The modification of peptides and proteins using side-chain fluorinated amino acids is a widely used strategy to modulate their biophysical and pharmaceutical properties. Systematic investigations can provide valuable insights into the behavior of these non-canonical amino acids in natural protein environments. To this end, the research conducted in this doctoral thesis made use of two well established model systems to evaluate the impact on coiled-coil structure and stability, and proteolytic stability of single substitutions with sterically demanding and highly fluorinated amino acids. First, the incorporation of hexafluoroleucine and two trifluorovaline stereoisomers at two different positions of the hydrophobic core of a parallel heterodimeric coiled-coil model system showed that these amino acids are readily accommodated into stable dimeric α-helical bundles. Remarkably, the single substitution of leucine with hexafluoroleucine leads to a significant increase in thermal stability due to its greater hydrophobicity and efficient packing. Second, fluorinated leucine and isoleucine derivatives in some cases improve the resistance of a model peptide towards different proteases; however, fluorine’s impact cannot be generalized as destabilization was also observed for certain sequences. This might be explained by specific interactions between the fluorinated residues and the respective enzyme binding sites. Noteworthy is that trifluoroisoleucine is able to significantly protect peptides from proteolysis by all tested enzymes when positioned N-terminal to the cleavage site. Finally, studies were carried out towards developing stable, fluorinated peptide based HIV-1 fusion inhibitors. Envelope protein subunit gp41 plays a key role in host cell infection due to the formation of a six-helical bundle consisting of three N-terminal (NHR) and three C-terminal heptad repeat (CHR) sequences. By generating synthetic, judiciously fluorinated CHR-analogues bundle formation and, therefore, cell entry may be inhibited. The previously designed CHR-derived peptide C31 serves as starting point for single substitutions with difluoroethylglycine, trifluoroisoleucine or hexafluoroleucine at a position crucial for helix bundle formation. The resulting fluorinated C31 peptides indeed undergo helix bundle formation with an NHR-peptide, but the resulting complexes exhibit decreased thermal stabilities. Although binding is entropically disfavored, the large negative enthalpy enables a spontaneous binding process. Two of the fluorinated analogues exhibit even higher binding affinities to the NHR-region compared to the native, non-fluorinated parent. Moreover, a hetero-tetrameric scaffold was synthesized that enables a trimeric oligomerization of the NHR-derived segment and will be applied in surface plasmon resonance experiments for a more detailed analysis of the kinetic parameters underlying helical assembly. The results of this thesis will contribute to the rational application of fluorinated amino acids to the development of stable, peptide-based drug candidates.

Einleitung: Gemeinsames Ziel der hier vorgestellten Arbeiten war die Entwicklung, online-Implementierung und Evaluierung einer international, interprofessionell und interdisziplinär einsetzbaren Curriculumskarte, welche verschiedene Empfehlungen bzgl. der kompetenzbasierten, medizinischen Ausbildung synthetisiert und Widersprüche zwischen diesen auflöst. Gleichzeitig sollten kritische Punkte bei der Entwicklung kompetenzbasierter, lernerzentrierter Curricula identifiziert und Konzepte zur Lösung dieser Probleme erarbeitet und evaluiert werden. Inhaltliche und organisatorische Aspekte der Curriculumsentwicklung und -kartierung sollten dabei gleichberechtigt nebeneinander stehen, damit die ordnungsgemäße Umsetzung der geplanten Curricula weder die Forschung noch die Krankenversorgung beeinträchtigt. Methoden: Auf Basis eines studentischen Needs-Assessments wurde die Curriculumskarte konzipiert und gleichzeitig eine Webplattform („LOOOP“) entwickelt, mit deren Hilfe diese Karte abgebildet werden konnte. Anschließend wurde die Karte schrittweise in LOOOP implementiert und die Auswirkungen auf Unterrichtsqualität und Prüfungsleistungen sowie das Nutzerverhalten evaluiert. Parallel zu dieser Implementierung wurde zur Unterstützung des selbstbestimmten Lernens ein computerbasierter Test zur Messung der medizinischen Entscheidungskompetenz („ASCLIRE“) entwickelt und evaluiert, um den Studierenden ein Feedback zu dieser Schlüsselkompetenz der medizinischen Ausbildung geben zu können. Zur semantischen Navigation durch das Curriculum wurde im Rahmen einer systematischen Literaturrecherche die am besten geeignete Ontologie identifiziert. Im Vorfeld der Einführung des nationalen, kompetenzbasierten Lernzielkatalogs Medizin (NKLM) wurde das studentische Peer-Teaching-Programm der Charité gegen ein nationales Rahmenwerk kartiert und dabei der Prozess der Kartierung analysiert. Zur Sicherstellung der Verfügbarkeit geeigneter Patientinnen und Patienten für den klinischen Unterricht wurde ein Algorithmus entwickelt und evaluiert, der mit Hilfe der im Krankenhausinformationssystem hinterlegten Patientendiagnosen den Unterricht am Krankenbett bestmöglich zwischen geeigneten Kliniken verteilt. Um den Studierenden den optimalen Kompetenzerwerb auf dem Gebiet der klinischer Untersuchungstechniken bei gleichzeitiger Entlastung der Kliniken, Patientinnen und Patienten zu ermöglichen, wurden am Beispiel der Untersuchung der weiblichen Brust verschiedene, patientenferne Unterrichtsmethoden zum Erwerb klinischer Handlungskompetenz verglichen. Ergebnisse und Schlussfolgerungen: Die entwickelte Curriculumskarte bildet alle von verschiedenen Autoren empfohlenen Aspekte ab und setzt diese in Bezug zueinander. Der Einsatz führte zu einer von den Studierenden empfundenen signifikanten Verbesserung der Unterrichtsqualität sowie zu verbesserten Prüfungsleistungen. Der Nutzungsgrad des zugehörigen Webinterfaces LOOOP ist sehr hoch mit Steigerungsraten um 100% pro Jahr. Zwei Dozierendenbefragungen an der Charité und an einer unserer Partneruniversitäten ermittelten bzgl. aller Aspekte der Karte positive Einschätzungen. Der ASCLIRE-Test wurde ebenfalls positiv evaluiert: Die Teststruktur ergab im Strukturgleichungsmodell eine hohe Anpassungsgüte und verschiedene Aspekte der Entscheidungskompetenz wurden als teilweise voneinander unabhängige Parameter identifiziert. Die Medical Subject Headings wurden als die am besten geeignete Ontologie identifiziert und nach Anpassungen an die Bedürfnisse der studentischen Ausbildung an allen internationalen Partner-Fakultäten in LOOOP implementiert. Die exemplarische Kartierung eines studentischen Peer-Teaching Curriculums gegen eine Teilmenge des NKLM zeigte unter anderem eine geringe Interrater-Reliabilität im Rahmen der subjektiven Kartierung, so dass wir begonnen haben, im Sinne des Web 3.0 unterstützende Algorithmen für die Kartierung in LOOOP zu implementieren. Der entwickelte Algorithmus zur Optimierung der Patientenverfügbarkeit konnte ca. 70% der ermittelten Probleme lösen und wurde ebenfalls unterstützend in LOOOP integriert. Am Beispiel schambesetzter Untersuchungen konnten wir zeigen, dass das Erlernen an einer Simulationspatientin zu signifikant besseren Prüfungsergebnissen verglichen mit dem Erlernen am Modell führte.

