The objective of the present case-control study was to detect the occurrence of equine parasitic helminths in a comprehensive clinical patient group of a total of 620 horses. On the basis of this data collection it was aimed to determine a potential correlation of the parasitic infection to the occurrence of colic, based on coprological, serological and clinical data. The age structure of the tested horses was at a median of 12 ± 7 years whereby the majority in the study were adult animals (94.7%), as opposed to 1-3 years old horses and foals at 4.4% and 1% respectively. Eggs of gastrointestinal strongyles were present in 50.2% of all horses dewormed at least 8 weeks before, with a 95% confidence interval of 45.7 to 54.9%, ascarid and tapeworm eggs in 0.5% [CI: 0; 1.2] and 1% [CI: 0.2; 2] respectively, in all tested horses. An association between colic and the detection of these helminth eggs has not been established.

The risk of a S. vulgaris-seropositive finding in horses with presence of strongyle eggs in their faeces was higher by a factor of 1.4 (p = 0.035) and 1.7 (p = 0.017), than if the same eggs were not present. In the reverse line blot analysis (RLB) every cyathostomin species detectable with that assay was present, however, there was no correlation to colic here either. Only in case of 58.5% of all samples with detected strongyle eggs larvae of the small strongylids could be identified in the RLB. From a detection limit of 50 eggs per gram faeces this prevalence was at 94.8%. In the serologic S. vulgaris and A. perfoliata assays no statistical correlation could be established for the various antibody concentrations between the horses suffering from colic and the control group. 10.7% [CI: 8.4; 13.1] of all horses were seropositive for anti-A.perfoliata-IgG(T). While in 4% [CI: 1.3; 6.7] of all initiated coprocultures and in 1.1% of all horses tested in the study larval DNA of S. vulgaris has been found in the real-time PCR, unexpectedly high serological prevalence values have been found at a significant 32.3% [CI: 28.5; 36.4] for this strongyle species. The results of this Anti-SvSXP-ELISA indicate that this test has at least a significant potential in the detection of prepatent infections, even if statements about an acute infection should only be made with care, and by including further laboratory parametric and clinical results. A significant correlation with colic could not be established hereby. It should further be considered that positive results could not be confirmed with high probability due to the limited specificity of the tests applied, but even with the consideration of potential cross reactions. In the serum electrophoresis seropositive horses had significantly higher total protein and ß-globulin values and a lower A/G-quotient than horses that tested negative for anti-S.vulgaris antibodies.

Without reaching statistical significance the odds ratio for a positive strongyle egg test in horses with diarrhoea in comparison to those without these symptoms was 1.9 (p = 0.386). Obstipations localised in the jejunum of the horse usually had a 17 times (p = 0.053) higher chance for testing positive for tapeworm eggs in comparison to those with constipation of the colon ascendens and descendens, respectively. Furthermore, this study points at the significance of deworming treatments in association with occurrence of colic. Herein horses dewormed less than 7 days before compared to horses that were dewormed more than 8 weeks ago, showed a 2.4 times (p = 0.025) increased chance for colic. Accordingly, the time period between the onset of colic and the last deworming should always be considered in the patient history.

Finally, it should be emphasised that the detection of prepatent infections to date remains a diagnostic challenge, especially with regard to migrating or hypobiotic strongylid larvae. Faecal samples testing negative should not lead to the conclusion of the examined horse being parasite-free. Without comparative autopsy examinations the actual infection status and consequently the real association with colic remains uncertain. Further case-control studies are required to improve our understanding of the potential associations between colic and a parasitic infection. Therefore, for the practicing veterinarian the final diagnosis of a parasitic colic event should not be based on the results of a single test. This should be rather established after the evaluation of clinical symptoms as well as comprehensive laboratory test results.

Namibia is one of the countries where both dog rabies as well as wildlife rabies commonly occur. Since 1977, the country has experienced two epidemics of rabies in kudu antelope, manifesting in recurring cycles (Figure 20), with the second epidemic persisting until today, to aa point where rabies in kudu can be regarded as endemic. This phenomenon of rabies in kudu is unique to Namibia and does not occur in any other part of natural range of this antelope species in the rest of Africa. The disease is responsible for large numbers of fatalities in the Namibian kudu population, resulting in severe economic losses to the game farming and hunting industry. There is no indication that the disease in kudu will abate any time soon. Although genetic studies of the RABV isolated from kudu suggest that the rabies virus affecting kudu may originate from jackal, epidemiological surveys, clinical observations and transmission experiments confirm that non-bite transmission of rabies in kudu, through direct or indirect contact, is possible. This route of infection may be the most important mode of transmission and spread of the disease in kudu, also explaining the serious extent of the disease once it flares up in a susceptible population. Intra-muscular vaccination using a commercial inactivated vaccine has been shown to be effective in protecting kudu against rabies but it remains a costly method with practical limitations and no information on the duration of immunity available so far. Experiments have delivered definite proof that protective immunity against rabies can be achieved in kudu using an oral vaccine, but methods and protocols need to be improved in order to achieve protective immunity in a sufficient number of animals. Different types of suitable bait were developed and their uptake by kudu tested successfully. It should therefore be possible to further develop this approach into an effective delivery method for the rabies vaccine. Serological tests required to effectively monitor the immune response to rabies vaccines, validated for the use in this species, need to be developed. Taking everything into consideration, it should be possible develop the necessary tools, methods and protocols to effectively protect kudu antelope against rabies, within the foreseeable future.

Eine der verheerendsten weltweit verbreiteten Erkrankungen der Honigbiene ist die durch Paenibacillus larvae verursachte Amerikanische Faulbrut (AFB), welche ausschließlich die Brut schädigt. Honigbienenlarven infizieren sich über sporenhaltiges Futter und nach Auskeimung der Sporen lebt P. larvae zunächst kommensal im Larvendarm, wo er sich massiv vermehrt. P. larvae baut die peritrophe Membran ab und geht ab einem bestimmten Zeitpunkt in die invasive Lebensphase über und greift das Darmepithel der Larve an. Nach dem Durchbruch des Darmepithels kommt es mit dem Übertritt von P. larvae in das Hämocoel zu einer generalisierten Infektion und zum Tod der Larve. Ziel der vorliegenden Arbeit war die weitere Aufklärung molekularer Details der Wirt-Pathogen-Interaktion im Verlauf der Pathogenese einer Infektion von Bienenlarven mit P. larvae. Dazu erfolgte die weitere Untersuchung zweier bereits gezeigter Virulenzfaktoren: das von den P. larvae Genotypen ERIC I und ERIC II produzierte PlCBP49 sowie das ERIC II-spezifische S-layer Protein SplA. Zunächst erfolgte die weitere Charakterisierung von PlCBP49, einem Virulenzfaktor mit chitinbindender und -abbauender Aktivität. Dieser allgemeine Virulenzfaktor wird sowohl vom P. larvae Genotyp ERIC I als auch dem Genotyp ERIC II genutzt, um die peritrophe Membran (PM) abzubauen. Da der Abbau der PM den Übergang von der nicht-invasiven zur invasiven Lebensphase von P. larvae markiert und PlCBP49 von beiden P. larvae Genotypen sezerniert wird, könnte dies ein möglicher Interventionspunkt in der Bekämpfung der AFB sein. Im Rahmen dieser Arbeit konnten weitere Gemeinsamkeiten von PlCBP49 und CBP21 von Serratia marcescens, einem bereits beschriebenen Mitglied der AA10 Familie lytischer Polysaccharid-Monooxygenasen (LPMOs), gezeigt werden. Hierfür wurde cbp49 erstmals erfolgreich heterolog in E. coli exprimiert und in funktionellen Assays weiter biochemisch charakterisiert. Neben der Substratpräferenz für β-Chitin konnten die besten Substratumsätze bei zweistündiger Inkubation bei pH 7 beobachtet werden. Diese Ergebnisse sowie das erstmals gezeigte Produktprofil von PlCBP49 weisen viele Gemeinsamkeiten mit CBP21 auf. Die Vermutung, dass PlCBP49 Chitin wie CBP21 ebenfalls über einen metallionen-abhängigen oxidativen Mechanismus abbaut, konnte weiter bekräftigt werden und die Ergebnisse dieser Arbeit beschreiben die Rahmenbedingungen für vertiefende Studien. Das ERIC II-spezifische S-layer Protein SplA wurde im Rahmen dieser Arbeit in dem natürlicherweise SplA-defizienten ERIC I Stamm ATCC9545 exprimiert. Die heterologe Expression konnte in vivo mit Fluoreszenzfarbstoff markierten monoklonalen Antikörpern und Fluoreszenzmikroskopie erfolgreich nachgewiesen werden. In Larveninfektionsversuchen mit der ERIC I+splA Mutante konnte keine Hypervirulenz im Vergleich zum Wildtyp festgestellt werden. Die Klonierung eines einzelnen Virulenzfaktors reicht demnach nicht aus, um die Pathogenesestrategie von P. larvae ERIC II auszulösen. Es sind also vermutlich noch weitere unbekannte Faktoren notwendig, um die komplexe Pathogenesestrategie auszulösen. Die Untersuchung der Immunantwort der Larve bei Infektion mit P. larvae war bereits Gegenstand einiger Studien und führte meist zu widersprüchlichen Ergebnissen. Der Einfluss des infizierenden P. larvae Genotyps wurde dabei nicht weiter beachtet. Durch die in dieser Studie durchgeführte vergleichende Transkriptomanalyse mittels RNA-Seq konnte gezeigt werden, dass die Infektion mit den P. larvae Genotypen ERIC I bzw. ERIC II drei Tage nach Infektion zu einer veränderten Expression immunrelevanter Gene führt. Die gesteigerte Expression antimikrobieller Peptide (AMPs) trat besonders hervor. Je nach infizierendem P. larvae Genotyp wurde eine unterschiedliche Kombination von AMPs signifikant exprimiert. Außerdem konnte eine stärkere Immunantwort in ERIC II-infizierten Larven festgestellt werden, was die vermutete Maskierung von P. larvae ERIC II durch das S-layer Protein widerlegt. Diese Ergebnisse weisen stark auf eine genotypspezifische Immunantwort der Larve hin. Obwohl Insekten kein adaptives Immunsystem besitzen, konnte in dieser Studie gezeigt werden, dass nicht nur die Spezies des Pathogens, sondern auch der infizierende Genotyp von entscheidender Bedeutung ist und die Immunantwort des Wirts maßgebliche beeinflusst. Bei der weiteren Untersuchung der Wirt-Pathogen-Interaktionen zwischen der Bienenlarve und P. larvae muss der infizierende Genotyp des Pathogens ebenfalls berücksichtigt werden. In einem weiteren Experiment konnte die Analyse der Expression ausgewählter Immungene in individuellen Larven, die Ergebnisse der bioinformatischen Analyse der RNA-Seq-Daten bestätigten. Neben der Expression unterschiedlicher AMPs, je nach infizierendem Genotyp, konnte eine stärkere Immunreaktion in ERIC II-infizierten Larven bestätigt werden. Da ERIC II-infizierte Larven innerhalb kürzester Zeit versterben und eine stärkere Immunreaktion aufweisen, liegt die Vermutung nahe, dass die aufgebrachte kostspielige Immunantwort am vorzeitigen Tod der Larve beteiligt sein könnte. Zusammenfassend wurde im Rahmen dieser Arbeit der allgemeine Virulenzfaktor PlCBP49 weiter biochemisch charakterisiert sowie die Pathogenesestrategie von P. larvae ERIC II durch die heterologe Expression von SplA in P. larvae ERIC I weiter untersucht. Darüber hinaus wurde die Immunantwort der Larve untersucht und es konnte gezeigt werden, dass nicht nur die Spezies des Pathogens, sondern auch dessen Genotyp entscheidend für die Immunantwort des Wirts sind. Diese Ergebnisse erweitern das Verständnis molekularer Details der Pathogen-Wirt-Interaktion zwischen P. larvae und der Honigbienenlarve.

