Characterization of the role of Drosophila JAK/STAT signalling in cellular proliferation

Der Janus Kinase / signal transducer and activator of transcription (JAK/STAT) Signal- transduktionsweg wird für viele Entwicklungsvorgänge benötigt und spielt eine zentrale Rolle bei der Hämatopoese und bei der Immunantwort. Obwohl der JAK/STAT-Signalweg in den vergangenen Jahren Gegenstand intensiver Forschung war, erschwert die Redundanz des Signalwegs bei Wirbeltieren genetische Untersuchungen zur Identifizierung derjenigen Mechanismen, die den JAK/STAT-Signalweg regulieren. Der JAK/STAT-Signaltransduktionsweg ist evolutionär konserviert und ebenfalls bei der Taufliege Drosophila melanogaster vorhanden. Im Gegensatz zu Wirbeltieren ist der Signaltransduktionsweg von Drosophila weniger redundant und beinhaltet folgende Hauptkomponenten: den Liganden Unpaired (Upd), den Transmembranrezeptor Domeless (Dome), die einzige JAK-Tyrosinkinase Hopscotch (hop), sowie den Transkriptionsfaktor STAT92E. In der vorliegenden Arbeit wird die Rolle des JAK/STAT-Signalwegs bei der zellulären Proliferation mithilfe der Modellsysteme der Flügel- und der Augen-Imaginalscheiben von Drosophila charakterisiert. "Loss-of-function"- und "Gain-of-function"-Experimente zur Verminderung beziehungs-weise Erhöhung der Signalaktivität zeigten, dass der JAK/STAT-Signalweg eine Rolle bei der zellulären Proliferation der Flügel-Imaginalscheiben spielte, ohne die Zellgröße oder Apoptose zu verändern. Bei der Flügelentwicklung während des zweiten und des frühen dritten Larvalstadiums war die Aktivität des JAK/STAT-Signalwegs sowohl notwendig für die zelluläre Proliferation als auch hinreichend, um Überproliferation anzutreiben. Allerdings änderte sich während der späten dritten Larvalstadien die JAK/STAT-Signalaktivität, sodass endogene STAT92E-Mengen einen anti-proliferativen Effekt im gleichen Gewebe aufwiesen. Weiterhin reichte die ektopische Aktivierung des JAK/STAT-Signalwegs zu diesem späten Entwicklungszeitpunkt aus, um die Mitose zu inhibieren und die Zellen in der Phase G2 des Zellzyklus zu arretieren. Diese Ergebnisse legen den Schluss nahe, dass der JAK/STAT-Signalweg sowohl pro-proliferativ in frühen Flügelscheiben als auch anti-proliferativ zu späten Stadien der Flügelscheiben-Entwicklung wirken kann. Dieser späte anti-proliferative Effekt wurde durch einen nicht-kanonischen Mechanismus der STAT92E-Aktivierung vermittelt, da späte hop defiziente Zellverbände im Vergleich zu Wildtyp-Zellen keine Veränderungen im Ausmaß der zellulären Proliferation aufwiesen. Ferner konnte gezeigt werden, dass eine während der Larvalstadien exprimierte dominant-negative und im N-Terminus deletierte Form von STAT92E (?NSTAT92E) nicht für den anti-proliferativen Effekt verantwortlich ist. Diese Tatsache ist ein weiteres Indiz dafür, dass das vollständige STAT92E den späten anti-proliferativen Effekt verursacht. Um Modulatoren für die von JAK/STAT vermittelte zelluläre Proliferation zu identifieren, wurde ein P-Element-basierter genetischer Interaktions-Screen in einem sensibilisierten genetischen Hintergrund durchgeführt. Insgesamt wurden dazu 2267 unabhängige P-Element-Insertionen auf ihre Wechselwirkung mit der JAK/STAT-Signalaktivität untersucht und 24 interagierende Loci identifiziert. Diese Kandidaten können in folgende Gruppen eingeordnet werden: Zellzyklusproteine, Transkriptionsfaktoren, DNA und RNA bindende Proteine, ein Mikro-RNA-Gen, Komponenten anderer Signaltransduktionswege und Zelladhäsionsproteine. In den meisten Fällen wurden mehrere Allele der interagierenden Kandidatengene getestet. 18 Kandidatengene mit übereinstimmend interagierenden Allelen wurden dann zur weiteren Analyse ausgewählt. Von diesen 18 Kandidaten-Loci wurden 7 mögliche JAK/STAT-Signalwegskomponenten und 6 neue Zielgene des Signalwegs gefunden. Zusammenfassend wurde das Verständnis um STAT92E verbessert. Dieses Protein hat die gleiche Funktion wie das STAT3-Protein der Wirbeltiere und treibt die zelluläre Proliferation voran. Analog zu STAT1 hat STAT92E aber auch einen anti-proliferativen Effekt. Ferner wurden 24 mögliche Modulatoren der JAK/STAT-Signalaktivität identifiziert. Die Charakterisierung dieser Wechselwirkungen eröffnet vielversprechende Wege zu dem Verständnis, wie JAK/STAT die zelluläre Proliferation reguliert und könnte bei der Entwicklung von neuartigen therapeutischen Targets zur Behandlung von Krebskrankheiten und Entwicklungsstörungen beitragen.

