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Xiaodong Wu

Publications and source records attributed to Xiaodong Wu.

At least 19 recordsLinked to original sources

Multiomic Analyses Reveal the Molecular Mechanisms of Arid Adaptation in a Desert Rodent Species.

Organisms living in desert habitats face multiple simultaneous pressures, such as high temperatures and arid, and the population dynamics and community diversity of small rodents are strongly affected by climate extremes. However, the potential mechanisms by which desert rodents adapt to arid remain largely unexplored. Here, we assembled a 3.18 Gb genome, including 25,812 protein-encoding genes, for Orientallactaga sibirica, which is widely distributed across both arid and semihumid environments in Eurasia. Orientallactaga sibirica has longer ears and hind limbs to enhance heat dissipation, which may be related to the positively selected genes, such as Fgf10, Fgf11, Hoxc4, Hoxd1, and Bmp4. The renal transcriptome revealed increased fat and carbohydrate metabolism for metabolic water production in O. sibirica residing in arid habitats. Pathways such as material metabolism, oxidative stress response, osmoregulation, and water and salt reabsorption were enriched in candidate genes, such as Avp, Ang, and Ace, under positive selection in O. sibirica. Moreover, amino acid replacement was observed in the protein sequences of seven candidate genes, including Aldh7a1, Lnpep, Wnk4, C1qc, and Awat2, and these specific amino acid replacements of genes such as Umod and Scnn1a were related to unique osmoregulation, osmotic protection, and water retention compensation mechanisms. Water deprivation under laboratory conditions induced the upregulation of Umod and Aldh7a1 expression, further supporting the results observed in the wild population. These findings demonstrate that the positively selected genes related to limb development and specific amino acid replacements in the genes Umod and Scnn1a for unique osmoregulation in the renal vascular system may contribute to arid adaptation in the desert rodent species O. sibirica. This study provides novel insights into the adaptive evolution of desert small mammals and can serve as a reference for future research on renal damage-related diseases, such as human kidney stones and salt-sensitive hypertension.

Animals↗

Identification and optimization of anthranilic sulfonamides as novel, selective cholecystokinin-2 receptor antagonists.

A high throughput screening approach to the identification of selective cholecystokinin-2 receptor (CCK-2R) ligands resulted in the discovery of a novel series of antagonists, represented by 1-[2-[(2,1,3-benzothiadiazol-4-ylsulfonyl)amino]-5-chlorobenzoyl]-piperidine (1; CCK-2R, pK(I) = 6.4). Preliminary exploration of the structure-activity relationships around the anthranilic ring and the amide and sulfonamide moieties led to a nearly 50-fold improvement of receptor affinity and showed a greater than 1000-fold selectivity over the related cholecystokinin-1 receptor. Pharmacokinetic evaluation led to the identification of 4-[4-iodo-2-[(5-quinoxalinylsulfonyl)amino]benzoyl]-morpholine, 26d, a compound that demonstrates promising pharmacokinetic properties in the rat and dog with respect to plasma clearance and oral bioavailability and is a potent inhibitor in vivo of pentagastrin-stimulated acid secretion in the rat when dosed orally.

Animals↗

Novel function of IFN-gamma: negative regulation of dendritic cell migration and T cell priming.

IFN-gamma is considered to be a Th1 cytokine with immunomodulatory effects on a variety of immune cells. In this study, we determined whether dendritic cell (DC) function was aberrant in IFN-gamma knockout (GKO) mice. The results demonstrated that IFN-gamma deficiency did not interfere with bone marrow-derived DC development and maturation in vitro. However, functional analysis showed that bone marrow-derived DC from GKO mice had altered cytokine secretion, allostimulatory and Ag presentation capacity, chemokine receptor expression, and in vitro chemotaxis. LPS induced the recruitment of DC from different organs into the spleen; epicutaneously sensitized DC with hapten (FITC) accumulated in the draining lymph nodes and CD11c(+) DC levels in the draining lymph nodes from autoantigen (interphotoreceptor retinoid-binding protein) immunized mice were enhanced in GKO mice as compared with wild-type mice. After treatment of GKO mice with i.p. IFN-gamma injection restored IFN-gamma levels in vivo, DC migration decreased in response to LPS or FITC. IFN-gamma altered the adaptive immune responses in vivo, since T cell priming and IL-2 production were increased in interphotoreceptor retinoid-binding protein-immunized GKO mice. Furthermore, in IFN-gamma-treated GKO mice, experimental autoimmune uveitis score enhancement and T cell activation were eliminated. Taken together, IFN-gamma appears to play a negative regulatory role on in vivo DC function, resulting in suppression of Ag-specific T cell priming.

