Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable gamma-Secretase Inhibitor

During the course of our research efforts to develop a potent and selective gamma-secretase inhibitor for the treatment of Alzheimer's disease, we investigated a series of carboxamide-substituted sulfonamides. Optimization based on potency, Notch/amyloid-beta precursor protein selectivity, and brain efficacy after oral dosing led to the discovery of 4 (BMS-708163). Compound 4 is a potent inhibitor of gamma-secretase (A beta 40 IC50 = 0.30 nM), demonstrating a 193-fold selectivity against Notch. Oral administration of 4 significantly reduced A beta 40 levels for sustained periods in brain, plasma, and cerebrospinal fluid in rats and dogs.

Experimental demonstration of particle energy, conversion efficiency and spectral shape required for ion-based fast ignition

Research on fusion fast ignition (FI) initiated by laser-driven ion beams has made substantial progress in the last years. Compared with electrons, FI based on a beam of quasi-monoenergetic ions has the advantage of a more localized energy deposition, and stiffer particle transport, bringing the required total beam energy close to the theoretical minimum. Due to short pulse laser drive, the ion beam can easily deliver the 200 TW power required to ignite the compressed D-T fuel. In integrated calculations we recently simulated ion-based FI targets with high fusion gain targets and a proof of principle experiment [1]. These simulations identify three key requirements for the success of ion-driven fast ignition (IFI): (1) the generation of a sufficiently high-energetic ion beam (approximate to 400-500 MeV for C), with (2) less than 20% energy spread at (3) more than 10% conversion efficiency of laser to beam energy. Here we present for the first time new experimental results, demonstrating all three parameters in separate experiments. Using diamond nanotargets and ultrahigh contrast laser pulses we were able to demonstrate >500 MeV carbon ions, as well as carbon pulses with Delta E/E

Dynamics of relativistic transparency and optical shuttering in expanding overdense plasmas

Overdense plasmas are usually opaque to laser light. However, when the light is of sufficient intensity to drive electrons in the plasma to near light speeds, the plasma becomes transparent. This process—known as relativistic transparency—takes just a tenth of a picosecond. Yet all studies of relativistic transparency so far have been restricted to measurements collected over timescales much longer than this, limiting our understanding of the dynamics of this process. Here we present time-resolved electric field measurements (with a temporal resolution of ~ 50 fs) of the light, initially reflected from, and subsequently transmitted through, an expanding overdense plasma. Our result provides insight into the dynamics of the transparent-overdense regime of relativistic plasmas, which should be useful in the development of laser-driven particle accelerators, X-ray sources and techniques for controlling the shape and contrast of intense laser pulses.

Three-Dimensional Dynamics of Breakout Afterburner Ion Acceleration Using High-Contrast Short-Pulse Laser and Nanoscale Targets

Breakout afterburner (BOA) laser-ion acceleration has been demonstrated for the first time in the laboratory. In the BOA, an initially solid-density target undergoes relativistically induced transparency, initiating a period of enhanced ion acceleration. First-ever kinetic simulations of the BOA in three dimensions show that the ion beam forms lobes in the direction orthogonal to laser polarization and propagation. Analytic theory presented for the electron dynamics in the laser ponderomotive field explains how azimuthal symmetry breaks even for a symmetric laser intensity profile; these results are consistent with recent experiments at the Trident laser facility. © 2011 American Physical Society.

Mono-energetic ion beam acceleration in solitary waves during relativistic transparency using high-contrast circularly polarized short-pulse laser and nanoscale targets

In recent experiments at the Trident laser facility, quasi-monoenergetic ion beams have been obtained from the interaction of an ultraintense, circularly polarized laser with a diamond-like carbon target of nm-scale thickness under conditions of ultrahigh laser pulse contrast. Kinetic simulations of this experiment under realistic laser and plasma conditions show that relativistic transparency occurs before significant radiation pressure acceleration and that the main ion acceleration occurs after the onset of relativistic transparency. Associated with this transition are a period of intense ion acceleration and the generation of a new class of ion solitons that naturally give rise to quasi-monoenergetic ion beams. An analytic theory has been derived for the properties of these solitons that reproduces the behavior observed in kinetic simulations and the experiments. © 2011 American Institute of Physics.

Beam profiles of proton and carbon ions in the relativistic transparency regime

Ion acceleration from relativistic laser solid interactions has been of particular interest over the last decade. While beam profiles have been studied for target normal sheath acceleration (TNSA), such profiles have yet to be described for other mechanisms. Here, experimental data is presented, investigating ion beam profiles from acceleration governed by relativistic transparent laser plasma interaction. The beam shape of carbon C6+ ions and protons has been measured simultaneously with a wide angle spectrometer. It was found that ion beams deviate from the typical Gaussian-like shape found with TNSA and that the profile is governed by electron dynamics in the volumetric laser-plasma interaction with a relativistically transparent plasma; due to the ponderomotive force electrons are depleted from the center of the laser axis and form lobes affecting the ion beam structure. The results are in good agreement with high resolution three-dimensional-VPIC simulations and can be used as a new tool to experimentally distinguish between different acceleration mechanisms.