Biomedical subjects

D Liao

Publications and source records attributed to D Liao.

At least 19 recordsLinked to original sources

PubMed2001

Cardiovascular risk factors and cognitive decline in middle-aged adults.

OBJECTIVE: To perform serial neuropsychological assessments to detect vascular risk factors for cognitive decline in the Atherosclerosis Risk in Communities cohort, a large biracial, multisite, longitudinal investigation of initially middle-aged individuals. METHODS: The authors administered cognitive assessments to 10,963 individuals (8,729 white individuals and 2,234 black individuals) on two occasions separated by 6 years. Subjects ranged in age at the first assessment from 47 to 70 years. The cognitive assessments included the delayed word recall (DWR) test, a 10-word delayed free recall task in which the learning phase included sentence generation with the study words, the digit symbol subtest (DSS) of the Wechsler Adult Intelligence Scale-Revised and the first-letter word fluency (WF) test using letters F, A, and S. RESULTS: In multivariate analyses (controlling for demographic factors), the presence of diabetes at baseline was associated with greater decline in scores on both the DSS and WF (p < 0.05), and the presence of hypertension at baseline was associated with greater decline on the DSS alone (p < 0.05). The association of diabetes with cognitive decline persisted when analysis was restricted to the 47- to 57-year-old subgroup. Smoking status, carotid intima-media wall thickness, and hyperlipidemia at baseline were not associated with change in cognitive test scores. CONCLUSIONS: Hypertension and diabetes mellitus were positively associated with cognitive decline over 6 years in this late middle-aged population. Interventions aimed at hypertension or diabetes that begin before age 60 might lessen the burden of cognitive impairment in later life.

Adult↗

PubMed2001

A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis.

Previous work has implicated PPAR gamma in the regulation of CD36 expression and macrophage uptake of oxidized LDL (oxLDL). We provide evidence here that in addition to lipid uptake, PPAR gamma regulates a pathway of cholesterol efflux. PPAR gamma induces ABCA1 expression and cholesterol removal from macrophages through a transcriptional cascade mediated by the nuclear receptor LXR alpha. Ligand activation of PPAR gamma leads to primary induction of LXR alpha and to coupled induction of ABCA1. Transplantation of PPAR gamma null bone marrow into LDLR -/- mice results in a significant increase in atherosclerosis, consistent with the hypothesis that regulation of LXR alpha and ABCA1 expression is protective in vivo. Thus, we propose that PPAR gamma coordinates a complex physiologic response to oxLDL that involves particle uptake, processing, and cholesterol removal through ABCA1.

ATP Binding Cassette Transporter 1↗

PubMed2001

PPAR-gamma dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation.

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is highly expressed in lipid-accumulating macrophages of the coronary artery. In light of this, the wide-spread clinical use of thiazolidinediones (TZDs) in the treatment of type II diabetes raises concerns about the role of PPAR-gamma in macrophage function and disease progression. To define the role of PPAR-gamma in macrophage biology, we used homologous recombination to create embryonic stem cells that were homozygous for a null mutation in the PPAR-gamma gene. We demonstrate here that PPAR-gamma is neither essential for nor substantially affects the development of the macrophage lineage both in vitro and in vivo. In contrast, we show it is an important regulator of the scavenger receptor CD36, which has been genetically linked to lipid accumulation in macrophages. Both 15-deoxy-Delta12,14prostaglandin J2 and thiazolidinediones have anti-inflammatory effects that are independent of PPAR-gamma. We show that PPAR-gamma is required for positive effects of its ligands in modulating macrophage lipid metabolism, but that inhibitory effects on cytokine production and inflammation may be receptor independent.

3T3 Cells↗

PubMed2001

Abnormal glucose tolerance and increased risk for cardiovascular disease in Japanese-Americans with normal fasting glucose.