Verzögerte Knochenheilung, aber besonders die ausbleibende Heilung, die in einer Pseudarthrose enden kann, bedeuten für den Patienten nicht nur große Schmerzen und Funktionsverlust der betroffenen Gliedmaße, sondern auch starke Einschränkung der Lebensqualität (Victoria et al. 2009, Garcia et al. 2013). Knochenheilung ist ein komplexer Vorgang, an dem viele Faktoren beteiligt sind. Neben einer guten vaskulären Versorgung entscheiden systemische Regulationsfaktoren, mechanische Einflüsse und deren Zusammenspiel über Erfolg oder Misserfolg der Heilung (Augat et al. 2005). Dabei heilen etwa 5-10 % der Frakturen nicht vollständig und gehen in eine verzögerte oder ausbleibende Heilung über (Kloen et al. 2002, Claes 2017). Es gibt viele Ansätze Pseudarthrosen bzw. Non-Unions zu behandeln. Nichtsdestotrotz sind alle Strategien bisher noch mit Nachteilen behaftet, darunter der bisherige Goldstandard, das Autotransplantat. Es ist verbunden mit geringem verfügbarem Knochenvolumen und erhöhter Spendermorbidität (Rihn et al. 2010, Boerckel et al. 2011a). Auch der viel versprechende Wachstumsfaktor BMP-2, der ähnliche Effekte auf die Knochenheilung wie das Autotransplantat erzielt (Jones et al. 2006, Axelrad und Einhorn 2009), ist durch seine hohen Dosierungen mit Nebenwirkungen wie Tumorbildung (Lad et al. 2013), Infektionen, Osteolyse (Carragee et al. 2011) und heterotoper Knochenbildung (Axelrad et al. 2008) verbunden. Dadurch besteht weiterhin die Notwendigkeit, neue Behandlungsstrategien zu entwickeln.

Diese Promotion untersucht das Zusammenspiel von mechanischer und biologischer Stimulation in einem etablierten Pseudarthrose-Rattenmodell (Mehta et al. 2011a) anhand der Expressionsanalyse ausgewählter Gene, die an der Knochenheilung beteiligt sind. Ein kritischer 5 mm Defekt wurde dazu mit 5 µg rhBMP-2 (beladen auf einem Kollagenvlies) behandelt und einem Fixateur externe unterschiedlicher Steifigkeit stabilisiert. Anhand der Fixateur–Steifigkeiten: 1) rigide (100 %), 2) semi-rigide (40 %) und 3) flexibel (10 %), wurden die Ratten in drei Versuchsgruppen eingeteilt und auf ihre Unterschiede in der Genexpression mittels quantitativer real-time PCR an Tag 3, 7, und 14 nach der Operation analysiert. Begleitet wurden diese Gruppen von einer Positivkontrolle (1 mm Osteotomie), die eine physiologische Heilung darstellen soll, und einer Negativkontrolle (unbehandelte 5 mm Osteotomie), die eine Knochendefektheilung widerspiegelt. Zum einen wurden Expressionsunterschiede zwischen der physiologischen Heilung und der gestörten Heilung deutlich. Zum anderen konnte festgestellt werden, dass die Knochenheilungskaskade durch BMP-2 alleine und in Kombination mit der Steifigkeit des Fixators beeinflusst wird. In den Steifigkeitsgruppen zeigte sich vor allem für die flexible Gruppe eine erhöhte Expression an Tag 14 für alle untersuchten Gene. Wohingegen die Expressionswerte der semi-rigiden Gruppe darauf hindeuteten, dass sie bereits an Tag 3 alle Gene (außer c-Fos und Noggin) höher exprimierte als die rigide und flexible Gruppe. Der Einfluss von BMP-2 auf die Expression der ausgewählten Gene wurde durch den Vergleich der rigiden Gruppe mit der Negativkontrolle untersucht. Die BMP-2-Gabe bewirkte bei BMPR II, BMPR IB und c-Fos an Tag 3 (BMPR IB auch Tag 7) ein signifikant niedrigeres Expressionsniveau als in der Negativkontrolle, wohingegen die rigide Gruppe an Tag 14 Kollagen Typ I verglichen mit der NK höher exprimierte. Noggin und c-Fos wiesen an Tag 14 in der rigiden Gruppe und NK eine ähnliche Expression auf. Weiterhin zeigte die flexible Gruppe bei allen Genen eine starke Tendenz der Expressionshochregulierung. Die BMP-Rezeptoren BMPR II und BMPR 1A, Kollagen Typ I, Noggin und ID-1 wurden in der Positivkontrolle signifikant höher als in der Negativkontrolle exprimiert. C-Fos und BMPR 1B wurden dagegen an Tag 3 von der Negativkontrolle deutlich stärker hochreguliert. An Tag 14 erreichten die beiden Kontrollgruppen für c-Fos und BMPR 1B ein ähnliches Expressionsniveau.

Zwar wurden die Wirkung von BMP-2 und der Einfluss des vorherrschenden interfragmentären mechanischen Milieus in der Literatur schon analysiert, aber bisher gibt es noch keine Studie, die sich mit den Auswirkungen des Zusammenspiels von biologischen und mechanischen Stimuli in Form von BMP-2 und unterschiedlichen Fixationssteifigkeiten im Knochendefektmodell auf die Expression ausgewählter Gene auseinandergesetzt hat.

Diese Dissertation ist Teil einer umfangreichen Studie, welche mit nachfolgenden Methoden den Heilungsverlauf in den Steifigkeitsgruppen bzw. Kontrollgruppen untersucht hat: I) die hier vorgestellte Expressionsanalyse mittels quantitativer real-time PCR, II) MicroArray- Analyse, III) Histologie IV) Mikrocomputertomografie und V) biomechanische in vitro-Testung.

Im Gesamtbild der angewandten Methoden in der Studie (Schwarz et al. 2018) zeigte der semi-rigide Fixateur externe in Kombination mit BMP-2 tendenziell eine bessere Knochenheilung in einem 5 mm Defekt der Ratte im Vergleich zu einer rigiden und flexiblen Fixation. Für die klinische Anwendung könnte dies eine vielversprechende Tendenz in Bezug auf eine schnellere Aktivierung der Heilungskaskade und damit verbundene kürzere Regenerationsphase, durch frühzeitige Hochregulation der an der Knochenheilung beteiligten Gene bedeuten. Weitere Untersuchungen hinsichtlich kombinierter Behandlung mit einem moderat mechanischen Stimulus und BMP-2, stellen die Möglichkeit in den Raum, die BMP-2 Dosierung, die damit verbundene Patientenmorbidität, die Behandlungskosten sowie -zeit zu minimieren.