Animals↗

Noninvasive thermometer for HIFU and its scaling.

Acoustic-inversion method for a noninvasive temperature measurement in tissue is presented. A set of B-scan operating in M-mode was used as a signal-equipment. The echoes reflected from an assigned surface in tissue were acquired before and after heating, and the corresponding spectra were then obtained by FFT. In order to conduct the acoustic-inversion method, a theoretical formula given by authors in another paper was invoked. The optimization algorithm was implemented to fit the spectra to the measured data and calculate changes in temperature.

Animals↗

Epithelial sodium channel allele T594M is not associated with blood pressure or blood pressure response to amiloride.

The T594M allele of the epithelial sodium channel beta-subunit has been proposed as a gain-of-function mutation leading to salt-sensitive hypertension in blacks that is particularly responsive to the specific sodium channel antagonist amiloride. However, the positive associations derive from small convenience samples, and the amiloride challenge study lacked a control group. We determined whether the T594M allele was associated with hypertension and blood pressure (BP) response to amiloride in 2 well-characterized random population samples including 3137 Dallas County subjects and 1666 Jamaican blacks. In multivariate models, the T594M allele was not predictive of systolic BP (adjusted odds ratio for hypertension 1.1; 95% confidence interval, 0.7 to 1.8). Amiloride treatment did not lower the BP of 6 T594M heterozygotes significantly more than in 22 control subjects (P=0.8). We conclude that the T594M allele does not contribute significantly to BP in blacks and does not predict a significantly superior response to amiloride therapy.

Adult↗

An updated meta-analysis of genome scans for hypertension and blood pressure in the NHLBI Family Blood Pressure Program (FBPP).

A meta-analysis of the results from a multicenter genome-wide linkage study for hypertension and blood pressure (BP) based on an initial sample of 6,245 individuals was published in 2003. We report here a combined linkage analysis of hypertension and BP using the complete Family Blood Pressure Program (FBPP) dataset, which includes a total of 12,028 genotyped individuals. Genome-wide linkage analyses for hypertension and BP were first performed in each of the studied ethnic group within each network and the results were combined with a meta-analysis using a modified Fisher's method of combining P values. Our meta-analysis of genome scans for the latest FBPP dataset reveals suggestive linkage for hypertension and BP at several regions on the human genome. Strong evidence for linkage at two of these regions, 2p14 and 3p14.1, have also been published in previous meta-analyses, making them good candidate locations for susceptibility variants.

Adult↗

Meta-analysis of genome-wide scans for blood pressure in African American and Nigerian samples. The National Heart, Lung, and Blood Institute GeneLink Project.

BACKGROUND: In many genetic studies of complex traits, sample sizes are often too small to detect linkages of low-to-moderate effects. However, the combined linkage evidence across several studies can be synthesized using meta-analysis with the aim of providing more definitive support of linkage. METHODS: In the current study using the National Heart, Lung, and Blood Institute (NHLBI) GeneLink Project, a meta-analysis based on a modification of Fisher's method of pooling P values was used to investigate linkage for systolic blood pressure (SBP) and diastolic blood pressure (DBP) values across three studies involving African American and Nigerian families (HyperGEN, Health, Risk Factors, Exercise Training and Genetics [HERITAGE], and Genetics of Hypertension in Blacks). RESULTS: The meta results suggest two regions (2p and 7p) provide enhanced linkage evidence compared with the individual study results. The maximal meta Lod score of 2.9 on 2p14-p13.1 (64-78 cM) represented approximately 1-Lod unit increase over the respective individual study scores. This general region has been implicated previously involving primarily families of white ethnicity and provides confirmatory evidence that this QTL is common across ethnic groups. The second finding at 7p21.3-p15.3 (8-25 cM) provided a meta Lod of 3.5. Although region was implicated primarily in the Nigerian subjects the low-level but consistent support involving the African American families (individual Lod score of 1.0) suggests a novel QTL with respect to BP variation in individuals of black ethnicity. CONCLUSIONS: Follow-up studies involving positional cloning efforts of the combined families showing linkage evidence in these regions (particularly 2p) may be warranted to verify these findings and identify the genes and causative variants.

