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Biomedical subjects

Bin He

Publications and source records attributed to Bin He.

At least 91 records · Page 5Linked to original sources
PubMed2003

Substituted pyrazolopyridopyridazines as orally bioavailable potent and selective PDE5 inhibitors: potential agents for treatment of erectile dysfunction.

Novel pyrazolopyridopyridazine derivatives have been prepared as potent and selective PDE5 inhibitors. Compound 6 has been identified as a more potent and selective PDE5 inhibitor than sildenafil (1). It is as efficacious as sildenafil in in vitro and in vivo PDE5 inhibition models, and it is orally bioavailable in rats and dogs. The superior isozyme selectivity of 6 is expected to exert less adverse effects in humans when used for erectile dysfunction treatment.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2003

Phosphorylation of NF-kappaB proteins by cyclic GMP-dependent kinase. A noncanonical pathway to NF-kappaB activation.

The transcription factor NF-kappaB is activated in cellular stress responses. This requires rapid regulation of its function, which is accomplished, in part, by various modes of phosphorylation. Even though diverse DNA binding subunits of NF-kappaB proteins may transactivate from distinct recognition sequences, the differential regulation of transcription from the large number of NF-kappaB responsive sites in various gene promoters and enhancers has been incompletely understood. The cyclic GMP-dependent kinase (PKG) is an important mediator of signal transduction that may induce gene expression through cAMP response element binding protein (CREB) and through other, yet undefined, mechanisms. We have previously characterized a signal transduction pathway that leads to activation-induced cell death in T-lymphocytes and involves the activation of PKG. Here we demonstrate that the NF-kappaB proteins p65, p49 (also called p52), and p50 are specific substrates for this kinase. PKG dose-dependently increases the transactivating activity of p65 from the NF-kappaB consensus sequence. It also mediates dose-dependently an increase in transcriptional activity by p49 or p50 from a unique CCAAT/enhance binding protein (C/EBP)-associated NF-kappaB site, but not from the consensus site. Phosphorylation of p65, p50, or p49 does not alter their subcellular distribution. Because the release of cytosolic p65/p50 heterodimers into the nucleus is by itself insufficient to differentiate all the numerous NF-kappaB promoter sequences, phosphorylation of the DNA-binding subunits reveals a form of differential regulation of NF-kappaB activity and it implies a novel pathway for PKG-induced gene transcription. These observations may bear on mechanisms of programmed cell death in T-lymphocytes. They may also be relevant to ongoing efforts to induce cancer cell apoptosis through activation of PKG.

Amino Acid Sequence↗
PubMed2003

Body surface Laplacian electrocardiogram of ventricular depolarization in normal human subjects.

INTRODUCTION: The body surface Laplacian electrocardiogram (ECG) mapping provides a noninvasive means for spatiotemporal mapping of cardiac electrical events. The aim of the present study was to explore the relationship between the Laplacian ECG and the underlying cardiac activities during ventricular depolarization in healthy human subjects. METHODS AND RESULTS: A 95-channel body surface potential ECG was recorded over the anterolateral chest from 11 healthy male subjects. The surface Laplacian (SL) ECG was estimated from the recorded potentials during QRS complex by means of a novel spline SL estimator, as well as by the conventional 5-point SL estimator for comparison purpose. A simulation study was also conducted using a realistic geometry heart-torso model in an attempt to qualitatively interpret the experimental results. For all subjects, more spatial details were observed in the SL ECG maps compared with the potential ECG maps, with spline SL more robust against noise than the 5-point SL. In total, three positive activities (denoted as P1, P2, P3) and four negative activities (denoted as N1, N2, N3, N4) in the spline SL ECG maps were observed during ventricular depolarization. Initial localized P1 and N1 activities were observed in 11 and 8 subjects, respectively. Then, the initial P1 was divided into three positive activities (P1, P2, P3) in 9 subjects. After the appearance of multiple positive activities, three negative activities (N2, N3, N4) appeared in 11, 8, and 9 subjects, respectively. Similar findings were obtained in the computer simulation study. CONCLUSION: The present study demonstrates that the SL ECG provides more spatial details than the potential ECG, and multiple simultaneously active ventricular activities could be revealed in the SL ECG maps. The results suggest that the SL ECG may provide an alternative for noninvasive mapping of cardiac electrical activity.

