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Biomedical subjects

X Wan

Publications and source records attributed to X Wan.

At least 19 recordsLinked to original sources
PubMed2007

Nonlinear local electrovascular coupling. II: From data to neuronal masses.

In the companion article a local electrovascular coupling (LEVC) model was proposed to explain the continuous dynamics of electrical and vascular states within a cortical unit. These states produce certain mesoscopic reflections whose discrete time series can be reconstructed from electroencephalography (EEG) and functional magnetic resonance imaging (fMRI). In this article we develop a recursive optimization algorithm based on the local linearization (LL) filter and an innovation method to make statistical inferences about the LEVC model from both EEG and fMRI data, i.e., to estimate the unobserved states and the unknown parameters of the model. For a better understanding, the LL filter is described from a Bayesian point of view, providing the particulars for the case of hybrid data (e.g., EEG and fMRI), which could be sampled at different rates. The dynamics of the exogenous synaptic inputs going into the cortical unit are also estimated by introducing a set of Gaussian radial basis functions. In order to study the dynamics of the electrical and vascular states in the striate cortex of humans as well as their local interrelationships, we applied this algorithm to EEG and fMRI recordings obtained concurrently from two subjects while passively observing a radial checkerboard with a white/black pattern reversal. The EEG and fMRI data from the first subject was used to estimate the electrical/vascular states and parameters of the LEVC model in V1 for a 4.0 Hz reversion frequency. We used the EEG data from the second subject to investigate the changes in the dynamics of the electrical states when the frequency of reversion is varied from 0.5-4.0 Hz. Then we made use of the estimated electrical states to predict the effects on the vasculature that such variations produce.

Bayes Theorem↗
PubMed2006

Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism.

Rapamycin and several analogs, such as CCI-779 and RAD001, are currently undergoing clinical evaluation as anticancer agents. In this study, we show that inhibition of mammalian target of rapamycin (mTOR) signaling by rapamycin leads to an increase of Akt phosphorylation in Rh30 and RD human rhabdomyosarcoma cell lines and xenografts, and insulin-like growth factor (IGF)-II-treated C2C12 mouse myoblasts and IGF-II-overexpressing Chinese hamster ovary cells. RNA interference-mediated knockdown of S6K1 also results in an increase of Akt phosphorylation. These data suggest that mTOR/S6K1 inhibition either by rapamycin or small interfering RNA (siRNA) triggers a negative feedback loop, resulting in the activation of Akt signaling. We next sought to investigate the mechanism of this negative feedback regulation from mTOR to Akt. Suppression of insulin receptor substrate (IRS)-1 and tuberous sclerosis complex-1 by siRNAs failed to abrogate rapamycin-induced upregulation of Akt phosphorylation in both Rh30 and RD cells. However, pretreatment with h7C10 antibody directed against insulin-like growth factor-1 receptor (IGF-1R) led to a blockade of rapamycin-induced Akt activation. Combined mTOR and IGF-1R inhibition with rapamycin and h7C10 antibody, respectively, resulted in additive inhibition of cell growth and survival. These data suggest that rapamycin mediates Akt activation through an IGF-1R-dependent mechanism. Thus, combining an mTOR inhibitor and an IGF-1R antibody/inhibitor may be an appropriate strategy to enhance mTOR-targeted anticancer therapy.

Animals↗
PubMed2006

Optimizing detection of tissue anisotropy by fluorescence recovery after photobleaching.

Fluorescence recovery after photobleaching (FRAP) has been widely used to measure fluid flow and diffusion in gels and tissues. It has not been widely used in detection of tissue anisotropy. This may be due to a lack of applicable theory, or due to inherent limitations of the method. We discuss theoretical aspects of the relationship between anisotropy of tissue structure and anisotropy of diffusion coefficients, with special regard to the size of the tracer molecule used. We derive a semi-mechanistic formula relating the fiber volume fraction and ratio of fiber and tracer molecule diameters to the expected anisotropy of the diffusion coefficients. This formula and others are tested on simulated random walks through random simulated and natural media. We determine bounds on the applicability of FRAP for detection of tissue anisotropy, and suggest minimum tracer sizes for detection of anisotropy in tissues of different composition (fiber volume fraction and fiber diameter). We find that it will be easier to detect anisotropy in monodisperse materials than in polydisperse materials. To detect mild anisotropy in a tissue, such as cartilage, which has a low fiber fraction would require a tracer molecule so large that it would be difficult to deliver to the tissue. We conclude that FRAP can be used to detect tissue anisotropy when the tracer molecule is sufficiently large relative to the fiber diameter, volume fraction, and degree of polydispersivity, and when the anisotropy is sufficiently pronounced.