Mit Hilfe der vorliegenden sechs Arbeiten dieser Habilitationsschrift sind neue Erkenntnisse zu Ähnlichkeiten und Unterschieden zwischen stoffgebundenen und stoffungebundenen Süchten erbracht worden. Alkohol und Spielen - same same but different. Hierzu wurden Studien bezüglich Familienanamnese für Alkoholabhängigkeit, Folgen von Rauschtrinken bei Jugendlichen, Nalmefen, einer pharmakologischen Behandlungsmöglichkeit, sowie PET-Studien mit unterschiedlichen Radioliganden zu pathologischem Glücksspiel herangezogen. Es konnte gezeigt werden, dass Probanden mit einer positiven Familienanamnese für Alkoholabhängigkeit im experimentellen i.v.-Alkohol-Selbstverabreichungsverhalten höhere Spiegel als Probanden mit negativer Familienanamnese präferieren. Auch auf Grundlage früherer Studien kann dies ein weiterer wichtiger Aspekt zur Klärung von Faktoren für die spätere Entwicklung einer alkoholbezogenen Störung sein. Eine retrospektive Aktenrecherche zu alkoholintoxikationsbedingten stationären Aufnahmen bei Jugendlichen erbrachte einen Geschlechterunterschied bezüglich alkohol-bedingter Beeinträchtigung (ABB), ein Maß, das einfach aus zwei klinischen Parametern (BAC und GCS) berechnet werden und zur möglichen Beurteilung der Entwicklung einer späteren Alkoholabhängigkeit herangezogen werden kann. Verändertes Belohnungsverhalten als ein Merkmal von Abhängigkeitserkrankungen konnte in einer fMRT-Studie unter Alkoholeinfluss nach einer Einzeldosis Nalmefen bei alkoholabhängigen Probanden ohne Therapiemotivation modifiziert werden. Dies liefert erste Erklärungen für zugrundeliegende neurobiologische Nalmefen-Effekte. Eine 11C-Carfentanyl-PET-Replikations-Studie erbrachte die Bestätigung, dass eine orale pharmakologische Amphetamin-Challenge in Kombination mit 11C-Carfentanyl-PET eine gute Möglichkeit bietet, psychiatrische Erkrankungen, bei denen das Opiatsystem eine zentrale Rolle einnimmt, zu charakterisieren. Auf Grundlage derer konnte mit einer 11C-Carfentanyl-PET-Studie mit Amphetamin-Challenge bei Probanden mit pathologischem Glücksspiel eine gedämpfte endogene Opioid-Freisetzung bei zugleich im Gegensatz zu stoffgebundene Süchten fehlender erhöhter Baseline μ-Opiatrezeptor-Verfügbarkeit nachgewiesen werden. Auch im GABAergen System bei Probanden mit pathologischem Glücksspiel konnten mithilfe von 11C-Ro15-4513-PET Unterschiede zu stoffgebundenen Süchten gezeigt werden. Bei gleichzeitig positiver Korrelation mit stimmungsbezogener Impulsivität zeigte sich im rechten Hippocampus eine erhöhte 11C-Ro15-4513-Bindungsaffinität im Vergleich zu gesunden Probanden. In früheren Studien zu stoffgebundenen Süchten war eine verminderte 11C-Ro15-4513-Bindungsaffinität nachgewiesen worden.

Bei der vorliegenden Arbeit handelt es sich um eine retrospektive Analyse aller durch kraniomaxillofaziale Distraktionsosteogenese (DO) in der Klinik für Mund-, Kiefer- und Gesichtschirurgie der Charité Universitätsmedizin Berlin am Campus Virchow Klinikum behandelten Patienten. Zwischen Januar 2003 und Dezember 2017 war ein festes Behandlerteam für das Patientenmanagement und die operative Umsetzung verantwortlich. Für die Auswertung wurden die für jeden behandelten Patienten angefertigten Distraktionsprotokolle sowie die zugehörigen Fotodokumentationen genutzt. Insgesamt wurden 193 Distraktionen bei 171 Patienten vorgenommen. Dies entspricht einem Anteil von weniger als 1% aller im Untersuchungszeitraum behandelten Patienten (>30.000). Obwohl die Methode im Hinblick auf die Fallzahl keinen großen Stellenwert hat, ist sie ein wichtiges Therapiemittel zur Rekonstruktion des „Craniofacial Framework“. Dies konnte im Rahmen der vorliegenden retrospektiven Untersuchung gezeigt werden. Bei Beachtung der bereits von G. A. Ilizarov angegebenen Prinzipien lassen sich vorhersehbare und stabile Resultate erzielen. Da sich das Patientengut als ausgesprochen heterogen erwies, war eine statistische Auswertung mit evidenzbasierten Empfehlungen nicht möglich. Allerdings konnten Patientengruppen definiert werden, für die sinnvolle Aussagen zur Anwendung der DO getroffen wurden: Vertikale Alveolarkammdefekte konnten suffizient ausgeglichen werden, sodass langzeitstabile implantatprothetische Versorgungen möglich waren (n=9).

Transversale Defizite in Ober- (n=138) und Unterkiefer (n=11) konnten langzeitstabil korrigiert werden. Damit haben Transpalatinaldistraktion und Symphysendistraktion einen festen Stellenwert im Rahmen der interdisziplinären Korrektur dentofazialer Anomalien. Auch bilaterale mandibuläre Distraktionen zeigten stabile symmetrische Resultate (n=4).

