The plant hormone cytokinin controls various processes in plant development and responses to environmental stresses. Cytokinin degradation is catalyzed by a group of CKX enzymes. Cellular levels of these proteins significantly impact the cytokinin homeostasis in plants and it is, therefore, important to understand the mechanisms regulating their activities. In this study, several CKX-interacting proteins, belonging to a plant-unique protein family (HIPP), were molecularly characterized and their biological function elucidated, particularly in respect to the regulation of cytokinin homeostasis. In the first part of this work, the molecular basis of the CKX-HIPP interaction, such as the essential interaction motifs, interaction specificity, and the subcellular compartmentation of the CKX-HIPP complex, were investigated. Interaction assays performed in yeast and in planta revealed protein-protein interactions between specific members of the CKX and HIPP protein families. CKX1 interacted with HIPP proteins from the phylogenetic cluster I and III, but not other members of the family. The analyzed cluster I-HIPP proteins interacted additionally with most CKX proteins targeted to the secretory system but did not interact with the cytosolic CKX7 isoform. The CKX1-HIPP7 interaction required the prenylation motif at the C-terminus of HIPP7, implying that the lipid modification mediates the CKX-HIPP interaction. In addition, the tested HIPP proteins were found to form homodimers, which required both the functional prenylation and HMA domains, suggesting that metal binding could mediate the HIPP homodimerization. The Arabidopsis CKX1 protein, a case example in this study, has been shown to be a type II membrane protein that localizes predominantly to the ER. However, the subcellular localization studies in this work revealed that HIPP1, HIPP5 and HIPP7 are localized apparently outside of the secretory system, predominantly in the cytosol and nucleus. To address this discrepancy, bimolecular fluorescence complementation (BiFC) assays were performed. The fluorescence of the BiFC CKX1/HIPP7 complex clearly showed that the interaction occur at the cortical and perinuclear ER. Moreover, a strong BiFC signal mainly localized in the nucleus and cytosol was detected for the CKX1/HIPP1 pair. These results suggest that CKX1 in the detected complexes represents a protein form that was relocated to the cytosolic site of the ER membrane. The second part of this work aimed to uncover the biological function of the identified HIPP proteins, especially in respect to their potential role in regulating CKX protein levels and cytokinin responses in Arabidopsis. The HIPP-overexpressing plants displayed cytokinin-related phenotypic changes and were hypersensitive to cytokinin. This was correlated with an increased cytokinin activity in these plants. It could be further shown that HIPP proteins differentially affected the abundance of the CKX1 protein. Given that CKX1 has been previously shown to be an ERAD substrate protein, it is proposed that the analyzed HIPP proteins might play a role during the retrotranslocation of CKX proteins from ER into the cytosol or during their cytosolic proteasomal degradation. It is hypothesized that the increased cytokinin activity displayed by HIPP-overexpressing plants is due to reduced levels of CKX proteins in the ER, which results in more cytokinin being sensed by the AHK cytokinin receptors localized in this compartment. Analysis of the concentration of other phytohormones or key genes determining their biosynthesis revealed that HIPP-overexpression resulted in the accumulation of stress-related hormones, i.e. ABA and SA, and downregulation of genes related to GA biosynthesis. These changes probably accounted for the enhanced drought tolerance and delayed onset of flowering of the HIPP-overexpressing plants. These data suggest that HIPPs may have broader biological activity beyond the regulation of CKX. Additionally, the effects of hipp loss-of-function mutations and the expression patterns of the analyzed HIPP genes were investigated in this work. In comparison to the phenotypic changes of the HIPP-overexpressing plants, hipp single and double mutants did not display obvious phenotypic changes, suggesting a higher degree of functional redundancy among the cluster I HIPP genes in controlling cytokinin responses and plant development. The HIPP genes were found to be expressed in distinct tissues, including mainly root and shoot apical meristems, and vascular tissues. Interestingly, HIPP transcript levels were repressed by exogenous cytokinin applications, suggesting a regulatory feedback loop between cytokinin and analyzed HIPP genes.

Elevated levels of arsenic (As) in soils and groundwaters remain a pressing global challenge due to its widespread occurrence and distribution, high toxicity and mobility. In oxygen-limited subsurface conditions, redox-active mineral phases can be important substrates in controlling the fate and mobility of As in the environment. Among these redox-active minerals, green rust (GR) phases, an Fe(II)-Fe(III)-bearing layered double hydroxide, have been shown to be able to sequester a wide range of toxic metals and metalloids, including As. However, very little is known regarding how GR phases interact with As species and what is the fate of the immobilized As under dynamic geochemical conditions. GR phases are suggested to form through the transformation of metastable iron mineral phases in non-sulfidic, reducing environments. However, the exact mechanism and pathway of this transformation, as well as the fate of mineral-associated As (i.e. whether it is re-released back into the groundwater by desorption, dissolution or redox transformation) is not yet known but critically needed for modelling As cycling in contaminated environments. To address these knowledge gaps, I conducted a series of experimental geochemical studies and combined them with various laboratory- and synchrotron-based solid and liquid phase characterization methods to examine the interaction between GR sulfate (GRSO4) and As species [As(III) and As(V)]. Specifically, I performed several batch experiments under anoxic and near-neutral pH conditions to determine As-GR interaction mechanisms during GR formation and transformation. Moreover, I also quantified how these transformation reactions affect the toxicity and mobility of As species in contaminated environments. From the batch adsorption experiments, I showed that synthetic GRSO4 can adsorb up to 160 and 105 mg of As(III) and As(V) per g of solid, respectively. These adsorption capacities are among the highest reported for iron (oxyhydr)oxides that form in soils and groundwaters. Results from this study also show that As removal by GRSO4 can be inhibited by several geochemical parameters such as pH, high ionic strength, presence of co-existing inorganic ions (e.g., Mg2+, PO43-, Si) and low temperature. I also employed an integrated nano-scale solid-state characterization approach to elucidate As-GRSO4 interactions. Specifically, I combined scanning transmission electron microscopy (STEM) coupled with energy dispersive X-ray (EDX) spectroscopy together with bulk synchrotron-based X-ray techniques including high energy X-ray total scattering, pair distribution function (PDF) analysis and X-ray absorption spectroscopy (XAS). With these, I was able to directly visualize and pinpoint As binding sites at the GR surface sites and to identify the binding mechanism for both As(III) and As(V). In the case of As(III)-reacted GR, STEM-EDX maps showed that As(III) were preferentially adsorbed at the GR crystal edges, primarily as bidentate binuclear (2C) inner-sphere surface complexes based from the differential PDF and As K-edge XAS data. For the As(V)-reacted GR, As(V) was sequestered as a newly-formed As-bearing mineral phase parasymplesite and as adsorbed As(V) species at the GR edges (in 2C geometry). To assess the fate of As in subsurface environments, I studied As during GR formation and transformation to quantify As uptake and/or its potential release back into solution and the stability of GR and other Fe (oxhydr)oxide phases in this process. During the Fe2+-induced transformation of As(V)-bearing ferrihydrite, I followed the changes in aqueous behavior and speciation of As, as well as the changes in composition of the Fe mineral phases, as a function of varying Fe2+(aq)/Fe(III)solid ratios (0.5, 1 ,2). In all the ratios tested, GRSO4, goethite and lepidocrocite formed in the early stages of transformation (≤ 2h). However, at low ratios (<2), the initially formed GRSo4 and/or lepidocrocite disappeared as the reaction progressed, leaving goethite and unreacted ferrihydrite after 24 h. At an Fe2+(aq)/Fe(III)solid ratio of 2, GRSO4 was formed and remained in the solids until the end of the 24-h transformation, with goethite and unreacted ferrihydrite. The initial As(V) was partially reduced to As(III) by the surface-associated Fe2+-GT redox couple, and extent of reduction increased from 34 to 44% as Fe2+(aq)/Fe(III)solid ratios increased. Despite this reduction to the more mobile and more toxic As(III) species, no significant As release was observed during the mineral transformation reactions. Finally, I tested the long-term stability and reactivity of GR by aging synthetic GRSO4 in pristine and As-spiked natural groundwater at ambient (25 °C) and low (4 °C) temperatures. The spiked As in the groundwater was completely removed after 120 days at 25 °C while the removal rate was ~2 times slower at 4 °C with only ~66% As removal after 120 days. On the other hand, the stability of synthetic GRSO4 in groundwater was strongly affected by the presence of adsorbed As species and temperature. At ambient temperature, the initial GRSO4 aged in As-free groundwater was converted to GRCO3 by ion exchange within a few days and both GR phases eventually transformed to magnetite after 120 days. Remarkably, both the addition of As species in groundwater and lowering the temperature increased long-term GRSO4 stability through the inhibition of (a) ion exchange in the GRSO4 interlayer (i.e., slower conversion to GRCO3) and (b) transformation of GR to magnetite. Moreover, a synergistic stabilization effect was observed with both As addition and low temperature, significantly enhancing GR stability up to a year. Overall, the work presented in this thesis clearly emphasizes the potential role of GR phases in controlling the mobility and toxicity of As species in subsurface environments. Specifically, I contributed to the fundamental understanding of the reactions involving As(III) and As(V) at GR surfaces, elucidating the relevant binding mechanisms and visualizing specific binding sites of immobilized As species. This work also identified critical geochemical factors that affect As removal and GR formation and transformation under anoxic and circum-neutral pH conditions. More importantly, I was able to show the enhanced long-term stability of GR in natural groundwaters and its prolonged reactivity for As sequestration.