The social dimension: a neglected policy item in the Bologna Process

Since its beginning in 1999, the Bologna Process has influenced various aspects of higher education in its member countries, e.g., degree structures, mobility, lifelong learning, social dimension and quality assurance. The social dimension creates the focus of this research. The social dimension entered the Bologna Process agenda in 2001. Despite a decade of reforms, it somehow remained as a vague element and received low scholarly attention. This research addresses to this gap. Firstly, different meanings of the social dimension according to the major European policy actors are analysed. Unfolding the understandings of the actors revealed that the social dimension is mostly understood in terms reflecting the diversity of population on the student body accessing to, progressing in and completing higher education, with a special concern on the underrepresented groups. However, it is not possible to observe a similar commonality concerning the actual policy measures to achieve this goal. Divergence occurs with respect to the addressed underrepresented groups, i.e., all underrepresented groups or people without formal qualifications and mature learners, and the values and institutional interests traditionally promoted by these actors. Secondly, the dissertation discusses the reflection of this social dimension understanding at the national level by looking at cases of Finland, Germany and Turkey. The in-depth analyses show an awareness of the social dimension among most of the national Bologna Process actors and a common understanding of the social dimension goals. However, this understanding has not triggered action in any of the countries. The countries acted on areas which they defined problematic before the Bologna Process. Finally, based on these findings the dissertation discusses the social dimension as a policy item that managed to get into the Bologna Process agenda, but neither grew into an implementable policy, nor drop out of it. To this aim, it makes use of the multiple streams framework and explains the low agenda status social dimension with: i. the lack of a pressing problem definition: the lack of clearly defined indicators and a comprehensive monitoring system, ii. the lack of a viable solution alternative: the proposal of developing national strategies and action plans closed the way to develop generic guidelines for the social dimension to be translated into national policy processes, iii. low political perceptivity: the recent trends opt for increasing efficiency, excellence and exclusiveness discourses rather than ensuring equality and inclusiveness iv. high constraints: the social dimension by definition requires more public funding which is less appreciated and strategic constraints of the actors in allocating their resources v. the type of policy entrepreneur: the social dimension is promoted by an international stakeholder, the European Students’ Union, instead of the ministers responsible for higher education The social dimension remains a policy item in the Bologna Process which is noble enough to agree but not urgent enough to act on.

Individual Decision-Making and Inflation Persistence

The traditional task of a central bank is to preserve price stability and, in doing so, not to impair the real economy more than necessary. To meet this challenge, it is of great relevance whether inflation is only driven by inflation expectations and the current output gap or whether it is, in addition, influenced by past inflation. In the former case, as described by the New Keynesian Phillips curve, the central bank can immediately and simultaneously achieve price stability and equilibrium output, the so-called ‘divine coincidence’ (Blanchard and Galí 2007). In the latter case, the achievement of price stability is costly in terms of output and will be pursued over several periods. Similarly, it is important to distinguish this latter case, which describes ‘intrinsic’ inflation persistence, from that of ‘extrinsic’ inflation persistence, where the sluggishness of inflation is not a ‘structural’ feature of the economy but merely ‘inherited’ from the sluggishness of the other driving forces, inflation expectations and output. ‘Extrinsic’ inflation persistence is usually considered to be the less challenging case, as policy-makers are supposed to fight against the persistence in the driving forces, especially to reduce the stickiness of inflation expectations by a credible monetary policy, in order to reestablish the ‘divine coincidence’. The scope of this dissertation is to contribute to the vast literature and ongoing discussion on inflation persistence: Chapter 1 describes the policy consequences of inflation persistence and summarizes the empirical and theoretical literature. Chapter 2 compares two models of staggered price setting, one with a fixed two-period duration and the other with a stochastic duration of prices. I show that in an economy with a timeless optimizing central bank the model with the two-period alternating price-setting (for most parameter values) leads to more persistent inflation than the model with stochastic price duration. This result amends earlier work by Kiley (2002) who found that the model with stochastic price duration generates more persistent inflation in response to an exogenous monetary shock. Chapter 3 extends the two-period alternating price-setting model to the case of 3- and 4-period price durations. This results in a more complex Phillips curve with a negative impact of past inflation on current inflation. As simulations show, this multi-period Phillips curve generates a too low degree of autocorrelation and too early turnings points of inflation and is outperformed by a simple Hybrid Phillips curve. Chapter 4 starts from the critique of Driscoll and Holden (2003) on the relative real-wage model of Fuhrer and Moore (1995). While taking the critique seriously that Fuhrer and Moore’s model will collapse to a much simpler one without intrinsic inflation persistence if one takes their arguments literally, I extend the model by a term for inequality aversion. This model extension is not only in line with experimental evidence but results in a Hybrid Phillips curve with inflation persistence that is observably equivalent to that presented by Fuhrer and Moore (1995). In chapter 5, I present a model that especially allows to study the relationship between fairness attitudes and time preference (impatience). In the model, two individuals take decisions in two subsequent periods. In period 1, both individuals are endowed with resources and are able to donate a share of their resources to the other individual. In period 2, the two individuals might join in a common production after having bargained on the split of its output. The size of the production output depends on the relative share of resources at the end of period 1 as the human capital of the individuals, which is built by means of their resources, cannot fully be substituted one against each other. Therefore, it might be rational for a well-endowed individual in period 1 to act in a seemingly ‘fair’ manner and to donate own resources to its poorer counterpart. This decision also depends on the individuals’ impatience which is induced by the small but positive probability that production is not possible in period 2. As a general result, the individuals in the model economy are more likely to behave in a ‘fair’ manner, i.e., to donate resources to the other individual, the lower their own impatience and the higher the productivity of the other individual. As the (seemingly) ‘fair’ behavior is modelled as an endogenous outcome and as it is related to the aspect of time preference, the presented framework might help to further integrate behavioral economics and macroeconomics.