Influenza viruses are negative sense segmented enveloped RNA viruses covered with 2 surface peplomers: the trimeric hemagglutinin (HA), which catalyzes virus entry by binding to sialic acid containing receptors and by performing fusion of viral with endosomal membranes and the neuraminidase (NA), which is required for release of virus particles from infected cells. Among the influenza virus proteins, only HA and the proton-channel M2 are sitespecifically modified with fatty acids (S-acylated), which is essential for virus replication. Whereas two cysteines in the short cytoplasmic tail of HA contain only palmitate, stearate is exclusively attached to one cysteine located close to the cytoplasmic border of the transmembrane region (TMR). M2 is palmitoylated at a cysteine positioned in an amphiphilic helix near the TMR. The enzymes catalyzing acylation of HA and M2 have not been identified, but ZDHHC enzyme family who acylate cellular proteins are obvious candidates. In the first part of this thesis, the expression of 23 ZDHHC family members was analyzed in human lung cells using qPCR. Results showed that all ZDHHCs (except ZDHHC19) are expressed. Interestingly, ZDHHC22 was upregulated during influenza virus infection suggesting that it might be involved in acylation of viral proteins. However, CRISPR/Cas9 mediated knockout of ZDHHC22 did not affect acylation of both intracellularly expressed HA and M2 as revealed by Acyl-RAC and click chemistry as well as HA incorporated into virus particles as shown by MALDI-TOF MS analysis. However, I confirmed that ZDHHC22 is an acyltransferase using LC/MS comparative palmitome analysis, which identified more than 50 proteins as substrates of ZDHHC22. Furthermore, I identified the nonstructural protein 1 (NS1) as the triggering factor for ZDHHC22 upregulation during influenza infection using expression vectors and virus deletion mutants. In the second part, I identified for the first time 4 ZDHHC enzymes that are involved in acylation of hemagglutinin (HA). For screening, I used a siRNA library to knockdown expression of each of the 23 human ZDHHCs in HA-expressing Hela cells. siRNAs against ZDHHC2 and 8 had the strongest effect on acylation of HA as demonstrated by acyl-RAC and confirmed by 3H-palmitate labelling. The subsequent CRISPR/Cas9 knockout of ZDHHC2 and 8 in HAP1 cells, but also of the phylogenetically related ZDHHCs 15 and 20 strongly reduced acylation of group 1 and group 2 HAs and of M2, but individual ZDHHCs exhibit slightly different substrate preferences. These ZDHHCs co-localize with HA at membranes of the exocytic pathway in a human lung cell line. ZDHHC2, 8, 15 and 20 are not required for acylation of the hemagglutinin-esterase-fusion protein of Influenza C virus that contains only stearate at one transmembrane cysteine. Surprisingly, knockout of these ZDHHCs also did not compromise acylation of HA of Influenza B virus that contains two palmitoylated cysteines in its cytoplasmic tail.

Die Bedeutung sozialer Determinanten für die Gesundheitsversorgung speist sich aus dem postulierten Ziel einer gesundheitlichen Chancengleichheit. Systematische Unterschiede aufgrund sozialer Determinanten verweisen auf eine Chancenungleichheit. Ziel der Habilitationsschrift war es, anhand ausgewählter Bereiche der gesundheitlichen Versorgung zu einem besseren Verständnis und einem Informationsgewinn hinsichtlich des Zusammenhangs von sozialen Determinanten und gesundheitlicher Versorgung beizutragen. Im Unterschied zur gängigen Praxis in der Sozialepidemiologie und den Gesundheitswissenschaften lag der Fokus hierbei nicht primär auf vertikalen Determinanten (Einkommen, Beruf, Bildungsstatus). Vielmehr wurde eine integrierte Herangehensweise gewählt, die vertikale Determinanten und horizontale Determinanten (Alter, Geschlecht, Familienstand, etc.) gleichermaßen betrachtet. Zudem wurden Erklärungsansätze für Unterschiede aufgrund sozialer Determinanten diskutiert. Die Ergebnisse beruhen auf verschiedenen Datengrundlagen (Routine-, Kohorten-, Surveydaten). Die statistischen Analysen erfolgten anhand binär logistischer Regressionen, Trend- und Clusteranalysen, Diskriminanzanalysen sowie verschiedener Tests (Hosmer-Lemeshow, Omnibus-Tests, Interaktionsterme). Als bedeutende soziale Determinante zeigt sich in allen Teilstudien das Lebensalter – dies beruht zum einen auf der Tatsache, dass mit einem höheren Lebensalter eine höhere Krankheitslast einhergeht. Zum anderen verweisen die Analysen aber auch auf soziale Konnotationen des Alters, etwa in Hinblick auf das diskutierte „Zufriedenheitsparadox“, Unterschiede in der Gesundheitskompetenz oder hinsichtlich der Erwartungshaltungen zur Gesundheitsversorgung (Kapitel 3.1 und 3.2). Die horizontale Determinante „Partnerschaft“ spielt im Kontext von Pflegebedürftigkeit eine signifikante Rolle (Kapitel 2.2). Alte und sehr alte Menschen, die angaben, in einer Partnerschaft zu leben, waren seltener pflegebedürftig. Die multivariablen Analysen deuten darauf hin, dass sich die protektive Wirkung einer Partnerschaft über die Unterstützung im Alltag erklärt, so dass etwa das Sturzrisiko abgefedert oder die Mobilität befördert werden kann. Unterschiede zwischen Männern und Frauen wurden in keiner der Untersuchungen festgestellt, wenn nach Morbiditäten, geriatrischen Assessment-Parametern oder der subjektiven Gesundheit kontrolliert wurde. Analog zu den geschlechtsspezifischen Ergebnissen zeigen sich auch keine bildungsspezifischen Unterschiede im Pflegerisiko mehr, wenn Morbiditäten berücksichtigt (adjustiert) werden (Kapitel 2.2). Die vertikale Determinante Bildung spielt darüber hinaus im Bereich der ambulanten, gesundheitlichen Versorgung eine signifikante Rolle. Anhand der Ergebnisse wurde deutlich, dass höher Gebildete die untersuchten Aspekte der Health System Responsiveness besonders kritisch bewerten (Kapitel 3.2) sowie den niedrigsten Kenntnisstand zu Neuregelungen im Gesundheitssystem aufweisen – das letztgenannte Ergebnis bezieht sich allerdings nicht auf alle höher Gebildeten, sondern nur auf Erwerbstätige im mittleren Alter (Kapitel 3.3). Zukünftige Studien zu sozialen Determinanten in der Gesundheitsversorgung sollten neben vertikalen Determinanten vermehrt auch horizontale Determinanten analysieren. Die vertikalen sozialen Determinanten Bildung, Einkommen und/oder beruflicher Status sind zwar, da es sich um „erworbene“ Eigenschaften handelt, augenscheinlich zugänglicher für Präventionsmaßnahmen als die „zugeschriebenen“ Merkmale wie Alter oder Geschlechts-zugehörigkeit. Allerdings zeigen gerade die Ergebnisse der vorliegenden Arbeit, dass diese quasi biologischen Kategorien für Prävention und Interventionsansätze von hoher Relevanz sind. Daher ist eine integrierte und im besten Fall verschränkte Sicht verschiedener sozialer Determinanten der Ungleichheit empfehlenswert.

The ability to recognize movement pattern of lame horses accurately, requires practice and experience from equine clinicians. Hindlimb lameness evaluation is known to be more difficult than the forelimb counterpart. Even among experienced veterinarians agreement in hind limb lameness evaluation was only reported to be in acceptable range. This leads to the potential inaccuracy of subjective assessment of diagnostic analgesia. Moreover, veterinarians as subjective individuals are prone to bias. Therefore, numeral objective lameness measuring methods have been developed in the past decades in order to aid veterinarians. The objective system used in this study is a body-mounted inertial sensor system (BMISS) which has been proved to have adequate accuracy and sufficient repeatability. In the first study, the agreement among veterinarians (interobserver agreement) and the agreement between veterinarians and the BMISS have been investigated. The results emphasised that hindlimb lameness examination is challenging even for experienced equine veterinarians. The BMISS showed to have high agreement with clinicians in clinical live situation when evaluating hindlimb lameness, and with a group of highly experienced veterinarians when assessing the changes after diagnostic analgesia. These results should encourage the use of the BMISS as an aid in lameness examination. The second study has taken the benefits of the BMISS as a bias-free objective method to evaluate improvement of lameness after the analgesia of the deep branch of lateral plantar nerve (DBPLN) and the analgesia of the tarsometatarsal joint (TMT) in horses with suspected pain in the lower hock area. In 63% of the horses with suspected lower hock pain an improvement of lameness was observed after the analgesia of the DBLPN, but not after the analgesia of the TMT. Based on this result, the analgesia of the DBLPN did desensitise a different source of pain than the TMT analgesia. However, in the other 37% of the horses lameness improved after both analgesia. Therefore, it was not possible to differentiate source of lameness in this second group of horses. There are several possible explanations for the different pattern of lameness improvement in the 2 groups such as diffusion of anesthetic agent, inadvertent placement of the needle or concurrent pathologies. Nevertheless, since sonography and radiography were only the imaging modalities used in this study, it is still an open question what the exact cause of lameness was. In order to gain more understanding about the pathologies and improvement of lameness after these analgesia, similar studies using more advanced imaging modalities such as MRI or scintigraphy should be performed.