Carbohydrates are found in all kinds of living organisms, fulfilling structural functions or playing a role in diverse biological processes. Distinct carbohydrate chains are fundamental for events such as cell adhesion, pathogen-host interaction and numerous cell-signaling processes. Synthetic oligosaccharides are essential in the study of glycan function, and the development of tools for disease prevention, diagnostics and treatment. Difficulties in glycan synthesis arise from the intrinsic complexity of oligosaccharide structures. Oligosaccharide synthesis is a streamlined process, and each step of this process represents a bottleneck that needs to be addressed. Automated Glycan Assembly (AGA) has facilitated access to a wide variety of mammalian, plant, and microorganism glycans. The approach is based on the establishment of an automated platform and compatible orthogonally protected monosaccharide building blocks (BBs, Chapter 1). The aim of this thesis was to develop methods to further expedite carbohydrate synthesis, and to provide access to synthetic glycans for their use in biology and chemistry research. Two projects were conducted to address distinct bottlenecks in glycan synthesis. The first part of this thesis concentrated on expediting the oligosaccharide assembly of Lewis antigens, a family of complex glycans in high demand for biological studies. The focus was set on developing a method that, with a minimum set of orthogonally-protected monosaccharide BBs and by means of AGA, would provide access to an entire family of structurally-related glycans (Chapter 2). Conjugation-ready glycans were produced for ready use in diverse biological investigations. Of special interest within the Lewis family was tumor-associated carbohydrate antigen KH-1, a branched nonasaccharide containing three α-linkages, which was synthesized for its application in the research of cancer therapy. While an increasing number of BBs of common use are commercially available, for some glycans the bottleneck still remains in BBs synthesis. A solution to a persistent limitation in galactosamine (GalN) building block synthesis was developed (Chapter 3). GalN BBs are required for the synthesis of mammalian, fungal and bacterial oligosaccharides. A key step during BB synthesis is the azidophenylselenylation (APS) of 3,4,6-tri-O-acetyl-D-galactal to prepare the corresponding 2-deoxy-2-N-glycoside. Poor reproducibility and the use of azido reagents, that lead to the production of potentially explosive and toxic species, limits this reaction on larger scales in batch. A continuous flow procedure for the safe and scalable APS of galactal was established. Engaging in basic research to establish safe and scalable reactions at the BB synthesis stage will facilitate expanding the AGA scope to other structural families.

Dass eine Interpretation dem Text, auf den sie sich bezieht, *angemessen* sein soll, ist eine nirgends bezweifelte, aber auch so gut wie nie überhaupt thematisierte Vorstellung. Sie wird explizit vor allem in literaturwissenschaftlichen Methodenkontroversen formuliert, etwa wenn diskutiert wird, ob eine werkimmanente oder eine kulturgeschichtliche Methode der Literatur angemessener sei. Beide Positionen behaupten dann typisch die Angemessenheit der eigenen beziehungsweise die Unangemessenheit der abgelehnten Methodologie. Implizit wird die Angemessenheitsbehauptung aber in jeder Textinterpretation mitgeführt, und sie liegt auch allen methodologischen Texten über die Interpretation zugrunde. Die Angemessenheit ist gleichsam der unhinterfragte Rahmen, das unausgesprochene Ziel jeder methodologischen Reflexion in den textinterpretierenden Disziplinen. Unabhängig davon, wie man eine solche Angemessenheit inhaltlich füllt, verweist sie auf die jeder hermeneutischen Operation vorgängige Objektkonstitution, also auf die Frage, was überhaupt ein literarischer Text ist. Nur wer eine Vorstellung vom „Wesen“ der Literatur hat, kann sinnvoll behaupten, diese oder jene Methode, diese oder jene Interpretation sei einem literarischen Text angemessen oder nicht.

Dabei wird schnell klar, dass über die hermeneutische Objektkonstitution prinzipiell nicht abschließend entschieden werden kann: In der Geschichte der philologischen Disziplinen gibt es eine Vielzahl unterschiedlicher, oft sogar entgegengesetzter Auffassungen darüber, was Literatur eigentlich sei und was es zu erklären gelte, wenn man einen literarischen Text analysiert. Die Arbeit fasst die hermeneutische Angemessenheit aus diesem Grund nicht als *Begriff*, sondern als einen argumentativen *Topos*. Topos meint in diesem Kontext eine implizite Prämisse, die ein Argument stützt, ohne ihrerseits explizit behauptet werden zu müssen. Es wird also nicht nach Kriterien gefragt, die erfüllt sein müssen, damit man eine Interpretation als angemessen oder unangemessen bezeichnen darf. Vielmehr wird die „Angemessenheit“ als Argumentationsfigur beschrieben, auf die man sich berufen kann, um den eigenen Ansatz methodologisch zu plausibilisieren, obwohl die basalen Fragen nach dem hermeneutischen Gegenstand prinzipiell unentscheidbar sind. Der Topos der Angemessenheit, so kann das systematische Resultat der Arbeit zusammengefasst werden, invisibilisiert die vorausgesetzte Objektkonstitution und behauptet zugleich deren inhaltliche Richtigkeit. Ausgehend von diesen allgemeinen Überlegungen analysiert die Arbeit die Verwendungsweise des Angemessenheitstopos in der hermeneutischen Theoriebildung in mehreren historischen Fallstudien. Es wird sichtbar, dass, wenngleich alle untersuchten Theorien auf den Topos rekurrieren, damit jeweils recht unterschiedliche Vorstellungen verknüpft werden.

Zunächst stellt sich für die Analyse ein methodisches Problem: Anders als zunächst erwartet werden mag, tauchen die Wörter „angemessen“ und „Angemessenheit“ in den hermeneutischen Theorien an keiner Stelle in terminologischer Bedeutung auf. Es ist deshalb rechtfertigungsbedürftig, welche Stellen in den analysierten Theorien man überhaupt als Aktualisierung des Angemessenheitstopos identifizieren kann. Aus diesem Grund beginnt die Arbeit mit der Erarbeitung eines heuristischen Suchbegriffs. Dazu wird zunächst die Frage gestellt, was Angemessenheit in der klassischen Rhetorik meint, da sie hier oft als die wichtigste der rhetorischen Stilqualitäten angesehen wird. Es werden in unterschiedlichen Texten, vor allem bei Aristoteles, Cicero und Quintilian, jene Aspekte gesammelt, die thematisch sind, wenn von „Angemessenheit“ die Rede ist. Fünf mögliche Bedeutungsfelder lassen sich unterscheiden: (1) Die Angemessenheit der Rede an ihre Umstände, (2) das richtige Maß und die Mitte zwischen zwei Extremen, (3) die richtige Stelle, also das Verhältnis von Teil und Ganzem, (4) eine spezifisches Urteilsvermögen des Redners, sowie (5) die Vorstellung, die Sache selbst „erfordere“ die ihr angemessene Behandlungsart. Diese Aspekte dienen im Durchgang der Analysen als Suchbegriffe: Jene Stellen in den hermeneutischen Texten, an denen auf diese Aspekte Bezug genommen wird, werden dann als Aktualisierungen des Angemessenheitstopos behandelt. In den drei sich anschließenden Kapiteln erfolgen detaillierte Analysen des Topos bei ausgewählten Autoren aus der hermeneutischen Tradition. Es zeigt sich, dass sich idealtypisch drei Paradigmen mit je eigenen Problemkonstellationen und je besonderer Gewichtung der fünf unterschiedenen Angemessenheitstopoi unterscheiden lassen: Ein *rhetorisches* Paradigma, das sich vornehmlich auf das erste Bedeutungsfeld bezieht, ein *ästhetisches*, das mit Schlagworten wie „Gefühl“ und „philologischer Takt“ vor allem den vierten Aspekt betont, und ein *philosophisches*, das die Angemessenheitsvorstellung vor allem durch den fünften Aspekt rechtfertigt.

Zuerst wird nach der Verwendung der Angemessenheitstopik in den logischen Hermeneutiken des 18. Jahrhunderts gefragt, vornehmlich anhand der Texte von Johann Martin Chladenius und Georg Friedrich Meier. Es fällt auf, dass dort zwar regelmäßig eine bestimmte Bedeutung der Angemessenheit aufgerufen wird, dass es sich dabei aber nicht um die hermeneutische Angemessenheit im Sinne einer Gegenstandsangemessenheit der Interpretation handelt, sondern um eine epistemologische Lesart des Begriffs: Die Aufklärungshermeneutiken gehen von einer rationalistischen Semiotik aus, wonach die Zeichen nach eindeutigen Konventionen den Dingen zugeordnet sind, und wonach alle vernünftigen Autoren sich strikt an diese Regeln halten. Weil die Textinterpretationen bei der „Entschlüsselung“ der Texte den selben Regeln folgen, stellt sich in diesem Modell das Problem der Angemessenheit noch nicht. Interpretieren wird in diesen Theorien als logische Operation konzipiert, die eindeutig richtig oder falsch ist; zu sagen, sie sei zusätzlich „angemessen“ oder „unangemessen“ macht dann demgegenüber entweder keinen Sinn oder keinen Unterschied.

