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Articles by X Yang
Total Records ( 14 ) for X Yang
  B Hou , F Li , X Yang and G. Hong

In Rhizobium leguminosarum bv. viciae, NodD, as a member of the LysR-type transcriptional regulators (LTTRs), exerts auto-regulation and activates transcription of other nod genes in the presence of naringenin. LTTRs were typically composed of N-terminal DNA-binding domain and C-terminal regulatory domain. In this study, by systematic insertion mutation, a region of 12 amino acids in length of NodD was identified as functional domain. Insertion mutants in this region appeared to acquire the ability of constitutively activating nodA gene and retained their auto-regulation properties. This identified region was shown to be a hinge of NodD as revealed through the model built using Swiss-PDB Viewer software. It is the first time to report that as a member of LysR family, NodD has been shown to contain a short intramolecular domain that influences its performance.

  B Hou , F Li , X Yang and G. Hong

In Rhizobium leguminosarum bv. viciae, NodD, a member of the LysR-type transcriptional regulators, while auto-regulating, activates transcription of other nod genes in the presence of naringenin. A hinge region of NodD was previously identified in our laboratory as a functional region independent of its N-terminal DNA-binding and C-terminal regulatory domain. Further study was carried out to see the possible effect of the length variation in the hinge region on NodD's properties. To our surprise, as many as seven classes of phenotypes were observed. Class I is deficient of activating nodA transcription and abolishes auto-regulation; class II is able to activate nodA transcription independently of naringenin and abolishes auto-regulation; class III retains auto-regulating but partial activating ability; class IV is able to activate transcription independently of naringenin and retains auto-regulation; in class V, nodA is transcribed constitutively but the transcription level is drastically down-regulated in the presence of naringenin; in class VI, nodA is transcribed constitutively with higher induction ratio; in class VII, nodA is transcribed constitutively with lower induction ratio. To learn more about the possible mechanism, circular permutation assays were done, which showed that the length variation of the hinge of NodD caused by mutation led to the change in bend angles of nod promoter. This finding should help to get an insight into how transcriptional regulation is mediated by NodD at the molecular level as well as to understand the regulatory system of this important family.

  L Guo , W Ying , J Zhang , Y Yuan , X Qian , J Wang , X Yang and F. He

Mutations in the TSC1 and TSC2 genes lead to tuberous sclerosis complex (TSC), which is characterized clinically by mental retardation, epilepsy, and benign tumors affecting multiple tissues. Numerous components of the TSC protein complex remain uncharacterized. Here we report the purification of the TSC1 complex under physiological conditions using a proteomic strategy. We purified the TSC1 protein complex using a tandem affinity purification method and identified a protein complex containing 139 components. Two known binding proteins of TSC1 (TSC2 and DOCK7) were identified along with other new potential partners, which cover reported and novel TSC1 functional categories. Bioinformatics and biochemical methods were used to evaluate the observed protein–protein interactions. A comparative analysis with a published expression proteomics/genomics study of TSC1 revealed more than 20 common candidates that might be functionally relevant. The data set provides new directions in which to expand our knowledge of the functions of TSC1 and the mechanisms of TSC. The results are highly reliable, which is reflected by the identification of a few reported partners of TSC1 and many TSC1/2-regulated proteins. Interestingly, many new functional categories were identified, such as DNA repair, which provide novel hints to the function of TSC1. Moreover, a few neuronal disease-related proteins that might regulate the normal functions of neurons were identified. Thus, the results suggest that many of the new interactions should be biologically significance. It will be interesting to further investigate the regulatory mechanisms of these components.

  Z Tian , T Ye , X Zhang , E Liu , W Wang , P Wang , G Liu , X Yang , G Hu and Z. Yu

Objective  To investigate the association between sleep duration and risk of hyperglycemia among preschool Chinese children.

Design  A population-based cross-sectional study.

Setting  Seventy-one randomly selected kindergartens in Tianjin, China.

Participants  Six hundred nineteen obese (body mass index z score ≥1.65) and 617 nonobese (body mass index z score <1.65) children aged 3 to 6 years were recruited and matched by age.