Post-weaning diarrhea is a widespread problem in pig rearing. Common causative agents are enterotoxigenic E. coli bacteria. Since post-weaning diarrhea is associated with a high morbidity and mortality rate, innovative prevention and therapy strategies are required. The probiotic strain E. faecium NCIMB 10415 has been demonstrated to be a promising tool to counter this disease. With regard to immunological events, host-pathogen interactions include recognition via innate immune receptors, such as NLR, some of which form inflammasomes. These multiprotein complexes license caspase-1 to process the pro-inflammatory cytokines IL-1β and IL-18. Little is known about the involvement of inflammasome signaling pathways in post-weaning diarrhea in piglets or about the role of the NLRP3 inflammasome in promoting probiotic effects. The objective of the present work was to analyze inflammasome responses to pathogenic ETEC IMT4818 with relevance for post-weaning diarrhea and probiotic E. faecium NCIMB 10415, an authorized feed additive for sows and piglets, in in vitro and ex vivo experiments in various porcine cells and tissues. Since myeloid cells are well suited for investigations into the functions of inflammasomes, the first study of the current thesis was carried out on porcine DC derived from blood monocytes. To determine whether inflammasome signaling contributes to probiotic effects of E. faecium NCIMB 10415, porcine MoDC were pretreated with the probiotic prior to a pathogenic ETEC challenge. Moreover, inflammasome activation processes were further monitored in the presence and absence of a priming signal displayed by LPS. LPS priming induced the transcription of inflammasome components, a characteristic of the first step of inflammasome activation. Inflammasome stimulation occurred upon incubation with ETEC, but not with E. faecium. As compared with LPS-preincubated cells, the observed ETEC effects appeared at later time points when the MoDC were left unprimed. In the applied experimental setup, preincubation with probiotic E. faecium did not mediate protective effects during a pathogenic ETEC challenge via the NLRP3 inflammasome in porcine DC. In the second study, a porcine intestinal co-culture model consisting of IEC (cell line IPEC-J2) and immune cells (MoDC) was established in order to mimic the bidirectional interplay between these two cell types. The aim was to unravel any alterations in the immune response patterns of IPEC-J2 cells and DC to the added bacteria attributable to mutual IEC/immune cell interactions. In addition, the question was addressed as to which soluble factors mediate this communication. Furthermore, the expression of caspase-13 was analyzed, as it has been suggested as a potential candidate driving non-canonical inflammasome activation in pigs. MoDC revealed a more tolerogenic phenotype in the presence of IPEC-J2 cells showing attenuated inflammasome and IL-8 responses. Porcine caspase-13 was affected by bacterial incubation in each cell type. In the cell line IPEC-J2, non-canonical inflammasome signaling appeared to be initiated by ETEC infection and by co-cultivation with DC. With regard to possible mediators of IPEC-J2/MoDC crosstalk, evidence was found for TSLP secretion by IPEC-J2 cells and MoDC. The detected tolerogenic activity of co-cultured MoDC might be partly explained by an autocrine TSLP regulation in these cells. The third part of the present thesis comprises a systematic investigation in which inflammasome components have been examined in tissues from the small and large intestine of pigs at two different ages. A feeding trial was aimed at testing the impact of probiotic E. faecium on inflammasome expression in piglets. To verify the results obtained in vitro, porcine jejunal epithelia were incubated ex vivo with the aforementioned bacterial strains in mono- and coincubation setups (probiotic preincubation and a subsequent challenge with ETEC) employing the Ussing chamber technique. The systematic analysis showed that, similar to their human counterparts, the expression of certain inflammasome components (particularly NLRP6, ASC, and caspase-1) decreased gradually from the jejunum to the colon. Probiotic supplementation had only a weak impact on inflammasome expression levels. However, E. faecium was capable of reducing ETEC-triggered IL-1β protein liberation in the experiments challenging jejunal tissues. In contrast to the in vitro results, this indicated the involvement of the inflammasome pathway in probiotic effects of E. faecium NCIMB 10415. In conclusion, infection with ETEC IMT4818 caused inflammasome activation in vitro and ex vivo. The results of probiotic treatment with E. faecium NCIMB 10415 varied between in vitro and ex vivo approaches, with inflammasome-related advantageous effects being detected solely in the ex vivo study involving the ETEC challenge of porcine jejunum. In the established IPEC-J2/MoDC co-culture model, the presence of IPEC-J2 cells induced a tolerogenic phenotype in co-cultured MoDC indicating that reciprocal interactions between IEC and underlying immune cells orchestrate immunological responses.

In captivity, cheetahs (Acinonyx jubatus) continue to be a challenge to breed. Scientists have worked for decades to identify the underlying reasons for this problem. Until recently, it was assumed that the genetic bottleneck the cheetah population is assumed to have gone through during its history contributed to its low reproductive performance. However, studies on free-ranging populations showed that cheetahs reproduce regularly and successfully when they live in ecosystems without their main competitors, the lions (Panthera leo) and spotted hyenas (Crocuta crocuta) which kill their cubs. This is different in zoological gardens where there is no impact of competitors but where successful breeding is still a rare event. Various potential causes for this lack of apparent fertility have been suggested and investigated. One suggestion was that housing and environmental conditions in captive cheetahs may be responsible for a higher allostatic load (“stress”) in the zoo animals, which in turn might result in a low reproductive performance. However, some facilities have successfully and regularly bred cheetahs. Even if allostatic load in cheetahs under human care may be higher than in the wild, zoological gardens with high breeding success should differ in one or several factors from those with low breeding success. This dissertation was conducted to identify these factors and develop recommendations on how to improve the success of cheetah breeding programs in zoological gardens. The first step was the investigation of the allostatic load of study animals in European zoological gardens. The concentration of glucocorticoids in the body is commonly used as a biological marker of the allostatic load of vertebrates. However, the conventional procedure of collecting blood under anesthesia causes itself an immediate increase of glucocorticoids in the blood which makes an assessment of the true value impossible. In order to avoid any distortions of glucocorticoid concentrations through handling of animals, samples must be obtained in a minimally invasive manner. In feline species, feces are particularly well suited to measure glucocorticoids. Previously, there was no validated enzyme-immunoassay (EIA) available that measured and had characterised fecal glucocorticoid metabolites (fCGM) in cheetahs and that determined the affinity of the EIA. The existing radio-immunoassays (RIA) are often avoided because of the radioactivity involved in the measurements. Chapter 2 therefore presents the characterization and biological as well as technical validation of an EIA for cheetahs. The EIA demonstrated a significant increase in fGCM after experimental injection of adrenocorticotropic hormone (ACTH) in a male and a female cheetah. This experimental injection of hormones and the proof of the predicted result is called a “hormone challenge” and is equivalent to a biological validation. ACTH activates the adrenal cortex and results in a fast increase of glucocorticoids in the blood. This increase can be detected with a delay of approximately one day in the feces. Glucocorticoids such as cortisol belong to the steroid hormones. Cortisol metabolites slightly differ in their biochemical structure from other steroid hormone metabolites such as testosterone. Therefore, a clear differentiation of fGCM from other steroid hormone metabolites was essential. In chapter 3, another EIA was characterized and validated to detect testosterone metabolites in feces. It also demonstrates the differentiation between fecal testosterone metabolites (fTM) and other steroid hormone metabolites. Further, this EIA allows to conduct minimally invasive measurements on the reproductive activity of male cheetahs. The testosterone assay was also biologically validated with hormone challenges. After injection of gonadotropin releasing hormone (GnRH), an increase of fTM was detected. GnRH causes a release of gonadotropins (follicle stimulating hormone (FSH), luteinizing hormone (LH)) in the pituitary gland. In male vertebrates, LH activates the Leydig cells in the testis and leads to an increase of testosterone in the blood. This increase was detected in the feces of cheetah males. Chapter 4 compared fGCM of reproducing and non-reproducing cheetah females in zoological gardens to examine whether they differ in their allostatic load. This was not the case. It was already known that low reproductive performance is not linked to the low genetic variability (“genetic monomorphism hypothesis”) in cheetahs nor to an endogenous seasonal trigger (“innate rhythm hypothesis”). Therefore, in this dissertation, the predictions of two other hypotheses were investigated to understand which factors might influence the reproductive success of female cheetahs. The hypotheses investigated were (1) a lack of reproduction because of reproductive suppression by conspecifics, (2) a lack of reproduction because of the faster ageing of inner reproductive organs (ARA = asymmetric reproductive aging) in those females which did not reproduce early in their life. The life history data on reproducing and non-reproducing female cheetahs in five European zoological gardens were consistent with the predictions by both hypotheses. The discussion of the entire thesis and its scientific results is compiled in chapter 5. It also introduces recommendations for zoological gardens and the European breeding program (EEP) to improve the reproductive success of this species in the future and make reproductive failure of cheetah part of history.

Police deviance covers all forms of illegal and unethical conduct by police. Previous research has revealed that the occurrence of police criminal and corrupt activities not only destabilizes the police organization’s legitimacy, but also affects that of the State. This qualitative study analyzes in detail the circumstances in which police deviance occurred in Ecuador after the democratic transition (1979-2010), as well as the factors influencing this behaviour. The study also examines the distinct strategies employed by female offenders to resist their victimisation by the police. By taking into consideration the perspectives and experiences of both police officers and female offenders, this study demonstrates that police officers had two main motivations when engaging in this behaviour: extreme pressure faced by the police to produce results against increasing criminality in the country, and the search for individual, group or organizational gain. It also reveals that the tolerance of other criminal justice system officials for police misconduct together with the lack of an institutionalised Public Defense service which would protect offenders’ rights and assist them in their defense, encouraged this behaviour. Moreover, it was found that women were seen as suitable targets for police abuse during most years of the period examined. Deep-rooted societal prejudices against certain minority women made them even more suitable targets for police deviant actions. As the end of the research period approached, officers began to change their perceptions of female suspects, and believed these became a threat to their careers. The study was based on 51 oral testimonies from female inmates and 50 in-depth interviews with police officers. The qualitative part of the research was complemented by archival information found in court documents and female prisoner’s files produced between 1979 and 2010, as well as by other official and secondary sources.

