Proprioception, the sense of body position in space, is critical for generating coordinated movements and reflexive actions. Proprioceptive sensory neurons (pSN) reside in the dorsal root ganglia and constantly monitor muscle stretch and tension with their mechanoreceptive organs (muscle spindles and Golgi-tendon organs) and relay this information to central circuits that generate coordinated motor actions. In particular, group Ia pSN afferents (muscle spindle) provide direct sensory feedback to motor neurons controlling the activity of the same muscle while avoiding motor neurons of antagonistic muscle groups. This precise connectivity pattern represents the basis of the stretch reflex arc and suggests the existence of proprioceptor subtypes defined by the muscle they innervate. However, molecular programs controlling critical aspects of pSN subtype identities, such as the central and peripheral connectivity, are mainly unknown. In this study, we devised a single-cell transcriptomic approach that takes advantage of the topographic organization of the pSN system to reveal molecular features of cardinal proprioceptor subtypes defined by their connectivity to limb, back, and abdominal muscles. First, we identified and validated molecular signatures for each pSN muscle-type population. Second, we found that molecular programs defining these identities are acquired early in development and maintained until early postnatal stages. Last, we discovered distinct expression patterns of axon guidance molecules of the ephrin-A/EphA family that distingush axial- and limb-pSN. In particular, we found that the absence of ephrin-A5 affects the peripheral connectivity of limb-pSN with specific hindlimb muscles, thus implying an important role for ephrin-A signaling in controlling the assembly of sensorimotor circuits. Altogether, this work reveals the molecular foundation of pSN muscle-type identity and paves the way for studying the development and function of muscle-specific sensory feedback circuits.

Marek’s disease virus (MDV) is a highly contagious alphaherpesvirus that causes neurological disorders, immunosuppression, and deadly lymphomas in chickens. The virus causes substantial economic losses in poultry production worldwide due to high mortality rates and the costs of the vaccination. Despite the widespread use of live attenuated vaccines that provide excellent protection against clinical disease, the virus still infects vaccinated animals and continuously evolved towards a higher virulence. MDV encodes many viral factors, from proteins to non-coding RNAs, which orchestrate the complex viral lifecycle and/or contribute to pathogenesis. Several MDV-specific genes have been shown to be involved in viral pathogenesis and tumorigenesis. Comprehensive MDV transcriptome analyses revealed that the coding capacity of the MDV genome is far greater than previously anticipated and identified some putative MDV-specific genes and splice isoforms. In-depth characterization of the genetic factors of MDV is an essential step toward understanding the complex viral lifecycle, from viral infection, lytic replication, latency, to tumor formation. Here, we set out to assess three MDV-specific hypothetical genes (MDV082, RLORF11, and SORF6) and a putative vIL-8 exon (vIL-8-E3′). Using FLAG-tagged recombinant viruses based on the very virulent MDV strain RB1B, we identified a novel protein encoded by MDV082 and a novel spliced vIL-8-E3′protein. We demonstrate that the novel pMDV082 and vIL-8 splice variant are not essential for virus replication, spread, and tumor formation, but pMDV082 contributes to the rapid onset of Marek’s disease. These studies shed light on the expression of MDV-specific genes and the splice forms of the CXC chemokine and unraveled the role of pMDV082 in MDV pathogenesis. In addition to viral virulence factors, the lymphomagenic properties of oncogenic MDV is also directly linked to viral integration, a process which occurs during the establishment of viral latency. Telomeric repeat arrays present at the ends of the MDV genome facilitate this integration into host telomeres, but the integration mechanism remains poorly understood. To shed further light on the MDV integration mechanism, we developed and validated a cell culture-based integration assay, providing an optimal basis for investigating the role of viral and cellular factors that could be involved in the integration of MDV.

HERVs sind Sequenzen von exogenen Retroviren, die vertikal über die Keimbahnzellen vererbt werden. In gesunden Zellen wird die Expression epi-genetisch kontrolliert. Unter bestimmten pathophysiologischen Bedingungen (Tumore und Autoimmunerkrankungen) kann jedoch eine Reaktivierung er-folgen. In diesem Fall werden virale Partikel gebildet, sodass eine de novo Infektion oder eine Retrotransposition möglich sind. Im Zuge der Arbeit wurden deshalb diverse Restriktionsverfahren analysiert. Zunächst wurde der inhibitorische Effekt der verschiedenen zellulären Rest-riktionsfaktoren (APOBEC 3G und PYHIN-Proteine) auf die HERV-K(HML-2)-Partikelproduktion untersucht. Die erhaltenen Ergebnisse belegen, dass die nukleären PYHIN Proteine MNDA und IFIX, ebenso wie IFI16, die HERV-K(HML-2)-Partikelproduktion signifikant reduzieren. Darüber hinaus wurde im Rahmen der Arbeit nachgewiesen, dass durch die Expression von HERV-K(HML-2) eine Stressreaktion mit einhergehender Ausbildung einer Stressgranula erfolgt. Durch die Ausbildung der Stressgra-nula wird die zelluläre Proteinexpression herunter reguliert und somit auch die virale Proteinsynthese beeinflusst. Die gewonnenen Daten belegen, dass im Gegensatz zu HIV-1, HERV-K(HML-2) dies nicht unterbinden kann. In einem weiteren Teil der Arbeit wurde untersucht, welche antiretroviralen HIV-1-Medikamente die HERV-K(HML-2)-Infektion und die Bildung von reifen viralen Partikeln inhibieren können. Dafür wurden VSV-G-pseudotypisierte infektiöse HIV-1- und HERV-K(HML-2)-Viren mit einem GFP-Reporter her-gestellt und humane Zelllinien in der Anwesenheit von verschiedenen Inhi-bitorkonzentrationen (NRTI, NtRTI, NNRTI & Integraseinhibitoren) infiziert. Die Proteaseinhibitoren wurden während der Herstellung der Viren hinzuge-geben. Es konnten nukleosidische und nukleotidische reverse Transkriptas-einhibitoren sowie Integraseinhibitoren mit hoher Aktivität gegenüber HERV-K(HML-2) identifiziert werden. Alle getesteten NNRTIs und Proteaseinhibito-ren zeigten keine Aktivität gegen HERV-K(HML-2).

