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Biomedical subjects

Z Guo

Publications and source records attributed to Z Guo.

At least 307 records · Page 17Linked to original sources
PubMed1997

Structural transitions of a GG-platinated DNA duplex induced by pH, temperature and box A of high-mobility-group protein 1.

[1H, 15N] and 1H NMR, and CD spectroscopy are used to show that the duplex d(A-T-A-C-A-T-Pt 7G-Pt7G-T-A-C-A-T-A).d(T-A-T-G-T-A-C-C-A-T-G-T-A-T), where Pt7G is platinated guanine, containing the cis-[Pt(NH3)2]2+ adduct, undergoes reversible temperature-induced (T0.5 310 K) and pH-induced (pKa approximately 4.8) transitions between kinked-duplex and distorted forms, with the latter forms predominating at high temperature and low pH. A related pH-induced structural change was observed for the unplatinated duplex (pKa 4.69, Hill coefficient n = 1.4) but was less cooperative than for the platinated duplex (n = 2). The pH-induced transition is attributed to protonation of cytosine residues and has wider implications, since many reported NMR studies of DNA are carried out near pH 5 to minimize NH-exchange rates. The [Pt(en)]2+ (where en is 1,2-ethanediamine) GG chelate of the same duplex is shown to exist in kinked and distorted forms, and the [1H,15N]-NMR shifts for the kinked form are indicative of the presence of highly stereospecific interactions with the Pt-NH protons. On binding of the duplex platinated with [Pt(NH3)2]2+ to high-mobility-group protein 1 (HMG1) box A, similar changes in shifts of the Pt-NH3 resonances to those induced by raising the temperature or lowering the pH were observed. The specific changes in 1H-NMR chemical shifts of HMG1 box A are consistent with binding of the platinated duplex (intermediate exchange rate on the 1H-NMR time-scale) to the concave face of the protein via helices I and II and the intervening loop.

Base Composition↗
PubMed1997

Thermodynamics of protein folding: a statistical mechanical study of a small all-beta protein.

The thermodynamic properties of a 46-mer beta-barrel protein model are investigated using Langevin dynamics and the histogram analysis method. By obtaining the density of states distribution and using the methods of statistical mechanics, we are able to identify the thermodynamic transitions for this model protein and characterize the nature of these transitions. Consistent with an earlier study of this model, we find that the transition from a random coil state to a manifold of collapsed but nonnative states is a continuous transition, and the transition from the manifold of collapsed states to the native state is first order-like. However, our calculations indicate that the folding transition is only weakly first order. Most importantly, we are able to characterize the free energy surface of the protein model, as well as the processes of compaction and native structure formation, from a statistical point of view. We also examined the thermodynamic transition state. By combining the earlier kinetic analysis for the same protein model, we provide a more complete description of this model protein and propose possible further modifications of the model to improve its stability and foldability.

Kinetics↗
PubMed1997

Time-frequency analysis of heart murmurs. Part II: Optimisation of time-frequency representations and performance evaluation.

The basic parameters of the spectrogram, the Choi-Williams, and the Bessel distributions are adjusted to provide the best time-frequency representations (TFRs) of the simulated murmur signals of mitral stenosis, mitral regurgitation, aortic stenosis, aortic regurgitation, and of two musical murmurs. The initial adjustment of the parameters of each TFR technique is performed by computing and minimising the relative averaged absolute error between the frequency contours at -3 dB and -10 dB of each TFR of the simulated murmurs and those of the theoretical distribution of the same signals. The results show that the spectrogram generally provides very good to excellent performance in representing the TFRs of stenotic and regurgitant murmurs. Improvements provided by the Choi-Williams and the Bessel distributions are minor but not systematic for the two signal-to-noise ratios tested (0 and 30 dB) and for the two frequency contours estimated. The Bessel and the Choi-Williams distributions provide the best performance for the musical murmurs. The study shows that although a single technique cannot be optimal for all six murmurs, the spectrogram using a Hamming window of 30 ms is an acceptable compromise to detect the six simulated heart murmurs.

Computer Simulation↗
PubMed1997

Time-frequency analysis of the first heart sound. Part 2: An appropriate time-frequency representation technique.

