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We explore a combinatorial framework which efficiently quantifies the asymmetries between minima and maxima in local fluctuations of time series. We first showcase its performance by applying it to a battery of synthetic cases. We find rigorous results on some canonical dynamical models (stochastic processes with and without correlations, chaotic processes) complemented by extensive numerical simulations for a range of processes which indicate that the methodology correctly distinguishes different complex dynamics and outperforms state of the art metrics in several cases. Subsequently, we apply this methodology to real-world problems emerging across several disciplines including cases in neurobiology, finance and climate science. We conclude that differences between the statistics of local maxima and local minima in time series are highly informative of the complex underlying dynamics and a graph-theoretic extraction procedure allows to use these features for statistical learning purposes.
The long-chain fatty acid receptor FFAR1 is highly expressed in pancreatic β-cells. Synthetic FFAR1 agonists can be used as antidiabetic drugs to promote glucose-stimulated insulin secretion (GSIS). However, the physiological role of FFAR1 in β-cells remains poorly understood. Here we show that 20-HETE activates FFAR1 and promotes GSIS via FFAR1 with higher potency and efficacy than dietary fatty acids such as palmitic, linoleic, and α-linolenic acid. Murine and human β-cells produce 20-HETE, and the ω-hydroxylase-mediated formation and release of 20-HETE is strongly stimulated by glucose. Pharmacological inhibition of 20-HETE formation and blockade of FFAR1 in islets inhibits GSIS. In islets from type-2 diabetic humans and mice, glucose-stimulated 20-HETE formation and 20-HETE-dependent stimulation of GSIS are strongly reduced. We show that 20-HETE is an FFAR1 agonist, which functions as an autocrine positive feed-forward regulator of GSIS, and that a reduced glucose-induced 20-HETE formation contributes to inefficient GSIS in type-2 diabetes.
Der Beitrag bietet eine Übersicht zu den Zusammenhängen zwischen Immaterialgüterrechten (IP [intellectual property]-Rechte), Privatautonomie und Innovation. Demnach beruht das IP-Recht auf der Annahme, dass erst die Kombination aus fungiblen Ausschließlichkeitsrechten und Privatautonomie – also die juristische Form der Marktwirtschaft – einen innovationsförderlichen Effekt verspricht. Dementsprechend kombiniert das geltende Recht ein hohes materielles IP-Schutzniveau mit einer weitreichenden Anerkennung der Privatautonomie der Berechtigten. Dieser Regulierungsansatz hat den Vorteil, dass sehr anpassungsfähige Rahmenbedingungen für Innovationen geschaffen werden. Wer für seine Innovation eine umfassende Exklusivität benötigt, kann unter Geltung der beiden genannten Prinzipien ebenso operieren wie Akteure, die auf IP-Schutz teilweise oder ganz verzichten möchten, weil ihnen dies unter den gegebenen Wettbewerbsbedingungen vorzugswürdig erscheint. Und doch erläutert der Beitrag, dass die naheliegende Folgerung zu kurz greift, der Gesetzgeber könne sich darauf beschränken, möglichst umfassende und zugleich fungible IP-Rechte zu kodifizieren, da der Markt stets für eine effiziente und auch sonst sozial wünschenswerte Ressourcenallokation sorge. Denn die mit ausschließlichen IP-Rechten verbundenen Transaktionskosten stehen diesem Ziel nicht selten im Wege. Damit zeigt sich, dass keine noch so elaborierte Vertragsrechtstheorie die Frage nach dem Sinn des logisch vorrangigen Eigentums erübrigt.
Das Immaterialgüterrecht bildet eine der ältesten und inzwischen umfangreichsten Materien des Einheitsprivatrechts. Fast alle Staaten der Erde sind Mitglieder der World Intellectual Property Organization und bekennen sich als solche zur Förderung des „geistigen Eigentums“. Allerdings ist der Rechtsschutz nach dem seinerseits universell anerkannten Territorialitätsprinzip auf das Territorium des jeweiligen Gesetzgebers beschränkt. Zu dieser geografischen Fragmentierung treten fremdenrechtliche Beschränkungen des Zugangs zum lokalen Rechtsschutz hinzu. Der Beitrag erläutert, welche Akteure die Spannung zwischen globaler Kommunikation und fragmentiertem Immaterialgüterrechtsschutz auf welche Weisen regulativ bearbeiten. Dabei wird unterschieden zwischen der Rechtsangleichung bei fortdauernder Fragmentierung, der Schaffung supranational einheitlicher Verfahren, Immaterialgüterrechte und Gerichte sowie informellen Kooperationen zwischen Privaten und Patentämtern. Die Leitfrage der Bestandsaufnahme lautet, ob all diese Phänomene im Sinne von Kropholler und David als funktionales Einheitsrecht begriffen werden können, ob es sich also um Rechtssätze handelt, bei denen die Einheitlichkeit ihrer Geltung im Interesse des unverfälschten internationalen Handels zu einem besonderen Rechtszweck erhoben wurde, oder ob man lediglich objektiv-formal eine rechtlich bindende Einheitlichkeit konstatieren kann, die primär ein anderes Ziel verfolgt, nämlich: die weltweite Stärkung des Immaterialgüterrechtsschutzes. Den Abschluss bildet eine kritische Stellungnahme zur verbreiteten Annahme, die weit fortgeschrittene Vereinheitlichung des Immaterialgüterrechts sei ein großartiger Erfolg.