Dies ändert sich mit der Ablösung des rhetorischen durch ein ästhetisches Paradigma zur Beschreibung der Textproduktion, die in Deutschland gegen Ende des 18. Jahrhunderts stattfindet. Hierdurch ändern sich die Anforderungen an die Hermeneutik. Der literarische Text wird nun nicht mehr als Aktualisierung einer Regel beschrieben, sondern als ein lebendiger Organismus. Wenn aber jedes Kunstwerk einzigartig ist, dann muss auch die Hermeneutik sich jedes Mal neu fragen, ob sie ihm wohl gerecht wird. Gerade weil das Werk seinen Umständen nicht mehr (im rhetorischen Sinne) angemessen sein muss, muss sich die Hermeneutik ihrerseits dem Werk anmessen, das heißt: Sie muss die Maßstäbe der Interpretation auf jedes Kunstwerk je neu anpassen. Dies ist der Punkt, an dem die rhetorische Angemessenheit des Textes zur hermeneutischen Angemessenheit der Interpretation an den Text wird. In Analysen der hermeneutischen Theorien von Friedrich August Wolf, Friedrich Schlegel, Schleiermacher und August Boeckh wird gezeigt, wie bestimmten Aspekten der Angemessenheit nun eine konstitutive Rolle für die Bedeutungszuschreibung eingeräumt wird. Der Angemessenheitstopos organisiert nun maßgeblich die teils sehr ambivalente Positionierung der Philologie zwischen genialischer „Kunst“ der Auslegung einerseits und einer strenger wissenschaftlichen Konzeption andererseits.

In einem weiteren Kapitel wird anhand zweier einflussreicher Hermeneutiken, der Theorien Diltheys und Gadamers, nach den Transformationen der Angemessenheitstopik im 20. Jahrhundert gefragt. Diese Theorien setzen die Objektkonstitutionen nicht mehr topisch voraus, sondern erörtern sie ausführlich im Sinne eines philosophischen Problems. Die Angemessenheitstopik spielt zwar nach wie vor eine Rolle, der Bezug darauf ist nun aber ein grundlegend anderer. Die hermeneutischen Theorien des 20. Jahrhunderts müssen so als Versuche angesehen werden, die Repräsentationsfunktion der Kunst durch philosophische Analysen gegen die sich zunehmend verbreitende Einsicht in die Beobachterrelativität allen Wissens zu retten.

Im weiteren Verlauf der Theoriediskussion scheint die Frage nach der Angemessenheit oder Unangemessenheit ihre Bedeutung, die sie Ende des 18. Jahrhunderts erhalten hatte, und deren Karriere auch im 20. Jahrhundert beachtlich ist, verloren zu haben. Zwei zentrale Strukturmomente der Angemessenheitstopik, ihre *Latenz* und ihre *Exklusivität*, verlieren nämlich im 20. Jahrhundert ihre Plausibilität: Die Leitbegriffe werden, indem die Methodenwahl nun zu einer bewusst zu vollziehenden Entscheidung wird, nicht mehr latent angenommen, sondern typisch vor Beginn der Analyse expliziert; die resultierende Perspektive erscheint dann nicht mehr die einzig angemessene, sie hebt nur bestimmte Aspekte hervor, um die es dem Interpreten besonders geht.

Es ist der Anspruch der Arbeit, einen Beitrag zum Verständnis der Wissenschaftsgeschichte der Philologien zu leisten. Die geisteswissenschaftliche Wissensproduktion sollte weniger anhand des logisch-deduktiven Modells beschrieben werden, sondern als eine primär topische Konfiguration. Anstatt die Hermeneutik anzusehen als die Serie von Antworten auf *eine* Frage – was ist Verstehen und wie kann man es herstellen? – kann es instruktiv sein, die strukturellen Gemeinsamkeiten zu betonen und danach zu fragen, wie bestimmte Setzungen in methodologische Anweisungen übersetzt werden. Anstatt zu fragen, *was* Verstehen ist, würde die literaturwissenschaftlichliche Hermeneutik dann fragen, *wie* philologische Methoden plausibilisiert werden.

Modern geodetic measurements have extraordinarily broadened our knowledge about plate tectonic kinematics by providing spatially and temporally dense crustal deformation constraints. Those measurements are particularily important for understanding tectonic processes at the Earth´s subduction zones that have been generating most devastating seismic events and tsunamis since the beginning of historical records. The hazard assessment of an active convergent margin mostly relies on geologic archive data as input for the earthquake recurrence concept that can be highly improved by robust kinematic models relating in-situ ground surface measurements to plate interface slip motion. In my thesis, I present an extensive analysis of crustal deformation variations during a subduction zone earthquake cycle in Northern Chile and hence contribute to the refinement of the subduction zone seismic cycle concept. I use GPS and InSAR measurements to constrain the purely tectonic signal and integrate a joint slip inversion model approach at the inter-, co- and postseismic stage of the mature Northern Chile-Southern Peru seismic gap. The characterization of crustal deformation is based on the case-study of the recent Mw 8.1 Iquique-Pisagua earthquake that ruptured the central part of the seismic gap on 1st April 2014. I compare interseismic ground motion rates of a dense continuous and survey-mode GPS network including a time-series of more than ten years with postseismic deformation rates two years after this megathrust event. Moreover, I generate an updated interseismic coupling map of the Northern Chilean subduction zone and present afterslip at different stages of the postseismic period. The joint inversion of InSAR data from two different satellites (Radarsat-2 and TerraSAR-X) and GPS measurements yields different coseismic slip models of the mainshock and separately of the largest aftershock two days later. The Iquique-Pisagua earthquake ruptured a highly coupled patch of the subduction zone interface (Camarones segment). Presented coseismic slip models range at the lower magnitudinal level of published models, are less compact in their geometry and stop at the Iquique Low coupling zone at 21° S. Afterslip is also limited southwards interpreted as impediment through a seismotectonic barrier at this latitudinal range. Postseismic deformation lasts for about two years before relocking rates are equal to interseismic ground motion velocity. Causal factors for the barrier that may behaves as seismotectonic segment limitation involve crustal (forearc) strength heterogeneities, interface coupling discontinuities potentially triggered by variations in seafloor roughness and differences in the subducting plate geometry. GPS observations south of the inferred seismotectonic barrier reveal a deformation rate increase in the second year after the earthquake. Afterslip models suggest a down-dip coupling increase as main driver for the rate increase, perhaps bringing the highly coupled southern Loa segment closer to failure. A megathrust event in Northern Chile was expected for more than thirty years based on slip deficit analysis and recurrence estimations. The fact that the Iquique-Pisagua earthquake 2014 did not rupture the entire Northern Chile- Southern Peru seismic gap like the last big event in 1877 (Mw 8.6 Iquique earthquake) is due to (1) tectonic pre-conditions that lowered the slip deficit as aseismic slow slip events and/or partial unlocking induced by seismic triggering of a foreshock sequence preceding the mainshock and (2) time-dependent, changing interface coupling conditions that may also change seismotectonic segment limitations over time. The Iquique-Pisagua event was not characteristic in the sense of the 1877 Mw 8.6 Iquique earthquake, but maybe for another smaller magnitudinal category of megathrust events that rupture more freuquently. The Northern Chile case-studie clearly demonstrates that subduction zone earthquakes are not only dependent on the slip deficit, but also on limitations of seismotectonic segments and tectonic pre-conditions as interface coupling variations. Thus, subduction zone earthquakes do not necessarily show same rupture characteristics over time. Taken together, the results of my thesis reveal (1) the interaction between different areas undergoing stress release and stress build-up in a major seismic gap, (2) constraints for the temporal variation of coupling degree and interface slip at different stages of the seismic cycle and (3) the influence of large earthquakes at adjacent segments at a subduction zone location and inferred implications for future seismic risk assessment.

