Biomedical subjects
Publications and source records attributed to S Zhang.
The HBV serum marker of 2925 new students was detected by enzyme linked immunosorbent assay. This produced results with a high degree of precision in a large study sample. The detection results showed that the HBsAg positive rate of new students is closely related to the family location, being either from urban districts or rural areas, and also the educational levels of their parents.
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Plasma leaking from damaged retinal blood vessels can have a significant impact on the pathologies of the posterior segment of the eye. Inflammation in the eye and metabolic change resulting from diabetes mellitus causes vascular leakage with alteration of the phenotype of retinal pigment epithelial (RPE) cells and fibrocytes, resulting in changes in cell function. Phenotypically altered cells then significantly contribute to the pathogenesis of retinopathies by being incorporated into tractional membranes in the vitreous, where they secrete matrix molecules, such as fibronectin, and express altered cell surface antigens. We hypothesize that there is a direct relationship between the leaking of plasma and the proliferation and phenotypic change of RPE cells and fibroblasts, thus exacerbating the pathology of retinal disease. If the hypothesis is correct, control of vascular leakage becomes an important target of therapy in proliferative vitreoretinopathy.
Ca2+ influx through N-methyl-D-aspartate (NMDA) receptors activates signal transduction pathways critical for many forms of synaptic plasticity in the brain. NMDA receptor-mediated Ca2+ influx also downregulates the gating of NMDA channels through a process called Ca2+-dependent inactivation (CDI). Recent studies have demonstrated that the calcium binding protein calmodulin directly interacts with NMDA receptors, suggesting that calmodulin may play a role in CDI. We report here that the mutation of a specific calmodulin binding site in the CO region of the NR1 subunit of the NMDA receptor blocks CDI. Moreover, intracellular infusion of a calmodulin inhibitory peptide markedly reduces CDI of both recombinant and neuronal NMDA receptors. Furthermore, this inactivating effect of calmodulin can be prevented by coexpressing a region of the cytoskeletal protein alpha-actinin2 known to interact with the CO region of NR1. Taken together, these results demonstrate that the binding of Ca2+/calmodulin to NR1 mediates CDI of the NMDA receptor and suggest that inactivation occurs via Ca2+/calmodulin-dependent release of the receptor complex from the neuronal cytoskeleton.
The current model of the nutrient sensing mechanism in pancreatic beta-cells implies that malonyl-CoA plays a key role. According to this hypothesis, glucose activation of acetyl-CoA carboxylase triggers a rapid production of malonyl-CoA which inhibits carnitine palmitoyltransferase 1 and the importation of fatty acyl-CoA into the mitochondria for oxidation. The increase in cytosolic long chain fatty acyl-CoA leads to the exocytosis of insulin by a mechanism which has not yet been clearly defined. To obtain direct evidence that ACC plays a central role in this process, we generated stable transfectants of an insulin secreting cell line (INS-1) that express ACC specific antisense mRNA. The amounts of ACC mRNA and the protein level were specifically decreased in these stable clones compared to those of the control cells. The glucose activation of ACC in these cells was also significantly diminished. Both acute and long-term induction of insulin secretion by glucose were decreased. This decrease was inversely correlated to the levels of ACC activity in clones. In these clones, the insulin secretion induced by other nutrients, amino acids and ketocaproate, is also impaired, while the KCl-induced insulin secretion remains unchanged. Decreased ACC expression was accompanied by impaired malonyl-CoA production and elevated fatty acid oxidation. The expressions of the pancreatic specific glucokinase, glucose transporter 2 or beta-actin in these cells, as well as glucose utilisation were not affected, suggesting that the effect of the expression of the ACC mRNA specific gene on insulin secretion is specifically related to the decrease in the amount of ACC gene products. These results provide direct evidence of a causal relationship between ACC and insulin secretion.
