Starting point to molecular design: efficient automated 3D model builder Key3D

Obtaining three-dimensional (3D) structures from structural formulae is a crucial process in molecular design. We have developed a new 3D model builder, Key3D, in which the simplified distance geometry technique and structure optimization based on the MMFF force field are combined. In an evaluation study using 598 crystal structures, the high performance and accuracy of Key3D were demonstrated. In the "flexible-fitting" test, which is focused on practical usefulness in the molecular design process, 88% of the Key3D structures acceptably reproduced the reference crystal structures (root-mean-square deviation <0.6 A) upon rotation of acyclic bonds. These results indicate that Key3D will be very effective in providing starting points for practical molecular design.     

Superparamagnetic iron oxide-enhanced MR imaging for early and late radiation-induced hepatic injuries

Superparamagnetic iron oxide (SPIO)-enhanced MRI was performed in twenty-one patients undergoing proton-beam radiotherapy for hepatocellular carcinomas. Patients were divided into two groups: early and late phase hepatic injuries. Each group was investigated 3 to 9 weeks and 4 to 65 months after the start of irradiation, respectively. T(1)-weighted, T(2)-weighted, and T(2)*-weighted images were obtained before and after SPIO administration. In all postcontrast sequences in the early phase, irradiated livers demonstrated relatively higher intensity than nonirradiated livers and the radiation-to-liver contrast-to-noise ratio (C/N) was improved. Postcontrast T(2)*-weighted images showed the highest C/N. In the late phase, the irradiated areas showed high intensity on T(2)-weighted images and low intensity on T(1)-weighted images without SPIO, while high intensity on T(1)-weighted images with SPIO. The C/N increased with SPIO in all sequences and postcontrast T(2)-weighted images showed the highest C/N in the late phase. SPIO-enhanced MRI is useful to evaluate this entity both in the early and late phase of clinical studies.     

GREEN: A program package for docking studies in rational drug design

Summary A program package, GREEN, has been developed that enables docking studies between ligand molecules and a protein molecule. Based on the structure of the protein molecule, the physical and chemical environment of the ligand-binding site is expressed as three-dimensional grid-point data. The grid-point data are used for the real-time evaluation of the protein-ligand interaction energy, as well as for the graphical representation of the binding-site environment. The interactive docking operation is facilitated by various built-in functions, such as energy minimization, energy contribution analysis and logging of the manipulation trajectory. Interactive modeling functions are incorporated for designing new ligand molecules while considering the binding-site environment and the protein-ligand interaction. As an example of the application of GREEN, a docking study is presented on the complex between trypsin and a synthetic trypsin inhibitor. The program package will be useful for rational drug design, based on the 3D structure of the target protein.     

Optimum spray congealing conditions for masking the bitter taste of clarithromycin in wax matrix

The effects of operating conditions in the spray-congealing process on the release and the micromeritic properties of clarithromycin (CAM) wax matrix were evaluated. CAM wax matrix with 30% CAM, 60% glyceryl monostearate (GM) and 10% aminoalkyl methacrylate copolymer E (AMCE) was manufactured at various atomizer wheel speeds and liquid feed rates with a spray dryer. Release of CAM from the matrix exhibited a two-phase pattern, probably due to the dissolution of the fine portions broken on the surface of the matrix. The slope and the extrapolated y-intercept of the subsequent release pattern were defined as the release rate and the initial amount of release of CAM from the matrix, respectively. These release parameters, as well as the volume median diameter and the specific surface area of matrix, were selected as response variables, and multiple regression analysis was performed. For specific surface area and initial amount of release, a minimum point was observed on the contour curve when the atomizer wheel speed was constant and the liquid feed rate was varied. For the release rate, a maximum point was observed on the contour curve under the same conditions. These points were considered preferable for masking the bitter taste of CAM preparation. Microscopic observation revealed that a small spherical matrix with a smooth surface could be obtained with a high atomizer wheel speed and optimum liquid feed rate. This matrix also possessed excellent properties for taste masking, with small initial amount of release and subsequent high rate of release. In conclusion, the congealing speed of melt droplets was the dominant factor in masking the bitter taste of CAM.     

