Stabilizing role of platelet P2Y(12) receptors in shear-dependent thrombus formation on ruptured plaques

Background: In most models of experimental thrombosis, healthy blood vessels are damaged. This results in the formation of a platelet thrombus that is stabilized by ADP signaling via P2Y(12) receptors. However, such models do not predict involvement of P2Y(12) in the clinically relevant situation of thrombosis upon rupture of atherosclerotic plaques. We investigated the role of P2Y(12) in thrombus formation on (collagen-containing) atherosclerotic plaques in vitro and in vivo, by using a novel mouse model of atherothrombosis. Methodology: Plaques in the carotid arteries from Apoe(-/-) mice were acutely ruptured by ultrasound treatment, and the thrombotic process was monitored via intravital fluorescence microscopy. Thrombus formation in vitro was assessed in mouse and human blood perfused over collagen or plaque material under variable conditions of shear rate and coagulation. Effects of two reversible P2Y(12) blockers, ticagrelor (AZD6140) and cangrelor (AR-C69931MX), were investigated. Principal Findings: Acute plaque rupture by ultrasound treatment provoked rapid formation of non-occlusive thrombi, which were smaller in size and unstable in the presence of P2Y(12) blockers. In vitro, when mouse or human blood was perfused over collagen or atherosclerotic plaque material, blockage or deficiency of P2Y(12) reduced the thrombi and increased embolization events. These P2Y(12) effects were present at shear rates >500 s(-1), and they persisted in the presence of coagulation. P2Y(12)-dependent thrombus stabilization was accompanied by increased fibrin(ogen) binding. Conclusions/Significance: Platelet P2Y(12) receptors play a crucial role in the stabilization of thrombi formed on atherosclerotic plaques. This P2Y(12) function is restricted to high shear flow conditions, and is preserved in the presence of coagulation

Heme Oxygenase Protects against Placental Vascular Inflammation and Abortion by the Alarmin Heme in Mice.

Both infectious as non-infectious inflammation can cause placental dysfunction and pregnancy complications. During the first trimester of human gestation, when palatogenesis takes place, intrauterine hematoma and hemorrhage are common phenomena, causing the release of large amounts of heme, a well-known alarmin. We postulated that exposure of pregnant mice to heme during palatogenesis would initiate oxidative and inflammatory stress, leading to pathological pregnancy, increasing the incidence of palatal clefting and abortion. Both heme oxygenase isoforms (HO-1 and HO-2) break down heme, thereby generating anti-oxidative and -inflammatory products. HO may thus counteract these heme-induced injurious stresses. To test this hypothesis, we administered heme to pregnant CD1 outbred mice at Day E12 by intraperitoneal injection in increasing doses: 30, 75 or 150 μmol/kg body weight (30H, 75H or 150H) in the presence or absence of HO-activity inhibitor SnMP from Day E11. Exposure to heme resulted in a dose-dependent increase in abortion. At 75H half of the fetuses where resorbed, while at 150H all fetuses were aborted. HO-activity protected against heme-induced abortion since inhibition of HO-activity aggravated heme-induced detrimental effects. The fetuses surviving heme administration demonstrated normal palatal fusion. Immunostainings at Day E16 demonstrated higher numbers of ICAM-1 positive blood vessels, macrophages and HO-1 positive cells in placenta after administration of 75H or SnMP + 30H. Summarizing, heme acts as an endogenous "alarmin" during pregnancy in a dose-dependent fashion, while HO-activity protects against heme-induced placental vascular inflammation and abortion

Prospects for joint radio telescope and gravitational wave searches for astrophysical transients

The radio skies remain mostly unobserved when it comes to transient phenomena. The direct detection of gravitational waves will mark a major milestone of modern astronomy, as an entirely new window will open on the universe. Two apparently independent phenomena can be brought together in a coincident effort that has the potential to boost both searches. In this paper we will outline the scientific case that stands behind these future joint observations and will describe the methods that might be used to conduct the searches and analyze the data. The targeted sources are binary systems of compact objects, known to be strong candidate sources for gravitational waves. Detection of transients coincident in these two channels would be a significant smoking gun for first direct detection of gravitational waves, and would open up a new field for characterization of astrophysical transients involving massive compact objects.Comment: 12 pages, Amaldi 8 Conference (New York, 2009) proceedings pape

Experimental evidence for the sensitivity of the air-shower radio signal to the longitudinal shower development

We observe a correlation between the slope of radio lateral distributions, and the mean muon pseudorapidity of 59 individual cosmic-ray-air-shower events. The radio lateral distributions are measured with LOPES, a digital radio interferometer co-located with the multi-detector-air-shower array KASCADE-Grande, which includes a muon-tracking detector. The result proves experimentally that radio measurements are sensitive to the longitudinal development of cosmic-ray air-showers. This is one of the main prerequisites for using radio arrays for ultra-high-energy particle physics and astrophysics.Comment: 6 pages, 5 figures, accepted for publication by Physical Review

The wavefront of the radio signal emitted by cosmic ray air showers

Analyzing measurements of the LOPES antenna array together with corresponding CoREAS simulations for more than 300 measured events with energy above $10^{17}\,$eV and zenith angles smaller than $45^\circ$, we find that the radio wavefront of cosmic-ray air showers is of approximately hyperbolic shape. The simulations predict a slightly steeper wavefront towards East than towards West, but this asymmetry is negligible against the measurement uncertainties of LOPES. At axis distances $\gtrsim 50\,$m, the wavefront can be approximated by a simple cone. According to the simulations, the cone angle is clearly correlated with the shower maximum. Thus, we confirm earlier predictions that arrival time measurements can be used to study the longitudinal shower development, but now using a realistic wavefront. Moreover, we show that the hyperbolic wavefront is compatible with our measurement, and we present several experimental indications that the cone angle is indeed sensitive to the shower development. Consequently, the wavefront can be used to statistically study the primary composition of ultra-high energy cosmic rays. At LOPES, the experimentally achieved precision for the shower maximum is limited by measurement uncertainties to approximately $140\,$g/cm$^2$. But the simulations indicate that under better conditions this method might yield an accuracy for the atmospheric depth of the shower maximum, $X_\mathrm{max}$, better than $30\,$g/cm$^2$. This would be competitive with the established air-fluorescence and air-Cherenkov techniques, where the radio technique offers the advantage of a significantly higher duty-cycle. Finally, the hyperbolic wavefront can be used to reconstruct the shower geometry more accurately, which potentially allows a better reconstruction of all other shower parameters, too.Comment: accepted by JCA

Time-Resolved Photometry of the Optical Counterpart of Swift J2319.4+2619

Time-resolved CCD photometry is presented of the V~17 optical counterpart of the newly-discovered, hard-X-ray-emitting polar Swift J2619.4+2619. A total of ~20 hr of data obtained over five nights in various bandpasses (B, V, R, and I) reveals a strong quasi-sinusoidal modulation in the light curve at a best-fitting period of 0.1254 d (3.01 hr), which we associate with the orbital period of the system (one-day aliases of this period at 0.1114 d and 0.1435 d are considered, but appear to be ruled out by our analysis). The amplitude of the modulation increases with wavelength from ~0.8 mag in B to ~1.1 mag in R and I. The increase in amplitude with wavelength is typical of polar systems where the modulated radiation comes from cyclotron emission. The combination of the relatively long orbital period and the emission of hard X-rays suggest that Swift J2619.4+2619 may be a good candidate for an asynchronous polar system.Comment: 15 pages, 5 figures, Accepted for publication in the April 2008 PAS