Main Exposure  Sleep duration.

Main Outcome Measures  Hyperglycemia, defined as a fasting glucose level of 100 mg/dL or higher.

Results  Obese children were more likely to have shorter sleep duration (≤8 hours) compared with their nonobese counterparts (P < .001). Compared with those who slept for 9 or 10 hours per night, those who slept for 8 hours or less had a significantly higher likelihood of having hyperglycemia, controlling for age and sex (odds ratio [OR], 1.65; 95% confidence interval [CI], 1.12-2.45). After further adjustment for other potential confounders, the association still remained statistically significant (OR, 1.64; 95% CI, 1.09-2.46). In the stratified multivariable analyses, those who were obese and slept for 8 hours or less had an increased risk of having hyperglycemia (OR, 2.12; 95% CI, 1.06-4.21) compared with those who were nonobese and slept for 9 hours or more.

Conclusions  Shorter sleep duration is associated with an increased risk of having hyperglycemia among preschool Chinese children. Whether adequate sleep may help maintain euglycemia among children, especially for those who are overweight or obese, warrants further investigation.

  X Yang , Y Zhou , R Jin and C. Chan

Motivation: Reconstructing gene networks from microarray data has provided mechanistic information on cellular processes. A popular structure learning method, Bayesian network inference, has been used to determine network topology despite its shortcomings, i.e. the high-computational cost when analyzing a large number of genes and the inefficiency in exploiting prior knowledge, such as the co-regulation information of the genes. To address these limitations, we are introducing an alternative method, knowledge-driven matrix factorization (KMF) framework, to reconstruct phenotype-specific modular gene networks.

Results: Considering the reconstruction of gene network as a matrix factorization problem, we first use the gene expression data to estimate a correlation matrix, and then factorize the correlation matrix to recover the gene modules and the interactions between them. Prior knowledge from Gene Ontology is integrated into the matrix factorization. We applied this KMF algorithm to hepatocellular carcinoma (HepG2) cells treated with free fatty acids (FFAs). By comparing the module networks for the different conditions, we identified the specific modules that are involved in conferring the cytotoxic phenotype induced by palmitate. Further analysis of the gene modules of the different conditions suggested individual genes that play important roles in palmitate-induced cytotoxicity. In summary, KMF can efficiently integrate gene expression data with prior knowledge, thereby providing a powerful method of reconstructing phenotype-specific gene networks and valuable insights into the mechanisms that govern the phenotype.

  J. L Wang , X Yang , K Xia , Z. M Hu , L Weng , X Jin , H Jiang , P Zhang , L Shen , J Feng Guo , N li , Y. R Li , L. F Lei , J Zhou , J Du , Y. F Zhou , Q Pan , J Wang , R. Q Li and B. S. Tang

Autosomal-dominant spinocerebellar ataxias constitute a large, heterogeneous group of progressive neurodegenerative diseases with multiple types. To date, classical genetic studies have revealed 31 distinct genetic forms of spinocerebellar ataxias and identified 19 causative genes. Traditional positional cloning strategies, however, have limitations for finding causative genes of rare Mendelian disorders. Here, we used a combined strategy of exome sequencing and linkage analysis to identify a novel spinocerebellar ataxia causative gene, TGM6. We sequenced the whole exome of four patients in a Chinese four-generation spinocerebellar ataxia family and identified a missense mutation, c.1550T–G transition (L517W), in exon 10 of TGM6. This change is at a highly conserved position, is predicted to have a functional impact, and completely cosegregated with the phenotype. The exome results were validated using linkage analysis. The mutation we identified using exome sequencing was located in the same region (20p13–12.2) as that identified by linkage analysis, which cross-validated TGM6 as the causative spinocerebellar ataxia gene in this family. We also showed that the causative gene could be mapped by a combined method of linkage analysis and sequencing of one sample from the family. We further confirmed our finding by identifying another missense mutation c.980A–G transition (D327G) in exon seven of TGM6 in an additional spinocerebellar ataxia family, which also cosegregated with the phenotype. Both mutations were absent in 500 normal unaffected individuals of matched geographical ancestry. The finding of TGM6 as a novel causative gene of spinocerebellar ataxia illustrates whole-exome sequencing of affected individuals from one family as an effective and cost efficient method for mapping genes of rare Mendelian disorders and the use of linkage analysis and exome sequencing for further improving efficiency.

