Clarifying the importance of CYP2C19 and PON1 in the mechanism of clopidogrel bioactivation and in vivo antiplatelet response

AimsIt is thought that clopidogrel bioactivation and antiplatelet response are related to cytochrome P450 2C19 (CYP2C19). However, a recent study challenged this notion by proposing CYP2C19 as wholly irrelevant, while identifying paraoxonase-1 (PON1) and its Q192R polymorphism as the major driver of clopidogrel bioactivation and efficacy. The aim of this study was to systematically elucidate the mechanism and relative contribution of PON1 in comparison to CYP2C19 to clopidogrel bioactivation and antiplatelet response.Methods and resultsFirst, the influence of CYP2C19 and PON1 polymorphisms and plasma paraoxonase activity on clopidogrel active metabolite (H4) levels and antiplatelet response was assessed in a cohort of healthy subjects (n = 21) after administration of a single 75 mg dose of clopidogrel. There was a remarkably good correlation between H4 AUC (0-8 h) and antiplatelet response (r2 = 0.78). Furthermore, CYP2C19 but not PON1 genotype was predictive of H4 levels and antiplatelet response. There was no correlation between plasma paraoxonase activity and H4 levels. Secondly, metabolic profiling of clopidogrel in vitro confirmed the role of CYP2C19 in bioactivating clopidogrel to H4. However, heterologous expression of PON1 in cell-based systems revealed that PON1 cannot generate H4, but mediates the formation of another thiol metabolite, termed Endo. Importantly, Endo plasma levels in humans are nearly 20-fold lower than H4 and was not associated with any antiplatelet response.ConclusionOur results demonstrate that PON1 does not mediate clopidogrel active metabolite formation or antiplatelet action, while CYP2C19 activity and genotype remains a predictor of clopidogrel pharmacokinetics and antiplatelet response. © 2012 The Author

Giant magnetothermopower of magnon-assisted transport in ferromagnetic tunnel junctions

We present a theoretical description of the thermopower due to magnon-assisted tunneling in a mesoscopic tunnel junction between two ferromagnetic metals. The thermopower is generated in the course of thermal equilibration between two baths of magnons, mediated by electrons. For a junction between two ferromagnets with antiparallel polarizations, the ability of magnon-assisted tunneling to create thermopower $S_{AP}$ depends on the difference between the size $\Pi_{\uparrow, \downarrow}$ of the majority and minority band Fermi surfaces and it is proportional to a temperature dependent factor $(k_{B}T/\omega_{D})^{3/2}$ where $\omega_{D}$ is the magnon Debye energy. The latter factor reflects the fractional change in the net magnetization of the reservoirs due to thermal magnons at temperature $T$ (Bloch's $T^{3/2}$ law). In contrast, the contribution of magnon-assisted tunneling to the thermopower $S_P$ of a junction with parallel polarizations is negligible. As the relative polarizations of ferromagnetic layers can be manipulated by an external magnetic field, a large difference $\Delta S = S_{AP} - S_P \approx S_{AP} \sim - (k_B/e) f (\Pi_{\uparrow},\Pi_{\downarrow}) (k_BT/\omega_{D})^{3/2}$ results in a magnetothermopower effect. This magnetothermopower effect becomes giant in the extreme case of a junction between two half-metallic ferromagnets, $\Delta S \sim - k_B/e$.Comment: 9 pages, 4 eps figure

Global Directional Control of a Slender Autonomous Underwater Vehicle

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/77142/1/AIAA-20475-500.pd

Guided Electromagnetic Discharge Pulses Driven by Short Intense Laser Pulses: Characterisation and Modelling