OBJECTIVE: To compare the American Diabetes Association (ADA) fasting glucose and the World Health Organization (WHO) oral glucose tolerance test (OGTT) criteria for diagnosing diabetes and detecting people at increased risk for cardiovascular disease (CVD). RESEARCH DESIGN AND METHODS: Study subjects were 596 Japanese-Americans. Fasting insulin, lipids, and C-peptide levels; systolic and diastolic blood pressures (BPs); BMI (kg/m2); and total and intra-abdominal body fat distribution by computed tomography (CT) were measured. Study subjects were categorized by ADA criteria as having normal fasting glucose (NFG), impaired fasting glucose (IFG), and diabetic fasting glucose and by WHO criteria for a 75-g OGTT as having normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and diabetic glucose tolerance (DGT). RESULTS: Of 503 patients with NFG, 176 had IGT and 20 had DGT These patients had worse CVD risk factors than those with NGT . The mean values for NGT, IGT, and DGT, respectively, and analysis of covariance P values, adjusted for age and sex, are as follows; intra-abdominal fat area by CT 69.7, 95.0, and 101.1 cm2 (P < 0.0001); total CT fat area 437.7, 523.3, and 489.8 cm2 (P < 0.0001); fasting triglycerides 1.40, 1.77, and 1.74 mmol/l (P = 0.002); fasting HDL cholesterol 1.56, 1.50, and 1.49 mmol/l (P = 0.02); C-peptide 0.80, 0.90, 0.95 nmol/l (P = 0.002); systolic BP 124.9, 132.4, and 136.9 mmHg (P = 0.0035); diastolic BP 74.8, 77.7, and 78.2 mmHg (P = 0.01). CONCLUSIONS: NFG patients who had IGT or DGT had more intra-abdominal fat and total adiposity; higher insulin, C-peptide, and triglyceride levels; lower HDL cholesterol levels; and higher BPs than those with NGT. Classification by fasting glucose misses many Japanese-Americans with abnormal glucose tolerance and less favorable cardiovascular risk profiles.

Adult↗

PubMed2000

Association of educational achievement with pulsatile arterial diameter change of the common carotid artery: the Atherosclerosis Risk in Communities (ARIC) Study, 1987-1992.

Education is strongly inversely associated with common carotid artery intima-media thickness in the Atherosclerosis Risk in Communities (ARIC) Study. The authors extended the ARIC study of preclinical atherosclerosis by evaluating the cross-sectional association of education with common carotid artery elasticity. This study included 10,091 Black and White men and women aged 45-64 years who were free of clinical coronary heart disease and stroke/transient ischemic attack. Arterial elasticity was assessed by pulsatile arterial diameter change (PADC), derived from phase-locked echo-tracking. The smaller the PADC, the stiffer the artery. Education was categorized into grade school, high school without graduation, high school with graduation, vocational school, some college, and graduate/professional school. PADC was directly associated with educational attainment. The mean PADCs, adjusted for age, height, diastolic diameter, systolic blood pressure, pulse pressure (linear and squared), ethnicity, gender, and smoking status, in successively higher education strata were 402 (standard error (SE) 5), 403 (SE 4), 407 (SE 3), 413 (SE 4), 416 (SE 2), and 417 (SE 4) microm (p = 0.007). To the authors' knowledge, this is the first time such an association has been reported. If arterial dilation impairment precedes arterial wall thickening in the atherosclerotic process, as recent studies on endothelial dysfunction suggest, these results indicate that low socioeconomic status may be associated with early arterial pathophysiologic changes-an effect that appears to be mediated by established cardiovascular disease risk factors.

Anthropometry↗

PubMed2000

Low heart rate variability in a 2-minute rhythm strip predicts risk of coronary heart disease and mortality from several causes: the ARIC Study. Atherosclerosis Risk In Communities.

BACKGROUND: Low heart rate variability (HRV) is associated with a higher risk of death in patients with heart disease and in elderly subjects and with a higher incidence of coronary heart disease (CHD) in the general population. METHODS AND RESULTS: We studied the predictive value of HRV for CHD and death from several causes in a population study of 14 672 men and women without CHD, aged 45 to 65, by using the case-cohort design. At baseline, in 1987 to 1989, 2-minute rhythm strips were recorded. Time-domain measures of HRV were determined in a random sample of 900 subjects, for all subjects with incident CHD (395 subjects), and for all deaths (443 subjects) that occurred through 1993. Relative rates of incident CHD and cause-specific death in tertiles of HRV were computed with Poisson regression for the case-cohort design. Subjects with low HRV had an adverse cardiovascular risk profile and an elevated risk of incident CHD and death. The increased risk of death could not be attributed to a specific cause and could not be explained by other risk factors. CONCLUSIONS: Low HRV was associated with increased risk of CHD and death from several causes. It is hypothesized that low HRV is a marker of less favorable health.

