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Articles by G Zhang
Total Records ( 7 ) for G Zhang
  L Sun , X Shen , Y Liu , G Zhang , J Wei , H Zhang , E Zhang and F. Ma
 

The mechanism underlining human papillomaviruses (HPVs) causing cancer has been studied extensively, and it was concluded that the high-risk HPVs' E6 targeted and degraded tumor suppressor protein p53, leading to infected cells malignant transformation. In contrast, the low-risk HPVs only cause proliferative but non-invasive lesions of infected epithelia. Therefore, we hypothesized that low-risk HPVs' E6 might interact with p53 in a different pattern. We used a mammalian green fluorescent protein (GFP) expression system to express HPV-18E6 and HPV-6E6 fusion proteins in wild-type (wt) p53 cell lines, 293T and HEK293 cells, to investigate the traffic and location of E6s and p53. The results indicated GFP-18E6 was mainly expressed in nucleus, whereas GFP-6E6 was expressed exclusively in cytoplasm. Endogenous wt p53 was shown to be localized in the nuclei of cells transfected with GFP-18E6. Interestingly, for the first time, we observed that p53 was trapped in the cytoplasm and never translocated into the cell nuclei transfected with GFP-6E6. In conclusion, HPV-6E6 was responsible for the cytoplasmic localization of p53. Therefore, our experiments provide a new insight into the pathogenesis of HPV.

  D. F McGinnity , G Zhang , J. R Kenny , G. A Hamilton , S Otmani , K. R Stams , S Haney , P Brassil , D. M Stresser and R. J. Riley
 

Prototypic CYP3A4 inducers were tested in a pregnane X receptor (PXR) reporter gene assay, Fa2N-4 cells, HepaRG cells, and primary human hepatocytes, along with negative controls, using CYP3A4 mRNA and activity endpoints, where appropriate. Over half of the compounds tested (14 of 24) were identified as time-dependent inhibitors of CYP3A4 and high mRNA/activity ratios (>10) were consistent with CYP3A4 time-dependent inhibition for compounds such as troleandomycin, ritonavir, and verapamil. Induction response was compared between two human donors; there was an excellent correlation in the EC50 estimates (r2 = 0.89, p < 0.001), and a weak but statistically significant correlation was noted for maximum observed induction at an optimum concentration (Emax) (r2 = 0.38, p = 0.001). Emax and EC50 estimates determined from the PXR reporter gene assay and Fa2N-4 and HepaRG cells were compared with those from hepatocytes. Overall, EC50 values generated using hepatocytes agreed with those generated in the PXR reporter gene assay (r2 = 0.85, p < 0.001) and Fa2N-4 (r2 = 0.65, p < 0.001) and HepaRG (r2 = 0.99, p < 0.001) cells. However, Emax values generated in hepatocytes were only significantly correlated to those determined in Fa2N-4 (r2 = 0.33, p = 0.005) and HepaRG cells (r2 = 0.79, p < 0.001). "Gold standard" cytochrome P450 induction data can be generated using primary human hepatocytes, but a restricted, erratic supply and interdonor variability somewhat restrict routine application within a drug discovery setting. HepaRG cells are a valuable recent addition to the armory of in vitro tools for assessing CYP3A4 induction and seem to be an excellent surrogate of primary cells.

  D. F McGinnity , G Zhang , J. R Kenny , G. A Hamilton , S Otmani , K. R Stams , S Haney , P Brassil , D. M Stresser and R. J. Riley
 

Prototypic CYP3A4 inducers were tested in a pregnane X receptor (PXR) reporter gene assay, Fa2N-4 cells, HepaRG cells, and primary human hepatocytes, along with negative controls, using CYP3A4 mRNA and activity endpoints, where appropriate. Over half of the compounds tested (14 of 24) were identified as time-dependent inhibitors of CYP3A4 and high mRNA/activity ratios (>10) were consistent with CYP3A4 time-dependent inhibition for compounds such as troleandomycin, ritonavir, and verapamil. Induction response was compared between two human donors; there was an excellent correlation in the EC50 estimates (r2 = 0.89, p < 0.001), and a weak but statistically significant correlation was noted for maximum observed induction at an optimum concentration (Emax) (r2 = 0.38, p = 0.001). Emax and EC50 estimates determined from the PXR reporter gene assay and Fa2N-4 and HepaRG cells were compared with those from hepatocytes. Overall, EC50 values generated using hepatocytes agreed with those generated in the PXR reporter gene assay (r2 = 0.85, p < 0.001) and Fa2N-4 (r2 = 0.65, p < 0.001) and HepaRG (r2 = 0.99, p < 0.001) cells. However, Emax values generated in hepatocytes were only significantly correlated to those determined in Fa2N-4 (r2 = 0.33, p = 0.005) and HepaRG cells (r2 = 0.79, p < 0.001). "Gold standard" cytochrome P450 induction data can be generated using primary human hepatocytes, but a restricted, erratic supply and interdonor variability somewhat restrict routine application within a drug discovery setting. HepaRG cells are a valuable recent addition to the armory of in vitro tools for assessing CYP3A4 induction and seem to be an excellent surrogate of primary cells.