Das Cholangiokarzinom beim Menschen zeigt ein aggressives Wachstum und ist weitgehend resistent gegen Chemotherapie und Bestrahlung. Die einzige kurative Therapiemöglichkeit ist die Resektion, wobei die Rezidivrate sehr hoch ist. Salinomycin ist ein Polyether-Antibiotikum, das in der Geflügelindustrie als Antikokzidium eingesetzt wird und eine Wirksamkeit gegen diverse solide und nicht-solide Tumorentitäten aufweist. Der zu Grunde liegende molekulare Wirkmechanismus ist noch weitestgehend unverstanden; eine Interferenz mit der Autophagie der Tumorzellen wird vermutet. Die Autophagie ist das dynamische Recyclingsystem der Zelle, das vor allem intrazelluläres Material abbaut. Das arbeitsleitende Ziel dieser Dissertation war es zum einen, Grundlagen zur Etablierung eines Cholangiokarzinom-Mausmodell zu schaffen, um die Wirksamkeit von Salinomycin in vivo analysieren zu können. Dafür wurden Versuche zur Proliferation, Migration, Invasion und Apoptoseinduktion nach Behandlung mit Salinomycin in den beiden murinen Cholangiokarzinomzelllinien p246 und p254 durchgeführt. Zum anderen sollte der Wirkmechanismus von Salinomycin in den humanen Cholangiokarzinomzelllinien TFK-1 und EGI-1 untersucht und dabei die Hypothese überprüft werden, ob Salinomycin einen Einfluss auf die Autophagieaktivität der Zellen hat. Dafür wurden die Methoden Western Blot, Durchflusszytometrie, Fluoreszenzmikroskopie, Polymerasekettenreaktion und WST-1 Assay verwendet. Salinomycin hemmte dosisabhängig die Proliferation, Migration, Invasion und induzierte die Apoptose in murinen Cholangiokarzinomzellen. In den humanen Cholangiokarzinomzellen hemmte Salinomycin die basale und die pharmakologisch aktivierte Autophagie. Dabei kam es in den Zellen zu einer Akkumulation dysfunktionaler Mitochondrien und reaktiver Sauerstoffverbindungen. Eine Vorbehandlung mit dem Antioxidans N-Acetylcystein verbesserte die Vitalität der Zellen nicht. Die Beeinflussung selektiver Autophagiegene (ATG) nach Behandlung mit Salinomycin war in den beiden humanen Cholangiokarzinomzelllinien unterschiedlich. In TFK-1 Zellen war die Expression einzelner ATG vermindert während bei EGI-1 Zellen eine erhöhte Expression einzelner Autophagiegene gemessen wurde. Diese Arbeit liefert Ergebnisse für die Etablierung eines Cholangiokarzinom-Mausmodells. Zusätzlich konnte gezeigt werden, dass die Behandlung von humanen Cholangiokarzinomzellen mit Salinomycin zu einer Inhibition der Autophagie mit konsekutiver Akkumulation dysfunktionaler Mitochondrien und reaktiven Sauerstoffspezies und einer Beeinflussung der Autophagiegene führt.

Der Energiebedarf von Hochleistungskühen wird entscheidend von der Laktation geprägt und führt zu Veränderungen in der Energiebilanz (EB) und im Stoffwechsel. Sobald der Energiebedarf die über das Futter aufgenommene Energie übertrifft, mobilisieren hochleistende Milchkühe verstärkt ihre Körperreserven, vorallem von Fett. Während es nach dem Kalben und in der Frühlaktation (FL) vermehrt zur Fettmobilisierung (Lipolyse) kommt, findet in den späteren Laktationsphasen und in der Trockenstehzeit eine Fetteinlagerung (Lipogenese) statt. In der während der Lipolyse auftretenden Phase der negativen EB wirkt sich der Energiemangel auf die Energieversorgung der Zellen aus. Dabei wird ein großer Teil der zellulären Energieversorgung von den Mitochondrien, die ein eigenes Genom besitzen (mtDNA), bereitgestellt. Oxidative Schäden an der DNA der Mitochondrien, die durch eine langfristig hohe Stoffwechselbelastung (oxidativer Stress) hervorgerufen werden, können zu zellulären Fehlfunktionen und zur Beeinträchtigung des Energiestoffwechsels führen und den Alterungsprozess beschleunigen. Die Zellalterung kann einerseits über die DNA-Methylierung und andererseits durch Telomere gesteuert werden. Ziel dieser Arbeit war es, in einem ersten Versuch den Einfluss der Laktation und die Auswirkungen von oxidativem Stress auf die zelluläre Energieversorgung sowie auf den Alterungsprozess zu untersuchen und zu prüfen, ob diese Prozesse in einem Zusammenhang stehen. Ein weiterer Schwerpunkt bestand im zweiten Versuch in der Fragestellung, ob sich die Telomerlänge (TL) auch in der Nasenschleimhaut von Kühen mit zunehmendem Alter verkürzen und ob somit nichtinvasive Probenentnahmen in Form von nasalen Tupfern die invasiven Blutprobenentnahmen zur TL-Bestimmung bei Milchkühen ersetzen können. Für die Untersuchungen innerhalb des ersten Versuches wurden tragende Färsen (n = 8) mit einer Kontrollgruppe, die aus gleichaltrigen, nicht tragenden Färsen (n = 8) bestand, über einen Zeitraum von zwei Laktationen (Trächtigkeit (TK); 1. FL; 1. Spätlaktation (SL); 2. FL) miteinander verglichen. Den Tieren wurden Biopsien aus der Leber und dem subkutanen Fettgewebe im Bereich des Schwanzansatzes sowie Blutproben entnommen. In den Proben wurde oxidativer Stress, die Mitochondriendichte und -aktivität, Apoptose und die Adipozytengröße, die mtDNA-Kopienanzahl, die relative Anzahl an Telomerprodukten (qT) und die DNA-Methylierung (DNMT1, DNMT3a) untersucht. In einem zweiten Versuch, der in 3 Teilversuche untergliedert war, wurden 60 Tiere der Rasse Deutsche Holstein in 3 Versuchsgruppen eingeteilt. Die erste Gruppe bestand aus 20 Kälbern, die zweite Gruppe aus 20 Färsen und die dritte Gruppe aus 20 laktierenden Kühen mit der Laktationszahl 1 bis 3. Im 1. Teilversuch wurde bei allen 60 Tieren im Bereich der Nasenschleimhaut mit Hilfe von nasalen Tupfern Proben entnommen. Im 2. Teilversuch wurde die Kälbergruppe erneut mit nasalen Tupfern 6 und 18 Monate nach der ersten Probenentnahme (Teilversuch 1) beprobt. Im 3. Teilversuch wurden bei je 6 laktierenden Kühen der 2. und 3. Laktation 3 Monate nach der ersten Beprobung (Teilversuch 1) Milch-, Heparin-Vollblut- und nasale Tupferproben entnommen, um anschließend in den gesamten Proben die qT zu bestimmen. Die Ergebnisse des ersten Versuches zeigten, dass oxidativer Stress in Form einer gesteigerten Energieversorgung innerhalb der Zellen des Fettgewebes die Energieverfügbarkeit beeinflusst. Sowohl der mtDNA-Gehalt der Zellen des Leber- und Fettgewebes als auch die Adipozytengröße und die Apoptoserate im subkutanen Fettgewebe verändern sich laktationsbedingt, wobei die laktationsabhängige Adipozytengröße zu einer energetischen Unterversorgung der Zellen führt und dies im Zelltod endet. Eine Laktation bei Milchkühen hat im subkutanen Fettgewebe keinen Einfluss auf die TL und somit einem beschleunigtem Alterungsprozess, wohingegen die DNA-Methylierung im Leber- und Fettgewebe durch eine Laktation beeinflusst wird. Im zweiten Versuch zeigte sich, dass sich die TL mit zunehmendem Alter verkürzt, dass weibliche Kälber von Geburt an tendenziell mit längeren Telomeren ausgestattet sind als Männliche und dass die TL-Verkürzung umso größer ist, je länger die Ausgangs-TL ist. Nasale Tupferproben könnten im Gegensatz zu Milchproben eine nichtinvasive Alternative zur TL-Bestimmung bei Kühen darstellen. Die Ergebnisse der vorliegenden Studie geben nur einen begrenzten Einblick. Um die umfassenden Mechanismen der zellulären Energieversorgung bei Milchkühen zu verstehen und den Einfluss mehrerer Laktationen in weiteren Gewebearten zu untersuchen, sind zukünftige Studien notwendig. Auch eine größere Probenanzahl und weitere potenzielle nichtinvasive Alternativen, wie Haarproben, zur TL-Bestimmung sollten in nachfolgenden Studien berücksichtigt werden.