Aged↗

PubMed2000

Serum albumin level as a predictor of incident coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) study.

Various studies have reported an inverse association between serum albumin level and incident coronary heart disease (CHD), though biologic mechanisms have not been established. The authors examined the association between serum albumin level and CHD in the Atherosclerosis Risk in Communities cohort, comprising 14,506 White and African-American middle-aged men and women. The mean albumin level in this population was 3.9 g/dl (standard deviation 0.3). During 5.2 years of follow-up, 470 incident CHD events occurred. The hazard ratio for incident CHD associated with a 1-standard deviation decrease in serum albumin level was 1.26 (95% confidence interval (CI): 1.15, 1.38) after adjustment for age, gender, and ethnicity and 1.18 (95% CI: 1.07, 1.30) after additional adjustment for covariates related to CHD. Hazard ratios were similar across gender and ethnic groups. However, there was statistically significant effect modification by smoking status, with hazard ratios of 1.01 (95% CI: 0.84, 1.22) among never smokers, 1.09 (95% CI: 0.92, 1.30) among former smokers, and 1.35 (95% CI: 1.17, 1.54) among current smokers. Further adjustment for factors related to renal disease, nutrition, platelet aggregation, inflammation, use of angiotensin-converting enzyme inhibitors, and hemostasis factors attenuated the albumin-CHD relation only slightly. In this study, serum albumin was inversely associated with incident CHD at the baseline examination in current smokers but not in never or former smokers. Albumin level may be a marker of susceptibility to the inflammatory response that results from smoking.

Biomarkers↗

PubMed2000

Gene conversion drives within genic sequences: concerted evolution of ribosomal RNA genes in bacteria and archaea.

Multiple copies of a given ribosomal RNA gene family undergo concerted evolution such that sequences of all gene copies are virtually identical within a species although they diverge normally between species. In eukaryotes, gene conversion and unequal crossing over are the proposed mechanisms for concerted evolution of tandemly repeated sequences, whereas dispersed genes are homogenized by gene conversion. However, the homogenization mechanisms for multiple-copy, normally dispersed, prokaryotic rRNA genes are not well understood. Here we compared the sequences of multiple paralogous rRNA genes within a genome in 12 prokaryotic organisms that have multiple copies of the rRNA genes. Within a genome, putative sequence conversion tracts were found throughout the entire length of each individual rRNA genes and their immediate flanks. Individual conversion events convert only a short sequence tract, and the conversion partners can be any paralogous genes within the genome. Interestingly, the genic sequences undergo much slower divergence than their flanking sequences. Moreover, genomic context and operon organization do not affect rRNA gene homogenization. Thus, gene conversion underlies concerted evolution of bacterial rRNA genes, which normally occurs within genic sequences, and homogenization of flanking regions may result from co-conversion with the genic sequence.

Archaea↗

PubMed2000

GRASP-1: a neuronal RasGEF associated with the AMPA receptor/GRIP complex.

The PDZ domain-containing proteins, such as PSD-95 and GRIP, have been suggested to be involved in the targeting of glutamate receptors, a process that plays a critical role in the efficiency of synaptic transmission and plasticity. To address the molecular mechanisms underlying AMPA receptor synaptic localization, we have identified several GRIP-associated proteins (GRASPs) that bind to distinct PDZ domains within GRIP. GRASP-1 is a neuronal rasGEF associated with GRIP and AMPA receptors in vivo. Overexpression of GRASP-1 in cultured neurons specifically reduced the synaptic targeting of AMPA receptors. In addition, the subcellular distribution of both AMPA receptors and GRASP-1 was rapidly regulated by the activation of NMDA receptors. These results suggest that GRASP-1 may regulate neuronal ras signaling and contribute to the regulation of AMPA receptor distribution by NMDA receptor activity.