Strong electromagnetic pulses (EMP) are generated from intense laser interactions with solid-density targets, and can be guided by the target geometry, specifically through conductive connections to the ground. We present an experimental characterization, by time- and spatial-resolved proton deflectometry, of guided electromagnetic discharge pulses along wires including a coil, driven by 0.5 ps, 50 J, 1e19 W/cm2 laser pulses. Proton-deflectometry data allows to time-resolve first the EMP due to the laser-driven target charging and then the return EMP from the ground through the conductive target stalk. Both EMPs have a typical duration of tens of ps and correspond to currents in the kA-range with electric-field amplitudes of multiple GV/m. The sub-mm coil in the target rod creates lensing effects on probing protons, due to both magnetic- and electric-field contributions. This way, protons of 10 MeV-energy range are focused over cm-scale distances. Experimental results are supported by analytical modelling and high-resolution numerical particle-in-cell simulations, unraveling the likely presence of a surface plasma, which parameters define the discharge pulse dispersion in the non-linear propagation regime

Evidence of high-n hollow ion emission from Si ions pumped by ultraintense x-rays from relativistic laser plasma

We report on the first observation of high-n hollow ions (ions having no electrons in the K or L shells) produced in Si targets via pumping by ultra-intense x-ray radiation produced in intense laser-plasma interactions reaching the radiation dominant kinetics regime. The existence of these new types of hollow ions in high energy density plasma has been found via observation of highly-resolved x-ray emission spectra of silicon plasma, and confirmed by plasma kinetics calculations, underscoring the ability of powerful radiation sources to fully strip electrons from the inner-most shells of light atoms. Hollow ions spectral diagnostics provide a unique opportunity to characterize powerful x-ray radiation of laboratory and astrophysical plasmas

Effect of plastic coating on the density of plasma formed in Si foil targets irradiated by ultra-high-contrast relativistic laser pulses

The formation of high energy density matter occurs in inertial confinement fusion, astrophysical, and geophysical systems. In this context, it is important to couple as much energy as possible into a target while maintaining high density. A recent experimental campaign, using buried layer (or "sandwich" type) targets and the ultrahigh laser contrast Vulcan petawatt laser facility, resulted in 500 Mbar pressures in solid density plasmas (which corresponds to about 4.6×107J/cm3 energy density). The densities and temperatures of the generated plasma were measured based on the analysis of X-ray spectral line profiles and relative intensities

Time evolution and asymmetry of a laser produced blast wave

Studies of a blast wave produced from carbon rods and plastic spheres in an argon background gas have been conducted using the Vulcan laser at the Rutherford Appleton Laboratory. A laser of 1500 J was focused onto these targets, and rear-side observations of an emission front were recorded using a fast-framing camera. The emission front is asymmetrical in shape and tends to a more symmetrical shape as it progresses due to the production of a second shock wave later in time, which pushes out the front of the blast wave. Plastic spheres produce faster blast waves, and the breakthrough of the second shock is visible before the shock stalls. The results are presented to demonstrate this trend, and similar evolution dynamics of experimental and simulation data from the FLASH radiation-hydrodynamics code are observed

Using X-ray spectroscopy of relativistic laser plasma interaction to reveal parametric decay instabilities : A modeling tool for astrophysics

By analyzing profiles of experimental x-ray spectral lines of Si XIV and Al XIII, we found that both Langmuir and ion acoustic waves developed in plasmas produced via irradiation of thin Si foils by relativistic laser pulses (intensities ∼1021 W/cm2). We prove that these waves are due to the parametric decay instability (PDI). This is the first time that the PDI-induced ion acoustic turbulence was discovered by the x-ray spectroscopy in laser-produced plasmas. These conclusions are also supported by PIC simulations. Our results can be used for laboratory modeling of physical processes in astrophysical objects and a better understanding of intense laser-plasma interactions

Exotic dense-matter states pumped by a relativistic laser plasma in the radiation-dominated regime

In high-spectral resolution experiments with the petawatt Vulcan laser, strong x-ray radiation of KK hollow atoms (atoms without n = 1 electrons) from thin Al foils was observed at pulse intensities of 3 x 10(20) W/cm(2). The observations of spectra from these exotic states of matter are supported by detailed kinetics calculations, and are consistent with a picture in which an intense polychromatic x-ray field, formed from Thomson scattering and bremsstrahlung in the electrostatic fields at the target surface, drives the KK hollow atom production. We estimate that this x-ray field has an intensity of >5 x 10(18) W/cm(2) and is in the 3 keV range