Anisotropy↗
PubMed2005

Fusing EEG and fMRI based on a bottom-up model: inferring activation and effective connectivity in neural masses.

The elucidation of the complex machinery used by the human brain to segregate and integrate information while performing high cognitive functions is a subject of imminent future consequences. The most significant contributions to date in this field, known as cognitive neuroscience, have been achieved by using innovative neuroimaging techniques, such as electroencephalogram (EEG) and functional magnetic resonance imaging (fMRI), which measure variations in both the time and the space of some interpretable physical magnitudes. Extraordinary maps of cerebral activation involving function-restricted brain areas, as well as graphs of the functional connectivity between them, have been obtained from EEG and fMRI data by solving some spatio-temporal inverse problems, which constitutes a top-down approach. However, in many cases, a natural bridge between these maps/graphs and the causal physiological processes is lacking, leading to some misunderstandings in their interpretation. Recent advances in the comprehension of the underlying physiological mechanisms associated with different cerebral scales have provided researchers with an excellent scenario to develop sophisticated biophysical models that permit an integration of these neuroimage modalities, which must share a common aetiology. This paper proposes a bottom-up approach, involving physiological parameters in a specific mesoscopic dynamic equations system. Further observation equations encapsulating the relationship between the mesostates and the EEG/fMRI data are obtained on the basis of the physical foundations of these techniques. A methodology for the estimation of parameters from fused EEG/fMRI data is also presented. In this context, the concepts of activation and effective connectivity are carefully revised. This new approach permits us to examine and discuss some future prospects for the integration of multimodal neuroimages.

Brain↗
PubMed2004

Selective GABA-receptor actions of amobarbital on thalamic neurons.

1. We studied amobarbital's effects on membrane properties and currents, and electrically evoked inhibitory postsynaptic currents (IPSCs) mediated by gamma-aminobutyric acid (GABA) in rat thalamic slices. Using concentration-response relationships, we compared amobarbital's effects in nociceptive nuclei and non-nociceptive nucleus reticularis thalami (nRT). 2. Amobarbital decreased input resistance by activating GABA(A) receptors. Amobarbital produced a larger decrease in ventrobasal than nRT neurons. 3. Amobarbital depressed burst and tonic firing. Depression of burst firing was more effective, particularly in ventrobasal and intralaminar neurons. Depression was reversed by GABA(A) antagonists, and surmountable by increasing current injection, implicating a receptor-mediated shunt mechanism. 4. Amobarbital did not affect the tetrodotoxin-isolated low threshold Ca(2+) spike during GABA(A) blockade. Amobarbital reduced excitability without altering outward leak, or hyperpolarisation-activated inward currents. 5. Amobarbital increased mean conductance and burst duration of single GABA(A) channels. Consistent with this, amobarbital increased amplitude and decay time of IPSCs with distinct EC(50)s, implicating actions at two GABA(A) receptor sites. 6. Activation of GABA(A) receptors by low concentrations, fast IPSC amplitude modulation, and failure to affect intrinsic currents distinguished amobarbital's mechanism of action from previously characterised barbiturates. The selective actions of amobarbital on GABA(A) receptor may have relevance in explaining anaesthetic and analgesic uses.

Amobarbital↗
PubMed2003

Pentobarbital modulates intrinsic and GABA-receptor conductances in thalamocortical inhibition.