The cellular localisation of time- and temperature-dependent 125I-insulin binding, insulin-sensitive signalling proteins and the insulin-induced protein tyrosine phosphorylation cascade were assessed in subcellular fractions isolated on Iodixanol gradients from control and insulin-treated H35 hepatoma cells. Western blot analysis demonstrated that the concentrations of IRS-1, Shc, GRB-2, SOS, Syp, PI 3-kinase, MAP kinase and Gi alpha were at least 10-fold higher in cell surface-derived, caveolin-enriched fraction than in a cell surface-derived, caveolin-poor fraction (i.e., the plasma membranes). Insulin treatment caused a 15-fold increase in tyrosine phosphorylation of IRS-1 in the caveolin-enriched fraction in 5 min at 37 degrees C compared with a 3-fold increase in plasma membranes and a 6-fold increases in the cytosol and endosomes. Insulin also increased tyrosine phosphorylation of both a 72-kDa protein and the 46-kDa Shc isoform only in the caveolin-enriched fraction. Insulin treatment did not change the concentrations of insulin receptors or Shc but increased IRS-1 in the caveolin-enriched fraction, possibly recruited from the cytosolic pool. Insulin also increased the concentrations of insulin receptors, IRS-1 and Shc in endosomes, suggesting insulin-induced internalization of the insulin receptors and proteins activated with them. Electron microscopic analysis, with the use of a combination of colloidal gold-labelled insulin to label the insulin receptor and immunolabelling to detect caveolin or IRS-1, demonstrated the co-localisation of insulin receptors in caveolin- and IRS-1 containing vesicular structures. Differences in the insulin-induced protein tyrosine phosphorylation and concentrations of these proximal signalling proteins in the caveolin-enriched fraction, plasma membranes, and cytosol suggest that insulin receptors in the caveolae play a major role in initiating insulin's signal transduction processes.
RATIONALE AND OBJECTIVES: The authors evaluated the use of electron-beam computed tomographic (CT) angiography and three-dimensional (3D) reconstruction for evaluation of coronary artery bypass grafts (CABGs). MATERIALS AND METHODS: Sixty patients (53 men and seven women; mean age, 56 years +/- 8) with 152 CABGs (29 internal mammary artery and 123 saphenous vein grafts) underwent electron-beam CT with 3D reconstruction. The time from bypass surgery to CT scanning was 7 days to 120 months (mean, 17 months +/- 28). Enhanced single-section and flow mode studies were performed in all cases. The results were correlated with CABG operation records, and patency was determined with time-attenuation curves. RESULTS: All patients were successfully examined. On the basis of time-attenuation curve criteria, 124 (81.6%) of 152 grafts were patent. The patency rate for the internal mammary artery subgroup was 93% (27 of 29 grafts); for the saphenous vein graft subgroup, 78.9% (97 of 123 grafts). CONCLUSION: Used in contrast-enhanced, single-section mode and flow studies with time-attenuation curves, electron-beam CT angiography with 3D reconstruction can provide quantitative data for evaluation of CABG patency.
This study found that in lightly-anesthetized rats a unilateral micro-injection of glutamate (200 mm, 0.5 µl) into the thalamic nucleus submedius (Sm) markedly depressed the radiant heat-evoked tail flick (TF) reflex. After injection, the mean TFL increased 25.6+/-6.5% (n=24) of the baseline at 5 min, up to a peak value (48.4+/-7.2%) at 20 min, and recovered to the baseline level at 60 min. This inhibitory effect was dose-related and repeatable over a time interval of 1.0-1.5 h in the same animal. Furthermore, micro-injections of gamma-aminobutyric acid (GABA) (100 mm) into the ipsilateral ventrolateral orbital cortex (VLO) (0.7 µl), or bilaterally into the lateral or ventrolateral parts of the periaqueductal gray (PAG) (0.5 µl on each side), eliminated the Sm-evoked inhibition. After GABA was injected into VLO or PAG, the Sm applications of glutamate failed to produce any significant changes in TFL, with the TFL changes being similar to the saline control (p>0.05). These results confirmed our previous findings that electrical stimulation of Sm depressed the rat TF reflex and that this inhibitory effect was blocked by electrolytic lesion of the VLO or PAG. Therefore, the present study provides further support for the hypothesis that Sm plays an important role in modulation of nociception, and that its effects are mediated by the VLO-PAG pathway, leading to activation of the brainstem descending inhibitory system and depression of the nociceptive inputs at the spinal cord level. Copyright 1998 European Federation of Chapters of the International Association for the Study of Pain.
