Pneumonie. Insbesondere wiesen sie mehr Bakterien in Milz und tendenziell auch im Blut 48 hpi auf. Interessanterweise weist das PGLYRP2 keinen direkten, antibakteriellen Effekt gegenüber S. pneumoniae auf und es konnten ebenfalls keine Veränderungen des Darmmikrobioms festgestellt werden. Vielmehr wurden die Effekte durch eine Verringerung an proinflammatorischen Zytokinen und folglich einer geringeren Rekrutierung an PMN in die Lunge der PGLYRP2-KO Mäuse verursacht. Infolgedessen zeigten die PGLYRP2-KO Tiere einen beschleunigten Krankheitsverlauf. Im Gegensatz zu den PGLYRP2-KO Mäusen, wiesen die PGLYRP4-KO Mäuse einen verbesserten klinischen Verlauf gegenüber WT Mäusen auf. Diese Verbesserung war mit einer signifikant geringeren Bakterienlast sowohl in den Lungen, als auch im Blut der infizierten Tiere verbunden. Die bessere Eliminierung der Pneumokokken in PGLYRP4-KO gegenüber WT Mäusen wurde von einer stärkeren inflammatorischen Immunantwort, mit einer Infiltration von PMN, T und B Zellen in die Lunge, sowie einer stärkeren Aktivierung von PMN durch lösliche Faktoren von AEC ausgelöst. Zusätzlich wurde eine stärkere alveoläre Barriere festgestellt, die eine Dissemination der Bakterien in die Peripherie vermutlich reduziert. Des Weiteren konnte gezeigt werden, dass die PGLYRP4-KO Mäuse über ein vermehrt proinflammatorisches Mikrobiom im Darm verfügen. Durch Übertragung dieser Mikrobiota auf keimfreie WT Mäuse konnte belegt werden, dass die Veränderungen im Mikrobiom keine Folge des proinflammatorischen Phänotyps, sondern ursächlich für den Schutz der PGLYRP4 KO Mäuse vor einer Pneumokokken-induzierten Pneumonie sind. Zusammenfassend konnte der Einfluss von zwei PGLYRP auf die S. pneumoniae-induzierte Pneumonie belegt werden. Dabei nimmt PGLYRP2 in diesem Modell eine proinflammatorische Rolle und PGLYRP4 eine anti-inflammatorische und Mikrobiom-modulierende Rolle ein. Fortführende Arbeiten könnten, durch die Aufklärung der genauen Mechanismen und beteiligten Bakterien, möglicherweise neue Behandlungsstrategien für Infektionserkrankungen, insbesondere der Pneumonie, ermöglichen.