Adult↗
PubMed2003

Noninvasive localization of the site of origin of paced cardiac activation in human by means of a 3-D heart model.

A recently developed heart-model-based localization approach is experimentally evaluated in noninvasively localizing the site of origin of cardiac activation in a patient with a pacemaker. The heart-torso model of the patient was constructed from the contrast ultrafast computed tomography images. The site of initial paced activation in the patient was quantitatively localized and compared with the tip position of the pacemaker lead. The localization error of the inverse estimation was found to be 5.2 mm with respect to the true lead tip position. The promising result of this pilot experimental study suggests the feasibility of localizing the site of origin of cardiac activation in an experimental setting. The heart-model-based localization approach may become an alternative tool in localizing the site of origin of cardiac activation.

Aged↗
PubMed2003

Noninvasive imaging of cardiac transmembrane potentials within three-dimensional myocardium by means of a realistic geometry anisotropic heart model.

We have developed a new approach for imaging cardiac transmembrane potentials (TMPs) within the three-dimensional (3-D) myocardium by means of an anisotropic heart model. The cardiac TMP distribution is estimated from body surface electrocardiograms by minimizing objective functions of the "measured" body surface potential maps (BSPMs) and the heart-model-generated BSPMs. Computer simulation studies have been conducted to evaluate the present 3-D TMP imaging approach using pacing protocols. Simulations of single-site pacing at 24 sites throughout the ventricles, as well as dual-site pacing at 12 pairs of sites in the vicinity of atrio-ventricular ring were performed. The present simulation results show that the correlation coefficient (CC) and relative error (RE) between the "true" and inversely estimated TMP distributions were 0.9915 +/- 0.0041 and 0.1266 +/- 0.0326, for single-site pacing, and 0.9889 +/- 0.0034 and 0.1473 +/- 0.0237 for dual-site pacing, respectively, when 10 microV Gaussian white noise (GWN) was added to the BSPMs. The effects of heart and torso geometry uncertainty were also evaluated by shifting the heart position by 10 mm and altering the torso size by 10%. The CC between the "true" and inversely estimated TMP distributions was above 0.97 when these geometry uncertainties were considered. The present simulation results demonstrate the feasibility of noninvasive estimation of TMP distribution throughout the ventricles from body surface electrocardiographic measurements, and suggest that the present method may become a useful alternative in noninvasive imaging of distributed cardiac electrophysiological processes within the 3-D myocardium.

Body Surface Potential Mapping↗
PubMed2003

Statistical accuracy of a moving equivalent dipole method to identify sites of origin of cardiac electrical activation.

While radio frequency (RF) catheter ablation (RCA) procedures for treating ventricular arrhythmias have evolved significantly over the past several years, the use of RCA has been limited to treating slow ventricular tachycardias (VTs). In this paper, we present preliminary results from computer and animal studies to evaluate the accuracy of an algorithm that uses the single equivalent moving dipole (SEMD) model in an infinite homogeneous volume conductor to guide the RF catheter to the site of origin of the arrhythmia. Our method involves measuring body surface electrocardiographic (ECG) signals generated by arrhythmic activity and by bipolar current pulses emanating from a catheter tip, and representing each of them by a SEMD model source at each instant of the cardiac cycle, thus enabling rapid repositioning of the catheter tip requiring only a few cycles of the arrhythmia. We found that the SEMD model accurately reproduced body surface ECG signals with a correlation coefficients > 0.95. We used a variety of methods to estimate the uncertainty of the SEMD parameters due to measurement noise and found that at the time when the arrhythmia is mostly localized during the cardiac cycle, the estimates of the uncertainty of the spatial SEMD parameters (from ECG signals) are between 1 and 3 mm. We used pacing data from spatially separated epicardial sites in a swine model as surrogates for focal ventricular arrhythmic sources and found that the spatial SEMD estimates of the two pacing sites agreed with both their physical separation and orientation with respect to each other. In conclusion, our algorithm to estimate the SEMD parameters from body surface ECG can potentially be a useful method for rapidly positioning the catheter tip to the arrhythmic focus during an RCA procedure.