Protecting the environment and remediating it from the consequences of anthropogenic activities has become an important challenge in today’s world. Advancements in the field of catalysis, as an integral part of sustainable and green chemistry, play a major role in the development of new environmentally benign technologies to achieve this. In this regard, the field of nanotechnology opened up new possibilities for the design and synthesis of robust enzyme mimics (nanozymes) that fulfill the criteria of a green catalyst. In particular, gold nanoparticles (Au-NPs) functionalized with catalytically active peptides (Pep-Au-NPs) have proven to be a promising strategy towards the creation of artificial enzymes with remarkable properties in molecular recognition and catalysis. However, the field is still in its infancy. To extent the contemporary insights into the field of Pep-Au-NPs and establish first design rules, one part of the research conducted in this thesis deals with the systematic study of design principles of Pep-Au-NPs. More specifically, research was focused to systematically elucidate the effect the position of the catalytic center along the peptide sequence has on the catalytic properties of the corresponding Pep-Au-NP assemblies. A correlation was found between the hydrophobic nature of the employed substrate and the region in which catalysis takes place within the generated peptide-monolayer. The other two studies included in this work were directed to broaden the application scope of these conjugates. First, Pep-Au-NP were studied in their ability to act as a multifunctional cascade catalyst that performs two sequential reactions on a given substrate. By utilizing the hybridity of the system, a peptide-monolayer was established that catalyzed ester hydrolysis, while the Au-NP surface functioned as an efficient hydrogenation catalyst. The reaction was performed as a one-pot reaction in aqueous solution. Second, a Pep-Au-NP was designed to function as an artificial carbonic anhydrase (CA) mimic for the conversion of CO2 to HCO3- in water. The artificial CA was able to catalyze CO2-hydration and showed superior catalytic activity over the unconjugated peptide variant. Recycling of the Pep-Au-NP was possible without significant loss in activity even after treatment at elevated temperatures. The results of this work, on the one hand, contribute to the rational design and synthesis of Pep-Au-NPs as artificial nano-enzymes; on the other hand, provide proof-of-concepts that Pep-Au-NPs are able to perform reactions applied in environmental-friendly processes.

Previous research has substantially contributed to further developing psychological interventions that aim to alleviate symptoms of psychopathology. In contrast, interventions that aim to build happiness are still in their infancy. Evidence from the past two decades indicates that positive-psychological interventions—relatively simple intentional activities that are designed to cultivate positive thoughts, emotions, and behaviors increase various indicators of well-being. Their effects, however, are typically small and decrease over time, which may be resolved by further developing them. Effective further development requires comprehensive knowledge of the effects, mediators, and moderators of positive-psychological interventions. In this context, three important questions remain wholly or partially unanswered: First, what are the effects of positive-psychological interventions (e.g., practical significance, additional effects, etc.)? Second, how do positive-psychological interventions operate (i.e., what are relevant mediators)? Third, for whom and under which conditions do positive-psychological interventions show greater effects (i.e., what are relevant moderators)? The aim of this thesis is to provide answers to these questions in order to help increasing the effectiveness of positive-psychological interventions. To allow for a detailed and nuanced discussion, this thesis focuses on three prominent positive-psychological interventions: the best-possible-self intervention, the gratitude letter exercise, and self-compassionate writing. Researchers proposed that these three interventions lastingly increase well-being through either specific mechanisms (e.g., adopting a grateful outlook) or common mechanisms (e.g., activation of positive emotions or positive self-relevant thoughts). In addition, it has been suggested that these interventions yield better results for certain types of people, largely depending on whether features of the activity fit characteristics of participants. Current evidence on this topic, however, is either weak or inconclusive and recommendations on how to further develop positive psychological interventions are rarely feasible. To address this issue, three empirical studies were conducted. The aim of the first study was to investigate goal ambivalence and positive future expectations as mediators of the effect of the best-possible-self intervention on positive affect. Results from a longitudinal randomized controlled trial with baseline, immediate posttest, and 1-week follow-up assessments show that participating in the best-possible-self intervention increased positive affect and reduced goal ambivalence. Positive future expectations were not significantly affected. In addition, mediation analysis results from two latent cross-lagged panel design models indicate that neither goal ambivalence nor positive future expectations immediately after the intervention predicted increased positive affect in the following week. The aim of the second study was to examine unique and shared effects of the best-possible-self intervention, the gratitude letter exercise, and self-compassionate writing. In addition, emotional self-awareness and trait gratitude were investigated as moderators. Results from an online randomized controlled trial with four groups show that participants in the best-possible-self intervention reported higher state optimism and more positive self-relevant thoughts immediately after the activity, whereas participants in the gratitude letter exercise reported higher state gratitude and more positive self-relevant thoughts. Self-compassionate writing showed no effects. Neither emotional self-awareness nor trait gratitude moderated the effects. The aims of the third study were to comprehensively examine the effects of the best-possible-self intervention and to investigate contextual moderators. Meta-analytic results based on 34 randomized controlled intervention trials that were identified through a systematic literature search show small effects on positive affect and optimism. Effects were pronounced if the outcome was measured immediately after the intervention relative to a few days later. In addition, effects were larger if positive affect was assessed asking participants how they feel “at the moment” rather than how they feel “in general” and if optimism was conceptualized as positive future expectations rather than a general orientation in life. Descriptive results indicate no effects approximately one week after the intervention. There were no significant effects on negative affect, life satisfaction, depressive symptoms, or happiness. Administering the best-possible-self intervention online showed no significant effect on positive affect. In conclusion, effects of positive-psychological intervention may have been overestimated in the past. Specifically, the best-possible-self intervention, when administered as a stand-alone exercise, is insufficient to perpetuate lasting increases in well-being. Positive psychology practitioners who apply the intervention to clients should be aware of this limitation and must ensure that clients expectations are reasonable. The best-possible-self intervention may, however, be suitable to temporarily increase positive affect and optimism. In addition, the exercise has been shown to reduce ambivalent feelings regarding one’s life goals, which may be particularly relevant for career coaching clients who face a transition period. Moreover, the best-possible-self intervention and the gratitude letter exercise show both unique and shared effects that might serve as mediators. Thus, further developing these interventions might start with both strengthening specific mechanisms (e.g., explicitly encouraging participants to adopt a grateful outlook while writing a gratitude letter) and extending general working principles (e.g., providing opportunities that allow participants to see themselves in a positive light, for example, as a grateful person). Current theoretical frameworks focus either on specific or common mechanisms and future researchers should develop a framework that incorporates both types of mechanisms. In addition, online variations of the best-possible-self intervention seem to be less effective than in-person administrations. Alternative explanations for this observation could not be ruled out. Thus, future researchers should replicate this finding in more controlled settings. Finally, besides differences between online and in-person administrations, positive-psychological interventions seem to work equally well for different types of people and under varying circumstances. More research on the differential effects of positive-psychological interventions is needed to better understand when and how such interventions should be applied.

