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S Ye

Publications and source records attributed to S Ye.

At least 19 recordsLinked to original sources
PubMed2006

Effect of renal injury-induced neurogenic hypertension on NO synthase, caveolin-1, AKt, calmodulin and soluble guanylate cyclase expressions in the kidney.

Single injection of a small quantity of phenol into the cortex of one kidney in rats results in development of persistent hypertension (HTN) which is thought to be mediated by activation of renal afferent and efferent sympathetic pathways and sodium retention. Nitric oxide (NO) plays a major role in regulation of renal vascular resistance, tubular Na(+) reabsorption, pressure natriuresis, and thereby systemic arterial pressure. The present study was performed to test the hypothesis that chronic renal injury-induced HTN may be associated with dysregulation of NO system in the kidney. Accordingly, urinary NO metabolite (NO(x)) and cGMP excretions as well as renal cortical tissue (right kidney) expressions of NO synthase (NOS) isoforms [endothelial, neuronal, and inducible NOS, respectively (eNOS, nNOS, and iNOS)], NOS-regulatory factors (Caveolin-1, phospho-AKt, and calmodulin), and second-messenger system (soluble guanylate cyclase [sGC] and phosphodiesterase-5 [PDE-5]) were determined in male Sprague-Dawley rats 4 wk after injection of phenol (50 mul of 10% phenol) or saline into the lower pole of left kidney. The phenol-injected group exhibited a significant elevation of arterial pressure, marked reductions of urinary NO(x) and cGMP excretions, downregulations of renal tissue nNOS, eNOS, Phospho-eNOS, iNOS, and alpha chain of sGC. However, renal tissue AKt, phospho-AKT, Calmodulin, and PDE-5 proteins were unchanged in the phenol-injected animals. In conclusion, renal injury in this model results in significant downregulations of NOS isoforms and sGC and consequent reductions of NO production and cGMP generation by the kidney, events that may contribute to maintenance of HTN in this model.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2006

Duplications of proximal 16q flanked by heterochromatin are not euchromatic variants and show no evidence of heterochromatic position effect.

Extra euchromatic material was found within the major heterochromatic block of chromosome 16 (16qh) in one de novo case and seven members of two families. In contrast to the euchromatic variants of chromosome 9 (9qh), which are derived from pericentromeric euchromatin, molecular cytogenetics confirmed that these duplications were of 16q11.2-->q12.2 in the de novo case, of 16q11.2-->q13 in three members of family 1 and 16q11.2-->q12.1 in four members of family 2. The duplication had arisen as a post-zygotic mitotic event in the mother of family 1 and been transmitted paternally in family 2. An insertional mechanism of origin is proposed for the duplications in case 1 and family 1. Expression at the 16q13 matrix metalloproteinase-2 (MMP2)locus in families 1 and 2 was proportional to genomic copy number and not therefore consistent with position effect silencing due to the flanking blocks of heterochromatin. We conclude that proximal 16q duplications within 16qh are not novel euchromatic variants but associated with a variable phenotype including developmental delay, speech delay, learning difficulties and behavioural problems. The behavioural problems in families ascertained through affected children are much less severe than those encountered in previous patients ascertained as adults.

Adolescent↗
PubMed2005

Association of the lymphotoxin-alpha gene Thr26Asn polymorphism with severity of coronary atherosclerosis.

A recent large-scale, genome-wide association study of single nucleotide polymorphisms showed a strong association between susceptibility to myocardial infarction and the Thr26Asn polymorphism in the lymphotoxin-alpha (LTA) gene. In the present study, we investigated whether the LTA Thr26Asn polymorphism was associated with the extent of coronary atherosclerosis in a large cohort (n=1082) of well-documented coronary artery disease patients. Thr26Asn genotypes showed a significant different distribution in male patients, when stratified according to the number of diseased coronary arteries, with an odds ratio of 1.98 (95% CI 1.22-3.22) for multiple-vessel disease in patients of the Asn/Asn genotype, compared with patients of the Thr/Thr or Thr/Asn genotype (P=0.006). Thus, further to the recent finding that LTA gene variation is associated with susceptibility to coronary heart disease, the present study provides evidence of an association between LTA genotype and the extent of coronary atherosclerosis.

Asparagine↗
PubMed2005

VEGF polymorphisms and severity of atherosclerosis.

