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Biomedical subjects

Ming Zheng

Publications and source records attributed to Ming Zheng.

At least 19 recordsLinked to original sources
PubMed2026

Ten millennia of purifying selection on HLA-B27 reveals an ancient epidemic-scale burden of spondyloarthritis in West Eurasia.

HLA-B27 exemplifies an evolutionary trade-off between protection against infection and susceptibility to inflammatory disease. To investigate its long-term population history, this study examined three HLA-B27-tagging variants-rs116488202, rs4349859, and rs116666910-in present-day populations from UK biobank and 1000 Genomes Project, and in 15,836 ancient West Eurasian individuals. The estimated frequency of HLA-B27 reached 49.0% approximately 8500 years before present, then declined progressively to 3.9% in the present-day reference population. Comparison with genome-wide association study (GWAS) data for ankylosing spondylitis (AS) showed that HLA-B27-linked alleles conferring increased disease risk had negative selection coefficients, indicating sustained selection against HLA-B27 over the past 10,000 years. The decline coincided with major Holocene changes in settlement and subsistence patterns, microbial exposure, and enteric infection, which may have increased the inflammatory costs of HLA-B27. Because previous paleopathological studies have largely been limited to identifying advanced skeletal manifestations of AS, this ancient genetic study may provide currently the most sensitive population-level record of an otherwise largely undetectable, epidemic-scale disease burden in antiquity. These findings support the hypothesis that HLA-B27-associated spondyloarthritis was sufficiently prevalent and severe to influence human evolution in prehistoric West Eurasia.

Humans↗
PubMed2006

Racemic single-walled carbon nanotubes exhibit circular dichroism when wrapped with DNA.

We have found that racemic mixtures of chiral single-walled nanotubes (SWNTs) wrapped with d(GT)20 DNA oligomer exhibit circular dichroism (CD). We attribute the CD signal to induced CD arising from the coupling of transition moments of the SWNTs and the DNA. Although the nanotube mixture appears to contain both enantiomers in equal amounts, DNA-SWNT transition moment interaction is more constructive for one SWNT enantiomer over the other, resulting in an overall CD signal.

Circular Dichroism↗
PubMed2006

Photoinduced charge transfer mediated by DNA-wrapped carbon nanotubes.

We report our observation of solution photochemical reactions catalyzed by carbon nanotubes. Addition of sub-millimolar Ag+ ions into a solution of DNA-wrapped carbon nanotubes (DNA-CNT) leads to a strong charge-transfer band in the UV region of the optical absorption spectrum. Light irradiation of the Ag+/DNA-CNT mixture results in reduction of Ag+ to Ag nanoparticles and concomitant oxidation of water.

DNA↗
PubMed2006

Subtype-specific alpha1- and beta-adrenoceptor signaling in the heart.

Recent studies of adrenoceptors have revealed subtype-specific signaling, promiscuous G-protein coupling, time-dependent switching of intracellular signaling pathways, intermolecular interactions within or between adrenoceptor subfamilies, and G-protein-independent signaling pathways. These findings have extended the classical linear paradigm of G-protein-coupled receptor signaling to a complex "signalome" in which an individual adrenoceptor initiates multiple signaling pathways in a temporally and spatially regulated manner. In particular, persistent stimulation of beta-adrenoceptor subtypes causes a time-dependent switch of signaling pathways and elicits different, even opposing, functional roles of these receptors in regulating cardiac structure and function. Recent progress in the understanding of subtype-specific functions and signaling mechanisms of cardiac adrenoceptor subtypes, particularly beta(1)-adrenoceptors, beta(2)-adrenoceptors, alpha(1A)-adrenoceptors and alpha(1B)-adrenoceptors, might have important pathogenic and therapeutic implications for heart disease.

Animals↗
PubMed2006

Controlled two-dimensional pattern of spontaneously aligned carbon nanotubes.