Amino Acid Sequence↗

PubMed2000

Activation of p53 or loss of the Cockayne syndrome group B repair protein causes metaphase fragility of human U1, U2, and 5S genes.

Infection by adenovirus 12, transfection with the Ad12 E1B 55 kDa gene, or activation of p53 cause metaphase fragility of four loci (RNU1, PSU1, RNU2, and RN5S) each containing tandemly repeated genes for an abundant small RNA (U1, U2, and 5S RNA). We now show that loss of the Cockayne syndrome group B protein (CSB) or overexpression of the p53 carboxy-terminal domain induces fragility of the same loci; moreover, p53 interacts with CSB in vivo and in vitro. We propose that CSB functions as an elongation factor for transcription of structured RNAs, including some mRNAs. Activation of p53 would inhibit CSB, stalling transcription complexes and locally blocking chromatin condensation. Impaired transcription elongation may also explain the diverse clinical features of Cockayne syndrome.

Acetylation↗

PubMed2000

Treatment preferences among depressed primary care patients.

OBJECTIVE: To understand patient factors that may affect the probability of receiving appropriate depression treatment, we examined treatment preferences and their predictors among depressed primary care patients. DESIGN: Patient questionnaires and interviews. SETTING: Forty-six primary care clinics in 7 geographic regions of the United States. PARTICIPANTS: One thousand one hundred eighty-seven English- and Spanish-speaking primary care patients with current depressive symptoms. MEASUREMENTS AND MAIN RESULTS: Depressive symptoms and diagnoses were determined by the Composite International Diagnostic Interview (CIDI) and the Center for Epidemiological Studies Depression Scale (CES-D). Treatment preferences and characteristics were assessed using a self-administered questionnaire and a telephone interview. Nine hundred eight-one (83%) patients desired treatment for depression. Those who preferred treatment were wealthier (odds ratio [OR], 3.7; 95% confidence interval [95% CI], 1.8 to 7.9; P =.001) and had greater knowledge about antidepressant medication ( OR, 2.6; 95% CI, 1.6 to 4.4; P </=.001) than those who did not want treatment. A majority ( 67%, n = 660) of those preferring treatment preferred counseling, with African Americans (OR, 2.2; 95% CI, 1.0 to 4.8, P =. 04 compared to whites) and those with greater knowledge about counseling (OR, 2.1; 95% CI, 1.6 to 2.7, P </=.001) more likely to choose counseling. Three hundred twelve ( 47%) of the 660 desiring counseling preferred group over individual counseling. Depression severity was only a predictor of preference among those already in treatment. CONCLUSIONS: Despite low rates of treatment for depression, most depressed primary care patients desire treatment, especially counseling. Preferences for depression treatment vary by ethnicity, gender, income, and knowledge about treatments.

Adolescent↗

PubMed2000

Adenovirus E1B 55-kilodalton oncoprotein inhibits p53 acetylation by PCAF.

The adenovirus E1B 55-kDa protein binds to cellular tumor suppressor p53 and inactivates its transcriptional transactivation function. p53 transactivation activity is dependent upon its ability to bind to specific DNA sequences near the promoters of its target genes. It was shown recently that p53 is acetylated by transcriptional coactivators p300, CREB bidning protein (CBP), and PCAF and that acetylation of p53 by these proteins enhances p53 sequence-specific DNA binding. Here we show that the E1B 55-kDa protein specifically inhibits p53 acetylation by PCAF in vivo and in vitro, while acetylation of histones and PCAF autoacetylation is not affected. Furthermore, the DNA-binding activity of p53 is diminished in cells expressing the E1B 55-kDa protein. PCAF binds to the E1B 55-kDa protein and to a region near the C terminus of p53 encompassing Lys-320, the specific PCAF acetylation site. We further show that the E1B 55-kDa protein interferes with the physical interaction between PCAF and p53, suggesting that the E1B 55-kDa protein inhibits PCAF acetylase function on p53 by preventing enzyme-substrate interaction. These results underscore the importance of p53 acetylation for its function and suggest that inhibition of p53 acetylation by viral oncoproteins prevent its activation, thereby contributing to viral transformation.

