The NO/cGMP pathway inhibits Rap1 activation in human platelets via cGMP-dependent protein kinase I
- The NO/cGMP signalling pathway strongly inhibits agonist-induced platelet aggregation. However, the molecular mechanisms involved are not completely defined.We have studied NO/cGMP effects on the activity of Rap1, an abundant guanine-nucleotidebinding protein in platelets. Rap1-GTP levels were reduced by NO-donors and activators of NO-sensitive soluble guanylyl cyclase. Four lines of evidence suggest that NO/cGMP effects are mediated by cGMP-dependent protein kinase (cGKI): (i) Rap1 inhibition correlated with cGKI activity as measured by the phosphorylation state ofVASP, an established substrate of cGKI, (ii) 8-pCPT-cGMP, a membrane permeable cGMP-analog and activator of cGKI, completely blocked Rap1 activation, (iii) Rp- 8pCPT-cGMPS, a cGKI inhibitor, reversed NO effects and (iv) expression of cGKI in cGKI-deficient megakaryocytes inhibited Rap1 activation. NO/cGMP/cGKI effects were independent of the type of stimulus used for Rap1 activation.Thrombin-,ADPand collagen-induced formation of Rap1-GTP in platelets as well as turbulence-induced Rap1 activation in megakaryocytes were inhibited. Furthermore, cGKI inhibited ADP-induced Rap1 activation induced by the G a i -coupled P2Y12 receptor alone, i.e. independently of effects on Ca2+-signalling. From these studies we conclude that NO/cGMP inhibit Rap1 activation in human platelets and that this effect is mediated by cGKI. Since Rap1 controls the function of integrin a IIbß 3 , we propose that Rap1 inhibition might play a central role in the anti-aggregatory actions of NO/cGMP.
[Rezension zu:] Gisela Brünner. 2011. Gesundheit durchs Fernsehen. Linguistische Untersuchungen zur Vermittlung medizinischen Wissens und Aufklärung in Gesundheitssendungen. Duisburg: Universitätsverlag Rhein-Ruhr. 528 S.
Nina Jeanette Hofferberth
David Sebastian Sauer
Verso il Danubio : La passeggiata di Thomas Bernhard
- Avventurarsi e poi inoltrarsi nell'opera di Thomas Bernhard non è precisamente come fare una passeggiata, ma la passeggiata è un motivo ricorrente nell'opera bernhardiana (insieme a quella di Handke, di Sebald, di Walser, per fare solo alcuni nomi di passeggiatori nel Novecento di lingua tedesca). Le figure di Bernhard camminano, marciano, corrono, ma in una "direzione opposta" rispetto a quella indicata da Stifter. Talvolta i loro percorsi si snodano nella natura, come quando entrano in un bosco per non fare più ritorno (Gelo, Al limite boschivo, La partita a carte), a volte marciano nel chiuso della loro "casa-prigione", seguendo i percorsi labirintici e infiniti della loro mente (La Fornace, Cemento), altre volte ancora si muovono in un contesto cittadino e metropolitano, a Roma in Estinzione (dove la passeggiata con l'allievo Gambetti conserva un alone aristotelico, il peripatetico) o - più spesso - a Vienna.
Dialettica negativa e Antropologia negativa : Adorno - Anders
- Un titolo quale "Dialettica negativa e antropologia negativa" sembrerebbe preannunciare un lavoro di confronto tra Th. W. Adorno e Ulrich Sonnemann, sulla scia di una indicazione mutuata dalla "Introduzione" di "Dialettica negativa" (1966). E invece, disattendendo una simile aspettativa, la "Negative Anthropologie" cui ci si riferisce in questo saggio è quella di Günther Stern/Anders. L’idea di un confronto tra le due prospettive nasce dalla curiosità di capire la corrispondenza tra la "dialettica negativa" e l'"antropologia negativa", laddove con il secondo sintagma si intende la concezione andersiana di un'umanità inadeguata al mondo. Che poi non si tratti di una stranezza ma di un interrogativo legittimo lo conferma, indirettamente, lo stesso Adorno, che in una nota contenuta nella sezione della "Dialettica negativa" dedicata alla lettura del pensiero di Heidegger, chiama in causa proprio la lezione di Anders.