We report a simple solution process to form controlled patterns of aligned single-walled carbon nanotubes on solid substrates. The essential step of the process is to deposit a dilute solution of DNA-wrapped carbon nanotubes (DNA-CNTs) on a SiO(2) surface covered with a thin hydrophobic layer. This leads to deposition of fully aligned CNTs. The alignment pattern can be controlled by metal electrodes in the deposition region and can be quantitatively modeled by the behavior of a quasi-two-dimensional DNA-CNT nematic phase near the solution/SiO(2) interface. These results point to the possibility of rational design and economical fabrication of CNT alignment patterns on solid substrates.

Crystallization↗
PubMed2006

In vitro and in vivo metabolism of a gamma-secretase inhibitor BMS-299897 and generation of active metabolites in milligram quantities with a microbial bioreactor.

BMS-299897 is a gamma-secretase inhibitor that has the potential for treatment of Alzheimer's disease. The metabolism of [(14)C]BMS-299897 was investigated in human liver microsomes, in rat, dog, monkey and human hepatocytes and in bile duct cannulated rats. Seven metabolites (M1-M7) were identified from in vitro and in vivo studies. LC-MS/MS analysis showed that M1 and M2 were regioisomeric acylglucuronide conjugates of BMS-299897. Metabolites M3, M4 and M6 were identified as monohydroxylated metabolites of BMS-299897 and M5 was identified as the dehydrogenated product of monooxygenated BMS-299897. In vivo, 52% of the radioactive dose was excreted in bile within 0-6 h from bile duct cannulated rats following a single oral dose of 15 mg/kg of [(14)C]BMS-299897. Glucuronide conjugates, M1 and M2 accounted for 80% of the total radioactivity in rat bile. In addition to M1 and M2, M7 was observed in rat bile which was identified as a glucuronide conjugate of an oxidative metabolite M5. For structure elucidation and pharmacological activity testing of the metabolites, ten microbial cultures were screened for their ability to metabolize BMS-299897 to form these metabolites. Among them, the fungus Cunninghamella elegans produced two major oxidative metabolites M3 and M4 that had the same HPLC retention time and mass spectral properties as those found in in vitro incubations. NMR analysis indicated that M3 and M4 were stereoisomers, with the hydroxyl group on the benzylic position. However, M3 and M4 were unstable and converted to their corresponding lactones readily. Based on x-ray analysis of the synthetically prepared lactone of M3, the stereochemistry of benzylic hydroxyl group was assigned as the R configuration. Both the hydroxy metabolites (M3 and M4) and the lactone of M3 showed gamma-secretase inhibition with IC(50) values similar to that of the parent compound. This study demonstrates the usefulness of microbial systems as bioreactors to generate metabolites of BMS-299897 in large quantities for structure elucidation and activity testing. This study also demonstrates the biotransformation profile of BMS-299897 is qualitatively similar across the species including rat, dog, monkey and human which provides a basis to support rat, dog and monkey as preclinical models for toxicological testing.

Amyloid Precursor Protein Secretases↗
PubMed2006

[Studies on extraction process optimization of Panax notogingseng saponins].

OBJECTIVE: To optimize the conditions for the extraction of panax notogingseng saponins (PNS). METHODS: After selected extraction solvent and suitable particle, we employed orthogonal experimental design to examine the conditions for the extraction by determination of PNS. RESULTS: Significant effect was observed only in extraction times. CONCLUSION: The optimum condition for extraction of PNS was to extract panax notogingseng (Burk.) F. H. Chen with 10 times 70% ethanol for 1.5 hours for 3 times.

Drugs, Chinese Herbal↗
PubMed2006

[Quantitative study on occlusal balance of normal occlusion in intercuspal position].