Die stratosphärische Ozonchemie übt durch ihre Kopplung an Strahlung und Dynamik der Atmosphäre einen markanten Einfluss auf den Zustand der Stratosphäre und der Troposphäre aus. Dieser Einfluss bleibt im Großteil der für dekadische und Klimavorhersagen genutzten Modelle jedoch unberücksichtigt. Klimamodelle, die die Ozonchemie mit komplexen interaktiven Chemieschemata berücksichtigen, benötigen deutlich mehr Rechenzeit als Klimamodelle, die Ozonmischungsverhältnisse als externe Felder vorschreiben. Eine alternative Methode, mit der die atmosphärische Chemie in Klimamodellen berücksichtigt werden kann, ist das schnelle stratosphärische Ozonschema SWIFT, das die heterogene Ozonchemie im stratosphärischen Polarwirbel mit minimalem Zuwachs der Rechenzeit bestimmen kann. In dieser Arbeit wurde die SWIFT-Chemie in das Klima-Chemiemodell ECHAM/MESSy Atmospheric Chemistry (EMAC) eingebaut und validiert. Es wird gezeigt, dass EMAC mit SWIFT die chemische Entwicklung von Spurenstoffen im Polarwirbel, die durch heterogene Prozesse verursacht wird, im Vergleich zu EMAC mit komplexer, interaktiver Chemie, gut wiedergeben kann. Weiterhin wird gezeigt, dass SWIFT auch für multidekadische Simulationen mit sich ändernden Konzentrationen relevanter atmosphärischer Spurenstoffe genutzt werden kann. Mit SWIFT in EMAC wurde ein Ensemble mit 10 Mitgliedern für das RCP6.0-Szenario berechnet und mit einer Simulation mit komplexer interaktiver Chemie und mit einer Simulation mit vorgeschriebenen Ozonmischungsverhältnissen verglichen. Es wird gezeigt, dass der Einfluss der internen Variabilität auf die Anzahl und saisonale Verteilung Großer Stratosphärenerwärmungen (SSWs) stärker ist als die Unterschiede durch der Berücksichtigung der Ozonchemie. Außerdem wird die Stärke des Einflusses von Änderungen in der polaren unteren Stratosphäre auf den Strahlstrom in den mittleren Breiten in Simulationen mit vorgeschriebenen Ozonfeldern unterschätzt. Es wird gezeigt, dass die äquatorwärtige Verschiebung des Strahlstroms in der 1. Hälfte des 21. Jahrhunderts auf der Wirkung der abnehmenden ozonzerstörenden Substanzen beruht, die polwärtige Verschiebung des Strahlstroms in der 2. Hälfte des 21. Jahrhunderts jedoch auf dem Treibhausgasanstieg. Aspekte der Stratosphären-Troposphärenkopplung, die durch die Verteilung von polarem Ozon beeinflusst werden, kann EMAC mit SWIFT gut wiedergeben. Mit SWIFT in EMAC ist es möglich multidekadische Simulationen mit interaktiver Chemie unter Berücksichtigung der internen Variabilität rechenzeitgünstig durchzuführen. Durch die so verbesserte Berücksichtigung der Stratosphären-Troposphärenkopplung können die Vorhersagen für dekadische und multidekadische Modellsysteme verbessert werden.

Malaria is one of the most relevant parasitic diseases and caused by infection with Plasmodium parasites. More than 3 billion people are at risk of Plasmodium infection worldwide. Populations in malaria endemic areas are subject to evolutionary selection of genetic polymorphisms conferring relative protection against the disease. Primarily, those genetic variants affect host erythrocytes. In addition, polymorphisms in genes related to molecules regulating the immune system also influence susceptibility to malaria as well as its pathophysiology. The available knowledge with respect to malaria-related traits is more extensive as regards falciparum malaria than vivax malaria. Moreover, P. vivax, traditionally thought to be benign, is increasingly reported to cause severe malaria, particularly in India. However, the available data are scarce and ambiguous. Similar limitations apply to the extent and spread of antimalarial drug resistance. In Mangaluru, southern India, firstly, we assessed the manifestation pattern of malaria and in particular of P. vivax infection. This study shows that in Mangaluru malaria is mostly uncomplicated and affects predominantly young men from a low-socio-economic background, who are majorly migrant workers from other parts of India. Severe vivax malaria occurs at a rate slightly lower than in falciparum malaria but its low prevalence contrasts with considerably higher figures reported from other parts of the country. Secondly, in a case-control study, we examined the association of polymorphisms in the Duffy antigen receptor for chemokines (DARC) with malaria. DARC is a central component in P. vivax invasion into the red blood cells. DARC 298A carriage increased the odds of malaria per se and more prominently of P. vivax infection. Interestingly, FYB carriage appeared to confer protection against severe falciparum malaria. We also expanded the existing knowledge on host genetic associations with falciparum malaria in Africa, in particularly among pregnant women and children in Africa. The O blood group was observed to confer protection against falciparum malaria in primiparous Ghanaian women, whereas a common polymorphism in miRNA 146a, rs2910164 G > C was associated with increased odds of malaria in pregnancy. In addition, we examined the association of a common TP53 polymorphism previously suggested to be malaria protective. However, this variant was not associated with falciparum malaria among Ghanaian primiparae or Rwandan children.

As to antimalarial drug resistance, we assessed associated molecular markers in Plasmodium isolates from Africa and India. The present work observed an infrequent occurrence of Kelch 13 gene variants in P. falciparum isolates from Rwanda but detected two mutations (P574L and A675V) associated with artemisinin resistance in Southeast Asia. Among the P. falciparum isolates from India, no K13 variants were present. Sulfadoxine-pyrimethamine (SP) plus artesunate is the current first-line antimalarial in India. Based on the antifolate resistance allele distribution, we assume that SP resistance in the study area is pronounced but not yet intense, thereby limiting the useful therapeutic lifespan of artesunate-SP. Moreover, the near fixation of the pfmdr1 allele combination N86-184F-D1246 suggests that artemether-lumefantrine, introduced in the northeastern parts of this country, is not a promising alternative in the study area. Chloroquine (CQ) is primarily used to treat vivax malaria and pvmdr1 variants have been associated with CQ resistance. However, the virtual absence of such variants among the P. vivax isolates as well as almost complete parasite clearance within 2-3 days suggest that CQ is still effective.

Overall, the present thesis provides new insights or expands the present knowledge on the roles of host genetic variation in various study settings which, in turn, may contribute to a better understanding of malaria pathophysiology. Moreover, this study improves the remarkably limited characterisation of the manifestation of malaria in India. Most lastly, the data show the threat of the effectiveness of the first-line antimalarials in India and Rwanda.

The increasing need to provide more efficient delivery of drugs for different illnesses is a key topic in the biomedical field. Synthetic polymers find wide employment in the development of diverse tools that perform their activity on the disease or can help to deliver small molecules like drugs to the desired site of action. In this thesis, biodegradable polyglycerol-based polymers for the treatment of inflammatory diseases and the delivery of hydrophobic guests were presented. Hyperbranched polyglycerol, which is a highly biocompatible polymer, with easy synthesis, hydrophilic character, and numerous end groups suitable for further functionalization, was chosen to develop new biodegradable compounds. The copolymerization of glycidol with Ɛ-caprolactone resulted in a biodegradable version of the well-established hyperbranched polyglycerol (hPG), thanks to the presence of ester bonds in the backbone. The copolymer has been further functionalized, characterized, and studied invitro regarding its biocompatibility, biodegradability, and suitability for the application in the biomedical field. In the first project, this new copolymer was functionalized to obtain a biodegradable sulfated derivate ((hPG-co-PCL)S), which has been investigated for possible applications in the treatment of inflammatory states. Previous studies have highlighted the high affinity of dendritic polyglycerol sulfate (dPGS) to L-selectin but also demonstrated its accumulation in organs such as the spleen and liver, remarking the necessity of biodegradable compounds for in vivo applications. In this work, it was observed that the biodegradable version of dPGS is a valid alternative to the well-established one and, depending on the molecular weight and the degree of sulfation, it was possible to achieve diverse performance profiles concerning the inhibition of the binding of L-selectin towards its ligands, a crucial step in the recruitment of leukocytes to the site of inflammation. The (hPG-co-PCL)S was also capable to reduce the activity of the complement system, showing at the same time only a restrained effect on blood coagulation. Moreover, the new copolymer was biodegradable and had low cytotoxicity, before and after degradation, which was demonstrated with different cell lines. In the second project, the biodegradable hPG-co-PCL was used as macroinitiator for the synthesis of pH responsive nanocarrier for the treatment of pancreatic cancer. It is well established that, while the human body generally presents a neutral pH, the cancer is characterized by a local acidic pH. This feature can be employed to induce the release of the guest molecules only at the desired site of action. The hPG-co-PCL core was used to graft a polycarbonate block, which was further functionalized with a tertiary amine, namely, N,N’-dibutylethylene diamine. The new polymer was used both for the covalent conjugation and physical encapsulation of the anticance drug gemcitabine (GEM). The nanocarrier was able to deliver its cargo in a pH-dependent fashion, with different rates depending on the type of loading. In the third project, the upscaling of the synthesis of hPG-co-PCL and its employment as a nanocarrier for hydrophobic guests, both before and after sulfation, was investigated. The parameters, which govern the synthesis of the hPG-co-PCL, were inspected to determine the conditions that lead to different molecular weights while improving the gram scale of the product. The production on large scale at low costs is a primary need to access the market. Moreover, the relationship between tumor and inflammation is generally accepted. The dPGS has already demonstrated to be capable of targeting the tumoral environment, which suggests using new abovementioned nanocarriers for the delivery of anticancer drugs. Two possible guests were physically encapsulated in the biodegradable copolymers: the anticancer drug doxorubicin, and a near infrared (NIR) dye. A great interaction both with doxorubicin and the dye was observed. The sulfated compounds displayed the best capacity of delivering the guest to the tumor cell line Hela in vitro, with increased performance depending on the molecular weight and correlating loading capacity. Moreover, the best candidate for the delivery of doxorubicin was loaded with the hydrophobic NIR dye S 0796 and tested in vivo to explore the capacity of the polymer in targeting the tumor. Accumulation in the tumor was observed 24 h after the injection, confirming the affinity of the sulfated compound to inflamed and cancerous tissue. These preliminary results show the potential for the employment of the new biodegradable sulfated nanocarriers for tumor therapy. These outcomes describe the potential of the new nanocarriers for biomedical application, but further studies are needed to expand these findings. In vivo studies, which demonstrate the stability of the nanocarriers in the blood stream and a sufficient circulation time, would be necessary to confirm their suitability as nanocarriers. Due to the large diversity of anticancer drugs, a screening of the possible guests should be performed to determine which cancer type represents an appropriate target for the above-presented nanocarriers. The increase in the hydrophobic caprolactone component might be taken in account to ensure a better loading capacity of small molecules like dexamethasone. The influence of the encapsulation method, namely the conjugation in comparison to the physical entrapment, of both the anticancer drugs and NIR dye should be studied to understand its role on the drug delivery in vivo. Moreover, the possibility to use the new biodegradable carriers for theranostics applications shall be further explored.