A simulated first heart sound (S1) signal is used to determine the best technique for analysing physiological S1 from the following five time-frequency representations (TFR): the spectrogram, time-varying autoregressive modelling, binomial reduced interference distribution, Bessel distribution and cone-kernel distribution (CKD). To provide information on the time and frequency resolutions of each TFR technique, the instantaneous frequency and the -3 dB bandwidth as functions of time were computed for each simulated component of the S1. The performance index for selecting the best technique was based on the relative error and the correlation coefficient of the instantaneous frequency function between the theoretical distribution and the computed TFR. This index served to select the best technique. The sensitivity of each technique to noise and to small variations of the signal parameters was also evaluated. The results of the comparative study show that, although important limitations were found for all five TFRs tested, the CKD appears to be the best technique for the time-frequency analysis of multicomponent signals such as the simulated S1.

Heart↗
PubMed1997

Blood pressure and dementia in the elderly: epidemiologic perspectives.

High blood pressure is associated with an increased risk of vascular dementia as a result of ischemic stroke and other cerebrovascular events or lesions. However, there is insufficient epidemiologic evidence indicating that blood pressure is involved in the etiology of Alzheimer's disease. Clinical studies suggest that episodes of hypotension may cause cerebral hypoperfusion and play a role in the development of dementia. Lowering of blood pressure in dementia, especially Alzheimer's disease, may be due to the dementia process itself or to the characteristics of the disease. Recent large clinical trials have shown that antihypertensive drugs may not significantly affect cognitive performance, but no data are available regarding their potential effects in decreasing the risk of dementia by lowering the incidence of cerebrovascular events. Some data suggest that the blood pressure-dementia relationship may be age-dependent.

Aged↗
PubMed1997

The nucleation-collapse mechanism in protein folding: evidence for the non-uniqueness of the folding nucleus.

BACKGROUND: Recent experimental and theoretical studies have shown that several small proteins reach the native state by a nucleation-collapse mechanism. Studies based on lattice models have been used to suggest that the critical nucleus is specific, leading to the notion that the transition state may be unique. On the other hand, results of studies using off-lattice models show that the critical nuclei should be viewed as fluctuating mobile structures, thus implying non-unique transition states. RESULTS: The microscopic underpinnings of the nucleation-collapse mechanism in protein folding are probed using minimal off-lattice models and Langevin dynamics. We consider a 46-mer continuum model which has a native beta-barrel-like structure. The fast-folding trajectories reach the native state by a nucleation-collapse process. An algorithm based on the self-organized neural nets is used to identify the critical nuclei for a large number of rapidly folding trajectories. This method, which reduces the determination of the critical nucleus to one of 'pattern recognition', unambiguously shows that the folding nucleus is not unique. The only common characteristics of the mobile critical nuclei are that they are small (containing on average 15-22 residues) and are largely composed of residues near the loop regions of the molecule. The structures of the transition states, corresponding to the critical nuclei, show the existence of spatially localized ordered regions that are largely made up of residues that are close to each other. These structures are stabilized by a few long-range contacts. The structures in the ensemble of transition states exhibit a rather diverse degree of similarity to the native conformation. CONCLUSIONS: The multiplicity of delocalized nucleation regions can explain the two-state folding by a nucleation-collapse mechanism for small single-domain proteins (such as chymotrypsin inhibitor 2) and their mutants. Because there are many distinct critical nuclei, we predict that the folding kinetics of fast-folding proteins will not be drastically changed even if some of the residues in a 'typical' nucleus are altered.

Algorithms↗
PubMed1997

Aryl acetylenes as mechanism-based inhibitors of cytochrome P450-dependent monooxygenase enzymes.