The transcription factor MYC, encoded by the MYC gene, plays a central role in many cellular processes, such as cell growth, apoptosis and cell communication. However, as an oncogene, MYC also plays a central role in initiation and progression of many different types of cancers, including malignant lymphomas, and is therefore the focus of many oncological studies. Malignant lymphomas do not refer to a single disease entity, but describe a broad range of lymphatic neoplasias that derive from mature lymphoid cells. They can be subclassified into over 60 subtypes based on their differentiation, morphology and/or clinical course. Based on histology, malignant lymphomas can be generally distinguished into Hodgkin's lymphoma (HL) and Non-Hodgkin's lymphoma (NHL). NHL can be further sub-grouped according to their cell of origin into B- and T-cell NHL. Further subclassification exists based on additional histological, clinical and molecular criteria including chromosomal alterations and gene expression profiles. The present work deals with Burkitt's lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL), which both belong to aggressive high-grade B-cell lymphoma. Here, we explore the role of the transcription factor MYC in the pathogenesis and clinical course of these lymphoma types. One hallmark of BL is the t(8;14) chromosomal translocation, leading to an overexpression of MYC protein. MYC translocations are however, not restricted to BL, but can also occur in DLBCL, although at a much lower frequency. MYC break-positive BL differ significantly from the MYC break-positive DLBCL in their clinical course, with BL associated with a complete cure of the majority of cases. To investigate the molecular differences between these two lymphoma subtypes, we performed a metabolic and proteomic study, identifying pyruvate as one of the discriminatory metabolites. This metabolic phenotype was further confirmed by proteomic studies of pyruvate metabolism-associated proteins (Schwarzfischer, et al., 2017). In a second study, the genome-wide MYC binding pattern of BL, MYC breakpositive and -negative DLBCL was analyzed by chromatin immunoprecipitation followed by next generation sequencing (ChIP-Seq) and RNA-based next generation sequencing (RNA-Seq). Significant differences in the MYC DNA-binding patterns were identified, which were also mirrored in the different gene expression patterns. One of these differentially expressed genes code for the cell surface receptor CD97 (ADGRE5), which is significantly over-expressed in BL, but absent in MYC breakpositive and -negative DLBCL. This finding was confirmed by independent validation experiments, including immunohistological staining of cell lines and primary patient samples (Kleo et al 2018 – submitted). This doctoral thesis was complemented by an investigation of long noncoding RNAs (lncRNAs) and their role in modulating the MYC-driven cellular transcriptome. Using NGS, we identified 13 lncRNAs, which were differentially expressed between BL and DLBCLs, one of which was strongly regulated by MYC. This IncRNA was able to modulate MYC-induced cell cycle genes with a strong impact on cell cycle progression. We therefore called this lncRNA MINCR (MYC-induced non-coding RNA) (Doose, et al., 2015). Taken together, this thesis provides additional evidence that MYC is not merely an on/off amplifier of gene activity but exerts specific actions on the gene expression program and – as a consequence – on cellular functions, a finding also true for aggressive lymphoma. Based on the MYC differences between BL and DLBCL, the identification of biomarkers for their distinction appears to be possible. Therefore it is justified to conclude that MYC plays an essential but diverse role in the pathogenesis of various lymphoma types, a finding which might be important for future treatment modalities. The analyses of this work were partly conducted in cooperation with other research groups and led to three publications, which provide the scientific basis for this cumulative thesis.

Since humans evolved, they have influenced and changed their environment, which started with hunting pressure and has culminated in climate change. Urbanized areas are arguably the most altered environments on earth, with the process of urbanization transforming natural landscapes in into human-dominated areas. Previous research has found urbanized areas are associated with higher biodiversity, provide refugee habitats for species from various taxa and support high population densities. However, high urbanization can also lead to declining population numbers, local extinction, higher invasion rates of species and potential yet undescribed consequences. Especially the consequences of elevated stressors, which are not exclusive to cities, but are more pronounced than in natural habitats, still need to be elucidated. Therefore model species for the urban living wildlife have to be identified. The Western European hedgehog (Erinaceus europaeus, hereafter hedgehog ) could serve as such a model species as it is geographically widespread. These days, hedgehogs are found in higher density close to urbanised areas while its numbers are declining in some areas of its range. Furthermore, hedgehogs might suffer from the densification of urban areas. The construction of infrastructure causes fragmentation and fragmentation can impede the movement of individuals. This fragmentation can influence gene flow between subpopulations when there is no or only restricted access to mates. Hedgehogs, in particular, could be affected by their restricted dispersal and susceptibility to barriers. Thus, the species characteristics and ecology make them an appropriate model species to understand the effect of humans on small ground-dwelling overlooked species in cities. Therefore the genetic diversity and behavioural plasticity of hedgehogs in a suitable study site like Berlin have to be investigated. In the first genetic study on hedgehogs in a city of this size (~1050 km²), we found, against our expectations, no genetic structure in the population. In a different analysis approach, we could identify ‘family-clan’ structures, which could be an early sign of inbreeding in subpopulations. With our study on the genetic structure of hedgehogs and the identification of new genetic markers, we provide the foundation for future projects to identify the effects of urbanisation on genetic diversity of hedgehogs and evidence-based population management in future. Together with the results of the ecological studies and effects of disturbance and fragmentation on the behaviour of selected hedgehog populations we can draw a better picture of small mammals in cities. For the ecological studies, we developed novel attachment methods in a species-specific manner. We improved methods by considering the welfare of the studied animals, the cost efficiency and flexibility of the attachment system. This system enabled us to collect spatial and temporal high-resolution data with longer durations than ever before (GPS units). Thus it was possible to follow hedgehogs through an occurring festival in a semi-natural park and in a fragmented zoological garden, identifying population and individual coping strategies, which highlight the behavioural flexibility of hedgehogs. While we were able to show that research is necessary at both the population level and individual level, without continued monitoring of population genetic and individual behaviours using specialized techniques such as ours, we will never be able to fully understand the greater intricacies of such complex ecosystem as we have in urban centres. We now have the technologies and methods to make evidence-based management decisions and harbour species in cities. It is clear, that cities need to give nature space. As long as flora, fauna and funga have enough connections between fragmented “green” areas it might help to sustain healthy populations and could even provide source populations in the process of rural restoration. However, it is also clear that cities are not enough to harbour all wildlife alone in the long-term, especially if the remaining green spaces vanish and cities continue to condense.

In group-living species, the choice of the breeding group and the social rank in the hierarchy of the group strongly influence an individual’s fitness. Yet the causes and consequences of variation in breeding-group choice and dispersal propensity, and the proximate mechanisms through which social rank influences an individual’s ability to access mates and reproduce remain poorly understood. This thesis has three main aims: (i) identify the drivers of the coexistence of dispersal and philopatry among males in the spotted hyena (Crocuta crocuta), a large, group-living carnivore; (ii) assess whether and how social rank and social and physiological constraints influence reproductive investment and success in male hyenas; (iii) improve the applicability of non-invasive hormone concentration measurements. The thesis combines long-term data on the behaviour, physiology, survival and reproductive success of male spotted hyenas with demographic data from all eight social groups of a free-ranging hyena population in Tanzania. In Chapter 3, I show that philopatric male and dispersers are of similar phenotypic quality, follow the same process and apply the same rules to choose and settle in a breeding group, and have similar survival and reproductive success. I also show that social rank is a strong determinant of male access to mates and reproductive success in spotted hyenas. Philopatric males gain reproductive benefits associated with their high social rank and these benefits increase the propensity of males to choose their natal group as a breeding group. The results demonstrate that the distribution of breeding females across natal and nonnatal groups is an important determinant of dispersal patterns and of the coexistence of philopatry and dispersal in male spotted hyenas. In Chapter 4, I develop a novel method to standardise hormone metabolite concentration measurements when substantial changes in the accuracy of an immunoassay occur. The method is based on repeated assaying of a small number of samples and restores the comparability of the measurements. The method constitutes an effective alternative to the often impracticable re-assaying of complete sample sets. In Chapter 5, I show that males with a high social rank are less constrained by physiological stress than low-ranking males, owing to their greater opportunities to express dominance and enjoy the buffering effect of social bonds. This allows high-ranking males, including philopatric males, to allocate more time than low-ranking males to fitness-enhancing social and sexual activities, and to focus their sexual investment on females of high reproductive value. These results are consistent with the results of Chapter 3 and may explain why philopatric males and high-ranking immigrants are particularly successful at siring offspring with females of high reproductive value. The thesis provides insights into (i) the role of demographic variability and the distribution of breeding partners in driving the evolution of dispersal and in shaping dispersal patterns within populations; (ii) the traits that underpin differences in competitive ability and reproductive performance between males of different social rank; and (iii) the role of social rank and of social and physiological constraints in shaping differences in life history and reproductive success among males in group-living species.

Zusammenfassung:

Neue Erkenntnisse der Embryologie zur Entwicklung des Herzens . Eine Literaturstudie

Das Herz entsteht als erstes funktionales Organ im Vertebratenembryo. Die eminente Bedeutung für Human- und Veterinärmedizin in Verbindung mit sich stetig verbessernden labortechnischen Methoden haben die Erforschung der Genese dieses Organs im Verlauf des letzten Jahrhunderts massiv vorangetrieben. Gängige Lehrbücher der Veterinärmedizin berücksichtigen zeitgemäße wissenschaftliche Fakten zur Kardiogenese jedoch kaum und verbreiten überholte Paradigmen sowie didaktisch ungeeignetes, gar irreführendes Bildmaterial. Die vorliegende Arbeit beleuchtet die Schwachstellen überlieferter Anschauungen und bietet ein schlüssiges, auf aktuellem Stand der Wissenschaft beruhendes Gesamtkonzept der Kardio-genese, das die Morphogenese im Zusammenhang mit den beteiligten molekularen Regula-tionsmechanismen erfasst.

Dazu wurde nach der Recherche in elektronischen Datenbanken, Katalogen und Portalen englisch- und deutschsprachige Fachliteratur zu diesem Sachgebiet ausgewertet. Die gesammelten Daten wurden anschließend unter Einbeziehung zahlreicher Abbildungen in einem fortlaufenden Text teils chronologisch, teils systematisch dargestellt.

