Effect of apolipoprotein E and butyrylcholinesterase genotypes on cognitive response to cholinesterase inhibitor treatment at different stages of Alzheimer's disease

Factors that influence response to drug treatment are of increasing importance. We report an analysis of genetic factors affecting response to cholinesterase inhibitor therapy in 165 subjects with Alzheimer's disease (AD). The presence of apolipoprotein E e4 (APOE e4) allele was associated with early and late cognitive response to cholinesterase inhibitor treatment in mild AD (Mini-Mental State Examination (MMSE) greater than or equal to21) (P

The inhibitor profiling of the caspase family of proteases using substrate-derived peptide glyoxals.

A series of substrate-based a-keto-ß-aldehyde (glyoxal) sequences have been synthesised and evaluated as inhibitors of the caspase family of cysteine proteases. A number of potent inhibitor sequences have been identified. For example, a palmitic acid containing sequence pal-Tyr-Val-Ala-Asp-glyoxal was demonstrated to be an extremely effective inhibitor of caspase-1, inhibiting not only the action of the protease against synthetic fluorogenic substrates (Ki = 0.3 nM) but also blocking its processing of pro-interleukin-1beta (pro-IL-1ß). In addition, the peptide Ac-Asp-Glu-Val-Asp-glyoxal, which is based on the consensus cleavage sequence for caspase-3, is a potent inhibitor of this protease (Ki = 0.26 nM) yet only functions as a comparatively modest inhibitor of caspase-1 (Ki = 451 nM). Potent inhibitor sequences were also identified for caspases-6 and -8. However, the degree of discrimination between the family members is limited. The ability of Ac-Asp-Glu-Val-Asp-glyoxal to block caspase-3 like activity in whole cells and to delay the development of apoptosis was assessed. When tested against caspase-3 like activity in cell lysates, Ac-Asp-Glu-Val-Asp-glyoxal displayed effective inhibition similar to that observed against recombinant caspase-3. Treatment of whole cells with this potent caspase-3 inhibitor was however, not sufficient to significantly stall the development of apoptosis in-vitro.

Laser-driven quasimonoenergetic proton burst from water spray target

A narrow band proton bursts at energies of 1.6 +/- 0.08 MeV were observed when a water spray consisting of empty set(150 nm)-diameter droplets was irradiated by an ultrashort laser pulse of about 45 fs duration and at an intensity of 5 X 10(19) W/cm(2). The results are explained by a Coulomb explosion of sub-laser-wavelength droplets composed of two ion species. The laser prepulse plays an important role. By pre-evaporation of the droplets, its diameter is reduced so that the main pulse can interact with a smaller droplet, and this remaining bulk can be ionized to high states. In the case of water, the mixture of quite differently charged ions establishes an

Tomography of an ultrafast laser driven proton source

Using a multichannel Thomson spectrometer we have implemented a tomographic approach allowing the reconstruction of the emission characteristic of a laser driven proton source with high energy and spatial resolution. The results demonstrate the complexity of the temporal and spatial characteristics of such a source. The emitted proton beam, which is laminar and divergent at high energies, becomes convergent at low energies. This implies that a fraction of the proton beam having this kinetic energy is emitted in a collimated way from the target at the

Proton radiography of a shock-compressed target

In this paper we report on the radiography of a shock-compressed target using laser produced proton beams. A low-density carbon foam target was shock compressed by long pulse high-energy laser beams. The shock front was transversally probed with a proton beam produced in the interaction of a high intensity laser beam with a gold foil. We show that from radiography data, the density profile in the shocked target can be deduced using Monte Carlo simulations. By changing the delay between long and short pulse beams, we could probe different plasma conditions and structures, demonstrating that the details of the steep density gradient can be resolved. This technique is validated as a diagnostic for the investigation of warm dense plasmas, allowing an in situ characterization of high-density contrasted plasmas.

Progress in proton radiography for diagnosis of ICF-relevant plasmas

Proton radiography using laser-driven sources has been developed as a diagnostic since the beginning of the decade, and applied successfully to a range of experimental situations. Multi-MeV protons driven from thin foils via the Target Normal Sheath Acceleration mechanism, offer, under optimal conditions, the possibility of probing laser-plasma interactions, and detecting electric and magnetic fields as well as plasma density gradients with similar to ps temporal resolution and similar to 5-10 mu m spatial resolution. In view of these advantages, the use of proton radiography as a diagnostic in experiments of relevance to Inertial Confinement Fusion is currently considered in the main fusion laboratories. This paper will discuss recent advances in the application of laser-driven radiography to experiments of relevance to Inertial Confinement Fusion. In particular we will discuss radiography of hohlraum and gasbag targets following the interaction of intense ns pulses. These experiments were carried out at the HELEN laser facility at AWE (UK), and proved the suitability of this diagnostic for studying, with unprecedented detail, laser-plasma interaction mechanisms of high relevance to Inertial Confinement Fusion. Non-linear solitary structures of relevance to space physics, namely phase space electron holes, have also been highlighted by the measurements. These measurements are discussed and compared to existing models.

Simulation of a collisionless planar electrostatic shock in a proton-electron plasma with a strong initial thermal pressure change

The localized deposition of the energy of a laser pulse, as it ablates a solid target, introduces high thermal pressure gradients in the plasma. The thermal expansion of this laser-heated plasma into the ambient medium (ionized residual gas) triggers the formation of non-linear structures in the collisionless plasma. Here an electron-proton plasma is modelled with a particle-in-cell simulation to reproduce aspects of this plasma expansion. A jump is introduced in the thermal pressure of the plasma, across which the otherwise spatially uniform temperature and density change by a factor of 100. The electrons from the hot plasma expand into the cold one and the charge imbalance drags a beam of cold electrons into the hot plasma. This double layer reduces the electron temperature gradient. The presence of the low-pressure plasma modifies the proton dynamics compared with the plasma expansion into a vacuum. The jump in the thermal pressure develops into a primary shock. The fast protons, which move from the hot into the cold plasma in the form of a beam, give rise to the formation of phase space holes in the electron and proton distributions. The proton phase space holes develop into a secondary shock that thermalizes the beam.