We investigated interactions of an anesthetic barbiturate, pentobarbital, with non-ligand gated channels and identified inhibitory synaptic transmission in thalamic neurons. Using whole cell voltage-clamp, current-clamp and single channel recording techniques in rat ventrobasal neurons of slices and dispersed preparations, we determined the mechanisms of pentobarbital actions on ionic currents and inhibitory postsynaptic currents (IPSCs), mediated by aminobutyric acid (GABA). We investigated pentobarbital effects on intrinsic currents using hyperpolarizing voltage commands from rest and tetrodotoxin blockade of action potentials. At concentrations near 8 microM, pentobarbital increased input conductance and induced net outward current, I(PB), at potentials near action potential threshold. The reversal potential of I(PB) was -75 mV, implicating K+ and other ions. Cs+ (3 mM) which inhibits both K+ currents and inward rectifier (Ih), completely blocked IPB, whereas the selective Ih blocker, ZD-7288 (25 microM), or Ba2+ (2 mM) which suppresses only K+ currents, reduced IPB. Pentobarbital inhibited the Ih, consistent with a ZD-7288-induced shift in reversal potential for IPB toward K+ equilibrium potential. Pentobarbital increased the inward K+ rectifier, IKir, and leak current, Ileak. We determined the susceptibility of IPSCs, evoked by reticular stimulation, to antagonism by bicuculline, picrotoxinin and 2-hydroxysaclofen and identified their receptor subclass components. At EC50 = 53 microM, pentobarbital increased the duration of IPSCs. The prolonged IPSC duration during pentobarbital was attributable to enhanced open probability of GABAA channels, because combined with GABA, pentobarbital application increased mean channel open time without affecting channel conductance. At concentrations up to 100 microM, pentobarbital did not directly activate GABAA receptors. The concentration-response relationships for pentobarbital effects on the intrinsic currents and IPSCs overlapped, implying multiple sites of action and possible redundancy in anesthetic mechanisms. This is the first study to show that an i.v. anesthetic modulates the intrinsic currents, Ih, IKir, and Ileak, as well as IPSC time course in the same neurons. These effects likely underlie inhibition in thalamocortical neurons during pentobarbital anesthesia.

Action Potentials↗
PubMed2003

A topographical study of mechanical and electrical properties of single myocytes isolated from normal guinea-pig ventricular muscle.

Major regional differences in the electrical properties of myocytes from ventricular muscle have been described previously, on the basis of samples taken from a maximum of three regions in each heart. In order to define the topographical basis for such differences, we studied the electrical and mechanical properties of single myocytes isolated from 20 regions throughout the ventricles in the normal guinea-pig heart. Single myocytes were isolated using an enzymatic dispersion method, and were studied under conditions that were close to physiological. Cell capacitance and action potentials were recorded using the switch-clamp technique, and cell length and evoked shortening were measured using a photodiode array system. In the left ventricular free wall, mid-myocardial cells were longer and had greater capacitative surface area than surface myocytes. There were transmural but not longitudinal differences in APD90 (action potential duration to 90% repolarization), with the longest APD90 in subendocardial and the shortest in subepicardial myocytes. We found a septum-left ventricular free wall-right ventricular free wall gradient, with the longest APD90 in the septum and the shortest in the right ventricular free wall. The regional distribution of APD90 was closely mirrored by relaxation time. Peak cell shortening was greater in subendocardial myocytes than in subepicardial myocytes in the left ventricular free wall, and in myocytes from the left side of the septum compared with the right. We concluded that the regional distribution of APD is closely and inversely related to the sequence of ventricular depolarization, and that the regional variations in cell shortening amplitude are related principally to reported regional variations in wall stress.

Action Potentials↗
PubMed2002

PTEN augments staurosporine-induced apoptosis in PTEN-null Ishikawa cells by downregulating PI3K/Akt signaling pathway.

Staurosporine is a potent apoptosis inducer, but its mechanism remains to be clarified. We investigated the involvement of PTEN in staurosporine-induced apoptosis. Ishikawa cells, from an endometrial carcinoma cell line, expressed a high amount of PTEN mRNA but did not express the PTEN protein because of protein truncations. We isolated clones expressing the steady-state level of the PTEN protein from PTEN-null Ishikawa cells by transfection. The obtained clones showed reduced proliferative activity and reduced anchorage-independent cell growth with the augmented p27(Kip1). These cell lines were sensitized to apoptosis by staurosporine. A low concentration of UCN-01 did not affect apoptosis, but a high concentration augmented apoptosis in the PTEN-expressing clone. Alpha-sphingosine and H-7 did not affect apoptosis in these cell lines. PI3K inhibition augmented staurosporine-induced apoptosis in the parental cell line, but not in the PTEN-expressing clone. In the clone, phosho-Akt/PKB and phospho-Bad (Ser-136) were downregulated. Staurosporine reduced the levels of phospho-Akt/PKB and phospho-Bad (Ser-136) in all the cell lines, but the reduction was most significant in the PTEN-expressing clone. These results suggest that inhibition of the PI3K/Akt/PKB signaling pathway might be associated with staurosporine-induced apoptosis in Ishikawa cells.

