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Articles by Y Xu
Total Records ( 18 ) for Y Xu
  Y Xu , G Yang and G. Hu
 

Interferon-induced transmembrane protein 1 (IFITM1) is an essential mediator of interferon--induced anti-proliferation. Here, we reported the interaction between IFITM1 and caveolin-1 (CAV-1), and their inhibitory regulatory function on extracellular signal-regulated kinase (ERK). The immunofluorescence staining result showed that IFITM1 localized in caveolae of the plasma membrane and could interact with CAV-1. Deletion mutagenesis clearly revealed that the hydrophobic transmembrane domains were responsible for the interaction between IFITM1 and CAV-1. It has been reported that CAV-1 has inhibitory effect on the phosphorylation of ERK, and subsequently ERK-mediated transcription. Our study showed the interaction of IFITM1- and CAV-1-enhanced CAV-1's inhibitory effect on ERK activation, whereas the IFITM1 did not activate ERK directly. This inhibitory effect was further confirmed by knocking down the endogenous CAV-1 using RNA interference. These results revealed that the interaction between IFITM1 and CAV-1 could enhance the inhibitory effect of CAV-1 on ERK activation.

  X Zhang , Z Zhang , G Chen , M Zhao , D Wang , Z Du , Y Xu and X. Yu
 

Previous studies have shown that histone deacetylase inhibitors (HDACis) can kill cancer cells. In addition, HDACis can induce mitotic catastrophe in cancer cells due to insufficient localization of chromosomal passenger complex (CPC) to the centromere. However, the mechanisms behind these phenomena remain unclear. In this study, we found that a HDACi, FK228, affected multiple epigenetic modification characteristics of the centromere, including enhanced acetylation of histone H3 lysine 9 (H3K9), decreased trimethylation of H3K9, and decreased phosphorylation of histone H3 serine 10 (H3S10) and centromere protein A (CENP-A). These epigenetic changes implied that H3K9 hyperacetylation inhibits the CPC recruitment, induces impaired centromere assembly and function, and eventually leads to aberrant mitosis. These data suggested that hypoacetylation of histone in the pericentromere is the most important landmark for recruiting CPC and leading to the mitotic catastrophe in HDACi-induced killing of cancer cells.

  J Zhang , L Wang , L. B Anderson , B Witthuhn , Y Xu and J. Lu
 

Because the Selenium (Se) and Vitamin E Cancer Prevention Trial (SELECT) failed to show the efficacy of selenomethionine for prostate cancer prevention, there is a critical need to identify safe and efficacious Se forms for future trials. We have recently shown significant preventive benefit of methylseleninic acid (MSeA) and Se-methylselenocysteine (MSeC) in the transgenic adenocarcinoma mouse prostate (TRAMP) model by oral administration. The present work applied iTRAQ proteomic approach to profile protein changes of the TRAMP prostate and to characterize their modulation by MSeA and MSeC to identify their potential molecular targets. Dorsolateral prostates from wild-type mice at 18 weeks of age and TRAMP mice treated with water (control), MSeA, or MSeC (3 mg Se/kg) from 8 to 18 weeks of age were pooled (9-10 mice per group) and subjected to protein extraction, followed by protein denaturation, reduction, and alkylation. After tryptic digestion, the peptides were labeled with iTRAQ reagents, mixed together, and analyzed by two-dimensional liquid chromatography/tandem mass spectrometry. Of 342 proteins identified with >95% confidence, the expression of 75 proteins was significantly different between TRAMP and wild-type mice. MSeA mainly affected proteins related to prostate functional differentiation, androgen receptor signaling, protein (mis)folding, and endoplasmic reticulum–stress responses, whereas MSeC affected proteins involved in phase II detoxification or cytoprotection, and in stromal cells. Although MSeA and MSeC are presumed precursors of methylselenol and were equally effective against the TRAMP model, their distinct affected protein profiles suggest biological differences in their molecular targets outweigh similarities. Cancer Prev Res; 3(8); 994–1006. ©2010 AACR.

