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Biomedical subjects

W Zhao

Publications and source records attributed to W Zhao.

At least 289 records · Page 16Linked to original sources
PubMed1996

Bright Spots, Structure, and Magmatism in Southern Tibet from INDEPTH Seismic Reflection Profiling

INDEPTH seismic reflection profiling shows that the decollement beneath which Indian lithosphere underthrusts the Himalaya extends at least 225 kilometers north of the Himalayan deformation front to a depth of approximately 50 kilometers. Prominent reflections appear at depths of 15 to 18 kilometers near where the decollement reflector apparently terminates. These reflections extend north of the Zangbo suture to the Damxung graben of the Tibet Plateau. Some of these reflections have locally anomalous amplitudes (bright spots) and coincident negative polarities implying that they are produced by fluids in the crust. The presence of geothermal activity and high heat flow in the regions of these reflections and the tectonic setting suggest that the bright spots mark granitic magmas derived by partial melting of the tectonically thickened crust.

Journal Article↗
PubMed1996

INDEPTH Wide-Angle Reflection Observation of P-Wave-to-S-Wave Conversion from Crustal Bright Spots in Tibet

Three-component wide-angle seismic data acquired in southern Tibet during Project INDEPTH show strong P-to-S converted reflections from reflectors that are aligned at a depth of approximately 15 kilometers beneath the northern Yadong-Gulu rift. These converted reflections are locally higher in amplitude than the corresponding P-wave reflections. Modeling of reflection mode conversion as a function of incidence angle indicates that this condition obtains for a reflector that is a solid over fluid interface; it is not typical of a solid-solid interface. The likely candidates for a fluid trapped within the crystalline crust of southern Tibet are granitic magma and water (brine).

Journal Article↗
PubMed1996

Evidence from Earthquake Data for a Partially Molten Crustal Layer in Southern Tibet

Earthquake data collected by the INDEPTH-II Passive-Source Experiment show that there is a substantial south to north variation in the velocity structure of the crust beneath southern Tibet. North of the Zangbo suture, beneath the southern Lhasa block, a midcrustal low-velocity zone is revealed by inversion of receiver functions, Rayleigh-wave phase velocities, and modeling of the radial component of teleseismic P-waveforms. Conversely, to the south beneath the Tethyan Himalaya, no low-velocity zone was observed. The presence of the midcrustal low-velocity zone in the north implies that a partially molten layer is in the middle crust beneath the northern Yadong-Gulu rift and possibly much of southern Tibet.

Journal Article↗
PubMed1996

Quantitative evaluation of blood-brain barrier permeability following middle cerebral artery occlusion in rats.

A sensitive quantitative fluorescence method was used to explore the time course and regional pattern of blood-brain barrier (BBB) opening after transient middle cerebral artery occlusion (MCAo). Male Sprague-Dawley rats were anesthetized with halothane and subjected to 2 h of temporary MCAo by retrograde insertion of an intraluminal nylon suture, coated with poly-L-lysine, through the external carotid artery into the internal carotid artery and MCA. Damage to the BBB was judged by extravasation of Evans Blue (EB) dye, which was administered either 2, 3, 24 or 48 h after onset of MCAo. Fluorometric quantitation of EB was performed 1 or 2 h later in six brain regions. Cerebral infarction volumes were quantitated from histopathological material at 72 h. EB extravasation first became grossly visible in the ipsilateral caudoputamen and neocortex following 3 h of MCAo, was grossly unapparent at 24-26 h, and was maximal at 48-50 h. Fluorescence quantitation confirmed that BBB opening was absent at 2-3 h but present at all later times. In the hemisphere ipsilateral to MCAo, a 179% mean increase in extravasation of EB (compared to sham rats) was measured at 4 h, 407% at 5 h, 311% at 26 h and 264% at 50 h. (in each case, P < 0.05 vs. sham). The volume of infarcted tissue at 72 h in this model was 163.6 +/- 7.7 mm3. Our results indicate that an initial, acute disruption of the BBB occurs between 3 and 5 h following MCAo, and that a later, more widespread increase in regional BBB permeability is present at 48 h. Regional measurement of Evans Blue extravasation offers a precise means of quantitating BBB disruption in focal cerebral ischemia; this method will be of considerable utility in assessing the BBB-protective properties of pharmacological agents.

