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OBJECTIVE We have recently shown that priming of synovial fibroblasts (SFs) drives arthritis flares. Pathogenic priming of SFs is essentially mediated by epigenetic reprogramming. Bromodomain and extra-terminal motif (BET) proteins translate epigenetic changes into transcription. Here we used a BET inhibitor to target inflammatory tissue priming and reduce flare severity in experimental arthritis. METHODS BALB/c mice were treated intraperitoneally or locally into the paw with I-BET151, which blocks interaction of BET proteins with acetylated histones. Effect of I-BET151 on acute arthritis and/or inflammatory tissue priming was assessed in a model of repeated injections of monosodium urate crystals or zymosan into the paw. I-BET151 was given either from before arthritis induction, at peak inflammation, or after healing of the first arthritis bout. Transcriptomic (RNA-Seq), epigenomic (ATAC-Seq) and functional analysis (invasion, cytokine production, migration, senescence, metabolic flux) was performed on murine and human SFs treated with I-BET151 in vitro or in vivo. RESULTS Systemic I-BET151 administration did not affect acute inflammation but abolished inflammatory tissue priming and diminished flare severity in both preventive and therapeutic treatment settings. I-BET151 was also effective when applied locally in the joint. BET inhibition also inhibited osteoclast differentiation, while macrophage activation in the joint was not affected. Flare reduction after BET inhibition was mediated, at least in part, by rolling back the primed transcriptional, metabolic and pathogenic phenotype of SFs. CONCLUSION Inflammatory tissue priming is dependent on transcriptional regulation by BET proteins, which makes them promising therapeutic targets for preventing arthritis flares in previously affected joints.

Zugleich: Dissertation, Universität Kassel, 2020

At the forefront of macroeconomic research on the causes of the Great Financial Crisis (GFC) was and still is the usage of dynamic stochastic general equilibrium (DSGE) models. To capture the nonlinearities of the GFC, these models were enriched with a variety of fiÂ…nancial frictions. This paper focuses on a special subset of these frictions, the shadow banking system. We provide a structured review of the strand of literature that considers shadow banking in DSGE setups and draw particular attention to the modeling approach as well as impact of shadow banking. Our analysis allows the following conclusions: fiÂ…rstly, models featuring shadow banking are better able to simulate realistic movements in the business cycle that are of comparable magnitude to the GFC. Secondly, the models consider ampliÂ…cation channels between the fiÂ…nancial sector and the real economy that proved to be of importance during the crisis. Thirdly, the models display a good explanatory power of Â…financial stability measures in the light of shadow banking.

This paper studies the interaction of international shadow banking with monetary and macroprudential policy in a two-country currency union DSGE model. We find evidence that cross-country financial integration through the shadow banking system is a source of financial contagion in response to idiosyncratic real and financial shocks due to harmonization of financial spheres. The resulting high degree of business cycle synchronization across countries, especially for financial variables, makes union-wide policy tools more effective. Nevertheless, optimal monetary policy at the union-level is too blunt an instrument to adequately stabilize business cycle downturns and needs to be accompanied by macroprudential regulation. Our welfare analysis reveals that the gains from the availability of country-specific prudential tools vanish with the degree of financial integration as union-wide macroprudential regulation is able to effectively reduce losses among the union members.

Using a DSGE framework, we discuss the optimal design of monetary policy for an economy where both retail banks and shadow banks serve as financial intermediaries. We get the following results. During crises times, a standard Taylor rule fails to reach sufficient stimulus. Direct asset purchases prove to be the most effective unconventional tool. When maximizing welfare, central banks should shy away from interventions in the funding process between retail and shadow banks. Liquidity facilities are the welfare-maximizing unconventional policy tool. The effectiveness of unconventional measures increases in the size of the shadow banking sector. However, the optimal response to shocks is sensitive to the resource costs of the implementation which may differ across central banks. Hence, optimal unconventional monetary policy is country-specific.