  G Jin , L Xu , Y Shu , T Tian , J Liang , Y Xu , F Wang , J Chen , J Dai , Z Hu and H. Shen
 

Chromosome 5p15.33, containing TERT and CLPTM1L genes, was recently identified as one of the susceptible regions for lung cancer in Caucasian populations. We hypothesized that single-nucleotide polymorphisms (SNPs) identified in this region in Caucasians are also important in the development of lung cancer in Chinese population. To test this hypothesis, we genotyped two most significant SNPs reported in Caucasians, rs2736100A/C and rs402710C/T at 5p15.33, in a case–control study with 1221 non-small cell lung cancer (NSCLC) cases and 1344 cancer-free controls in a Chinese population. We found that rs2736100C allele in TERT gene was associated with a significantly increased risk of NSCLC with adjusted odds ratios of 1.26 [95% confidence interval (CI) = 1.05–1.51] and 1.31 (95% CI = 1.04–1.66) for one or two copies of the variant C allele, respectively. This significant association was more prominent among female (P for heterogeneity: 0.044), non-smokers (P for heterogeneity: 0.054) and/or the subjects with adenocarcinoma (P for heterogeneity: 0.058). However, no significant association was found between rs402710C/T and NSCLC risk. These results suggest that genetic variants in 5p15.33, especially in TERT gene, may also predispose the susceptibility of lung cancer, especially adenocarcinoma, in Chinese population.

  X. Y Zhao , T. T Chen , L Xia , M Guo , Y Xu , F Yue , Y Jiang , G. Q Chen and K. W. Zhao
 

The expression of galectin-1, one of the most important lectins participating in the malignant tumor development, has been shown to be regulated by hypoxia, but its exact mechanism remains elusive. Here, we find that ectopically expressed hypoxia-inducible factor (HIF) 1 protein, an oxygen-sensitive subunit of HIF-1 that is a master factor for cellular response to hypoxia, significantly increases galectin-1 expression in both messenger RNA and protein levels in all four colorectal cancer (CRC) cell lines tested. However, hypoxia-induced galectin-1 expression cannot be seen in sentrin/SUMO-specific protease 1 homozygous-null mouse embryonic fibroblasts that fail to accumulate HIF-1 protein. Furthermore, silence of HIF-1 or HIF-1β expression by specific short hairpin RNAs (shRNAs) antagonizes hypoxia-induced galectin-1 expression. All these results propose that galectin-1 is a direct target of transcriptional factor HIF-1. Applying luciferase reporter assay and chromatin immunoprecipitation, we identify that two hypoxia-responsive elements located at –441 to –423 bp upstream to transcriptional start site of galectin-1 gene are essential for HIF-1-mediated galectin-1 expression. Finally, the knockdown of galectin-1 by its specific shRNA can significantly reduce hypoxia-induced invasion and migration of CRC cell line, and the ectopic expression of galectin-1 can remarkably restore invasion and migration abilities of HIF-1-knocked SW620 cells, proposing that galectin-1 mediates the HIF-1-induced migration and invasion of CRC cells during hypoxia. Taken together, our results shed new light for understanding mechanism for hypoxia/HIF-1-mediated migration/invasion of CRC cells.

  H Calkins , M. R Reynolds , P Spector , M Sondhi , Y Xu , A Martin , C. J Williams and I. Sledge
 

Background— Although radiofrequency catheter ablation (RFA) has evolved from an experimental procedure to an important treatment option for atrial fibrillation, the relative safety and efficacy of catheter ablation relative to that of antiarrhythmic drug (AAD) therapy has not been established.

Methods and Results— Two separate systematic reviews were conducted: one on RFA and the other on AAD to provide accurate and broadly representative estimates of the clinical efficacy and safety of both therapies in the treatment of atrial fibrillation. Electronic searches were conducted in EMBASE and MEDLINE from 1990 to 2007. For the RFA review, all study designs were accepted. For the AAD review, articles were limited to prospective studies on the following drugs of interest: amiodarone, dofetilide, sotalol, flecainide, and propafenone. Data were extracted by 1 reviewer, with a second reviewer performing independent confirmation of extracted data. Sixty-three RFA and 34 AAD studies were included in the reviews. Patients enrolled in RFA studies tended to be younger (mean age, 55 versus 62 years), had longer duration of atrial fibrillation (6.0 versus 3.1 years), and had failed a greater number of prior drug trials (2.6 versus 1.7). The single-procedure success rate of ablation off AAD therapy was 57% (95% CI, 50% to 64%), the multiple procedure success rate off AAD was 71% (95% CI, 65% to 77%), and the multiple procedure success rate on AAD or with unknown AAD usage was 77% (95% CI, 73% to 81%). In comparison, the success rate for AAD therapy was 52% (95% CI, 47% to 57%). A major complication of catheter ablation occurred in 4.9% of patients. Adverse events for AAD studies, although more common (30% versus 5%), were less severe.

