Novel hepatitis C virus protease inhibitors: thiazolidine derivatives

This study evaluated the inhibitory effects of thiazolidine derivatives on hepatitis C virus (HCV) protease and other human serine proteases. The inhibition efficacy was tested with a reversed-phase high-performance liquid chromatography (HPLC) assay system using a NS3-NS4A fusion protein as the HCV protease and a synthetic peptide substrate that mimics the NS5A-5B junction. Nine thiazolidine derivatives showed more than 50% inhibition at 50 microg/ml. The most potent derivative was RD4-6250, with 50% inhibition at a concentration of 2.3 microg/ml; this concentration was lower than those of other protease inhibitors reported previously. The most selective derivative was RD4-6205, with 50% inhibition at a concentration of 6.4 microg/ml, a lower concentration than those on other serine proteases (chymotrypsin, trypsin, plasmin, and elastase). These results suggest that the RD4-6205 skeleton is an important structure for inhibitory activity on the HCV protease NS3-NS4A.     

Effects of Al and Zn additions on mechanical properties and precipitation behaviors of Mg-Sn alloy system

For the Mg-Sn-Al alloys, the ultimate strength (UTS) of an extruded Mg-9wt.%Al-2wt.%Sn alloy reached 390 MPa. TEM observation indicated that plate-like Mg₁₇Al₁₂ precipitates having Burgers orientation relationship with the matrix are responsible for the strength. This alloy also exhibits an age hardening behavior: the peak hardness appears after 15-20 h of heat treatment at 473 K. On the other hand, the UTS of the Mg-Mg-Sn-Zn alloys are on the order of 300 MPa. The precipitates in these alloys are composed of the Mg₂Sn and MgZn₂ particles. It was found that these phases often precipitate together, suggesting that the MgZn₂ phase can act as a nucleation sites for Mg₂Sn.     

Syntheses of full-density nanocrystalline titanium nitride compacts by plasma-activated sintering of mechanically reacted powder

Nearly equiatomic nanocrystalline titanium nitride (Ti₅₆N₄₄) powder with an average grain size of 5 nm has been synthesized by ball milling elemental Ti powder under nitrogen gas flow at room temperature. During the first stage of reactive ball milling (RBM) (time <3.6 ks), the metallic Ti powder tends to agglomerate to form powder particles with a larger diameter. At the second stage (3.6 to 22.0 ks), the agglomerated particles of Ti fragment to form smaller particles. These smaller particles that have new or fresh surfaces begin to react with the milling atmosphere (nitrogen) during the third stage of milling (22 to 86 ks) to form TiN powder coexisting with unreacted Ti powder. Toward the end of milling (86 to 173 ks), a single phase of nanocrystalline TiN (NaCl structure) is obtained. The powder of this end-product has a spherical-like morphology with an average particle size of about 0.4 μm diameter. A sintering procedure using plasma activation has been employed to consolidate the powder particles at several stages of the RBM. The as-milled and as-consolidated powders have been characterized as a function of the RBM time by means of X-ray diffraction (XRD), transmission electron microscopy (TEM), scanning electron microscopy (SEM), optical metallography, and chemical analyses. Density measurements of the consolidated samples show that after 86 to 173 ks of the RBM time, the compacted samples are essentially fully dense (above 96 pct of the theoretical density for TiN). The results also show that the consolidated TiN compacts still maintain their unique nanocrystalline properties with an average grain size of about 65 nm. The hardness and some mechanical properties of the consolidated TiN compacts have been determined as a function of the RBM time.     

Exchangeability of actin in cardiac myocytes and fibroblasts as determined by fluorescence photobleaching recovery

OBJECTIVE: To assess whether hypertension is a risk factor for hysterectomy performed for benign diseases. METHODS: Self-report questionnaires were collected from 77% of 2301 Danish women aged 30, 40, 50, or 60 years selected at random in 1982 for a prevalence study. Information about cardiovascular diseases, hypertension, use of medicine, weight and dieting history, life-styles, psychologic factors, gynecologic history (including history of hysterectomy), and social background were recorded. Weight, height, and blood pressure were measured. In an incidence study, the cohort was followed during 1982-1990 via central registers to assess the incidence of hysterectomy. Logistic and Cox regressions were used to analyze data. RESULTS: In the prevalence study, history of hypertension partly explained the relation between hysterectomy and cardiovascular diseases. In the incidence study, history of hypertension and use of diuretics were significant risk factors for hysterectomy. After confounder control, use of diuretics was explained by weight-related variables, and hypertension was a risk factor for hysterectomy in educated women (adjusted relative risk [RR] 2.88, 95% confidence interval [CI] 1.07, 7.76) and in women with weight fluctuations (adjusted RR 3.31, 95% CI 1.35, 8.14). Weight cycling and lack of education remained significant risk factors for hysterectomy in women with and without hypertension, respectively. CONCLUSION: History of hypertension, weight cycling, and lack of education are closely related risk factors for premenopausal hysterectomy. These three risk factors contribute to women undergoing hysterectomy having an increased risk for cardiovascular diseases. We proposed that hypertension might be a plausible biological cause of menorrhagia and an indication for hysterectomy.     

