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Institute
Demographic change belongs to the mega-trends of the 20th and the 21st century. The ongoing aging process in major industrialized countries gives rise to the relative scarcity of raw labor and the relative abundance of physical capital. Standard macroeconomic models suggest that this depresses asset returns and increases wages which, in turn, provides incentives for more human capital accumulation. This thesis quantifies the macroeconomic effects of demographic change and reveals the importance of human capital adjustments for price and welfare effects within and across generations. Chapter 1 investigates the distributions of income, skills, and welfare in the German economy along the inter- and the intra-generational dimension. It shows that demographic change leads to a more capital- and skill-intensive economy and that high-school households loose compared to college households in terms of welfare. Chapter 2 disentangles the effect of demographic change on returns to risk-free and risky assets in the U.S. and measures the net effect on the equity premium. It shows that both returns decline while the equity premium increases slightly. Endogenous human capital adjustments are crucial for relatively small effects. Chapter 3 develops a method for computing transitional dynamics in heterogeneous agent models with aggregate risk if these transitions are induced by exogenous deterministic dynamics such as demographic change. The application of the method to a simple illustrative example shows a large reduction in total computing time while approximation errors are small.
Unraveling the activation mechanism of taspase1 which controls the oncogenic AF4–MLL fusion protein
(2015)
We have recently demonstrated that Taspase1-mediated cleavage of the AF4–MLL oncoprotein results in the formation of a stable multiprotein complex which forms the key event for the onset of acute proB leukemia in mice. Therefore, Taspase1 represents a conditional oncoprotein in the context of t(4;11) leukemia. In this report, we used site-directed mutagenesis to unravel the molecular events by which Taspase1 becomes sequentially activated. Monomeric pro-enzymes form dimers which are autocatalytically processed into the enzymatically active form of Taspase1 (αββα). The active enzyme cleaves only very few target proteins, e.g., MLL, MLL4 and TFIIA at their corresponding consensus cleavage sites (CSTasp1) as well as AF4–MLL in the case of leukemogenic translocation. This knowledge was translated into the design of a dominant-negative mutant of Taspase1 (dnTASP1). As expected, simultaneous expression of the leukemogenic AF4–MLL and dnTASP1 causes the disappearance of the leukemogenic oncoprotein, because the uncleaved AF4–MLL protein (328 kDa) is subject to proteasomal degradation, while the cleaved AF4–MLL forms a stable oncogenic multi-protein complex with a very long half-life. Moreover, coexpression of dnTASP1 with a BFP-CSTasp1-GFP FRET biosensor effectively inhibits cleavage. The impact of our findings on future drug development and potential treatment options for t(4;11) leukemia will be discussed.