  X Yang , S Yang , C McKimmey , B Liu , S. M Edgerton , W Bales , L. T Archer and A. D. Thor

Genistein is a major isoflavone with known hormonal and tyrosine kinase-modulating activities. Genistein has been shown to promote the growth of estrogen receptor positive (ER+) MCF-7 cells. In ER-negative (ER–)/erbB-2-overexpressing (erbB-2+) cells, genistein has been shown to inhibit cell growth through its tyrosine kinase inhibitor activity. The effects of genistein on cell growth and tamoxifen response in ER+/erbB-2-altered breast cancers (known as luminal type B and noted in ~10 to 20% of breast cancers) have not been well explored. Using erbB-2-transfected ER+ MCF-7 cells, we found that genistein induced enhanced cellular proliferation and tamoxifen resistance when compared with control MCF-7 cells. These responses were accompanied by increased phosphorylation of ER and ER signaling, without increase in ER protein levels. Genistein-treated MCF-7/erbB-2 cells also showed enhanced activation/phosphorylation of erbB-2, Akt and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase. Blockade of the phosphatidylinositol 3-kinase and/or MAPK pathways abrogated genistein-induced growth promotion, suggesting that genistein effects involve both critical signaling pathways. We also found that p27/kip1 was markedly downregulated in genistein-treated MCF-7/erbB-2 cells. Overexpression of p27/kip1 attenuated genistein-mediated growth promotion. In aggregate, our data suggest that the concomitant coexpression of ER and erbB-2 makes breast cancers particularly susceptible to the growth-promoting effects of genistein across a wide range of doses. The underlying mechanisms involve enhanced ER–erbB-2 cross talk and p27/kip1 downregulation.

  D Zhang , X Jiang , P Fang , Y Yan , J Song , S Gupta , A. I Schafer , W Durante , W. D Kruger , X Yang and H. Wang

Background— Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular disease. Monocytes display inflammatory and resident subsets and commit to specific functions in atherogenesis. In this study, we examined the hypothesis that HHcy modulates monocyte heterogeneity and leads to atherosclerosis.

Methods and Results— We established a novel atherosclerosis-susceptible mouse model with both severe HHcy and hypercholesterolemia in which the mouse cystathionine β-synthase (CBS) and apolipoprotein E (apoE) genes are deficient and an inducible human CBS transgene is introduced to circumvent the neonatal lethality of the CBS deficiency (Tg-hCBS apoE–/– Cbs–/– mice). Severe HHcy accelerated atherosclerosis and inflammatory monocyte/macrophage accumulation in lesions and increased plasma tumor necrosis factor- and monocyte chemoattractant protein-1 levels in Tg-hCBS apoE–/– Cbs–/– mice fed a high-fat diet. Furthermore, we characterized monocyte heterogeneity in Tg-hCBS apoE–/– Cbs–/– mice and another severe HHcy mouse model (Tg-S466L Cbs–/–) with a disease-relevant mutation (Tg-S466L) that lacks hyperlipidemia. HHcy increased monocyte population and selective expansion of inflammatory Ly-6Chi and Ly-6Cmid monocyte subsets in blood, spleen, and bone marrow of Tg-S466L Cbs–/– and Tg-hCBS apoE–/– Cbs–/– mice. These changes were exacerbated in Tg-S466L Cbs–/– mice with aging. Addition of l-homocysteine (100 to 500 µmol/L), but not l-cysteine, maintained the Ly-6Chi subset and induced the Ly-6Cmid subset in cultured mouse primary splenocytes. Homocysteine-induced differentiation of the Ly-6Cmid subset was prevented by catalase plus superoxide dismutase and the NAD(P)H oxidase inhibitor apocynin.

Conclusion— HHcy promotes differentiation of inflammatory monocyte subsets and their accumulation in atherosclerotic lesions via NAD(P)H oxidase–mediated oxidant stress.