OBJECTIVE: To assess occlusal balance of normal occlusion in intercuspal position with maximal bite force. METHODS: Maximal bite force was recorded in intercuspal position by use of T-Scan II system from 123 subjects with normal intact dentitions. Occlusal balance of normal occlusion was quantitatively analyzed from center of force, percentage of bite force, and occlusal contacts. RESULTS: The relative position of the center of bite force, the difference in bilateral force percentage, and unsymmetrical coefficient followed normal distributions. The 95% reference ranges for corresponding testing items were -6.60 to 6.68 mm, -15.50% to 12.10%, and 0.65 to 1.39. There was no statistic difference (P = 0.915) in occlusal contacts between left and right sides. The 98.4% of normal occlusion subjects had the center of bite force locating in posterior region of dentition when biting with maximal force in intercuspal position. CONCLUSIONS: Occlusal balance could be evaluated by T-Scan II system. Occlusion of normal subjects biting with maximal force was stable and bilaterally balanced in intercuspal position.

Adolescent↗
PubMed2005

High-resolution length sorting and purification of DNA-wrapped carbon nanotubes by size-exclusion chromatography.

We report a size-exclusion chromatography (SEC) process to purify DNA-wrapped carbon nanotubes (DNA-CNT) and to sort them into fractions of uniform length. A type of silica-based column resin was identified that shows minimum adsorption of DNA-CNT. Three such columns in series with pore sizes of 2000, 1000, and 300 A were found to separate DNA-CNT into fractions of very narrow length distribution, as measured directly by atomic force microscopy. The average length decreases monotonically from > 500 nm in the early fractions to < 100 nm in the late fractions, with length variation < or = 10% in each of the measured fractions. Using UV-vis-NIR spectroscopy, we showed that SEC is very effective in removing graphitic impurities that contribute to the spectral baseline and a broad absorption peak at approximately 270 nm. This result highlights the importance of CNT purification in the study of optical properties of CNT.

Chromatography, Gel↗
PubMed2005

A high-resolution map of active promoters in the human genome.

In eukaryotic cells, transcription of every protein-coding gene begins with the assembly of an RNA polymerase II preinitiation complex (PIC) on the promoter. The promoters, in conjunction with enhancers, silencers and insulators, define the combinatorial codes that specify gene expression patterns. Our ability to analyse the control logic encoded in the human genome is currently limited by a lack of accurate information regarding the promoters for most genes. Here we describe a genome-wide map of active promoters in human fibroblast cells, determined by experimentally locating the sites of PIC binding throughout the human genome. This map defines 10,567 active promoters corresponding to 6,763 known genes and at least 1,196 un-annotated transcriptional units. Features of the map suggest extensive use of multiple promoters by the human genes and widespread clustering of active promoters in the genome. In addition, examination of the genome-wide expression profile reveals four general classes of promoters that define the transcriptome of the cell. These results provide a global view of the functional relationships among transcriptional machinery, chromatin structure and gene expression in human cells.

Chromatin↗
PubMed2005

Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid.

PURPOSE: Three large, randomized trials of patients with bone metastases recently demonstrated that zoledronic acid reduces the risk of skeletal-related events. These trials provide an opportunity for investigating the correlation between bone metabolism and clinical outcome during bisphosphonate therapy. PATIENTS AND METHODS: Urinary measurements of N-telopeptide (Ntx) and serum bone alkaline phosphatase (BAP) were obtained in 1,824 bisphosphonate-treated patients-1,462 with zoledronic acid (breast, 490; prostate, 411; myeloma, 210; non-small-cell lung, 183; other, 168) and 362 with pamidronate (breast, 254; myeloma, 108). This exploratory cohort analysis grouped patients by baseline and most recent levels of Ntx as low (< 50 nmol/mmol creatinine), moderate (50 to 99 nmol/mmol creatinine), or high (> or = 100 nmol/mmol creatinine), and BAP as low (< 146 U/L) or high (> or = 146 U/L). The relative risks for negative clinical outcomes were estimated for each group using multiple-event and Cox regression models with time-varying covariates. RESULTS: Patients with high and moderate Ntx levels had 2-fold increases in their risk of skeletal complications and disease progression compared with patients with low Ntx levels (P < .001 for all). High Ntx levels in each solid tumor category were associated with a 4- to 6-fold increased risk of death on study, and moderate Ntx levels a 2- to 4-fold increased risk compared with low Ntx levels (P < .001 for all). Bone alkaline phosphatase also showed some correlation with risk of negative clinical outcomes. CONCLUSION: The bone resorption marker Ntx provides valuable prognostic information in patients with bone metastases receiving bisphosphonates.