Mit dem ersten Abschnitt der Arbeit sollte ein Einblick in die Fütterung, Haltung und das Managements von Transitkühen in deutschen Milchviehbetrieben gegeben werden. Zu diesem Zweck wurde das Transitkuhmanagement beim Einsatz saurer Salze in 18 ostdeutschen Milchviehbetrieben untersucht. Jeder Betrieb wurde zweimal im Abstand von 14 Tagen besucht. Während der zwei Betriebsbesuche fand in den 18 Betrieben eine eingehende Charakterisierung statt. Im Rahmen dessen wurde neben den allgemeinen Betriebsdaten, (1) die Haltung, (2) die Stallform, (3) die Fütterung und (4) die Tiergesundheit von trockenstehenden Kühen, hochtragenden Färsen und Frischmelkern beurteilt. Dafür wurde in den Milchviehbetrieben unter anderem die Belegungsdichte in den Transitgruppen bestimmt. Weiterhin wurde in jedem Betrieb bei mindestens 12 Tieren in der Vorbereitergruppe die pHWerte, Netto-Säuren-Basen-Ausscheidungen (NSBA) und die Calciumkonzentrationen im Harn sowie die NEFA- und BHB-Konzentrationen im Blut analysiert. Zur Überwachung des Fütterungsmanagements wurde die TMR bezüglich der Inhaltsstoffe, Misch- und Verteilungsgenauigkeit analysiert, die Futterselektion sowie die Trockenmasseaufnahme in den Transitgruppen bestimmt. Des Weiteren wurde zur Überprüfung des Futtertischmanagements in den Gruppen der Vorbereiter und Frischmelker eine Zeitrafferkamera installiert. Es konnten einige praxisrelevante Schwachstellen des Herdenmanagements aufgedeckt werden. Im Rahmen der betriebseigenen Kontrolle und Überwachung des Einsatzes saurer Salze besteht großer Handlungsbedarf. Es ist dringend notwendig, die Ansäuerung der Vorbereiterkühe mittels regelmäßiger Harn-pH-Kontrollen zu überprüfen. Dies erfolgte in nur 2 von 18 untersuchten Milchviehbetrieben. Die fehlende Überwachung der Ansäuerung spiegelte sich deutlich in den pH-Werten, der NSBA und den Calciumkonzentrationen im Harn wider. In nur 6 der 18 untersuchten Herden lag der durchschnittliche Harn-pH zu beiden Untersuchungszeitpunkten in dem Zielbereich von 5,8 bis 7,0. Des Weiteren konnte in den untersuchten Vorbereitergruppen eine große Variation der pH-Werte sowohl innerhalb einer wöchentlichen Stichprobe (n ≥ 12 Tiere) als auch zwischen den wöchentlichen Stichproben festgestellt werden. Außerdem waren mehr als 50 % der untersuchten Vorbereitergruppen überbelegt, wodurch den Tieren kein adäquates Angebot an Fressplatz, Tränkeplatz und Liegeplatz zur Verfügung stand. Durch die Auswertungen der Zeitrafferkameras konnte gezeigt werden, dass die Tiere in den Transitgruppen keinen permanenten Zugang zu Futter hatten und dass die Dauer des Futterentzuges sehr lang war. Nur in vereinzelten Vorbereiter- und Frischmelkergruppen (1/18 und 2/13) konnte den Tieren ein nahezu permanenter Futterzugang gewährleistet werden. Zudem war die Wasserversorgung in 75 % der untersuchten Transitgruppen (43/57) nicht ausreichend. Die daraus resultierende Konkurrenz um Futter, Wasser und Liegeplätze kann zu einem erhöhten Stresslevel führen und negative Auswirkungen vor allem für rangniedrige, kleinere und jüngere Färsen und Kühe auf ihre Gesundheit und Leistung haben. In 16 Betrieben stellten die Abkalbeställe Gruppenhaltung von 2 bis 15 Tieren dar. Zudem war in 6 Betrieben, abgesehen von der Umstallung zur Kalbung in einen dafür vorgesehenen Abkalbestall, eine Umstallung der Tiere während der Vorbereitungsdauer (≈1 bis 10 Tage) fest in das Transitkuhmanagement etabliert. Diese können aufgrund des damit verbundenen Stressniveaus zu einer verringerten Trockenmasseaufnahme, Liegezeit sowie Milchproduktion führen. Die Prävalenz der Hypocalcämie (< 2,0 mmol/L) betrug in der Gesamtheit der untersuchten Milchviehbetrieben (n = 18) 32,8 % (63/192). In 4 von 18 Herden war die Prävalenz hypocalcämischer Tiere als problematisch einzuordnen (> 41,7%). Die erhöhte Prävalenz der subklinischen Ketose in den untersuchten Betrieben (38,4 %) lag über den Angaben der internationalen Literatur. Die Ergebnisse der Arbeit zeigen, dass der Einsatz saurer Salze zur Optimierung der peripartalen Calciumhomöostase hohe Anforderungen an das Herdenmanagement, insbesondere im Rahmen der Haltung und Fütterung, stellt. Bei der Anwendung einer Anionenration ist die wöchentliche Bestimmung des Harn-pH zur Kontrolle des erreichten Ansäuerungsgrades in der Herdenüberwachung von großer Wichtigkeit. Dem Herdenmanagement wird auch bezüglich der Ketoseprävalenz eine große Wichtigkeit zugeschrieben. Deshalb sollte die Aufmerksamkeit vor allem, durch permanenten Futterzugang sowie Minimierung des sozialen und umweltbedingten Stressniveaus der Tiere, auf der Optimierung der Trockenmasseaufnahme und Energiezufuhr liegen. Mit dieser Arbeit konnte gezeigt werden, dass im Rahmen des Transitkuhmanagement beim Einsatz saurer Salze in ostdeutschen Milchviehbetrieben Optimierungsbedarf besteht. Das Ziel des zweiten Teils der Arbeit war es herauszufinden, inwieweit beim Einsatz saurer Salze die Verweildauer in der Vorbereitungsgruppe die Tiergesundheit und Milchleistung in der nachfolgenden Laktation beeinflusst. Während des Beobachtungszeitraumes, haben in den 18 untersuchten Betrieben 20.373 Tiere gekalbt. In die finale statistische Auswertung wurden insgesamt 13.314 Tieren (3.871 Jungkühe und 9.443 Altkühe), eingeschlossen. Es konnte eine große Variation der Vorbereitungsdauer zwischen den Betrieben beobachtet werden. Bei Erstlaktierenden bestand ein linearer Zusammenhang zwischen der Verweildauer in der Vorbereitergruppe und der Einsatzleistung (P < 0,001). Eine Vorbereitungsdauer von 35 bis 36 Tagen war mit der höchsten Einsatzleistung (35,45 kg/Tag; 35,43 kg/Tag) assoziiert. Erstlaktierende mit einer Vorbereitungsdauer von 35 Tagen hatten eine 3,47 kg höhere Einsatzleistung als Erstlaktierende mit einer Vorbereitungsdauer von 7 Tagen. Mehrkalbskühe mit einer Vorbereitungsdauer von 26 Tagen verzeichneten die höchste Einsatzleistung (41,64 kg ± 0,33 SEM). Mehrkalbskühe mit einer Vorbereitungsdauer von 26 Tagen hatten eine 2,9 kg höhere Einsatzleistung als Mehrkalbskühe mit einer Vorbereitungsdauer von 7 Tagen. Ein Plateau der Milchleistung konnte bei einer Vorbereitungsdauer von 22 bis 29 Tagen beobachtet werden. Bei einer Vorbereitungsdauer über 29 Tage hinaus nahm die Einsatzleistung der Mehrkalbskühe jedoch wieder leicht ab. Zwischen der Vorbereitungsdauer und dem Fett-Eiweiß-Quotienten der Mehrkalbskühe bestand ein linearer Zusammenhang (P< 0,001). Der Fett-Eiweiß-Quotient stieg bei einer langen Vorbereitungsdauer leicht an. Die Vorbereitungsdauer hatte bei Erstlaktierenden (P = 0,005) und Mehrkalbskühen (P = 0,011) einen signifikanten Einfluss auf den Gehalt an somatischen Zellen in der Milch. Je länger die Verweildauer der Kühe in der Vorbereitergruppe war, desto höher war der somatische Zellgehalt in der Milch am Tag der ersten MLP. In der vorliegenden Arbeit bestand weder bei den Erstlaktierenden noch bei den Mehrkalbskühen ein signifikanter Zusammenhang zwischen der Vorbereitungsdauer und dem Risiko für eine Totgeburt. Die Vorbereitungsdauer hatte einen signifikanten Einfluss auf die Merzungsrate innerhalb der ersten 60 Tage in Milch für Mehrkalbskühe (P = 0,025). Die Mehrkalbskühe verzeichneten bei einer Verweildauer von 1 bis 6 Tagen in der Vorbereitergruppe das größte Risiko für einen vorzeitigen Abgang. Es konnte weder bei Alt- noch bei Jungkühen ein signifikanter Zusammenhang zwischen der Vorbereitungsdauer und der Länge der Güstzeit innerhalb der ersten 150 Tage in Milch festgestellt werden. Eine kurze Vorbereitungsdauer sollte zur Steigerung der Einsatzleistung und Minimierung des Merzungsrisikos der Mehrkalbskühe vermieden werden. Wiederum hat eine lange Vorbereitungsdauer (> 30 Tage) negative Effekte auf die Einsatzleistung und Milchinhaltsstoffe der Mehrkalbskühe und auf den Zellgehalt in der Milch bei Erstlaktierenden und Mehrkalbskühen. Demnach könnte für Mehrkalbskühe eine Vorbereitungsdauer von 22 bis 29 Tagen unter Einsatz saurer Salze als optimal angesehen werden. Für die Färsen besteht ein linearer Zusammenhang zwischen der Vorbereitungsdauer und der Einsatzleistung. Bei den Kühen als auch bei den Färsen sollte eine Vorbereitungsdauer von < 7 Tagen vermieden werden.

The probiotic Enterococcus faecium NCIMB 10415 (hereafter called E. faecium) is a licensed feed additive for pigs in the EU. Piglets supplemented with E. faecium showed a decreased incidence and severity of post-weaning diarrhea in previous studies. The main cause of postweaning diarrhea in piglets is infection with enterotoxigenic Escherichia coli (ETEC). However, the underlying cellular mechanisms of the protective effects of E. faecium against ETEC infection have only rarely been analyzed. Therefore, the present study investigated the effects of the probiotic E. faecium on epithelial barrier properties and cytokine expression in the intestinal porcine epithelial cell line J2 (IPEC-J2) during an infection with ETEC in vitro. A decrease of the transepithelial electrical resistance (Rt) in ETEC-infected cells was detected that was not seen in cells pre-incubated with E. faecium. These observations confirmed the results of a former study conducted at our institute. The expression of tight junction (TJ) proteins analyzed in the present study was not influenced by incubation with the bacterial strains. However, a modulation of the cell structure was seen in ETEC-infected cells, i.e. cells arranged on top of each other, indicating increased cell shedding. This was not seen in ETEC-infected cells pre-incubated with E. faecium. The rate of apoptosis was not modulated by ETEC. However, the cytotoxicity that significantly increased in ETEC-infected cells, was ameliorated by pre-incubation with E. faecium. At the mRNA level, ETEC upregulated the proinflammatory cytokine tumor necrosis factor (TNF)-α and increased the release of the cytokines TNF-α, interleukin (IL)-1α, and IL-6 at the protein level. A protective effect of the probiotic could be detected for the ETEC-induced increased TNF-α mRNA expression and IL-6 protein release. Both were decreased by preincubation of cells with E. faecium. The second messenger 3′,5′-cyclic adenosine monophosphate (cAMP) was also elevated by ETEC, but this was counteracted in cells preincubated with E. faecium. In a further part of the present study, the inflammasome was analyzed as a potential mediator of probiotic effects. First, the basal expression of inflammasome components was analyzed at the mRNA level in the intestine of piglets and fattening pigs. The expression of nucleotidebinding oligomerization domain-like receptor protein 3 (NLRP3), NLRP6, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase-1, IL-1β, and IL-18 was detected in the jejunum, ileum, and colon of pigs. A characteristic expression pattern was revealed for NLRP6, ASC, and caspase-1 in 29-day-old piglets that showed a decreasing expression of these components in an oral-aboral direction. Such expression pattern could not be detected in 70-day-old fattening pigs. Furthermore, the effects of the probiotic E. faecium on the mRNA expression of inflammasomes and inflammasome components were analyzed in a feeding trial. Piglets supplemented with E. faecium showed increased mRNA expression of ASC in the jejunum. The mRNA expression of NLRP3, NLRP6, caspase-1, IL-1β, and IL-18 was not modulated by the probiotic. In order to analyze probiotic effects during an infection with a pathogen, the jejunum of 80-dayold pigs was incubated with E. faecium, ETEC, E. faecium and ETEC, or without bacteria in an Ussing chamber experiment ex vivo. The mRNA expression of the inflammasome components was not modulated by the bacterial strains. However, at the protein level, the release of IL-1β was significantly increased by ETEC. A protective effect was found for the probiotic E. faecium. ETEC-induced increased release of IL-1β protein was significantly reduced by pre-incubation with E. faecium. In conclusion, several protective effects of the probiotic E. faecium have been detected at the cellular level during ETEC infection in the present work. The probiotic effects were mediated via the reduced decrease in Rt, the downregulated expression and release of inflammatory cytokines, the decreased intracellular concentrations of cAMP, the maintenance of the physiological epithelial cell structure, and the lessening of cytotoxic effects during ETEC infection. A characteristic oral-aboral expression pattern was revealed for the inflammasome NLRP6 and the inflammasome component ASC and caspase-1 in the intestine of piglets. The detected expression pattern was similar to the expression pattern in humans thereby reinforcing the use of pigs as an animal model for preclinical and translational inflammasome research. Pre-incubation with E. faecium reduced the ETEC-induced release of IL-1β protein. IL-1β release is associated with inflammasome activation. Hence, the present study provides evidence for the inflammasome as a mediator of protective probiotic effects at the functional level during infection with ETEC ex vivo. The protective effects of E. faecium demonstrated in this study represent important findings concerning the cellular mode of action of the probiotic during ETEC infection. Based on these findings, the prophylactic use of E. faecium can be considered for the reduction of the incidence and severity of ETEC infections in piglets as a very promising strategy. The latter has the potential to decrease the necessity of the therapeutic use of antibiotics in pig farming.