  X Yang , J Wang and X. Yi

Model abstraction plays an important role in model checking of source codes of programs. Slicing execution is a lightweight symbolic execution procedure to extract the models of C programs in an over-approximated way. In this paper, we present an approach to improving slicing execution with a novel concept called partial weakest precondition (PWP) to alleviate the space explosion problem. PWPs specify the corresponding weakest precondition conservatively by only considering part of program variables. We present how to integrate PWP with slicing execution, which leads to a compact model with much smaller state space compared with the one obtained by the original slicing execution. A new PWP implementation is also presented to avoid possible exponential PWP formula size and support pointers and aliases as well. The distinguished features of the implementation are that it does not need to translate the program to the passive form beforehand, and it supports loops very well. Comparing with slicing execution without PWP, the experimentation on SSL protocol based on the C source code openssl-0.9.6c shows that the state space may be reduced to only 1/10 after applying PWP.

  X Yang , M Feng , X Jiang , Z Wu , Z Li , M Aau and Q. Yu

The Rb–E2F pathway drives cell cycle progression and cell proliferation, and the molecular strategies safeguarding its activity are not fully understood. Here we report that E2F1 directly transactivates miR-449a/b. miR-449a/b targets and inhibits oncogenic CDK6 and CDC25A, resulting in pRb dephosphorylation and cell cycle arrest at G1 phase, revealing a negative feedback regulation of the pRb–E2F1 pathway. Moreover, miR-449a/b expression in cancer cells is epigenetically repressed through histone H3 Lys27 trimethylation, and epigenetic drug treatment targeting histone methylation results in strong induction of miR-449a/b. Our study reveals a tumor suppressor function of miR-449a/b through regulating Rb/E2F1 activity, and suggests that escape from this regulation through an aberrant epigenetic event contributes to E2F1 deregulation and unrestricted proliferation in human cancer.

  K Salehi Ashtiani , C Lin , T Hao , Y Shen , D Szeto , X Yang , L Ghamsari , H Lee , C Fan , R. R Murray , S Milstein , N Svrzikapa , M. E Cusick , F. P Roth , D. E Hill and M. Vidal

Although a highly accurate sequence of the Caenorhabditis elegans genome has been available for 10 years, the exact transcript structures of many of its protein-coding genes remain unsettled. Approximately two-thirds of the ORFeome has been verified reactively by amplifying and cloning computationally predicted transcript models; still a full third of the ORFeome remains experimentally unverified. To fully identify the protein-coding potential of the worm genome including transcripts that may not satisfy existing heuristics for gene prediction, we developed a computational and experimental platform adapting rapid amplification of cDNA ends (RACE) for large-scale structural transcript annotation. We interrogated 2000 unverified protein-coding genes using this platform. We obtained RACE data for approximately two-thirds of the examined transcripts and reconstructed ORF and transcript models for close to 1000 of these. We defined untranslated regions, identified new exons, and redefined previously annotated exons. Our results show that as much as 20% of the C. elegans genome may be incorrectly annotated. Many annotation errors could be corrected proactively with our large-scale RACE platform.

  X Yang , B Zhang , C Molony , E Chudin , K Hao , J Zhu , A Gaedigk , C Suver , H Zhong , J. S Leeder , F. P Guengerich , S. C Strom , E Schuetz , T. H Rushmore , R. G Ulrich , J. G Slatter , E. E Schadt , A Kasarskis and P. Y. Lum