Summary The dissertation investigates Gomphrena L. and allied genera with morphological and molecular data in order to test the phylogenetic relationships and to better understand the evolutionary history of this linage. An emphasis is on the actual Gomphrena clade and as well the diversity in Bolivia. Gomphrena (Gomphrenoideae) is the largest genus of the Amaranthaceae with an estimated number of 120 species. The areas of main diversity of this genus comprise South America with about two thirds of the species, Central and North America (about 15%), and Australia (about 20%). This genus largely grows in tropical climates. Some of the species are used as medicinal plants, and a few are cultivated as ornamental plants exhibiting attractive pigmentation in their tepals. The first chapter presents the state of knowledge and a general introduction into Gomphrena. It is important to note that previous molecular phylogenetic studies revealed that Gomphrena in the widely used circumscription of Schinz (1934) is a polyphyletic group. These past studies included only few species of Gomphrena and distinguished two main clades. The first clade includes the type species of the genus, G. globosa L., and certain Australian and American species, plus the allied genera Gossypianthus Hook., Lithophila Sw., and Philoxerus R.Br. (= Blutaparon Raf.) with not fully understood relationships. This group of Gomphrena s. str. is here called “Gomphrena clade” whereas the second group that includes G. elegans Mart., G. mandonii R.E.Fr. and others is part of a lineage called Pfaffia clade (not studied here). In addition, the first chapter presents the complex taxonomic history of Gomphrena. The second chapter focuses on the morphological characteristics of the Gomphrena clade. As a result 22 vegetative and floral morphological characters were defined with their respective states and assessed for 27 representative samples. The photosynthesis type (absence or presence of C 4 photosynthesis) was coded in the form of a single trait including morpho-anatomical characteristics. For chapter three a combined data set of chloroplast sequences (matK-trnK + trnL-F + rpl16) of the Gomphrena clade (including the allied segregate genera) and outgroups from Gomphrenoideae was analyzed with parsimony (MP), maximum likelihood (ML) and Bayesian inference (BI) methods. The 22 morphological characters were optimized on the Bayesian Maximum clade credibility tree using Bayes Traits. The results show that most vegetative characters including the annual life form have evolved multiple times, whereas some floral character states were identified as synapomorphies. An important result reveals that many of the nine characters defined for the androecium, most of which were used historically for the pre- phylogenetic delimitation of Gomphrena and other genera, appear homoplastic. The presence of a fused stamen tube without stamen tube appendages (but with lateral filament appendages in some species) is confined to the Gomphrenoid clade (Gomphrena clade plus Froelichia, iv Xerosiphon, and the Pfaffia clade) whereas the Alternantheroid clade (here represented by Pedersenia) differs by the presence of stamen tube appendages. The important character is the difference between inner and outer tepals showing that all members of the newly found core C 4 Gomphrena clade have a difference in the size of the two inner tepals. To the contrary, all other species present five tepals of similar size. Another interesting result is the detection of pseudanthia, acting as a visual attractant for pollinators. The pseudanthial leaves are typical for a “Mostly Andean clade”. But pseudanthial leaves also were derived two more times independently in G. boliviana and allies and G. meyeniana and allied. The combined plastid tree also shows with high support that the species of Philoxerus, Lithophila and Gossypianthus are nested within the core C 4 Gomphrena clade. For this reason, it is proposed here to include the three genera into Gomphrena and a respective treatment is provided. The extended taxon sampling for matK-trnK (80 samples) and nrITS (82 samples) show that most of the major lineages are congruently resolved between plastid and nuclear data with one exception in the early branching G. mollis - rupestris clade (that is C3). It is sister to all C 4 species of Gomphrena in the nrITS tree whereas it appears as a second branch after the G. prostrata - Guilleminea clade in all plastid trees. Ancestral character state reconstruction shows that C 4 photosynthesis arose in the common ancestor of the Gomphrena clade plus Froelichia but reversed back to C 3 in the lineage of G. mollis and G. rupestris. The age of the crown group of the core C 4 Gomphrena clade plus Froelichia is inferred as 18 Ma (10.2-28.4, 95% HPD), which corresponds to the mid-Miocene climatic optimum (c. 18-16 Ma) when an increase in temperature and aridity and later drop in concentrations of CO 2 occurred. This result is also consistent with the emergence of C 4 photosynthesis in Chenopodiaceae and Poaceae. The core Gomphrena clade stands out by being a C 4 clade that diversified at least twice into high elevation Andean environments. Species such as G. fuscipellita (growing at elevations of 3600-4300 m) and G. meyeniana Walp. (3200-4700 m) constitute at the moment the highest populations of any herb C 4 . The mostly Andean clade diverged around 8 Ma (4.0-13.6, 95 % HPD) from lowland ancestors whereas the crown group has an age of just 4.3 Ma (1.8-10.3. 95% HPD). The majority of the species from the inter Andean dry valleys, Prepuna and Puna ecoregions in the extensively sampled matK-trnK and ITS trees are included in two major subclades of the “Mostly Andean clade”. The molecular time divergence estimate concurs with the maximum Andean mountain upheaval that occurred at 5 Ma, which created new habitats through the geomorphological and climatic modifications. The dry climates led to the recent and multiple evolution of annual species such as G. phaeotricha, G. pallida or G. umbellata. The sister of the Mostly Andean clade is the Australian clade., The results of this thesis (chapter 3) show with high support that the disjunctly distributed Australian species are closely related to the coastal species of Lithophila and Philoxerus. The latter is distributed on the Pacific coast of central America includes morphologically similar species that are endemics on the Galapagos islands. the same applies to Lithophila with one widely distributed Caribbean species and Galapagos endemics. The species of Lithophila and Philoxerus present adaptations to live in high concentrations of salt such as fleshy leaves, adventitious roots allowing vegetative reproduction from broken-off stems. The current distribution of Philoxerus vermicularis is restricted to the west coast of tropical Africa, and the species has not further extended into Africa, which decreases the possibilities for dispersal between Africa and Australia. The stem age of the clade comprising Lithophila, Philoxerus and the Australian Gomphrena spp. 10 Ma (5.7-16.9 95 % HPD). This confirms that the disjunction occurred recently so that Gondwanan vicariance is not possible a tectonic. It is therefore hypothesized that the dispersal to Australia involved long distance dispersal (LDD). Ancestors of Lithophila or Philoxerus -like plants came across the Pacific Ocean, perhaps even from Galapagos that acted as a stepping stone through marine currents such as the South Ecuatorial Current, which then leads over into the East Australian current and which were present since about 6 Ma. The chapter four provides a taxonomic treatment for the species of the core C 4 Gomphrena clade in Bolivia, including keys for identification detailed morphological descriptions and distribution maps. In the introductory part to this chapter dot distribution maps are presented, which are layed over by maps with environmental data in order to better standardize the habitat types of the species for the descriptions of their respective ecology. The results are based on extensive field and herbarium studies and now recognize 30 species of core Gomphrena in Bolivia, which is an increase in eight over the state of knowledge in the Catálogo de Plantas Vasculares de Bolivia that was published in 2014 with 22 species of core Gomphrena. These eight species represent discoveries new to science.

Die Zielsetzung der vorliegenden Arbeit war, festzustellen, ob hochgradig pathologisch-anatomisch veränderte Lungen die Fleischreifung in Richtung DFD lenken. Hierzu wurden im Zeitraum Mai bis Oktober 1995 an einem EG-Schlachthof im Regierungsbezirk Detmold, Kreis Gütersloh, an 20 Schlacht- tagen und an insgesamt 11.950 Schweinen aus 68 Lieferungen Untersuchungen durchgeführt. Neben den Transportdaten "Fahrtdauer","Ladedichte", "Temperatur" und "Luftfeuchtigkeit" sowie "Ausruhzeit auf dem Schlachthof" wurde die Lungengesundheit anhand pathologisch-anatomischer Veränderungen erfasst. Abschlieýend lässt sich anhand der vorliegenden Ergebnisse feststellen, dass die Fleischreifung von Schweinen durch hochgradige Lungenveränderungen deutlich in Richtung DFD verschoben wird. Somit kann die zentrale Fragestellung der Untersuchung eindeutig positiv beantwortet werden, so dass die Zielsetzung der Arbeit erreicht wurde.

Der akute Nierenschaden (AKI, acute kidney injury) ist eine plötzlich auftretende Verschlechterung der glomerulären Filtrationsrate (GFR). Viele unterschiedliche Ursachen sind bekannt. Klassischerweise werden sie in prärenal, renal und postrenal eingeteilt. Seit vielen Jahren ist die Biomarker Forschung beim AKI von großem Interesse. Themen mit besonders hoher Beachtung sind die frühzeitige Diagnosestellung des AKI, die Identifkation von Ursachen des Nierenschadens und die Prognoseabschätzung. In meinen Arbeiten haben wir uns mit der Identifikation solcher Biomarker beschäftigt und dazu unter anderem difference gel electrophoresis (DIGE) als analytische Methode eingesetzt. Wir haben mit DIGE differentiell regulierte Proteine nach herzchirurgischen Operationen im Urin identifiziert, welche auf die Ursache eines Nierenschadens hinweisen. Ausserdem haben wir Marker für die Prognose des AKIs gesucht und insulin-like growth factor binding protein 7 (IGFBP-7) als neuen Biomarker für die renale Prognose identifiziert. In einer weiteren Studie zeigte sich die Kynurenin-Säure als potentieller Marker für die renale Prognose beim AKI. In einer klinischen Studie haben wir die GFR vor und nach perkutanem Aortenklappenersatz beobachtet. Dabei konnten wir feststellen, dass sich bei mehr als 50 % der Patienten die GFR nach Behebung der Aortenstenose verbesserte. Wir konnten mehrere Risikofaktoren für das Auftreten eines AKIs bei diesen Patienten identifizieren, wie den transapikale Zugang, das Auftreten einer Inflammation mit erhöhtem CRP oder erniedrigter Thrombozytenzahl sowie die Transfusion von Erythrozyten. Bei Patienten mit Aortenaneurysma aufgrund eines Marfan Syndroms haben wir mit DIGE eine erhöhte Fragmentierung von Filamin-A festgestellt. Ursache dieser Fragmentierung war eine erhöhte Aktivität der Protease Calpain-2. Zusammengefasst haben wir durch unterschiedliche Methoden Biomarker bei renalen und vaskulären Erkrankungen identifiziert.