At the time of writing, the expectation for a peace settlement on the Korean peninsula is greater than ever due to ongoing inter-Korean summits as well as the historic encounters between the two leaders of the US and North Korea. Although the second Hanoi DPRK-US summit in February, 2019 ended without reaching an agreement, it is still a positive sign that formerly hostile nations are willing to talk to find a way of coexistence. However, at the same time, the degree of inner conflict within the South has grown significantly since the impeachment of former President Park Geun-hye in 2017, and there exist deep discrepancies over how to approach and how to pursue cooperation with the North. The dissertation examines how and why a variety of reforms led by the progressive administrations of South Korea, ranging from foreign policies toward the North and the US to domestic policies, have intensified social conflicts and division, rather than contributing to the conflict transformation and reconciliation that they originally aimed at. In doing so, this research contributes to the field of identity politics and peacebuilding by offering novel insights into the role of narrative identity and history in contexts of protracted, identity-based conflict, and the peacebuilding process. Its particular focus is on the Korean peninsula, one of the areas where the legacy of the Cold War is still lingering and history is deeply contested and politicized. This study primarily claims that the social and political polarization within South Korea stems from fundamental disagreements over two important concepts in the formation of national identity: 1) the self, how to define South Korea, which means whether the birth of a South Korean government should be celebrated as a lawful and legitimate process, or treated as failure to establish one united nation; and 2) the significant others, the question of how to identify North Korea and the US. The research highlights the fact that narratives on the national identity of South Korea were initially crafted in the context of intractable conflicts with the North. Narrative identities created during or after the war have been formed with a strong certainty of the good self and evil others, thus being resistant to change. In particular, the narrative of conservatives was formed with the firm certainty about the North as an evil enemy. Thus, those who see the reality of the nation through the lens of this narrative find it extremely difficult to adapt to the alternative that identifies the North as a normal neighboring state with which to coexist. Secondly, this study argues that it is identity politics, in which the rhetoric of othering/exclusion is frequently applied, that has significantly affected the intensification of social and political polarization in South Korea through creating a dichotomy of good self and evil others. Both narratives have constructed antagonism toward their own hostile “others”: North Korean sympathizers, whether called pro-North, the reds, commies, or anti-South forces, in the “state-centered nationalism narrative” of conservatives that identifies the North as an arch enemy; and anti-nationalists, including pro-Japanese and pro-American collaborators, and ruling elites, in the “ethnic nationalism narrative” of progressives that views the North as part of the self based on the ethnic notion of the Korean nation, and thus as a partner for coexistence and ultimately for unification. More importantly, both of these contradictory narratives have been politicized to delegitimize political opponents, consequently intensifying societal and political conflicts within South Korea. Lastly, the study maintains that reforms led by progressive regimes failed to create an open and inclusive “dialogical space” where competing parties can reassess and redefine their narratives in the process of policy decision making and its enactment, thus deepening conflicts. Establishing a positive domestic context toward peace through creating consensus and cooperation with those who have different values and ideologies is a necessary condition for conflict transformation and peace settlement on the peninsula. Attempts to transform the master narrative on the national identity of South Korea led by progressive regimes without efforts to engage in cooperation with their political opponents have simply replaced an old narrative with a new one, rather than constructing a transcendent and integrative narrative on which conflicting parties can agree. Hence, conservatives’ resistance to narrative transformation and related policy changes has grown intensified. The present study can not only contribute to extending generality in the study of the narrative basis of conflict, but also offer theoretical grounds for rethinking inner conflicts in South Korea to lead to conflict transformation and an ultimate peace settlement on the Korean peninsula. We have seen in post-conflict societies like Germany or Northern Ireland that a political declaration or peace agreement does not necessarily lead to genuine peaceful relations and reconciliation between the former adversaries. This justifies the argument that the narrative of rightists in South Korea who construct a strong national identity that still views the North as an arch enemy should be taken into consideration in advancing peaceful relations with the North. It is a challenging task to transform narrative identity with firm certainty based on a dichotomy of good self and evil other crafted in the context of intractable conflicts. In the process of the engagement policy toward the North and peace initiatives on the peninsula, however, some degree of consensus and cooperation between conflicting groups in South Korea who have radically different conceptions of national identity is a prerequisite for ultimate peace settlement between the two Koreas.

This study focuses on elucidating spatio-temporal and causal factors of the major changes in Eneolithic textile technologies that might be associated with raw fibre material innovation. It reports on a large textile tool sample, collected within a broad 26-site cluster across the Pannonian Plain region. Textile tools, mainly spindle whorls, were analysed according to the methodological standards of the respective field of textile archaeology. More specifically, their functional analysis was chosen as a starting point for investigating different fibre material use and procurement strategies, in order to clarify the advent and spread of wool-bearing sheep husbandry. Results of the spindle whorl analysis illustrate the extent of the exploitation of both sheep wool and flax plant fibres within the contexts of the investigated textile productions. Together with the results of the textile tool analysis that build the central part of this thesis, different strains of evidence, such as indications of climate change, altering subsistence strategies and herding patterns, suggest that animal exploitation, most probably including fibre use, was driven by local environmental conditions already in the 4th millennium BC. Archaeobotanical evidence from the investigated area and neighbouring regions propose that gathering and processing of wild and domesticated plants was also a significant component of the local textile productions. Furthermore, comparison of the investigated spindle whorl assemblages revealed that the Eneolithic textile productions were ‘culture-specific’. More precisely, both typological standards and technological specifications of these tools displayed a statistically significant dependence on the ‘archaeological culture’. Finally, the examination of social aspects of fibre processing practice indicated intensification and most probably early specialization of the spinning craft. It is possible to conclude that all the considered and analysed evidence argue an adjustment to new raw fibre material resources during the Eneolithic period in the investigated area.

This cumulative thesis is composed of three major parts: Introduction, Publications and Synthesis. The main part put forward in the second Publications chapter consists of five previously published articles and manuscripts. Appendices consist of complete datasets, which are also already available through an open-source publication. For more comfortable use of primary sources all the publications are included in their original form, while being embedded in a comprehensive binding text that consists of introductory and concluding chapters.