INTRODUCTION: Vascular endothelial growth factor (VEGF) is a potent angiogenic factor, and neovascularisation has been shown to be important in atherosclerotic plaque development. There is some disagreement as to whether VEGF acts as a pro-atherosclerotic or anti-atherosclerotic factor. In the present study we have sought to clarify this by determining genotypes and haplotypes for three reportedly functional VEGF SNPs in a large series of well documented coronary atherosclerosis patients. METHODS: VEGF -2578, -1154, and -634 single nucleotide polymorphisms were genotyped in 984 subjects from the Southampton Atherosclerosis Study, using the 5' nuclease assay for allelic discrimination (TaqMan). RESULTS: VEGF -2578 genotypes showed a significantly different distribution in patients without myocardial infarction when stratified according to number of diseased arteries. VEGF -2578 was also associated with mean number of stenotic segments in the same patient group. The AA genotype was a risk factor and CC was protective. These associations were significant before and after adjustment for classic risk factors, and were reflected in associations between VEGF haplotypes and the number of diseased arteries and stenotic segments. As VEGF -2578 CC has been provisionally shown to be associated with higher VEGF expression than the AA genotype, these results are consistent with a protective effect for VEGF in atherosclerosis development. Some changes in VEGF -1154 genotype frequencies were also detected, but no significant associations were detected for any one particular genotype. CONCLUSIONS: This study provides preliminary evidence that VEGF polymorphism is associated with development of atherosclerosis, possibly via regulation of VEGF expression, supporting a protective effect for VEGF in atherosclerosis. These results require replication in an independent study group, combined with study of additional candidate polymorphisms in the VEGF gene.

Coronary Artery Disease↗
PubMed2005

Angiotensin II type I receptor gene polymorphism: anthropometric and metabolic syndrome traits.

BACKGROUND: The renin angiotensin system is important in the regulation of vascular tone and fluid and electrolyte balance. The angiotensin converting enzyme gene (ACE) genotype has been shown to affect exercise response and glucose load response dependent on birth weight. Angiotensin II type I receptor (AGTR1) A1166C has previously been associated with the development of hypertension and coronary disease, but its metabolic effects have not been investigated. METHOD: AGTR1 A1166C was genotyped by allele specific PCR in 378 individuals from Hertfordshire, UK, who had been characterised for metabolic syndrome traits. RESULTS: Genotype counts were: AA, 183; AC, 170; CC, 25, consistent with Hardy-Weinberg equilibrium. The CC genotype was associated with significantly lower body mass index (by 1.7 units) in men (p = 0.03), and the same magnitude effect in women with significant lower weight in both genders (p = 0.01), also lower waist circumference and waist-hip ratio (p = 0.01) in men, with a trend for lower waist circumference in women also. Additionally, the CC genotype and/or C allele was associated with lower fasting glucose and insulin, and 30 and 120 min glucose in men (respectively, p = 0.08, 0.04, 0.01, 0.06). Lower means of systolic blood pressure, pulse pressure, cholesterol, and fasting triglyceride were also observed for the CC genotype in both genders though these were not statistically significant. CONCLUSIONS: The AGTR1 1166 CC genotype appears to predispose to favourable anthropometric and metabolic traits, relative to cardiovascular risk.

Aged↗
PubMed2004

Target-, limb-, and context-dependent neural activity in the cingulate and supplementary motor areas of the monkey.

Very little is known about the role of the cingulate motor area (CMA) in visually guided reaching compared to other cortical motor areas. To investigate the hierarchical role of the caudal CMA (CMAc) during reaching we recorded the activity of neurons in CMAc in comparison to the supplementary motor area proper (SMA) while a monkey performed an instructed delay task that required it to position a cursor over visual targets on a computer screen using two-dimensional (2D) joystick movements. The direction of the monkey's arm movement was dissociated from the direction of the visual target by periodically reversing the relationship between the direction of movement of the joystick and that of the cursor. Neurons that responded maximally with a particular limb movement direction regardless of target location were classified as limb-dependent, whereas neurons that responded maximally to a particular target direction regardless of the direction of limb movement were classified as target-dependent. Neurons whose activity was directional in one of the two visuomotor mapping conditions and non-directional or inactive in the other were categorized as context-dependent. Limb-dependent activity was observed more frequently than target-dependent activity in both CMAc and SMA proper during both the delay period (preparatory activity; CMAc, 17%; SMA, 31%) and during movement execution (CMAc, 49%, SMA, 48%). A modest percentage of neurons with preparatory activity were target-dependent in both CMAc (11%) and SMA proper (8%) and a similar percentage of neurons in both areas demonstrated target-dependent, movement activity (CMAc, 8%; SMA, 10%). The surprising finding was that a very large percentage of neurons in both areas displayed context-dependent activity either during the preparatory (CMAc, 72%; SMA, 61%) or movement (CMAc, 43%, SMA 42%) epochs of the task. These results show that neural activity in both CMAc and SMA can directly represent movement direction in either limb-centered or target-centered coordinates. The presence of target-dependent activity in CMAc, as well as SMA, suggests that both are involved in the transformation of visual target information into appropriate motor commands. Target-dependent activity has been found in the putamen, SMA, CMAc, dorsal and ventral premotor cortex, as well as primary motor cortex. This indicates that the visuomotor transformations required for visually guided reaching are carried out by a distributed network of interconnected motor areas. The large proportion of neurons with context-dependent activity suggests, however, that while both CMAc and SMA may play a role in the visuomotor transformation of target information into movement parameters, their activity is not solely coding parameters of movement, since their involvement in this process is highly condition-dependent.