BACKGROUND: . Structure-function studies on the Alzheimer's disease peptide sh w that a central hydrophobic cluster - Abeta(17-21), LVFFA - is a prominent structural feature linked to plaque competence. The origin and stability of this cluster was probed in a 17-residue fragment which includes flanking residues that potentially help stabilize the cluster. RESULTS: After residue substitution, the measurement of pKas, amide exchange rates and other NMR data show that any coulombic interactions between His14 and Glu22 are not required for the stability of the central hydrophobic cluster. In contrast, a single substitution within the cluster disrupts its integrity and causes the largest pKa shift for flanking residues, while increasing the solvent accessibility of the backbone. CONCLUSIONS: The integrity of the structurally dominant cluster relies primarily upon local hydrophobic interactions, rather than on interactions between the sidechains of charged flanking residues. Moreover, the conformational disposition of the cluster affects the pKas of flanking residues, underscoring its structural dominance.
The ability to control integration, inheritance, and expression of multiple transgenes is a prerequisite for manipulating biosynthetic pathways and complex agronomic characteristics in plants. One hundred and twenty-five independent transgenic rice plants were regenerated after cobombarding embryogenic tissues with a mixture of 14 different pUC-based plasmids. Eighty-five percent of the R0 plants contained more than two, and 17% more than nine, of the target genes. Plants containing multiple transgenes displayed normal morphologies and 63% set viable seed. Multigene cotransformation efficiency was correlated with the ratio in which the plasmids were mixed with respect to the selectable marker. All target genes had an equal chance of integration, indicating that the nature of the coding region had no effect on the efficiency of integration. Three plant lines containing 11, 10, and 9 transgenes, respectively, were analyzed for patterns of integration and inheritance until the R3 generation. Integration of multiple transgenes occurred at either one or two genetic loci, with inheritance conforming to a 3:1 Mendelian ratio. Coexpression of four marker genes was investigated until the R2 generation.
The phenylethanolamines, ifenprodil and CP-101,606, are NMDA receptor antagonists with promising neuroprotective properties. In recombinant NMDA receptors expressed in Xenopus oocytes, we found that these drugs inhibit NMDA receptors through a unique mechanism, making the receptor more sensitive to inhibition by protons, an endogenous negative modulator. These findings support a critical role for the proton sensor in gating the NMDA receptor and point the way to identifying a context-dependent NMDA receptor antagonist that is inactive at physiological pH, but is a potent inhibitor during the acidic conditions that arise during epilepsy, ischemia and brain trauma.
Our previous reports have shown that laminin-glycopeptides (LN-GPs), the total glycopeptides prepared from laminin (LN), can prevent the experimental lung metastasis and liver metastasis of mouse cancer cells. In order to explore the anti-metastatic mechanism of LN-GPs, we studied the effects of LN-GPs on metastasis-related behaviors of cancer cells in vitro. LN-GPs did not affect cell survival. However, LN-GPs inhibited cell attachment and spreading of S180 cells on LN- and Matrigel-substrate in dose-dependent and time-dependent manners. Moreover, inhibition of cell attachment and spreading on Matrigel substrates were much greater on Matrigel substrate than on LN substrate. In the presence of LN-GPs, S180 cells on LN substrate changed from a flattened polygonal shape to a round one, the migration of S180 cells on LN substrate decreased, and the number of a highly invasive human pulmonary giant carcinoma PG cells invading Matrigel filter in a Boyden chamber was reduced. LN-GPs thus have multiple inhibitory effects on cancer metastasis-related behaviors.
A phase I clinical trial of E1A-liposome complex is currently ongoing in patients with HER-2/neu-overexpressing breast or ovarian cancers. To optimize the E1A-liposome complex for a further stage of clinical trial, several aspects of the current protocol have been examined in an animal model. In the orthotopic ovarian cancer model, different doses of lipid in the the E1A-liposome complex, which is currently used in clinical trials, were tested for the in vivo gene-transfer efficacy and tumor-suppression function. A lowered lipid dose--1/13 of the previous amount--produced gene expression level and E1A tumor-suppression efficacy similar to that of the original protocol. Mini-E1A, an E1A construct without its immortalization domain and yet capable of repressing HER-2/neu, was proved to be as potent as E1A in suppressing tumor development in vivo. These changes in the E1A-liposome complex will significantly reduce any potential adverse effects caused by lipid vector and E1A DNA. To examine further whether residual E1A DNA may still exist in normal organs after the E1A-liposome treatment, PCR was used to detect E1A DNA in mice that survived for 1 1/2 years after the last treatment. E1A DNA was detected only in the lungs and kidneys, but not in livers, hearts, spleens, brains, uterus or the ovaries. Furthermore, resistance of the E1A DNA extracted from tissues to the digestion of Dpnl restriction enzyme, which can cleave the methylated E1A plasmid DNA generated by methylation-competent bacteria, suggested integration of E1A DNA into the chromosome of the lungs and kidneys. Experimental results presented here provide important information for safety concerns and for the design of future phase II and phase III trials.