The present thesis “Corporate Governance and Earnings Quality in China” investigates different factors affecting earnings quality of listed firms in the Chinese stock markets. It extends the prior research on the way of attempting to find out which elements do generate a significant effect on earnings quality. The first paper “CEO’s International Experience and Earnings Management: Evidence from Chinese Listed Firms” attempts to confirm whether CEO’s international study and work experience brings a brain gain into the improvement of earnings quality, commonly measured by less earnings management. By gathering and analyzing a dataset from 2010 to 2014 on all the listed firms in Shanghai and Shenzhen stock markets, no evidence is found to support a correlation between CEO’s international experience and earnings management, no matter if earnings management is measured by discretionary accruals, meeting or beating analysts’ earnings forecasts or conditional conservatism. However, after dividing the whole sample into subsamples according to different kinds of international experience, it is concluded that CEOs with both international study and work experience try to restrain earnings management through discretionary accruals (Coef.=-0.0164, t-value=-2.39) at a significant level of 5%. Nevertheless, these CEOs with both types of international experience do not intend to meet or beat analysts’ earnings forecasts in an immature stock market, in which imprecise earnings forecasts from analysts lead to no significant response from institutional investors when they are making decisions on investments. Besides, CEOs with international study experience only are less likely to recognize loss timely, an indication of less conditional conservatism. The second paper “Internal Control Weakness and Earnings Quality in China” examines the relation between internal control weakness (ICW) and earnings quality in the main market, which refers to all the stocks in the Shanghai Stock Market and stocks in the Shenzhen Stock Market with an ID’s beginning of 002. The sample is constrained to the main market, because the mandatory disclosure on internal control report (ICR)and internal control auditing report (ICAR) is required only on the main market from the year 2014. By hand-collecting a dataset from 2014 to 2016, I define the moving sum of absolute discretionary accruals (MSDA) as the main measurement for earnings quality, and the more MSDA is, the worse the according earnings quality would be. ICW is defined as a dummy variable which equals to 1 when a firm discloses material and/or important ICWs, and 0 otherwise. As the multivariate analysis shows, the expected negative effect of ICW on earnings quality in prior research is not detected. Alternative robustness tests based on the new measurement of earnings quality, the absolute discretionary accruals (ABSDA) and income smoothing, further confirm the finding. Further, I consider different types of ICWs: Financial ICWs and non-financial ICWs and find no evidence on a relation between both types of ICWs and earnings quality, no matter measured by MSDA or ABSDA. Nevertheless, the non-financial ICWs have a marginally significant and negative effect on income smoothing (T-value=-1.75). In this paper, I also test the effect of the strictness of the standards to identify material ICW on earnings quality. Following Tan et al. (2016), strictness is defined in the range from 0 to 4, and the larger it is, the stricter the standard is set. Results suggest an insignificant relation between strictness and earnings quality, measured by both MSDA and ABSDA. However, a significantly positive relation at a marginal level (T-value=1.74) is found between strictness and income smoothing. The third paper “Board Gender Diversity, Gender Bias and Earnings Management: Evidence from China” examines the effect of board gender diversity and gender bias on earnings management in the listed firms in China. Gender Diversity is measured by the proportion of female directors on the board, a common measure from prior research. Gender Bias is only defined in the special Chinese condition with long-term son preference and decades of one-child policy from the 1980s, which makes the sex ratio at birth (male births per female births) at provincial level an exogenous measure for gender bias. Earnings management is measured by the absolute value of discretionary accruals. A sample of 7704 observations from 2015 to 2017 in the Chinese stock markets is hand-collected and analyzed. Each firm in the sample is allocated with its provincial sex ratio at birth based on the headquarter of the firm. Although we do not find evidence to support a significant effect from board gender diversity on earnings management, gender bias is negatively associated with earnings management at 5% level. However, it is hard to believe that more gender bias is combined with less earnings management. Therefore, we suppose that this link could be indirect and add provincial GDP per capita as an additional independent variable. Gender bias loses its significance, while provincial GDP (T-value=2.52) is significantly and positively correlated with earnings management. A further 2SLS regression suggests that gender bias is significantly and negatively associated with provincial GDP per capita in the first stage and the fitted value of provincial GDP per capita remains positively related to earnings management. This result indicates that listed firms in well-developed provinces tend to engage more in earnings management.

Lymphomas are a complex group of cancers arising from mature lymphoid cells. Despite advances in the treatment and management of this disease, it remains a health challenge as response to treatment and survival outcomes differ in various lymphoma subtypes. The exact causes driving lymphomagenesis remain unknown, and although several risk factors have been identified, the complexity of this disorder indicates that different molecular mechanisms drive the disease. One primary event evident in this disease is the presence of epigenetic alterations. Epigenetic alterations could arise due to changes in the pattern of deoxyribonucleic acid (DNA) methylation or histone modifications. Enhancer of zeste homolog 2 (EZH2) modifies histone and mediates gene silencing by selectively catalyzing lysine 27 trimethylation on histone H3 (H3K27me3). Consequently, genes responsible for tumor suppression and differentiation are repressed, cells undergo uncontrolled proliferation, and this leads to tumor formation. EZH2 has been mentioned to be a driver oncogene that plays an important role in tumor initiation and progression, especially when overexpressed or when gain-of function mutations occur in this gene. These hotspot gain-of-function mutations (Tyr646, Ala682 and Ala692) that result in increased EZH2 activity, are associated with increased H3K27me3 in several cancer types including lymphomas. Therefore, EZH2 inhibition could be an alternative strategy for lymphoma therapy. We treated aggressive B-cell lymphoma cell lines with 3-Deazaneplanocin A (DZNep), an epigenetic drug that inhibits EZH2 indirectly and promotes apoptosis in various tumor entities including lymphomas. We aimed to investigate the apoptotic efficacy of DZNep in these lymphoma cell lines, to understand the mechanisms of resistance to DZNep and to determine predictive biomarkers that could be of importance for EZH2 inhibition with DZNep. Using a combination of molecular and cell biological techniques such as flow cytometry, Western blot, Sanger sequencing, fluorescence in situ hybridization (FISH) and real-time reverse transcriptase polymerase chain reaction (RT-PCR), we showed that DZNep possesses a strong apoptotic and anti-proliferative effect on B-cell lymphoma cell lines. This effect was independent of the lymphoma type, the presence of EZH2 gain-of-function mutations or the presence of known prognostic lymphoma biomarkers such as translocations of MYC, BCL2 and BCL6. To investigate the molecular mechanism behind resistance to DZNep, we generated a DZNep-resistant clone from a B-cell lymphoma cell line that was initially sensitive to DZNep. This clone was used as a model to elucidate this mechanism. Upon molecular characterization, comparison of this clone with the parent cell line of origin revealed differences in the karyotype, copy number alterations, proliferation rate and response to DZNep. Clonality studies of the rearranged immunoglobulin genes however, demonstrated that the resistant clone and the parent cell line were clonally identical. Whole exome sequencing performed on this clone in relation to its corresponding control revealed among others, a genomic amplification of the AHCY gene - a direct target of DZNep. Methods such as copy number variation assays, FISH, gene expression assays and immunohistochemistry were used to validate this massive AHCY gain at the DNA, chromosomal, transcriptional and translational levels respectively. Functional validation of AHCY showed that in a DZNep-sensitive osteosarcoma cell line, AHCY overexpression was associated with resistance to DZNep. Unfortunately, reproduction of AHCY function in lymphoma cell lines was not successful due to technical reasons. Further evaluation of the whole exome sequencing data from DZNep-resistant cell lines demonstrated in one of the cell lines, a mutation in the AHCY gene. This mutation was predicted from online databases to have a likely damaging effect on the protein. This study thus presents alterations in the AHCY gene as a potential mechanism of resistance to DZNep. It also reveals that molecular mechanisms of acquired resistance are quite distinct from those of intrinsic resistance to DZNep, which themselves, may further differ from one DZNep-resistant lymphoma entity to the next. AHCY could therefore, be a promising biomarker to evaluate prior to the initiation of therapy with DZNep.