Adult↗
PubMed2005

Emerging concepts and therapeutic implications of beta-adrenergic receptor subtype signaling.

The stimulation of beta-adrenergic receptor (betaAR) plays a pivotal role in regulating myocardial function and morphology in the normal and failing heart. Three genetically and pharmacologically distinct betaAR subtypes, beta1AR, beta2AR, and beta3AR, are identified in various types of cells. While both beta1AR and beta2AR, the predominant betaAR subtypes expressed in the heart of many mammalian species including human, are coupled to the Gs-adenylyl cyclase-cAMP-PKA pathway, beta2AR dually activates pertussis toxin-sensitive Gi proteins. During acute stimulation, beta2AR-Gi coupling partially inhibits the Gs-mediated positive contractile and relaxant effects via a Gi-Gbetagamma-phosphoinositide 3-kinase (PI3K)-dependent mechanism in adult rodent cardiomyocytes. More importantly, persistent beta1AR stimulation evokes a multitude of cardiac toxic effects, including myocyte apoptosis and hypertrophy, via a calmodulin-dependent protein kinase II (CaMKII)-, rather than cAMP-PKA-, dependent mechanism in rodent heart in vivo and cultured cardiomyocytes. In contrast, persistent beta2AR activation protects myocardium by a cell survival pathway involving Gi, PI3K, and Akt. In this review, we attempt to highlight the distinct functionalities and signaling mechanisms of these betaAR subtypes and discuss how these subtype-specific properties of betaARs might affect the pathogenesis of congestive heart failure (CHF) and the therapeutic effectiveness of certain beta-blockers in the treatment of congestive heart failure.

Animals↗
PubMed2005

Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer.

PURPOSE: To describe the natural history of nonmetastatic prostate cancer and rising prostate-specific antigen (PSA) despite androgen deprivation therapy. PATIENTS AND METHODS: The 201 patients in this report were the placebo control group from an aborted randomized controlled trial to evaluate the effects of zoledronic acid on time to first bone metastasis in men with prostate cancer, no bone metastases, and rising PSA despite androgen deprivation therapy. Relationships between baseline covariates and clinical outcomes were assessed by Cox proportional hazard analyses. Covariates in the model were baseline PSA, Gleason sum, history of bilateral orchiectomies, regional lymph node metastases at diagnosis, prior prostatectomy, time from androgen deprivation therapy to random assignment, time from diagnosis to random assignment, and PSA velocity. RESULTS: At 2 years, 33% of patients had developed bone metastases. Median bone metastasis-free survival was 30 months. Median time to first bone metastases and overall survival were not reached. Baseline PSA level greater than 10 ng/mL (relative risk, 3.18; 95% CI, 1.74 to 5.80; P < .001) and PSA velocity (4.34 for each 0.01 increase in PSA velocity; 95% CI, 2.30 to 8.21; P < .001) independently predicted shorter time to first bone metastasis. Baseline PSA and PSA velocity also independently predicted overall survival and metastasis-free survival. Other covariates did not consistently predict clinical outcomes. CONCLUSION: Men with nonmetastatic prostate cancer and rising PSA despite androgen deprivation therapy have a relatively indolent natural history. Baseline PSA and PSA velocity independently predict time to first bone metastasis and survival.

Aged↗
PubMed2005

Theory of structure-based carbon nanotube separations by ion-exchange chromatography of DNA/CNT hybrids.