Groundwater is the primary source of drinking water in India, and the Chennai River Basin (CRB) is no exception. However, available resources of both groundwater and surface water, are constantly decreasing because of overexploitation and contamination. Well fields in the northern part of the CRB control the water supply for the region, including the Chennai Metropolitan Area (CMA), the capital of the state of Tamil Nadu. Thus, any changes in groundwater storage and availability in the basin directly affect the 11-million people who live in the CMA. So, even though the focus of this study is on the CMA, the entire basin must be considered in order to understand the hydrogeological condition and groundwater situation. This research aims to provide a holistic study of the topographic condition of the basin, the amount of water stress, the identification and mapping of the groundwater potential zones, a review of the groundwater recharge estimation techniques on national scale, and most importantly, the creation of an estimate of the natural groundwater recharge in the CRB and how climate and landuse patterns affect the recharge process.

A critical review has been made of popular groundwater recharge estimation practices. The suitability of each method is found to be dependent on time-space, hydrogeological condition, and data availability. Considering the hydrogeological and climatic conditions, the Water Table Fluctuation (WTF) method is the most appropriate method of recharge estimation. Groundwater recharge is largely controlled by topographical factors such as morphometric and hypsometric analysis and understanding these factors is necessary in water resource development planning. Shuttle Radar Topographic Mission (SRTM) and Digital Elevation Model (DEM) data were used in the Geographical Information System (GIS) platform to derive the morphometry and hypsometry. The CRB is an elongated basin of the 7th order and has been classified into 11 sub-basins. Major linear, areal and relief aspects were calculated and discussed based on their hydrologic significance. Steep slopes in the basin may affect the infiltration rate and, subsequently, recharge. Hypsometric curves show the concave type for most of the sub-basins, indicating an old stage. These results provide vital information about the hydrological conditions of the basin.

Protecting the resource from depletion and identifying potential zones is essential for sustainable development. Remote Sensing (RS) and GIS technologies with field data were used to map groundwater potential zones in the CRB. For the most accurate results, a total of 11 controlling factors were brought into the GIS platform and a multi-criteria decision making (MCDM) tool, Analytical Hierarchal Process (AHP), was also used. Based on this analysis, groundwater potential zones were classified into five categories- very poor, poor, moderate, good, and very good. The final groundwater potential map showed that 35% of the total area has good to very good groundwater potential, 27% has moderate potential, and 38% has poor to very poor potential. Comparison of the specific capacity obtained from borehole data with these results showed that the predicted groundwater potential identified in this study matches 80% of the area.

Groundwater potential depends on climatic conditions such as droughts, atmospheric temperatures, and monsoonal patterns. Using long-term temperature and rainfall data, meteorological drought has been calculated and agricultural drought has been determined using NDVI, NDWI and VCI indices. Agricultural drought indices showed that the vegetation is healthy in the northern and southern regions. However, more than 40% of the area was found to be water stressed. The calculation was made on a decadal scale and the highest water stress was observed in the year 2010. Agricultural drought is more prominent than meteorological drought in the CRB.

Chennai faces a severe water shortage in the summer season and flooding in the rainy seasons. The groundwater recharge rate for the Chennai River Basin has been estimated using the empirical method, the rainfall infiltration (RIF) technique, a GIS based distributed model, and the Water Table Fluctuation (WTF) method. The average groundwater recharge rates for different methods vary, with results of 196mm/ year (Empirical formula), 127mm/year (WTF method) and 122mm/year (RIF method). The ratio of effective recharge to rainfall is found as 10% for RIF and WTF methods and 16% using the empirical formula. Considering the conditions in India, as recommended by the Groundwater Estimation Committee (GEC), the WTF method was found to be the most reliable. Still, using multiple methods is suggested for a more fully accurate estimate.

This is one of the first extensive studies that covers aspects such as terrain characteristics, proposing the most suitable groundwater recharge estimating methods, groundwater potential zone identification, water stress analysis and natural groundwater recharge estimations in the Chennai River Basin. During this study, large amount of field data on water level, atmospheric temperature, rainfall, and aquifer parameters was collected from different institutions and brought into a single scale. All this data has been brought into the GIS platform and created maps. Thus, a baseline has been created for future groundwater studies. After considering variable recharge estimates and the effective recharge ratio (approx. 10%), it is suggested that groundwater recharge be improved either by repairing existing structures or implementing artificial recharge structures based on the groundwater potential identified. This thesis contains both basic and advanced levels of scientific information, all that is necessary for policymakers to begin improvements, and even provides a number of recommendations for the most effective approach to groundwater management.

Asymmetric dimethylarginine (ADMA) is a well-established cardiac biomarker in humans. The purpose of this prospective study was to investigate if measuring serum ADMA concentration via ELISA allows detection of cardiac disease in horses. In this context, ADMA reference values in horses were established. Furthermore, a change in ADMA serum concentration before and after a 160 km endurance race was assessed and the differences in ADMA concentration between horses that completed the race and horses that did not was evaluated. For this propose 78 horses with no known medical history were compared to 23 horses with confirmed structural cardiac disease with or without arrhythmias. Horses with heart disease were staged based on the severity of cardiac disease from I to II. Furthermore, 52 healthy endurance horses competing in a 160 km race were assessed. The endurance horses were assigned to three groups: horses that successfully completed the race, horses that failed to qualify at the veterinary check for primarily metabolic reasons and horses that failed to qualify at the veterinary check for primarily gait related reasons. The latter two groups were combined to form a final group of “non-finishers” that were excluded for either “gait related” or “metabolic” disorders. Horses underwent physical examination, electrocardiography, echocardiography, and venous blood sampling. In the endurances horses venous blood samples were taken before and after the endurance race. Asymmetric dimethylarginine was measured via ELISA, with a subset cross-checked using liquid chromatograph triple quadrupole mass spectrometry. Reference intervals with 90th percent confidence intervals were established according to ASVCP-guidelines. Standard software was used to test for significant differences in ADMA, and the L-arginine/ADMA ratio between groups. The reference range for ADMA in healthy horses was 1.7 - 3.8 μmol/L. Serum ADMA was higher in horses with heart disease compared to healthy horses (p<0.01) and highest in horses with stage II heart disease (p=0.02). However, only a few horses with stage II heart disease exceeded the reference range. The L-Arginine/ADMA ratio was significantly lower in healthy animals than in those with cardiac disease (p=0.001). ADMA (p=0.002) increased significantly after the endurance race in the finisher group. The longer the completed distance the higher was the ADMA concentration. No differences between the groups “finisher”, “metabolic” or “gait related” could be found. This study confirms the association between heart disease and increased serum ADMA concentration as well as a decreased L-Arginine/ADMA ratio in horses. Regardless of clinical assessment, there was a strong correlation between ADMA concentration and the completed distance in endurance horses. Our results did not support our hypothesis that ADMA would be higher before racing or increase more after racing in horses that failed to complete the race. Although the physiological reasons for higher serum ADMA concentration in horses with cardiac disease and horses completing a 160 km endurance race remain elusive, this study demonstrates that ADMA is a promising biomarker not just in humans, but also shows diagnostic potential in identifying cardiac disease respectively cardiac stress in horses under routine conditions.

Die Dissertation arbeitet Grundlagen zum Verständnis von Hate Speech und der Subversion verletzender Worte aus. Im 1. Kapitel wird anhand einer Untersuchung von fünf empirischen Interventionen gegen verletzende Worte (zwei Interventionen gegen Hate Speech an Berliner Universitäten, Hate Poetry, Kanak Sprak und Kanak Attak) eine Unterscheidung zwischen prohibitiven und subversiven Interventionen eingeführt. Anschließend werden die Vorzüge subversiver Interventionen herausgearbeitet. Im 2. Kapitel wird Derridas Konzept der Iterabilität systematisch rekonstruiert und weiterentwickelt, indem es mit einem Präzedenzfallmodell sprachlicher Praxis zusammengeführt wird. Auf dieser Grundlage wird die Möglichkeit subversiver Praktiken mit verletzenden Worten erklärt, und Butlers Konzeption der subversiven Resignifizierung wird weiterentwickelt. Im 3. Kapitel wird auf der Grundlage einer Weiterentwicklung von Austins Unterscheidung zwischen illokutionären und perlokutionären Sprechakten eine Unterscheidung zwischen einer sozialen und einer psychisch-somatischen Dimension sprachlicher Verletzungen eingeführt. Auf Grundlage dieser Unterscheidung werden die Möglichkeiten des Scheiterns und der Subversion verletzender Worte erklärt und differenzierte Positionen zu sprachpolitischen Debatten entwickelt. Im 4. Kapitel werden soziale Faktoren herausgearbeitet, die relevant dafür sind, dass subversive Praktiken mit verletzenden Worten vollzogen werden können und erfolgreich wirksam werden. Hierfür werden rhetorische Tropen, Verkörperungsformen, soziale Positionierungen und Diskurse untersucht. Es wird gezeigt, inwiefern die sozialen Faktoren selbst durch Iterabilität konstituiert und insofern veränderbar sind. Im 5. Kapitel werden schließlich die akteursbezogenen Faktoren der Subversion verletzender Worte untersucht. Hierfür wird Bourdieus Konzept des Habitus rekonstruiert und mit der Logik der Iterabilität zusammengeführt. Damit wird Handlungsfähigkeit gegenüber verletzenden Worten auf Grundlage von Iterabilität, Reflexivität und rhetorischen Tropen erläutert.

Vessel calcifications are a main risk factor for the development of cardiovascular diseases, a leading cause of morbidity and mortality in western societies. Even though vascular calcifications have been researched for centuries, patients still suffer from a huge therapeutic gap, because neither an effective prophylaxis, nor an effective treatment is available. Currently, consent exists that vascular calcification is an active cellular process that resembles bone formation. Vascular Smooth Muscle Cells (VSMCs) and their transdifferentiation into osteoblast like cells are considered decisive in the formation of vascular calcifications. Several stimuli can induce osteoblastic transdifferentiation, including cellular aging processes, oxidative stress and inflammation. These factors can be linked into a concept termed inflammaging via the formation of damage associated molecular patterns, persistent DNA damage and induction of a senescence associated secretory phenotype. The objective of this dissertation was to analyse the effects of the cellular stressors Azathioprine and Doxorubicin and the pro-inflammatory cytokine interleukin 1ß on the induction of osteoblastic transdifferentiation of VSMCs and vascular calcification in different experimental settings. The cellular stressors induce the formation of reactive oxygen species, cellular senescence, secretion of pro-inflammatory cytokines such as interleukin 1ß and interleukin 6, upregulation of NLRP3 inflammasome components as well as osteoblastic transdifferentiation and calcification of VSMCs. Stimulation with interleukin 1ß induced a pro-inflammatory auto-loop, osteoblastic transdifferentiation and calcification of VSMCs, but did not induce markers of senescence in VSMCs apart from components of the cellular senescence associated secretory phenotype. For both, cellular stressors and interleukin 1ß, the NLRP3 inflammasome is decisively involved in the calcification process, as inhibition of NLRP3 significantly reduces the calcification induced by cellular stressors and interleukin 1ß. This dissertation is in line with other recent research that emphasizes the involvement of inflammaging in the pathology of vascular calcification. Several therapeutic targets arise from the insight that oxidative stress, inflammation and senescence are crucially involved in the pathophysiology of VSMC calcification. These new therapeutic approaches can help to meet the high unmet clinical need of patients suffering from vascular calcifications.