Molecular screening of both the promoter and the protein coding regions in the human ob gene in Japanese obese subjects with non-insulin-dependent diabetes mellitus

OBJECTIVE: Although the molecular mechanism of obesity has been poorly understood, recent studies indicate that leptin plays a critical role in regulating both food intake and body weight. Because obesity decreases the sensitivity to insulin, the human ob gene is presumed to be one of the candidate genes for non-insulin-dependent diabetes mellitus (NIDDM) associated with obesity. Although the protein coding region in the ob gene has been screened for mutations, the promoter region and the non-coding first exon have not yet been studied. We investigated the involvement of the human ob gene, especially mutations at the promoter region and the non-coding first exon, in the development of NIDDM associated with obesity. SUBJECTS: The study group comprised 60 Japanese obese subjects with NIDDM (body mass index (BMI) 43.6 > or = BMI > or = 26.4, 29.0+/-0.41 (mean+/-S.E.M.)) and 24 obese individuals with impaired glucose tolerance (IGT) (30 > or = BMI > or = 26.4, 27.1+/-0.22). METHODS: Mutations at both the promoter region and all three exons in the human ob gene were screened by the single-stranded conformational polymorphism analysis. When aberrantly migrated bands were recognized, the PCR-amplified DNA fragment was directly sequenced. RESULTS: In the protein coding region a silent mutation in the second exon was detected. The non-coding first exon and the about 100 bp 5'-flanking region of the gene which contains a proximal CCAAT/enhancer-binding protein site were screened, but no mutations were found. CONCLUSION: These results suggest that no mutations in either the promoter region at the about 100 bp 5'-flanking region of the gene, or in any of the three exons, are involved in the development of NIDDM or IGT associated with obesity.     

Advanced HSLA Steels for Automotive Use

Characteristic HSLA steels for automotive use are introduced in which both of precipitation and microstructure is controlled to obtain suitable mechanical properties.For outer panels such as fender,the combination of low yield strength,high tensile strength and deep-drawability were realized by controlling the distribution of NbC and precipitation free zone.The other steel,developed for chassis parts such as lower arm,utilizes extremely fine interphase precipitation to obtain high yield strength and excellent hole expansionability.Both steels have contributed to the reduction of weight in car body.     

Fracture behavior of niobium by hydrogenation and its application for fine powder fabrication

Fracture behavior of pure niobium (Nb) by several hydrogenation procedures has been investigated to elucidate the fundamental mechanisms of hydrogen pulverization, which can then be used to produce fine Nb powders with high purity. Concentric cracks and microcracks were introduced in recrystallized Nb specimens, leading to pulverization, when they absorb hydrogen enough to form a large volume of the face-centered orthorhombic β-NbH phase. This hydride phase exhibits anisotropic expansion of Nb lattice and embrittlement. Thus, the fracture of Nb plates occurs in the following sequence: hydrogen absorption, the formation of the ordered hydride phase, strain generation arising from the phase transformation, and crack nucleation and propagation. The authors also show that Nb powders less than 1 μm were prepared by hydrogenation and ball-milling at a temperature below 203 K, in which hydrogen was removed by dehydrogenation at above 724 K. Thus, fine and contamination-free Nb powders can be effectively fabricated by using hydrogenation, ball-milling, and dehydrogenation procedures.     

Synovial osteochondromatosis of the temporo-mandibular joint

A rare case of synovial osteochondromatosis of the temporo-mandibular joint is presented. Important diagnostic information can be obtained by CT, MRI, 99m Tc bone scan and aspiration biopsy. Observation using a light microscope showed mild cellular atypia, but the hallmarks characteristic of chondrosarcoma were not found. Observation using an electron microscope showed the mature chondrocytes contained a well-developed rough endoplasmic reticulum. Histological evaluation indicated that the present case was benign synovial osteochondromatosis in an early stage.