Sestrin-2, a repressor of PDGFRβ signalling, promotes cigarette smoke-induced pulmonary emphysema in mice and is upregulated in patients with COPD
K. C. Kent Lloyd
Harald von Melchner
- Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. COPD is caused by chronic exposure to cigarette smoke and/or other environmental pollutants that are believed to induce reactive oxygen species (ROS) that gradually disrupt signalling pathways responsible for maintaining lung integrity. Here we identify the antioxidant protein Sestrin 2 (Sesn2) as a repressor of PDGFRβ signalling and PDGFRβ signalling as an upstream regulator of alveolar maintenance programs. In mice, the mutational inactivation of Sesn2 prevents the development of cigarette-smoke induced pulmonary emphysema by upregulating PDGFRβ expression via a selective accumulation of intracellular superoxide anions (O2-). We also show that SESN2 is overexpressed and PDGFRβ downregulated in the emphysematous lungs of patients with COPD and to a lesser extent in human lungs of habitual smokers without COPD, implicating a negative SESN2/PDGFRβ interrelationship in the pathogenesis of COPD. Taken together, our results imply that SESN2 could serve as both a biomarker and as a drug target in the clinical management of COPD.
Integer point sets minimizing average pairwise L1 distance: What is the optimal shape of a town?
Erik D. Demaine
Sándor P. Fekete
- An n-town, n[is an element of]N , is a group of n buildings, each occupying a distinct position on a 2-dimensional integer grid. If we measure the distance between two buildings along the axis-parallel street grid, then an n-town has optimal shape if the sum of all pairwise Manhattan distances is minimized. This problem has been studied for cities, i.e., the limiting case of very large n. For cities, it is known that the optimal shape can be described by a differential equation, for which no closed-form solution is known. We show that optimal n-towns can be computed in O(n[superscript 7.5]) time. This is also practically useful, as it allows us to compute optimal solutions up to n=80.
Analyst behaviour: the geography of social interaction
- An analyst who works in Germany is more likely to publish a high (low) price target regarding a DAX30 stock if other Germany based analysts are also optimistic (pessimistic) about the same stock. This finding is not biased by the fact that DAX30 companies are headquartered in Germany. In times of bull markets, price targets of analysts who regularly exchange their opinion are higher correlated compared to other analysts. This effect vanishes in a bearish market environment. This suggests that communication among analysts indeed plays an important role. However, analysts’ incentives induce them not to deviate too much from the overall average during an economic downturn.
Does social interaction destablise financial markets?
- With this paper, I propose a simple asset pricing model that accounts for the influence from social interaction. Investors are assumed to make up their mind about an asset’s price based on a forecasting strategy and its past profitability as well as on the contemporaneous expectations of other market participants. Empirically analysing stocks of the DAX30 index, I provide evidence that social interaction rather destabilises financial markets. Based on my results, I state that at least, it does not have a stabilising effect.
Fluctuations of social influence: evidence from the behaviour of mutual fund managers during the economic crisis 2008/09
- In this paper, I analyse the reciprocal social influence on investment decisions within an international group of roughly 2000 mutual fund managers that invested in companies of the DAX30. Using a robust estimation procedure, I provide empirical evidence that in the average a fund manager puts 0.69% more portfolio weight on a particular stock, if other fund managers increase the corresponding position by 1%. The dynamics of this influence on portfolio weights suggest that fund managers adjust their behaviour according to the prevailing market situation and are more strongly influenced by others in times of an economic downturn. Analysing the working locations of the fund managers, I conclude that more than 90% of the magnitude of influence is due to pure observation. While this form of influence varies much in time, the magnitude of influence resulting from the exchange of opinion is more or less constant.
Sandrart.net: Eine Online-Edition eines Textes des 17. Jahrhunderts
- Der folgende Text stellt ein Online-Projekt vor, das seit April 2007 mit einer Laufzeit von fünf Jahren auf Initiative
des Kunstgeschichtlichen Instituts in Frankfurt und des Kunsthistorischen Instituts in Florenz entwickelt,
zusammen mit den Partnerinstitutionen Städel Museum und Historisches Museum in Frankfurt
durchgeführt und gemeinsam von der Deutschen Forschungsgemeinschaft und der Max-Planck-
Gesellschaft finanziert wird.