Extreme precipitation events can have serious adverse consequences for the population. Their severity and possible impacts are mainly determined by their intensity and duration. Therefore, when planning and operating water management systems or protecting infrastructure from flooding, it is important to consider the frequency at which particularly intense or long-lasting heavy rainfall events can be expected. This information is commonly summarized in intensity-duration-frequency (IDF) curves. The methods used to estimate IDF curves are based on extreme value statistics, where the challenge is modeling events of rarely occurring magnitude or those not even observed yet. A further obstacle is the availability of data, since the time series of precipitation measurements with a high temporal resolution are usually relatively short and the spatial coverage of precipitation gauges is sparse. Therefore, the estimation of IDF curves is often associated with considerable uncertainties. This is problematic, because overestimation leads to major additional construction costs, while underestimation implies an unreasonable residual risk of failure and might result in severe consequences.

Therefore, the objective of this work is to develop IDF models that allow for estimation with reduced uncertainties. We achieve this by more efficient usage of the available data. Thus, as a first step, we model the annual precipitation intensity maxima over a range of durations simultaneously within one model. To this end, we use a duration-dependent Generalized Extreme Value (d-GEV) distribution. We demonstrate that this results in a significant reduction of uncertainties, especially in the estimation of the shape parameter. This parameter determines the upper tail of the distribution and thus comprises information on very rare, severe events.

Within our first study, we extend the d-GEV model by incorporating spatial variations (in the form of covariates). This provides two advantages: on the one hand, we can combine information from different stations, which leads to a further reduction of uncertainties. On the other hand, we are able to spatially interpolate the IDF relationship, which allows us to obtain estimates at any location within the study area, including locations without observations. We analyze the performance of the model in a case study in detail. Our results show that including spatial variations into the model improves the estimation of rare events and yields reliable estimates at locations with little or no data. Using two examples of heavy rainfall events in Berlin, we further demonstrate how the spatial d-GEV model can be applied to analyze the extremeness of events on different timescales and in space. However, another result of our first study indicates a disadvantage of the d-GEV model: it is not flexible enough to describe a wide range of durations, as it does not improve the estimates for every duration. In our second study, we therefore investigate possible extensions of the model and discuss for which applications certain enhancements might be beneficial.

Since the d-GEV distribution is commonly applied to model annual maxima, only a small fraction of the observations is used to estimate IDF curves. In our third study, we implement seasonal variations into the model, allowing us to use monthly maxima, instead. This again results in a significant reduction in uncertainties. Moreover, we can investigate the influence of seasonal variations on the IDF curves. Our results suggest that especially at stations with large differences in the seasonality of short and long-lasting extreme events, the initial d-GEV model does not provide a good approximation. At these stations, the flexible d-GEV model is clearly able to better describe the IDF relationship. Additionally, modeling monthly instead of annual maxima allows for more reliable estimation of the shape parameter, therefore, we are able to perform a more careful analysis of the dependence of the shape parameter on duration.

The methods presented in this thesis not only serve to reduce uncertainties in the estimation of IDF curves but also provide a consistent and parameter parsimonious approach to model variations of extreme rainfall. Future studies can benefit from our insights to investigate the influence of climate change on the intensity and frequency of extreme events on different timescales with greater accuracy.

Strain accumulation and stress release along multiscale geological fault networks are fundamental mechanisms for earthquake and rupture processes in the lithosphere. Due to long periods of seismic quiescence, the scarcity of large earthquakes and incompleteness of paleoseismic, historical and instrumental record, there is a fundamental lack of insight into the multiscale, spatio-temporal nature of earthquake dynamics in fault networks. This thesis constitutes another step towards reliable earthquake prediction and quantitative hazard analysis. Its focus lies on developing a mathematical model for prototypical, layered fault networks on short time scales as well as their efficient numerical simulation.

This exposition begins by establishing a fault system consisting of layered bodies with viscoelastic Kelvin-Voigt rheology and non-intersecting faults featuring rate-and-state friction as proposed by Dieterich and Ruina. The individual bodies are assumed to experience small viscoelastic deformations, but possibly large relative tangential displacements. Thereafter, semi-discretization in time with the classical Newmark scheme of the variational formulation yields a sequence of continuous, nonsmooth, coupled, spatial minimization problems for the velocities and states in each time step, that are decoupled by means of a fixed point iteration. Subsequently, spatial discretization is based on linear and piecewise constant finite elements for the rate and state problems, respectively. A dual mortar discretization of the non-penetration constraints entails a hierarchical decomposition of the discrete solution space, that enables the localization of the non-penetration condition. Exploiting the resulting structure, an algebraic representation of the parametrized rate problem can be solved efficiently using a variant of the Truncated Nonsmooth Newton Multigrid (TNNMG) method. It is globally convergent due to nonlinear, block Gauß–Seidel type smoothing and employs nonsmooth Newton and multigrid ideas to enhance robustness and efficiency of the overall method. A key step in the TNNMG algorithm is the efficient computation of a correction obtained from a linearized, inexact Newton step.

The second part addresses the numerical homogenization of elliptic variational problems featuring fractal interface networks, that are structurally similar to the ones arising in the linearized correction step of the TNNMG method. Contrary to the previous setting, this model incorporates the full spatial complexity of geological fault networks in terms of truly multiscale fractal interface geometries. Here, the construction of projections from a fractal function space to finite element spaces with suitable approximation and stability properties constitutes the main contribution of this thesis. The existence of these projections enables the application of well-known approaches to numerical homogenization, such as localized orthogonal decomposition (LOD) for the construction of multiscale discretizations with optimal a priori error estimates or subspace correction methods, that lead to algebraic solvers with mesh- and scale-independent convergence rates.

Finally, numerical experiments with a single fault and the layered multiscale fault system illustrate the properties of the mathematical model as well as the efficiency, reliability and scale-independence of the suggested algebraic solver.

The development of our society relying on utilization of raw materials from Earth has left unprecedented marks on our planet’s environment. A key issue is the climate change phenomenon caused by the continuous increase in the atmospheric concentration of the greenhouse gas CO2 due to combustion of fossil fuels as main energy source. The mitigation of the CO2 emissions via its capture and conversion, increase in the utilization of renewable energy and recycling technologies, and eliminating the dependence from fossil fuels is a strategy for building sustainable society. A promising concept for tackling the CO2 emission via its conversion into valuable products (hydrocarbons and alcohols etc.) is the electrochemical reduction of CO2 (CO2ER), that has many advantages over the other conversion concepts. Cu is unique in terms of material that can intrinsically catalyze CO2 reduction into hydrocarbons and alcohols. However, there are many Cu catalyst/experimental conditions/engineering - related challenges and other issues of various nature that affect the product selectivity and therefore still hinder the large-scale application of the CO2ER. Regarding the catalyst and experimental conditions challenges, possible alternative for overcoming the selectivity issues is step- wise CO2ER i.e., two-electron electrochemical reduction of CO2 into CO and subsequent conversion of CO into hydrocarbons, alcohols and other valuable products. Furthermore, another two-electron product, that is formic acid (HCOOH) or formate (HCOO–) that find various industrial applications and are also promising alternative as fuel in fuel cells, together with CO can be produced with high selectivity on various cheap and abundant electrocatalysts. Namely, the Cu rich Cu-Sn materials appear to be promising catalysts for CO2ER into CO, while Sn rich Cu-Sn and Cu-S for production of HCOO–, and therefore they are worth and inspiring to be more thoroughly studied in terms of their composition- structure relations with the catalytic activity for electrochemical conversion of CO2. Hence, the first main goal of this thesis is dedicated to study of the composition-structure-CO2ER activity relations in the Cu-Sn and Cu-S based electrocatalyst materials. On the other hand, the second main goal encompasses providing simple, cheap and fast synthesis methods for both Cu-Sn and Cu-S based materials, and moreover, including a successful proof-of-concept for recycling/repurposing waste for deriving CO selective Cu-Sn electrocatalyst, which are prerequisites toward possible application of these materials for large-scale conversion of CO2 and building a sustainable society based on recycling in order to mitigate and finally cease the extraction of natural resources. The thesis is divided into three studies, from which the first study represents determination of the composition and speciation of Cu and Sn in Cu-Sn electrocatalysts under CO2 electrolysis in order to reveal the relationship between these parameters and the CO2ER selectivity alteration between CO and HCOO– at various applied potentials. For the purpose of this study, SnO2 functionalized CuO nanowires with varying thickness of surface SnO2 layers (low and high Sn), were synthesized. The CO2ER product quantification was performed using chromatography, while the material characterization methods comprised of mainly spectroscopy-based techniques including ex-situ soft x-ray XAS, in-situ hard x-ray XAS and quasi in-situ XPS, supported by microscopy/electron diffraction (EF-TEM, HR-TEM and SAED) and computational modeling (DFT). The results show that thin layer of SnO2 (low Sn) functionalized CuO nanowires electrocatalysts that are selective for CO2ER into CO, reaching maximal FE of ~80% at –0.7 V, undergo surface transformation generating Cu0 and SnOx (Snd+) species under all examined potentials. The presence of Snd+ is supporting the Sn to Cu charge redistribution mechanism and therefore promoting desorption of the Cu bound *CO intermediate, leading to significantly higher CO evolution, compared to the activity of pristine Cu. On the other hand, the results show that the increase in the surface Sn content is beneficial for CO2ER into HCOO–, achieving the highest FE (80%) at –0.9 V for the catalyst with highest Sn content. Altering the potential toward more negative values is leading to increase in the surface fraction of metallic Sn specie that readily bind the *OCHO* intermediate following the HCOO– pathway, accompanied with significant suppression of the competitive hydrogen evolution reaction (HER) due to weak binding of the *H intermediate. Even though these Cu-Sn materials can reach very high selectivity for both CO and HCOO– in dependence of the surface Sn content, sophisticated, expensive and time-consuming approach, that includes atomic layer deposition (ALD) of SnO2, was used for their synthesis. An important requirement for future practical application of the CO2ER catalysts is definitely simple, cheap and fast synthesis. Therefore, in the scope of the second study, facile one-step electrochemical method was developed for deriving Cu-Sn foam with low Sn content from waste bronze. The bronze derived Cu-Sn foam reached 80% FE for CO at –0.8 V, competing with the best catalysts for this purpose, which makes it promising for future large-scale application. This study is showing that recycling/repurposing waste material for CO2ER catalyst synthesis is achievable, which is an important step towards sustainable supply of materials for this purpose. The third study is based on investigation of the composition-structure relations in Cu-S catalysts selective for CO2ER into HCOO–, and moreover presenting a facile method for synthesis of these materials based on direct reaction between elemental Cu and S dissolved in toluene, hence avoiding usage of expensive and extremely toxic precursors. The most important finding in this study, based on examination of the Cu-S catalysts with quasi in-situ XPS, reveals that under CO2 electrolysis the materials do not undergo complete reduction and Cu+ surface species persist at all examined potentials (–0.5 to –0.9 V), compared to pristine Cu which is completely reduced to metallic under identical conditions. The presence of residual surface sulfur species is most probably stabilizing the Cu+ with oxophilic nature on which the *OCHO* intermediate favorably binds and further converts into HCOO–. However, the HCOO– selectivity that can reach up to 70-75% is dependent on activation of the electrocatalyst that is related to the Cu:S surface composition and various electrode-electrolyte interface effects. Namely, besides the S2–, presence of unexpected SO42– specie is found on the surface of the electrocatalysts that are subjected to applied potential of –0.9 V, most probably due to local pH increase effects. These local effects are not fully understood from this study which is inspiring for further research that involve probing the electrode-electrolyte interface with other surface sensitive methods under in- situ conditions such as Raman and infrared spectroscopy. Finally, the future challenges include an adaptation of the facile synthesis methods developed in this work to prepare gas-diffusion electrodes loaded with Cu-Sn and Cu-S catalysts. Examining their CO2ER activity in gas-diffusion electrolyzers is important to achieve high current densities and, hence, industrial relevant conversion rates that are required for future large-scale applications.