Conclusions— Studies of RFA for treatment of atrial fibrillation report higher efficacy rates than do studies of AAD therapy and a lower rate of complications.

  H Ding , Y Xu , X Wang , Q Wang , L Zhang , Y Tu , J Yan , W Wang , R Hui , C. Y Wang and D. W. Wang
 

Background— Recent studies on genome-wide association have identified common variants on chromosome 9p21 associated with coronary artery disease (CAD). Given that ischemic stroke and CAD share several aspects of etiology and pathogenesis, we investigated the association of variants on chromosome 9p21 with ischemic stroke and CAD in the Chinese Han population by capturing the majority of diversity in this locus using haplotype-tagging single-nucleotide polymorphisms.

Methods and Results— We performed a shared control-cases study using 15 tagging single-nucleotide polymorphisms and 2 previously reported susceptibility single-nucleotide polymorphisms spanning 58 kb of the chromosome of 9p21 in a set of 558 patients with ischemic stroke, 510 patients with CAD, and 557 unaffected participants (controls) in the Chinese Han population. The association analyses were performed at both SNP and haplotype levels. We further verified our findings in an independent cohort of 442 ischemic stroke cases and 502 control subjects. In the first study, rs2383206, rs1004638, and rs10757278 in block 3 were significantly associated with CAD but not with ischemic stroke independent of traditional cardiovascular risk factors in additive model (P=0.002 to 0.0001, q=0.026 to 0.004). Analysis from all blocks revealed that haplotype profiles of block 3 on 9p21 were significantly different between shared control and cases of CAD (P=1.3x10–10, q=1.2x10–9) and ischemic stroke (P=1.7x10–6, q=7.7x10–6). In the expanded second case-control study, block 3 on 9p21 remained associated with ischemic stroke (P=2.6x10–4, q=6.3x10–4).

Conclusions— Our results suggest for the first time that 9p21 is a shared susceptibility locus, strongly for CAD and weakly for ischemic stroke, in a Chinese Han population.

  B Sun , Y Xu , K. H Ng and T. Ito
 

Developmental regulation of the floral meristem ensures that plants of the same species have similarly sized flowers with a fixed number of floral organs. The maintenance of stem cells in the floral meristem is terminated after the production of a fixed number of floral organ primordia. Precise repression of the Arabidopsis thaliana homeobox gene WUSCHEL (WUS) by the floral homeotic protein AGAMOUS (AG) plays a major part in this process. Here we show that KNUCKLES (KNU) mediates the repression of WUS in floral meristem determinacy control. AG directly induces the transcription of KNU, which encodes a C2H2-type zinc finger protein with a conserved transcriptional repression motif. In turn, KNU represses WUS transcription to abolish stem cell activity. We also show that the timing of KNU induction is key in balancing proliferation and differentiation in flower development. Delayed KNU expression results in an indeterminate meristem, whereas ectopic KNU expression prematurely terminates the floral meristem. Furthermore, KNU induction by AG is preceded by changes in repressive histone modification at the KNU locus, which occurs in an AG-dependent manner. This study provides a mechanistic link between transcriptional feedback and epigenetic regulation in plant stem cell proliferation.

  Y Kong , G Zhou , U Avci , X Gu , C Jones , Y Yin , Y Xu and M. G. Hahn
 

Several genes in Arabidopsis, including PARVUS/AtGATL1, have been implicated in xylan synthesis. However, the biosynthesis of xylan in woody plants, where this polysaccharide is a major component of wood, is poorly understood. Here, we characterize two Populus genes, PdGATL1.1 and PdGATL1.2, the closest orthologs to the Arabidopsis PARVUS/GATL1 gene, with respect to their gene expression in poplar, their sub-cellular localization, and their ability to complement the parvus mutation in Arabidopsis. Overexpression of the two poplar genes in the parvus mutant rescued most of the defects caused by the parvus mutation, including morphological changes, collapsed xylem, and altered cell wall monosaccharide composition. Quantitative RT–PCR showed that PdGATL1.1 is expressed most strongly in developing xylem of poplar. In contrast, PdGATL1.2 is expressed much more uniformly in leaf, shoot tip, cortex, phloem, and xylem, and the transcript level of PdGATL1.2 is much lower than that of PdGATL1.1 in all tissues examined. Sub-cellular localization experiments showed that these two proteins are localized to both ER and Golgi in comparison with marker proteins resident to these sub-cellular compartments. Our data indicate that PdGATL1.1 and PdGATL1.2 are functional orthologs of PARVUS/GATL1 and can play a role in xylan synthesis, but may also have role(s) in the synthesis of other wall polymers.

