Computer-aided design of a factor Xa inhibitor by using MCSS functionality maps and a CAVEAT linker search

We have investigated a new approach to efficiently find a novel inhibitor against a serine protease (i.e. an activated coagulation factor X, FXa) by using de novo design programs and the X-ray crystal structure of the target enzyme. FXa is a coagulant enzyme that generates thrombin (a serine protease) and participates in both intrinsic and extrinsic coagulation pathways. We adopted multiple copy simultaneous search (MCSS) and CAVEAT linker search techniques, which disclosed a novel FXa inhibitor (T01312) consisting of two binding moieties (the benzamidinyl and adamantyl groups) and a linker unit (the carboxybenzylamine group). The inhibitory activity of T01312 against FXa was determined to be a small K(i)-value of 48nM, which is two orders of magnitude smaller than that against thrombin. An X-ray crystal analysis of T01312 complexed with trypsin (an analogue of FXa) and docking studies of T01312 with trypsin and FXa showed that: (i) the benzamidinyl group is a predominant binding moiety in the anionic pocket (S1 site) with an asparatic acid residue; (ii) a hydrophobic pocket (S4 site) is the binding site of the adamantyl group; (iii) the carboxylate group of the linker contributes to the selectivity for FXa against thrombin. Thus, the combination of the knowledge of the X-ray crystal structure of the target molecule with MCSS and CAVEAT linker search techniques proved to be an effective hit-finding method that does not require the screening of huge compound libraries.     

Preparation and characterization of the Sb-doped TiO2 photocatalysts

Doped TiO₂ photocatalysts have been prepared by a coprecipitation method. Uniformly doped nanocrystalline TiO₂ of 10–20 nm sizes was synthesized by calcinating the coprecipitated gels at 400–650°C. Photocatalytic characterization along with the microstructural investigation for each catalyst provides better understanding of the photocatalytic behavior. It was found that the photodegradation of methylene blue (MB) was a complex function of the doping type and its concentration and the microstructural characteristics of the catalysts. Antimony doing significantly improved photocatalytic performance as compared to the undoped TiO₂. Post-treatment of the as-precipitated wet doped Ti gels in an organic solvent also increased the surface area, forming approximately 8 nm size doped TiO₂ with surface area 149 m²/g. Superior catalytic activity was observed in the Sb-doped TiO₂ samples at a doping concentration ranging from 1 to 5 at%. Using the 5 at% Sb-doped TiO₂ catalyst treated in butanol, 100 ppm of MB could be decomposed completely within 1 h, which was better than the commercial Degussa P-25.     

Characterization of endogenous enzymes of milled rice and its application to rice cooking

The relationship between the activities of endogenous enzymes in milled rice and accumulation of chemical components in the rice grains during cooking was investigated. Maltose and soluble starch were optimally hydrolyzed around 60 °C by both crude extracts and purified α-glucosidases of milled rice. Gelatinization onset temperature of rice flour was determined to be 63 °C with DSC analysis under usual cooking condition. Hydrolytic activities on carbohydrates and proteolytic activities of milled rice were enhanced at pH 5 compared to pH 7 at the range of 4–80 °C. When rice was cooked at pH 5, glucose and amino acids highly accumulated with soaking for 16 h before heating. We propose a new method of cooking with prolonged soaking at acidic pH, which is effective for increasing the amounts of chemical components in cooked rice.     

Optical properties of photoluminescent polycrystalline CuLa0.98Eu0.02O2 thin film prepared by pulsed laser deposition at room temperature

Smooth CuLa_0.98Eu_0.02O₂ thin film has successfully been prepared by pulsed laser deposition method at room temperature. Crystal structure of the obtained film was almost same as that of CuLa_0.98Eu_0.02O₂ polycrystalline ceramic. Orange luminescence with high intensity due to ⁵D₀ – ⁷F_0,1 transitions of Eu³⁺, which was an evidence of Eu³⁺ substitution for La³⁺ site in LaO₆ octahedra with the inversion symmetry, was also observed in the obtained film. The optical band gap of CuLa_0.98Eu_0.02O₂ was measured to be 2.85 eV from absorption spectroscopy.     