The function of the Mediator subunit Med12 on gene regulation has been widely studied and its interaction and regulation of protein coding genes broadly documented. However, only recently has its interaction with non-coding genes been verified. Analysis of transcriptome data from Med12 deficient embryonic stem cells (ESCs) revealed hundreds of misregulated protein coding genes, including multiple Wnt targets and genes involved in the developmental processes that were found affected in embryos previously generated with these cells. In addition to the protein coding genes, multiple misregulated non-coding genes were found during the analysis of transcriptome data generated from Med12 mutant cells, including several putative novel transcripts. Among these, an uncharacterized long non-coding (lnc)RNA was found to be differentially expressed cells, tissues and mouse embryos. This gene, designated as LN-BP18, encodes for antisense transcripts of Sall1, a gene also misregulated in the analysed cells. In humans, mutations in this gene are associated with Townes-Brocks syndrome (TBS), which shows several overlapping characteristics with MED12-associated X-linked intellectual disability syndromes. These features led to the deeper characterization of LN-BP18. Detailed gene and transcript analyses of this novel lncRNA led to the identification of two distinct transcription start sites (TSSs), termed TSS1 and TSS2. While TSS1 was active in all analysed tissues, TSS2 was found active only in ESCs. In vitro differentiation of ESCs confirmed this observation, with expression of transcripts originating from TSS1 increasing throughout the differentiation protocol, while the opposite dynamic occurring for TSS2 transcripts. Characterization of the gene structure revealed a complex splicing pattern, with its 7 exons spliced into 9 different isoforms, including spliced variants for three of the exons. Multiple analyses confirmed the lack of coding potential of all identified isoforms. BLAST searches revealed no homologous transcripts in other species, however, a non-conserved predicted lncRNA was described in human, which was also present in a divergent configuration relative to SALL1, suggesting a potential functional similarity to LN-BP18 despite the low sequence similarity. Expression analyses of the different mutant ESCs generated revealed a dynamic expression of LN-BP18. TSS2 transcripts, which were only detected in ESCs and not in embryonic tissues, showed a positive correlation with different pluripotency markers. This correlation, together with the ESC-specific activation of this TSS, suggested a potential role in the pluripotency network for isoforms originating from TSS2. Sall1 and LN-BP18 TSS1 transcripts were downregulated in Med12 depleted ESCs. Additionally, in Sall1-depleted cells, LN-BP18 was downregulated, with a strong effect observed for the TSS1 transcripts compared to TSS2. These observations, together with the co-expression of these two genes in embryonic tissues, suggested LN-BP18, specifically the TSS1, as a target of Sall1 activation. This activation is potentially Med12-dependent, since the effect on LN-BP18 expression was stronger upon Med12 depletion than in Sall1 deplete cells. A heterozygous LN-BP18-β-galactosidase reporter mutant ESC line was generated to detect expression of LN-BP18 in a more sensitive way. Expression of the reporter gene identified in addition to embryonal limb and caudal end expression seen by whole mount in situ hybridization (WISH), a clear expression in the pronephros, somites, neural tube, forebrain/midbrain- and midbrain/hindbrain-boundaries, demonstrating the importance of this reporter line for studying LN-BP18 expression and function during development. Finally, RNA-seq data from Med12 depleted ESC mutant cells was analysed together with public Med12 chromatin immunoprecipitation sequencing (ChIP-seq) data from ESCs. This analysis allowed identifying 12 lncRNAs, both annotated as well as new predictions, representing candidate lncRNAs whose expression is mediated by Med12. Compiled information for these genes presented here, offer insight into possible systems to analyse these genes in future studies as well as putative targets. Data from this thesis describe the genetic structure and expression of a previously uncharacterized lncRNA. These data, together with the different mutants generated of this gene establish the ground work for future studies clarifying the functions of LN-BP18 in ESCs, but also during embryonic development.

The vaporization of high melting compounds for matrix-isolation spectroscopic investigations has always been a challenging experimental endeavor. Here, pulsed laser deposition is used to vaporize non-volatile halides and pseudohalides for subsequent codeposition of the ablation products with an excess of matrix gases. This method is shown to yield good results in a fraction of the time compared to Knudsen effusion and, more importantly, allows for the isolation of free anions. Pulsed laser deposition of alkali fluorides and chlorides (MF and MCl, M= Li-Cs) and their co-deposition with dihalogen (F2 and Cl2) led to the observation of new vibrational bands of free F3– and some alkali ion pairs (MF3 and MCl3) in solid neon and the first observation of free Cl3–. Matrix isolation of laser ablation products of the pseudohalide KCN yielded, among a variety of polycarbon and polynitrogen compounds, the novel ion pairs KC3 and KN3. Molecular potassium azide (KN3) was shown to exist as a side-on and an end-on isomer. As a further developement of the plain salt ablation, it was possible to investigate molecular alkali ion pairs of the tetrafluorido aurate (AuF4–) by co-deposition of laser-ablated MF/AuF3 mixtures in solid neon matrices. All results were validated by high-level quantum-chemical calculations and are here presented in the context of the present state of research.

Das Gesamtvolumen genomischer Sequenzierungsdaten nimmt, dank der Entwicklung der DNA-Hochdurchsatz-Sequenziertechniken, in den letzten Jahren in unglaublichem Tempo zu. Dies erweitert unser Wissen des humanen Genoms über dessen Aufbau, die Struktur und die räumliche Organisation. Die Erkenntnis um den komplexen Aufbau wird in naher Zukunft in die Interpretation von Variationen auch im klinischen Kontext einfließen müssen, birgt sie doch zahlreiche potentielle Möglichkeiten in der Diagnostik. Whole Genome Sequencing hat schon jetzt den Sprung aus den Forschungslaboren in die angewandte Diagnostik von Krankenhäusern geschafft und erlaubt damit die Einführung der Präzisionsmedizin für alle Patienten. Für eine optimale klinische Interpretation genomischer Varianten ist es wichtig, konsistente und passende Referenzen zu verwenden. Hierzu zählt neben der Auswahl des Referenzgenoms auch die verwendete Datenbank zur Annotierung von funktionalen Einheiten auf der DNA. Diese Arbeit geht auf zwei wichtige Schritte auf dem Weg zum Einsatz des WGS im klinischen Alltag ein. Der erste Schritt beinhaltet, möglichst schnell die gefundenen Varianten zu genomischen Eigenschaften und Featu- res (in Relation zu einer Referenz) zuzuordnen. Dies ist aufgrund der großen Datenmengen ein zunehmendes Problem geworden. Mit Jannovar wird hier eine Softwarebibliothek vorgestellt, welche hervorragend an diese Ansprüche angepasst ist. Die Bibliothek ist schnell, flexibel und kann leicht in Annotationspipelines und eigene Programme integriert werden. Die so annotierten und charakterisierten Veränderungen des Genotyps bilden eine Basis für die weitere Interpretation und Beurteilung durch andere Programme. Die Repräsentation der Genomreferenz entwickelt sich hin zu einem Graphengenom, um die populationsspezifische Variabilität zumindest ansatzweise abzubilden. Diese kann einen enormen Einfluss auf die Interpretation von Varianten haben. Im zweiten Schritt geht es darum, diese populationsspezifische Komplexität zu erläutern. Mit ASDPex wird ein heuristischer Algorithmus vorgestellt, welcher für WGS-Daten eines Individuums das Auftreten von alternativen Haplotypsequenzen vorhersagt. Dafür verwendet es die Verteilung der Allelfrequenzen der individuellen Varianten und gleicht sie mit einer Art Fingerabdruck aus haplotypspezifischen Varianten ab. Das Wissen um die alternativen Sequenzen kann die Verlässlichkeit der klinischen Interpretation weiter verbessern. Zukünftig wird es darum gehen, noch mehr Daten in die Varianteninterpretation zu integrieren, um noch mehr falsch positive/falsch negative Assoziationen zu verhindern und irrelevante Varianten herauszufiltern.