Für Patienten mit syndromalen kraniofazialen Wachstumsstörungen scheint die Nachentwicklung betroffener Regionen durch DO beinahe alternativlos zu sein(n=17). In Abhängigkeit von der individuellen Situation konnten mit internen und externen Distraktoren gute funktionelle und ästhetische Ergebnisse erzielt werden. Die Anwendung der Distraktionsosteogenese ist anspruchsvoll und kann mit technischen Schwierigkeiten verbunden sein, die erkannt werden müssen, um ein adäquates Management zu gewährleisten. Die distraktionsassoziierte Komplikationsrate war insgesamt niedrig. In nur zwei Fällen kam es zu relevanten Folgeschäden. Es muss betont werden, dass komplexe Defizite des „Craniofacial Framework“ durch Distraktionstechniken häufig nicht vollständig ausgeglichen werden können. Daher kann für die adäquate Korrektur die Kombination verschiedener operativer und rekonstruktiver Verfahren erforderlich werden. Die Indikationsstellung zur DO orientiert sich an der vorliegenden individuellen Situation und stellt eine patientenspezifische Entscheidung dar. Die Technik erfordert eine entsprechende Motivation und Kooperation des Patienten, da sie mit mehr zeitlichem Behandlungsaufwand verbunden ist als „einzeitige“ chirurgische Verfahren. Bei korrekter Indikationsstellung und Anwendung der Distraktionsosteogenese lassen sich bei akzeptablem Nebenwirkungsprofil sehr gute Ergebnisse erzielen. Während des 15-jährigen Untersuchungszeitraums kam es zu verschiedenen Innovationen, die betroffenen Patienten neue Behandlungsperspektiven ermöglichen.

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.

Stable flies (Stomoxys calcitrans) are a common problem in animal husbandry worldwide. Nuisance, especially by biting flies, can have a considerable negative impact on animal well-being, health and productivity. Furthermore, stable flies are known vectors of a range of pathogens. Insecticides constitute the mainstay for their control. However, if insecticides are applied in a non-strategic manner, there are risks of developing insecticide resistance within a few generations due to the high reproductive rate of stable flies. The objective of this study was to assess the occurrence of insecticide resistance in Stomoxys calcitrans on dairy farms in Brandenburg, Germany. Moreover, it aspired to propose best-bet strategies for on-farm pest control aiming to minimize the use of insecticides. Based on a telephone questionnaire survey performed in June 2015 with 52 dairy farms in Brandenburg, 40 farms were selected for an on-farm cross-sectional survey. In this survey the FlyBox®-method was used in order to evaluate the susceptibility of stable flies to a deltamethrin impregnated polyester fabric. For confirmatory evaluation, Stomoxys populations from 10 farms were caught and colonies established in the laboratory. The susceptibility of the emerging F1 to F3 generations was tested with current methods under controlled conditions. In a first step, the LD95 of deltamethrin and azamethiphos were defined with established sensitive laboratory strains of S. calcitrans. Then the toxicity of both was assessed by topical application of the LD95 and multiples of it. The larvicidal effects of two insect growth regulators, cyromazine and pyriproxyfen, were evaluated at different concentrations based on the manufacturers’ recommendations. The questionnaire survey revealed that pyrethroids are the most frequently used insecticides (78.9 %) with deltamethrin being the dominant active ingredient (41 %). Furthermore, the on-farm survey using the FlyBox®-method indicated deltamethrin resistance in all of the 40 tested strains (100 %). In the laboratory tests, 24 hours following topical application of deltamethrin and azamethiphos to all of the 10 strains using the LD95 of 2.3 and 4.9 ng/fly, respectively, mortalities below 90 % were encountered. This led to the conclusion that these populations were resistant to the tested insecticides. Nine out of the 10 populations (90 %) even showed a mortality below 40 % at the LD95 of both deltamethrin and azamethiphos. Forty to 80 % of the mortality rates of multiples of the LD95 of azamethiphos and deltamethrin, respectively, were below 90 %. The insect growth regulators cyromazine and pyriproxyfen tested at the recommended concentrations resulted in an inhibition rate of 100 % of all 10 populations. The study revealed that there is an urgent need to conduct further field surveys in different livestock production systems in order to draw general conclusions concerning the resistance status in Germany and the EU. Those studies would facilitate the elaboration of better integrated pest management strategies in order to warrant the use of insecticides as a last resort only within a given cascade of possible control measures. This would sensitise farmers as well as veterinarians on resistance development and its impact on the environment. The design of genetic markers for the detection of insecticide resistance should be promoted in order to simplify further testing. In conclusion, the legal regulation of some insecticides should be evaluated regularly protecting human health and preventing negative impacts on honey bees, hymenoptera and other non-target insects.

Zusammenfassung: Vorliegende Arbeit untersucht Einsatz und Wirken der Allegorie im filmischen Werk Pier Paolo Pasolinis und legt dabei besonderes Augenmerk auf das Wechselspiel von textueller Abstraktion und filmischer Konkretion. In der kritischen Literatur zu Pasolinis filmischem Werk fällt der Begriff der Allegorie häufig. Doch obwohl die Allegorie als eine von Pasolinis grundlegenden poetischen Figuren erkannt wird, werden Begriff und Einsatz der Allegorie kaum näher analysiert. Dies holt diese Arbeit nach und setzt damit zugleich an jenem Aspekt von Pasolinis Filmen an, der nach wie vor als einer der interessantesten seines Werkes gilt: Pasolinis außergewöhnliche Zusammenführung einer überladenen, exponierten Zeichenhaftigkeit auf der einen Seite mit einer irreduziblen und emphatischen Körperlichkeit auf der anderen. Ausgehend von einem Überblick über die Geschichte der Allegorie und ihrer kontroversen Bestimmungen in Kunst-, Literatur- und Filmwissenschaften, arbeite ich im ersten Kapitel ein für den Film geeigneten Allegoriebegriff heraus. Darauf folgt eine Untersuchung von Pasolinis filmtheoretischen Schriften nach Anschlusspunkten für eine allegorische Praxis. Detaillierte Analysen der Filme Accattone (1961), Uccellacci e Uccellini (1966) und Porcile (1969) zeigen anschließend die Konsistenz, mit der sich Pasolini der Allegorie bedient hat, und geben zugleich Einblick in die Bandbreite, in der die Allegorie im Film wirken kann.

Abstract: This dissertation examines the allegorical practice in the films of Pier Paolo Pasolini, paying special attention to the question of textual abstraction and filmic concreteness. While critics often use the term allegory or allegorical when discussing Pasolini’s films, and even acknowledge the fundamentally allegorical nature of his poetical outlook in general, they rarely engage further in what this actually means. The allegorical mode more often than not is taken as a known term or, when explained further, reduced to only some of its aspects. In the following, I will start with a historical overview of the practice and aesthetic discussions of allegory and distill from it a definition of allegorical practice suited particularly to film. I will then analyze to what extent Pasolini’s own writings on cinema can be seen to reflect his allegorical practice. Detailed analyses of the films Accattone (1961), Uccellacci e Uccellini (1966) und Porcile (1969) subsequently show how consistently Pasolini employed allegory, and how differently it can be put into filmic play.

