Novel non-peptide fibrinogen receptor antagonists. 1. Synthesis and glycoprotein IIb-IIIa antagonistic activities of 1,3,4-trisubstituted 2-oxopiperazine derivatives incorporating side-chain functions of the RGDF peptide

Based on the lead tetrapeptide RGDF, two possible non-peptide glycoprotein (GP) IIb-IIIa antagonists possessing an (S)-2-oxopiperazine-3-acetic acid moiety as a scaffold incorporating the indispensable Asp fragment were prepared, and (S)-4-[[trans-[4-(guanidinomethyl)-cyclohexyl]carbonyl]glycyl]-2- oxopiperazine-1,3-diacetic acid, 1a, was identified as a potential lead. A series of 3-substituted 2-oxopiperazine-1-acetic acids bearing the Arg-Gly equivalent at the 4-position were prepared and evaluated for their ability to prevent platelet aggregation and for their binding affinity for the GP IIb-IIIa receptor purified from human HEL cells. (S)-4-[(4-Amidinobenzoyl)glycyl]-3-[(methoxycarbonyl)methyl]- 2-oxopiperazine-1-acetic acid, 9 (TAK-029), inhibited in vitro human platelet aggregation with an IC50 value of 0.03 microM and GP IIb-IIIa-fibrinogen binding with an IC50 value of 0.49 nM. The [4-(2-aminoethyl)benzoyl]glycyl derivative 26 showed activity comparable to that of 9 (IC50 = 0.093 microM, guinea pig platelet aggregation assay). Compound 9 dose-dependently inhibited ex vivo platelet aggregation in guinea pigs (0.03 and 0.1 mg/kg, i.v.), and long-lasting inhibition of platelet aggregation was observed upon oral administration of 9 (3 mg/kg) to guinea pigs. On the other hand, the activity of 26 disappeared within 1 h after a dose of 1 mg/kg (i.v.). Compound 9 may therefore be useful in the clinical treatment of arterial thrombotic diseases.     

A suppressor mutation which suppresses adenylyl cyclase mutations in Neurospora crassa

Membranous obstruction of the inferior vena cava at the suprahepatic level is rare. The present report summarizes direct operative repair. A review of alternative therapeutic strategies is presented.     

Parallel computing of high‐speed compressible flows using a node‐based finite‐element method

An efficient parallel computing method for high‐speed compressible flows is presented. The numerical analysis of flows with shocks requires very fine computational grids and grid generation requires a great deal of time. In the proposed method, all computational procedures, from the mesh generation to the solution of a system of equations, can be performed seamlessly in parallel in terms of nodes. Local finite‐element mesh is generated robustly around each node, even for severe boundary shapes such as cracks. The algorithm and the data structure of finite‐element calculation are based on nodes, and parallel computing is realized by dividing a system of equations by the row of the global coefficient matrix. The inter‐processor communication is minimized by renumbering the nodal identification number using ParMETIS. The numerical scheme for high‐speed compressible flows is based on the two‐step Taylor–Galerkin method. The proposed method is implemented on distributed memory systems, such as an Alpha PC cluster, and a parallel supercomputer, Hitachi SR8000. The performance of the method is illustrated by the computation of supersonic flows over a forward facing step. The numerical examples show that crisp shocks are effectively computed on multiprocessors at high efficiency. Copyright © 2003 John Wiley & Sons, Ltd.     

An Efficient Boundary Handling with a Modified Density Calculation for SPH

We propose a new boundary handling method for smoothed particle hydrodynamics (SPH). Previous approaches required the use of boundary particles to prevent particles from sticking to the boundary. We address this issue by correcting the fundamental equations of SPH with the integration of a kernel function. Our approach is able to directly handle triangle mesh boundaries without the need for boundary particles. We also show how our approach can be integrated into a position‐based fluid framework.     

Catalytic conversion of organosilanes. 1. Disproportionation of alkylsilanes over solid acid and base catalysts

Catalytic conversions of diethylsilane (E2), triethylsilane (E3) and diethyldimethylsilane (E2M2) were examined at 373–573 K in a closed recirculation reactor by using various solid acid and base catalysts. Basically two types of reaction were found: decomposition and disproportionation. Strongly acidic catalysts such as silica-alumina (SA), alumina and sulfated ZrO₂ (SO₃/ZrO₂) exhibited high disproportionation activity, while weakly acidic and basic catalysts showed low catalytic activity and gave mainly cracking products. The order of disproportionation reactivity of three silanes tested were E2M2 > E3 > E2 over SA and SO₃/ZrO₂, while it was E2E3 > E2M2 over an alumina catalyst.     

Evaluation of the Effects of Microgravity on Activated Primary Human Hepatic Stellate Cells

In recent years, research has been conducted to develop new medical treatments by simulating environments existing in space, such as zero-gravity. In this study, we evaluated the cell proliferation and gene expression of activated primary human hepatic stellate cells (HHSteCs) under simulated microgravity (SMG). Under SMG, cell proliferation was slower than in 1 G, and the evaluation of gene expression changes on day 1 of SMG by serial analysis of gene expression revealed the presence of Sirtuin, EIF2 signaling, hippo signaling, and epithelial adherence junction signaling. Moreover, reactive oxygen species were upregulated under SMG, and when N-acetyl-cystein was added, no difference in proliferation between SMG and 1 G was observed, suggesting that the oxidative stress generated by mitochondrial dysfunction caused a decrease in proliferation. Upstream regulators such as smad3, NFkB, and FN were activated, and cell-permeable inhibitors such as Ly294002 and U0126 were inhibited. Immunohistochemistry performed to evaluate cytoskeletal changes showed that more β-actin was localized in the cortical layer under SMG.     

Staurosporine induces the outgrowth of neurites from the dorsal root ganglion of the chick embryo and PC12D cells

Staurosporine, a potent inhibitor of protein kinases, caused the rapid outgrowth of neurites from cultured dorsal root ganglia of chick embryos and from PC12D cells, a subline of PC12 cells. Treatment of dorsal root ganglia with 1 to 20 nM staurosporine resulted in the extensive outgrowth of neurites that were indistinguishable from those induced by NGF, as assessed by phase-contrast microscopy, electron microscopy and cytochemical staining of actin and tubulin. However, neurites generated from the ganglia in response to the higher concentrations of staurosporine (40-100 nM) seemed to have different characteristics, possibly as a result of the inhibition of cell migration from ganglia. The sequential changes in morphology of PC12D cells in response to staurosporine and to NGF were revealed by staining of actin. Ruffling membranes emerged at the margins of PC12D cells within 4 min after the addition of staurosporine or of NGF. From 10 min to 24 h after the addition of either compound, the ruffles were transformed into several projections that became growing neurites. The formation of ruffles and the outgrowth of neurites were both apparent at a concentration of staurosporine of 10 nM. The neurites that emerged from PC12D cells in response to staurosporine and in response to NGF were indistinguishable under the phase-contrast microscope and after staining of actin and tubulin. However, staurosporine never promoted survival of PC12D cells in serum-free conditions as that promoted by NGF. The observations indicate that staurosporine at nanomolar concentrations may reproduce the neurogenic changes that induced by NGF in primed neuronal cells, although it can not mimic the action of NGF that supports survival of neurons.