It is challenging to overcome the stratum corneum (SC) barrier to deliver drugs into the skin. Nanoparticle (NP)-based drug delivery systems show the advantages of cutaneous penetration improvement and controllable and targeted drug release. Besides, solvents, as a big group of penetration enhancers, provide another strategy, which is easily accessible, low-cost, and flexibly changeable in components. Apart from the skin penetration enhancement based on formulations, the disrupted barrier of diseased skin could change the skin penetration of drugs too. Thus, the present thesis investigated the influences of the SC barrier function, a pH-sensitive Eudragit® L00 nanoparticle, and the solvents of water and ethanol on cutaneous drug delivery. To determine the influence of the SC barrier on drug delivery, the SC thickness remaining on the skin after different numbers of tape stripping (TS) or cyanoacrylate stripping (CS) were quantified using two-photon microscopy, and the correlation of the SC reduction with the skin permeability changes was studied. The amount of SC removed by each tape decreased along with the skin depth, while a nearly constant SC thickness was removed by each CS. CS can remove the SC, viable skin layers and the hair follicle (HF), while TS can only remove the SC. Nevertheless, the removal of the entire human SC can be attained by both TS and CS, which were 4 times CS or 50 tape strips. The skin permeability to the model drug PCA linearly increased with the reduction of the SC thickness on the skin. These findings provide useful references to separating different skin layers for the quantification of drugs in the skin and establishing ex vivo barrier-disrupted skin models with different extents of barrier disruption. Especially, the barrier-disrupted skin, obtained by performing 30 tape strips on the intact porcine ear skin, could simulate atopic dermatitis (AD) skin to some extent. This ex vivo skin model could be used for evaluating dermal formulations in the initial development stage and reduce the number of animal and human studies. Next, the influences of the SC barrier on the skin penetration behavior of DxPCA-loaded pH-sensitive Eudragit® L100 NPs were investigated by EPR and CLSM using intact and barrier disrupted porcine skin. The pH-sensitive NP exhibited a triggered drug release in vitro at a pH above 5.9. When applied to the skin, the drug DxPCA was slowly released from the NPs in the case of the barrier-disrupted skin, whereas this was under the EPR detect limited for the intact skin. The disrupted SC barrier increased the exchange of the endogenous fluid of the skin with the external medium of the NP dispersion. Due to the exchange, the pH of the external medium of the NPs was increased, leading to the change in the NP structure and thus to the drug release. The improved drug release of the NPs is part of the reason for the higher drug penetration into the viable skin layers of the barrier-disrupted skin compared to the intact skin. These results indicate the feasibility of using this pH-sensitive NP to realize the targeted drug release and enhanced drug delivery into the viable skin layers of the AD skin lesions so that the side effects of the drug Dx could be reduced. Concerning the spatial localization of the NP, the EPR results indicate that the pH-sensitive NPs cannot pass through the disrupted SC of the skin, let alone the intact SC barrier. Besides, the accumulation of Nile red-loaded NPs in HFs and the transfolliclular penetration of Nile red was observed, which indicates that HFs can serve as a reservoir where drugs are sustained released from the NPs and provide a shortcut for drugs to penetrate across the HF into the deep viable skin layers. The drug release of the pH-sensitive NPs inside HFs may be due to the high sebum content and the high HF pH. Lastly, water and ethanol are omnipresent in topical formulations, serving as dispersion media for NPs, low-toxic dissolution media, and penetration enhancers. The solvent effects of ethanol, PBS and the cosolvent ethanol-PBS (1:1, V/V) on the penetration of the hydrophilic model drug PCA into the excised human skin and porcine ear skin were investigated by EPR. Absolute ethanol showed poor ability to deliver PCA into the skin due to the crystallization of PCA caused by ethanol evaporation. PBS and the cosolvent are superior to ethanol, delivering a similar high amount of PCA into the skin. Despite a similar total amount of PCA in the skin, the cosolvent delivered more drugs into the viable skin compared to PBS. This shows the solvents effects on the macroscopic localization of drugs in the skin. Nevertheless, more than 95% of the penetrated drugs accumulated in the SC regardless of the solvents, showing that the SC is a predominant barrier and the main reservoir for the skin penetration of hydrophilic PCA. Furthermore, the solvents influenced the microscopic localization of PCA in the SC. PCA distributed in both the intercellular skin lipids and corneocytes when using the three solvents. From PBS to ethanol, with more ethanol in the solvent, the fraction of PCA distributed in the intercellular lipids decreased from 74% to 37%. The reason may be that ethanol enhances the diffusion of PCA from the intercellular lipids into the corneocytes, implying the coexistence of intercellular and transcellular skin pathways for PCA. In conclusion, the studies conducted in this thesis i) provide correlation of the extent of the SC barrier disruption with the number of applied TS or CS and show the feasibility of using TS to establish an ex vivo barrier-disrupted skin model that mimics AD skin to some degree; ii) give insights of the influence of the SC barrier on the drug release of NPs on the skin and the following skin penetration of drugs, and show the promising application of the pH-sensitive NP in reducing the side effects of Dx for the treatment of AD; iii) expand the knowledge of solvent effects on the spatial localization of drugs in the SC and give a hint for the skin pathway of hydrophilic drugs.

In practice, almost every survey suffers from the problem of non-response. The problem of non-response arises mainly due to the refusal of the persons to respond, and sometimes when there is unavailability of some persons, households, firms because of invalid addresses or wrong telephone numbers, inability of the interviewer to reach the household in remote areas or failure to collect the required information from a sample member in the mail surveys (Armstrong and Overton, 1977; Hox and deLeeuw, 1994). In the context of panel surveys, non-response occurs when the sample members don’t participate in a particular wave of the study. This kind of non-response is called wave non-response. On the other hand, when a sample member participates in the initial wave of the survey but refuses to participate in the later waves of the survey, this kind of non-response is called panel attrition. Panel attrition is a common problem in panel surveys, which reduces sample size and can lead to biased inferences when the propensity to drop out is systematically related to the substantive outcome of interest. In this thesis, we are mainly concerned with the problem of non-response in panel surveys. Like any non-mandatory survey, a panel survey suffers from substantial non-response at its start. 30 to 70% of the initial sample persons refuse to cooperate. The motivation and causation for this behaviour don’t distinguish from standard cross-sectional surveys. However, in panel surveys, the respondents are repeatedly interviewed in later waves. With this repeated measurement it is possible to analyze gross-change, i.e., individual change, for example, changes between poverty and non-poverty. These individual changes have a substantial impact on the distribution of the variable interest in later waves of the panel. As a consequence, an initial bias resulting from selective non-response at the start of the panel may “fade-away” in later panel waves. The fade-away phenomenon can be empirically observed for those rare cases where a panel is selected from the register and where it is possible to make statistical inferences also for the non-responders based on the register information. Motivated by examples from the Finnish sub-samples of the European Community Household Panel (ECHP), the European Statistics on Income and Living Conditions (EU-SILC) and the German Panel Labor Market and Social Security (PASS) Alho et al. (2017) have developed a statistical framework in the context of Markov chains which explains the fade-away effect of initial non-response bias. Non-response in surveys may create a bias in the estimates. However, one advantage of panel surveys over cross-sectional surveys is that under some regularity conditions an initial non-response bias may fade-away over later panel waves. Sisto (2003) and Rendtel (2013) studied the effect of initial non-response on the income quintiles estimates from the European Community Household Panel (ECHP) and poverty rates from the European Union Statistics of Income and Living Conditions (EU-SILC). They reported that the effect of initial non-response bias declines very fast for income quintiles and poverty states in the subsequent panel waves. Such a hypothesis of the fade-away effect doesn’t only base on the information provided by the respondent sample but also depends on the information obtained from the non-respondent sample, where information about the non-respondents is available via registers. Rendtel (2013) used the concept of the Markov chain to explain the fade-away phenomenon. The purpose of using this approach is the possibility to use the steady-state distribution of the Markov chain. If the transition law of the Markov chain is stable over time, then under some regularity conditions the distribution on the state space of the Markov chain converges to a stable distribution, called the steady-state distribution. Alho (2015) extends the approach to regression analysis. He uses a two wave panel to explain the fade-away phenomenon of initial non-response bias in the framework of regression analysis with a single covariate. In the proposed regression model the covariate and the error term are decomposed into permanent and nonpermanent variance components. Alho concludes that the initial non-response bias fades-away in the case of low non-permanent components of the covariate and/or the error term. The thesis is divided into three parts: Part I contains the theoretical foundations for the fade-away effect of initial non-response bias in panel surveys. In part II of this thesis, a simulation study is conducted to investigate the fade-away effect of the initial non-response bias in a multi-wave panel survey. The purpose of the simulation study is to investigate the accuracy of the bias approximation in a simulation setting and check the size of the fade-away effect in later panel waves with no analytical bias approximation. Alho (2015) has investigated the bias of cross-sectional OLS estimates under not missing at random (NMAR) non-response at the start of the panel. He derived analytical bias approximation for the OLS estimate of the slope coefficient of the variable of interest. His underlying model used a variance component model with two components: a fixed individual component and an auto-regressive shock component (Alho’s model will be discussed in Subsection 2.3.2 of Chapter 2). However, in multi-wave panel surveys, the analytical expression for Alho’s bias approximation formula becomes very intractable for later waves. Therefore, we extend the results to a longer panel wave via a simulation study. In Chapter 3 of this thesis, we have conducted a simulation study to verify the approximate results of Alho (2015), and investigated the accuracy of the bias approximation in a simulation setting. We checked the size of the fade-away in later panel waves with no analytical bias approximation. The speed of the fade-away effect of the initial non-response bias is then investigated for different stability scenarios of covariates and error terms, with and without any attrition patterns in later panel waves. As the speed of the fade-away depends on the stability of the covariates and error terms it is important to investigate this effect not only for simulated data but also for real longitudinal data. Therefore, in the application part (Part III) of this thesis, we switch to real data from the German Socio Economic Panel (SOEP): specifically to income data and life satisfaction scores data of the SOEP.