Aryl acetylenes have been investigated as inhibitors of cytochrome P450 (P450)-dependent alkoxyresorufin dealkylation dealkylation activities in liver microsomes prepared from rats exposed to beta-naphthoflavone, isosafrole, or phenobarbital. Many of the acetylenes investigated produce pseudo-first-order time-dependent and NADPH-dependent losses of the dealkylation activities characteristic of mechanism-based irreversible inactivation (suicide inhibition). Replacing the terminal hydrogen of aryl acetylenes with a methyl group to convert ethynes into propynes enhances the inhibition of P450 1A enzymes; in some instances, this modification converts a reversible inhibitor of P450s into a suicide inhibitor. In contrast, ethynes are more effective suicide inhibitors of P450 2B-dependent dealkylations than the corresponding propynes. Aryl acetylenes with an ethynyl group on the 2 position of naphthalene or on the 9 position of phenanthrene and arylalkyl acetylenes with alkyl chains containing 2, 3, or 4 methylene groups are selective inhibitors of P450 2B1/2B2 in liver microsomes from rats. Aryl acetylenes also act as suicide inhibitors of P450 1A2 in human liver microsomes, of purified P450 1A2 from rabbit or rat liver in reconstituted systems, and of purified recombinant human P450 1A2 and 1A1 in reconstituted systems. 4-(1-Propynyl)biphenyl (4PBi) inactivated P450 1A2-dependent ethoxyresourfin deethylation (EROD) activity in human liver microsomes in an NADPH-dependent process (k(inactivation), 0.23 min-1; KI, 2.3 microM). 4PBi also inactivated purified recombinant human P450 1A2 (k(inactivation), 0.24 min-1; KI, 4.3 microM). In agreement with previous reports [Yun, C.-H., Hammons, G. J., Jones, G., Martin, M. V., Hopkins, N. E., Alworth, W. L., and Guengerich, F. P. (1992) Biochemistry 31, 10556-10563], 2-ethynylnaphthalene (2EN) was not a suicide inhibitor of the P450 1A2 activity in human liver microsomes but did inactivate purified human P450 1A2. Neither 4PBi nor 2EN affected diagnostic activities of human microsomal P450 2E1, 2C9/10, 3A4, or 2C19. In the systems examined, the losses of P450-dependent activity produced by these aryl acetylenes were not accompanied by corresponding decreases in the measured P450 absorption spectra. Thus P450 inactivation by these aryl acetylenes does not involve labeling and destruction of the heme. Incubation of 4PBi with microsomal P450 1A1 or 1A2 from rat liver under conditions that lead to P450-dependent, enzyme inactivations generates a 2-biphenylylpropionic acid product. This suggests that the suicide inhibition of P450s by propynylaryl acetylenes proceeds via a methylaryl ketene formed by a 1,2-methyl rearrangement, analogous to the mechanism of suicide inhibition by ethynyl acetylenes that proceed via ketene intermediates formed by 1,2-hydrogen shifts [Ortiz de Montellano, P. R., and Kunze, K. L. (1981) Arch. Biochem. Biophys. 209, 710-712].

Acetylene↗
PubMed1997

Comparison of CYP3A activities in a subclone of Caco-2 cells (TC7) and human intestine.

PURPOSE: To compare the activity of the CYP3A enzyme expressed by TC7, a cell culture model of the intestinal epithelial cell, to the activity of human intestinal CYP3A4, using terfenadine as a substrate. METHODS: The metabolism of terfenadine was investigated in intact cells and microsomal preparations from TC7, human intestine, and liver. The effect of two CYP3A inhibitors, ketoconazole and troleandomycin (TAO), on the metabolism of terfenadine was also examined. RESULTS: Only hydroxy-terfenadine was detected in TC7 microsomal incubations. In contrast, azacyclonol and hydroxy-terfenadine were detected in human intestinal and hepatic microsomal incubations. The Km values for hydroxy-terfenadine formation in TC7 cells, intestine and liver microsomes were 1.91, 2.5, and 1.8, microM respectively. The corresponding Vmax values were 2.11, 61.0, and 370 pmol/min/mg protein. Km values for azacyclonol in intestinal and hepatic samples were 1.44 and 0.82 microM and the corresponding Vmax values were 14 and 60 pmol/min/mg protein. The formation of hydroxy-terfenadine was inhibited by ketoconazole and TAO in human intestine and TC7 cell microsomes. The Km and Vmax values for terfenadine metabolism in intact TC7 cells were similar to those from TC7 cell microsomes. CONCLUSIONS: Our results indicate that TC7 cells are a potentially useful alternative model for studies of CYP3A mediated drug metabolism. The CYP3A expressed by TC7 cells is not CYP3A4, but probably CYP3A5, making this cell line suitable for studies of colonic drug transport and metabolism.