Die vorliegende Arbeit setzt sich mit den Briefen Papst Alexanders IV. auseinander, die während seines Pontifikats zwischen 1254 und 1261 entstanden sind. Knapp 3260 dieser Schreiben haben sich im Hauptregister des Papstes erhalten, zahlreiche Weitere zudem in Empfängerüberlieferung. Diese Litterae dienen der Wissenschaft bis heute, um einen Einblick in die päpstliche Politik um die Mitte des 13. Jahrhunderts zu erlangen. Dabei wurde gerade der Pontifikat Alexanders IV. von früheren Historikern häufig als ein „Bild hilfloser Schwäche“ abgetan. Dagegen stellt sich diese Arbeit, die von der Hypothese ausgeht, dass diese Litterae nicht als schlichte Tatsachenberichte zu deuten sind, sondern in einem hohen Maß durch Rhetorik ausgeschmückt wurden. Es ist anzunehmen, dass durch die Verwendung gewisser Formulierungen und Darstellungsweisen seitens der päpstlichen Kurie ein spezifisches Bild vom Papsttum konstruiert wurde. Um diese These zu überprüfen, wurden die Briefe Alexanders IV. innerhalb zweier Querschnittuntersuchungen eingehend epistolographisch untersucht. Zum einen wurden die Verhandlungen um das Königreich Sizilien, zum anderen die Verbindung zwischen Alexander IV. und den Bettelorden betrachtet. So konnten die Grundlagen der sprachlichen Gestaltung der päpstlichen Kanzlei erkannt und die Frage nach der darstellerischen Inszenierung Alexanders IV. beantworten werden. Es wurde nicht nur der kuriale Briefaufbau aufgeschlüsselt, sondern auch spezielle Allegorien aufgezeigt, die der päpstlichen Inszenierung dienten. Für die Analyse der einzelnen Briefe wurde dabei der Ansatz Tanja Brosers genutzt, den sie für ihre eigene Untersuchung der Biefe Papst Clemensʼ IV. auf den Grundlagen der Briefanalyse von Carl Erdmann entwickelt hat. Anhand dieser epistolographischen Untersuchung konnte tatsächlich ein „Bild hilfloser Schwäche“ ausgemacht werden. Hierbei handelt es sich jedoch nachweislich um einen Teil der päpstlichen Inszenierung, die seitens der Kanzlei als Argumentationsmuster genutzt wurde. Ähnliches ließ sich in vergleichenden Analysen auch für die Vorgänger Alexanders IV. Gregor IX. und Innocenz IV. nachweisen. Auf der Grundlage dieser Ergebnisse konnte damit auch das bisherige Urteil der Wissenschaft über Alexander IV. relativiert werden.

Freshwater systems have always been under the most variate disturbance regimes. However, the number of multi-stressors and the frequency/intensity of stochastic pulse perturbations they will face in the future is predicted to increase. Stochastic pulse perturbations such as storms and floods are well known to temporarily disrupt ecosystem services that are fundamental for global existence within short time scales - as drinking water supply, irrigation, and food provision. Eutrophication - one of the main freshwater press perturbations deteriorating water quality - may enhance harmful cyanobacterial blooms, modify the structure of food webs, and alter long-term ecological stability, resulting in substantial ecological, social, and economic losses. Despite all our knowledge on the effects of stochastic events and eutrophication operating in isolation, we know little about how their interactions can shape the resilience of aquatic ecosystems.

The aim of this thesis is to identify general processes of recovery and response pathways taking place after mortality pulse perturbations and assess how resource availability can modify them. For that, the existing literature was reviewed, and experiments were executed using aquatic systems of different ecological complexity. Chapter 2 starts with a global review of how climate change may modify in-lake processes that are prone to escalate into feedback loops of relevance to freshwater biogeochemistry (i.e., mixing regimes modifying nutrient upwelling). Chapter 3 explored if Early- Warning Signals of Regime Shift (EWS) could produce sufficient mechanistic empirical evidence to be used as a reliable methodological framework for quantifying Ecological Resilience. For that, we reviewed the literature for aquatic experiments that have designed interactions between pulse and press perturbations. Using the lessons learned from both reviews, the experiment of Chapter 4 used an eco-evolutionary microcosm with complex intraspecific interactions to focus on methodological constraints of using recovery rate and time for addressing engineering and ecological resilience. Also, this experiment investigated the role of resource availability on the processes ruling the recovery from pulse perturbations at a community-alike level. Last, in chapter 5, ecological complexity was scaled up using mesocosms filled with natural lake water to identify key processes involving the effect of nutrient availability on the microbial community response to pulse perturbations. Here the focus was on how eutrophication changes the phytoplankton resistance and resilience to mortality events that cause internal nutrient turnover. Together, these four chapters provided the core of the thesis.

Overall, we identified that climate change can indeed create feedback loops capable of altering the nutrient dynamics in lakes, as well as the direction of change depending on the lake characteristics. We scrutinized processes that can lead to an increase of total nutrients in the epilimnion in the long run while creating longer periods of dissolved nutrient limitation within a season. Those processes are related to In-lake mixing regimes, which are susceptible to atmospheric conditions and responsible for the internal mixing of nutrients in lakes. Therefore, the presence of feedback loops in lake dynamics might become increasingly relevant under ongoing climate change.

When reviewing the reliability of EWS to address the loss of ecological resilience in aquatic systems, we observed that the field is still at the stage of proof-of-concept. Complex experiments designed to assess the interaction between pulse and press perturbations were virtually absent. Most experiments considered either a pulse or a press perturbation affecting the system, and often without a mechanistic understanding of why an EWS was observed or not. Amongst all EWS, recovery rate or time were the most capable of bringing together how long-term changes in the system affect the response to stochastic pulse perturbations. Recovery rates showed reliable results when predicting population collapses; however, the translation of individual populational-level recovery rates to more complex community-based ecosystem dynamics is far from consolidated.

Moving on into process-based approaches, our experiments highlighted that the effects of resource availability can be decomposed into two distinguished processes of recovery. One is the capability of the system to fully recover from disturbance. Another is the recovery pattern that the system will embody after the pulse perturbation. In both experiments we observed the importance of biotic interaction for determining how the system responds to perturbations and the effect of resource availability on shaping the direction of those interactions. Competition, facilitation, intrinsic growth rates, population turnover, the complexity of ecological interactions, and rates of energy transfer, all played a role in the processes underlying 'resilience' (latu sensu).

The eco-evolutionary microcosm taught us that resource availability modulates the speed of the recovery process (rate and time) but not necessarily the level of recovery. Systems with low resource availability showed weaker recovery rates and longer recovery times for both compositional and functional dimensions compared to when resources were high. However, all tested systems showed substantial plasticity in absorbing and recovering from a pulse perturbation (complete recovery). Therefore, the slower recovery process caused by low resource availability did not change “the measure of the persistence of the system” or “their ability to absorb change and disturbance and still maintain the same relationships between populations or state variables" – the formal definition of ecological resilience (Holling, 1973). When dealing with systems of different resource availability, ecological (sensu Holling) and engineering resilience (sensu Pimm) may potentially decouple in time. Therefore, we must be especially careful when using recovery from perturbation as a proxy of ecological resilience if resource availability is the main driver of ecosystem change.

When scaling up the trophic complexity to a mesocosms level, we observed that pulse perturbations increased the amount of autochthonous nutrients in the system, selecting for 'small and fast-growers' at first. As more resources were allocated in the system before the pulse perturbation, more nutrients were released during the mortality event; and with more dissolved nutrients available for uptake, higher peaks of phytoplankton concentration were observed as a response to the pulse perturbation. However, the level of resource availability in the mesocosms did not change the resistance or the recovery from a mortality pulse perturbation. Together, the chlorophyll-a displacement declined after each sequential pulse perturbation despite increases in resource availability. The more perturbed the system was, the less responsive it became, and this can be interpreted as a possible community pathway towards stability. The mesocosms experiment indicated the capability of the system to adapt to sequential pulse perturbations in a way to reduce its impacts and that resource availability and sequential pulse perturbations are antagonistic forces shaping the response of the system to mortality events.