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.

Magnesium (Mg) is an important macronutrient for all living cells and is abundant in the environment. At the Earth’s surface its stable isotopes are fractionated by both abiotic (mineral dissolution, primary and secondary mineral formation from solution) and biotic processes (uptake into and translocation through organisms). The objectives of this doctoral thesis were to investigate, in controlled laboratory experiments, the fractionation of Mg stable isotopes during (1) uptake and translocation of Mg into microbes focusing on microbial species, cell physiology, and the dependence on pH; and (2) mineral dissolution under abiotic conditions and in the presence of a fungus. Given that large Mg fluxes pass through biological pools, the fingerprints I identified is useful for Mg cycling studies, and for tracing Mg pathways through ecosystems. To reduce the complexity of natural systems I conducted laboratory batch experiments using unicellular model organisms. Growth experiments showed a pH-dependence of Mg stable isotope fractionation during uptake by the rock-inhabiting microcolonial fungus Knufia petricola. The fungal cell was enriched in heavy Mg isotopes relative to the growth solution, where at pH 6 the 26Mg/24Mg ratio (expressed as δ26Mg) was 0.65 ± 0.10‰ higher than that in the growth solution, and at pH 3 δ26Mg was 1.11 ± 0.34‰ higher. In contrast, the cyanobacterium Nostoc punctiforme incorporated lighter Mg isotopes from the growth solution and the cells’ δ26Mg was -0.27 ± 0.14‰ lower than that of the growth solution. Chlorophyll extracted from the cyanobacterium, however, preferentially incorporated the heavier Mg isotopes, with a δ26Mg value that was 1.85 ± 0.14‰ higher than the growth solution. To explore how Mg metabolic pathways in these organisms set these isotope composition, a mass-balance model was designed. The results can be explained by three fractionation processes and the mass balance associated with them: (1) during uptake, where Mg with a slightly lower 26Mg/24Mg isotope ratio is preferred by cells; (2) during incorporation of a substantial portion (>95%) of intracellular Mg into Mg-bonded compounds (ATP, ribosomes and chlorophyll) where Mg with higher 26Mg/24Mg is preferred; and (3) during efflux and, possibly, additional fractionation of the remaining free Mg that obtains the 26Mg/24Mg isotope ratio complementary to that of the Mg taken up into the bonded compounds. In the fungus K. petricola the efflux rate of free Mg low in 26Mg/24Mg is high; this Mg gets replenished by Mg from the growth solution that is higher in 26Mg/24Mg. The bulk K. petricola cell Mg isotope signature is thus dominated by the isotopically heavy intracellular Mg bonded to compounds like ATP and ribosomes. The pH-dependence on Mg isotope fractionation observed in the fungus K. petricola cells is due to differences in fluxes of Mg entering and leaving the cell. The cyanobacterium N. punctiforme, in contrast, has large intracellular Mg inventories (10 times greater than K. petricola) and partitions almost all Mg entering into the cell into its bonded compounds. Therefore the bulk cell obtains the isotope composition of the Mg that entered the cell. As a result, an inverse relationship arises between cellular Mg concentrations and the bulk cell Mg isotope fractionation. This model explains published field and laboratory measurements of the Mg isotope composition of leaves, roots, bulk plant, fungi and cyanobacteria, which are also characterized by an inverse relationship between Mg concentration and bulk Mg isotope fractionation. I suggest that the model of cellular processes and Mg metabolic pathways thus developed is predictive of Mg isotope fractionation in ecosystems. Once the fractionation by the fungal cells was established, the rates and mechanisms of olivine (Mg,Fe)2(SiO4) dissolution in the presence of the fungus K. petricola were determined in laboratory batch experiments. After 94 days, olivine dissolution rates (1.04 × 10-15 moles cm-2 s-1) at pH 6 in presence of the fungus were seven-fold higher than in the abiotic control. Mg/Si ratios in the supernatant reflected an initial non-stoichiometric phase during which the dissolution rate was higher than the rate in a later stoichiometric phase. The initial non-stoichiometric phase was attributed to rapid exchange of Mg2+ with H+ along with simultaneous polymerization of Si tetrahedra, whereas the stoichiometric phase was attributed to the buildup of a Si-rich amorphous layer that acts to slow dissolution rates. Mg isotopic analysis of the supernatant in both abiotic and biotic experiment showed an enrichment in 24Mg relative to the mineral in the initial non-stoichiometric phase, interpreted to be due to kinetic isotope fractionation, while during the later stoichiometric phase the isotopic composition of the supernatant was similar to that of the dissolving olivine and thus dissolution was isotopically congruent. No difference in the temporal evolution of stoichiometry and isotope ratios was found between the biotic and the abiotic experiments. This similarity indicates that olivine dissolution mechanisms are identical whether fungus is present or not. However, I propose that the fungus accelerates olivine dissolution by (1) attachment of fungal cells to mineral surfaces that acidify the micro-environment of the contact zone by releasing protons; and (2) dissolving Fe(III) precipitates present in the Si-rich amorphous layer through chelation with siderophores excreted by the fungus. The accelerating effect on mineral dissolution by the fungus found in this study not only provides insights into biogenic mineral weathering but is also of relevance to the efficiency “enhanced weathering” employed as means of CO2 sequestration.