3-Phosphoinositide-Dependent Protein Kinases↗
PubMed2002

Childhood invasive pneumococcal disease in Tasmania, 1994-2000.

OBJECTIVE: To describe the burden of invasive pneumococcal disease in Tasmanian children, including age-specific incidence and antibiotic-resistance pattern. METHODS: A population-based retrospective study was carried out, examining cases of childhood disease associated with isolates of Streptococcus pneumoniae from normally sterile sites, identified via scrutiny of laboratory records at all major Tasmanian laboratories during a 7-year period between January 1994 and December 2000. Medical records were sub-sequently examined for information describing the clinical syndrome and course of disease. RESULTS: Invasive pneumococcal disease was identified in 76 children during the 7-year period. The incidence per 100 000 children was 28.5 (95% CI 22.0-36.3) in children under 5 years and 54.3 (95% CI 40.2-71.8) in children under 2 years. The incidence of meningitis in children younger than 2 years was 12.2 (95% CI 6.1-21.8). Penicillin resistance was observed in 2.6% of cases, with no high level resistance. Predisposing conditions were identified in 34% of children with invasive disease. CONCLUSIONS: The incidence of invasive pneumococcal disease was comparable to many urban populations in Australia. The high rate of predisposing conditions supports the recommendations of the Australian Technical Advisory Group on Immunisation for targeted immunization in this group. The paucity of data describing Indigenous status is an argument for improved data collection in this area. The low level of penicillin resistance necessitates ongoing surveillance, and the lack of serotype information requires prospective data collection.

Adolescent↗
PubMed2001

Cross-linking of EphB6 resulting in signal transduction and apoptosis in Jurkat cells.

Eph kinases are the largest family of receptor tyrosine kinases (RTK), and their ligands are cell surface molecules. The known functions of Eph kinases are mainly pattern formation in the CNS. Although several Eph kinases are expressed at high levels in hemopoietic cells and in the thymus, we have no knowledge of the functions of any Eph kinase in the immune system. In this study, we have demonstrated that an Eph kinase, EphB6, was expressed at high levels in Jurkat leukemic T cells. Co-cross-linking of EphB6 and CD3 led to an altered profile of lymphokine secretion along with proliferation inhibition of Jurkat cells. The cells subsequently underwent Fas-mediated apoptosis. Although EphB6 has no intrinsic kinase activity, its cross-linking triggered general protein tyrosine phosphorylation in Jurkat cells. EphB6 was found to associate with a number of molecules in the signaling pathways, notably Cbl. EphB6 cross-linking resulted in Cbl dephosphorylation and dissociation from Src homology 2 domain-containing tyrosine phosphatase-1 (SHP-1). Our results show that EphB6 has important functions in T cells, and it can transduce signals into the cells via proteins it associates with.

Animals↗
PubMed2001

A proteasome inhibitor effectively prevents mouse heart allograft rejection.

BACKGROUND: We have previously demonstrated in vitro that proteasome inhibitors could suppress proliferation and induce apoptosis of activated T cells. This finding suggests that such inhibitors could be used as a novel category of immunosuppressants in blocking allograft rejection. METHODS: The proteasome inhibitor dipeptide boronic acid (DPBA) was tested in vitro for its inhibitory effect on mouse T-cell proliferation and lymphokine secretion. DPBA was also used in vivo to treat mouse heterotopic heart allograft rejection. Possible side effects of this compound were examined according to blood chemistry of mice treated with DPBA. RESULTS: DPBA suppressed the T-cell proliferation and potently inhibited interleukin (IL)-2, IL-6, IL-10, IL-13, and IFN-gamma produced by anti-CD3-activated T cells. Given i.p. starting 1 day after transplantation at 0.66 mg/kg per day for 16 days, or at 1 mg/kg per day for 4 days followed by 0.5 mg/kg per day for 12 days, DPBA could prolong heart allograft survival to 35.5 days (mean survival time, MST) and to 36.2 days, respectively. The control group had MST of 7.3 days. When administrated 72 hr post operation at 1 mg/kg per day for 4 days, DPBA could prolong the graft survival to 19.8 days. During the course of these effective dosages, DPBA had no apparent toxicity in the liver, kidney, pancreas, or heart, according to analysis of blood chemistry. CONCLUSIONS: The proteasome inhibitor could repress allograft rejection in mice without apparent side-effects at the effective dosages. This finding has opened a new dimension in development of novel immunosuppressants for organ transplantation.

