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Articles by L Xu
Total Records ( 12 ) for L Xu
  D Ouyang , X He , L Xu , X Wang , Q Gao and H. Guo
 

The major histocompatibility complex class I allele Mamu-B*17 of rhesus macaques is an elite controller of simian immunodeficiency virus (SIV) infection whereas Mamu-B*01 has no inhibitory effect on SIV replication. The mechanism is still elusive. In this study, the so-called ‘missing G’ in the leading peptide sequence of Mamu-B*1703 allele was artificially inserted back through PCR amplification, and the new sequence was renamed as Mamu-B*1703(+G). The plasmids harboring Mamu-B*1703, Mamu-B*1703(+G) and Mamu-B*0101 cDNA sequence fused to EGFP gene were transfected into K562 and Cos-7 cells, respectively. Our data showed that these plasmids had similar transfection efficiencies and expression potentials in K562 cells, but the surface density of Mamu-B*1703 complexes, which was slightly influenced by the artificial change of the leading peptide length, was much higher than that of Mamu-B*0101 molecules. These results might partially account for the differential effects of Mamu-B*17 and Mamu-B*01 alleles on SIV replication in rhesus macaques.

  L French , S Lane , T Law , L Xu and P. Pavlidis
 

Motivation: Many microarray datasets are available online with formalized standards describing the probe sequences and expression values. Unfortunately, the description, conditions and parameters of the experiments are less commonly formalized and often occur as natural language text. This hinders searching, high-throughput analysis, organization and integration of the datasets.

Results: We use the lexical resources and software tools from the Unified Medical Language System (UMLS) to extract concepts from text. We then link the UMLS concepts to classes in open biomedical ontologies. The result is accessible and clear semantic annotations of gene expression experiments. We applied the method to 595 expression experiments from Gemma, a resource for re-use and meta-analysis of gene expression profiling data. We evaluated and corrected all stages of the annotation process. The majority of missed annotations were due to a lack of cross-references. The most error-prone stage was the extraction of concepts from phrases. Final review of the annotations in context of the experiments revealed 89% precision. A naive system, lacking the phrase to concept corrections is 68% precise. We have integrated this annotation pipeline into Gemma.

Availability: The source code, documentation and Supplementary Materials are available at http://www.chibi.ubc.ca/GEOMMTX. The results of the manual evaluations are provided as Supplementary Material. Both manual and predicted annotations can be viewed and searched via the Gemma website at http://www.chibi.ubc.ca/Gemma. The complete set of predicted annotations is available as a machine readable resource description framework graph.

Contact: paul@chibi.ubc.ca

  L Yang , L Xu and L. He
 

Motivation: Serious adverse drug reaction (SADR) is an urgent, world-wide problem. In the absence of any well-organized gene-oriented SADR information pool, a database should be constructed. Since the importance of a gene to a particular SADR cannot simply be defined in terms of how frequently the two are cited together in the literature, an algorithm should be devised to sort genes according to their relevance to the SADR topics.

Results: The SADR-Gengle database, which is made up of gene–SADR relationships extracted from Pubmed, has been constructed, covering six major SADRs, namely cholestasis, deafness, muscle toxicity, QT prolongation, Stevens–Johnson syndrome and torsades de points. The CitationRank algorithm, which inherits the principle of the Google PageRank algorithm that a gene should be highly ranked when biologically related to other highly ranked genes, is devised. The algorithm performs robustly in recovering SADR-related genes in the presence of extraneous noise, and the use of the algorithm has been extended to sorting genes in our database. Users can browse genes in a Google-type system where genes are ordered according to their descending relevance to the SADR topic selected by the user. The database also provides users with visualized gene–gene knowledge chain networks, helping them to systematize their gene-oriented knowledge chain whilst navigating these networks.

  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.

  M. G Chang , Y Zhang , C. Y Chang , L Xu , R Emokpae , L Tung , E Marban and M. R. Abraham
 

Rationale: Reentry underlies most ventricular tachycardias (VTs) seen postmyocardial infarction (MI). Mapping studies reveal that the majority of VTs late post-MI arise from the infarct border zone (IBZ).

Objective: To investigate reentry dynamics and the role of individual ion channels on reentry in in vitro models of the "healed" IBZ.

Methods and Results: We designed in vitro models of the healed IBZ by coculturing skeletal myotubes with neonatal rat ventricular myocytes and performed optical mapping at high temporal and spatial resolution.