Analysis of Variance↗
PubMed1996

Phosphopleckstrin inhibits gbetagamma-activable platelet phosphatidylinositol-4,5-bisphosphate 3-kinase.

Pleckstrin, the prototypic protein containing two copies of the pleckstrin homology domain, is a prominent substrate of protein kinase C in platelets and neutrophils. Both cell types have p85 subunit-containing phosphoinositide 3-kinase (p85/PI3K) and non-p85-containing PI3K (PI3Kgamma) that is activated by betagamma subunits of heterotrimeric GTP-binding proteins. We have shown that a PI3K product, phosphatidylinositol (PI) 3,4,5-trisphosphate, promotes pleckstrin phosphorylation in platelets. Since pleckstrin homology domains are thought to interact with Gbetagamma heterodimers and/or PI(4,5)P2, we have examined the effects of recombinant pleckstrins on platelet PI3Kgamma and p85/PI3K activities. Depending upon its phosphorylation/charged state, pleckstrin inhibits PI3Kgamma, but not p85/PI3K. Pleckstrin-mediated inhibition of PI3Kgamma is overcome by excess Gbetagamma and is restricted to PI(4,5)P2 as substrate, i.e. pleckstrin does not inhibit phosphorylation of PI()P or PI. Consistent with this, activation of protein kinase C by exposure of platelets to beta-phorbol diester (to increase endogenous pleckstrin phosphorylation) prior to platelet lysis causes inhibition of Gbetagamma-stimulatable PI3K activity only with respect to PI(4,5)P2 substrate. This phosphopleckstrin-mediated inhibition is overcome by increasing concentrations of Gbetagamma. We propose that phosphorylation of pleckstrin may constitute an important inhibitory mechanism for PI3Kgamma-mediated cell signaling.

Amino Acid Sequence↗
PubMed1996

Anti-CD40 ligand antibody treatment prevents the development of lupus-like nephritis in a subset of New Zealand black x New Zealand white mice. Response correlates with the absence of an anti-antibody response.

Systemic lupus erythematosus is characterized by B cell production of pathogenic autoantibodies dependent upon cooperation from CD4+ Th cells. The interaction between CD40 on B cells and CD40 ligand (CD40L) on Th cells is necessary for normal thymus-dependent Ab production. An anti-murine CD40L mAb blocks binding of CD40L to CD40 and prevents primary and secondary immune responses to thymus-dependent Ags. In this study, New Zealand Black x New Zealand White lupus-prone mice treated with this anti-CD40L Ab from ages 4 to 10 mo had reduced anti-DNA autoantibody production and renal disease and significantly prolonged survival compared with control mice. Pathologic examination verified the absence of significant renal damage or immune deposition in responding mice. Mice that responded to treatment did not develop an Ab response to the administered Ab. Long-term survivors mounted a substantial Ab response to keyhole limpet hemocyanin after completion of anti-CD40L Ab treatment, suggesting that some of the immunosuppressive effects of the Ab may be reversible. These results suggest a human form of this Ab may have therapeutic utility in human systemic lupus erythematosus.

Animals↗
PubMed1996

Atypical cytochrome P450 induction profiles in glomerular mesangial cells at the mRNA and enzyme level. Evidence for CYP1A1 and CYP1B1 expression and their involvement in benzo[a]pyrene metabolism.

Recent studies in this laboratory have shown that benzo[a]pyrene (BaP) modulates growth factor-related gene expression and proliferation of renal glomerular mesangial cells (GMCs) in vitro. Because many of the toxic and biochemical effects of this polycyclic aromatic hydrocarbon are mediated through oxidative metabolism, the present studies were conducted to examine the patterns of cytochrome P450IA1 (CYP1A1) and P4501B1 (CYP1B1) inducibility in mesangial cells and the molecular consequences of this response. Exposure of cultured GMCs to BaP (30 microM) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, 10 nM) for 24 hr induced CYP1A1 mRNA levels, a response abolished by cotreatment with 10 microM cycloheximide. The pattern of hydrocarbon inducibility was atypical in that BaP was a more effective inducer of CYP1A1 gene expression than TCDD, and both hydrocarbons induced aryl hydrocarbon hydroxylase (AHH) activity, but not ethoxyresorufin-O-deethylase activity. Cotreatment with alpha-naphthoflavone (alpha NF, 1 microM) or ellipticine (ELLIP, 0.1 nM) only partially inhibited the induction of AHH activity by BaP (30 microM). BaP and TCDD also induced expression of the CYP1B1 protein and the pattern of induction was comparable to that observed for CYP1A1. Treatment of GMCs with 30 microM BaP was associated with the formation of eight DNA adducts, and their occurrence could be inhibited by pretreatment with alpha NF (1 microM), but not ELLIP (0.1 nM). These results demonstrate that CYP1A1 and CYP1B1-related activities are induced in GMCs by BaP and TCDD and this induction is associated with metabolism of BaP to reactive intermediates that bind covalently to DNA.