Einleitung: Bei der Behandlung angeborener Herzfehler kann ein akutes Nierenversagen heutzutage häufig verhindert werden. Eine Nierenschädigung ist jedoch eine gefürchtete Komplikation besonders im Rahmen von postoperativen Verläufen oder nach Einsatz von Kontrastmittel. Der späte Anstieg des Kreatinins macht die frühe Diagnose schwer, daher etablierten sich in den letzten Jahren neue Biomarker. Ziel der Studie war die Untersuchung dieser neuen Biomarker und deren Nutzbarkeit bei der Überwachung von Kontrastmittel induzierter akuter Nierenschädigung. Methodik: Dafür wurden Urinproben von 99 Patienten gesammelt, die sich aufgrund elektiver Herzkatheteruntersuchungen im DHZB befanden. Es wurde jeweils vor der Untersuchung ein Urin und der erste Spontanurin nach dem Herzkatheter gesammelt. Ausgewertet wurden davon 87 Patientenproben, bei denen es gelang, einen Urin vor und einen nach dem Herzkatheter zu gewinnen. Aus diesen wurden unter anderem die Biomarker NGAL, VEGF, Cystatin C und Calbindin bestimmt. Ergebnisse: Bei der Auswertung der Biomarker zeigte sich kein signifikanter Anstieg zwischen den vor und nach Herzkatheter gesammelten Proben, vielmehr konnte häufig ein Absinken der Werte unter den Ausgangswert verzeichnet werden. Außerdem zeigten mehrere Biomarker, wie NGAL oder Cystatin C, ebenfalls eine Abhängigkeit von Einflussfaktoren, wie Alter und Geschlecht - ähnlich wie Kreatinin. Dabei zeigten sich bei NGAL bei weiblichen Patienten höhere Werte. Außerdem nahmen die Konzentrationen von NGAL bei steigendem Alter zu, während Calbindin bei Patienten bis zum ersten Lebensjahr die höchsten Konzentrationen zeigte. Schlussfolgerung: Eine akute Nierenschädigung nach Herzkatheter konnte in dieser Studie nicht nachgewiesen werden. Viele Biomarker zeigen zwar einen schnelleren Anstieg als Kreatinin, jedoch sind diese auch nicht unabhängig von multiplen Einflussfaktoren. Das Absinken der Werte unter den Ausgangswert kann möglicherweise durch die Dehydration vor Herzkatheter erklärt werden. Es bedarf größerer Studien und eine Kombination von Biomarkern, um die Biomarker in Zukunft auch im klinischen Alltag sinnvoll nutzen zu können.

Introduction Adenomyosis (AM) is a prevalent disease among women in the reproductive-age. It is histopathologically defined by the ectopic presence of endometrial tissue deep in the underlying myometrium. Although the disease pathogenesis is so far unclear, a translocation of fragments of the basal endometrium into the myometrium, through micro-dehiscences in the inner myometrium, is the most widely accepted theory. These micro-dehiscences are caused by a uterine hyperperistalsis. The latter induces a tissue micro-trauma at the endometrial myometrial junctional zone (EMJZ) in AM-uteri. In our study, possible microscopic and ultra-microscopic evidence of micro- trauma and corresponding tissue-translocation in the EMJZ was investigated.

Materials and methods Uterine wall biopsies were collected from clinically and histopathologically diagnosed AM (n=18) and non-AM (n=14) patients, to study any structural difference in favour of a micro-trauma at EMJZ. The biopsies were examined with Transmission Electron Microscopy (TEM), Van Gieson stain (for extra cellular collagen fibres) and immune-labelled for markers of: myofibroblasts (ASMA, collagen I), mature smooth muscle (desmin), Transforming Growth Factor beta receptor 1 (TGFβR1), TGFβR2, TGFβR3, cell-cell contact (E-cadherin) and hematopoietic cells (CD45, CD68).

Results The EMJZ in AM-uteri showed both microscopic as well as ultra-microscopic changes as following: (1) A disarray of the smooth muscle fibres in the inner myometrium of AM-uteri was evident, compared to the parallel arrangement in non-AM uteri. (2) A disruption of the smooth interface between the endometrium and myometrium in AM was clearly seen, but lacked in non-AM. Nevertheless, neither cell disruption nor translocation of fragments of the basal endometrial glands into the stroma in AM-uteri was seen. (3) Interestingly, uterine pale cells were described in the basal endometrial glands in both AM and non-AM-uteri. However, only in the AM group were these cells migrating into the stroma, through ultra-microruptures of the glandular basement membrane at different locations. (4) As a consequence of tissue trauma, both ASMA-immunolabeled stromal cells in the endometrium as well as collagen I immunolabeling in the inner myometrium were significantly higher in AM uteri than in non-AM uteri.

Conclusion The different morphological changes at the EMJZ support the theory of occurrence of a micro-trauma in AM-uteri being part of the pathogenesis of the disease. However, there is no evidence of a translocation of the basal endometrium in AM uteri. Moreover, the migrating uterine pale cells in AM-uteri demand an in-depth in-vitro characterization to elucidate if they are involved in the disease pathogenesis.

Einleitung Der Einsatz von Fluoroskopie ist bei kathetergestützter Ablation von Vorhofflimmern und bei Deviceimplantation in den meisten Kliniken Mittel der Wahl zur Katheter- bzw. Sondenvisualisierung. Röntgenstrahlung kann zu deterministischen Strahlenschäden führen, von denen das Hauterythem und der posteriore Katarakt am häufigsten sind. Stochastische Strahlenschäden wie Neoplasien können auch durch geringste Dosen ausgelöst werden. Demnach sind auch im Niedrigdosisbereich Maßnahmen zur Reduktion der Strahlenbelastung von Patient und Personal von großer Bedeutung.

Methodik Die vorliegende Arbeit besteht aus zwei retrospektiven Studien, für welche Patienten zwischen 2014 und 2017 konsekutiv eingeschlossen wurden. Sie umfassen 150 Patienten mit Indikation zur linksatrialen Ablation bei Vorhofflimmern bzw. 140 Patienten mit Indikation zur Deviceimplantation. Jeweils die Hälfte der Patienten wurde unter Einsatz eines Dosisreduktionsprogramms behandelt, was aus einer niedrigen Bildrate von 2 Frames Per Second (FPS) und der Entfernung des Streustrahlenrasters (SSR) bestand. In der jeweils anderen Hälfte, der Vergleichsgruppe, wurde ein Programm mit 4 FPS und Verwendung des SSR gewählt. In allen Gruppen wurden eine niedrige Detektoreingangsdosis, ein Kupferfilter, eine variable Fokusgröße und eine kurze Pulsdauer verwendet. Für alle Prozeduren wurde das gleiche biplane Röntgensystem benutzt (Siemens Axiom Artis dBc). Als Maß für die Strahlenbelastung der Patienten wurde das Flächendosisprodukt (DAP) mittels Ionisationskammer erhoben.

Ergebnisse Das neue Dosisreduktionsprogramm führte zu einer Reduktion des DAP um 64,07% bei linksatrialen Ablationen (630,28 ± 550,96 vs. 226,44 ± 277,44 cGy*cm², p<0,001) und um 73,15% bei Deviceimplantationen (1205,54 + 2015,37 vs. 323,68 + 421,98 cGy*cm²; p<0,001). Die verringerte Bildqualität durch Entfernung des SSR und die geringe Bildrate führten in beiden Studien nicht zu prolongierter Fluoroskopie- oder Untersuchungsdauer. Auch waren die Rate des prozeduralen Erfolgs und der Komplikationen statistisch nichtsignifikant verändert. Das neue DRP wurde von allen Untersuchern bis auf bei vier (linksatriale Ablationen) bzw. fünf Fällen (Deviceimplantationen) beibehalten, bei denen das SSR wiedereingeführt wurde. Eine Subgruppenanalyse zeigte, dass die Reduktion des DAP bei adipösen Patienten sowohl bei linksatrialen Ablationen als auch bei Deviceimplantationen fast zweimal so hoch war wie bei nichtadipösen Patienten.

Schlussfolgerung Die Verwendung einer niedrigen Bildrate von 2 FPS und die Entfernung des SSR sind einfach durchführbare Maßnahmen, die sowohl bei linksatrialen Ablationen als auch bei Deviceimplantationen zu einer signifikanten Reduktion des DAP führten. Diese Maßnahmen gingen zwar mit einer reduzierten Bildqualität einher, hatten jedoch keinen negativen Einfluss auf die Durchleuchtungs- und Untersuchungsdauer, die Rate des prozeduralen Erfolgs und die Rate der Komplikationen.