Nach der Ankunft der aus dem posterioren Epiblasten stammenden kardiovaskulären Vorläuferzellen im Primitivstreifen erfolgt durch die Aktivierung des Transkriptionsfaktors Mesp1 die Festlegung auf ein kardiogenes Schicksal sowie die Restriktion ihrer Entwicklungspotenz. Im Zuge der Gastrulation siedeln sie sich im Seitenplattenmesoderm als kardiogenes Mesoderm an. Die BMP2-induzierte Expression des Transkriptionsfaktors und „Master-Regulators“ der Kardiogenese, Nkx2.5, determiniert die kardiogenen Vorläuferzellen endgültig und leitet die Differenzierung ein. Nach der Rotation des kardiogenen Mesoderms fusioniert es in der ventralen Mittellinie zum geraden Herzschlauch, der lediglich die Vorläuferzellen des linken Ventrikels enthält. Das weitere Wachstum erfolgt durch die Akquirierung von Vorläuferzellen aus einem Zellpool, der sich vom kranialen zum kaudalen Herzpol über die Dorsalwand der Perikardhöhle erstreckt, dem sogenannten Zweiten Herzfeld. Die Vorläuferzellen des primitiven Herz-schlauchs werden demgegenüber als Erstes Herzfeld bezeichnet. Der bereits vor der Gastrulation am Primitivknoten initiierte Bruch mit der bilateralen Symmetrie des Embryos vollzieht sich auf genetischer Ebene über eine Kaskade, an deren Ende die linksseitige Pitx2C-Expression steht. Dieser Transkriptionsfaktor ist ein entscheidender Regulator der asymmetrischen Morphogenese des Herzens. Während seiner Elongation rotiert der Herzschlauch in der engen Perikardhöhle entgegen dem Uhrzeigersinn. An der äußeren Kurvatur des durch fortgesetztes Wachstum S-förmigen Herzschlauchs wölben sich durch massive Proliferation die atrialen und ventrikulären Regionen hervor. Weitere Konformationsänderungen bringen schließlich die Herzkompar-timente in ihre definitiven topographischen Beziehungen zueinander. Die an diesem Prozess beteiligten intrinsischen und extrinsischen Kräfte sind äußerst vielfältig und ihre Verknüpfung miteinander noch unzureichend verstanden. Das Epikard, die äußere Umhüllung des Herzens, bildet sich während des Loopings aus einer Proliferationszone der kaudalen Wand der Perikardhöhle, die ihren Ursprung im kardiogenen Mesoderm hat. Diese durch frühzeitigen Verlust der Nkx2.5-Expression und Expression der Transkriptionsfaktoren Tbx18 und WT1 genotypisch einzigartige kardiogene Progenitorpopu-lation versorgt auch den Sinus venosus mit Vorläuferzellen. Am Ende des Loopings beginnen die eng miteinander verwobenen Vorgänge der Septierung von Vor- und Hauptkammern, des Atrioventrikularkanals sowie des Ausflusstrakts und der Herzklappenbildung. Die Vorläuferzellen des Septum interatriale rekrutieren sich via dorsalem Mesokard aus dem Zweiten Herzfeld. Das Septum interventriculare entsteht eher passiv durch die Aneinanderlagerung der fortwährend apikal expandierenden Wände von linkem und rechtem Ventrikel am Sulcus interventricularis. Seine Position wird durch die Grenze zwischen den Expressionsdomänen der Transkriptionsfaktoren Tbx5 und Tbx20 , der den linken resp. den rechten Ventrikel spezifiziert, festgelegt. Mit dem Einsetzen der Septierungvorgänge in Atrien und Ventrikeln entstehen an den Wänden des Atrioventrikularkanals dorsal und ventral sich gegenüberliegend zwei Endokard-kissen. Nach ihrer Fusion zum Septum atrioventriculare bilden rechts- und linksventrikuläre Auswüchse entlang des muskulären Ventrikelseptums die Grundlage für die septalen Klap-penblätter der Atrioventrikularklappen. Die wandständigen Klappenblätter entstehen etwas später aus neu gebildeten Endokardkissen im Atrioventrikularkanal. Durch Reorganisation und Kondensation von Zellen der Endokardkissen und des darunterliegenden Myokards sowie des extrazellulären Materials entstehen die reifen Klappenblätter und deren Halteapparat. Die Semilunarklappen entstehen im Ausflusstrakt analog zu den Atrioventrikularklappen ebenfalls aus zwei Paaren von Endokardkissen, von denen das zuerst erscheinende Endokard-kissenpaar auch an der Separierung der Ausflussbahn in Aorta und Truncus pulmonalis beteiligt ist. Aus der Neuralleiste einwandernde Zellen, sog. cardiac neural crest cells, sind unerlässlich sowohl für die Septierung des Ausflusstrakts als auch für die Remodellierung der Semilunarklappen. Der sich von der Ventrikelbasis bis zur perikardialen Grenze erstreckende embryonale Ausflusstrakt ist hoch dynamisch und versteht sich eher als eine Art Transitzone für Progeni-torzellen von Myokard, glatten Muskelzellen sowie kardialen Neuralleistenzellen. Während seine myokardialen Wände zunehmend in den rechten Ventrikel inkorporiert werden und die spiraligen Ausflusstraktkissen sowie die Aortensackprotrusion miteinander fusionieren, mi-grieren Vorläuferzellen für glatte Muskulatur aus dem Sekundären Herzfeld sowie Neural-leistenzellen ein und bilden die definitiven Gefäßwände für die nachfolgend getrennten Gefäßstämme von Aorta und Truncus pulmonalis. Die definitive Form der sich umeinander windenden Arterienstämme resultiert aus einem Zusammenspiel von Rotation des Ausfluss-trakts, asymmetrischer Zellproliferation im Zweiten Herzfeld und Apoptose, was u.a. durch die Wachstumsfaktoren BMP4 und FGF8 sowie die Transkriptionsfaktoren Tbx1 und Pitx2C gesteuert wird. Auch der Einflusstrakt des Herzens ist starken Remodellierungsvorgängen unterworfen. Venae vitellinae, die initial die Hauptzuflüsse zum Herzen sind, und Venae umbilicales unterliegen tierartspezifischen Regressions- bzw. Remodellierungsvorgängen, während die Venae cardinales communes die dominanten Zuflüsse zum Herzen werden. Die myokardiale Umhüllung des Sinus venosus, einer transienten embryonalen Struktur generiert sich, wie auch das Epikard, aus dem Epithel der kaudalen Perikardhöhle mit Tbx18- und WT1-Signatur. Unter Verlängerung der linken V. cardinalis communis und Inkorporation des rechten Sinushorns verlagern sich die Eintrittsorte der venösen systemischen Zuflüsse schließlich nach rechts. Die Vena pulmonalis entsteht als endothelialer „Strang“ de novo im dorsalen Mesokard aus Isl-1- und Nkx2.5-positiven kardiogenen Progenitoren des Zweiten Herzfelds. Ihre originär bilaterale Einmündung in den Einflusstrakt wird im Zuge der Rechtsverlagerung des Sinus venosus in den linken Vorhof transponiert. Die myokardiale Hülle der Vena pulmonalis generiert sich aus nicht-atrialen mesenchymalen Zellen am Übergang zum Atrium, die proliferierend schließlich den gesamten endothelialen „Strang“ umwachsen.

Die starke Expansion von Kompaktmyokard in den apikalen Regionen auf Kosten des ursprünglichen trabekulären Myokards der Ventrikel und Atrien erfordert die Etablierung eines intrinsischen vaskulären Systems. Die Vorläuferzellen dieses Koronargefäßsystems entspringen der Proepikardialen Serosa, dem Sinus-venosus-Endothel und dem Endokard. Nach der Migration proepikardialer Zellen zur Herzoberfläche und Etablierung der Epikardschicht bilden sich in Folge eines intensiven Signalaustauschs zwischen Epi- und Myokard alsbald zunächst subepikardiale, später intra-myokardiale primitive Gefäßgeflechte aus endothelialen Vorläuferzellen. Etwas verzögert werden in mesenchymale Zellen transformierte Epikardzellen akquiriert zum Aufbau von Tunica media und adventitia der Koronargefäße. Die Fähigkeit aller Kardiomyozyten des primitiven Herzschlauchs, spontan Aktionspotentiale zu erzeugen und diese weiterzuleiten, gründet auf der spezifischen Ausstattung der Zellen mit Ionenkanälen und Gap junctions. Mit der Entstehung des Arbeitsmyokards an der äußeren Kurvatur beschränkt sich diese Eigenschaft zunehmend auf die Regionen der inneren Kurvatur und des ursprünglichen trabekulären Myokards. Endokardial produzierte Signalmoleküle sind an der Induktion der Expression Schrittmacher-typischer Gene beteiligt. Der Sinusknoten als dominanter Schrittmacher mit der höchsten Exzitationsrate entwickelt sich aus einer Subdomäne im rechten Teil des Sinus venosus. Die Schrittmacheraktivität beruht auf einem Zusammenspiel zwischen der „internen Kalziumuhr“ und plasmalemmalen Ionenkanälen. Der aus dem Myokard des Atrioventrikularkanals entstehende Atrioven-trikularknoten verzögert die Impulspropagation von den Atrien zu den Ventrikeln. Im Gegensatz dazu weisen die ventrikulären Komponenten des Reizleitungssystems, Atrio-ventrikularbündel, Bündelverzweigungen und Purkinjefasern, die aus dem ursprünglichen, trabekulären Myokard der Ventrikel hervorgehen, eine hohe Leitungsgeschwindigkeit auf.

In dieser Arbeit wurden die neuesten Erkenntnisse zur Kardiogenese bei Vögeln und Säugetieren zusammengetragen. Neben der kritischen Auseinandersetzung mit überholten Konzepten und unzeitgemäßer Nomenklatur, die auch in gegenwärtiger Literatur noch präsent sind, liegt der Schwerpunkt auf der Verknüpfung molekularer Regulationsmechanismen mit spezifischen morphogenetischen Ereignissen. So wird ein wissenschaftlich fundiertes und gleichzeitig übersichtliches und nachvollziehbares Abbild dieser Vorgänge dargelegt. Darü-berhinaus werden Ansatzpunkte für weitere Forschungsaktivitäten aufgezeigt.

