Computer simulations of microstructures related to the olivine spinel transition

Tiefherd-Beben, die im oberen Erdmantel in einer Tiefe von ca. 400 km auftreten, werden gewöhnlich mit dem in gleicher Tiefe auftretenden druckabhängigen, polymorphen Phasenübergang von Olivine (α-Phase) zu Spinel (β-Phase) in Verbindung gebracht. Es ist jedoch nach wie vor unklar, wie der Phasenübergang mit dem mechanischen Versagen des Mantelmaterials zusammenhängt. Zur Zeit werden im Wesentlichen zwei Modelle diskutiert, die entweder Mikrostrukturen, die durch den Phasenübergang entstehen, oder aber die rheologischen Veränderungen des Mantelgesteins durch den Phasenübergang dafür verantwortlich machen. Dabei sind Untersuchungen der Olivin→Spinel Umwandlung durch die Unzugänglichkeit des natürlichen Materials vollständig auf theoretische Überlegungen sowie Hochdruck-Experimente und Numerische Simulationen beschränkt. Das zentrale Thema dieser Dissertation war es, ein funktionierendes Computermodell zur Simulation der Mikrostrukturen zu entwickeln, die durch den Phasenübergang entstehen. Des Weiteren wurde das Computer Modell angewandt um die mikrostrukturelle Entwicklung von Spinelkörnern und die Kontrollparameter zu untersuchen. Die Arbeit ist daher in zwei Teile unterteilt: Der erste Teil (Kap. 2 und 3) behandelt die physikalischen Gesetzmäßigkeiten und die prinzipielle Funktionsweise des Computer Modells, das auf der Kombination von Gleichungen zur Errechnung der kinetischen Reaktionsgeschwindigkeit mit Gesetzen der Nichtgleichgewichtsthermodynamik unter nicht-hydostatischen Bedingungen beruht. Das Computermodell erweitert ein Federnetzwerk der Software latte aus dem Programmpaket elle. Der wichtigste Parameter ist dabei die Normalspannung auf der Kornoberfläche von Spinel. Darüber hinaus berücksichtigt das Programm die Latenzwärme der Reaktion, die Oberflächenenergie und die geringe Viskosität von Mantelmaterial als weitere wesentliche Parameter in der Berechnung der Reaktionskinetic. Das Wachstumsverhalten und die fraktale Dimension von errechneten Spinelkörnern ist dabei in guter Übereinstimmung mit Spinelstrukturen aus Hochdruckexperimenten. Im zweiten Teil der Arbeit wird das Computermodell angewandt, um die Entwicklung der Oberflächenstruktur von Spinelkörnern unter verschiedenen Bedigungen zu eruieren. Die sogenannte ’anticrack theory of faulting’, die den katastrophalen Verlauf der Olivine→Spinel Umwandlung in olivinhaltigem Material unter differentieller Spannung durch Spannungskonzentrationen erklärt, wurde anhand des Computermodells untersucht. Der entsprechende Mechanismus konnte dabei nicht bestätigt werden. Stattdessen können Oberflächenstrukturen, die Ähnlichkeiten zu Anticracks aufweisen, durch Unreinheiten des Materials erklärt werden (Kap. 4). Eine Reihe von Simulationen wurde der Herleitung der wichtigsten Kontrollparameter der Reaktion in monomineralischem Olivin gewidmet (Kap. 5 and Kap. 6). Als wichtigste Einflüsse auf die Kornform von Spinel stellten sich dabei die Hauptnormalspannungen auf dem System sowie Heterogenitäten im Wirtsminerals und die Viskosität heraus. Im weiteren Verlauf wurden die Nukleierung und das Wachstum von Spinel in polymineralischen Mineralparagenesen untersucht (Kap. 7). Die Reaktionsgeschwindigkeit der Olivine→Spinel Umwandlung und die Entwicklung von Spinelnetzwerken und Clustern wird durch die Gegenwart nicht-reaktiver Minerale wie Granat oder Pyroxen erheblich beschleunigt. Die Bildung von Spinelnetzwerken hat das Potential, die mechanischen Eigenschaften von Mantelgestein erheblich zu beeinflussen, sei es durch die Bildung potentieller Scherzonen oder durch Gerüstbildung. Dieser Lokalisierungprozess des Spinelwachstums in Mantelgesteinen kann daher ein neues Erklärungsmuster für Tiefbeben darstellen.