Target-specific treatment modalities are currently not available for triple-negative breast cancer (TNBC), and acquired chemotherapy resistance is a primary obstacle for the treatment of these tumors. Here we employed derivatives of BT-549 and MDA-MB-468 TNBC cell lines that were adapted to grow in the presence of either 5-Fluorouracil, Doxorubicin or Docetaxel in an aim to identify molecular pathways involved in the adaptation to drug-induced cell killing. All six drug-adapted BT-549 and MDA-MB-468 cell lines displayed cross resistance to chemotherapy and decreased apoptosis sensitivity. Expression of the anti-apoptotic co-chaperone BAG3 was notably enhanced in two thirds (4/6) of the six resistant lines simultaneously with higher expression of HSP70 in comparison to parental controls. Doxorubicin-resistant BT-549 (BT-549rDOX20) and 5-Fluorouracil-resistant MDA-MB-468 (MDA-MB-468r5-FU2000) cells were chosen for further analysis with the autophagy inhibitor Bafilomycin A1 and lentiviral depletion of ATG5, indicating that enhanced cytoprotective autophagy partially contributes to increased drug resistance and cell survival. Stable lentiviral BAG3 depletion was associated with a robust down-regulation of Mcl-1, Bcl-2 and Bcl-xL, restoration of drug-induced apoptosis and reduced cell adhesion in these cells, and these death-sensitizing effects could be mimicked with the BAG3/Hsp70 interaction inhibitor YM-1 and by KRIBB11, a selective transcriptional inhibitor of HSF-1. Furthermore, BAG3 depletion was able to revert the EMT-like transcriptional changes observed in BT-549rDOX20 and MDA-MB-468r5-FU2000 cells. In summary, genetic and pharmacological interference with BAG3 is capable to resensitize TNBC cells to treatment, underscoring its relevance for cell death resistance and as a target to overcome therapy resistance of breast cancer.
Germany Inc. was an idiosyncratic form of industrial organization that put financial institutions at the center. This paper argues that the consumption of private benefits in related party transactions by these key agents can be understood as a compensation for their coordinating and monitoring function in Germany Inc. As a consequence, legal tools apt to curb tunneling remained weak in Germany from the perspective of outside shareholders. While banks were in a position to use their firm-level knowledge and influence to limit rent-seeking by other related parties, their own behavior was not subject to meaningful controls. With the dismantling of Germany Inc. banks seized their monitoring function and left an unprecedented void with regard to related party transactions. Hence, a “traditionalist” stance which opposes law reform for related party transactions in Germany negatively affects capital market development, growth opportunities and ultimately social welfare.
We characterize the optimal linear tax on capital in an Overlapping Generations model with two period lived households facing uninsurable idiosyncratic labor income risk. The Ramsey government internalizes the general equilibrium feedback of private precautionary saving. For logarithmic utility our full analytical solution of the Ramsey problem shows that the optimal aggregate saving rate is independent of income risk. The optimal time-invariant tax on capital is increasing in income risk. Its sign depends on the extent of risk and on the Pareto weight of future generations. If the Ramsey tax rate that maximizes steady state utility is positive, then implementing this tax rate permanently generates a Pareto-improving transition even if the initial equilibrium is dynamically efficient. We generalize our results to Epstein-Zin-Weil utility and show that the optimal steady state saving rate is increasing in income risk if and only if the intertemporal elasticity of substitution is smaller than 1.
This paper investigates the roles psychological biases play in empirically estimated deviations between subjective survival beliefs (SSBs) and objective survival probabilities (OSPs). We model deviations between SSBs and OSPs through age-dependent inverse S-shaped probability weighting functions (PWFs), as documented in experimental prospect theory. Our estimates suggest that the implied measures for cognitive weakness, likelihood insensitivity, and those for motivational biases, relative pessimism, increase with age. We document that direct measures of cognitive weakness and motivational attitudes share these trends. Our regression analyses confirm that these factors play strong quantitative roles in the formation of subjective survival beliefs. In particular, cognitive weakness is an increasingly important contributor to the overestimation of survival chances in old age.
This paper is the national report for Germany prepared for the to the 20th General Congress of the International Academy of Comparative Law 2018 and gives an overview of the regulation of crowdfunding in Germany and the typical design of crowdfunding campaigns under this legal framework. After a brief survey of market data, it delineates the classification of crowdfunding transactions in German contract law and their treatment under the applicable conflict of laws regime. It then turns to the relevant rules in prudential banking regulation and capital market law. It highlights disclosure requirements that flow from both contractual obligations of the initiators of campaigns vis-à-vis contributors and securities regulation (prospectus regime). After sketching the most important duties of the parties involved in crowdfunding, the report also looks at the key features of the respective transactions’ tax treatment.
This paper revisits the macroeconomic effects of the large-scale asset purchase programmes launched by the Federal Reserve and the Bank of England from 2008. Using a Bayesian VAR, we investigate the macroeconomic impact of shocks to asset purchase announcements and assess changes in their effectiveness based on subsample analysis. The results suggest that the early asset purchase programmes had significant positive macroeconomic effects, while those of the subsequent ones were weaker and in part not significantly different from zero. The reduced effectiveness seems to reflect in part better anticipation of asset purchase programmes over time, since we find significant positive macroeconomic effects when we consider shocks to survey expectations of the Federal Reserve’s last asset purchase programme. Finally, in all estimations we find a significant and persistent positive impact of asset purchase shocks on stock prices.