Shadow Banking and the Design of Macroprudential Policy in a Monetary Union

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

Optimal Unconventional Monetary Policy in the Face of Shadow Banking

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 e¤ective 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 di¤er across central banks. Hence, optimal unconventional monetary policy is country-specific

Die Rolle von Ubiquitinierung und des p97-UBXD1 Komplexes in der Regulation des endosomalen Transports von Caveolin-1

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.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

Latest Pleistocene and Holocene Floodplain Evolution in Central Europe—Insights from the Upper Unstrut Catchment (NW-Thuringia/Germany)

The upper Unstrut River is located in Germany at the modern Central European climate boundary of Cfb and Dfb climate. The river drains a loess landscape, which has experienced important environmental changes throughout the last 12,000 years. To evaluate the impacts of these changes on floodplain evolution, a multi-proxy research program, consisting of 2D electrical resistivity tomography profiling (ERT), vibracoring, and sedimentological investigations, 14C and OSL dating were applied. From base to top the investigations the following fluvial deposits were revealed: (1) gravels embedded in a fine-grained sediment matrix (interpreted as fluvial bedload deposits); (2) silty sediment with pedogenic features (interpreted as overbank floodplain deposits); (3) peat and tufa deposits (interpreted as wetland deposits) intercalated by pedogenetically influenced silty sediments (interpreted as overbank deposits); (4) humic silty sediment with some pedogenic features (interpreted as overbank floodplain deposits); and (5) silty sediments (interpreted as overbank deposits). Radiocarbon and luminescence dates yielded the following periods for sediment formation: (1) Younger Dryas to Preboreal period (around 11.6 cal ka BP); (2) Preboreal to early Atlantic period (approx. 11.6 to 7.0 cal ka BP); (3) early Atlantic to late Subboreal period (approx. 7.3 to 3.4 cal ka BP); (4) late Subboreal to early Subatlantic period (2.9 to 2.3 cal ka BP); and (5) late Subatlantic period (approx. 1.0 to 0.6 cal ka BP). The results suggest that floodplain development during the latest Pleistocene and early Holocene (approx. 11.6 to 7.0 cal ka BP) was considerably controlled by climatic conditions and short-term climate variabilities, which caused gravel deposition and overbank sedimentation. Afterwards floodplain conditions varied between rather stable (peat and tufa development, initial soil formation) and active periods (deposition of overbank fines)

Impact of Siponimod on Enteric and Central Nervous System Pathology in Late-Stage Experimental Autoimmune Encephalomyelitis.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). Although immune modulation and suppression are effective during relapsing-remitting MS, secondary progressive MS (SPMS) requires neuroregenerative therapeutic options that act on the CNS. The sphingosine-1-phosphate receptor modulator siponimod is the only approved drug for SPMS. In the pivotal trial, siponimod reduced disease progression and brain atrophy compared with placebo. The enteric nervous system (ENS) was recently identified as an additional autoimmune target in MS. We investigated the effects of siponimod on the ENS and CNS in the experimental autoimmune encephalomyelitis model of MS. Mice with late-stage disease were treated with siponimod, fingolimod, or sham. The clinical disease was monitored daily, and treatment success was verified using mass spectrometry and flow cytometry, which revealed peripheral lymphopenia in siponimod- and fingolimod-treated mice. We evaluated the mRNA expression, ultrastructure, and histopathology of the ENS and CNS. Single-cell RNA sequencing revealed an upregulation of proinflammatory genes in spinal cord astrocytes and ependymal cells in siponimod-treated mice. However, differences in CNS and ENS histopathology and ultrastructural pathology between the treatment groups were absent. Thus, our data suggest that siponimod and fingolimod act on the peripheral immune system and do not have pronounced direct neuroprotective effects

Selective release of a potent anticancer agent from a supramolecular hydrogel using green light

Light-triggered drug release from hydrogels is a promising method to improve efficiency of antitumor treatment, as an alternative to existing photodynamic therapies. Here we report a photochromic supramolecular low-MW hydrogel that can quickly and selectively release a physically encapsulated potent anticancer agent upon green light irradiation under physiological conditions

Feel-good robotics: requirements on touch for embodiment in assistive robotics

The feeling of embodiment, i.e., experiencing the body as belonging to oneself and being able to integrate objects into one’s bodily self-representation, is a key aspect of human self-consciousness and has been shown to importantly shape human cognition. An extension of such feelings toward robots has been argued as being crucial for assistive technologies aiming at restoring, extending, or simulating sensorimotor functions. Empirical and theoretical work illustrates the importance of sensory feedback for the feeling of embodiment and also immersion; we focus on the the perceptual level of touch and the role of tactile feedback in various assistive robotic devices. We critically review how different facets of tactile perception in humans, i.e., affective, social, and self-touch, might influence embodiment. This is particularly important as current assistive robotic devices – such as prostheses, orthoses, exoskeletons, and devices for teleoperation–often limit touch low-density and spatially constrained haptic feedback, i.e., the mere touch sensation linked to an action. Here, we analyze, discuss, and propose how and to what degree tactile feedback might increase the embodiment of certain robotic devices, e.g., prostheses, and the feeling of immersion in human-robot interaction, e.g., in teleoperation. Based on recent findings from cognitive psychology on interactive processes between touch and embodiment, we discuss technical solutions for specific applications, which might be used to enhance embodiment, and facilitate the study of how embodiment might alter human-robot interactions. We postulate that high-density and large surface sensing and stimulation are required to foster embodiment of such assistive devices