A fragment multipole approach to long-range Coulomb interactions in Hartree–Fock calculations on large systems

An efficient ab initio method for electronic structure calculations on extended molecular systems is presented, along with some illustrative applications. A division of the system into subunits allows the interactions to be separated into short- and long-range contributions, leading to a reduction of the computational effort from the original fourth-power size-dependence to one that is approximately quadratic. The short-range contributions to the Fock matrix are obtained in an essentially conventional fashion, while the long-range interactions are evaluated using a two-center multipole expansion formalism. The number of short-range contributions grows only linearly with the number of subunits, while the long-range contributions grow as N². Systematic studies of the computational efforts for systems of up to 99 water molecules organized as one-stranded chains, three-stranded chains, and three-dimensional clusters, as well as alkane chains with up to 69 carbon atoms, have been performed. In these model systems, the overall computational effort grows as N^K where 1 < K < 2.     

Effect of matrix modifier and furnace material on the determination of traces of fluoride by electrothermal molecular absorption spectrometry of aluminum monofluoride

In the determination of fluoride by AlF absorbance measurements, the interference from strontium nitrate is avoided by using magnesium nitrate or barium nitrate added to aluminum solution as the matrix modifier. The effects of the graphite-furnace material on AlF absorbance are investigated. Glassy carbon and synthetic carbon gave longer furnace lifetimes and better sensitivity than the other materials tested. The maximum sensitivity (4.2 μg ml^?1 fluoride for 0.0044 absorbance with a 10-μl injection) was obtained with synthetic carbon. The r.s.d, was <5% for 0.1 μg ml^?1 fluoride (n=10). Na⁺, K⁺, Pb²⁺, Zn²⁺, Cu²⁺ and Ag⁺ did not affect the measurements up to 500 μg ml^?1, but Ni²⁺, Co²⁺, Fe²⁺, Sr²⁺ and especially Ca²⁺ depressed the absorbance.     

Percolation in the hyperbolic plane

We study percolation in the hyperbolic plane and on regular tilings in the hyperbolic plane. The processes discussed include Bernoulli site and bond percolation on planar hyperbolic graphs, invariant dependent percolations on such graphs, and Poisson-Voronoi-Bernoulli percolation. We prove the existence of three distinct nonempty phases for the Bernoulli processes. In the first phase, , there are no unbounded clusters, but there is a unique infinite cluster for the dual process. In the second phase, , there are infinitely many unbounded clusters for the process and for the dual process. In the third phase, , there is a unique unbounded cluster, and all the clusters of the dual process are bounded. We also study the dependence of in the Poisson-Voronoi-Bernoulli percolation process on the intensity of the underlying Poisson process.

     

Boundary trace of reflecting Brownian motions

We establish a uniform dimensional result for normally reflected Brownian motion (RBM) in a large class of non-smooth domains. Hausdorff dimensions for the boundary occupation time and the boundary trace of RBM are determined. Extensions to stable-like jump processes and to symmetric reflecting diffusions are also given.Mathematics Subject Classification (2000):Primary 60G17, 60J60, Secondary 28A80, 30C35, 60G52, 60J50     

Peliosis hepatis and neoplastic/dysplastic lesions in aged male Long-Evans Cinnamon rats: MR imaging with pathologic correlation

The Long-Evans Cinnamon (LEC) rat, an animal model of Wilson's disease, abnormally accumulates copper in the liver. There have been a lot of reports on preneoplastic and neoplastic hepatic tumors in LEC rats, but few studies have been focused on other lesions. The aim of this study was to describe the MR findings of the liver of LEC rats with pathologic correlation to characterize the hepatic lesions developed in them. We measured MR images of the liver of six aged (over the age of 70 weeks old) male LEC rats. Measurements of T(1), T(2)-weighted images, and the dynamic and delayed studies after i.v. gadolinium injection were performed. The rats were sacrificed immediately after the measurements, and the diagnosis was histologically made. We identified seven lesions of peliosis hepatis, three neoplastic/dysplastic lesions, three cysts and one cholangiofibrosis. Peliosis hepatis was characterized as showing a significantly long T(2) relaxation time of 57.9 +/- 13.3 ms (mean +/- standard deviation) compared with 41.3 +/- 1.7 ms in normal liver, and prolonged enhancement after a gadolinium injection. Neoplastic/dysplastic lesions tended to show prolonged T(2), and they showed isointensity on T(1)-weighted images. They were best characterized by early enhancement followed by a rapid wash-out after a gadolinium injection. In conclusions, the frequent occurrence of peliosis hepatis observed in the present study suggests this can be a characteristic lesion in aged LEC rats. The characteristic MR findings enable us to distinguish between peliosis hepatis and neoplastic/dysplastic lesions.     

K-generic Projective Planes have Morley Rank Two or Infinity

We show that K-generic projective planes have Morley rank either two or infinity. We also show give a direct argument that such planes are not Desarguesian. Mathematics Subject Classification: 03C45, 05C90, 51A35.