A New Lead Identification Strategy: Screening an sp3-rich and Lead-like Compound Library Composed of 7-Azanorbornane Derivatives

Although the advantages of sp³-rich, sterically complicated molecules in drug development have been pointed out, modern screening libraries are filled with planar, sp²-rich components. Compounds that are sp³-rich are difficult to synthesize, and thus we aimed to invent an efficient method to construct sp³-rich libraries. By modifying sp³-rich 7-azanorbornane scaffolds through click chemistry, we efficiently prepared a small set of compounds. These compounds were not only sp³-rich, but also had sufficient “lead-like” properties in view of molecular weights and hydrophobicity. Screening assays of this library provided weak κ opioid receptor agonists and growth hormone secretagogue receptor agonists with high hit rates. These results indicate that the 7-azanorbornane scaffold may be a “privileged structure” for lead identification in drug discovery.     

Dosimeter properties of CaO transparent ceramic prepared by the SPS method

We have studied photoluminescence (PL), scintillation and thermally-stimulated luminescence (TSL) dosimeter properties of CaO transparent ceramic, in comparison with those of MgO transparent ceramic as a reference. Both samples were made by a Spark Plasma Sintering method. In the PL spectra, both samples showed emission peaks due to F and F⁺ centers. Moreover, in addition to these peaks, a scintillation emission peak was detected at 330 nm for both CaO and MgO, which was caused by surface defects. The TSL glow curves showed a main peak around 55 °C for CaO and 140 °C for MgO. The TSL response was confirmed to monotonically increase with irradiation dose over the dose range from 0.1 to 1000 mGy.     

EXAFS and FTIR characterization of tetrarhodium carbonyl clusters attached on tris-(hydroxymethyl)phosphine grafted silica catalytically active for olefin hydroformylation

A series of perovskites of the formula Ca_1–x Sr _x Ti_1–y M _y O_3–, M=Fe, Co, Cr or Ni,x = 0–1,y = 0–0.6, has been synthesized by a modified sol-gel method using citrate. Several of these materials were proved to be stable under operating conditions in reducing atmospheres of air and hydrocarbons. An outline of the synthesis procedure is given, together with the results of XRD, SEM, BET, TG, DTA and IR characterization before and after catalytic testing. The solubility of Ni and Cr in this perovskite was very limited, and the solubility of Co decreased abruptly above 1173 K. The solubility range of Ca and Sr on alkaline earth sites is 100%.     

Crystalline Phases and YAG Laser-Induced Crystallization in Sm2O3–Bi2O3–B2O3 Glasses

The glass formation region, crystalline phases, second harmonic (SH) generation, and Nd:yttrium aluminum garnet (YAG) laser-induced crystallization in the Sm₂O₃–Bi₂O₃–B₂O₃ system were clarified. The crystalline phases of Bi₄B₂O₉, Bi₃B₅O₁₂, BiBO₃, Sm _x Bi_{1− x} BO₃, and SmB₃O₆ were formed through the usual crystallization in an electric furnace. The crystallized glasses consisting of BiBO₃ and Sm _x Bi_{1− x} BO₃ showed SH generations. The formation of the nonlinear optical BiB₃O₆ phase was not confirmed. The formation (writing) region of crystal lines consisting of Sm _x Bi_{1− x} BO₃ by YAG laser irradiation was determined, in which Sm₂O₃ contents were∼10 mol%. The present study demonstrates that Sm₂O₃–Bi₂O₃–B₂O₃ glasses are promising materials for optical functional applications.     

Strictly Conserved Residues in Euphorbia tirucalli β‐Amyrin Cyclase: Trp612 Stabilizes Transient Cation through Cation–π Interaction and CH–π Interaction of Tyr736 with Leu734 Confers Robust Local Protein Architecture

The functions of Trp612, Leu734, and Tyr736 of Euphorbia tirucalli β‐amyrin synthase were examined. The aliphatic variants (Ala, Val, Met) of Trp612 showed almost no activity, but the aromatic variants exhibited high activities: 12.5 % of the wild‐type activity for the W612H variant, 43 % for W612F, and 63 % for W612Y. That is, the enzymatic activities of the variants increased in proportion to the increase in π‐electron density. Thus, the major function of Trp612 is to stabilize transient cations through a cation–π interaction. The Phe and Tyr variants caused a distorted folding conformation, especially at the E‐ring site, which generated the aberrantly cyclized products germanicol and lupeol. The L734G and L734A variants exhibited significantly decreased activities but yielded taraxerol in a high production ratio. The Val, Ile, and Met variants showed markedly high activities (56–78 % of wild‐type activity); therefore, appropriate steric bulk is required at this position. The aliphatic variants of Tyr736 showed markedly decreased activities, but the Phe mutant exhibited high activity (67 %), which indicates that the π electrons are critical for catalysis. Homology modeling indicated that Tyr736 and Leu734 are perpendicular to the substrate and are situated face to face, which suggests that a CH–π interaction occurs between Tyr736 and Leu734, reinforcing the protein architecture, and that Tyr736 cannot stabilize cationic intermediates through a cation–π interaction.     