Kurzfassung / Abstract

1. Kulturtechniken verhandeln die Grundbedingungen menschlichen Daseins unter den Prämissen von Kultur, Medien und Technik. Sie erlauben es, die vier kantischen Fragen zu ergänzen: Was oder wer gestattet mir, dass ich etwas weiß? Wenn ich etwas tue, was tue ich dann und womit? Welches Verständigungsinstrument steht uns für das Wissen und das Tun überhaupt zur Verfügung? Warum muss ich wissen: Was ist der Mensch? Der Gebrauch von Bildern, Schriften, Zahlen, Riten und Sitten gehört ebenso zu Kulturtechniken wie Verdauungsfragen, Partnerbeziehungsarbeit, Staudamminstandhaltung oder Raketenstarts. Kulturtechniken operieren an der Schnittstelle von diskursiven Verfahren, Handlungstheorien, medialer Materialität und Wissenspoetologie. 2. Besonders geeignet für eine kulturtechniktheoretische Herangehensweise ist das Werk Alexander Kluges, weil es nicht nur von kulturtechniktypischen Motiven durchsetzt ist, sondern diese auch in breiter Form zur Anwendung bringt. Denkende Därme, subjektiv-objektive Verhältnisse, Tote, die zu den Lebenden reden, der Kinofilm an der Wand und der Film in mir – Kluge arbeitet auf breiter Ebene mit Kulturtechniken. Für deren Artikulation bietet er ein breites Arsenal an Medienformaten an, in denen sich Kulturtechniken sowohl repräsentiert sehen als auch an ihrer eigenen Konstitution mitwirken. Kennzeichnend für Kluges Schaffen ist eine kontinuierliche theoretische Reflexion der Bedingungen des eigenen Werks hinsichtlich seiner Inhalte sowie eine poetische Ausformulierung in konkreten Medien wie Filmen, literarische Texten, Fernseharbeiten, digitalen Kanälen, Hörspielen und Ausstellungen. 3. Kluges Interesse gilt dabei den verschiedenen Erscheinungsweisen von Kollektiven. Um die Katastrophen der menschlichen Geschichte für die Zukunft zu vermeiden, arbeitet er mit seinen Werken permanent an einer "Umproduktion von Öffentlichkeit", in dessen Mittelpunkt die menschliche Erfahrung steht. Zivilisationen, Städte, Türme und Gärten werden ebenso wie Wasserphänomene und die schöpferische Kraft der Arbeit danach befragt, in welchen Konstellationen sie einen Erkenntnisgewinn für das Gemeinwesen zur Verfügung stellen. Sie fordern dafür den Rezipienten heraus, sich an dem ästhetischen Gelingen des Werks aktiv zu beteiligen. Emanzipation ist für Kluge ein Schlüsselbegriff, den er durch ein Weiterspinnen der aufklärerischen Ideale zu realisieren versucht. 4. Die Kritische Theorie hatte bislang einen maßgeblichen Einfluss auf die Rezeption Alexander Kluges. Ihre richtigen Prämissen können durch eine Lektüre per Kulturtechniken nicht nur ergänzt, sondern auch produktiv erweitert werden. Mit dem Begriff der Gesamtarbeit als Träger kollektiver kulturtechnischer Leistungen kann vor dem Hintergrund der Poetik Kluges eine Aufklärung der Aufklärung, wie sie die Kritische Theorie verfolgt, reformuliert werden.

Abstract

1. Cultural techniques negotiate the basic conditions of human existence under the premises of culture, media and techniques. They make it possible to amend the four Kantian questions thus: what or who allows me to know something? If I do something, what am I actually doing and with what? Which instrument of understanding is available to us for knowledge and action? Why do I have to know: what is the human? The use of images, words, numbers, rites and customs is just as much a part of cultural techniques as digestion issues, partner relationship work, dam maintenance or rocket launches. Cultural techniques operate at the interface of discursive methods, action theories, media materiality and poetology of knowledge. 2. The work of Alexander Kluge is particularly suitable for a theoretical approach to cultural techniques, because it is not only permeated with motifs that are typical of cultural techniques, but also applies them at a high level. Thinking intestines, subjective-objective conditions, dead people talking to the living, the movie on the wall and the film within me - Kluge works with cultural techniques on a large scale. For their articulation, he offers a broad arsenal of media formats in which cultural techniques are both represented and involved in their own constitution. Characteristic of Kluge’s work is a continuous theoretical reflection of the conditions of his own work with regard to its contents as well as a poetic formulation in concrete media such as films, literary texts, television works, digital channels, radio plays and exhibitions. 3. Kluge is interested in the various manifestations of collectives. In order to avoid the catastrophes of human history for the future, he constantly engages, in his artistic productions, on a "remaking of the public sphere" which focuses on human experience. Civilizations, cities, towers and gardens as well as water phenomena and the creative power of work are questioned about the constellations they offer for the community to gain knowledge. They call for the recipient to participate actively in the aesthetic success of the work. Emancipation is a key concept for Kluge, which he tries to implement by developing Enlightenment ideals. 4. Critical Theory has had a significant influence on the reception of Alexander Kluge. Its premises regarding appropriateness can be supplemented and expanded productively using the notion of cultural techniques. Against the background of the Poetics of Kluge, the concept of the gesamtarbeit as the bearer of collective cultural achievements can be expressed as an enlightenment of the Enlightenment as described in Critical Theory.

From a critical perspective, the thesis studies the role of the International Criminal Court (the ICC) in the provision of reparations to victims of international crimes. The study focuses on the Democratic Republic of Congo as a situation country at the ICC. Victims of human rights violations have a right to enforceable remedies. International law demands that reparations ordered must have an enforceability element for them to be certain, meaningful, and effective. The study demonstrates that the implementation framework for the ICC reparations suffers from two major shortcomings. First, impecunious defendants, and, secondly, scarcity of resources. From the standpoint of legal pragmatism, I posit that the ICC’s practice of ordering reparations against indigent defendants and seeking to enforce them through the Trust Fund for Victims (The TFV) creates uncertainty. The uncertainty stems from the failure of the Court to appreciate the fact that; first, the impossibility of providing meaningful reparation through impecunious defendants, and secondly, the need to develop a reparation mechanism that ensures full accountability by extending enforcement responsibilities to other complicity actors such as states and organisations. The right to an effective remedy is satisfied when the court’s decisions or judgments are fully enforced. It is argued that a formal existence of the right to reparation under Article 75 of the ICC Statute is of no relevance to the victims if the court’s reparation orders are inexecutable. As held in the European Court of Human Rights decision in Airey, positive international law guarantees rights that are ‘practical and effective’. To make the victim’s right to reparation practical and effective, the ICC needs to craft an enforcement mechanism that would deplete the effects of defendant’s indigence and scarce resources at the TFV. A case is made for reparative complementarity that presupposes an active role for states in redressing the victims. The ICC Statute recognises that individual criminal responsibility does not absolve states of their responsibilities under international law. To enforce reparative complementarity through the ICC reparation system, I present state-defendant reparative co-responsibility as an enforcement mechanism under Article 75(3) of the ICC Statute to mitigate limitations of conviction-based reparations. Considering that Article 75 is a human rights provision, it could be interpreted broadly to respond to pragmatic challenges facing the ICC reparation system. An evolutive approach to reparation adjudications under Article 75 would not be averse to the fact that individuals are not mere perpetrators of core crimes. Reparative accountability at the ICC should be reflective of potentially multi-layered perpetration dynamics of core international crimes. That underscores the significance of state-defendant partnership in providing redress to the victims. In justifying my proposal, I respond to the question as to whether state-defendant reparative co-responsibility for reparations would be inconsistent with the ICC Statute and international law as alluded to under Article 21(1)(c) of the ICC Statute; and whether it would affect rights of defendants. I argue that, state-individual joint liability for reparations in atrocity crime cases is legally justifiable on account of the following reasons. First, the ICC is not legally obligated to order reparations against the defendants. The use of the word ‘may’ under Article 75(2) of the ICC Statute is indicative that ordering reparations against defendants is a “discretionary power as opposed to the mandatory cause of action”. Victims could still receive reparations even when there is no court order against the defendants. The relevant Article 75(2) is not a source of substantive rights for the victims but a mere procedural provision on how to effectuate a reparations award for the victims. Victims’ substantive right to reparation is captured under Article 75(1) of the ICC Statute which obligates the Court to establish reparation principles in respect of reparations to the victims. Since Article 75(1) does not espouse as to when, how, and under what circumstances can the Court establish such reparation principles, the Court may establish reparative accountability precepts that can also be applied to complicity states or organisations. Secondly, state obligation to provide reparation under international law does not depend on the result of a criminal trial. Whether there is a conviction or an acquittal, territorial states are obligated to provide reparations to the victims. Thirdly, the drafting history of the ICC Statute and even the current reparation framework of the ICC point to the fact that states are indispensable in the provision of meaningful reparations to the victims in mass crime situations. Fourthly, co-responsibility is not an introduction of a new norm under international law, but a modality on how state responsibility could be operationalised under the ICC legal regime without upsetting the individuality of criminal responsibility. Fifthly, the prevailing international criminal tribunal’s jurisprudence is unanimous that large scale reparations for mass crime victims can only be successfully implemented by governments and not individual defendants. State-defendant reparative co-responsibility could be operationalised in two ways. First, it would be legally acceptable for the ICC to order reparations against states or directly requesting state assistance in implementing reparation orders if a particular state has voluntarily accepted responsibility and participated in reparation proceedings pursuant to Article 75(3) of the ICC Statute and Rule 98(4) of the Rules of Procedure and Evidence (the ICC RPE). Similarly, Rule 98(4) of the ICC RPE provides for judicial consultations in consequence to which the Court may order that reparations be implemented by national authorities. Therefore, the basis of a court’s reparation order against a state would be its voluntary acceptance of responsibility to provide redress to the victims under the auspices of the ICC. Secondly, State’s Reparative Responsibility could be invoked by Recommendatory Orders. Considering that individual criminal responsibility does not negate state responsibility, and in response to the state’s violation of the duty to prevent and protect territorial people against violations, the ICC could invoke international human rights law principles through Article 21(3) of the ICC Statute by demanding that territorial states should provide redress to the victims. When a territorial state does not trigger the Article 75(3) mechanism to accept responsibility, the ICC could issue semi-binding recommendatory orders by requesting such states to, first, implement certain complex and resource-intensive reparations measures, and secondly, ask them to cooperate effectively in the enforcement of reparation judgments against defendants. I refer to such orders as semi-binding recommendations as they would not emanate from the court’s express statutory powers, but from customary international law. Alternatively, recommendatory orders for reparations could also be issued under the obligation to cooperate provision. Since the obligation to cooperate provisions are meant to ensure that international tribunals operate smoothly, the Court could use Article 86 of the ICC Statute to ask for state participation in specific reparation measures for the victims.