Antibodies↗
PubMed1997

Enhanced discrimination of single nucleotide polymorphisms by artificial mismatch hybridization.

In order to increase the discrimination of single nucleotide polymorphisms in DNA hybridization, artificial mismatches are inserted into probe oligonucleotides using the base analog 3-nitropyrrole. Differences in thermal stability (delta Tm) between hybrids formed with normal and single-nucleotide-variant DNA targets are increased by as much as 200% over conventional hybridization, and are strongly dependent upon the spacing between mismatches. The increased specificity is demonstrated by hybridization analysis and allele-specific amplification within the HLA-DRB locus.

Alleles↗
PubMed1997

5-HT spinal antinociception involves mu opioid receptors: cross tolerance and antagonist studies.

The antinociceptive effects of intrathecal 5-HT, fentanyl, ICI197067 and U50488H were assessed by electrical current nociceptive threshold and tail flick latency measurements. Equieffective doses of these agonists were then given intrathecally with a range of doses of naloxone or the highly selective mu opioid antagonist, beta-funaltrexamine. Antagonist dose-response curves were plotted. Other rats were made tolerant to either fentanyl or 5-HT by intrathecal injections of these drugs seven times daily and the antinociceptive effects of intrathecal fentanyl and 5-HT were assessed in each group. All intrathecal drugs caused spinally mediated antinociception in both tests. The antinociceptive effects of intrathecal 5-HT assessed by the electrical test (ECT) but not by tail flick latency (TFL) were suppressed by both opioid antagonists at doses similar to those required to suppress all of the effects of intrathecal fentanyl. The ED50 values were 0.22 (fentanyl, ECT), 0.25 (fentanyl, TFL) and 0.18 (5-HT, ECT) mumol kg-1 for naloxone and for beta-funaltrexamine 2.2 fmol (5-HT, ECT), the same order as that required to produce similar suppression of the antinociceptive effects of fentanyl (46 amol: fentanyl, ECT; 4.6 fmol: fentanyl, TFL) and very different from the ED50 for beta-FNA suppression of the antinociceptive effects of the kappa opioid, U50488H (5.88 pmol). Cross tolerance in both directions was demonstrated between intrathecal fentanyl and 5-HT in the electrical test but not in the tail flick test. We conclude that intrathecal 5-HT caused spinally mediated antinociceptive effects revealed by electrical current and tail flick latency tests. The antinociceptive effects in the electrical test involved spinal cord mu opioid receptors.

Analgesics, Opioid↗
PubMed1997

Biovar diversity is reflected by variations of genes encoding urease of Ureaplasma urealyticum.

Five oligonucleotide primers derived from the gene encoding urease of Ureaplasma urealyticum were designed to evaluate the relationship between the urease gene and biovar diversity of this organism. Five combinations of these primers were tested by PCR and the result revealed that there were variations in urease genes among different serovars of U. urealyticum. This result, in agreement with other PCRs based on other functionally unrelated (rRNA and MB antigen) genes, may reflect the phylogenetic relationship among organisms taxonomically classified as U. urealyticum.

DNA Primers↗
PubMed1997

Clinical correlates of low blood pressure in very old people: the importance of cognitive impairment.

OBJECTIVE: To identify the medical conditions associated with low blood pressure in very old people. DESIGN: A population-based, cross-sectional study. SETTING: Two neighboring communities in Stockholm, Sweden. SUBJECTS: Participants were 319 male and 1070 female participants, with the mean age of 85.0 years (SD = 5.8). MEASUREMENTS: Blood pressure recording, pulse rate counting, and Mini-Mental State Examination (MMSE) were conducted by trained nurses. Information on illness condition and activities of daily living (ADL) status was self-reported or gathered from proxy respondents. The computerized inpatient register system was also used for collecting the data of illness condition. Systolic pressure less than 130 mm Hg and diastolic pressure less than 70 mm Hg were defined as low systolic and diastolic pressure, respectively. MMSE score less than 24 was considered to indicate cognitive impairment. MAIN RESULTS: In multiple logistic regression analyses, low systolic pressure was related to slower pulse rate (< or = 60 per minute), heart failure, ADL limitation, and cognitive impairment, and low diastolic pressure was related to increasing age, slower pulse rate, cardiac dysrhythmia, ADL limitation, and cognitive impairment. People with diabetes mellitus were less likely to be in the low systolic pressure group. 34.9% of the prevalence of low systolic pressure, and 17.9% of the prevalence of low diastolic pressure was associated with cognitive impairment. CONCLUSIONS: Low blood pressure in the very old may be associated with poor functional status, cardiac insufficiency and, more importantly, cognitive impairment. It would be expected that low blood pressure is associated with increased mortality in this age group.