Animals↗
PubMed1996

Cyclosporin A, an inhibitor of calcineurin, impairs memory formation in day-old chicks.

Considerable evidence exists that changes in the phosphorylation state of neuronal proteins are correlated with learning and that inhibition of various protein kinases disrupts memory formation. Given the reversible nature of protein phosphorylation, a role for protein phosphatases in memory processing also seems likely. It has been shown recently that administration of the phosphatase inhibitor, okadaic acid, disrupts memory formation in day-old chicks, with retention deficits first appearing at approximately 40 min post-training [93]. In the present study the intracranial administration of the immunosuppressant cyclosporin A was also found to produce retention deficits in day-old chicks trained on a single-trial, passive-avoidance task, but the deficits were not significant until 85 min post-training. The difference could not be attributed to differences in the pharmacokinetics of the drugs. Since okadaic acid preferentially inhibits protein phosphatases 1 and 2A, while cyclosporin A is reported to inhibit only the Ca2+/calmodulin-dependent protein phosphatase, calcineurin, it is possible that different phosphatases may be involved in distinct stages of memory formation, as has been reported previously for protein kinases. The possibility that cyclosporin A may, in addition, act through inhibition of cyclophilin's peptidyl-prolyl-cis/transisomerase activity is also canvassed.

Animals↗
PubMed1996

Neuroprotective effects of hypothermia and U-78517F in cerebral ischemia are due to reducing oxygen-based free radicals: an electron paramagnetic resonance study with gerbils.

Free radicals are implicated as causative agents in various forms of tissue destruction. Considerable circumstantial evidence suggests that oxygen-based free radicals generated as blood flow returns to formerly ischemic brain areas are mainly responsible for the neurodegeneration that follows periods of cerebral ischemia. In general, oxygen-based free radicals are highly reactive and exist for only a brief period of time. This makes the direct measurement of many of these free radicals rather difficult. Much of the current knowledge of free radicals in cerebral ischemia is based on observations of chemical changes brought about by the free radicals rather than on direct observations of the free radicals themselves. Low temperature electron paramagnetic resonance spectroscopy is one method that allows the direct study of free radicals. Compared to samples from sham-operated controls, samples of hippocampus taken from gerbils exposed to 15 min of forebrain ischemia followed by 15 min of reperfusion, frozen in liquid nitrogen less than 20 sec after sacrifice, and scanned by low temperature (100 K) electron paramagnetic resonance, show a significant increase in oxygen-based free radicals and a decrease in carbon-based ubiquinone-like free radicals. The ischemia-induced increase in oxygen-based free radicals is prevented by the intraperitoneal injection of the antioxidant drug U-78517F at the start of reperfusion and by hypothermia. However, neither intervention alters the ischemia-induced reduction in the ubiquinone-like free radicals. This suggests that the neuroprotective actions of hypothermia and U-78517F include a direct reduction in the oxygen-based free radical burden of the post-ischemic tissue.

Animals↗
PubMed1996

Neurobehavioral consequences of induced spreading depression following photothrombotic middle cerebral artery occlusion.