In culture, neonatal rat ventricular myocytes mature to form striated myocytes and electrically uncoupled skeletal myotubes simulate fibrosis seen in the healed IBZ. High resolution mapping revealed that skeletal myotubes produced localized slowing of conduction velocity (CV), increased dispersion of CV and directional-dependence of activation delay without affecting myocyte excitability. Reentry was easily induced by rapid pacing in cocultures; treatment with lidocaine, a Na+ channel blocker, significantly decreased reentry rate and CV, increased reentry path length and terminated 30% of reentrant arrhythmias (n=18). In contrast, nitrendipine, an L-type Ca2+ channel blocker terminated 100% of reentry episodes while increasing reentry cycle length and path length and decreasing reentry CV (n=16). K+ channel blockers increased reentry action potential duration but infrequently terminated reentry (n=12).

Conclusions: Cocultures reproduce several architectural and electrophysiological features of the healed IBZ. Reentry termination by L-type Ca2+ channel, but not Na+ channel, blockers suggests a greater Ca2+-dependence of propagation. These results may help explain the low efficacy of pure Na+ channel blockers in preventing and terminating clinical VTs late after MI.

  T Du , M. R Lewin , H Wang , X Ji , H. H Bohn , T Xu , L Xu , Y Zhang and Y. Li
  Objective

To investigate the circadian and seasonal patterns in the presentation of acute upper gastrointestinal bleeding (AUGIB) in Beijing, China.

Methods

Medical records of the Beijing Emergency Medical Service System (EMSS) for 1 August 2005 to 31 July 2007 were reviewed; all patients diagnosed with AUGIB were included in the study.

Results

2580 patients were recorded in the EMSS system with a diagnosis of AUGIB during the study period. 1888 (73%) were male and 692 (27%) were female. Mean age was 53±20 years for male patients and 63±21 years for female patients. Significant differences in the presentation of AUGIB were noticed between seasons (p<0.001) and months (p<0.001). The number of cases in cold months (from December to April) was significantly higher than that in warm months (June to September). There was a significant circadian rhythm; there were fewer cases during daytime hours compared with night-time hours (p<0.001).

Conclusions

The presentation of AUGIB in Beijing has a clear seasonal and circadian rhythm. Circadian and seasonal rhythms associated with AUGIB may aid in identifying modifiable risk factors in individuals and populations.

  Y Yashiro Ohtani , Y He , T Ohtani , M. E Jones , O Shestova , L Xu , T. C Fang , M. Y Chiang , A. M Intlekofer , S. C Blacklow , Y Zhuang and W. S. Pear
 

Precise control of the timing and magnitude of Notch signaling is essential for the normal development of many tissues, but the feedback loops that regulate Notch are poorly understood. Developing T cells provide an excellent context to address this issue. Notch1 signals initiate T-cell development and increase in intensity during maturation of early T-cell progenitors (ETP) to the DN3 stage. As DN3 cells undergo β-selection, during which cells expressing functionally rearranged TCRβ proliferate and differentiate into CD4+CD8+ progeny, Notch1 signaling is abruptly down-regulated. In this report, we investigate the mechanisms that control Notch1 expression during thymopoiesis. We show that Notch1 and E2A directly regulate Notch1 transcription in pre-β-selected thymocytes. Following successful β-selection, pre-TCR signaling rapidly inhibits Notch1 transcription via signals that up-regulate Id3, an E2A inhibitor. Consistent with a regulatory role for Id3 in Notch1 down-regulation, post-β-selected Id3-deficient thymocytes maintain Notch1 transcription, whereas enforced Id3 expression decreases Notch1 expression and abrogates Notch1-dependent T-cell survival. These data provide new insights into Notch1 regulation in T-cell progenitors and reveal a direct link between pre-TCR signaling and Notch1 expression during thymocyte development. Our findings also suggest new strategies for inhibiting Notch1 signaling in pathologic conditions.

  L Xu , Y Ding , W. J Catalona , X. J Yang , W. F Anderson , B Jovanovic , K Wellman , J Killmer , X Huang , K. A Scheidt , R. B Montgomery and R. C. Bergan
  Background

Dietary intake of genistein by patients with prostate cancer has been associated with decreased metastasis and mortality. Genistein blocks activation of p38 mitogen-activated protein kinase and thus inhibits matrix metalloproteinase-2 (MMP-2) expression and cell invasion in cultured cells and inhibits metastasis of human prostate cancer cells in mice. We investigated the target for genistein in prostate cancer cells.

Methods

Prostate cell lines PC3-M, PC3, 1532NPTX, 1542NPTX, 1532CPTX, and 1542CPTX were used. All cell lines were transiently transfected with a constitutively active mitogen-activated protein kinase kinase 4 (MEK4) expression vector (to increase MEK4 expression), small interfering RNA against MEK4 (to decrease MEK4 expression), or corresponding control constructs. Cell invasion was assessed by a Boyden chamber assay. Gene expression was assessed by a quantitative reverse transcription–polymerase chain reaction. Protein expression was assessed by Western blot analysis. Modeller and AutoDock programs were used for modeling of the structure of MEK4 protein and ligand docking, respectively. MMP-2 transcript levels were assessed in normal prostate epithelial cells from 24 patients with prostate cancer from a phase II randomized trial comparing genistein treatment with no treatment. Statistical significance required a P value of .050 or less. All statistical tests were two-sided.

