Rapid Discovery of Aspartyl Protease Inhibitors Using an Anchoring Approach

Pharmacophore searches that include anchors, fragments contributing above average to receptor binding, combined with one-step syntheses are a powerful approach for the fast discovery of novel bioactive molecules. Here, we are presenting a pipeline for the rapid and efficient discovery of aspartyl protease inhibitors. First, we hypothesized that hydrazine could be a multi-valent warhead to interact with the active site Asp carboxylic acids. We incorporated the hydrazine anchor in a multicomponent reaction and created a large virtual library of hydrazine derivatives synthetically accessible in one-step. Next, we performed anchor-based pharmacophore screening of the libraries and resynthesized top-ranked compounds. The inhibitory potency of the molecules was finally assessed by an enzyme activity assay and the binding mode confirmed by several soaked crystal structures supporting the validity of the hypothesis and approach. The herein reported pipeline of tools will be of general value for the rapid generation of receptor binders beyond Asp proteases.     

Crystallization study of chemically vapour-deposited amorphous silicon films by in situ x-ray diffraction

The solid phase crystallization kinetics of chemically vapour-deposited amorphous silicon films were studied by in situ X-ray diffraction. We determined the crystalline volume directly from the Bragg peak intensities at various times during isothermal annealing in the temperature range 578 °C < T < 658 °C. From these experiments we deduced that the crystallization was due to nucleation predominantly at the substrate-film interface followed by crystal growth perpendicular to this interface. The crystal growth rate was thermally activated with an activation energy E_v of 3.1 eV. A strong 〈111〉 preferred orientation of the growing polycrystal was observed and the grain size remained constant at about 60 nm. Evidence of stresses at the amorphous-crystalline interface during the early stages of crystallization was observed. A comparison with previous conductivity measurements is also carried out.     

Pharmacologic control of a humanized gene therapy system implanted into nude mice

Systemic delivery of specific therapeutic proteins by a parenteral route of administration is a recognized practice in the management of several gene defects and acquired diseases. As an alternative to repetitive parenteral administration, gene therapy may provide a novel means for systemic delivery of therapeutic proteins while improving patient compliance and therapeutic efficacy. However, for gene therapy to be an efficacious and safe approach to the clinical management of such diseases, gene expression must be tightly regulated. These investigations demonstrate precise in vivo control of protein expression from cells that are engineered to secrete human growth hormone (hGH) in response to stimulation by rapamycin. The cells were implanted intramuscularly into nu/nu mice and stimulated by intravenous or oral administration of rapamycin. In vivo experiments demonstrate that the activity and pharmacokinetics of rapamycin determine the level of serum hGH that result from the engineered cells. In addition, responsiveness of the cells to rapamycin, number of cells implanted, hGH expression kinetics, and the pharmacokinetics of hGH itself, also influence the circulating levels of hGH after rapamycin stimulation. Controlled manipulation of several of these parameters, either independently or in combination, allows for precise regulation of circulating hGH concentration in vivo.     

Wide-band polarization-independent tensile-strained InGaAs MQW-SOAgate

A high-performance tensile-strained InGaAs multi-quantum-well semiconductor optical amplifier (MQW-SOA) gate developed for wavelength-division-multiplexing (WDM) applications is reported. The -0.47% InGaAs-strained SOA gate has a very low polarization dependence of 0.3 dB over a driving current between 30 and 60 mA and a wide-input signal wavelength range from 1530 to 1580 nm. The fabrication tolerance of the mesa stripe width is very large, ranging from 1.0 to 1.75 μm. The MQW-SOA gate has an extinction ratio of more than 40 dB. The fiber-to-fiber lossless operation current is less than 50 mA over the fiber-amplifier gain band. The gating speed is less than 1 ns     

10-Gb/s low-input-power SOA-PLC hybrid integrated wavelength converter and its 8-slot unit

We achieved successful low-input-power (-10 dBm) wavelength conversion at 10 Gb/s by using a hybrid integrated cross-phase modulation wavelength converter (XPM-WC). The input CW power was also -10 dBm and the total current was only 215 mA, and no signal preamplifiers were used. From the relationship between the eye-opening ratio and the injection current to the SOA, we clarified the optimal current condition for low-input-power operation. The XPM-WC consists of a two-channel spot-size converter integrated semiconductor optical amplifier (SS-SOA), which is mounted on a planar lightwave circuit (PLC) platform. We also fabricated an 8-slot unit. XPM-WC modules are inserted in every slot and can operate independently. Stable and uniform low-input-power operation is confirmed in all slots.     

Polarization insensitive traveling wave type amplifier usingstrained multiple quantum well structure

Signal gain agreement between TE and TM modes is realized under a specific operation condition in a traveling wave type amplifier using a strained multiple quantum well structure for the first time. The signal gain of the TM mode completely agrees with that of the TE mode at an amplifier driving current of 70 mA. The identical signal gain is 7.5 dB at present. However, the signal gain could be easily improved by using a device with a longer active region. In order to achieve polarization insensitive TWAs, the design parameter is the only confinement factor for the conventional bulk type