People working together can be very successful problem-solvers. Many real-life examples, from Wikipedia to citizen science projects, show that, under the right conditions, crowds can find remarkable solutions to complex problems. Yet, joining the capabilities of many people can be challenging. What factors make some groups more successful than others? How does the nature of the problem and the structure of the environment influence the group's performance? To answer these questions, I consider problem-solving as a search process -- a situation in which individuals are searching for a good solution. I describe and compare three different methods for structuring groups: (1) non-interacting groups, where individuals search independently without exchanging any information, (2) social groups, where individuals freely exchange information during their search, and (3) solution-influenced groups, where individuals repeatedly contribute to a shared collective solution. First, I introduce the idea of transmission chains - a specific type of solution-influenced group where individuals tackle the problem one after another, each one starting from the solution of its predecessor. I apply this method to binary choice problems and compare it to majority voting rules in non-interacting groups. The results show that transmission chains are superior in environments where individual accuracy is low and confidence is a reliable indicator of performance. This type of environment, however, is rarely observed in two experimental datasets. Then, I evaluate the performance of transmission chains for problems that have a complex structure, such as multidimensional optimization tasks. Again, I use non-interacting groups as a comparison, this time by selecting the best out of multiple independent solutions. Simulations and experimental data show that transmission chains outperform independent groups under two environmental conditions: either when problems are rather easy, or when group members are relatively unskilled. Next, I focus on social groups, where individuals influence each other during the search. To understand the social dynamics that operate in such groups, I conduct two studies: I first examine how people search for a solution independently from others, and then study how this individual process is impacted by social influence. The first study presents experimental data to show that the individual search behavior can be described by a take-the-best heuristic, that is, a simple rule-of-thumb that ignores all but one cue at a time. This heuristic reproduces a variety of behavioral patterns observed in different environments. Then, I extend this heuristic to include social interactions where multiple individuals exchange information during their search. My results show that, in this case, individuals tend to converge towards similar solutions. This induces a collective search dilemma: compared to non-interacting groups, the quality of the average individual's solution is improved at the expense of the best solution of the group. Nevertheless, further analyses show that this dilemma disappears for more difficult problems. Overall, this thesis shows that no collective problem-solving method is superior to the others in all environments and for all problems. Instead, the performance of each method depends on numerous factors, such as the nature of the task, the problem difficulty, the group composition, and the skill levels of the individuals. My work helps understanding the role of these different factors and their influence on collective problem-solving.

This dissertation pursues the objective to identify the neural mechanisms that drive the association between sleep and episodic memory consolidation across the adult lifespan. The inherent lifelong dynamics of brain and cognition provide an enormous potential to understand the neurobiological underpinnings of cognitive functions. Within this dissertation, aging is investigated as an illustrative period of cognitive and neural reorganization. Sleep-associated episodic memory consolidation is chosen as a model to illustrate methodological intricacies and highlight scientific gains that emerge when applying a lifespan perspective on cognitive neuroscience. This dissertation consists of four publications that offer a theoretical and empirical perspective on sleep-associated consolidation of episodic memories in old age. Paper I integrates the currently available literature on sleep, episodic memory, and aging, and links it to the active system consolidation account. Within this theoretical framework, we describe how, by the concerted interplay of brain rhythms during non-rapid eye movement (NREM) sleep, recently encoded memories become integrated into long-term storage sites in the neocortex. Joint age-related alterations in NREM sleep, brain structure, function, and neurochemistry are hypothesized to result in the formation of less persistent memory traces during sleep. Paper II argues that studying these changes in sleep physiology during aging requires the development of age-fair and individualized analytic procedures. Paper III complements this view by the use of an age-adapted associative memory task. The article highlights that variation in the encoding quality of memories can account for divergent effects of aging on overnight memory consolidation. Patterns of NREM sleep physiology and brain structure – identified as characteristic for advancing age by the use of multivariate statistical tools – were associated with age-related impairments in memory consolidation. However, I demonstrate that the mere occurrence of slow oscillations and spindles, indicative of NREM sleep and memory consolidation, does not explain inter-individual differences in memory consolidation. Following up on this notion, in Paper IV, I take the temporal coordination of slow oscillation and sleep spindles into account and show that their precise coupling disperses in old age. Across age groups, a precise coordination of slow oscillations and spindles was associated with better memory consolidation. Moreover, in older age, maintained structural integrity in sleep- and memory-relevant brain areas reinforced this beneficial slow oscillation–spindle coupling. Taken together, the findings of this dissertation suggest that prominent age-related changes in NREM sleep physiology may constitute a potential causal pathway for consolidation deficits observed in old age. In conjunction with structural brain atrophy, the generation and coordination of slow oscillation and spindles during NREM sleep is impacted, and the processes necessary to render stable episodic memories are impaired. Overall, this dissertation accomplishes two main goals: First, it reveals novel methodological avenues to derive and link age-fair and sensitive sleep and memory measures. Second, based on this, this dissertation enriches traditional views on sleep-associated memory consolidation and advances our understanding of memory aging, in general. Certainly, the application of an aging perspective to cognitive neuroscience challenges research theoretically, practically, and methodologically. I am confident that facing these challenges is worth the effort, as studying cognitive aging and its neural correlates holds exceptional scientific promise.

Wie kann es gelingen, die Professionalisierung von Lehrer~innen für das Fach Geschichte so zu gestalten, dass bereits in der ersten Phase Theorieskepsis und Transferwiderstände bei Studierenden abgebaut werden (Bühl-Gramer, 2018, S. 40)? Häufig zielen Antworten auf diese Frage entweder auf eine generelle Erhöhung der Praxisanteile im Studium (Baumert, 2007; Makrinus, 2013) oder auf eine anders spezifizierte Theorie-Praxis-Verzahnung im Studium (Fenn, 2013). Bisher ist insbesondere für das Fach Geschichte aber nicht geklärt, welche Wirkungen solche Maßnahmen konkret nach sich ziehen (Hascher, 2014) und wie solche Konzepte gewinnbringend für Studierende realisiert werden können (Albers et al., 2018). Daher sollten Praxisphasen gerade aus fachdidaktischer Perspektive oder genauer geschichtsdidaktischer Perspektive verstärkt in den Forschungsfokus genommen werden (Sauer, 2013). Kann das Lehren von Geschichte im Labor gelernt werden? In der hier vorliegenden Interventionsstudie mit quasi experimentellem Mixed-Methods-Design werden die Wirkungen eines innovativen Lehrformats – des Lehr-Lern-Labor-Seminars (LLLS) im Fach Geschichte – illustriert (Rehfeldt et. al., 2018). Das aus den naturwissenschaftlichen Didaktiken stammende Konzept der LLLS wurde auf Basis geschichtsdidaktischer Theorie adaptiert und so angelegt, dass komplexitätsreduzierte Praxisphasen mit einem theoretischen Seminar und Reflexionen fusioniert werden, um bei Studierenden Theorieskepsis und Transferwiderstände abzubauen (ebd.). Um die Wirkung der LLLS zu bestimmen, wurden in drei Durchläufen des LLLS zwei quantitative Skalen in Untersuchungsgruppe (LLLS) und Kontrollgruppe (Theorieseminar) eingesetzt. Die eingesetzte Skala zur wahrgenommenen Relevanz theoretischer Inhalte für die Praxis (Prenzel & Drechsel, 1996) zeigte in dieser Erhebung, dass sich mit einem LLLS die Bedeutungswahrnehmung geschichtsdidaktischer Theoriebildung bei den Studierenden deutlich steigern lässt. Die zweite eingesetzte Skala zur Lehrer~innenselbstwirksamkeitserwartung (Pfitzner-Eden, Thiel, & Horsley, 2014) (L-SWE) zeigte zudem, dass die L-SWE in den LLLS trotz zweimaliger Praxisphasen stabil bleibt. Im qualitativen Teil dieser Arbeit wurde in Gruppeninterviews nach den Professionalisierungsprozessen der Studierenden des LLLS gefragt. Theoretische Grundlage hierfür war das erziehungswissenschaftliche Konstrukt der Entwicklungsaufgaben (nach Hericks, 2006). Drei der vier Entwicklungsaufgaben von Hericks (2006) wurden mit Studienanforderungen sowie geschichtsdidaktischen Kategorien samt Forschungsständen adaptiert und als zu füllende „Hohlform“ (Hericks, 2006, S. 60) innerhalb der Interviews erfragt. Auf Befundlage der Studierendenaussagen konnten die drei Entwicklungsaufgaben als Amalgam zwischen objektiven Anforderungen und subjektiven Bearbeitungen anhand einer qualitativen Inhaltsanalyse (nach Kuckartz, 2014) interpretativ rekonstruiert werden. Die drei Entwicklungsaufgaben dieser Studie (die auf Hericks Annahmen basieren) Rollenfindung, Vermittlung und Anerkennung zeigen, dass wesentliche berufsbiographische Professionalisierungsprozesse bei den Studierenden durch LLLS angebahnt werden. Hierbei haben die Phasen der theoretischen Auseinandersetzung, der praktischen Erprobung und der Reflexion, die in einem LLLS fusioniert werden, in dieser Kombination einen positiven Einfluss auf die Studierenden. Zum einen setzen sie sich intensiv mit den Aufgaben und Anforderungen an Lehrer~innen und mit ihrer eigenen schulbiografischen Prägung im Geschichtsunterricht auseinander (Rollenfindung). Zum anderen durchdringen sie erste geschichtsdidaktische Prinzipien, begreifen Geschichte als Konstrukt und entwickeln eine Haltung der Theorieakzeptanz, sodass sie die dargebotene Theorie auch in unterrichtsnahe Settings transformieren können (Vermittlung). Letztlich setzen sich die Studierenden mit Subjektorientierung im Geschichtsunterricht auseinander (Anerkennung) und dies beinhaltet, dass es die Schüler~innen sind, für die sie den Unterricht vorbereiten. Insgesamt zeigt sich in dieser Studie, dass ein so wie hier beschriebenes und durchgeführtes LLLS im Fach Geschichte reinen Theorieseminaren überlegen ist und eine Geschichtslehrer~innenbildung möglich macht, in der Theorie und Praxis verzahnt werden, ohne dass das eine durch das andere zum Appendix wird.