Algorithms↗
PubMed2003

Dephosphorylation of eIF-2alpha mediated by the gamma(1)34.5 protein of herpes simplex virus type 1 is required for viral response to interferon but is not sufficient for efficient viral replication.

The gamma(1)34.5 protein of herpes simplex virus type 1 (HSV-1) functions to block the shutoff of protein synthesis involving double-stranded RNA-dependent protein kinase (PKR). In this process, the gamma(1)34.5 protein recruits cellular protein phosphatase 1 (PP1) to form a high-molecular-weight complex that dephosphorylates eIF-2alpha. Here we show that the gamma(1)34.5 protein is capable of mediating eIF-2alpha dephosphorylation without any other viral proteins. While deletion of amino acids 1 to 52 from the gamma(1)34.5 protein has no effect on eIF-2alpha dephosphorylation, further truncations up to amino acid 146 dramatically reduce the activity of the gamma(1)34.5 protein. An additional truncation up to amino acid 188 is deleterious, indicating that the carboxyl-terminal domain alone is not functional. Like wild-type HSV-1, the gamma(1)34.5 mutant with a truncation of amino acids 1 to 52 is resistant to interferon, and resistance to interferon is coupled to eIF-2alpha dephosphorylation. Intriguingly, this mutant exhibits a similar growth defect seen for the gamma(1)34.5 null mutant in infected cells. Restoration of the wild-type gamma(1)34.5 gene in the recombinant completely reverses the phenotype. These results indicate that eIF-2alpha dephosphorylation mediated by the gamma(1)34.5 protein is required for HSV response to interferon but is not sufficient for viral replication. Additional functions or activities of the gamma(1)34.5 protein contribute to efficient viral infection.

Animals↗
PubMed2003

Growth factor signaling induces metastasis genes in transformed cells: molecular connection between Akt kinase and osteopontin in breast cancer.

Malignant tumors are characterized by excessive growth, immortalization, and metastatic spread, whereas benign tumors do not express gene products that mediate invasion. The molecular basis for this difference is incompletely understood. We have screened signal transduction molecules associated with the epidermal growth factor (EGF) receptor and have identified constitutive phosphorylation, indicative of activation, of Akt kinase in MT2994 breast cancer cells. In contrast, cells of the benign breast epithelial cell lines Comma-D and FSK-7 are immortalized through pathways that are independent of the EGF-phosphatidylinositol 3-kinase-Akt kinase cascade, but this is not associated with invasiveness. Transfection of constitutively active Akt kinase causes accelerated cell division and osteopontin expression. Conversely, dominant-negative Akt kinase slows cell cycle progression and suppresses osteopontin expression. The manipulation of osteopontin expression in this setting by transfection of the gene or its antisense does not affect the growth rate of the cells but alters cell motility and anchorage independence. Therefore, Akt kinase activates two distinct genetic programs: the program of growth and survival, which is independent of osteopontin expression, and the program of invasiveness and anchorage independence, which is mediated by osteopontin. These studies define Akt kinase as a molecular bridge between cell cycle progression and dissemination.

Animals↗
PubMed2003

Electrostatic modulation in steroid receptor recruitment of LXXLL and FXXLF motifs.