Liver cytochrome P450s (P450s) play critical roles in drug metabolism, toxicology, and metabolic processes. Despite rapid progress in the understanding of these enzymes, a systematic investigation of the full spectrum of functionality of individual P450s, the interrelationship or networks connecting them, and the genetic control of each gene/enzyme is lacking. To this end, we genotyped, expression-profiled, and measured P450 activities of 466 human liver samples and applied a systems biology approach via the integration of genetics, gene expression, and enzyme activity measurements. We found that most P450s were positively correlated among themselves and were highly correlated with known regulators as well as thousands of other genes enriched for pathways relevant to the metabolism of drugs, fatty acids, amino acids, and steroids. Genome-wide association analyses between genetic polymorphisms and P450 expression or enzyme activities revealed sets of SNPs associated with P450 traits, and suggested the existence of both cis-regulation of P450 expression (especially for CYP2D6) and more complex trans-regulation of P450 activity. Several novel SNPs associated with CYP2D6 expression and enzyme activity were validated in an independent human cohort. By constructing a weighted coexpression network and a Bayesian regulatory network, we defined the human liver transcriptional network structure, uncovered subnetworks representative of the P450 regulatory system, and identified novel candidate regulatory genes, namely, EHHADH, SLC10A1, and AKR1D1. The P450 subnetworks were then validated using gene signatures responsive to ligands of known P450 regulators in mouse and rat. This systematic survey provides a comprehensive view of the functionality, genetic control, and interactions of P450s.

  L Song , X. Y Zhou , L Li , L. J Xue , X Yang and H. W. Xue

Light and brassinosteroids (BRs) have been proved to be crucial in regulating plant growth and development; however, the mechanism of how they synergistically function is still largely unknown. To explore the underlying mechanisms in photomorphogenesis, genome-wide analyses were carried out through examining the gene expressions of the dark-grown WT or BR biosynthesis-defective mutant det2 seedlings in the presence of light stimuli or exogenous Brassinolide (BL). Results showed that BR deficiency stimulates, while BL treatment suppresses, the expressions of light-responsive genes and photomorphogenesis, confirming the negative effects of BR in photomorphogenesis. This is consistent with the specific effects of BR on the expression of genes involved in cell wall modification, cellular metabolism and energy utilization during dark–light transition. Further analysis revealed that hormone biosynthesis and signaling-related genes, especially those of auxin, were altered under BL treatment or light stimuli, indicating that BR may modulate photomorphogenesis through synergetic regulation with other hormones. Additionally, suppressed ubiquitin-cycle pathway during light–dark transition hinted the presence of a complicated network among light, hormone, and protein degradation. The study provides the direct evidence of BR effects in photomorphogenesis and identified the genes involved in BR and light signaling pathway, which will help to elucidate the molecular mechanism of plant photomorphogenesis.

  N Mansouri Attia , J Aubert , P Reinaud , C Giraud Delville , G Taghouti , L Galio , R. E Everts , S Degrelle , C Richard , I Hue , X Yang , X. C Tian , H. A Lewin , J. P Renard and O. Sandra

At implantation the endometrium undergoes modifications necessary for its physical interactions with the trophoblast as well as the development of the conceptus. We aim to identify endometrial factors and pathways essential for a successful implantation in the caruncular (C) and the intercaruncular (IC) areas in cattle. Using a 13,257-element bovine oligonucleotide array, we established expression profiles at day 20 of the estrous cycle or pregnancy (implantation), revealing 446 and 1,295 differentially expressed genes (DEG) in C and IC areas, respectively (false discovery rate = 0.08). The impact of the conceptus was higher on the immune response function in C but more prominent on the regulation of metabolism function in IC. The C vs. IC direct comparison revealed 1,177 and 453 DEG in cyclic and pregnant animals respectively (false discovery rate = 0.05), with a major impact of the conceptus on metabolism and cell adhesion. We selected 15 genes including C11ORF34, CXCL12, CXCR4, PLAC8, SCARA5, and NPY and confirmed their differential expression by quantitative RT-PCR. The cellular localization was analyzed by in situ hybridization and, upon pregnancy, showed gene-specific patterns of cell distribution, including a high level of expression in the luminal epithelium for C11ORF34 and MX1. Using primary cultures of bovine endometrial cells, we identified PTN, PLAC8, and CXCL12 as interferon- (IFNT) target genes and MSX1 and CXCR7 as IFNT-regulated genes, whereas C11ORF34 was not an IFNT-regulated gene. Our transcriptomic data provide novel molecular insights accounting for the biological functions related to the C or IC endometrial areas and may contribute to the identification of potential biomarkers for normal and perturbed early pregnancy.

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