Both experiments executed in this thesis presented a convergent story. Resource availability did not change the capability of the systems to recover from pulse perturbations, despite changing their compositional structure and process rates. However, the evidence that resource availability is unlikely to influence the capability of systems to recover should not lead to underestimations of the risks related to changing process rates in ecological systems. Systems under low resource availability might become more vulnerable to changes in the frequency of pulse perturbations, while systems with high resource availability may present stronger responses immediately after the pulse perturbation (i.e., peaks of Chl-a concentrations). This is an important consideration when managing waterbodies with strict regulations (i.e., drinking water provision) since systems with a surplus of resource availability may more easily trespass regulatory guideline values (e.g., maximum Chl-a threshold levels for safe water supply) following a pulse perturbation, while oligotrophic systems may become especially vulnerable to changes in the frequency of sequential weather-related pulse perturbations.

Despite intense research efforts, epithelial ovarian cancer (EOC) invariably remains the most lethal gynecological malignancy in women. In the absence of biomarkers capable of detecting EOC at an early, still curable stage, altered glycosylation of proteins attracted attention as a potential source of complementary screening markers. While changes of total serum N-glycome in EOC patients have been broadly examined, there is so far only limited data available on glycosylation alterations occurring in individual serum-derived glycoproteins and ovarian cancer tissue. Therefore, to fill this gap of knowledge, EOC-related glycosylation changes were investigated in this thesis at the level of immunoglobulin G (IgG), the most abundant serum glycoprotein, and at the level of EOC tissue, implementing cutting-edge technology, MALDI mass spectrometry imaging (MALDI-MSI). In humans, IgG occurs as four subclasses, IgG1, IgG2, IgG3, and IgG4, which differ sharply in respect to their biological characteristics and effector functions despite high homology at the amino acid level. Although IgG glycosylation in EOC patients has already been investigated previously, EOC-related glycosylation alterations were determined at the level of enzymatically released N-glycans. In consequence, currently available data give only global information and is neither subclass- nor site (Fc/Fab)-specific. Therefore, in order to provide a deeper insight into glycomic changes accompanying the development and progression of EOC, in this work, glycosylation alterations were investigated in a subclass-specific manner, performing the analysis at the glycopeptide level. To this end, IgG was isolated from blood sera of 87 EOC patients (FIGO stage I-IV) and 74 age- and sex-matched healthy controls. In order to separate IgG2 and IgG3, whose peptide backbones encompassing the Asn297-glycosylation are frequently identical, a two-step affinity purification employing Protein A and Protein G Sepharose was performed. Isolated IgG fractions containing IgG1, IgG2, IgG4, and IgG3, respectively, were digested with trypsin, and the resulting glycopeptides were enriched using cotton-HILIC columns. Finally, measurements were performed by MALDITOF-MS in negative ionization mode. By summing up relative intensities of respective glycopeptide structures, six (or five in the case of IgG2) glycosylation traits, namely a-, mono-, digalactosylation, sialylation, bisection, and fucosylation, were calculated separately for IgG1-3 subclasses (analysis of IgG4 was omitted due to its very low serum concentration and overlapping glycopeptide signals). In all investigated IgG subclasses, mono- and digalactosylation were found to decrease in patients suffering from early- and late-stage EOC. Notably, as glycosylation profiles of all investigated subclasses were observed to alter with increasing age, the EOC-related alterations were more pronounced in younger patients. Additionally, the detected subclass-specific glycosylation features indicate that each IgG subclass responds slightly differently to the outbreak of the disease. Above all, IgG1 showed the most pronounced EOC-related glycosylation alterations, and its agalactosylation showed the strongest association with CA 125 routine diagnostic marker. Additionally, as compared to IgG2 and IgG3, the combination of IgG1 glycosylation with the CA 125 marker showed the best performance in distinguishing healthy controls from EOC patients, irrespective of patients’ age and EOC stage. Furthermore, the results of this work imply that a common analytical practice of simultaneous analysis of IgG2 and IgG3 subclasses should be avoided due to their noticeably different glycosylation phenotypes. The aim of the second part of this work was to determine glycosylation alterations occurring directly on glycoproteins expressed in ovarian cancer cells and their surroundings. Analyses were performed using MALDI-MSI technique that enables the visualization of the spatial distribution of numerous analytes in a single imaging experiment. The investigated material consisted of formalin-fixed paraffin-embedded tissue specimens of the most common and aggressive EOC type, high-grade serous ovarian cancer, less aggressive low-grade serous, clear cell, and endometrioid ovarian cancer as well as non-malignant borderline ovarian tumor. All tissue specimens were deparaffinized, rehydrated, and subjected to heat-induced antigen retrieval. Negatively charged sialic acids were chemically derivatized in a linkage-specific manner, after which all tissue-contained N-glycans were released in situ with PNGase F. Ultimately, released N-glycans were measured using a rapifleX MALDI Tissuetyper. The applied protocol allowed the detection of over 60 m/z species corresponding to high-mannose-, hybrid-, and complex-type neutral and sialylated N-glycans. Importantly, observed N-glycans were diversely distributed within distinct tissue regions, defined by a pathologist prior to the analysis. High-mannose N-glycans were predominantly detected in tumor regions, while neutral complex-type N-glycans were more abundant in non-tumor tissue areas. Due to the mass shift introduced via a chemical derivatization reaction, the sialylated structures carrying α2,3- and α2,6-linked sialic acids could be distinguished. Notably, this is the first study, in which in situ sialylation of EOC tissue was investigated in its stabilized form and a linkage-specific manner. Importantly, the distribution of differently sialylated N-glycan structures within the tissue was observed to vary. While α2,6-sialylated N-glycans were enriched in tumor and tumor-related necrotic regions, α2,3-sialylated N-glycans were predominantly present in non-tumor tissue. Ultimately, statistical analyses revealed tissue type-specific N-glycan structures, which support EOC diagnosis and pave the way to serve as biomarkers to discriminate between cancerous and noncancerousovarian tissue.

The Cassini spacecraft orbited Saturn from 2004 to 2017. During this period, Cassini’s onboard dust instrument – the Cosmic Dust Analyzer (CDA) – recorded numerous in situ time of flight mass spectra, generated from μm to sub-μm sized dust particles. Most of these spectra originate from ice particles sampled in Saturn’s large, diffuse E-ring. This ring is mainly sustained by material ejected from the cryo-volcanic plumes at the south polar terrain of Saturn’s icy moon Enceladus. Previous analyses of CDA spectra revealed the existence of three different compositional main types of ice particles: salt- and organic-poor (Type 1), salt-poor but enriched in organics (Type 2) and salt-rich (Type 3). A new compositional type was discovered during the course of this work, called Type 5. Its CDA spectra indicate a very high salt concentration; far above the level found for Type 3 particles of about 1 % by mass. So this work represents the first, large-scale investigation of the spatial distribution of these four types to study the compositional structure of the E-ring. For this purpose, more than 10000 CDA spectra of ice grains were analyzed for their composition and particle size with respect to the spacecraft position and trajectory.

The results of this investigation not only revealed distinct spatial correlations and trends but are also in good agreement with previously published E-ring results, obtained during close Enceladus flybys. Moreover, they show that, although the absolute number density of all E-ring grains drops when moving radially outwards from Enceladus or vertically away from Saturn’s equatorial ring plane, the relative frequencies of the compositional types vary significantly. Type 1 particles generally represent the majority of all ice particles in the E-ring and become relatively more frequent at larger radial and vertical distances. Type 2 particles exhibit the opposite trend with the relative frequency declining at larger distances. Thus, it is proposed that Type 2 particles are converted into secondary Type 1 particles, through photochemical degradation of the embedded organic molecules. For Type 3 particles the radial and vertical trends differ. Radially, the relative frequency first rises to a maximum and then decreases, while vertically it remains almost constant, with only a minor indication of a North-South asymmetry. The newly discovered particle type (Type 5) is most frequently detected in a relatively narrow region of the E-ring, between the orbital distances of Dione and Rhea, confirming existing theories about the dynamical evolution of E-ring grains. This argues against a direct Enceladian source, instead favoring a formation within the E-ring itself. Hence, it is proposed that Type 5 represents secondary particles, formed from Type 3 grains via plasma sputtering of the more volatile water component.

To understand the impact, that particle composition has on the determination of the particle size, particularly the organic substances in the ice particles, laboratory experiments were undertaken using a Laser-Induced Liquid Beam Ion Desorption (LILBID) approach. By irradiating a μm-sized liquid water beam with a pulsed, infrared laser, LILBID simulates the impact ionization process of ice grains in space. The experiments revealed a distinct difference in ion yields between salt-rich and organic-rich compositions. While the latter increases the ion yields just slightly, compared to pure water, the addition of salts increases them significantly. Considering these results, it is inferred that Type 2 particles are, on average, the largest particles. The average sizes of the other three types overlap within the errors, depending on the particular radial distance to Saturn. The overall shape of the radial size distribution seems to be intimately related to the particles’ salinities. The average sizes of the salt-poor particle types (Type 1 and 2) decrease linearly in the inner E-ring up to 10 RSaturn (Saturn radius RSaturn = 60268 km) from Saturn, then remain more or less constant. In comparison, salt-rich particles (Type 3 and 5) exhibit a similar initial decrease but reach their minima sooner, at around 8 RSaturn. These minima are followed by a distinct increase in the populations’ average grain sizes in the outer E-ring. Although it is currently unclear why the average grain sizes of salty ice grains increase again in the outer E-ring, the two different distribution shapes – those of the salt-poor types on one side and the salt-rich types on the other – again indicate that two different transformation processes, responsible for the transformation of Type 2 to Type 1 and Type 3 to Type 5, are occurring, as also inferred from the compositional data.