Acetylation↗

PubMed2000

Parental history of stroke predicts subclinical but not clinical stroke: the Atherosclerosis Risk in Communities Study.

BACKGROUND AND PURPOSE: An individual with a positive family history of a disease may be at increased risk for the disease. We sought to examine whether parental history of stroke is associated with subclinical or clinical stroke in the Atherosclerosis Risk in Communities (ARIC) Study, and whether any observed association is independent of established stroke risk factors. METHODS: Parental history of stroke was determined by home interview at the baseline examination. Cerebral MRI was performed on individuals from 2 ARIC field centers. Subclinical cerebral infarct cases (n=202) were defined by the presence of cerebral infarcts >3 mm. The comparison group for the subclinical cases included all individuals participating in the MRI examination who were not identified as a subclinical case (n=1533). Incidence of clinical ischemic stroke was determined by following the ARIC cohort for potential cerebrovascular events. Two hundred sixty-one validated ischemic strokes were identified; 13 775 individuals from the ARIC cohort did not experience an ischemic event. RESULTS: Parental history of stroke was significantly associated with subclinical stroke after adjusting for age, gender, and race (OR 1.67, 95% CI1.23 to 2.26) and after further adjustment for multiple stroke risk factors (OR1. 64, 95% CI1.20 to 2.24). Parental history of stroke was not a significant predictor of clinical stroke in either adjustment model. CONCLUSIONS: The observed increased risk of subclinical stroke among individuals with a parental history of stroke is consistent with the expression of genetic susceptibility, a shared environment, or both in the etiology of stroke. This effect did not appear to be mediated by established stroke risk factors. Parental history of stroke does not confer an increased risk of clinical stroke in this sample of middle-aged Americans.

Age Factors↗

PubMed2000

Arterial stiffness and the development of hypertension.

Evidence is accumulating in support of the plausible notion that lower arterial elasticity is associated with an increased risk of cardiovascular disease manifestations. Conventional indices of arterial stiffness are compared to a newer method (blood pressure-adjusted pulsatile arterial diameter change) in terms of blood pressure dependence. Impaired elasticity of larger arteries is an antecedent factor in the natural history of blood pressure elevation at the population level. Strong evidence supports the notion that lower arterial elasticity in the medium-sized arteries is associated with the development of hypertension.

Arteries↗

PubMed2000

[Preparation and identification of hammerhead ribozyme in vitro against rat caspase-3 mRNA fragment].

OBJECTIVE: To study the transcript effect and cleavage activity in vitro of rat Caspase-3 specific ribozyme (Rz107 and Rz544). METHODS: Rat caspase-3 gene fragment was cloned into T-vector under the control of T7 promoter. (32)P-labeled caspase-3 transcript was target-RNA. Rz107 and Rz544 genes against caspase-3 mRNA were cloned and transcribed in vitro. Cleavage reaction was detected. RESULTS: It was found that Rz107 was active at 37 degrees C and more so at higher temperature within allowing temperature range. The optimal temperature was 50 degrees C. For Rz107, Km and kcat was 14.13 nmol/L and 2.31 min(-1), respectively. However, the Rz544 had no cleavage activity at all. CONCLUSION: Rz107 prepared in vitro possesses the perfect specific catalytic cleavage activity. It is hopeful that Rz107 would be developed to be a new nucleic acid drug that could effectively inhibit the inflammation of hepatitis through cleaving the key gene, caspase-3, in apoptosis in vivo.

Animals↗

PubMed1999

Striking bimodal methylation of the repeat unit of the tandem array encoding human U2 snRNA (the RNU2 locus).