Das retinale Pigmentepithel (RPE) steht in direkter Interaktion mit Photorezeptoren. Die Ursache vieler degenerativer Erkrankungen des Auges ist daher mit einer Fehlfunktion vom RPE verbunden. Sekretorische Prozesse vieler Zelltypen werden über das Zusammenspiel spannungsabhängiger Kalzium- (Ca2+-) Kanäle und Rab- (Ras-related in brain) Proteinen, reguliert. Im RPE wird die Sekretion von Wachstumsfaktoren zur basolateralen Seite der Gefäßschicht über die Aktivierung von L-Typ-Ca2+-Kanälen vom Subtyp CaV1.3 sowie unteranderem von der GTPase, Rab27a, reguliert. Heterolog exprimierte CaV1.3/β3/α2δ1-Kanäle zeigten bei Koexpression mit Rab27a eine negative Spannungsabhängigkeit und eine um 70 % reduzierte Stromdichte. Die Oberflächenexpression von CaV1.3-Kanälen war bei Koexpression mit Rab27a nur um 10 % reduziert. Die Überexpression von Rab27a in einer humanen RPE-Zelllinie resultierte in einer Verschiebung der Spannungsabhängigkeit zu positiven Membranpotenzialen, einer Reduktion der Stromdichte endogener CaV1.3-Kanäle sowie einer verminderten Sekretion von vaskulären endothelialen Wachstumsfaktor (VEGF). Die Daten zeigen erstmals die direkte Modulation der Ca2+-Kanalaktivität durch Rab27a. Kennzeichnend für die Best`sche vitelliforme Makuladystrophie (BVMD), eine vererbbare autosomal-dominante Form der Makuladegeneration, ist der reduzierte Hellanstieg (LP) im Elektrookulogramm (EOG) von betroffenen Patienten. BVMD ist mit Mutationen im BEST1-Gen assoziiert. Das Genprodukt von BEST1, Bestrophin-1 (Best-1), ist ein integrales Protein der basolateralen Membran im RPE. Sowohl im EOG von Patienten nach Inhibierung von CaV1.3-Kanälen durch Dihydropyridin als auch im Elektroretinogramm im murinen CaV1.3-defizienten Modell ist ein reduzierter LP beschrieben worden. Die Hypothese, dass die Interaktion von Best-1 und CaV1.3-Kanälen von funktioneller Bedeutung für das RPE ist, und der schädigende Effekt von Mutationen im BEST1 durch die gestörte Interaktion des CaV1.3-Kanals und Best-1 entsteht, liegt somit nahe. Es wurden vier krankheitsassoziierte Missense-Mutationen im BEST1-Gen (R218C, T6P, F80L und F305S) untersucht. Alle Mutanten zeigten eine Interaktion mit dem CaV1.3/β4/α2δ-Kanalkomplex, obgleich die Effizienz in der Co-IP niedriger war als beim wildtypischen (WT) Best-1. Im heterologen Expressionssystem war die Stromdichte von CaV1.3-Kanälen in Anwesenheit der Mutanten reduziert und die Spannungsabhängigkeit in Anwesenheit von F80L und F305S verändert. Die verminderte Stromdichte korrelierte mit einer reduzierten Proteinlokalisation in der Plasmamembran, sowohl von mutanten Best-1 also auch von CaV1.3. In primären Schweine RPE-Zellen war mutantes Best-1 delokalisiert, was gleichzeitig in der Fehllokalisation von CaV1.3 und endogenem Best-1 resultierte. Zusätzlich waren T6P und F305S überwiegend apikal assoziiert. Die Ergebnisse konnten zusätzlich in humanen - aus induziert pluripotenten Stammzellen abgeleiteten - RPE-Zellen bestätigt werden. Die reduzierte Lokalisation von CaV1.3-Kanälen in der Plasmamembran könnte in einer verminderten Membranleitfähigkeit für Ca2+ resultieren, die wiederrum die sekretorische Aktivität vom RPE und die circadiane Regulation der Phagozytose modulieren könnte. Dies würde teilweise den reduzierten LP im EOG von BVMD-Patienten erklären.

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.

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.

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.