Adolescent↗

Species-dependent smooth muscle contraction to Neuromedin U and determination of the receptor subtypes mediating contraction using NMU1 receptor knockout mice.

The peptide ligand neuromedin U (NMU) has been implicated in an array of biological activities, including contraction of uterine, intestinal and urinary bladder smooth muscle. However, many of these responses appear to be species-specific. This study was undertaken to fully elucidate the range of smooth muscle-stimulating effects of NMU in rats, mice and guinea-pigs, and to examine the extent of the species differences. In addition, the NMU1 receptor knockout mouse was used to determine which receptor subtype mediates the contractile responses generated by NMU in the mouse. A range of isolated organ in vitro bioassays were carried out, which were chosen to re-confirm previous literature reports (uterine and stomach fundus contraction) and also to explore potentially novel smooth muscle responses to NMU. This investigation uncovered a number of previously unidentified NMU-mediated responses: contraction of rat lower esophageal sphinster (LES), rat ileum, mouse gallbladder, enhancement of electrically evoked contractions in rat and mouse vas deferens, and a considerable degree of cross-species differences. Studies using the NMU1 receptor knockout mice revealed that in the mouse fundus and gallbladder assays the NMU contractile response was mediated entirely through the NMU1 receptor subtype, whereas, in assays of mouse uterus and vas deferens, the response to NMU was unchanged in the NMU1 receptor knockout mouse, suggesting that the NMU response may be mediated through the NMU2 receptor subtype. NMU receptor subtype-selective antagonists are required to further elucidate the role of the individual receptor subtypes.

Animals↗

Novel inhibitors of fatty-acid synthase from green tea (Camellia sinensis Xihu Longjing) with high activity and a new reacting site.

Recent studies have shown that FAS (fatty acid synthase) is a potential therapeutic target of obesity. In the present paper we report that extract of green tea (Camellia sinensis Xihu Longjing) inhibits FAS effectively with an IC50 value of 12.2 microg dry weight/ml. The ability of GTE (green tea extract) to inhibit FAS is more potent than that of two known inhibitors in green tea leaves, EGCG (epigallocatechin gallate) and ECG (epicatechin gallate). We find that (-)-CG (catechin gallate) is a very potent inhibitor of FAS, with an IC50 of 1.5 microg/ml, and may contribute to the high inhibitory effect of GTE on FAS. The inhibitory mechanism of (-)-CG is not mainly involved in its binding to the beta-oxoacyl reductase domain to which both (-)-EGCG and (-)-ECG mainly bind. By analyses of the inhibitory kinetics and the structure of the gallated catechins, we found that the acyl transferase domain may be the main site reacting with (-)-CG, the structure consisting of a B ring, a C ring and a gallate ring, which is possibly essential for its inhibitory efficacy. The polyphenols rather than the alkaloids are the main fractions contributing to the inhibitory effect of GTE on FAS. During separation we also found that the total ability of this portion to inhibit FAS increases by 15-fold, and this may be due to some novel potent inhibitor of FAS other than (-)-CG being formed.

Camellia sinensis↗

Optimal surface segmentation in volumetric images--a graph-theoretic approach.