Coactivator recruitment by activation function 2 (AF2) in the steroid receptor ligand binding domain takes place through binding of an LXXLL amphipathic alpha-helical motif at the AF2 hydrophobic surface. The androgen receptor (AR) and certain AR coregulators are distinguished by an FXXLF motif that interacts selectively with the AR AF2 site. Here we show that LXXLL and FXXLF motif interactions with steroid receptors are modulated by oppositely charged residues flanking the motifs and charge clusters bordering AF2 in the ligand binding domain. An increased number of charged residues flanking AF2 in the ligand binding domain complement the two previously characterized charge clamp residues in coactivator recruitment. The data suggest a model whereby coactivator recruitment to the receptor AF2 surface is initiated by complementary charge interactions that reflect a reversal of the acidic activation domain-coactivator interaction model.

Acetyltransferases↗
PubMed2002

Noninvasive three-dimensional activation time imaging of ventricular excitation by means of a heart-excitation model.

We propose a new method for imaging activation time within three-dimensional (3D) myocardium by means of a heart-excitation model. The activation time is estimated from body surface electrocardiograms by minimizing multiple objective functions of the measured body surface potential maps (BSPMs) and the heart-model-generated BSPMs. Computer simulation studies have been conducted to evaluate the proposed 3D myocardial activation time imaging approach. Single-site pacing at 24 sites throughout the ventricles, as well as dual-site pacing at 12 pairs of sites in the vicinity of atrioventricular ring, was performed. The present simulation results show that the average correlation coefficient (CC) and relative error (RE) for single-site pacing were 0.9992+/-0.0008/0.9989+/-0.0008 and 0.05+/-0.02/0.07+/-0.03, respectively, when 5 microV/10 microV Gaussian white noise (GWN) was added to the body surface potentials. The average CC and RE for dual-site pacing were 0.9975+/-0.0037 and 0.08+/-0.04, respectively, when 10 microV GWN was added to the body surface potentials. The present simulation results suggest the feasibility of noninvasive estimation of activation time throughout the ventricles from body surface potential measurement, and suggest that the proposed method may become an important alternative in imaging cardiac electrical activity noninvasively.

Algorithms↗
PubMed2002

Mathematical modeling of noise and discovery of genetic expression classes in gliomas.

The microarray array experimental system generates noisy data that require validation by other experimental methods for measuring gene expression. Here we present an algebraic modeling of noise that extracts expression measurements true to a high degree of confidence. This work profiles the expression of 19 200 cDNAs in 35 human gliomas; the experiments are designed to generate four replicate spots/gene with switching of probes. The validity of the extracted measurements is confirmed by: (1) cluster analysis that generates a molecular classification differentiating glioblastoma from lower-grade tumors and radiation necrosis; (2) By what other investigators have reported in gliomas using paradigms for assaying molecular expression other than gene profiling; and (3) Real-time RT-PCR. The results yield a genetic analysis of gliomas and identify classes of genetic expression that link novel genes to the biology of gliomas.

Brain Neoplasms↗
PubMed2002

Distributions of arsenic and selenium in selected Chinese coal mines.

The contents of arsenic and selenium in 33 coals collected from the main coal mines in northeastern, northern and eastern China were determined by flow injection-hydride generation and non-dispersion atomic fluorescence spectrometry (HGAFS). The concentrations of As in the northeast region are relatively higher with the values > 100 microg g(-1); in the east they are lower with values < 100 microg g(-1). The contents of Se in these three areas are the opposite, most of them from the northeast mines are < 1 microg g(-1) and increase as the mine location advances south where the average contents are > 5 microg g(-1).

Arsenic↗
PubMed2002

Dependence of selective gene activation on the androgen receptor NH2- and COOH-terminal interaction.