In a model of experimental focal cerebral ischemia, we have recently reported a strong correlation between the magnitude of ischemic depolarizations in the peri-infarct borderzone and the extent of histological injury. In the present study, we assessed the neurobehavioral consequences of spontaneously occurring and induced ischemic depolarizations in rats following middle cerebral artery (MCA) occlusion, as well as the effects of induced spreading depression (SD) in intact animals. Halothane-anesthetized, artificially ventilated Sprague-Dawley rats underwent photothrombotic MCA occlusion coupled with ipsilateral common carotid artery (CCA) occlusion. The electroencephalogram and direct current (DC) potential were recorded in the parietal infarct borderzone-corresponding to the cortical forelimb area-for 3 h following MCA occlusion. Group 1 rats (n = 9) received MCA/CCA occlusion, and the spontaneously occurring negative DC shifts were recorded in the ischemic borderzone. In Group 2 animals (n = 9), the (non-ischemic) frontal pole of the ipsilateral hemisphere was electrically stimulated in order to double the frequency of peri-infarct DC shifts occurring over the initial 3 h postocclusion. Group 3 consisted of intact rats (n = 3) in which SD was repeatedly evoked in the frontal pole. Four animals served as sham-operated controls. A battery of sensorimotor behavioral tests, consisting of beam balance, postural reflex and elicited forelimb placing, was applied in a blinded fashion. Sham controls and animals of Groups 1 and 2 were tested 24 h after surgery, and Group 3 rats were tested 2, 6 and 24 h after generation of SDs. A cumulative neurobehavioral index, ranging from 0 to 144, was calculated by adding the individual test results. Brains were perfusion-fixed 24 h following surgery for calculation of volumes of infarction and scattered neuronal injury. Functional outcome at 24 h was significantly worse in Group 2 animals (spontaneous plus induced ischemic depolarizations) (neurobehavior index 43 +/- 19, mean +/- S.D.) compared to Group 1 rats, in which only spontaneous depolarizations occurred (neurobehavior index 24 +/- 19, P < 0.05). The cumulative neurobehavioral index of Group 1 and 2 animals correlated positively with the volume of total ischemic injury (r = 0.765, P < 0.001) and with the frequency of ischemic depolarizations (r = 0.474, P < 0.05). Correlations between severe forelimb placing deficits and severe degrees of histological injury (necrosis or ischemic cell change) in the corresponding primary sensorimotor cortical region FR1 were significant in these rats. Group 3 rats showed severe neurobehavioral deficits at 2 and 6 h following SD stimulation (index 57 +/- 1 and 39 +/- 1, respectively) but returned to normal at 24 h (4 +/- 0). The findings indicate that cortical spreading depression is accompanied by transient neurobehavioral deterioration and that SD in the ischemic hemisphere of animals subjected to MCA occlusion worsened functional outcome 24 h after surgery.

Animals↗
PubMed1996

3,4-Dichloropropionanilide-induced atrophy of the thymus: mechanisms of toxicity and recovery.

The herbicide 3,4-dichloropropionanilide (propanil) has several well-documented neurotoxic and immunotoxic effects on mice. We report here a detailed characterization of the effects of propanil exposure on the thymus. We found that at doses of 100-200 mg/kg, propanil induces significant thymic atrophy between 2 and 7 days postexposure. This atrophy is characterized by a decrease in thymus/body ratio and a decrease in cellularity. Flow cytometric analyses of thymuses from propanil- and vehicle-treated mice indicate that the CD4(+) CD8(+) population of immature cells, is most significantly decreased in propanil-exposed mice. We performed cell cycle analysis of thymocyte populations using two-color surface staining and the DNA binding dye 7-aminoactinomycin D to determine whether thymic atrophy was associated with changes in the percentages of cells in the S, G2, and M phases of the cell cycle. We found a high percentage of proliferating CD4(+)CD8(+) thymocytes 4 days after exposure. Thus, recovery of the thymus occurs following increases in thymocyte proliferation, most notably the immature CD4(+) CD8(+) thymocytes. We tested the hypothesis that glucocorticoids play a role in the observed atrophy by examining thymuses in adrenalectomized, propanil-treated mice. No atrophy was observed in those animals. These results suggest that propanil has an immunotoxic effect on the thymus that appears to be mediated, in part, by endogenous glucocorticoids.

Adrenalectomy↗
PubMed1996

Studies on bioactive saponins from Chinese medicinal plants.