Compact Tunable Narrowband Terahertz-Wave Source Based on Difference Frequency Generation Pumped by Dual Fiber Lasers in MgO:LiNbO<Subscript>3</Subscript>

We demonstrate a high-average-power, single longitudinal-mode, and tunable terahertz (THz)-wave source based on difference frequency generation (DFG) in a MgO:LiNbO₃ (MgO:LN) crystal. The waves for DFG are generated using a pair of Yb-doped pulsed fiber lasers with a master oscillator power fiber amplifier configuration. The average power of the THz-wave output reaches 450 μW at 1.07 THz (280 μm) at a linewidth of 7.2 GHz, and the tunability ranges from 0.35 to 1.07 THz under the pulse repetition frequency of 500 kHz. A short burn-in test of the THz wave is also carried out, and the output power stability is within ± 5% of the averaged power without any active stabilizing technique. The combination of MgO:LN-DFG and stable and robust fiber laser sources is highly promising for the development of high-average-power THz-wave sources, particularly in the high transmission sub-THz region. This approach may enable new applications of THz-wave spectroscopy in imaging and remote sensing.     

Effect of operating methods of wind turbine generator system on net power extraction under wind velocity fluctuations in fields

The effect of how a wind turbine generator system is operated is discussed from the viewpoint of net power extraction with wind velocity fluctuations in relation to the scale and the dynamic behavior of the system. On a wind turbine generator system consisting of a Darrieus-Savonius hybrid wind turbine, a load generator and a battery, we took up two operating methods: constant tip speed ratio operation for a stand-alone system(Scheme1) and synchronous operation by connecting a grid(Scheme2). With our simulation model, using the result of the net extracting power, we clarified that Scheme1 is more effective than Scheme2 for small-scale systems. Furthermore, in Scheme1, the appropriate rated power output of the system under each wind condition can be confirmed.     

Autotaxin May Have Lysophosphatidic Acid-Unrelated Effects on Three-Dimension (3D) Cultured Human Trabecular Meshwork (HTM) Cells

Purpose: The objective of the current study was to evaluate the effects of the autotaxin (ATX)–lysophosphatidic acid (LPA) signaling axis on the human trabecular meshwork (HTM) in two-dimensional (2D) and three-dimensional (3D) cultures of HTM cells. Methods: The effects were characterized by transendothelial electrical resistance (TEER) and FITC-dextran permeability (2D), measurements of size and stiffness (3D), and the expression of several genes, including extracellular matrix (ECM) molecules, their modulators, and endoplasmic reticulum (ER) stress-related factors. Results: A one-day exposure to 200 nM LPA induced significant down-sizing effects of the 3D HTM spheroids, and these effects were enhanced slightly on longer exposure. The TEER and FITC-dextran permeability data indicate that LPA induced an increase in the barrier function of the 2D HTM monolayers. A one-day exposure to a 2 mg/L solution of ATX also resulted in a significant decrease in the sizes of the 3D HTM spheroids, and an increase in stiffness was also observed. The gene expression of several ECMs, their regulators and ER-stress related factors by the 3D HTM spheroids were altered by both ATX and LPA, but in different manners. Conclusions: The findings presented herein suggest that ATX may have additional roles in the human TM, in addition to the ATX–LPA signaling axis.     

Impingement heat transfer by jet issuing from a cross-shaped nozzle

Heat transfer characteristics and flow patterns were measured over a plate for various separation distances between the nozzle exit and target plate when air issues from a sharp-edged cross-shaped nozzle and impinges on a plate. The local heat transfer coefficients in the radial direction for different circumferential positions were calculated using the wall temperatures measured by means of thermocouples, and flow patterns were observed using an oil-titanium IV oxide method. The isotherms of the infrared images were also measured using an infrared radiometer with a two-dimensional array of indium-antimony (InSb) sensors. The geometric axes were switched as a result of the self-induced velocity of a vortex filament; the convex corners became flat and the concave corners generated outward ejection. The distributions of the iso-heat transfer coefficient contours correspond well to the flow pattern and the isotherm contours. These contours extended diagonally and demonstrated the St. Andrew's cross pattern for short separations, subsequently changing to an octagonal pattern, and then becoming circular at large separations. The correspondence of the heat transfer characteristics to the flow behavior, as well as the heat transfer mechanism are also described. © 1998 Scripta Technica, Heat Trans Jpn Res, 27(3): 192–204, 1998     

Algorithm improvement and validation of National Institute for Environmental Studies ozone differential absorption lidar at the Tsukuba Network for Detection of Stratospheric Change complementary station

Recently, a data processing and retrieval algorithm (version 2) for ozone, aerosol, and temperature lidar measurements was developed for an ozone lidar system at the National Institute for Environmental Studies (NIES) in Tsukuba (36 degrees N,140 degrees E), Japan. A method for obtaining the aerosol boundary altitude and the aerosol extinction-to-backscatter ratio in the version 2 algorithm enables a more accurate determination of the vertical profiles of aerosols and a more accurate correction of the systematic errors caused by aerosols in the vertical profile of ozone. Improvements in signal processing are incorporated for the correction of systematic errors such as the signal-induced noise and the dead-time effect. The mean vertical ozone profiles of the NIES ozone lidar were compared with those of the Stratospheric Aerosol and Gas Experiment II (SAGE II); they agreed well within a 5% relative difference in the 20-40 km altitude range and within 10% up to 45 km. The long-term variations in the NIES ozone lidar also showed good coincidence with the ozonesonde and SAGE II at 20, 25, 30, and 35 km. The temperatures retrieved from the NIES ozone lidar and those given by the National Center for Environmental Prediction agreed within 7 K in the 35-50 km range.