Action Potentials↗
PubMed2004

Influence of the glia limitans on pial arteriolar relaxation in the rat.

We examined whether damage to the glia limitans (GL), via exposure to the gliotoxin l-alpha-aminoadipic acid (l-alphaAAA), alters hypercapnia-induced pial arteriolar dilation in vivo. Anesthetized female rats were prepared with closed cranial windows. Pial arteriolar diameters were measured using intravital microscopy. l-alphaAAA (2 mM) was injected into the space under the cranial windows 24 h before the study, and injury to the GL was confirmed by light microscopy. l-alphaAAA was associated with a reduction in pial arteriolar CO(2) reactivity to 40-50% of the level seen in vehicle-treated controls, with no further reduction in the CO(2) response after nitric oxide (NO) synthase (NOS) inhibition via N(omega)-nitro-l-arginine (l-NNA). Subsequent blockade of prostanoid synthesis, via indomethacin (Indo), reduced CO(2) reactivity to 10-15% of normal. In vehicle-treated controls, l-NNA, followed by Indo, reduced the response to approximately 50% and then to 15-20% of the normocapnic value, respectively. On the other hand, l-alphaAAA had no effect on vascular responses to the endothelium-dependent vasodilator acetylcholine or the NO donor SNAP and did not alter cortical somatosensory evoked responses. This indicates an absence of any direct l-alphaAAA actions on pial arterioles or influence on neuronal transmission. Furthermore, l-alphaAAA did not alter the vasodilation elicited by topical application of an acidic artificial cerebrospinal fluid solution, suggesting that the GL influences the pial arteriolar relaxation elicited by hypercapnic, but not local extracellular (EC), acidosis. That differences exist in the mechanisms mediating hypercapnia- versus EC acidosis-induced pial arteriolar dilations was further exemplified by the finding that topical application of a neuronal NOS (nNOS)-selective blocker (ARR-17477) reduced the response to hypercapnia (by approximately 65%) but not the response to EC acidosis. Disruption of GL gap junctional communication, using an antisense oligodeoxynucleotide (ODN) connexin43 knockdown approach, was accompanied by a 33% lower CO(2) reactivity versus missense ODN-treated controls. These results suggest that the GL contribution to the hypercapnic vascular response appears to involve the NO-dependent component rather than the prostanoid-dependent component and may involve gap junctional communication. We speculate that the GL may act to facilitate the spread, to pial vessels, of hypercapnia-induced vasodilating signals arising in the comparatively few scattered nNOS neurons that lie well beneath the GL.

2-Aminoadipic Acid↗
PubMed2003

Protein interaction for an interferon-inducible systemic lupus associated gene, IFIT1.

OBJECTIVE: To identify disease-related genes and immune-regulatory pathways in the pathogenesis of systemic lupus erythematosus (SLE) by using gene expression profiling and protein-protein interaction analysis. METHODS: Peripheral white blood cell gene expression profiles of 10 SLE patients were determined by oligonucleotide microarray analysis. Clustering of the gene expression profile was compared with the clinical immune phenotype. SLE-induced genes that were over- or under-expressed were determined and independently validated using a real-time polymerase chain reaction (PCR) method. To study their potential function and the possible pathways involved, a candidate gene was cloned and a GST (glutathione S-transferase) fusion protein was expressed in Escherichia coli. The fusion protein was further purified using the glutathione Sepharose 4B system, and was treated as bait to capture prey from SLE peripheral white blood cell lysate. MALDI-TOF (matrix-assisted laser desorption/ionization-time-of-flight) mass spectrometry was then performed to determine the prey protein. RESULTS: Similarity was found between the gene expression profile and the immune phenotype clusters of the SLE patients. More than 20 disease-associated genes were identified, some of which have not been related to SLE previously. Of these genes, a cluster of interferon-induced genes were highly correlated. IFIT1 (interferon-induced with tetratricopeptide repeats 1) was one of these genes, and overexpression of its mRNA was confirmed independently by real-time PCR in a larger population (40 SLE patients and 29 normal controls). An IFIT1 protein- protein interaction study showed that IFIT1 may interact with Rho/Rac guanine nucleotide exchange factor. CONCLUSION: The gene expression profile seems to be the molecular basis of the diverse immune phenotype of SLE. On the basis of the SLE-related genes found in this study, we suggest that the interferon-related immune pathway is important in the pathogenesis of SLE. IFIT1 is the first gene described as a candidate gene for SLE, and may function by activating Rho proteins through interaction with Rho/Rac guanine nucleotide exchange factor. IFIT1 and the interferon-related pathway may provide potential targets for novel interventions in the treatment of SLE.

