Artemisinins act through at least two targets in a yeast model

Artemisinin and related compounds are potent and widely used antimalarial drugs but their biochemical mode of action is not clear. There is strong evidence that ATP-dependent calcium transporters are a key target in the malarial parasite. However, work using Saccharomyces cerevisiae suggests that disruption of mitochondrial function is critical in the cell killing activity of these compounds. Here it is shown that, in the absence of reducing agents, artemisinin and artesunate targeted the S. cerevisiae calcium channels Pmr1p and Pmc1p. Both compounds affected the growth of yeast on fermentable and nonfermentable media. This growth inhibition was not seen in a yeast strain in which the genes encoding both calcium channels were deleted. In the presence of reducing agents, which break the endoperoxide bridge in the drugs, growth inhibition was only observed in nonfermentable media. This inhibition could be partially relieved by the addition of a free radical scavenger. These results suggest that the drugs have two biochemical modes of action - one acting by specific binding to calcium channels and one involving free radical production in the mitochondria.

Effect of atorvastatin on circulating hsCRP concentrations: A sub-study of the Achieve Cholesterol Targets Fast with Atorvastatin Stratified Titration (ACTFAST) study

Background: Elevated C-reactive protein (CRP) concentration is a risk factor for cardiovascular events that may add prognostic information. Statin treatment is associated with significant reductions in CRP concentrations, which appear to be unrelated to the magnitude of LDL-cholesterol reduction. We investigated the effect of atorvastatin, across its dose range, on high sensitivity (hs)CRP in subjects at high cardiovascular risk. Methods: ACTFAST was a 12 week, prospective, multicenter, open-label trial in which high-risk subjects were assigned a starting dose of atorvastatin (10, 20, 40 or 80 mg/d) based on LDL-C and status of statin use at screening (1345 statin-free [ SF] and 772 previously statin-treated [ST]). Results: At baseline, ST subjects had significantly lower hsCRP levels than SF subjects (ST group 2.31, 95% CI 2.15, 2.48 mg/L vs. SF group 3.16, 95% CI 2.98, 3.34 mg/L, p

On the investigation of fast electron beam filamentation in laser-irradiated solid targets using multi-MeV proton emission

The transverse filamentation of beams of fast electrons transported in solid targets irradiated by ultraintense (5 x 10(20) W cm(-2)), picosecond laser pulses is investigated experimentally. Filamentation is diagnosed by measuring the uniformity of a beam of multi-MeV protons accelerated by the sheath field formed by the arrival of the fast electrons at the rear of the target, and is investigated for metallic and insulator targets ranging in thickness from 50 to 1200 mu m. By developing an analytical model, the effects of lateral expansion of electron beam filaments in the sheath during the proton acceleration process is shown to account for measured increases in proton beam nonuniformity with target thickness for the insulating targets.

Observations of collimated ionization channels in aluminum-coated glass targets irradiated by ultraintense laser pulses

Filamentary ionization tracks have been observed via optical probing inside Al-coated glass targets after the interaction of a picosecond 20-TW laser pulse at intensities above 10(19) W/cm(2). The tracks, up to 700 mu m in length and between 10 and 20 mu m in width, originate from the focal spot region of the laser beam. Simulations performed with 3D particle-in-cell and 2D Fokker-Planck hybrid codes indicate that the observations are consistent with ionization induced in the glass target by magnetized, collimated beams of high-energy electrons produced during the laser interaction.

THE EXPANSION HISTORY OF ALUMINUM TARGETS RELEVANT TO X-RAY LASER SCHEMES

For the first time, the technique of point projection absorption spectroscopy - which uses an intense, point source of X-rays to project and spectrally disperse an image of a plasma onto a detector- has been shown to be applicable to the study of expanding aluminium plasmas generated by approximately 80ps (2-omega) laser pulses. Massive, stripe targets of approximately 125-mu-m width and wire targets of 25-mu-m diameter have been studied. Using a PET Bragg crystal as the dispersive element, a resolving power of approximately 3500 was achieved with spatial resolution at the 5-mu-m level in frame times of the order of 80ps. Reduction of the data for times up to 150ps after the peak of the incident laser pulse produced estimates of the temperature and densities present, as a function of space and time.

GAIN SCALING RELATIONSHIPS FOR NE-LIKE GE SLAB TARGETS

The gain coefficient of the strongest 3p --> 3s, J = 2 --> 1 lasing transition at 23.6 nm in the Ne-like Ge collisional excitation scheme has been measured, using the fundamental wavelength from a Nd:glass laser (1.06-mu-m), for a range of incident intensities on massive stripe targets up to 2.2 cm in length. From a threshold incident laser intensity of approximately 6 x 10(12) W/cm2, the gain coefficient rises to approximately 4.5 cm-1 for an irradiation intensity of approximately 2.5 x 10(13) W/cm2, tending towards still higher gain coefficients at higher incident intensities. For targets of maximum length, a gain-length product gL almost-equal-to 10 was reached with a resultant output power at 23.6 nm estimated to be at the approximately kW level. The beam divergence decreased with length to a minimum of approximately 7 mrad but no significant trend in beam pointing with plasma length was observed. From the trend in the gain coefficient, it appears that for a fixed energy laser irradiating a approximately 100-mu-m wide slab targets, an incident intensity of I(i) approximately 1.2 x 10(13) W/cm2 represents an optimum working level, assuming that plasma length is not limited by refractive effects. In addition to the usual valence electron excited 3p --> 3s transitions, the gain coefficient for the core excited 1s(2)2s2p(6)3d --> 1s(2)2s2p(6)3p transition at 19.9 nm has been measured to be approximately 1.5 cm-1 for an incident irradiance of approximately 2.5 x 10(13) W/cm2.

CHARACTERIZATION OF A LASER-PRODUCED PLASMA USING THE TECHNIQUE OF POINT-PROJECTION ABSORPTION-SPECTROSCOPY

The technique of point-projection spectroscopy has been shown to be applicable to the study of expanding aluminum plasmas generated by approximately 80 ps laser pulses incident on massive, aluminum stripe targets of approximately 125-mu-m width. Targets were irradiated at an intensity of 2.5 +/- 0.5 x 10(13) W/cm2 in a line focus geometry and under conditions similar to those of interest in x-ray laser schemes. Hydrogenic and heliumlike aluminum resonance lines were observed in absorption using a quasicontinuous uranium back-lighter plasma. Using a pentaerythrital Bragg crystal as the dispersive element, a resolving power of approximately 3500 was achieved with spatial resolution at the 5-mu-m level in frame times of the order of 100 ps. Reduction of the data for times up to 150 ps after the peak of the incident laser pulse produced estimates of the temperature and ion densities present, as a function of space and time. The one-dimensional Lagrangian hydrodynamic code MEDUSA coupled to the atomic physics non-local-thermodynamic-equilibrium ionized material package was used to simulate the experiment in planar geometry and has been shown to be consistent with the measurements.