Structural basis for human monoglyceride lipase inhibition.

Monoglyceride lipase (MGL) is a serine hydrolase that hydrolyses 2-arachidonoylglycerol (2-AG) into arachidonic acid and glycerol. 2-AG is an endogenous ligand of cannabinoid receptors, involved in various physiological processes in the brain. We present here the first crystal structure of human MGL in its apo form and in complex with the covalent inhibitor SAR629. MGL shares the classic fold of the alpha/beta hydrolase family but depicts an unusually large hydrophobic occluded tunnel with a highly flexible lid at its entry and the catalytic triad buried at its end. Structures reveal the configuration of the catalytic triad and the shape and nature of the binding site of 2-AG. The bound structure of SAR629 highlights the key interactions for productive binding with MGL. The shape of the tunnel suggests a high druggability of the protein and provides an attractive template for drug discovery.

Measurement of the subcycle timing of attosecond XUV bursts in high-harmonic generation.

The absolute timing of the high-harmonic attosecond pulse train with respect to the generating IR pump cycle has been measured for the first time. The attosecond pulses occur 190+/-20 as after each pump field maxima (twice per optical cycle), in agreement with the "short" quantum path of the quasiclassical model of harmonic generation.

Imaging and quality assessment of high-harmonic focal spots.

We present a direct method of studying the focusability of an intense, short-pulse extreme-ultraviolet (XUV) beam obtained by high-harmonic generation. We perform near-field imaging of the focal spot of five high-harmonic orders strongly focused by a broadband toroidal mirror. To visualize the focal spot directly, we image the fluorescence induced by an XUV beam on a cerium-doped YAG crystal on a visible CCD camera. We can thus measure the harmonic spot size on a single image, together with the Strehl ratio, to evaluate the quality of focusing. Such techniques should become instrumental in optimizing the focusing conditions and reaching intensities required for exploring attosecond nonlinear optics in the XUV range.

Global optimization of high harmonic generation.

We investigate the relevance of the absorption limit concept in the optimization of high harmonic generation. Thanks to the first direct observation of the coherence length of the process from high-contrast Maker fringes, we unravel experimental conditions for which the harmonic dipole response is enhanced when phase matching is realized within the absorption limit, leading to record conversion efficiencies in argon. Moreover, we show that harmonic generation in guided or freely propagating geometries are equivalent in the loose focusing regime. This analysis is generalized to other advanced phase-matching schemes, thereby predicting the possibility to boost the conversion efficiencies using light noble gases.

Observation of a train of attosecond pulses from high harmonic generation.

In principle, the temporal beating of superposed high harmonics obtained by focusing a femtosecond laser pulse in a gas jet can produce a train of very short intensity spikes, depending on the relative phases of the harmonics. We present a method to measure such phases through two-photon, two-color photoionization. We found that the harmonics are locked in phase and form a train of 250-attosecond pulses in the time domain. Harmonic generation may be a promising source for attosecond time-resolved measurements.

Chimeric smooth muscle-specific enhancer/promoters: valuable tools for adenovirus-mediated cardiovascular gene therapy.

Gene transfer with adenoviral vectors is an attractive approach for the treatment of atherosclerosis and restenosis. However, because expression of a therapeutic gene in nontarget tissues may have deleterious effects, artery-specific expression is desirable. Although expression vectors containing transcriptional regulatory elements of genes expressed solely in smooth muscle cells (SMCs) have proved efficient to restrict expression of the transgene, their use in the clinical setting can be limited by their reduced strength. In the present study, we show that low levels of transgene expression are obtained with the smooth muscle (SM)-specific SM22alpha promoter compared with the viral cytomegalovirus (CMV) enhancer/promoter. We have generated chimeric transcriptional cassettes containing either a SM (SM-myosin heavy chain) or a skeletal muscle (creatine kinase) enhancer combined with the SM22alpha promoter. With both constructs we observed significantly stronger expression that remains SM-specific. In vivo, reporter gene expression was restricted to arterial SMCs with no detectable signal at remote sites. Moreover, when interferon-gamma expression was driven by one of these two chimeras, SMC growth was inhibited as efficiently as with the CMV promoter. Finally, we demonstrate that neointima formation in the rat carotid balloon injury model was reduced to the same extent by adenoviral gene transfer of interferon-gamma driven either by the SM-myosin heavy chain enhancer/SM22alpha promoter or the CMV promoter. These results indicate that such vectors can be useful for the treatment of hyperproliferative vascular disorders.

Efficient and tunable continuous-wave diode-pumped Yb3+:Ca4GdO(BO3)3 laser.

A Yb(3+):Ca(4)GdO(BO(3))(3) (Yb:GdCOB) crystal has been diode pumped for the first time to our knowledge. We obtained 47.5% slope efficiency at 6 degrees C, producing 191 mW of power at 1050 nm, with a 2.4% output coupler. Temperature does not significantly affect the laser performance: At room temperature we still obtained 180 mW of power for the same cavity. We achieved tunability of the Yb:GdCOB laser from 1035 to 1088 nm with a 1.7% output coupler and 100-nm tunability with a low-transmission output coupling (T = 0.03%).