Activities of Daily Living↗
PubMed1997

Regional lipolytic responses to isoproterenol in women.

We previously found that epinephrine, a mixed beta- and alpha-adrenoreceptor agonist, stimulates systemic and nonsplanchnic upper body free fatty acid (FFA) release but not lower body FFA release in healthy nonobese women. To evaluate the role of beta-adrenergic-mediated effects on this regional difference in lipolysis, we measured systemic, leg, and splanchnic FFA kinetics ([3H]palmitate) in seven healthy nonobese women before and during an intravenous isoproterenol infusion. Isoproterenol increased systemic palmitate flux (87 +/- 12 vs. 100 +/- 10 mumol/min, P < 0.05) but failed to affect leg [10.8 +/- 1.2 vs. 11.4 +/- 2.3 mumol/min, P = not significant (NS)] or splanchnic (10.8 +/- 3.2 vs. 10.0 +/- 1.8 mumol/min, P = NS) palmitate release. Upper body nonsplanchnic palmitate release increased from 56 +/- 14 to 71 +/- 10 mumol/min. Systemic O2 consumption increased (227 +/- 11 to 241 +/- 10 ml/min, P = 0.006) during isoproterenol infusion, as did leg (318 +/- 42 vs. 404 +/- 53 ml/min, P < 0.01) and splanchnic (827 +/- 104 vs. 970 +/- 108 ml/min, P < 0.05) plasma flow. These results suggest that lower body adipose tissue lipolysis in women is less sensitive or responsive than nonsplanchnic upper body adipose tissue to beta-adrenergic stimulation and that regional differences in alpha 2-adrenergic-receptor responses were not responsible for the similar regional differences we observed previously with epinephrine.

Adult↗
PubMed1997

Low blood pressure and five-year mortality in a Stockholm cohort of the very old: possible confounding by cognitive impairment and other factors.

OBJECTIVES: Low blood pressure has often been reported to be related to excess mortality in people over the age of 75 years. This study examined whether other predictors may account for the association. METHODS: A community-based cohort of 1810 people who were aged 75 years and older was followed for 5 years. RESULTS: The relative risk of death was 1.39 (95% confidence interval [CI] = 1.11, 1.73) for people with systolic pressure lower than 130 mm Hg and 1.21 (95% CI = 1.02, 1.43) for those with diastolic pressure lower than 75 mm Hg, compared with corresponding reference groups, when all other variables were simultaneously considered in Cox proportional hazards models. The observed association was present mainly in subjects with at least two of the three conditions (cardiovascular disease, limitation in activities of daily living, or cognitive impairment). The effect of low diastolic pressure on mortality was also significant in those with only cognitive impairment. CONCLUSIONS: Preexisting cardiovascular disease, limitation in activities of daily living, and, more important, cognitive impairment may be responsible for the association of low blood pressure with increased mortality in the very old in that they cause both reductions in blood pressure and excess deaths.

Activities of Daily Living↗
PubMed1997

Are cognitive function and blood pressure related?

In this article, we look at the literature concerning the relationship between blood pressure and cognitive function. If untreated, hypertension leads to stroke or cerebral infarction, and may therefore increase the risk of dementia or cognitive impairment. Patients with hypertension perform less well in some, but not all, cognitive tasks compared with normotensive individuals, even in the absence of overt stroke. The mechanisms underlying hypertension-related cognitive changes are complex and are not yet fully understood. Antihypertensive drug therapy may prevent cognitive decline, but no longitudinal studies have been performed to verify this in the general population. The relationship between blood pressure and cognition may be more complicated in the very old than in other age groups.

Aged↗