有限变形理论能量释放率增率形式

基于有限变形理论中的能量原理和变分原理,考虑以有裂纹的瞬时位形为参考,建立增量变形引起的裂纹扩展方程能够更真实的描述裂纹尖端的扩展机制,在含有裂纹物体的瞬时变形的基础上,推导了裂纹体的能量释放率和增率的形式,提出了裂纹扩展判据.该判据反映了单位时间内裂纹扩展单位面积可以提供的能量与单位时间内裂纹扩展单位面积所需要的能量...     

Vasopeptidase inhibitors: incorporation of geminal and spirocyclic substituted azepinones in mercaptoacyl dipeptides

A series of 7-(di)alkyl and spirocyclic substituted azepinones were generated and incorporated as conformationally restricted dipeptide surrogates in mercaptoacyl dipeptides. Clear structure-activity relationships with respect to both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) activity in vitro were observed. The best in this series, compound 1g, a geminally dimethylated C-7-substituted azepinone, demonstrated excellent blood pressure lowering in animal models. Compound 1g (BMS-189921) is characterized by a good duration of activity and excellent oral efficacy in models relevant to ACE or NEP inhibition, and its activity is comparable to that of the clinically efficacious agent omapatrilat. Consequently this inhibitor has been advanced clinically for the treatment of hypertension and congestive heart failure.     

Serotonin 5-HT2 receptors in schizophrenia: a PET study using [18F]setoperone in neuroleptic-naive patients and normal subjects

BACKGROUND: In the FRISC trial, dalteparin 120 IU/kg body weight twice daily for unstable coronary artery disease was safe and reduced the risk of new coronary events. This risk reduction was maintained during the following extended treatment with a fixed dose of 7500 IU dalteparin once daily. METHODS AND RESULTS: Minor bleeding was more frequent in women compared with men: relative risk (CI) 2.88 (1.78 to 4.67) during the weight-adjusted and 2.36 (1.37 to 2.63) during the fixed dose treatment. The anti-Xa activity determined in samples (n = 175) obtained during the acute phase treatment was higher in women compared with men (P <.001) and in nonsmokers compared with smokers (<.001) in multiple regression analysis. Also, during the fixed-dose treatment (n = 131) an independent relation between anti-Xa activity and sex (P <.001), but not smoking habits, persisted. CONCLUSION: To improve future low-molecular-weight heparin dose regimens for the treatment of acute coronary syndromes, it might be important to consider the influence of sex and smoking habits.     

Human brain metabolic response to caffeine and the effects of tolerance

OBJECTIVE: Since there is limited information concerning caffeine's metabolic effects on the human brain, the authors applied a rapid proton echo-planar spectroscopic imaging technique to dynamically measure regional brain metabolic responses to caffeine ingestion. They specifically measured changes in brain lactate due to the combined effects of caffeine's stimulation of glycolysis and reduction of cerebral blood flow. METHOD: Nine heavy caffeine users and nine caffeine-intolerant individuals, who had previously discontinued or substantially curtailed use of caffeinated products because of associated anxiety and discomforting physiological arousal, were studied at baseline and then during 1 hour following ingestion of caffeine citrate (10 mg/kg). To assess state-trait contributions and the effects of caffeine tolerance, five of the caffeine users were restudied after a 1- to 2-month caffeine holiday. RESULTS: The caffeine-intolerant individuals, but not the regular caffeine users, experienced substantial psychological and physiological distress in response to caffeine ingestion. Significant increases in global and regionally specific brain lactate were observed only among the caffeine-intolerant subjects. Reexposure of the regular caffeine users to caffeine after a caffeine holiday resulted in little or no adverse clinical reaction but significant rises in brain lactate which were of a magnitude similar to that observed for the caffeine-intolerant group. CONCLUSIONS: These results provide direct evidence for the loss of caffeine tolerance in the human brain subsequent to caffeine discontinuation and suggest mechanisms for the phenomenon of caffeine intolerance other than its metabolic effects on elevating brain lactate.     