A total of 561 electronic terms of 48 transition metal molecules AB_n (A = Sc - Ni, B = Cu/Ag/Au, n = 1, 2) were systematically studied using multireference configuration interaction (MRCI) technique. All-electron calculations, employing valence quadruple zeta basis sets, were performed incorporating scalar relativistic effects by means of the Douglas-Kroll-Hess (DKH) Hamiltonian. For diatomic molecules, full and smooth potential energy curves have been constructed at the DKH-CASSCF and DKH-MRCI(+Q) levels of theory, whereby observable molecular properties - such as equilibrium internuclear distance (r_e), harmonic frequency (omega_e), anharmonicity constant (omega_e x_e), dissociation energy (D_e), and dipole moment (mu_e) - have been reported. Spin-orbit coupling, core correlation effects, and basis set incompleteness have been probed for some selected systems. In order to assess the perturbative treatment of spin-orbit coupling at the DKH-MRCI(+SO) level of theory, spin-orbit coupling was dealt with variationally at the exact 2-component level of theory. A ground state binary relation between the atomic ion A+ and the diatomic molecule AB has been unveiled. For triatomic molecules, two sets of potential energy surfaces have been constructed using spline interpolation. The D_{infty h} and C_{2v} molecular structures and the connection between them, are pictured by the first set, symbolised by E (theta_{BAB}, r_{AB}; ^{2S+1}Gamma). The second set, E(r_{AB}, r_{BB}; ^{2S+1}Lambda), represents the linear ABB form. These are assessed, first, by considering the molecular stabilities with respect to the asymptotes A+B_2, AB+B, and A+2B - all being in ground state. Secondly, structure optimisation calculations have been performed for the lowest states in each isomer.

Pollinators are declining globally and emerging pathogens are among the causative factors. Pathogens are shared between domesticated honey bees and wild pollinators with flowers as transmission hubs. In contrast to honey bees, pathogen impacts in wild bees remain mostly unstudied. This thesis aimed to investigate associations between honey bees infected with Nosema ceranae and wild bees in the field as well as direct effects in a solitary wild bee experimentally inoculated with N. ceranae. Chapter 1 used a field survey approach to test how the presence of honey bees infected with N. ceranae affects the community composition of wild bees sharing the habitat. The results demonstrate a negative correlation between functional diversity of wild bees and the presence of infected honey bees. However, this relationship differs between functional groups. The occurrence of the rare parasitic, the cavity-nesting ones and also the Red List species is negatively associated with pathogen presence in the surrounding honey bee hives whereas the opposite is shown for common social-polylectic species. Furthermore, a habitat analysis revealed that both the highly specialized solitary-oligolectic and the threatened Red List species were particularly dependent on high coverage of suitable foraging and nesting habitat. In conclusion, sensitivity to N. ceranae associated stressors has to be considered differentially for particular functional groups which argue for the support of a functionally diverse pollinator community and special arrangements for the most severely affected groups. In Chapter 2, the agriculturally managed wild bee Osmia bicornis was used as model for solitary bees in an inoculation experiment with N. ceranae. The results revealed that inoculation had negligible impacts only on male survival. Several different species of wild bees that shared floral resources with infected honey bees in the environment were screened for the pathogen and were shown to be widely positive for N. ceranae whereas the pathogen was not detected in wild bees collected at another field site with uninfected honey bees. O. bicornis could therefore be acting as a pathogen reservoir and vector enhancing the circulation of N. ceranae within the pollinator network which affects both managed and wild bees. Larvae of O. bicornis were exposed to spores of N. ceranae during development in Chapter 3. Exposed individuals were characterized by a greater mortality and a delay in the onset of pupation even though very few spores were detected in a few individuals. Exposure was also associated with a reduction in body size in males as well as an increase in head capsule width in both sexes. The individuals which were exposed to the pathogen as larvae did not show any fitness costs after hatching. The results indicate that even without proliferation, N. ceranae can have sublethal effects on particular life history stages of O. bicornis and affect development in this solitary bee model. Collectively, the results suggest indirect and direct impacts of N. ceranae on solitary wild bees but have to be extrapolated with caution regarding species-specific differences in pathogen impacts. Furthermore, in the environment, multiple stressors are afflicting wild bees and can interact synergistically. The present thesis delivers useful starting points for further inoculation experiments with a suitable solitary wild bee model and important information regarding pathogen reservoir species within the pollinator community. In conservation management, special support for particularly sensitive functional groups and life stages is required.

Ziel dieser Arbeit ist eine gattungstypologische Untersuchung der ersten italienischen Musikdramen mit mythologischer Handlung: Ottavio Rinuccinis Dafne (Florenz 1598) und Euridice (Florenz 1600), Alessandro Striggios Orfeo (Mantua 1607), Rinuccinis Arianna (Mantua 1608) und Stefano Landis La morte d’Orfeo (Rom 1619). In den dramatischen Gattungen des ausgehenden 16. Jahrhunderts lässt sich eine progressive Mischung der Gattungen konstatieren, welche sich in der Oper erstmals vollständig vollzieht: Die Gattungsmischung, welche von Ulrich Schulz-Buschhaus als epochale Signatur des Barock definiert wurde, wird zum proprium der neuen Gattung des Musikdramas. In dieser Arbeit wird die experimentelle und facettenreiche Gattungsmischung innerhalb der ersten Dramen ans Licht gebracht und analysiert, wobei insbesondere auf die Funktionalisierung der einzelnen Gattungselemente, die sich je nach historischer und ideologischer Situierung verändern, eingegangen wird.

Die Retinol Saturase (RetSat) stellt einen neuen Regulator des hepatischen Glukose- und Lipidstoffwechsels dar. Durch Beeinflussung der Aktivität des glukoseaktivierten Transkriptionsfaktors carbohydrate response element-binding protein (ChREBP) in der Leber, ist die RetSat mit an der Aufnahme von Kohlenhydraten und dessen Umwandlung zu Lipiden beteiligt. Der zugrundeliegende Mechanismus ist bisher noch nicht bekannt. Jedoch scheint die egg laying defective nine homolog 3 (EGLN3), ein durch RetSat-reguliertes proteinmodifizierendes Enzym, die ChREBP-Aktivität durch potentielle Prolinhydroxylierungen maßgeblich zu beeinflussen.

Die vorliegende Arbeit soll zu einem erweiterten Verständnis der physiologischen Funktion der RetSat in der Leber beitragen und den zugrundeliegenden Mechanismus der RetSat-ChREBP-Interaktion aufdecken. Insbesondere die identifizierten Prolinhydroxylierungen im ChREBP sollen hinsichtlich einer regulatorischen Funktion untersucht werden. Im Rahmen dessen soll eine hepatische RetSat-Depletion in adipösen Mäusen untersucht und primäre Maushepatozyten für Translokationsstudien von endogenem ChREBP verwendet werden. Um eine Aussage über eine Relevanz der RetSat im Glukose- und Lipidstoffwechsel im Menschen zu treffen sollen humane Leberproben analysiert werden. Mittels zielgerichteter Mutagenese sollen die Prolinhydroxylierungen an Position 141 und 536 im ChREBP in verschiedenen Zelllinien (HEK293, AML12) untersucht werden. Zusätzlich soll eine neue konditionale RetSat knockout-Mauslinie generiert werden.

Die RetSat ist an der Entstehung einer hepatischen Steatose beteiligt. So führte eine RetSat-Depletion in adipösen Mäusen zur Reduktion des Leberlipidgehaltes und damit zur Verbesserung der durch Hochfettdiät-induzierten hepatischen Steatose. Außerdem zeigten Mäuse mit hepatischer RetSat-Depletion eine verbesserte Glukosetoleranz. In humanen Leberproben konnte zusätzlich eine positive Korrelation zwischen RETSAT-Expression und dem Schweregrad einer bestehenden Steatose sowie dem Body-Mass-Index gezeigt werden. Als Ursache für die verminderte ChREBP-Aktivität infolge einer RetSat-Depletion konnte, durch konfokale Fluoreszenzmikroskopie von endogenem ChREBP, eine verminderte nukleäre Anreicherung in primären Maushepatozyten nachgewiesen werden. Zusätzlich konnte die Prolinhydroxylierung an Position 141 und 536 im ChREBP als eine neue regulatorische posttranslationale Modifikation identifiziert werden. Die Substitution der Proline an Position 141 und 536 im ChREBP ließen eine eingeschränkte (P536) bzw. stark dezimierte (P141) ChREBP-Aktivität nachweisen. Die neue konditionale RetSat knockout-Mauslinie konnte erfolgreich generiert und die Funktionalität durch eine induzierte RetSat-Deletion in der Leber bereits bestätigt werden. Damit steht diese Mauslinie in Zukunft für Kurz- und Langzeitstudien einer RetSat-Deletion in beliebigen Organen zur Verfügung.

Die Ergebnisse weisen darauf hin, dass die verminderte ChREBP-Aktivität infolge einer RetSat-Depletion von EGLN3 abhängig ist. Durch eine RetSat-Depletion könnte die prolinhydroxylierende Eigenschaft der EGLN3 abgeschwächt sein, wodurch die ChREBP-Aktivität infolge fehlender Prolinhydroxylierungen an Position 141 und 536 vermindert ist. Da metabolische Erkrankungen, wie Diabetes mellitus Typ 2 und NAFLD, häufig mit einer verstärkten ChREBP-Aktivität in der Leber assoziiert sind, könnte eine Inhibition der hepatischen RetSat therapeutischen Nutzen zur Behandlung einer hepatischen Steatose, Dyslipidämien sowie einer Hyperglykämie haben.