Adaptor Proteins, Signal Transducing↗
PubMed2003

The antennal system and cockroach evasive behavior. I. Roles for visual and mechanosensory cues in the response.

Cockroaches escape from predators by turning and then running. This behavior can be elicited when stimuli deflect one of the rostrally located and highly mobile antennae. We analyzed the behavior of cockroaches, under free-ranging conditions with videography or tethered in a motion tracking system, to determine (1) how antennal positional dynamics influence escape turning, and (2) if visual cues have any influence on antennal mediated escape. The spatial orientation of the long antennal flagellum at the time of tactile stimulation affected the direction of resultant escape turns. However, the sign of flagellar displacement caused by touch stimuli, whether it was deflected medially or laterally for example, did not affect the directionality of turns. Responsiveness to touch stimuli, and escape turn performance, were not altered by blocking vision. However, because cockroaches first orient an antenna toward stimuli entering the peripheral visual field, turn direction can be indirectly influenced by visual input. Finally, when vision was blocked, the run phase of escape responses displayed reduced average velocities and distances traveled. Our results suggest that tactile and visual influences are integrated with previously known wind-sensory mechanisms to achieve multisensory control of the full escape response.

Animals↗
PubMed2003

Promoter polymorphism influences the effect of dexamethasone on transcriptional activation of the LTC4 synthase gene.

The molecular mechanisms of corticosteroid action in asthma are gradually being elucidated. The LTC4S gene encodes for LTC(4) synthase, the terminal enzyme in the generation of cysteinyl-leukotrienes (cys-LTs), which are key mediators in the pathogenesis of asthma. We have identified a novel promoter polymorphism in LTC4S at position -1072 (G/A) and a -444 (A/C) polymorphism has previously been reported. We hypothesised that the LTC4S gene promoter may be a potential site of regulation by corticosteroids and that genetic polymorphism may determine their effects at this locus. Using in vitro transfection of promoter-reporter constructs, dexamethasone was shown to increase transcription of LTC4S by more than 50% for the -1072G/-444A, A-C and G-C haplotype constructs (P&<0.02), but to have no effect on the A-A haplotype (P=0.27). These data identify an interesting phenomenon that requires validation in a human study examining ex vivo production of LTC(4) in cells from genotyped asthmatic and nonasthmatic subjects. The 9% of the Caucasian asthmatic population with the A-A haplotype may have genetically predetermined lower cys-LT levels in the presence of corticosteroids compared to other patients. These findings have potential implications in the evaluation of combined corticosteroid and antileukotriene therapy in asthma.

Adult↗
PubMed2003

Analysis of gene expression profiles in human systemic lupus erythematosus using oligonucleotide microarray.

Epidemiologic studies suggest a strong genetic component for susceptibility to systemic lupus erythematosus (SLE). To investigate the genetic mechanism of pathogenesis of SLE, we studied the difference in gene expression of peripheral blood cells between 10 SLE patients and 18 healthy controls using oligonucleotide microarray. When gene expression for patients was compared to the mean of normal controls, among the 3002 target genes, 61 genes were identified with greater than a two-fold change difference in expression level. Of these genes, 24 were upregulated and 37 downregulated in at least half of the patients. By the Welch's ANOVA/Welch's t-test, all these 61 genes were significantly different (P<0.05) between SLE patients and normal controls. Among these genes with differential expression, IFN-omega and Ly6E (TSA-1/Sca-2) may play an important role in the mechanism of SLE pathogenesis. TSA-1 antigens may represent an important alternative pathway for T-cell activation that may be involved in IFN-mediated immunomodulation. Hierarchical clustering showed that patient samples were clearly separated from controls based on their gene expression profile. These results demonstrate that high-density oligonucleotide microarray has the potential to explore the mechanism of pathogenesis of systemic lupus erythematosus.