Comparison of Free Energy Surfaces Calculations from Ab Initio Molecular Dynamic Simulations at the Example of Two Transition Metal Catalyzed Reactions

We carried out ab initio molecular dynamic simulations in order to determine the free energy surfaces of two selected reactions including solvents, namely a rearrangement of a ruthenium oxoester in water and a carbon dioxide addition to a palladium complex in carbon dioxide. For the latter reaction we also investigated the gas phase reaction in order to take solvent effects into account. We used two techniques to reconstruct the free energy surfaces: thermodynamic integration and metadynamics. Furthermore, we gave a reasonable error estimation of the computed free energy surface. We calculated a reaction barrier of ΔF = 59.5 ± 8.5 kJ mol−1 for the rearrangement of a ruthenium oxoester in water from thermodynamic integration. For the carbon dioxide addition to the palladium complex in carbon dioxide we found a ΔF = 44.9 ± 3.3 kJ mol−1 from metadynamics simulations with one collective variable. The investigation of the same reactions in the gas phase resulted in ΔF = 24.9 ± 6.7 kJ mol−1 from thermodynamic integration, in ΔF = 26.7 ± 2.3 kJ mol−1 from metadynamics simulations with one collective variable, and in ΔF = 27.1 ± 5.9 kJ mol−1 from metadynamics simulations with two collective variables

NGS-guided precision oncology in metastatic breast and gynecological cancer: first experiences at the CCC Munich LMU

PURPOSE Comprehensive genomic profiling identifying actionable molecular alterations aims to enable personalized treatment for cancer patients. The purpose of this analysis was to retrospectively assess the impact of personalized recommendations made by a multidisciplinary tumor board (MTB) on the outcome of patients with breast or gynecological cancers, who had progressed under standard treatment. Here, first experiences of our Comprehensive Cancer Center Molecular Tumor Board are reported. METHODS All patients were part of a prospective local registry. 95 patients diagnosed with metastatic breast cancer or gynecological malignancies underwent extended molecular profiling. From May 2017 through March 2019, the MTB reviewed all clinical cases considering tumor profile and evaluated molecular alterations regarding further diagnostic and therapeutic recommendations. RESULTS 95 patients with metastatic breast or gynecological cancers were discussed in the MTB (68% breast cancer, 20% ovarian cancer, 5% cervical cancer, 3% endometrial cancer and 4% others). Genes with highest mutation rate were PIK3CA and ERBB2. Overall, 34 patients (36%) received a biomarker-based targeted therapy recommendation. Therapeutic recommendations were implemented in nine cases; four patients experienced clinical benefit with a partial response or disease stabilization lasting over 4~months. CONCLUSION In the setting of a multidisciplinary molecular tumor board, a small but clinically meaningful group of breast and gynecological cancer patients benefits from comprehensive genomic profiling. Broad and successful implementation of precision medicine is complicated by patient referral at late stage disease and limited access to targeted agents and early clinical trials. TRIAL REGISTRATION NUMBER 284-10 (03.05.2018)

Initial Results from the TechnoSat in-Orbit Demonstration Mission

Until now, Technische Universität Berlin successfully developed, built and operated sixteen satellites ranging from several single unit CubeSats to a 56 kg Earth observation mission. The recently launched TechnoSat mission has the primary objective to demonstrate and test novel small satellite technologies and components in Low Earth Orbit. To this end, the 20 kg spacecraft carries seven payloads. One payload, for example, is the fluid-dynamic actuator developed by Technische Universität Berlin. This novel attitude actuator is based on momentum storage via a liquid metal that is accelerated using an electromagnetic pump. The secondary mission objective of TechnoSat is the in-orbit verification of the newly developed satellite platform TUBiX20 of Technische Universität Berlin. This platform bases on a modular systems design and provides scalability regarding selected performance parameters, which allows for tailoring of the platform towards individual mission requirements. TechnoSat was launched into a 600 km Sun-synchronous orbit on the 14th of July 2017. Since then, experiments are successfully conducted regularly with all payloads and the analysis of the collected data is in progress. This paper presents first orbit results of the TechnoSat mission focusing on selected technology demonstration payload