Caveolin-1 (CAV1) is the main structural component of cholesterol-rich microdomains in the plasma membrane, called caveolae. Caveolae occur in most mammalian cells and are involved in the regulation of cell signaling, lipid homeostasis, and response to mechanical stress. For turnover, CAV1 is ubiquitinated and sequestered in the lumen of multivesicular endosomes that eventually fuse with lysosomes. In addition to components of the ESCRT machinery, lysosomal sorting of ubiquitinated CAV1 requires the AAA-ATPase p97 together with the cofactor UBXD1. However, it is unknown at which site CAV1 is ubiquitinated and how ubiquitination is linked to endosomal sorting of CAV1. Moreover, it is unknown how the p97-UBXD1 complex interacts with ubiquitinated CAV1 and if p97 is a general regulator of endosomal sorting. In this study, we show through systematic mutagenesis of lysine residues in CAV1 that ubiquitination of CAV1 occurs at any of the six lysines 5, 26, 30, 39, 47, and 57; and only the combined mutation of all six lysines together abolishes ubiquitination. The ubiquitination site is located in the flexible N-terminal region of CAV1 that is not involved in CAV1 oligomerization or membrane localization of CAV1. Importantly, mutation of the lysines 5 to 57 to arginine interfered with trafficking of CAV1 to early endosomes. As a consequence, the K5-57R variant accumulated at an early transport stage that was marked by the caveolar coat protein PTRF/cavin-1. Previous studies established that overexpression of dominant negative p97 prevents sorting of CAV1 into the lumen of late endosomes. Consistently, we showed here that the ubiquitination site in the N-terminal region of CAV1 was necessary for the interaction between CAV1 and p97-UBXD1 as well as recruitment of p97-UBXD1 to endosomes. Moreover, cellular depletion or pharmacological inhibition of p97 accumulated ubiquitinated CAV1. These results indicate that p97-UBXD1 acts downstream of CAV1 ubiquitination and is required for the turnover of ubiquitinated CAV1 on late endosomes. In this context, we demonstrated that p97 also mediated lysosomal degradation of ligand-activated EGF receptor and, thus, acts as a general regulator of endosomal sorting. Caveolin-1 (CAV1) ist ein wichtiger struktureller Bestandteil cholesterinreicher Mikrodomänen in der Plasmamembran, die Caveolae genannt werden. Caveolae finden sich in den meisten Säugerzellen und sind and der Regulation zellulärer Signalübertragung, des Fettstoffwechsels und der Reaktion auf mechanische Reize beteiligt. CAV1 wird für seinen eigenen Abbau ubiquitiniert und im Lumen multivesikulärer Endosomen, die letztendlich mit Lysosomen fusionieren, sequestriert. Der Transport von CAV1 zum Lysosom erfordert, neben Komponenten der ESCRT-Maschinerie, auch die AAA-ATPase p97 zusammmen mit dem Kofaktor UBXD1. Es ist allerdings unbekannt, an welcher Stelle CAV1 ubiquitiniert wird und wie Ubiquitinierung von CAV1 und endosomaler Transport miteinander verknüpft sind. Weiterhin ist unbekannt, wie genau der p97-UBXD1 Komplex mit CAV1 interagiert und ob p97 als allgemeiner Regulator für den endosomalen Transport fungiert. Wir zeigen hier mittels systematischer Mutagenese, dass die Ubiquitinierung von CAV1 an einem beliebigen der sechs Lysine 5, 26, 30, 39, 47 und 57 in der N-terminalen Region stattfinden kann und dass die Mutation aller sechs Lysine zusammen notwendig ist, um die Ubiquitinierung zu verhindern. Die Ubiquitinierungsregion befindet sich in der flexiblen N-terminalen Region von CAV1, die nicht an der Oligomerisierung oder der Membranlokalisierung von CAV1 beteiligt ist. Bemerkenswerterweise behinderte die Mutation der Lysine 5 bis 57 den Transport von CAV1 zu frühen Endosomen. In der Folge akkumulierte CAV1 in einem frühen Transportschritt, der durch das caveoläre Hüllprotein PTRF/cavin-1 gekennzeichnet war. Frühere Untersuchungen haben gezeigt, dass Expression einer dominant negativen Variante von p97 den Transport von CAV1 in das Lumen später Endosomen verhindert. In der Folge zeigten wir hier, dass die Ubiquitinierungsregion in CAV1 sowohl für die Interaktion zwischen CAV1 und dem p97-UBXD1 Komplex als auch die Rekrutierung von p97-UBXD1 zu Endosomen notwendig war. Weiterhin akkumulierte ubiquitiniertes CAV1 nach zellulärer Depletion oder pharmakologischer Inhibition von p97. Diese experimentellen Daten weisen darauf hin, dass p97-UBXD1 zeitlich nach der Ubiquitinierung von CAV1 agiert und notwendig für die Prozessierung von ubiquitiniertem CAV1 an späten Endosomen ist. In diesem Zusammenhang zeigten wir weiterhin, dass p97 den lysosomalen Abbau von aktiviertem EGF Rezeptor vermittelte und deshalb als ein allgemeiner Regulator des endosomalen Transports agiert.

We develop an equilibrium directed search model of the labor market where workers can simultaneously apply for multiple jobs. The main result is that all equilibria exhibit wage dispersion despite the fact that workers and firms are homogeneous. Wage dispersion is driven by the simultaneity of application choice. Risk-neutral workers apply for both ‘safe’ and ‘risky’ jobs. The former yield a high probability of a job offer, but for low pay, and act as a fallback option; the latter provide with higher potential payoff, but are harder to get. Furthermore, the density of posted wages is decreasing, consistent with stylized facts. Unlike most directed search models, the equilibria are not constrained efficient.