Effects of low-density lipoprotein receptor-related protein 4 and apolipoprotein E isoforms on bone metabolism in vivo

LRP4, member of the LDLR family, is a multifunctional membrane-bound receptor that is expressed in various tissues. The expression of LRP4 by osteoblasts, its novel interaction with Wnt-signaling inhibitors Dkk1 and SOST, and the lower levels of activated beta-catenin in different bone locations described here, adds another player to the long list of established factors that modulate canonical Wnt-signaling in bone. By demonstrating that in addition to Wise, LRP4 is able to interact with two additional important modulators of Wnt- and BMP-signaling, our perspective of the complexity of the integration of BMP and Wnt-signaling pathways on the osteoblast surface has expanded further. Nevertheless the recently described association of both the SOST and LRP4 genes with BMD in humans, together with our findings suggest that LRP4 plays a physiologically important role in the skeletal development and bone metabolism not only in rodents, but in humans as well. The efficiency with which LRP4 binds both SOST and Dkk1, presumably at the osteoblastic surface, LRP4 may act as a sink and competes with LRP5/6 for the binding of these Wnt antagonists, which then are no longer available for suppression of the signal through the LRP5/6 axis. rnApoE, a 299 amino acid glycoprotein, is a crucial regulator in the uptake of triglyceride, phospholipids, cholesteryl esters, and cholesterol into cells. ApoE has been linked to osteoporosis, and such a role is further strengthened by the present of a high bone mass phenotype in ApoE null mice. Until recently, the effects of respective ApoE isoforms E2, E3, and E4, and their impact on bone metabolism, have been unclear. Here we report that respective human ApoE knockin mice display diverse effects on bone metabolism. ApoE2 mice show decreased trabecular bone volume per total volume in femoral bone and lumbar spine in comparison to ApoE3 and E4 animals. In this context, urinary bone resorption marker DPD is increased in these animals, which is accompanied by a low ratio of osteoclastogenesis markers OPG/RANKL. Interestingly, serum bone formation markers ALP and OCN are diminished in ApoE4 mice. In contrast to this finding, ApoE2 mice show the lowest bone formation of all groups in vivo. These findings cannot be explained by the low receptor-affinity of ApoE2 and subsequent decreased uptake of triglyceride-rich lipoproteins by osteoblasts, resulting in elevated levels of undercarboxylated osteocalcin. Thus, other crucial pathways relevant for bone metabolism, e. g. Wnt/beta-catenin-signaling pathways, must be, compared to the ApoE3/4 isoforms, more affected by the ApoE2 isoform.

The role of NPxY domains in LRP1 receptor maturation and function

Analyses of low density lipoprotein receptor-related protein 1 (LRP1) mutant mouse embryonic fibroblasts (MEFs) generated from LRP1 knock-in mice revealed that inefficient maturation and premature proteasomal degradation of immature LRP1 is causing early embryonic lethality in NPxY1 and NPxY1+2 mutant mice. In MEFs, NPxY2 mutant LRP1 showed efficient maturation but, as expected, decreased endocytosis. The single proximal NPxY1 and the double mutant NPxY1+2 were unable to reach the cell surface as an endocytic receptor due to premature degradation. In conclusion, the proximal NPxY1 motif is essential for early sorting steps in the biosynthesis of mature LRP1.rnThe viable NPxY2 mouse was used to provide genetic evidence for LRP1-mediated amyloid-β (Aβ) transport across the blood-brain barrier (BBB). Here, we show that primary mouse brain capillary endothelial cells (pMBCECs) express functionally active LRP1. Moreover, demonstrate that LRP1 mediates [125I]-Aβ1-40 transcytosis across pMBCECs in both directions, whereas no role for LRP1-mediated Aβ degradation was detected. Aβ transport across pMBCECs generated from NPxY2 knock-in mice revealed a reduced Aβ clearance in both directions compared to WT derived pMBCECs. Finally, we conclude that LRP1 is a bona-fide receptor involved in bidirectional transcytosis of Aβ across the BBB.rn