Directed mutagenesis studies of the metal binding site at the subunit interface of Escherichia coli inorganic pyrophosphatase

Recent crystallographic studies on Escherichia coli inorganic pyrophosphatase (E-PPase) have identified three Mg2+ ions/enzyme hexamer in water-filled cavities formed by Asn24, Ala25, and Asp26 at the trimer-trimer interface (Kankare, J., Salminen, T., Lahti, R., Cooperman, B., Baykov, A. A., and Goldman, A. (1996) Biochemistry 35, 4670-4677). Here we show that D26S and D26N substitutions decrease the stoichiometry of tight Mg2+ binding to E-PPase by approximately 0.5 mol/mol monomer and increase hexamer stability in acidic medium. Mg2+ markedly decelerates the dissociation of enzyme hexamer into trimers at pH 5.0 and accelerates hexamer formation from trimers at pH 7.2 with wild type E-PPase and the N24D variant, in contrast to the D26S and D26N variants, when little or no effect is seen. The catalytic parameters describing the dependences of enzyme activity on substrate and Mg2+ concentrations are of the same magnitude for wild type E-PPase and the three variants. The affinity of the intertrimer site for Mg2+ at pH 7.2 is intermediate between those of two Mg2+ binding sites found in the E-PPase active site. It is concluded that the metal ion binding site found at the trimer-trimer interface of E-PPase is a high affinity site whose occupancy by Mg2+ greatly stabilizes the enzyme hexamer but has little effect on catalysis.     

Effect of multivitamins on plasma homocysteine and folate levels in patients on hemodialysis

Three new triterpene lactones, lancilactones A (1), B (2), and C (3), together with the known kadsulactone A (4), were isolated from the stems and roots of Kadsura lancilimba. Their structures and stereochemistries were determined primarily from mass and NMR spectral data. Compound 3 inhibited HIV replication with an EC50 value of 1.4 microg/mL and a therapeutic index of greater than 71.4.     

Identification of 130 kDa cell surface LDL-binding protein from smooth muscle cells as a partially processed T-cadherin precursor

Atypical cell surface lipoprotein-binding proteins of 105 kDa and 130 kDa are present in membranes of vascular smooth muscle cells. We recently identified the 105 kDa protein from human aortic media as T-cadherin, an unusual glycosylphosphatidylinositol (GPI)-anchored member of the cadherin family of cell adhesion proteins. The goal of the present study was to determine the identity of 130 kDa lipoprotein-binding protein of smooth muscle cells. We applied different approaches that included protein sequencing of purified protein from human aortic media, the use of human T-cadherin peptide-specific antisera, and enzymatic treatment of cultured cells with trypsin and GPI-specific phospholipase C. Our results indicate that the 130 kDa protein is a partially processed form of T-cadherin which is attached to the membrane surface of smooth muscle cells via a GPI anchor and contains uncleaved N-terminal propeptide sequence. Our data disclose that, in contrast to classical cadherins, T-cadherin is expressed on the cell surface in both its precursor (130 kDa) and mature (105 kDa) forms.     

Mercuric chloride induces increases in both cytoplasmic and nuclear free calcium ions through a protein phosphorylation-linked mechanism

The mechanism of the lymphocyte stimulatory action of sulfhydryl group-reactive mercuric ions was studied with respect to its potential ability to induce a protein tyrosine phosphorylation-linked signal for mobilization of free Ca2+ into cytoplasm and nucleus of the cell. Exposure of human leukamic T cell line (Jurkat) cells to high (1 mM) and low (0.01 mM) concentrations of HgCl2 induced tyrosine phosphorylation of multiple proteins in a concentration-dependent manner. Confocal microscopy directly visualized the time course localization of Ca2+ inside the cells after exposure to HgCl2. The onset and level of Ca2+ mobilization following HgCl2 exposure were in parallel to those of protein tyrosine phosphorylation. Interestingly, by either concentration of HgCl2, Ca2+ was mobilized in both cytoplasm and nucleus almost simultaneously, and the level of Ca2+ mobilization in the nucleus was more than that in the cytoplasm. All the HgCl2-mediated Ca2+ mobilization was prevented by addition of protein kinase inhibitor staurosporin prior to HgCl2. These results suggest that heavy metal stress triggers a protein tyrosine phosphorylation-linked signal that leads to a nuclear event-dominant Ca2+ mobilization.     

Nonimmune hydrops fetalis: fetal and neonatal outcome during 1983-1992

Prognostic factors for survival of 62 fetuses and neonates with nonimmune hydrops fetalis (NIHF) were studied retrospectively. Twenty-eight infants survived >/=28 days which is 45% for all fetuses and newborns diagnosed with NIHF and 61% for liveborns with unresolved NIHF. Univariate analysis identified that mortality was associated with the presence of >/=2 serous cavity effusions and a need for chest compressions at birth. Multivariate logistic regression analysis confirmed that the presence of >/=2 serous cavity effusions was significantly associated with mortality from NIHF <28 days after birth [OR = 48.2 (CI 3.6, 662.9) (p < 0.004)]. We conclude that, compared to published cases from the 1970s and early 1980s, survival of liveborns with NIHF seems improved. The decrease in stillbirths is more notable. The severity of hydrops at birth is the key determinant for survival.