Optimization of nanosuspensions produced by wet bead milling is a complex process involving many factors that affect milling efficiency. This thesis focused on the identification of key stabilizer properties that have a direct outcome in the formation of a stable nanosuspension. Furthermore, critical process parameters in the preparation of fixed dose combination (FDC) nanosuspensions were described. Finally, formulation parameters determining the long-term physical stability of FDC nanosuspensions were described. A comprehensive stabilizer screening was initially performed on the individual drugs. Loteprednol was milled in the presence of five surfactants at two concentrations. Higher concentration generally resulted in smaller particle sizes. Surfactant hydrophobicity (r = 0.68) and surface activity (r = 0.87) were observed to positively affect milling efficiency. For PEO PPO-PEP block polymers (Poloxamer) a sufficient PPO fraction was crucial to interact with the drug surface as indicated in decreasing contact angles at increasing milling efficiency. The best candidate for milling loteprednol was Poloxamer 407. Two factors could however be further optimized: milling to smaller particle sizes and a more monomodal particle size distribution. Poloxamer 407 milling efficiency was further tuned from a d90 of 550 to about 200 nm by introducing glycerol or NaCl to the milling media. Poloxamer 407 conformation as a function of osmotic agent concentration suggested a stretching of the polymer chains thus increasing the steric stabilization. Chain collapse due to high medium ionic strength was then also accompanied by a loss in milling efficiency. The success rate of high molecular weight polymers on the other hand was generally limited by insufficient wetting and increased media viscosity. In contrast to surfactants, milling with high molecular weight polymers left a significant µm fraction of about 50% of total volume, ending far below the milling efficiency of surfactants. Under accelerated storage at 40 °C/75%RH, surfactants however only insufficiently stabilized the loteprednol nanosuspensions, with a growth rate of at least 2.5 µm/month while particle size was completely maintained for non ionic polymers. It became apparent that a combination of 0.5% Poloxamer 407 and 0.125% HPMC E4M could significantly increase milling efficiency to a d90 of 200 nm and result in superior storage stability with a negligible growth rate of 0.005 µm/month. This was explained by a synergistic co-adsorption of both stabilizers.

Combination therapy with two drugs being classified as poorly soluble, could be formulated as an FDC nanosuspension. Several difficulties arise during formulation development of such products, especially regarding their production and characterization. This thesis presented the approach of selective dissolution, providing the in situ particle size of the individual compound within the FDC. The approach was based on the difference in drug solubilities, facilitating the in situ dissolution of nepafenac during the laser diffraction measurement and thus facilitating the particle size determination of loteprednol within the FDC. Two approaches were considered for the preparation of the FDC nanosuspensions, separate or combined milling of the two individual drugs. Using selective dissolution, precipitation of loteprednol was detected in the presence of the second drug nepafenac after dilution. This was attributed to critical changes in solubility after combining the two single nanosuspensions, making the approach of separate milling unfeasible for this FDC. It became apparent that milling nepafenac and loteprednol together increased milling efficiency of the more challenging compound loteprednol by 50% for surfactants and by 10 30% for non-ionic polymers compared to the single nanosuspension. The increase in loteprednol milling efficiency was attributed to an increase in total active milling volume due the presence of nepafenac. The same effect was seen in a combination of dexamethasone and nepafenac. Nepafenac reached nm-sizes very early in the process, which seemed an important factor as a simple increase in e.g. volume fraction did not alter loteprednol or dexamethasone milling efficiency. Drug brittleness was indicated as a key parameter. Brittleness of three drug powders was determined and brittleness was the highest for nepafenac, followed by loteprednol and dexamethasone. As particle size determines dissolution rate, dissolution studies were subsequently performed for the nepafenac-dexamethasone FDC and the beneficial effect of combined milling on the dissolution of dexamethasone and nepafenac FDC nanosuspensions could be shown. Nanosuspensions are thermodynamically unstable systems and tend to agglomerate or exhibit crystal growth upon storage. When preparing an FDC nanosuspension, both milling efficiency and storage stability were considered. Poloxamer 407 was the best candidate to obtain a loteprednol and nepafenac FDC nanosuspension with a d90 of 240 nm. It however failed to maintain the nanosuspension physically stable upon storage at 40 °C/75%RH. In contrast, high molecular weight polymers left a clear µm-fraction in the FDC nanosuspension after milling. Kinetic adsorption seemed to however be relevant over storage time, where minimum particle sizes with a d90 around 400 nm were reached within 2-month storage. This suggested, that the increased breakage rate during combined milling resulted in loteprednol breakage, with the fresh surfaces however not readily being covered with polymer. A relaxation of the system by either free polymer adsorption or deagglomeration due to repulsive effects explained the decrease in particle size over time. Aside stabilizer choice, other formulation parameters were investigated to increase the physical stability of the inherently unstable FDC nanosuspension. Increased viscosity and the introduction of a stabilizer combination both were successful in preventing physical instabilities and decreased crystal growth rate from 1.5 to 0.01 µm/month and below. Viscosity of the system was increased from 5 to 25 mPas which also was accompanied with a decrease in sedimentation velocity from 11 and 3 µm/s. Increasing the formulation’s viscosity however worsened redispersibility after 6-month storage. As crystals could not be maintained in a discrete suspended state, flocculation was induced by a stabilizer combination of 0.5% Poloxamer 407 and 0.125% HPMC E4M. Although flocs settled more rapidly than crystals at increased viscosity, flocculated crystals formed a lattice that resisted complete settling and thus was less prone to cake formation. The stabilizer combination was therefore the formulation approach with the highest milling efficiency and best characteristics upon storage for the FDC nanosuspension.

Sowohl theoretisch als auch empirisch konnte bereits die Schlüsselrolle von Familien im Entwicklungsprozess ihrer Kinder herausgestellt werden. Aus diesem Grund wird in neueren Modellen frühpädagogischer Qualität die Zusammenarbeit mit Familien auch als eigenständige Qualitätskomponente angenommen (vgl. Kluczniok & Roßbach, 2014). Hierbei liegt die Annahme zugrunde, dass eine familienergänzende Kindertagesbetreuung sich besonders positiv auf die Entwicklung der Kinder auswirken kann, wenn Fachkräfte neben den Kindern auch deren Familien in ihr pädagogisches Handeln miteinbeziehen. Im Fachdiskurs werden für die Zusammenarbeitsthematik unterschiedliche Begrifflichkeiten genutzt, die auch mit einem veränderten Verständnis von der Zusammenarbeit zwischen Kita und Familie einhergehen (vgl. Stange, 2012). In dieser Arbeit wird in Anlehnung an Betz (2015) unter der Qualitätsdimension Zusammenarbeit mit Familien jegliche Form der organisierten Kommunikation und Kooperation zwischen frühpädagogischen Fachkräften und Eltern verstanden; folglich gelten frühpädagogische Fachkräfte als verantwortlich für die Gestaltung der Zusammenarbeit und es ist Bestandteil ihres professionellen Aufgabenrepertoires, eine qualitativ hochwertige Zusammenarbeit umzusetzen (vgl. Roth, 2014). Betrachtet man bisherige Forschung im Bereich der Zusammenarbeitsthematik so wird deutlich, dass oftmals nur Belege für die Bedeutung der Elternbeteiligung sowie einem partnerschaftlichen Verhältnis zwischen Kita und Familie geliefert wurden (z. B. Fantuzzo et al., 2013; Mautone et al., 2015; Serpell & Mashburn, 2012). Unbeantwortet bleibt meist, welche Voraussetzungen seitens der Kita für eine erfolgreiche Zusammenarbeit geschaffen werden müssen. Das vorliegende Dissertationsvorhaben beabsichtigt daher, innerhalb vier Teilstudien zu neuen Erkenntnissen hinsichtlich der Zusammenarbeit mit Familien als Qualitätsdimension beizutragen. Die erste Teilstudie untersuchte die Struktur und Beschaffenheit der Qualität der Fachkraft-Eltern-Kommunikation im Rahmen der morgendlichen Bringsituation sowie Qualitätsunterschiede nach strukturellen Rahmenbedingungen der Einrichtungen anhand eines neu entwickelten Beobachtungsinstruments. Die Ergebnisse konfirmatorischer Faktorenanalysen zeigten, dass sich die Qualität der Fachkraft-Eltern-Kommunikation in die Dimensionen Gesprächs- und Interaktionsbereitschaft, Kommunikationsstrategien und Verabschiedung differenzieren ließ und sich somit die Prinzipien der personenzentrierten Gesprächsführung auf den frühpädagogischen Kontext übertragen lassen. Einrichtungen mit einem höheren Anteil an akademisch ausgebildetem Personal, mit günstigeren Fachkraft-Kind-Verhältnissen sowie mit einer Organisation der pädagogischen Arbeit in Stammgruppen wiesen eine höhere Qualität der Fachkraft-Eltern-Kommunikation auf. Unterschiede hinsichtlich des Anteils an Kindern mit Migrationshintergrund sowie der Einrichtungsgröße konnten nicht festgestellt werden. Die zweite Teilstudie nutzte das Beobachtungsinstrument aus Teilstudie 1 und untersuchte, inwieweit die beobachtete Qualität der Fachkraft-Eltern-Kommunikation, aber auch fragebogenbasierte Qualitätsmerkmale, die seitens der Familien eingeschätzt wurden, mit dem Vertrauen von Eltern zusammenhingen. Entsprechend gängiger Vertrauenstheorien wurde zudem getestet, inwiefern das Vertrauen mit familiären Hintergrundmerkmalen assoziiert ist. Die Ergebnisse zeigten, dass Familien in Einrichtungen mit einer höheren beobachteten Qualität ein höheres Vertrauen in das Personal aufwiesen. Mit Blick auf die Qualitätseinschätzungen der Familien sowie deren Zufriedenheit mit der Kommunikation im Rahmen der Tür- und Angelgespräche ließen sich ebenfalls signifikant positive Zusammenhänge feststellen. Die Analysen zeigten des Weiteren, dass Eltern mit einer anderen Familiensprache als Deutsch und Eltern mit verhaltensauffälligen Kindern ein signifikant niedrigeres Vertrauen in die Kita ihres Kindes besaßen. Ein statistisch bedeutsamer Zusammenhang zwischen dem Bildungsniveau der Eltern und ihrem Vertrauen konnte nicht nachgewiesen werden. Teilstudie 3 fokussierte sich auf die Angebotsstruktur der Einrichtungen zur Zusammenarbeit mit Familien sowie deren Bedeutung für das Vertrauen von Eltern. Des Weiteren wurde untersucht, inwieweit strukturelle Voraussetzungen der Einrichtungen und professionelle Kompetenzen frühpädagogischer Fachkräfte die Angebotsform und -intensität vorhersagen. Die Ergebnisse zeigten, dass die Anzahl an Aktivitäten zur Elternbildung sowie zur Partizipations- und Entscheidungsfindung positiv mit dem Vertrauen von Eltern zusammenhingen. Die anderen beiden Angebotsformen zur sozialen Vernetzung der Eltern sowie zur Einbeziehung der Familienkulturen standen in keinem statistisch bedeutsamen Zusammenhang zum elterlichen Vertrauen. Ferner zeigte sich, dass Kitas, die von einem höheren prozentualen Anteil an Kindern mit Anspruch auf das Bildungs- und Teilhabepaket besucht wurden, in den letzten zwölf Monaten mehr Aktivitäten zur Elternbildung angeboten haben. Kitas mit einem höheren prozentualen Anteil an Kindern mit Migrationshintergrund boten mehr Aktivitäten zur Einbeziehung der Familienkulturen an. Die vertraglich vereinbarte Vorbereitungszeit der Fachkräfte hingegen stand in einem signifikant positiven Zusammenhang zur Intensität der Angebote zur Partizipation und Entscheidungsfindung. Der Fachkraft-Kind-Schlüssel stand zu keiner der vier Angebotsformen in einem statistisch bedeutsamen Zusammenhang. Im Hinblick auf die professionellen Kompetenzen der Fachkräfte zeigte sich, dass in Kitas, in denen das Personal über ein umfangreiches Wissen zum Handlungsfeld Zusammenarbeit mit Familien verfügte, mehr Aktivitäten zur sozialen Vernetzung und zur Elternbildung angeboten wurden. Darüber hinaus wurde ein signifikant positiver Zusammenhang zwischen den Überzeugungen der Fachkräfte und der Anzahl der Angebote für soziale Vernetzung gefunden. Vor dem Hintergrund steigender Anforderungen im Handlungsfeld Zusammenarbeit mit Familien untersuchte Teilstudie 4, inwieweit sich pädagogische Fachberatung als Qualifizierungsressource für Einrichtungen und ihre pädagogischen Fachkräfte eignet. Hierzu wurde das fachdidaktische Wissen von Fachberatungen als bedeutsame Kompetenzfacette näher beleuchtet. Die Befunde zeigten, dass Fachberatungen zwar insgesamt viele Methoden zur Zusammenarbeit mit Familien kennen, jedoch deutliche Unterschiede zwischen den einzelnen Fachberatungen existieren. Im Rahmen einer Clusteranalyse konnten die folgenden vier Wissenstypen von Fachberatungen generiert werden: Novizen, Generalisten, Spezialisten und Experten. Fast ein Drittel der befragten Fachberatungen lässt sich dem Cluster Novizen zuordnen. Diese Fachberatungen nennen im Durchschnitt nicht einmal eine Methode. Einzelne Zusammenhänge zu den fachlichen Voraussetzungen der Fachberatungen können als Indiz für eine Vermittlung von Methodenwissen in Ausbildung, Praxis sowie Fort- und Weiterbildung gewertet werden. Insbesondere die Fort- und Weiterbildungsaktivität von Fachberatungen scheint ein geeignetes Instrument zur Qualifizierung von Fachberatungen im Bereich Zusammenarbeit mit Familien zu sein. Insgesamt lassen sich aus den Ergebnissen wichtige Erkenntnisse (1) über die Struktur der Qualität der Fachkraft-Eltern-Kommunikation sowie (2) über deren Beschaffenheit ziehen. Die Ergebnisse verdeutlichen ferner (2) die Bedeutsamkeit der Qualität der Fachkraft-Eltern-Kommunikation und der Angebotsform und -intensität für das Vertrauen von Eltern und zeigen, dass sowohl strukturelle Rahmenbedingungen der Einrichtungen als auch Kompetenzfacetten der frühpädagogischen Fachkräfte bedeutsame Voraussetzungen für die Qualität in der Zusammenarbeit darstellen. Die Bedeutung weiterer Professionalisierungsbestrebungen wird unterstrichen. Implikationen für die Forschung sowie die pädagogische Praxis werden diskutiert.