The role of oxidative stress in C. elegans aging

The free radical theory of aging postulates that aging is caused by damage induced by oxidative stress. Such stress is present when the production of reactive oxygen species (ROS) exceeds the cellular antioxidant capacity. Hydrogen peroxide (H2O2) is one of the most abundant ROS. It is produced as a by-product by several enzymes and acts as second messenger controlling the activity of numerous cellular pathways. To maintain H2O2 levels that are sufficiently high to allow signaling to occur, but low enough to prevent damage of cellular macromolecules, the production and removal of H2O2 must be tightly regulated.rnWhen we investigated the effects of peroxide stress in the nematode C. elegans, we found that exogenous as well as endogenous peroxide stress causes age-related symptoms. We identified 40 target proteins of hydrogen peroxide that contain cysteines that get oxidized upon peroxide stress. Oxidation of redox-sensitive cysteines has been shown to regulate numerous cellular functions and likely contributes to the peroxide-mediated decrease in motility, fertility, growth rate and ATP levels. By monitoring the oxidation status of proteins over the lifespan of C. elegans, we discovered that many of the identified peroxide-sensitive proteins are heavily oxidized at distinct stages in life. As the free radical theory of aging predicts, we found oxidation to be significantly elevated in senescent worms. However, we were also able to identify numerous proteins that were significantly oxidized during the development of C. elegans. To investigate whether a correlation exists between developmental oxidative stress and lifespan, we monitored protein oxidation in long- and short-lived strains. We found that protein oxidation in short-lived C. elegans larvae was significantly increased. Additionally short-lived worms were incapable of recovering from the oxidative stress experienced during development which resulted in the inability to establish reducing conditions for the following reproductive phase. Long-lived C. elegans, on the other hand, did only experience a mild increase in protein oxidation in the developmental phase and were able to recover faster from oxidative stress than wild type worms. rnBecause many proteins that are sensitive to oxidation by H2O2 became oxidized in aging C. elegans, we monitored endogenous hydrogen peroxide concentrations over C. elegans lifespan and discovered that peroxide levels are significantly elevated in development. This suggests that the observed developmental protein oxidation is peroxide-mediated. The early onset of oxidative stress might be a result of increased metabolic activity in C. elegans development but could also represent the requirement of ROS dependent signaling events. Our results indicate that longevity is dependent on the worm’s ability to cope with this early boost of oxidants.rn

Management control systems : subcomponents, optimal design and the role of time as a contingency

Management Control System (MCS) research is undergoing turbulent times. For a long time related to cybernetic instruments of management accounting only, MCS are increasingly seen as complex systems comprising not only formal accounting-driven instruments, but also informal mechanisms of control based on organizational culture. But not only have the means of MCS changed; researchers increasingly ap-ply MCS to organizational goals other than strategy implementation.rnrnTaking the question of "How do I design a well-performing MCS?" as a starting point, this dissertation aims at providing a comprehensive and integrated overview of the "current-state" of MCS research. Opting for a definition of MCS, broad in terms of means (all formal as well as informal MCS instruments), but focused in terms of objectives (behavioral control only), the dissertation contributes to MCS theory by, a) developing an integrated (contingency) model of MCS, describing its contingencies, as well as its subcomponents, b) refining the equifinality model of Gresov/Drazin (1997), c) synthesizing research findings from contingency and configuration research concerning MCS, taking into account case studies on research topics such as ambi-dexterity, equifinality and time as a contingency.

The role of SENP1 in B cell development and differentiation

SUMOylation is a highly dynamic and reversible posttranslational protein modification closely related to ubiquitination. SUMOylation regulates a vast array of different cellular functions, such as cell cycle, nuclear transport, DNA damage response, proliferation and transcriptional activation. Several groups have shown in in vitro studies how important SUMOylation is for early B cell development and survival as well as for later plasma cell differentiation. This thesis focuses on the deSUMOylation protease SENP1 and its in vivo effects on B cell development and differentiation. For this a conditional SENP1 knockout mouse model was crossed to the CD19-Cre mouse strain to generate a B cell specific SENP1 knockout mouse.rnIn our conditional SENP1ff CD19-Cre mouse model we observed normal numbers of all B cell subsets in the bone marrow. However in the spleen we observed an impairment of B cell survival, based on a 50% reduction of the follicular B cell compartment, whereas the marginal zone B cell compartment was unchanged. T cell numbers were comparable to control mice. rnFurther, impairments of B cell survival in SENP1ff CD19-Cre mice were analysed after in vivo blocking of IL7R signalling. The αIL7R treatment in mature mice blocked new B cell formation in the bone marrow and increased apoptosis rates could be observed in splenic SENP1 KO B cells. Additionally, a higher turnover rate of B cells was measured by in vivo BrdU incorporation.rnSince it is known that the majority of transcription factors that are important for the maintenance of the germinal centre reaction or for induction of plasma cell development are SUMOylated, the question arose, how defective deSUMOylation will manifest itself in these processes. The majority of in vitro cultured splenic B cells, stimulated to undergo class switch recombination and plasma cell differentiation underwent activation induced cell death. However, the surviving cells increasingly differentiated into IgM expressing plasma cells. Class switch recombination to IgG1 was reduced. These observations stood in line with observation made in in vivo sheep red blood cell immunization experiments, which showed increased amounts of germinal centres and germinal centre B cells, as well as increased amounts of plasma cells differentiation in combination with decreased class switch to IgG1.rnThese results lead to the conclusion that SENP1 KO B cells increasingly undergo apoptosis, however, B cells that survive SENP1 deficiency are more prone to undergo plasma cell differentiation. Further, the precursors of these plasma cells either are not as capable of undergoing class switch recombination or they do switch to IgG1 and succumb to activation induced cell death. One possible explanation for both scenarios could be a defective DNA damage response mechanisms during class switch recombination, caused by impaired deSUMOylation. rn