Understanding the formation and stabilization of Archean crust is important for our knowledge about geological processes that operated on the early Earth. The eastern Kaapvaal Craton in southern Africa represents a unique and well-preserved fragment of Paleo- to Mesoarchean continental crust that is ideal to shed some light on this conundrum. Hence, this dissertation aims to answer the following questions: I) Was the early Earth´s crust solely formed in the Archean or did Hadean crustal or mantle-derived material contribute to Archean crust formation?; if so, what was the nature of these Hadean reservoirs? II) How did the mantle sources that contributed material to crustal thickening evolve throughout the Paleo- to Mesoarchean, and in what kind of geological setting did this crust formation occur, early plate subduction or mantle plume-controlled magmatism? The methods applied to answer these two questions are major and trace element analysis in combination with analysis of the whole-rock 176Lu-177Hf, 147Sm-143Nd, and 146Sm-142Nd isotope systems. The long-lived 176Lu-177Hf and 147Sm-143Nd isotope systems were applied to trace mantle differentiation in the Archean, whereas the short-lived 146Sm-142Nd isotope system was applied to trace crust-mantle differentiation in the Hadean. To answer the first research question whether or not Hadean crust or mantle-derived material contributed to Archean crust formation, granitoids and amphibolites of the eastern Kaapvaal Craton, namely the Ancient Gneiss Complex (AGC) of Swaziland and the Barberton Greenstone Belt (BGB) in the Mpumalanga Province of South Africa were investigated for abundance variations of 142Nd. The well-preserved crustal and mantle-derived samples cover an age range from 3.66 to 3.22 Ga and are representative of major geological units of the AGC and the lower Onverwacht Group of the BGB. The investigated samples yielded μ142Nd values ranging from -8 ppm to +3 ppm with typical uncertainties smaller than ± 4.4 ppm, relative to the JNdi-1 terrestrial standard. The μ142Nd values of these 17 measured samples show a bimodal distribution with ten samples showing a tendency towards slightly negative μ142Nd anomalies and seven samples having μ142Nd values similar to the terrestrial reference. The only clearly resolvable μ142Nd anomalies were found in a 3.44 Ga Ngwane Gneiss sample of the AGC and in amphibolites of the ca. 3.45 Ga Dwalile Greenstone Remnant, infolded in the AGC, revealing μ142Nd values that range from 7.9 ± 4.4 to 6.1 ± 4.3 ppm. The μ142Nd deficits do not correlate with age, lithological unit, or sample locality. Instead, the mantle-derived rocks of the BGB and AGC were likely formed by derivation from two distinct mantle reservoirs that can be distinguished by their μ142Nd signatures. One mantle reservoir preserved the enriched 142Nd signature at least until 3.46 Ga, and one modern-like mantle reservoir that did not preserve a 142Nd signature. Furthermore, the granitoids showing negative μ142Nd anomalies likely formed by re-melting and incorporation of Hadean protocrustal material and preserved their negative μ142Nd signature at least until 3.22 Ga. However, it cannot be resolved whether the negative μ142Nd signature in this Hadean protocrustal material was ultimately derived from crust-mantle differentiation of a modern-like or from an already enriched mantle source. In contrast, the oldest gneisses showing no μ142Nd anomaly are up to 3.64 Ga in age, indicating that a modern terrestrial 142Nd reservoir was already present by early Archean times and coexisted with the enriched 142Nd mantle reservoir. To constrain the evolution of the mantle sources providing material to crustal thickening in the Paleo- to Mesoarchean, metabasalts and metakomatiites of the lower Onverwacht Group of the BGB, and ca. 2.9 to 2.8 Ga metabasalts collected in the vicinity of the Kubuta Ranch in central Swaziland (AGC) were investigated. The metabasalts of the 3.55 to 3.48 Ga Sandspruit and Theespruit Formations of the lower Onverwacht Group can be subdivided into three groups, based on their incompatible trace element characteristics: a light rare earth element (LREE) depleted group, a LREE-undepleted group, and a LREE-enriched group. Positive εHf(t) and εNd(t) values of ca. +3 to +4 and 0 to +2, respectively, together with depletions in Th and LaCN/YbCN below one for the LREE-depleted metabasalts indicate derivation from an incompatible element-depleted mantle source, possibly the ancient upper mantle. However, chondritic εHf(t) and εNd(t) values combined with positive Th and LaCN/YbCN of the LREE-enriched samples indicate a contribution from older AGC crust in the petrogenesis of these samples. Trace element patterns of metakomatiites and metabasalts of the 3.48 to 3.45 Ga Komati Formation of the lower Onverwacht Group are generally flat relative to primitive mantle, with slight depletions in heavy rare earth elements and Th and overall positive εHf(t) of +2.5 ± 3.5 (2s.d.) and εNd(t) of +0.5 ± 2.2 (2s.d.) for both metalava types. The similarity in trace element and Hf-Nd isotope characteristics suggests a common magmatic origin for the basalts and komatiites by high degrees of melting of an incompatible element-depleted mantle source containing residual garnet. Hence, the komatiites are interpreted as being plume generated, whereas the basalts are interpreted to be the products of fractional crystallization from the komatiitic parental magma. Based on the current data set, and in combination with previously published data, I propose a geodynamic evolution model for volcanic rocks of the lower Onverwacht Group that involves the evolution from a continent-type setting (for the Sandspruit and Theespruit Formations) to an oceanic setting (for the Komati Formation) as a consequence of continental rifting. The ca. 2.9 to 2.8 Ga Kubuta metavolcanic rocks are most likely genetically related to the ca. 3.0 Ga Usushwana Igneous Complex in west-central Swaziland and the ca. 2.9 Ga Hlagothi Complex located in KwaZulu-Natal Province of South Africa. The coeval ca. 3.0 Ga Nsuze and ca. 2.9 Ga Mozaan Groups of the Pongola Supergroup of south-central Swaziland and northern KwaZulu-Natal Province have similar elemental anomalies, albeit slightly elevated concentrations, compared to the Kubuta metavolcanic rocks. This study shows that the Nsuze and Mozaan Groups were sourced from komatiitic parental magmas derived from a weakly depleted mantle source, whereas the Usushwana, Hlagothi, and Kubuta units were sourced from a more depleted mantle reservoir comparable to modern depleted upper mantle. Prior to eruption, all mafic rocks underwent assimilation-fractional crystallization processes involving ca. 3.5 Ga crustal rocks of the AGC. Combining these geochemical observations with literature age data leads to a refined petrogenetic model for continental flood volcanism in a Mesoarchean large igneous province (LIP) on the eastern Kaapvaal Craton. This refined model includes the presence of two distinct mantle sources in the formation of this continental LIP – a deep mantle plume producing komatiite melts as well as ambient upper mantle producing more incompatible element-depleted melts such as the Kubuta rocks. Collectively, the Paleo- to Mesoarchean mantle-derived rocks investigated in this study record the transitional development from a submerged continental setting to an oceanic setting and back to a continental setting within a time period of about 600 Ma.

In vorliegender Arbeit wurden die biologische Aktivität einiger Fraktionen und gereinigter Stoffe aus Heilkräuter untersucht. GLP20 und JRP sind jeweils Polysaccharid-Fraktionen aus G. lucidum, bzw. T. aurantia lba. GLPss58 und JRP-SS sind die sulfatierten Fraktionen jeweils aus GLP20 und JRP. Sarg-Z ist Polysaccharide-Fraktion aus S. graminifolium. GLP20 und JRP-SS konnten den L-selektin-, Komplementssystem- oder Zytokin-vermittelte Entzündungsprozess herunterregulieren. Außer dem Anti-inflammatorischen Effekt zeigten GLPss58 und JRP-SS ein hohes Potential die Blutgerinnung verhindern zu können, insbesondere über den intrinsischen Weg. GLPss58 und JRP-SS zeigten auch einen Antitumor-Effekt, indem sie die Migration und Invation von Tumorzellen inhibieren und Wnt/ß-catenin-Signalweg in Melanomazellen aktivieren. Sarg-Z wies eine Multifunktion bei der Immunmodulation auf, sowohl bei der Aktivierung von Makrophagen und Lymphozyten, als auch bei der Regulierung von Entzündungsprozessen.