Animals↗
PubMed2001

Protein kinase C is involved in the regulation of hairless mRNA expression during mouse keratinocyte differentiation.

The hairless (hr) gene is a putative transcriptional factor whose mutations lead to hair loss in animals and humans. As a step toward understanding the role of the hr gene, we investigated the expression of hr mRNA in mouse keratinocyte differentiation. Treatment of mouse primary keratinocyte cultures with phorbol-12-myristate-13-acetate (PMA) reduced DNA synthesis and sequentially induced an up-regulation of p21Cip1/WAF1 (p21), hr and involucrin (inv) mRNAs in a time-dependent fashion, suggesting that an increase in hr gene expression is associated with keratinocyte differentiation. This up-regulation was blocked by the RNA synthesis inhibitor actinomycin D. However, an increase in hr mRNA, but not in inv mRNA, was seen in cells treated with the protein synthesis inhibitor cycloheximide, suggesting that new protein synthesis is involved in the suppression of hr transcription or in the degradation of hr mRNA in the steady state. The up-regulation of hr mRNA expression by PMA was blocked by the protein kinase C (PKC) inhibitor, GF109203X. These data indicate that PKC activation is involved in the up-regulation of hr mRNA expression during mouse keratinocyte differentiation.

Animals↗
PubMed2001

[Expression and clinopathological significance of HCCA1 in hepatocellular carcinoma].

OBJECTIVE: To explore the correlation of a newly cloned HCCA1 gene expression with hepatocellular carcinoma (HCC). METHODS: HCCA1 mRNA and protein expression were detected by Northern blotting and by immunohistochemistry respectively. Its clinopathological significance was also analyzed. RESULTS: HCCA1 mRNA expression was found in 59 (90.8%) out of 65 patients. Of these, 54 (91.5%) showed significantly elevated expression of HCCA1 mRNA in HCC tissues. There were 9 (13.8%) patients who had low level of HCCA1 mRNA expression in paracarcinoma, and 56 (86.2%) cases showed no detectable signals. HCCA1 mRNA expression was closely related to lower tumor grading and portal vein invasion. It was noted that HCCA1 mRNA levels were higher in tumor grading III-IV group than in grading I-II group, higher in portal vein thrombus group than in non-thrombus group. Immunohistochemical staining confirmed that the HCCA1 protein was preferentially expressed in HCC tissues. Amongst 38 patients examined, 20 (52.6%) revealed positive staining with anti-HCCA1. CONCLUSION: HCCA1 is a novel HCC associated gene which may play a role in HCC invasion and metastasis.

Adult↗
PubMed2001

Cytoplasmic/nuclear expression without mutation of exon 3 of the beta-catenin gene is frequent in the development of the neoplasm of the uterine cervix.

OBJECTIVE: The dual function of beta-catenin (e.g., as an intermediate protein between adherence junctions and the microfilaments, and as a mediator of the Wnt signaling pathway) is currently known. Stabilization of beta-catenin and subsequent activation of the Wnt signaling pathway are involved in the development of some malignancies. We analyzed the immunohistochemical localization of beta-catenin and the somatic mutation of exon 3 of the beta-catenin gene in the malignant phenotype of the uterine cervix. METHODS: Immunohistochemical localization of beta-catenin and mutation of exon 3 of the beta-catenin gene were analyzed in 38 precancerous lesions and 43 cancerous lesions. RESULTS: In normal cervix, beta-catenin was observed around the plasma membrane of the cells in the basal and parabasal layers of the epithelium. The frequency of cytoplasmic/nuclear beta-catenin expression correlated with a high histological grade of cervical intraepithelial neoplasia. Among invasive carcinomas, 11 (73%) of 15 samples showed cytoplasmic/nuclear localization to variable extents. A mutational analysis showed that mutation occurred in 7 of 68 specimens. Six cases with mutations revealed cytoplasmic/nuclear beta-catenin expression, though 32 (84%) of the 38 samples showing cytoplasmic/nuclear beta-catenin expression were not associated with the mutation. CONCLUSION: These results indicate that cytoplasmic/nuclear expression of beta-catenin is associated with the malignant phenotype of the cervix, but the contribution of mutation of the beta-catenin gene is limited.