A novel screening strategy has been developed for the identification of alpha-chymotrypsin inhibitors from a phage peptide library. In this strategy, the standard affinity selection protocol was modified by adding a proteolytic cleavage period to avoid recovery of alpha-chymotrypsin substrates. After four cycles of selection and further activity assay, a group of related peptides were identified by DNA sequencing. These peptides share a consensus sequence motif as (S/T)RVPR(R/H). Then, a corresponding short peptide (Ac-ASRVPRRG-NH2) was synthesized chemically and proved to be an inhibitor of alpha-chymotrypsin. The present work provides a useful way for searching proteinase inhibitors without detailed knowledge of the molecular structure.
Chinese patients (n = 113) with schistosomal hepatic fibrosis diagnosed by ultrasonography (grade I, II, or III) and 184 age- and sex-matched persons with no clinical information of schistosomal infection were typed for their HLA-DRB1 alleles by DNA typing. There was no single allele that conferred susceptibility or resistance to fibrosis. However, there were three groups of alleles that showed decreased (resistant), increased (susceptible), or neutral frequency in the patients with fibrosis. The susceptible alleles, DRBI *1202, DRB1 *1404, and DRBI *1405, shared a valine at amino acid residue 86, whereas the resistant alleles, DRB1*11011, DRB1*0409, and DRB1*0701, all had glycine at position 86. Therefore, this study focused on the glycine-valine dimorphism at aa 86, which influences the depth of the P1 pocket in the antigen binding groove, and found that the 86th valine allele was significantly increased in the patients with fibrosis (odds ratio = 2.2; 95% CI = 1.34-3.61, corrected P < .05).
Two purified proteinaceous fungal elicitors, parasiticein (an alpha elicitin) and cryptogein (a beta elicitin), as well as a fungal cell wall-derived carbohydrate elicitor all rapidly activated a 48-kD kinase in tobacco suspension cells. The maximum activation of this kinase paralleled or preceded medium alkalization and activation of the defense gene phenylalanine ammonia-lyase (PAL). In addition, the two elicitins, which also induced hypersensitive cell death, activated a 44- and a 40-kD kinase with delayed kinetics. By contrast, the cell wall-derived elicitor only weakly activated the 44-kD kinase and failed to activate the 40-kD kinase. The size and substrate preference of the 48-kD kinase are reminiscent of the recently purified and cloned salicylic acid-induced protein (SIP) kinase, which is a member of the mitogen-activated protein kinase family. Antibodies raised against a peptide corresponding to the unique N terminus of SIP kinase immunoreacted with the 48-kD kinase activated by all three elicitors from Phytophthora spp. In addition, the cell wall elicitor and the salicylic acid-activated 48-kD kinase copurified through several chromatography steps and comigrated on two-dimensional gels. Based on these results, all three fungal elicitors appear to activate the SIP kinase. In addition, inhibition of SIP kinase activation by kinase inhibitors correlated with the suppression of cell wall elicitor-induced medium alkalization and PAL gene activation, suggesting a regulatory function for the SIP kinase in these defense responses.
The rice Xa21 gene confers resistance to Xanthomonas oryzae pv oryzae in a race-specific manner. Analysis of the inheritance patterns and resistance spectra of transgenic plants carrying six Xa21 gene family members indicated that one member, designated Xa21D, displayed a resistance spectrum identical to that observed for Xa21 but conferred only partial resistance. Xa21D encodes a receptor-like protein carrying leucine-rich repeat (LRR) motifs in the presumed extracellular domain. The Xa21D transcript terminates shortly after the stop codon introduced by the retrotransposon Retrofit. Comparison of nucleotide substitutions in the LRR coding regions of Xa21 and Xa21D provided evidence of adaptive selection. Both functional and evolutionary evidence indicates that the Xa21D LRR domain controls race-specific pathogen recognition.