The rumen of cattle and sheep is a large fermentation chamber where symbiotic microbiota break down otherwise indigestible fibrous components of feed to short chain fatty acids (SCFA), which represent the most important energy source for ruminants. To obtain optimal conditions for ruminal fermentation, ruminal fluid needs to be buffered sufficiently to avoid acidic conditions, which involves buffering by bicarbonate (HCO3-) entering the rumen with saliva. Surprisingly, however, the buffering constants of the bicarbonate system have never been determined in ruminal fluid, compromising the ability to estimate the contribution of this system to ruminal buffering. Furthermore, ammonia can accumulate to toxic levels in the rumen due to fermentational deamination of protein and non-protein nitrogen. In part, this ammonia can be incorporated into high-grade microbial protein, but amounts exceeding microbial capacity must be absorbed from the rumen, hepatically detoxified and renally excreted, with detrimental consequences both for the protein efficiency of the ruminant and for the environment. Therefore, interest in identifying and characterizing the efflux pathway for ammonia from the rumen is considerable and enhanced by the fact that ruminal efflux of ammonia has long been known to involve absorption of the ionic form (NH4+) through a cation channel, thus contributing to elimination of protons and ruminal pH homeostasis. The present thesis aimed to answer two unsolved questions regarding to ruminal buffering: 1. What are the buffering constants for the bicarbonate buffering system in ruminal fluid? 2. What is the molecular identity of the transport protein that mediates the absorption of NH4+ from the rumen? The first part of the thesis focussed on the determination of the buffering constants of the bicarbonate system in ruminal fluid (Paper 1, Hille et al., 2016). In this open buffer system, ruminal protons are mainly buffered by HCO3- that enters the rumen with saliva or via secretion of the ruminal epithelium. To calculate the buffer capacity of ruminal fluid, the solubility of CO2 (α) and the equilibrium constant of CO2/HCO3- (pK) needed to be known, neither of which have previously been determined for ruminal fluid. Accordingly, ruminal fluid from cattle fed either hay or concentrate diets was investigated using both the classical Astrup technique and a newly developed titration technique. In both feeding scenarios, values were found to be similar to the values known for Ringer solution and human blood. The data show that SCFA- and HCO3- are the primary buffers in ruminal fluid and that at physiological levels of ruminal pH, HCO3- is almost completely converted to CO2, which leaves with eructation. This mechanism ensures both an efficient elimination of protons from the rumen, and the maintenance of the concentration gradient driving HCO3- secretion across the ruminal epithelium. Finally, the concept of base excess was introduced for ruminal fluid for the first time. The purpose of the second part of the present thesis was to identify and characterize possible transport proteins mediating the absorption of ammonium by the ruminal epithelium. Recent work shows that in vitro, ruminal transport of Na+ and NH4+ can be stimulated by certain agonists of the transient receptor potential family (TRP), and that the ruminal epithelium expresses mRNA for the bovine analogue of TRPV3 (bTRPV3) as a suitable candidate gene. The current thesis demonstrates that these modulators also stimulate the absorption of the essential nutrient Ca2+ in isolated ruminal epithelium in a dose dependent manner (Paper 2, Rosendahl et al., 2016). In a second step, the bTRPV3 channel was overexpressed in HEK-293 cells and characterized via the whole cell and single channel configuration of the patch clamp technique and via intracellular calcium imaging (Paper 3, Schrapers et al., 2018). It emerged that this channel reflects the properties of the conductance found in the native ruminal epithelium: the bTRPV3 conducts various cations, and the conductance of monovalent cations is modulated by the divalent cations and by TRPV3 agonists such as menthol and thymol. The conductance of different cations was measured using both the whole cell and single channel patch clamp technique, which revealed decreasing permeabilities in the order of NH4+ > Na+ > Mg2+ > Ca2+ > NMDG+. Furthermore, the application of various TRPV3 agonists increased Na+, NH4+ and K+ currents in the whole cell patch clamp configuration. Using intracellular calcium imaging, an increase in calcium influx after the addition of menthol could subsequently be found. The bovine TRPV3 should thus play an important role in mediating the ruminal transport of physiologically relevant cations such as Na+, K+, NH4+ and Ca2+. In summary, this thesis - determined the buffering constants for the bicarbonate buffer system in ruminal fluid for the first time, - demonstrated that TRP channel agonists can stimulate transport of Ca2+ across the native ruminal epithelium in vitro and - characterized the bovine representative of TRPV3 as an ion channel suitable for mediating the transport of Na+, K+ and NH4+ and Ca2+ across the rumen.

The kingdom of fungi comprises an enormous range of live styles and genetic variability. Different genomics approaches offer possibilities to investigate species diversity and ecological function of fungi. In this thesis I present improvements of metabarcoding methods for aquatic fungi and the application of whole genome sequencing and transcriptome sequencing to an exclusively aquatic fungus. Beside the standard metabarcoding marker for fungi, the ITS (internal transcribed spacer) region, the eukaryotic rRNA operon contains two other markers, the SSU (small subunit) and LSU (large subunit), that are also often used for metabarcoding. When choosing a metabarcode there is a tradeoff between high variability for fine grain species delineation and high conservation for good primer binding and high level classification of novel species, which are not represented in reference databases. In the work presented in chapter III, we investigated the possibility to use the information from the more conserved 5.8S sequence, that is part of many amplicons used for ITS2 sequencing. It is normally discarded, but we used it as a complementary marker to ITS2 and showed that it can improve classification of novel species with an incomplete reference database. In chapter IV this is taken one step further by using third generation sequencing to sequence the full ITS region together with the more conserved SSU and LSU in the same amplicon. This gives us the option to use different markers with different databases for classification in parallel and to circumvent the trade-off between high variability and high conservation. Fungi are ecologically very important decomposers of lignocellulose from plant biomass. The occurrence and expression of gene families for the degradation of lignin from lignocellulose has been extensively studied with whole genome and transcriptome sequencing in terrestrial, but not in aquatic fungi. In the work presented in chapter V, we used whole genome and transcriptome sequencing to investigate differential gene expression in the exclusively aquatic fungus Clavariopsis aquatica when grown on media with more and less lignin rich carbon sources and investigated the expression patterns of peroxidases, laccases and other protein families involved in plant biomass degradation. This observed up-regulation of laccases, peroxidases and genes from the cytochrome P450 super-family, as well as other gene families involved in cellulose and hemicellulose degradation, strongly suggests that C. aquatica is able to modify lignin to some extent; perhaps in order to facilitate the utilization of lignocellulose as a carbon and energy source.

Sudden death was observed in chimpanzees and gorillas in Côte d’Ivoire (Taï National Park) and Cameroon (Dja Reserve) in 2001 and 2004 and the causative agent was identified as a before unknown Bacillus anthracis-like bacterium designated Bacillus cereus biovar anthracis (Bcbva) (1, 2). Bcbva combines the chromosomal background of B. cereus with the virulence plasmids of B. anthracis and was shown to be as virulent as B. anthracis in small animal models (3). As part of an ongoing long-term study in Taï National Park (TNP), autopsies on all available deceased wildlife were performed and environmental samples were collected. Bcbva positive samples dated back up to 1991 and Bcbva was identified as a continuous cause of death for a number of large mammal species (4). The aim of the present study was to investigate the epidemiology and ecology of Bcbva in its natural rainforest habitat in TNP using a broad array of phylogenetic and serological methods. Bacterial isolates could be retrieved from various sample types (tissue samples, bones, carrion flies) and 178 whole Bcbva genomes were derived covering a period from 1996 to 2014. SNP-based phylogenomic analysis in a Bayesian statistical framework revealed that Bcbva chromosomes had measurably evolved over this time span. This allowed us to determine that the median time to their most recent common ancestor (tMRCA) was 146 years (95 % highest posterior density (HPD): 70-237) and that 0.2 new mutations are introduced in average per Bcbva chromosome/year. Bayesian Markov Chain Monte Carlo (BMCMC) analyses were run under several demographic models. No model outperformed a constant population size model, suggesting Bcbva population size did not vary much over this period. To further inform the latter, in vitro experiments were performed determining the whole genome mutation rate of Bcbva, which was shown to be comparable to the in vitro mutation rate of B. anthracis. Comparison of Bcbva evolutionary rate and in vitro mutation rate approximated hypothetical Bcbva activity to be in average 102 generations/year, pointing against a significant extra mammalian lifecycle of Bcbva.The whole genome sequencing data provided evidence for multiple co-existing transmission chains that appear to be localized within different areas of the park. Genomic and geographic distances were correlated, particularly when genomic distances were low, reflecting the carcass-mediated dynamics of the disease. To reveal further possible transmission pathways, carrion flies were trapped in the rainforest canopy and we were able to isolate Bcbva from flies caught up to 25m high. While we observe constant substantial pressure by Bcbva on the TNP fauna, only two monkeys were found to have significant amounts of antibodies against the disease in a serological study in five different wildlife species (n=59), indicating that Bcbva-infections in these species are likely often lethal. Combining data from TNP with sequence data from other sites of Bcbva occurrence revealed that Bcbva has been present in sub-Saharan Africa for millennia.