Hintergrund: Ungenügende Immunregulation durch CD4+CD25+ Forkhead Box (FOX)P3+ regulatorische T Zellen (Treg) kann Morbus Crohn verursachen. Treg wurden zunächst phänotypisch charakterisiert. Durch die Bildung von transformierten Wachstumsfaktor (TGF)β; -induzierten Treg (TiTreg) kann FOXP3 in T Zellen in vitro induziert werden. Welche Vorläufer-T-Zell-Subpopulation entweder naiv (CD4+CD25-CD45RA+) oder Effektor-T-Zellen (CD4+CD25-) erzeugt TiTreg mit regulatorischer Funktion?

Methoden: Mit durchflusszytometrischen Analysen wurde die Expression von CD127, CD49d und CD45RA untersucht. Naive und Effektor-T-Zellen, die aus peripheren mononukleären Blutzellen durch magnetische Zellsortierung isoliert wurden, wurden in vitro mit anti-CD3/CD28 und in Gegenwart von TGFβ; und Interleukin(IL) 2 behandelt. Die suppressive Kapazität wurde mit einer gemischte Lymphozytenreaktionen untersucht.

Ergebnisse: Patienten mit Morbus Crohn hatten signifikant mehr CD4+ CD25+ CD127- T Zellen, unabhängig von der Behanldung mit Infliximab oder der Krankheitsaktivität. Patienten mit Morbus Crohn wiesen signifikant mehr aktivierte Treg und gleich viele ruhende Treg als Gesunde. Naive und Effektor T Zellen ergeben ca. 60% -80% CD4+CD25+FOXP3+ T Zellen. Nur FOXP3+ T Zellen (TiTreg), die aus naiven CD4+ T-Zellen umgewandelt wurden, entwickeln suppressive Eigenschaften und exprimieren CCR4, beta7.

Schlussfolgerungen: Die Bildung von TiTreg aus naiven T-Zellen von Patienten ist möglich. Diese Zellen exprimieren Homing-Marker für eine mögliche Migration zu der Entzündung.

Einleitung Die Virusmyokarditis ist eine der häufigsten Ursachen für die Entwicklung einer Herzinsuffizienz oder das Erleiden eines plötzlichen Herztods bei jungen Erwachsenen. Wichtig für die Pathogenese sind myokardiale Entzündungsreaktionen, Apoptose und Remodeling. Verschiedene Untersuchungen konnten eine Beeinflussung dieser Prozesse durch erhöhte Aldosteron-Gewebekonzentrationen nachweisen. Studien an Herzinfarktpatienten zeigten eine Reduktion der Herzinsuffizienzentwicklung durch einen selektiven Mineralokortikoidrezeptor (MR)-Antagonismus. Die vorliegende Arbeit untersucht den Einfluss einer selektiven MR-Blockade in einem murinen Virusmyokarditis-Modell. Material und Methoden Die SWR/J-Mäuse wurden mit dem Coxsackievirus B3 (CVB3) infiziert und entwickelten eine Myokarditis. Eine Kontrollgruppe wurde scheininfiziert. Die Tiere wurden anschließend täglich mit dem selektiven MR-Antagonisten Eplerenon oder Plazebo behandelt. Nach 8 bzw. 28 Tagen wurde die kardiale Hämodynamik mittels Konduktanzkatheter untersucht. Anschließend wurden Entzündungsreaktion, Apoptoserate und myokardiales Remodeling mittels Zymographie, histochemischer sowie immunhistochemischer Untersuchungen und reverser Transkription mit konsekutiver quantitativer Echtzeit-Polymerasekettenreaktion (RT-qPCR) analysiert. Ergebnisse Die CVB3-infizierten Tiere entwickelten eine zeitlich progrediente linksventrikuläre Dilatation und Dysfunktion. Sie zeigten vor allem am 8. Versuchstag eine ausgeprägte myokardiale Entzündungsreaktion, erhöhte Apoptoserate und ein gesteigertes myokardiales Remodeling. Verglichen mit der Plazebo-Therapie reduzierte der selektive MR Antagonismus signifikant die Entwicklung der linksventrikulären Dilatation und Dysfunktion nach 8 und ausgeprägter nach 28 Therapietagen. Auch eine signifikante Reduktion der myokardialen Entzündungsreaktion war nachweisbar. Sie war deutlich nach 8 Tagen und geringer nach 28 Versuchstagen ausgeprägt. Ebenso war Apoptoserate nach 8-tägiger selektiver MR-Blockade im Vergleich zur Plazebo-Therapie vermindert. Das myokardiale Remodeling wurde ebenfalls positiv beeinflusst. Die Aktivität des Matrixmetalloproteasen (MMP)/ Tissue Inhibitors of Metalloproteases (TIMP)-Systems war hauptsächlich nach 8 und der Anstieg des Kollagen I- und Gesamtkollegengehaltes waren vor allem nach 28 Therapietagen signifikant geringer. Schlussfolgerung Der selektive MR Antagonismus verringert in einem CVB3 induzierten murinen Myokarditis-Modell die myokardiale Entzündungsreaktion, die Apoptoserate und das myokardiale Remodeling. Hierdurch werden die Entwicklung einer linksventrikulären Dilatation und Dysfunktion reduziert.

Objective: To identify the prevalence of autoantibodies to the presynaptic protein synapsin in patients with different neurological and psychiatric disorders and to characterize clinical findings in positive tested patients.

Methods: Blood sera of 375 patients with various neurological and psychiatric disorders and sera of 97 healthy controls were initially screened for IgG autoantibodies to synapsin using cell-based assays. HEK293 cells were stimulated by transfection for the expression of rat synapsin Ia, to which autoantibodies could bind. After incubation of the cells with the blood sera at a dilution of 1:320, bound antibodies were visualized by means of fluorescent anti-human IgG secondary antibodies. The presence of specific antibodies to synapsin in sera initially tested positive was further assessed by Western Blot using brain tissue from wildtype mice and synapsin knockout animals. In addition, positive sera were screened by murine hippocampal neuron cell cultures and cell-based essays in which HEK293 cells were transfected with human synapsin Ia and Ib.

Results: In 23 (6.1%) of 375 patient sera, IgG autoantibodies to rat synapsin transfected cells could be identified. No equivalent IgG antibodies were found in any of the 97 control sera (p = 0,007). The median titer was 1:1000 with a range titer of 1:320-1:100.000. Out of these 23 positive sera, twelve sera reacted with a protein of the molecular size of synapsin in the Western Blot of brain tissue from wildtype mice, but not in the Western Blot of brain tissue from synapsin knockout mice. 19 of the 23 positive sera were tested in further experiments, with 13 sera showing IgG autoantibodies to human synapsin Ia and 16 to human synapsin Ib in transfected HEK293 cells. Synapsin antibody positive blood sera stained fixed and permeabilized primary mouse hippocampal neurons. The positive patients had heterogenous neurological and psychiatric disorders, in particular bipolar affective disorders, depression, alcohol dependency and clinically isolated syndrome (CIS).

Conclusions: Following the identification of synapsin as autoantigenic target of intrathecally synthesized antibodies in a patient with a clinical phenotype of limbic encephalitis, the key finding of this large screen of sera was the detection of serum IgG to synapsin I in a number of additional patients with neurological and psychiatric disorders. Therefore, the detection of autoantibodies to synapsin in the index patient did not represent an isolated observation confined to a single case. Further investigation into the potential pathophysiological relevance of these antibodies is required.

Background: Modern Epidemiology offers essential methodological tools for the conduct of clinical research. This thesis presents two clinical study projects and their results, which emerged from routine problems in visceral surgery and have been evaluated in the framework of retrospective clinical study settings supported by epidemiologic methods. The presentation and discussion of these methods will accompany the summarization of the projects. Project 1 addresses the association of pelvic parameters (especially the pelvic volume) with postsurgical outcomes after rectal resection. Project 2 analyzes the problem of perioperative antithrombotic therapies in patients receiving elective inguinal hernia surgery. Methods: Two retrospective clinical studies have been planned and conducted especially using analytic epidemiologic methods. Besides the identification of a radiologic procedure to measure the pelvic volume of patients, the primary endpoint of project 1 was the quality of the resected tissue after total mesorectal excision (TME) subject to the different pelvic parameters. The primary endpoint of project 2 was the rate of postoperative hematomas/bleedings during continuous platelet inhibition. Results: The first project revealed that shorter obstetric conjugate diameters were associated with higher probability of worse TME quality according to Mercury (110.8 ± 10.2 mm vs. 105.0 ± 8.6 mm; OR 0.85; 95% confidence interval 0.73-0.99; p = 0.038) and thus represent a potential risk factor for adverse oncologic outcome. The second project did not prove a higher rate of hematomas or postoperative bleeding under continuous perioperative platelet inhibition in elective inguinal hernia surgery. Though, thorough monitoring of patients remains essential. Conclusions: Both study projects had limitations inherent to retrospective study settings: selection bias and low sample size. Data quality and statistical analysis methods are crucial for the validity of retrospective study settings. Sufficient planning and availability of large data sets provided, retrospective studies even have the potential to serve as an alternative to randomized trials. Both projects proved that retrospective clinical research could be harnessed to develop further hypotheses using means of epidemiologic methods and to plan potential clinical, epidemiologic projects.