In our recent studies on bioactive saponins, two Chinese medicinal plants: Mussaenda pubescens Ait.f (Rubiaceae) and Clematis chinensis Osbeck (Ranunculaceae), were investigated. Of the two medicinal plants, M. pubescens is a Chinese folk medicine which has been used as a diuretic, antiphlogistic, diaphoretic and antipyretic agent, and has also been used to detoxify mushroom poisons and to terminate early pregnancy. Clematis chinensis is a Chinese traditional medicine which has been used as an analgesic, diuretic, antitumor, antiinflammatory and insecticidal agent for ages. As a result of our studies, eighteen saponins were identified from M. pubescens, among which seventeen were new compounds, while eleven saponins were isolated from C. chinensis, three of which were new compounds. In the course of our structural studies, mass fragment analysis in FAB-mass spectra and 1H- and 13C-NMR spectra were used to determine the structures of the sapogenin and oligosaccharide moieties. In those more complicated and minor saponins, various 2D-NMR experiments were carried out on 400-, 500- or 600-MHz NMR instruments, which permitted the identification of new sapogenins in glycoside form. In addition, it was also possible to assign all the proton and carbon signals of the sugar units on the basis of 1H-1H DQF COSY, TOCSY and HMQC spectra, which further permitted the establishment of linkage sites and sequences among the sugar units and aglycones by means of NOESY, ROESY and HMBC spectra. When the proton signals of sugar units are overlapped seriously in 1H-NMR spectra, peracetylation is a very helpful technique which can spread proton signals in wider range, thus simplifying their assignment by means of 2D-NMR spectra. When some of the sugar proton signals of a peracetylate are also overlapped coincidentally, alternation of deuterated solvents for measuring NMR spectra can circumvent the difficulties. Pharmacological tests indicated that mussaendoside O, the most abundant saponin from M. pubescens, can inhibit significantly the secretions of the lachrymal and salivary glands induced by galanthamine, and can also inhibit the contraction of the isolated longitudinal muscle strip from guinea pig ileum evoked by an M-Ach receptor agonist (carbachol, 10(-6) M) at concentrations of 10(-4) and 10(-5) M. From these results, the saponin should be an antagonist of the M-Ach receptor, and was presumed to be responsible for its antitoxicity activity toward some mushroom poisons of medicinal plant origin. In addition, mussaendoside O also showed immunopromotive and hemolytic activities.

Animals↗
PubMed1996

Three-dimensional metabolic and hemodynamic imaging of the normal and ischemic rat brain.

Unique insights into the topography of local metabolism/blood flow interrelationships in focal cerebral ischemia have afforded by the recent development of powerful image-processing techniques permitting three-dimensional (3D) autoradiographic image-averaging and analysis of replicate studies by a novel method termed "disparity analysis". This method, based upon a linear affine transformation model, directly estimates scaling, translation and rotation parameters simultaneously. The method was validated in awake Wister rats studied for local cerebral glucose metabolism (lCMRgl) with 14C-2-deoxyglucose. Brains were subserially sectioned, aligned by disparity analysis, and mapped into a common template so as to generate aggregate 3D data sets of the mean and standard deviation of the entire series (n = 9). Internal anatomic architecture was faithfully represented in the average image, and Fourier analysis revealed satisfactory retention of low-frequency information. The method was then applied to study metabolism/blood flow relationships in the acute focal ischemic penumbra of Sprague-Dawley rats subjected to distal photothrombotic middle cerebral artery (MCA) occlusion, coupled with permanent ipsilateral and 1 h contralateral common carotid artery occlusions. Matched series were studied for lCBF at 1.5 h and for lCMRgl at 1.25-2 h post-occlusion. The averaged lCBF image revealed the ischemic penumbra (defined as lCBF 20-40% of control) to form a "shell" around the cortical ischemic core and a confluent aggregate at the anterior and posterior poles of the core-zone. lCMRgl in the penumbra was heterogeneous, ranging from near-normal to markedly increased. An average lCMRgl/lCBF ratio data set revealed marked metabolism-flow uncoupling in penumbral pixels, averaging nearly five-fold above control ratio values. Sustained deflections of the DC potential were recorded in the penumbra, the site of marked uncoupling. This analysis defined for the first time the 3D topography of the ischemic penumbra and substantiated marked metabolism/flow dissociation, which is believed to be a metabolic consequence of the energy demand imposed by repeated peri-infarct depolarizations.