Die pulmonalarterielle Hypertonie ist eine seltene, zum Tode führende Erkrankung, welche durch eine endotheliale Dysfunktion, pulmonale Vasokonstriktion, pulmonalvaskuläre Hyperreagibilität und pulmonalarterielles Remodeling gekennzeichnet ist. Das Endothelinsystem spielt in der Pathogenese der PAH eine zentrale Rolle. Die Ziele dieser Arbeit lagen zum einen in der Untersuchung des Endothelin-Systems in der PAH-assoziierten pulmonalen TH2-Inflammation und zum anderen in der Untersuchung altersabhängiger Endothelin-1-vermittelter Veränderungen von Herz und pulmonaler Zirkulation in der Maus. Die Induktion der pulmonalen TH2-Inflammation erfolgte mittels systemischer Ovalbumin-Sensibilisierung und nachfolgender Ovalbumin-Atemwegsexposition (OVA/OVA). Mit Hilfe transgener Mäuse konnten unter anderem im ex vivo Modell der isoliert perfundierten und ventilierten Mauslunge die Effekte der ETB-Defizienz (ETB-/-) und der humanen Prepro-Endothelin-1-Überexpression (ETtg) auf pulmonalarteriellen Mitteldruck und pulmonalvaskuläre (Hyper-) Reagibilität untersucht werden. Zudem erfolgten vergleichende histologische Analysen in Bezug auf pulmonale Kollagendeposition und perivaskuläre Inflammation. Mittels Fulton-Index erfolgte die Untersuchung rechtsventrikulärer Hypertrophie. Zytokin-Analysen aus der bronchoalveolären Lavage (BAL) und mRNS-Analysen aus dem Lungenhomogenat erlaubten eine genauere Charakterisierung der Inflammation und der Regulationsmechanismen in den einzelnen untersuchten Gruppen. ETB-defiziente Mäuse wiesen einen pulmonalen Hypertonus inklusive pulmonalvaskulärer Hyperreagibilität und rechtsventrikulärer Hypertrophie auf. Infolge der pulmonalen TH2-Inflammation aggravierten sowohl die pulmonalvaskuläre Hyperreagibilität als auch die rechtsventrikuläre Hypertrophie. Die perivaskulären Leukozyteninfiltrate, die pulmonale Kollagendeposition, die pulmonale Endothelin-1-Expression und die IL-12p40-Spiegel der BAL zeigten sich in den OVA/OVA-behandelten ETB-/--Mäusen im Vergleich zu den WT-Tieren deutlich verstärkt. Zudem konnte in den ETB-/--Mäusen eine deutliche Zunahme der Endothelin-1-vermittelten pulmonalvaskulären Thromboxan-Freisetzung nachgewiesen werden. Während die Prepro-Endothelin-1-Überexpression in den jungen ETtg-Tieren mit einer pulmonalvaskulären Hyperreagibilität einherging, kam es in den stark gealterten ETtg-Mäusen zu einem fixierten pulmonalen Hypertonus inklusive rechtsventrikulärer Hypertrophie. Zusammenfassend führte die ETB-Defizienz infolge der pulmonalen TH2-Inflammation zu einem vermehrten pulmonalen Leukozyteninflux mit deutlich erhöhten IL-12p40-Spiegeln und zu einer verstärkten Expression von Endothelin-1. Diese Veränderungen begünstigten möglicherweise die nach OVA/OVA-Behandlung detektierte Zunahme der rechtsventrikulären Hypertrophie und pulmonalvaskulären Hyperreagibilität, an der auch eine vermehrte pulmonalvaskuläre Thromboxanfreisetzung beteiligt zu sein scheint. Die hier erhobenen Daten unterstützen die Hypothese der protektiven Rolle des ETB-Rezeptors im pulmonalen Gefäßsystem. Zudem zeigen sie, dass Endothelin-1 als alleiniger Stimulus ausreicht, PAH-assoziierte Veränderungen an Herz und pulmonaler Zirkulation zu induzieren. Um zu klären, ob in der Behandlung der pulmonalarteriellen Hypertonie eine separate ETA-Inhibierung der dualen Endothelinrezeptor-Blockade überlegen sein könnte, sind jedoch weiterführende Analysen, inklusive separater und simultaner ETA- und/ oder ETB-Inhibierung, erforderlich.

An abdominal aortic aneurysm (AAA) is defined as a permanent local dilatation of the abdominal aorta, usually accompanied by thrombus formation. Once ruptured, an AAA is associated with an overall mortality rate of over 90%. Even though AAAs represent one of the leading causes of sudden death in developed countries, the exact etiology and pathophysiology have not yet been fully elucidated. Nowadays, AAAs are clinically diagnosed by either computed tomography, ultrasound or magnetic resonance imaging (MRI), yet those modalities only deliver information on the aneurysm anatomy, size and form. It is generally accepted that AAA size correlates with the probability for rupture and related clinical events. However, a growing body of literature argues that the pathophysiology of AAA expansion is more multifaceted, with inflammation and degradation of the extracellular matrix (ECM) playing a pivotal role. Visualizing the complex nature of aneurysms requires the development of novel imaging modalities that facilitate more detailed depiction of AAAs. Magnetic resonance elastography (MRE) is an imaging technology that combines lowfrequency vibrations and MRI to create stiffness maps of body tissues. Remodeling of the ECM during AAA progression leads to stiffness changes, providing a potential imaging marker. Therefore, we assessed murine aneurysms by ex vivo microscopic multifrequency magnetic resonance elastography (μMMRE). By examining the aneurysmal thrombus, we discovered that regional variations in stiffness were strongly correlated to local histology-quantified ECM accumulation. With this proof-of-concept study, we demonstrated that MRE represents a suitable method for detecting shear wave speed changes reflected in varying stiffness values in the aneurysmal thrombus that in turn are representative of ECM remodeling. With successful clinical translation, this imaging modality could help detect potential fatal changes in the biomechanical structure of the AAA mimicked by ECM changes. Magnetic particle imaging (MPI) is an innovative imaging modality, enabling a highly sensitive detection of magnetic nanoparticles (MNPs). Since MNPs are a suitable surrogate marker for molecular targeting of macrophages and the aneurysmal development involves inflammation as a fundamental process, we tested the feasibility of imaging AAA inflammation with MPI. We demonstrated that the MNP accumulation in ex vivo murine aneurysms can be visualized and quantified with MPI. In addition, the colocalization of macrophages and MNPs was visible in histology. The ability to detect the spatial distribution and local concentration of MNPs establishes MPI as a promising tool for monitoring inflammatory progression in AAAs.