Adult↗
PubMed2001

Acidic fibroblast growth factor overexpression partially protects 3T3 fibroblasts from apoptosis induced by synthetic retinoid CD437.

Retinoids are proapoptotic compounds with therapeutic potential for treating cancer. We evaluated the apoptotic effect of the novel retinoid CD437, and particularly its relationship to Akt and acidic fibroblast growth factor (aFGF). We hypothesized that the novel synthetic retinoid CD437 would exert its apoptotic effect by reducing the activity of Akt. We further hypothesized that aFGF would protect against CD437 apoptosis by preserving the activity of Akt. Initially we demonstrated that CD437 produces apoptotic cell death in NIH 3T3 fibroblasts, and that this effect is attenuated in fibroblasts transfected to express aFGF. Next we assessed Akt activity and showed that phospho-Akt is significantly reduced in 3T3 cells exposed to CD437. We showed that this effect is less pronounced in aFGF transfected 3T3 cells. Furthermore, we observed that the addition of exogenous aFGF to 3T3 cells significantly increases Akt phosphorylation. These findings tend to confirm our hypothesis that reduction in Akt activation is a mechanism involved in the apoptotic effect of the retinoid CD437, and that preservation of Akt phosphorylation occurs in response to aFGF and appears to explain the partially protective effect of aFGF for 3T3 cells vis a vis CD437.

3T3 Cells↗
PubMed2001

Root water flow and leaf stomatal conductance in aspen (Populus tremuloides) seedlings treated with abscisic acid.

Exogenous abscisic acid (ABA) applied to the roots and excised shoots of aspen (Populus tremuloides Michx.) inhibited stomatal conductance. However, the effect of ABA on stomatal conductance was more pronounced in the excised shoots compared with the intact seedlings. Approximately 10% of the ABA concentration applied to the roots was found in the xylem exudates of root systems exposed to a hydrostatic pressure of 0.3 MPa. A similar concentration of ABA applied to the excised shoots produced a faster and greater reduction of stomatal conductance. ABA applied to the roots had no effect on root steady-state flow rate over the 5-h experimental period. Moreover, pre-incubating root systems of intact seedlings for 12 h with 5 x 10(-5) M ABA did not significantly reduce volume flow density. Similarly, ABA had no effect on root hydraulic conductivity and the activation energy of root water flow rates.

Abscisic Acid↗
PubMed2001

Alternatively spliced variant deleting exons 7 and 8 of the human telomerase reverse transcriptase gene is dominantly expressed in the uterus.

The expression level of the human telomerase reverse transcriptase (hTERT) is a rate-limiting determinant of telomerase activity. Several alternatively spliced variants of hTERT transcript are currently known. We have studied the expression of the splicing variants arising in the transcript encoding the reverse transcriptase domain, and have compared this to the telomerase activity in 27 endometria, 14 myometria and 18 endometrial carcinomas. Telomerase activity and the full-length hTERT transcript were observed in endometrial samples from the proliferative and early secretory phases, but not in those from the late secretory phase. Steady-state expression of the hTERT splicing variant entirely lacking exon 7 and exon 8 was observed in the endometria throughout the menstrual cycle. In the analysed myometria, this type of splicing variant was the most commonly detected, and telomerase activity occurred in only three samples. In both endometria and myometria, the expression of the full-length transcript correlated well with the telomerase activity. In each of the endometrial carcinomas, telomerase activity was detected and the full-length transcript was found together with varying combinations of deletion splicing variants. These results suggest that regulation of splicing in the transcript encoding the hTERT reverse transcriptase domain is associated with telomerase activation in uterine tissues.

Adult↗