Stereoselective Synthesis of Phosphoryl‐Substituted Phenols

Copper‐catalyzed C X activation‐phosphorylation of aryls bearing different groups has been achieved using P(O) H compounds as efficient phosphorylation reagents without the assistance of any ligand. Optically active H‐phosphinates can also act as good substrates in the reaction, giving the (Sp)‐phosphoryl substituted phenolic compounds stereospecifically with retention of configuration at the phosphorus center. Furthermore, it is shown that the migration of phosphorus on O‐aryl phosphonates from oxygen to carbon also proceeds stereospecifically to produce the corresponding optically active (Rp)‐phosphoryl‐substituted phenolic compounds with retention of configuration at phosphorus via treatment with lithium diisopropylamide (LDA). Plausible mechanisms have been proposed for these reactions.

     

Risk of cancer and non-cancer diseases in the atomic bomb survivors

Late health effects of exposure to atomic bomb radiation have been evaluated in survivors. A cohort of 120 321 people has been followed since 1950 for mortality, including the cause of death using the Japanese population registry system (Life Span Study), and for cancer incidence using population-based cancer registries. Findings have included a markedly increased risk of leukaemia several years after the exposure, increased risk of various malignant tumours several decades after the exposure and, more recently, findings of increased rates of non-cancer diseases such as cardiovascular diseases.     

The effect of ion plating on the friction and wear of Ti6Al4V alloy

The effect of noble metal ion plating on the room temperature friction and wear of Ti6Al4V was investigated. Sliding wear experiments were conducted on a linear displacement machine which enabled the determination of coefficient of friction at regular intervals. The wear experiments were performed between two titanium alloy surfaces with various ion plating and dry lubrication conditions. Test results showed that the extent of wear damage of the titanium substrate was directly related to the rate of increase of the friction coefficient and not to its value. The best wear protection was provided either by gold ion plating on one surface combined with MoS₂ lubrication or by gold ion plating on both surfaces. The former case yielded a very low friction coefficient while the latter yielded a very high one. Modes of wear were determined by scanning electron microscopy of sectioned wear specimens.     

Depth profiling study on the migration of tritium in titanium induced by deuterium-ion bombardment

A thin titanium layer with uniformly absorbed tritium (T/Ti ˜1.0) was bombarded by 390 keV D₃⁺ ions (130 keV per deuteron). Bombardment was performed at low (111 K) and room temperatures up to fluences of 5.9 × 10¹⁸ D/cm² and 3.0 × 10¹⁸ D/cm², respectively. Depth profiles of tritium up to a depth of 0.8 mg/cm² (˜1.8 μm) were measured and the change of the profile with fluence was investigated by means of the T(d, )n nuclear reaction. At both of the temperatures, a dip was formed on the depth profile of tritium at the depth around the projected range, indicating that the deuteron bombardment induced the migration of tritium against the concentration gradient. At the low temperature, the dip showed a gradual growth with fluence and saturation of the growth at the higher fluences, which could not be described by the existing model for isotope mixing. The spectrum of protons from the D(d, p)T reaction obtained in the same measurement suggested that the release of deuterium suddenly started at the final stage of the present bombardment. The dip formed at room temperature was larger than that at the low temperature. The migration of tritium induced by the bombardment is discussed on the basis of the experimental results obtained.     

Melting and glass transition of radiation-induced graft polyethylene

Melting and glass transition data are reported employing DSC for styrene-grafted high-density polyethylene obtained by γ radiation. Judging from the data of the melting point and the heat of fusion, the grafted polystyrene had no effect on the polyethylene crystallites, but the half-width of the thermogram was observed to increase slightly, showing an effect on the crystallite size distribution. As no effect was observed on the glass transition temperature by grafting, the amorphous region of the polyethylene apparently was not affected. It is suggested, therefore, that the free volume or segmental mobility will not be decreased by radiation-induced grafting. Very few but long grafted chains had negligible effect on the average polyethylene chain length available for segmental motion, and grafted polystyrene should be expected to differ little from the styrene homopolymer in thermal motions.