American novelist, poet, painter and scholar Percival Everett (*1956) is an exceptional pioneer in the field of African American literature. The extensive yet under-studied literary project of the black Los Angeles-based writer includes bitingly comical satires of race and its present-day realities, which are both socially insightful and theoretically challenging. This study presents a comprehensive portrait of the author, launching a comparative inquiry into three novels. In these texts, Everett intervenes in the academic, commercial and social debates on race by conceptualizing a self-help satire of critical uplift (Glyph), a parodic requiem for protest fiction (erasure) and a comedic origin narrative of a black billionaire (I Am Not Sidney Poitier). The central claim of this study is that they present race not as a problem of identity but of language and, thus, of reading (expectations). In picaresque plotlines and cross-sectional scenes, Everett sends centromarginal characters from initial situations of intellectual (Ralph, a mute but extremely smart infant writer), cultural (“Monk,” an experimental writer of Greek myths) and economic privilege (the oddly-named look-alike of the original Sidney Poitier) through absurd episodes of racial oppression. These contradictory, awkward and elusive black characters cannot be integrated into the dominant social and cultural frameworks. They are misrecognized and marginalized as not black, not black enough and both. Mirroring the structural mechanisms of racism, rendering visible its regressive force, they provide dehabitualized readings of racial normativity, in which race remains an imperative yet insufficient coordinate.

The ceramic pottery production in the North Caucasus in the Bronze and Iron Age enables us to understand the production technology, technological development and transfer, craft system and mobility of the potters in the semi-sedentary and semi-mobile society. However, most prehistoric archaeological ceramics are heterogeneous composite materials containing various chemical and mineralogical compositions, firing states and alteration degrees, so that the ceramic production technology cannot be easily characterized and classified. Moreover, the amount of the excavated ceramic objects is huge, which causes additional difficulty for the analysis. In order to overcome these limitations, multiproxy- and multiscale-approach was employed step by step using polarization light microscopy (PM), scanning electron microscopy with energy/wavelength-dispersive spectroscopy (SEM/SEM-EDS/WDS), X-ray powder diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), synchrotron radiation Fourier transform infrared (SR-FTIR), Raman spectroscopy, three dimensional micro computed tomography (3D µ-CT) and image analysis. Firing conditions such as time, heating rate and temperature were concretized by the kinetics of the dehydroxylation of the clay mineral and finite different method (FDM) on the oxygen diffusion and heat transfer. This combined approach focused on resource gathering, firing and shaping techniques. The total 150 samples excavated at two archaeological sites in the North Caucasus, Ransyrt 1 (Middle/Late Bronze Age) and Kabardinka 2 (Late Bronze/Early Iron Age) were investigated. Samples of 21 ceramic sherds uncovered at Levinsadovka and Saf’janovo around the Sea of Azov, Russia (Late/Final Bronze Age) were compared to the mountain ceramics. According to the results, the mineralogy and shape parameters of sand grains and chemical composition of the ceramic matrix composed of grains smaller than 50 µm were able to distinguish the ceramic pastes from each site. This provides the potters’ practice of the main use of the local resource. The alignment of the large pore complex and grains enabled to identify the continuous or modular slab building by hands for the formation of the ceramic pottery body. The firing techniques were derived from the pyrometamorphic process under oxidizing and reducing conditions and corresponding firing behavior of the composite materials containing the common clay mineral, cis/trans-vacant (cv/tv) 1M illite. The complex combination of clay sintering, pore topology and its Euler characteristic and transformation of the indicator minerals such as calcite, hematite, spinel and gehlenite gave detailed clues for the firing temperature thresholds between under 675 and 1200 °C. In many ceramics fired in the oxidizing atmosphere, the reactivity between oxygen and Fe-, C- and S-bearing phases present in the ceramic pastes caused localization of the redox state within a sample, forming a color profile on the cross section of the object. In the middle of the cross section of those samples, earlier dehydroxylation of illite and corresponding total collapse occur due to the local reduction. The firing conditions derived from the dehydroxylation kinetics of illite and simulation of the oxygen diffusion and heat transfer indicate that the non-isothermal conditions with the high heating rate could produce the ceramic pottery with various firing degrees within a few hours by the instant firing without a furnace. The firing practice at both sites were similar, however the firing temperatures of the Kabardinka 2 ceramics are distributed in the wider range than those of the Ransyrt 1 ones, which might be related to the longer history of the settlement at Kabardinka 2. According to the combination of the archaeometric results and archaeological contexts, the local ceramic pottery production technologies at both sites were driven by similar human practice and site-specific resource. Although the individual decision making in the pottery production contributed to the heterogeneity of the ceramics as well, the resource-driven local technological styles dominated the pottery production at the studied sites in the Bronze and Iron Age. This characterization will shed light on the understanding of the development and transfer of the production technology in the North Caucasus.

Ziel: Die Genauigkeit der europäischen Formel von Cameriere et al. an einer Stichprobe norddeutscher Kinder, auf der Grundlage des Zahnalters (DA) für die Beurteilung des chronologischen Alters (CA) zu testen, und die verwendete Formel im Fall von regionalen Besonderheiten dieser Kindergruppe zu ändern. Methoden: Es wurden 1000 unselektierte schon vorhandene Panoramaschichtaufnahmen (PSA) von Kindern (444 Jungen und 556 Mädchen) im Alter von 5-17 Jahren ausgewertet. Die Wurzeln der Zähne des 3. Quadranten (außer 3. Molar) wurden evaluiert. Zähne mit vollständiger Wurzelentwicklung wurden gezählt (N0). Zähne mit unvollständiger Wurzelentwicklung wurden untersucht. Der Abstand zwischen den Innenseiten des offenen Scheitels der Apices wurde gemessen und mittels Dividieren durch die Zahnlänge normalisiert, um Vergrößerungs-Fehler zu vermeiden. Das Zahnalter (ZA) wurde nach der europäischen Formel von Cameriere berechnet. Das Zahnalter wurde für jedes Kind mit dem chronologischem Alter (CA) verglichen. Die Signifikanz der Differenz zwischen Chronologischer Alter und Zahnalter wurde statistisch durch den gepaarten t-Test analysiert. Ein multiples lineares Regressionsmodell mit Wechselwirkungen erster Ordnung wurde verwendet, um die Formel für eine Gruppe von 800 deutschen Kindern anzugleichen. Panoramaschichtaufnahmen einer anderen Gruppe von 200 Kindern wurden verwendet, um die Genauigkeit der neu angepassten Formel zu bewerten. Ergebnisse: Camerieres europäische Formel unterschätzt das Alter von Jungen um durchschnittlich 0,58 ± 1,02 Jahre und von Mädchen um 0,34 ± 0,96 Jahre. Die Ergebnisse der Regressionsanalyse zeigen, dass das Geschlecht, die Breitensumme der normalisierten offenen Apices, die Anzahl der Zähne mit geschlossenen Apices (N0) und die Wechselwirkung erster Ordnung zwischen der Apexweite des Eckzahns (X3) wesentlich zur Etablierung einer norddeutschen Kinderformel beigetragen haben. Die zuvor erwähnten Faktoren wurden in das Regressionsmodell eingeschlossen, woraus sich folgende Formel ergab: DA = 9,829 + 0,632N0 - 1,037s + 0,686g - 1,582 (N0 × X3) (g ist eine Variable: 1 für Jungen und 0 für Mädchen). Schlussfolgerung: Camerieres europäische Formel unterschätzte die meisten Alterskohorten beider Geschlechter. Die neu angepasste Formel erklärte 84,1 % der Gesamt-Devianz und eignet sich besser für die Schätzung des Zahnalters.