1,2,4-Oxadiazoles identified by virtual screening and their non-covalent inhibition of the human 20S proteasome.

Although several constitutive proteasome inhibitors have been reported these recent years, potent organic, noncovalent and readily available inhibitors are still poorly documented. Here we used a structure- and ligand-based in silico approach to identify commercially available 1,2,4-oxadiazole derivatives as non-covalent human 20S proteasome inhibitors. Their optimization led to the newly synthesized compound 4h that is a mixed proteasomal inhibitor of the chymotrypsin- like activity (K(i) of 26,1 nM and K'(i) of 7.5 nM) which is in addition selective versus the challenging cathepsin B and calpain proteases. Molecular modelling studies corroborated the mechanism of inhibition and suggest an unusual binding of the inhibitor within the S5 binding pocket (ß6 subunit). The cellular effects of our compounds validate their utility as potential pharmacological agents for anti-cancer pre-clinical studies.

Measured turbulent mixing in a small-scale circuit breaker model.

The performance of high voltage gas circuit breakers depends on the temperature distribution of hot gas or plasma from the arc zone mixed with cold gas that is present, for example, in the exhausts and mixing volume. Understanding the details of the mixing process is imperative to estimate the temperature distribution within the entire breaker volume. Design studies rely on computational fluid dynamics (CFD) simulations to search for the best way to achieve satisfactory mixing. One key uncertainty in the CFD simulations is the role of turbulence in this process and how to properly account for it. To gain knowledge of the mixing process between hot and cold gases, we have constructed a simplified breaker geometry that is flexible and accessible to diagnostics. Apart from standard measurements of current and arc voltage, we measure pressure in the arc zone and the mixing volume. Further, the mixing volume is specially designed to be transparent, allowing us to make shadowgraphy measurements of the turbulent mixing during and after the arcing phase. We report on experiments performed in air at atmospheric pressure.

[Coincidental outbreaks of rotavirus and respiratory syncytial virus in Paris: a survey from 1993 to 1998]. / Coïncidence des épidémies de rotavirus et de virus respiratoire syncytial à Paris: une enquête de 1993 à 1998.

PATIENTS AND METHODS: In a pediatric hospital of Paris, from 1993 to 1998, respiratory secretions were positive for respiratory syncytial virus (RSV) in 26.3% of 4,738 children (0-5 years) examined or hospitalized for lower respiratory tract infections. Rotavirus detection was positive in stools of 23.7% of the 8,537 children of the same age with acute diarrhea. RESULTS: The RSV epidemic peak occurred annually in Paris in December and the rotavirus outbreak peaks were observed in December/January. The winter seasonal peaks remained constant for both pathogens and the temporal appearance of these peaks was constant from 1993 to 1998. Fifty to sixty-one percent of rotavirus and 77 to 92% of RSV infections were observed in November, December or January. These simultaneous outbreaks provoked important problems in hospital organization and prevention of nosocomial infections. CONCLUSION: The coincidence of RSV and rotavirus peaks is not found in all countries. The epidemic patterns have to be checked in other parts of France and Europe because this could be important when active immunization programs will be available for these two pathogens.