Adolescent↗
PubMed2003

A study of mitochondrial DNA mutations in peripheral lymphocytes in an aging cohort.

Somatic mutation in the mitochondrial genome occurs much more rapidly than in the nuclear genome and is a feature, possibly contributory, of the aging of cells and tissues. Identifying mitochondrial sequence changes in blood DNA of elderly subjects may provide a maker for the epigenetic changes of mitochondrial DNA known to occur in tissues with lower cellular turnover, and would also have implications for immunosenescence. No large-scale epidemiological studies have been reported previously. In this study we have established long-PCR banks of the mitochondrial genome from peripheral lymphocytes for an elderly cohort of 716 individuals with a range of measured aging phenotypes, and we have established assays for three widely reported mutations: the 4977 bp and 8048 bp deletions and point mutation A3243G. No individuals were identified with detectable heteroplasmy for these changes. Implications for tissue and population prevalence are discussed. The mitochondrial long-PCR DNA banks established will be useful for a wide range of studies of somatic mutation and of germline haplotypes in relation to aging.

Aged↗
PubMed2003

Promoter polymorphism in the 5-lipoxygenase (ALOX5) and 5-lipoxygenase-activating protein (ALOX5AP) genes and asthma susceptibility in a Caucasian population.

BACKGROUND: 5-Lipoxygenase (5-LO) and 5-lipoxygenase-activating protein (FLAP) are essential for cysteinyl-leukotriene (cys-LT) production, critical mediators in asthma. OBJECTIVE: We sought to identify novel promoter polymorphisms within the FLAP (ALOX5AP) gene promoter and test the role of these and the previously identified 5-LO (ALOX5) Sp1 promoter polymorphism in asthma susceptibility. METHODS: To assess genetic association with asthma phenotypes, we genotyped 341 Caucasian families (containing two asthmatic siblings) and non-asthmatic control subjects (n=184). Genetic association was determined by case-control and transmission disequilibrium test (TDT) analyses. To determine the functional role of polymorphisms on basal transcription, we generated ALOX5AP-promoter-luciferase constructs and transiently transfected human HeLa cells. RESULTS: A novel G/A substitution at -336 bp and a poly(A) repeat (n=19 or 23) at position -169 to -146 bp were identified in the ALOX5AP promoter. Genotyping found the -336 A and poly(A19) alleles at frequencies of q=0.06 and 0.12, respectively. No ALOX5AP allele was associated with asthma or asthma-related phenotypes in case-control or TDT analyses. ALOX5AP-promoter-luciferase analyses did not support a functional role of the -336 or poly(A) polymorphism in determining basal transcription. The ALOX5 Sp1 polymorphism was predominantly homozygous wild-type 5/5 (frequency q=0.70) and heterozygous 4/5 (q=0.23) genotypes and no allele was associated with asthma or asthma-related phenotypes. CONCLUSION: Taken together, these data do not support a significant role for these polymorphisms in genetic susceptibility to asthma in the Caucasian population.

5-Lipoxygenase-Activating Proteins↗
PubMed2003

Epistatic interaction between variations in the angiotensin I converting enzyme and angiotensin II type 1 receptor genes in relation to extent of coronary atherosclerosis.

OBJECTIVE: To test the hypothesis that gene-gene interaction of the renin-angiotensin system is associated with an effect on the extent of coronary atherosclerosis. SETTING AND RESULTS: A cohort of 1162 patients with coronary artery disease were genotyped for genetic polymorphisms in the renin-angiotensin system. Patients carrying the D allele of the angiotensin I converting enzyme (ACE) gene had greater coronary extent scores (defined as the number of coronary segments with 5% to 75% stenosis) than those not carrying this allele (p = 0.006 in non-parametric analysis and p = 0.019 in parametric analysis). This association remained significant after adjusting for age, body mass index, hypertension, and diabetes, which were also significantly associated with coronary extent scores. There was a significant interaction (p = 0.033) between genotypes of ACE and angiotensin II type 1 receptor (AGTR1). The association between the ACE gene D allele and increased coronary extent scores was significant (p = 0.008 in non-parametric and p = 0.027 in parametric analysis) in those carrying the +1166 C allele of the AGTR1 gene, but was absent in those not carrying the AGTR1 gene +1166 C allele. CONCLUSION: These findings suggest that variation in the ACE and AGTR1 genes and their interaction may not only contribute to susceptibility of coronary artery disease as previously found but also modify the disease process, thus contributing to interindividual differences in severity of the disease.

Cohort Studies↗