  Y Xu , H Lei , H Dong , L Zhang , Q Qin , J Gao , Y Zou and X. Yan
 

Previous studies found that the forkhead transcription factor 2 (FOXL2) gene mutations are responsible for both types of blepharophimosis–ptosis–epicanthus inversus syndrome (BPES) but have not established any systematic statistic model for the complex and even contradictory results about genotype–phenotype correlations between them. This study is aimed to find possible mutations of FOXL2 gene in a Chinese family with type II BPES by using DNA sequencing and to further clarify genotype–phenotype correlations between FOXL2 mutations and BPES by using a systematic statistical method, namely Multifactor Dimensionality Reduction (MDR). A novel mutation (g.933_965dup) which could result in an expansion of the polyalanine (polyAla) tract was detected in all patients of this family. MDR analysis for intragenic mutations of FOXL2 gene reported in previous BPES studies indicated that the mutations which led to much stronger disturbance of amino acid sequence were responsible for more type I BPES, while other kinds of mutation were responsible for more type II BPES. In conclusion, the present study found a novel FOXL2 gene mutation in a Chinese BPES family and a new general genotype–phenotype correlation tendency between FOXL2 intragenic mutations and BPES, both of which expanded the knowledge about FOXL2 gene and BPES.

  O Tischenko , Y Xu and C. Hoeschen
 

This paper discusses the advantages of both geometry of data required for the reconstruction algorithm, orthogonal polynomial expansion on disc (OPED), and polynomial structure of this algorithm. We show that this type of geometry is a result of special parameterisation used within the OPED formalism. The practicability of the OPED data geometry is discussed and it is shown that the data of such geometry can be acquired directly. A method of reducing typical artefacts by using the polynomial structure of the algorithm is summarised as well.

  F Tang , W Zhuo , C Zhao , B Chen , Y Xu and L. He
 

For accurate measurements of 220Rn concentration with airflow-through scintillation cell method, a theoretical study was performed for discussing the influences of sampling flow rate, volumes of sampling tube and scintillation cell on the measurements. It is found that a high flow rate and a large inner volume of scintillation cell as well as a small inner volume of sampling tube are not only preferable for measuring low levels of 220Rn, but also helpful for enhancing the measurement accuracy. In calibration experiments, both the sampling flow rate and the sampling tube volume should be noted. The variations of the flow rate and tube volume should be considered for accurate measurements in the fields.

  N. L Millar , A. J Hueber , J. H Reilly , Y Xu , U. G Fazzi , G. A. C Murrell and I. B. McInnes
 

Background: The cellular mechanisms of tendinopathy remain unclear particularly with respect to the role of inflammation in early disease. The authors previously identified increased levels of inflammatory cytokines in an early human model of tendinopathy and sought to extend these studies to the cellular analysis of tissue.

Purpose: To characterize inflammatory cell subtypes in early human tendinopathy, the authors explored the phenotype and quantification of inflammatory cells in torn and control tendon samples.

Design: Controlled laboratory study.

Methods: Torn supraspinatus tendon and matched intact subscapularis tendon samples were collected from 20 patients undergoing arthroscopic shoulder surgery. Control samples of subscapularis tendon were collected from 10 patients undergoing arthroscopic stabilization surgery. Tendon biopsy samples were evaluated immunohistochemically by quantifying the presence of macrophages (CD68 and CD206), T cells (CD3), mast cells (mast cell tryptase), and vascular endothelium (CD34).

Results: Subscapularis tendon samples obtained from patients with a torn supraspinatus tendon exhibited significantly greater macrophage, mast cell, and T-cell expression compared with either torn supraspinatus samples or control subscapularis-derived tissue (P < .01). Inflammatory cell infiltrate correlated inversely (r = .5; P < .01) with rotator cuff tear size, with larger tears correlating with a marked reduction in all cell lineages. There was a modest but significant correlation between mast cells and CD34 expression (r = .4; P < .01) in matched subscapularis tendons from shoulders with supraspinatus ruptures.

Conclusion: This study provides evidence for an inflammatory cell infiltrate in early mild/moderate human tendinopathy. In particular, the authors demonstrate significant infiltration of mast cells and macrophages, suggesting a role for innate immune pathways in the events that mediate early tendinopathy. Clinical Relevance Further mechanistic studies to evaluate the net contribution and hence therapeutic utility of these cellular lineages and their downstream processes may reveal novel therapeutic approaches to the management of early tendinopathy.