The agonist-induced androgen receptor NH(2)- and COOH-terminal (N/C) interaction is mediated by the FXXLF and WXXLF NH(2)-terminal motifs. Here we demonstrate that agonist-dependent transactivation of prostate-specific antigen (PSA) and probasin enhancer/promoter regions requires the N/C interaction, whereas the sex-limited protein gene and mouse mammary tumor virus long terminal repeat do not. Transactivation of PSA and probasin response regions also depends on activation function 1 (AF1) in the NH(2)-terminal region but can be increased by binding an overexpressed p160 coactivator to activation function 2 (AF2) in the ligand binding domain. The dependence of the PSA and probasin enhancer/promoters on the N/C interaction for transactivation allowed us to demonstrate that in the presence of androgen, the WXXLF motif with the sequence (433)WHTLF(437) contributes as an inhibitor to AR transactivation. We further show that like the FXXLF and LXXLL motifs, the WXXLF motif interacts in the presence of androgen with AF2 in the ligand binding domain. Sequence comparisons among species indicate greater conservation of the FXXLF motif compared with the WXXLF motif, paralleling the functional significance of these binding motifs. The data provide evidence for promoter-specific differences in the requirement for the androgen receptor N/C interaction and in the contributions of AF1 and AF2 in androgen-induced gene regulation.

Amino Acid Motifs↗
PubMed2002

The FXXLF motif mediates androgen receptor-specific interactions with coregulators.

The androgen receptor (AR) activation function 2 region of the ligand binding domain binds the LXXLL motifs of p160 coactivators weakly, engaging instead in an androgen-dependent, interdomain interaction with an FXXLF motif in the AR NH(2) terminus. Here we show that FXXLF motifs are present in previously reported AR coactivators ARA70/RFG, ARA55/Hic-5, and ARA54, which account for their selection in yeast two-hybrid screens. Mammalian two-hybrid assays, ligand dissociation rate studies, and glutathione S-transferase adsorption assays indicate androgen-dependent selective interactions of these FXXLF motifs with the AR ligand binding domain. Mutagenesis of residues within activation function 2 indicates distinct but overlapping binding sites where specificity depends on sequences within and flanking the FXXLF motif. Mutagenesis of the FXXLF motifs eliminated interaction with the ligand binding domain but only modestly reduced AR coactivation in transcription assays. The studies indicate that the FXXLF binding motif is specific for the AR and mediates interactions both within the AR and with coregulatory proteins.

Amino Acid Motifs↗
PubMed2002

High-resolution EEG: on the cortical equivalent dipole layer imaging.

BACKGROUND: Brain electrical activity is a spatio-temporally distributed process. Cortical imaging techniques have been developed to reconstruct cortical activity from the scalp electroencephalographic or magnetoencephalographic measurements. Several cortical imaging approaches, such as the epicortical potentials and a dipole layer accounting for the cortical activity, have been used to represent brain electrical activity. METHODS: A closed cortical dipole layer source model is used to equivalently represent brain electrical activity. The relationship between the primary brain electrical sources and the cortical equivalent dipole layer is derived from the theory of electromagnetics. Computer simulation studies were conducted using a 3-concentric-sphere head model to validate the proposed theory. The cortical equivalent dipole layer imaging approach was tested in both computer simulation and human visual evoked potential (VEP) experiments. RESULTS: The strength of the cortical equivalent dipole layer is shown to be proportional to the electrical potential over the same surface generated by primary electrical sources, had the outer medium been replaced by air. The proposed theory was validated by computer simulation in a discrete system. Simulation and VEP experimental studies suggest the feasibility of applying the cortical equivalent dipole layer imaging approach for brain imaging. CONCLUSIONS: The cortical equivalent dipole layer model can equivalently represent the primary brain electrical sources throughout the entire brain surrounded by the dipole layer. The strength of the cortical equivalent dipole layer due to primary sources can be directly calculated according to the theory developed in the present study.

Brain Mapping↗
PubMed2002

Cortical potential imaging of episodic memory encoding.

Previous findings suggest that episodic memory encoding is subserved by different brain structures that interplay and transform experience into memories. The present study aims to identify topographic location of the underlying neural generators, and correlate their activities with the subsequent memory effect using electrophysiological neuroimaging of the event-related potentials (ERPs) recorded from 11 healthy subjects participating in word encoding tasks. Cortical potentials were imaged noninvasively from scalp ERPs. Different levels of brain activation were found in the left inferior prefrontal, left temporal and left parietal lobes with different latencies after onset of event. It is concluded that these regions work jointly across both spatial and temporal domains to promote verbal memory formation.

Adult↗