Efficient segmentation of globally optimal surfaces representing object boundaries in volumetric data sets is important and challenging in many medical image analysis applications. We have developed an optimal surface detection method capable of simultaneously detecting multiple interacting surfaces, in which the optimality is controlled by the cost functions designed for individual surfaces and by several geometric constraints defining the surface smoothness and interrelations. The method solves the surface segmentation problem by transforming it into computing a minimum s-t cut in a derived arc-weighted directed graph. The proposed algorithm has a low-order polynomial time complexity and is computationally efficient. It has been extensively validated on more than 300 computer-synthetic volumetric images, 72 CT-scanned data sets of different-sized plexiglas tubes, and tens of medical images spanning various imaging modalities. In all cases, the approach yielded highly accurate results. Our approach can be readily extended to higher-dimensional image segmentation.

Algorithms↗

Development of a monoclonal antibody-based immunohistochemistry method for BSE surveillance in China.

Five hybridoma cell lines secreting anti-PrP antibodies were established from the fusion between mouse myeloma Sp2/0 and spleen cells from mice immunized with recombinant Chinese Luxi yellow cattle (Bos taurus, Luxi) PrP (24-234) or recombinant Chinese small-tailed Han sheep PrP (94-227). According to their Western blot reactivity, five monoclonal antibodies (mAbs) could be divided into two groups. Group A, mAbs 1H2, 4C6, and 4C11 recognized re-PrP, PrP(C), and PrP(Sc) from both bovine and sheep. Group B, mAbs 2H3 and 4H10 only recognized re-PrP and PrP(Sc) of sheep, and especially, these two mAbs could not recognize PrP(C) from both bovine and sheep. In immunohistochemistry (IHC) test, mAb 4C11 immunostained the PrP(Sc) accumulation in tissue sections from BSE cattle and Scrapie sheep, and compared with mAb 6H4, it had the same immunohistochemical pattern. An IHC method based on mAb 4C11 for the detection of BSE was established and had been applied for the long-term surveillance of BSE in China. From 2001 to 2004, 12,692 samples from the whole country had been tested and all had negative results.

Animals↗

A genome-wide linkage and association study using COGA data.

BACKGROUND: Genome-wide association will soon be available to use as an adjunct to traditional linkage analysis. We studied alcoholism in 119 families collected by the Collaborative Study on the Genetics of Alcoholism and made available in Genetic Analysis Workshop 14, using genome-wide linkage and association analyses. METHODS: Genome-wide linkage analysis was first performed using microsatellite markers and a region with the strongest linkage evidence was further analyzed using single-nucleotide polymorphisms (SNPs). Family based genome-wide association test was also conducted using the SNPs. RESULTS: Nonparametric linkage analysis revealed weak linkage evidence on chromosome 7, and association analysis identified SNP tsc0515272 on chromosome 3 as significantly associated with alcoholism. CONCLUSION: Linkage analysis may require large sample sizes and high quality genotyping and marker maps to adequately improve power, while association analysis could hold more promise in efforts to identify variants responsible for complex traits.

Alcoholism↗

Identifying genetic variation affecting a complex trait in simulated data: a comparison of meta-analysis with pooled data analysis.

We explored the power and consistency to detect linkage and association with meta-analysis and pooled data analysis using Genetic Analysis Workshop 14 simulated data. The first 10 replicates from Aipotu population were used. Significant linkage and association was found at all 4 regions containing the major loci for Kofendrerd Personality Disorder (KPD) using both combined analyses although no significant linkage and association was found at all these regions in a single replicate. The linkage results from both analyses are consistent in terms of the significance level of linkage test and the estimate of locus location. After correction for multiple-testing, significant associations were detected for the same 8 single-nucleotide polymorphisms (SNP) in both analyses. There were another 2 SNPs for which significant associations with KPD were found only by pooled data analysis. Our study showed that, under homogeneous condition, the results from meta-analysis and pooled data analysis are similar in both linkage and association studies and the loss of power is limited using meta-analysis. Thus, meta-analysis can provide an overall evaluation of linkage and association when the original raw data is not available for combining.

Computer Simulation↗

Corin gene minor allele defined by 2 missense mutations is common in blacks and associated with high blood pressure and hypertension.