  Y Xu , L Yuan , J Mak , L Pardanaud , M Caunt , I Kasman , B Larrivee , R del Toro , S Suchting , A Medvinsky , J Silva , J Yang , J. L Thomas , A. W Koch , K Alitalo , A Eichmann and A. Bagri
 

If neuropilin-2 and the growth factor VEGF-C don’t come together, lymphatic vessels don’t branch apart.

  C. N Jenne , A Enders , R Rivera , S. R Watson , A. J Bankovich , J. P Pereira , Y Xu , C. M Roots , J. N Beilke , A Banerjee , S. L Reiner , S. A Miller , A. S Weinmann , C. C Goodnow , L. L Lanier , J. G Cyster and J. Chun
 

During a screen for ethylnitrosourea-induced mutations in mice affecting blood natural killer (NK) cells, we identified a strain, designated Duane, in which NK cells were reduced in blood and spleen but increased in lymph nodes (LNs) and bone marrow (BM). The accumulation of NK cells in LNs reflected a decreased ability to exit into lymph. This strain carries a point mutation within Tbx21 (T-bet), which generates a defective protein. Duane NK cells have a 30-fold deficiency in sphingosine-1-phosphate receptor 5 (S1P5) transcript levels, and S1P5-deficient mice exhibit an egress defect similar to Duane. Chromatin immunoprecipitation confirms binding of T-bet to the S1pr5 locus. S1P-deficient mice exhibit a more severe NK cell egress block, and the FTY720-sensitive S1P1 also plays a role in NK cell egress from LNs. S1P5 is not inhibited by CD69, a property that may facilitate trafficking of activated NK cells to effector sites. Finally, the accumulation of NK cells within BM of S1P-deficient mice was associated with reduced numbers in BM sinusoids, suggesting a role for S1P in BM egress. In summary, these findings identify S1P5 as a T-bet–induced gene that is required for NK cell egress from LNs and BM.

  J. R Martinez Francois , Y Xu and Z. Lu
 

Activity of cyclic nucleotide–gated (CNG) cation channels underlies signal transduction in vertebrate visual receptors. These highly specialized receptor channels open when they bind cyclic GMP (cGMP). Here, we find that certain mutations restricted to the region around the ion selectivity filter render the channels essentially fully voltage gated, in such a manner that the channels remain mostly closed at physiological voltages, even in the presence of saturating concentrations of cGMP. This voltage-dependent gating resembles the selectivity filter-based mechanism seen in KcsA K+ channels, not the S4-based mechanism of voltage-gated K+ channels. Mutations that render CNG channels gated by voltage loosen the attachment of the selectivity filter to its surrounding structure, thereby shifting the channel's gating equilibrium toward closed conformations. Significant pore opening in mutant channels occurs only when positive voltages drive the pore from a low-probability open conformation toward a second open conformation to increase the channels' open probability. Thus, the structure surrounding the selectivity filter has evolved to (nearly completely) suppress the expression of inherent voltage-dependent gating of CNGA1, ensuring that the binding of cGMP by itself suffices to open the channels at physiological voltages.

  J. R Martinez Francois , Y Xu and Z. Lu
 

Cyclic nucleotide–gated channels mediate transduction of light into electric signals in vertebrate photoreceptors. These channels are primarily controlled by the binding of intracellular cyclic GMP (cGMP). Glutamate residue 363 near the extracellular end of the ion selectivity filter interacts with the pore helix and helps anchor the filter to the helix. Disruption of this interaction by mutations renders the channels essentially fully voltage gated in the presence of saturating concentrations of cGMP. Here, we find that lowering extracellular pH makes the channels conduct in an extremely outwardly rectifying manner, as does a neutral glutamine substitution at E363. A pair of cysteine mutations, E363C and L356C (the latter located midway the pore helix), largely eliminates current rectification at low pH. Therefore, this low pH-induced rectification primarily reflects voltage-dependent gating involving the ion selectivity filter rather than altered electrostatics around the external opening of the ion pore and thus ion conduction. It then follows that protonation of E363, like the E363Q mutation, disrupts the attachment of the selectivity filter to the pore helix. Loosening the selectivity filter from its surrounding structure shifts the gating equilibrium toward closed states. At low extracellular pH, significant channel opening occurs only when positive voltages drive the pore from a low probability open conformation to a second open conformation. Consequently, at low extracellular pH the channels become practically fully voltage gated, even in the presence of a saturating concentration of cGMP.

 
 
 
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