Animals↗
PubMed1996

Immunogenicity and relative attenuation of different vaccinia-rabies virus recombinants.

Immunogenicity and relative attenuation were examined for the following Tian Tan strain vaccinia-rabies recombinant viruses: 1) NGc-1, which coexpresses the glycoprotein (G) and nucleocapsid protein (N) of the rabies virus Challenge Virus Standard (CVS) strain; 2) Nc-1, which expresses the CVS N; 3) Gc-2, Gc-3, Gc-4, and Gc-5, which express CVS G via promoters from different vaccinia strains or from different vaccinia genome loci; 4) Ga-1, which expresses the G of rabies virus strain aG; and 5) Gas-1; which expresses the carboxyltruncated G ectodomain (Gs) of strain aG. All but Nc-1 and Gas-1 induced rabies virus neutralizing antibodies (VNAs) and protected groups of mice at very high frequencies from intramuscular (IM) or intracranial (IC) challenge with CVS or SW1 Shanghai dog street rabies virus (SRV); Nc-1 and Gas-1 were partly protective, more frequently against IM challenge. NGc-1 and Gc-5 appeared to induce high levels of VNAs sooner after immunization than the other constructs in mice. Relative attenuation assessed by IM infection of neonatal mice, IC infection of adult mice, and intradermal infection of rabbits with varying doses was best for NGc-1. All the recombinants were at least 100-fold more attenuated than the parent, Tian Tan vaccinia virus. Gc-2, Gc-3, Gc-4, Gc-5, and NGc-1 induced VNAs after immunization of dogs, and a subset of VNA-positive animals vaccinated with NGc-1 or Gc-3 were protected against an otherwise lethal IM injection of SRV at 21 days after vaccination.

Animals↗
PubMed1996

Saponins from Mussaenda pubescens.

From the hydrophilic fractions of aerial parts of Mussaenda pubescens, three new saponins named mussaendosides D, E and H, along with a known saponin, mussaendoside S, were isolated. Their structures were elucidated on the basis of chemical and spectral evidence.

Carbohydrate Sequence↗
PubMed1996

Saponins from Mussaenda pubescens.

Two new triterpenoid saponins, named mussaendosides G and K, were isolated from aerial parts of Mussaenda pubescens by normal and reverse phase chromatography. On the basis of chemical and spectroscopic methods, their structures have been elucidated as heinsiagenin A 3-O-{alpha-L-rhamnopyranosyl(1-->2)-[beta-D-glucopyranosyl (1-->6)]-beta-D-glucopyranosyl(1-->2)}-alpha-L -rhamnopyranosyl(1-->4)-O-beta-D-glucopyranoside and 3 beta,19 alpha-dihydroxyl-olean-12-en-24, 28-dioic acid-24,28-di-O-beta-D-glucopyranoside, respectively.

Carbohydrate Conformation↗
PubMed1996

Computer-assisted image-averaging strategies for the topographic analysis of in situ hybridization autoradiographs.

We report the application of a computer-based image-averaging strategy to the quantitative topographic analysis of in situ hybridization autoradiographs, based upon a disparity-analysis algorithm. We illustrate this approach for a representative antisense riboprobe-the astrocytic marker, glial fibrillary acid protein (GFAP)-in the setting of fluid-percussion brain injury in rats. Sequential coronal autoradiographs in individual animals are first digitized and aligned by disparity analysis. Next, coronal sections of all brains of a given experimental group are placed in register with one another, using a common anatomic reference level. One brain of the series serves as a template, and corresponding sections of other brains are mapped into its contour at each level. In this manner, average and standard deviation image data sets may be generated. With thresholding techniques, individual data sets can be dichotomized with respect to a chosen threshold, and frequency maps can be generated at each coronal level, displaying numbers of brains showing supra-threshold levels of mRNA at each pixel location. Pixel-by-pixel statistical comparison of data sets obtained under two different conditions (e.g., 30 min vs. 24 h following brain trauma) is then feasible. A digitized functional-anatomic brain atlas may be fitted to the images to assist analysis. Computer-based image analysis of in situ hybridization autoradiographs greatly extends the utility and applicability of this technique.

Animals↗