BACKGROUND: The natriuretic peptide system contributes to blood pressure regulation. Atrial and brain natriuretic peptides are cleaved into smaller biologically active molecules by corin, a transmembrane serine protease expressed in cardiomyocytes. METHOD AND RESULTS: This genotype-phenotype genetic association study included replication samples and genomic control to correct for population stratification. Sequencing of the human corin gene identified 2 nonsynonymous, nonconservative single nucleotide polymorphisms (Q568P and T555I) in near-complete linkage disequilibrium, thus describing a single minor I555 (P568) corin gene allele. This allele was present in the heterozygote state in &12% of blacks but was extremely rare in whites (<0.5% were homozygous for the minor allele). In our primary population sample, the Dallas Heart Study, after adjustment for potential confounders, including population stratification, the corin I555 (P568) allele remained independently associated with increased risk for prevalent hypertension (odds ratio, 1.63; 95% CI, 1.11 to 2.38; P=0.013). The corin I555 (P568) allele also was associated with higher systolic blood pressure in subjects not using antihypertensive medication in unadjusted (133.7+/-20.7 versus 129.4+/-17.4 mm Hg; P=0.029) and adjusted (132.5+/-1.6 versus 128.9+/-0.6 mm Hg; P=0.029) analyses. The independent association of the minor corin allele with increased risk for prevalent hypertension was confirmed in the Multi-Ethnic Study of Atherosclerosis (odds ratio, 1.50; 95% CI, 1.09 to 2.06; P=0.014). In addition, the association of the minor corin I555 (P568) allele with higher systolic blood pressure was confirmed in adjusted analysis in the Chicago Genetics of Hypertension Study (125.8+/-1.9 versus 121.4+/-0.7 mm Hg; P=0.03). CONCLUSIONS: The corin I555 (P568) allele is common in blacks and is associated with higher blood pressure and an increased risk for prevalent hypertension.

Adult↗

Angiotensin-converting enzyme gene polymorphisms and obesity: an examination of three black populations.

We examined the association between obesity and 13 angiotensin-converting enzyme (ACE) gene polymorphisms, including the presence (I) or absence (D) of an Alu element in intron 16 (I/D polymorphism), and performed haplotype analysis using data collected from participants of a community survey of hypertension among blacks living in Ibadan, Nigeria; Spanish Town, Jamaica; and Chicago, IL. Transmission distortion of ACE gene polymorphisms and haplotypes from heterozygous parents to affected offspring was examined in each study population. To estimate haplotypes, polymorphisms were divided into three groups based on their position on the ACE gene. No ACE gene polymorphism was consistently overtransmitted from parents to obese offspring among the three populations. However, the haplotype ACE1-ACE5 TACAT, located in the promoter region, was significantly overtransmitted from parents to obese offspring in both the U.S. and Nigerian populations. No haplotype was significantly overtransmitted from parents to obese offspring among the Jamaicans. In conclusion, we noted the overtransmission of a particular ACE gene promoter region haplotype from parents to obese offspring in two separate black populations. These data suggest that ACE gene polymorphisms may influence the development of weight gain.

Adult↗

Genetic effects on blood pressure localized to chromosomes 6 and 7.

OBJECTIVE: To identify quantitative trait loci (QTL) contributing to the variation in blood pressure in a west African population. METHODS: We conducted a multi-stage genome scan in a population sample from rural Nigeria. A 10 centimorgan genome-wide screen for log-transformed systolic blood pressure (SBP) and diastolic blood pressure (DBP) was first performed based on 1054 individuals from 188 families. In the second phase we performed a similar analysis in an independent sample of 621 individuals from 101 families. In a third follow-up fine mapping phase we genotyped 25 additional markers in the three regions identified in the first two phases. RESULTS: Genome-wide significant linkage evidence was found for SBP on chromosome 7p (lod = 4.73, genome wide P < or = 0.01, point-wise P = 1.53 x 10) in the combined sample. Suggestive linkage evidence was also detected on 6q (lod = 2.9, point-wise P = 0.00013) and 7q (lod = 2.6, point-wise P = 0.00027) for SBP, and 7q (lod = 1.6, point-wise P = 0.003) for DBP. CONCLUSIONS: This study has identified several regions that may harbor genetic variants affecting the variation in blood pressure. Further association mapping under the linkage peaks will be required to refine the linkage evidence that has emerged from our analysis.