Results

Overexpression of MEK4 increased MMP-2 expression and cell invasion in all six cell lines. Decreased MEK4 expression had the opposite effects. Modeling showed that genistein bound to the active site of MEK4. Genistein inhibited MEK4 kinase activity with a half maximal inhibitory concentration of 0.40 µM (95% confidence interval [CI] = 0.36 to 0.45 µM). The MMP-2 transcript level in normal prostate epithelial cells was statistically significantly higher in the untreated group (100%) than in the genistein-treated group (24%; difference = 76%, 95% CI = 38% to 115%; P = .045).

Conclusions

We identified MEK4 as a proinvasion protein in six human prostate cancer cell lines and the target for genistein. We showed, to our knowledge for the first time, that genistein treatment, compared with no treatment, was associated with decreased levels of MMP-2 transcripts in normal prostate cells from prostate cancer–containing tissue.

  X Wang , Q Li , X Niu , H Chen , L Xu and C. Qi
 

Sspg1d, one of endopolygalacturonases, is an important fungal effector secreted by the necrotrophic fungus Sclerotinia sclerotiorum during early infection. Using sspg1d as bait, a small C2 domain protein (designated as IPG-1) was identified by yeast two-hybrid screening of a canola cDNA library. Deletion analysis confirmed that the C-terminus of IPG-1 is responsible for its interaction with sspg1d in the yeast two-hybrid assay. The sspg1d/IPG-1 interaction was further confirmed in plant cells by a biomolecular fluorescence complementation (BiFC) assay. A transient expression assay showed that the IPG-1–GFP fusion protein was targeted to the plasma membrane and nucleus in onion epidermal cells. Following treatment with a Ca2+ ionophore, it was distributed throughout the cytosol. Real-time PCR assay demonstrated that IPG-1 was highly induced by Sclerotinia sclerotiorum in canola leaves and stems. Southern blot analysis indicated the presence of about five homologues of IPG-1 in the canola genome. Two additional members of the IPG-1gene family were isolated by RT-PCR. Their sequence similarity with IPG-1 is as high as 95%. However, they did not interact with sspg1d in the yeast two-hybrid assay. Possible roles of IPG-1 and its association with sspg1d in the defence signalling pathway were discussed.

  L Xu , C He , C Shen , T Jiang , L Shi , K Sun , S. W Berquist and J. Feng
 

The geographical patterns of the genetic structure of Hipposideros armiger in China were assessed by analyzing sequence variation in the mitochondrial DNA control region. Analysis of molecular variance revealed a very strong genetic structure among 5 regions in H. armiger. A neighbor-joining tree, haplotype network construction by TCS and multidimensional scaling plots all showed significant geographic differentiation among 5 regions. The high genetic structure detected in H. armiger could be a consequence of poor dispersal ability, local adaptation, or marked female philopatry. The lack of genetic structure among 3 regions separated by the Gaoligong Range and the Qiongzhou Strait could be due to incomplete lineage sorting. Our estimated times of divergence for H. armiger populations suggested a relatively recent split. The S Yunnan population with the highest genetic diversity and the Hainan population with the lowest genetic diversity should be equally given priority for conservation. Although H. armiger has been shown to carry viruses implicated in human disease, we find little evidence for population mixing. We thus suggest minimizing disturbance to bats’ roosting caves for minimizing the potential risk of virus transmission.

  R Zunino , E Braschi , L Xu and H. M. McBride
 

The mechanisms that ensure an equal inheritance of cellular organelles during mitosis are an important area of study in cell biology. For the mitochondria fragment during mitosis, however, the cellular links that signal these changes are largely unknown. We recently identified a SUMO protease, SenP5, that deSUMOylates a number of mitochondrial targets, including the dynamin-related fission GTPase, DRP1. In interphase, SenP5 resides primarily within the nucleoli, in addition to a cytosolic pool. Here we report the relocalization of SenP5 from the nucleoli to the mitochondrial surface at G2/M transition prior to nuclear envelope breakdown. The recruitment of SenP5 results in a significant loss in mitochondrial SUMOylation, and a concomitant increase in the labile pool of DRP1 that drives mitochondrial fragmentation. Importantly, silencing of SenP5 leads to an arrest in the cell cycle precisely at the time when the protease is translocated to the mitochondria. These data indicate that transition of SenP5 to the mitochondria plays an important role in mitochondrial fragmentation during mitosis. The altered intracellular localization of SenP5 represents the first example of the mitochondrial recruitment of a SUMO protease and provides new insights into the mechanisms of interorganellar communication during the cell cycle.

 
 
 
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