Die eingangs formulierte Fragestellung "Ist Gender Mainstreaming eine geeignete Strategie die Gleichberechtigung der Geschlechter, die Chancengleichheit von Frauen und Männern in Deutschland zu verbessern? Welchen Beitrag kann eine Bezirksverwaltung dazu leisten?" kann zusammenfassend wie folgt beantwortet werden:

Ja, Gender Mainstreaming ist unter bestimmten Bedingungen eine geeignete Strategie die Gleichberechtigung der Geschlechter, die Chancengleichheit von Frauen und Männern in Deutschland zu verbessern. Gute Bedingungen sind internationales Engagement und internationale Vorbilder (UN, EU). Der Bericht "Gender equality in the 2030 agenda for sustainable development" der UN beschreibt dazu aktuell, wie Gender Mainstreaming in den 17 Zielen für nachhaltige Entwicklung umgesetzt wird. Die EU gibt uns klare Vorgaben und entwickelt Gender Mainstreaming zu Equality Mainstreaming.

National wären politische Vorgaben und steuernde Gesetze mit finanziellen Anreizen und Sanktionen sinnvoll. Hier könnte ein Top-Down-Prinzip greifen. Die Bundesregierung vermeidet aktuell leider den Begriff Gender Mainstreaming, setzt stattdessen auf Einzelmaßnahmen und formuliert die "Entwicklung" einer "ressortübergreifende Gleichstellungsstrategie" .

Eine Bezirks- bzw. Kommunalverwaltung kann durch ein gutes Konzept und engagierte Akteur*innen einen lokalen Beitrag im eingeschränkten Rahmen ihrer Verwaltungsaufgaben leisten, indem sie sich auf die nationalen gleichstellungspolitischen Herausforderungen bezieht. Zum guten Konzept gehören Zielvorgaben, klare Zuständigkeiten und eine gute Kommunikation.

Shale is a complex medium composed of clay, other mineral phases and pore space. The combined elastic properties of these components control the effective (anisotropic) properties of the composite solid. Deformation of the compliant porosity (e.g. micro-cracks, joints, grain boundary domains, faults) impacts the relationship between effective stress and rock elasticity. This leads to nonlinear stress dependency of seismic velocities and seismic anisotropy. Such phenomenon is often observed for brittle and semi-brittle rocks like shales or other siliciclastic sediments. Description and understanding of this relationship is important for any time-lapse geophysical or geo-hazard modelling.

This thesis presents the experimental measurements and the theoretical modelling of the stress-dependent elasticity. Such a combination enables a direct comparison and validation of the theoretical approach. The porosity deformation approach is used for a physical interpretation of the stress-dependent seismic velocities. The main objective of this thesis was to validate the applicability of the theoretical approach on the experimentally obtained data. This includes analysis of the special role of the compliant porosity and its influence on the stress-dependent elasticity. For this purpose were studied various shale samples under uniaxial and triaxial stress conditions. Two of the studied samples were saturated and measured under drained loading conditions. The samples have either vertical transverse isotropy or initial horizontal transverse isotropy, and one of the samples was initially orthorhombic. These samples were loaded and their elastic properties were measured during the loading. The strain gauges measured the deformation and the piezoelements simultaneously measured the ultrasonic velocities. Thirteen conducted experiments provide a comprehensive data bank of the elastic parameters. The value of this data bank is enhanced by the mineralogical description of studied samples, including the thin section analysis and the density measurements.

The first part of the thesis introduces the theoretical background and the theoretical approaches, which were applied in the frame of this work. The second part of the thesis includes experiments under the uniaxial loading conditions and application of the theory on the obtained data sets. In this part were studied four anisotropic samples. Finally, the third part presents results of experiments under the triaxial loading conditions and an example of the application of the theory on the obtained data set. Five triaxially loaded samples include dry and saturated rocks with different initial anisotropy.

The interpretation and analysis of the laboratory measurements initiated development of additional theoretical approaches. One of them is the constant anellipticity approach and it is used for the estimation of the off-axis (under an inclination to the symmetry axis) velocity depending on the stress. Another approach is called: "orthorhombic anisotropy due to an imperfect disorder" and it is a qualitative explanation of the orthorhombic stiffness tensor observed for a visually layered sample. Application of these approaches completed the experimentally obtained data sets.

The collection of the experimental data bank with contribution of the theoretical estimations made possible application of the porosity deformation approach. This approach formulates stress-dependence of the velocities via stress-induced deformation of the pore space. The closure of the compliant (crack-like) porosity impacts the stress sensitivity of the velocities, and the shape of this stress-dependence is nonlinear. Hereby, the physical non-linearity is assumed to be controlled by the compliant pore space deformation and the geometrical non-linearity is considered to be negligible. The key parameters within the theory are the porosity tensor and the tensor of stress sensitivity. The former is anisotropic and the latter is assumed to be isotropic (according to the latest extension of the theory).

In the frame of this study, the theoretical modelling validates the applicability of the porosity deformation approach, and developed further understanding of the key parameters, their influence on the stress-dependency and their mutual relations. It was shown, that the uniaxial stress changes the anisotropy, but does not impact the anellipticity parameter. The study demonstrates the distinct influence of stiff and compliant porosities on the stress-sensitivity of the elastic properties. Particularly, the modelling of the uniaxial experiments validate the different deformation mechanisms for the stiff and compliant porosities, depending on the direction of the stress application. The modelling of the triaxial data set approved universality of proposed theoretical description and provides an opportunity for a prediction of the stress-dependent elasticity.