The genes encoding human U2 small nuclear RNA are arrayed in tandem (the RNU2 locus) and have undergone concerted evolution for >35 Myr. Tandem organization of repetitive sequences may facilitate recombination that underlies concerted evolution, but could risk instability. Since DNA methylation plays a crucial role in genome stability, we investigated the methylation status of the RNU2 locus to understand the forces maintaining array stability and homogeneity. We found that a region of approximately 1.5 kb spanning the U2 promoter, U2 gene sequence, and CT microsatellite is completely unmethylated, whereas the rest of the repeat is heavily methylated. Since the U2 transcription enhancer DSE and CT microsatellite mark the boundaries between methylated and unmethylated domains, they might function as cis-acting elements for establishing and maintaining proper methylation at the RNU2 locus. Interestingly, the RNU2 locus in human fibrosarcoma line HT1080 is hypomethylated, and de novo methylation did not occur in an artificial U2 tandem array introduced by stable transfection. The observed bimodal methylation pattern may be important for both efficient transcription of U2 gene and maintenance of nearly perfect tandem arrays in somatic cells.

Cell Line↗

PubMed1999

Characterization of the glutamate receptor-interacting proteins GRIP1 and GRIP2.

The molecular mechanisms underlying the targeting and localization of glutamate receptors at postsynaptic sites is poorly understood. Recently, we have identified a PDZ domain-containing protein, glutamate receptor-interacting protein 1 (GRIP1), which specifically binds to the C termini of AMPA receptor subunits and may be involved in the synaptic targeting of these receptors. Here, we report the cloning of GRIP2, a homolog of GRIP1, and the characterization of the GRIP1 and GRIP2 proteins in the rat CNS. GRIP1 and GRIP2 are approximately 130 kDa proteins that are highly enriched in brain. GRIP1 and GRIP2 are widely expressed in brain, with the highest levels found in the cerebral cortex, hippocampus, and olfactory bulb. Biochemical studies show that GRIP1 and GRIP2 are enriched in synaptic plasma membrane and postsynaptic density fractions. GRIP1 is expressed early in embryonic development before the expression of AMPA receptors and peaks in expression at postnatal day 8-10. In contrast, GRIP2 is expressed relatively late in development and parallels the expression of AMPA receptors. Immunohistochemistry using the GRIP1 antibodies demonstrated that GRIP1 is expressed in neurons in a somatodendritic staining pattern. At the ultrastructural level, DAB and immunogold electromicroscopy studies showed that GRIP1 was enriched in dendritic spines near the postsynaptic density and was expressed in dendritic shafts and in peri-Golgi regions in the neuronal soma. GRIP1 appeared to be clustered at both glutamatergic and GABAergic synapses. These results suggest that GRIP1 and GRIP2 are AMPA receptor binding proteins potentially involved in the targeting of AMPA receptors to synapses. GRIP1 also may play functional roles at both excitatory and inhibitory synapses, as well as in early neuronal development.

Amino Acid Sequence↗

PubMed1999

A novel neuron-enriched homolog of the erythrocyte membrane cytoskeletal protein 4.1.

We report the molecular cloning and characterization of 4.1N, a novel neuronal homolog of the erythrocyte membrane cytoskeletal protein 4.1 (4.1R). The 879 amino acid protein shares 70, 36, and 46% identity with 4.1R in the defined membrane-binding, spectrin-actin-binding, and C-terminal domains, respectively. 4.1N is expressed in almost all central and peripheral neurons of the body and is detected in embryonic neurons at the earliest stage of postmitotic differentiation. Like 4.1R, 4.1N has multiple splice forms as evidenced by PCR and Western analysis. Whereas the predominant 4.1N isoform identified in brain is approximately 135 kDa, a smaller 100 kDa isoform is enriched in peripheral tissues. Immunohistochemical studies using a polyclonal 4.1N antibody revealed several patterns of neuronal staining, with localizations in the neuronal cell body, dendrites, and axons. In certain neuronal locations, including the granule cell layers of the cerebellum and dentate gyrus, a distinct punctate-staining pattern was observed consistent with a synaptic localization. In primary hippocampal cultures, mouse 4.1N is enriched at the discrete sites of synaptic contact, colocalizing with the postsynaptic density protein of 95 kDa (a postsynaptic marker) and glutamate receptor type 1 (an excitatory postsynaptic marker). By analogy with the roles of 4.1R in red blood cells, 4.1N may function to confer stability and plasticity to the neuronal membrane via interactions with multiple binding partners, including the spectrin-actin-based cytoskeleton, integral membrane channels and receptors, and membrane-associated guanylate kinases.

Amino Acid Sequence↗