Adult↗

Genome-wide linkage scans for fasting glucose, insulin, and insulin resistance in the National Heart, Lung, and Blood Institute Family Blood Pressure Program: evidence of linkages to chromosome 7q36 and 19q13 from meta-analysis.

Genome-wide linkage analyses were performed using a multipoint variance components method in eight study groups from four multicenter networks (whites and blacks in GenNet; whites, blacks, and Mexican Americans in GENOA; whites and blacks in HyperGEN; and Asians in SAPPHIRe) that comprise the National Heart, Lung, and Blood Institute Family Blood Pressure Program (FBPP), in order to identify quantitative trait loci (QTLs) influencing fasting glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR). These study populations were enriched with subjects who had elevated blood pressure. Participants fasting <8 h, those with a history of type 2 diabetes, or those on antidiabetic medications were excluded from the current investigation. These three phenotypes were suitably transformed to approximate normal distributions. Each phenotype was adjusted for the effects of age, BMI, and field center separately by sex within each of the eight network ethnicity groups before genetic analysis. A total of 8,664 subjects comprising 5,923 sibpairs from 4,043 families with 365 markers were available for conducting a meta-analysis using a modified Fisher's method of combining the P values from each of the eight scans. Evidence of linkages was found on chromosome 7q36 at 163 cM, with a logarithm of odds (LOD) score of 3.21 for HOMA-IR, and on chromosome 19q13 at 88 cM, with a LOD score of 3.33 for fasting glucose. We also found suggestive linkages (LOD score >/=2.2) on chromosome 7q36 at 163 cM, with LOD scores of 2.31 for fasting glucose and 2.26 for fasting insulin (versus the LOD score of 3.21 for HOMA-IR at this locus). In conclusion, QTLs were identified on chromosomes 7q36 and 19q13 for fasting glucose, insulin, and insulin resistance in large and multiple-ethnicity populations in the FBPP with good replications across several other independent studies for relevant traits. Follow-up dense mapping and association studies are warranted.

Adult↗

Safety and efficacy of tiered limited-dose gamma knife stereotactic radiosurgery for unilateral acoustic neuroma.

Stereotactic radiosurgery has become a more widely employed modality of treatment for acoustic neuromas, but controversy still arises regarding the safety and efficacy of the technique. In general, radiation doses have been reduced over time. Since beginning treatments of acoustic neuromas with the Gamma Knife at the University of Miami/Jackson Memorial Medical Center in 1994, a dose regimen was adopted by the first author employing limited doses selected on the basis of tumor size with the anterior and medial regions of the prescription isodose surface kept just inside the gadolinium-enhanced limit of the tumor, in order to protect the facial nerve and brainstem. The records of patients treated for unilateral tumors were retrospectively reviewed. Fifty-two patients, aged 23-83 years, were treated with peripheral tumor doses of 10-14 Gy at the 45-70% isodoses. No patient developed new facial weakness or sensory loss; 3 patients had minor transient facial twitching within a few months of treatment. Of 34 patients followed more than 1 year (range 14-100 months, mean 43.4 months, median 37 months), 17 tumors reduced in size, 16 remained unchanged, and 1 increased in size. One patient, who had radiosurgery as planned postoperative adjuvant treatment after partial resection of a large tumor, developed an enlarging peritumoral arachnoid cyst that required surgical resection 79 months after radiosurgery. Patients with good pretreatment hearing retained approximately the same subjective level of hearing. Very good control of unilateral acoustic neuroma has been achieved by a limited-dose scheme that produces minimal complications, but due to the frequently indolent course of these tumors, continued long-term monitoring will be necessary.

Adult↗