First Chapter: The period of jobless and wageless growth that followed the great recession in the United States raises the question why expansionary credit policies were less effective for the recovery in employment and real wages in comparison to output. Using a structural time series analysis of the US credit and labor markets since 1965, I find that, indeed, credit supply expansions have been associated with a negative impact on the aggregate labor share. This paper offers one explanation that relies on the composition effects of credit expansion. I provide evidence that the pass-through of aggregate credit supply fluctuations to employment growth is stronger for industries that face higher borrowing costs. Firms in these industries prefer collateralizable capital to labor, and pay lower wages. Consequently, by increasing their share in total output and employment, the change in composition following an expansion in credit supply exerts negative pressure on the aggregate labor share. I build a dynamic model of heterogeneous firms and an aggregate financial sector, which accounts for the interaction between financial and labor market frictions. The model reproduces the negative composition effects of an aggregate credit supply expansion, and reconciles them with the positive within-firm effects predicted by models that abstract from the role of financial heterogeneity across firms. The paper, therefore, raises the concern that credit easing may not target firms that have strong potential to hire or pay high wages. Second Chapter: The paper estimates the dynamic impact of structural oil market shocks on the balance sheet of US firms, using industry level data covering manufacturing, trade and mining sectors. For manufacturing firms, findings indicate that an unexpected disruption in oil supply that raises oil prices by 1$\%$ lowers firm profits by 1.3$\%$ on impact. On the other hand, profits rise by 0.39$\%$ in response to the same increase in the price of oil, when it is driven by a positive movement in the global demand for oil, and by 0.79$\%$ after an unexpected surge in speculative oil demand. The positive balance sheet effect of speculative oil shocks on the manufacturing sector contrasts their negative effect on global economic activity. An explanation follows from the industry level analysis, which suggests that speculation in the oil market creates a ripple effect in downstream industries and raises inventory demand for petroleum and chemical products. In contrast to its secondary role in explaining historical variations in the price of oil and profits in trade and mining sectors, oil supply shocks are found to have been the dominant oil market innovations in driving fluctuations in manufacturing firms' profits. The analysis also finds a limited response of production costs to exogenous changes in the oil price, disputing the classic notion that the cost share of oil in an industry determines its level of exposure to oil market shocks. Third Chapter: Large productivity gaps across sectors persist and the process of structural transformation is stagnant in many developing economies. This wedge between observed and optimal labor allocations reflects the presence of institutional and market frictions, which impose costs on the optimal reallocation of labor from low to high productivity sectors. Using a panel of cross-country sector-level data, I estimate a dynamic panel error correction model that captures the dynamics of sectoral labor flows. The model estimates provide a new set of stylized facts on the dynamics of the structural transformation process, and a measure of the magnitude of frictions facing labor flows. In addition, I analyze the contribution of labor regulations and reforms to the pace at which labor flows across economic sectors. Results suggest that policy reforms need to steer between the goal of easing job creation and destruction, while supporting labor supply incentives to reallocate through strong social nets, labor protection, and risk sharing.

Wildnager sind wichtige Zwischenwirte und paratenische Wirte für Parasiten von Hunden und Katzen. Dazu gehören auch Parasiten der Gattungen Toxoplasma, Echinococcus und Toxocara, die eine bedeutende Rolle als Zoonosen spielen. Wildnager können als Indikator für die Kontamination der Umwelt mit infektiösen Stadien dieser Pathogene genutzt werden und damit zur Einschätzung des Infektionsisikos für Menschen und Haustiere beitragen. In der vorliegenden Studie wurden im November 2010 sowie zwischen April und November 2011 an vier verschiedenen Standorten in Berlin Wildnager gefangen. Zwei der Standorte lagen im städtischen/urbanen Bereich und die anderen beiden waren periurban im Randbereich von Berlin lokalisiert. Die gefangenen Nager wurden einer kompletten parasitologischen Untersuchung unterzogen, in der verschiedene Organproben genommen wurden, um diese später auf Parasitenstadien zu untersuchen. Es wurden verschiedene PCRs durchgeführt, um DNA Protozoen speziell von T. gondii, und Helminthen, insbesondere von Toxocara spp., in Gewebeproben vom Gehirn (Toxocara und T. gondii) oder vom Muskel (Toxocara) der Tiere nachzuweisen. Zusätzlich wurden während der Sektion Metazestoden gesammelt, die ebenfalls über eine PCR gefolgt von Sequenzierung bestimmt wurden. Des Weiteren wurde ein ELISA zur Detektion von Antikörpern gegen T. canis durchgeführt. Insgesamt konnten 257 Wildnager über den Fangzeitraum gefangen werden. Es wurden bei 14,2 % der Nager Antikörper gegen T. canis nachgewiesen. In Muskulatur oder Gehirn wurden acht Tiere auf T. canis, vier für T. cati und ein Tier für Parascaris sp. positiv getestet. Der am häufigsten nachgewiesene Parasit war F. glareoli mit einer Prävalenz von 13,6 %. Erwartungsgemäß wurde dieser Parasit überwiegend in Rötelmäusen gefunden (44,1 % Prävalenz), er wurde hier aber erstmals auch in wenigen Gelbhals- und einer Brandmaus nachgewiesen. Lediglich in 12 Wildnagern wurde T. gondii detektiert, was einer Prävalenz von 4,7 % entspricht. Dabei waren Nager aus der Gattung Microtus signifikant häufiger T. gondii-positiv als solche der Gattung Apodemus. Es gab keinen Nachweis von Echinococcus und die vorhandenen Metazestoden wurden molekularbiologisch den Arten M. litteratus und T. martis zugeordnet. Außerdem wurde in einer Rötelmaus C. globifera identifiziert, ein Parasit der bei Greifvögeln vorkommt. Bei der statistischen Untersuchung der Daten ergab eine Analyse mittels „Non-metric multidimensional scaling“ (NMDS) in Kombination mit einer Clusteranalyse, dass die Parasitenfauna in eine urbane und periurbane Gruppe aufgeteilt werden können. In der urbanen Gruppe wurde ein hohes Vorkommen von Askariden-Larven positiven Tieren verzeichnet, hingegen wurde die periurbane Gruppe durch das Auftreten von F. glareoli geprägt. Abschließend lässt sich sagen, dass bei dieser durchgeführten Studie Parasiten mit zoonotischen Potential nachgewiesen wurden. E. multilocularis als bedeutendster zoonotischer Erreger wurde in keinem der Wildnager gefunden. Toxocara spp. war der am häufigsten nachgewiesene Parasit. In diesem Fall scheint die serologische Untersuchung mittels ELISA von Nagetieren eine sinnvolle Maßnahme um die Kontamination der Umwelt mit T. canis zu monitoren. Es scheint aber aufgrund der besonders schnell ansteigenden Zahl von Hauskatzen wünscheswert entsprechende Assays auch für T. cati zu entwickeln und einzusetzen.

Human herpesvirus-6 (HHV-6) is a betaherpesvirus that has been classified as two distinct virus species, HHV-6A and HHV-6B, based on the differences in their biological and genetic characteristics. Primary infection with HHV-6B causes a febrile illness in children called roseola infantum (sixth disease), which is occasionally associated with neurological issues like seizures and encephalitis. The clinical aspects and epidemiology associated with HHV-6A infections are inadequately understood. Following primary infection the virus establishes a lifelong persistence in infected individuals, termed as latency. Both HHV-6A and -6B are known to integrate their genome into host telomeres of latently infected cells. When integration of the virus occurs in germ cells it results in individuals that harbor the integrated virus in each and every nucleated cell in their body. This condition is commonly termed as inherited chromosomally integrated HHV-6 (iciHHV-6) and is present in about 1 % of the global human population. Both HHV-6A/B can reactivate from latently infected cells, as well as in iciHHV-6 patients, and is associated with several clinical conditions including encephalitis and graft rejection following transplantation. Human cord blood mononuclear cells (CBMC) and peripheral blood mononuclear cells (PBMC) provide efficient replication of HHV-6A and -6B. Various T-cell lines including JJHan and SupT1 cells are permissive to HHV-6A/B lytic replication as well. It is also interesting to note that the viruses can establish latency in these cell lines; however, it remains unknown how the decision between lytic replication and latency is made. In the target cells, after infection, the virus genome is confronted with the nuclear domain 10 (ND10) complex that possesses antiviral activity against a plethora of viruses. The three major constituents of the ND10 complex are namely, promyelocytic leukemia antigen (PML), speckled protein of 100kDa (Sp100) and human death domain-associated protein 6 (hDaxx). Numerous viruses belonging to the herpesviridae family encode proteins that have been shown to manipulate these components and disrupt the ND10 complex during the establishment of infection. For example, ICP0 of herpes simplex virus 1 (HSV-1) induces degradation of PML and Sp100. Similarly, the viral immediate early protein-1 (IE1) of human cytomegalovirus (HCMV) interacts with PML and induces dissociation of the ND10 complex. Additionally, HCMV pp71 induces degradation of hDaxx, which is an important step for productive HCMV gene expression. Majority of known human herpesviruses have been found to efficiently subvert the ND10 complex to establish a successful lytic infection in the host; however, the role of the ND10 complex in HHV-6 infection remains poorly understood. In this project I investigated the role played by the ND10 protein complex on the event of HHV-6A infection. Firstly, to determine the status of ND10 complex in HHV-6A infected cells I stained and checked for the status of PML (indicative of ND10 complex) in HHV-6A infected JJHan cells. Immunofluorescence studies revealed that ND10 bodies are not dissociated, but their number is reduced in lytically infected cells. To address the role of the ND10 complex, I knocked down the key constituents PML, Sp100 and hDaxx in HHV-6A permissive cells using shRNAs. Clonal cell lines were generated from the ployclonal knock down stock. In the follow up step I used the clonal KD10 knock down cells in an infection assay to determine the effect of the absence of ND10 constituents on viral replication. My data revealed that lytic replication of HHV-6A was significantly enhanced upon knockdown of the ND10 complex. Finally, I also investigated the effect of ND10 complex on suppression of viral gene expression. For this purpose I HHV-6A virus with a GFP tag on the late lytic gene U57 and infected ND10 knockdown cells. The data obtained clearly showed that viral gene expression was more efficient in cells upon knockdown of ND10 complex as compared to the parental cells. Taken altogether, my data provides the unique evidence that unlike other human herpesviruses HHV-6A replication within host cells are suppressed by the ND10 complex. Furthermore HHV-6A gene expression is also silenced because of the presence of the ND10 complex. Also, my study garners evidence of stronger lytic replication of HHV-6A in the absence of the ND10 complex, which provides a strong case for the ND10 complex as a key contributor towards HHV-6A latency.