Single-stranded DNA wrap helically around individual single-walled carbon nanotubes to form DNA/CNT hybrids, which are both stable and dispersible in aqueous solution. Subjected to ion-exchange chromatography, a hybrid elutes at an ionic strength that depends on the electronic character and diameter of the core nanotube, thus providing a mechanism for separating nanotubes by chirality. We present a theoretical model for this separation process that explains all the salient features observed experimentally to date, and provides accurate predictions for critical elution salt concentration. The competition between adsorption on the stationary phase and counterion condensation in the mobile phase is characterized by estimating the difference in free energy between the two states of the hybrid. Parametric study of the DNA wrapping geometry, SWNT dielectric properties, hybrid length, and diameter indicate that the elution is most sensitive to the hybrid's effective charge density, primarily governed by the DNA helical pitch. The model correctly predicts hybrids with metallic nanotubes are weaker binding than hybrids with semiconducting nanotubes and larger diameter nanotubes are eluted at later times.

Adsorption↗
PubMed2005

Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors.

BACKGROUND: Whether bone markers have prognostic value in patients with bone metastases is unknown. We investigated this question in patients with bone metastases secondary to prostate cancer and to non-small-cell lung cancer (NSCLC) and other solid tumors assigned to the placebo arms of two phase III trials of zoledronic acid. METHODS: Levels of the urinary bone resorption marker N-telopeptide and the serum bone formation marker bone-specific alkaline phosphatase were assessed every 3 months for patients with prostate cancer (n = 203) or NSCLC or other solid tumors (n = 238) and were categorized as low or high. Patients were monitored for skeletal-related events, bone disease progression, and death. The relative risks (RRs) and 95% confidence intervals (CIs) for these outcomes were estimated for patients with high versus low levels of each marker using intensity-based multiple event and Cox regression models. All statistical tests were two-sided. RESULTS: In each disease group and overall, high levels of each marker at the beginning of the study were statistically significantly associated with an increased risk of negative outcomes. Use of recent marker assessments as time-dependent covariates gave even greater prognostic significance. High N-telopeptide levels were a stronger prognostic indicator of negative outcomes than bone-specific alkaline phosphatase levels. In recent assessments, patients with high N-telopeptide levels had an increased relative risk of skeletal-related events (prostate cancer, RR = 3.25, 95% CI = 2.26 to 4.68, P<.001; NSCLC and other solid tumors, RR = 1.79, 95% CI = 1.15 to 2.79, P = .010), disease progression (prostate cancer, RR = 2.02, 95% CI = 1.48 to 2.74, P<.001; NSCLC and other solid tumors, RR = 1.91, 95% CI = 1.16 to 3.15, P = .011), and death (prostate cancer, RR = 4.59, 95% CI = 2.82 to 7.46, P<.001; NSCLC and other solid tumors, RR = 2.67, 95% CI = 1.85 to 3.85, P<.001) compared with patients with low N-telopeptide levels. CONCLUSIONS: Baseline and recent bone marker levels were predictive of negative clinical outcomes in patients with bone metastases secondary to prostate cancer and to NSCLC and other solid tumors. N-telopeptide levels were more consistent prognostic indicators than bone-specific alkaline phosphatase for all tumor types, reflecting the key role of osteolysis in the development of skeletal complications.

Adult↗
PubMed2004

Solution redox chemistry of carbon nanotubes.

UV/vis/NIR absorbance spectra were used to monitor electron transfer between small-molecule redox reagents and carbon nanotubes (CNTs). The oxidation of (6, 5)-enriched nanotubes in water with K(2)Ir(Cl)(6) reveals a valence electron density of 0.2-0.4 e(-)/100 carbon atoms and a reduction potential of approximately 800 mV versus NHE. The reduction potential of CNTs is found to increase with increasing band gap and to decrease with the introduction of an anionic dispersant. In light of this newly revealed redox chemistry of CNTs, we propose that the previously observed bleaching of the CNT absorbance spectrum at low pH is most likely a consequence of the oxidation of the nanotubes by oxygen. These results demonstrate facile oxidation and reduction of CNTs, provide a way to quantify the population of valence electrons, and point to possible applications of CNT in the catalysis of redox reactions.

Journal Article↗