  G Zhang , G Guo , X Hu , Y Zhang , Q Li , R Li , R Zhuang , Z Lu , Z He , X Fang , L Chen , W Tian , Y Tao , K Kristiansen , X Zhang , S Li , H Yang , J Wang and J. Wang
 

Understanding the dynamics of eukaryotic transcriptome is essential for studying the complexity of transcriptional regulation and its impact on phenotype. However, comprehensive studies of transcriptomes at single base resolution are rare, even for modern organisms, and lacking for rice. Here, we present the first transcriptome atlas for eight organs of cultivated rice. Using high-throughput paired-end RNA-seq, we unambiguously detected transcripts expressing at an extremely low level, as well as a substantial number of novel transcripts, exons, and untranslated regions. An analysis of alternative splicing in the rice transcriptome revealed that alternative cis-splicing occurred in ~33% of all rice genes. This is far more than previously reported. In addition, we also identified 234 putative chimeric transcripts that seem to be produced by trans-splicing, indicating that transcript fusion events are more common than expected. In-depth analysis revealed a multitude of fusion transcripts that might be by-products of alternative splicing. Validation and chimeric transcript structural analysis provided evidence that some of these transcripts are likely to be functional in the cell. Taken together, our data provide extensive evidence that transcriptional regulation in rice is vastly more complex than previously believed.

  K. G Chen , R. D Leapman , G Zhang , B Lai , J. C Valencia , C. O Cardarelli , W. D Vieira , V. J Hearing and M. M. Gottesman
  Background

Malignant melanomas are intrinsically resistant to many conventional treatments, such as radiation and chemotherapy, for reasons that are poorly understood. Here we propose and test a model that explains drug resistance or sensitivity in terms of melanosome dynamics.

Methods

The growth and sensitivity to cisplatin of MNT-1 cells, which are melanotic and enriched with mature stage III and IV melanosomes, and SK-MEL-28 cells, which have only immature stage I and II melanosomes, were compared using clonogenic assays. Differences in pigmentation, melanosome stages, melanosome number, and cellular structures in different cell lines in response to various treatments were examined by electron microscopy. The relative numbers of melanosomes of different stages were compared after treatment with 1-phenyl-2-thiourea. The relationship between drug transporter function and endogenous melanogenic toxicity was assessed by treating cells with the cyclosporin analog PSC-833 and by assessing vacuole formation and cell growth inhibition. All statistical tests were two-sided.

Results

Endogenous melanogenic cytotoxicity, produced by damaged melanosomes, resulted in pronounced cell growth inhibition in MNT-1 cells compared with amelanotic SK-MEL-28 cells. The sensitivity to CDDP of MNT-1 cells was 3.8-fold higher than that of SK-MEL-28 cells (mean IC50 for SK-MEL-28 and MNT-1 = 2.13 µM and 0.56 µM, respectively; difference = 1.57 µM, 95% confidence interval = 1.45 to 1.69; P = .0017). After treatment with 6.7 µM CDDP for 72 hours, the number of stage II-III melanosomes in surviving MNT-1 cells was 6.8-fold that of untreated cells. Modulation of MNT-1 cells to earlier-stage (II, II-III, III) melanosomes by treatment with the tyrosinase inhibitor 1-phenyl-2-thiourea dramatically increased CDDP resistance. Furthermore, PSC-833 principally suppressed MNT-1 melanotic cell growth via an elevation of autophagosome-like vacuolar structures, possibly by inhibiting melanosome membrane transporters.

Conclusions

Melanosome dynamics (including their biogenesis, density, status, and structural integrity) regulate the drug resistance of melanoma cells. Manipulation of melanosome functions may be an effective way to enhance the therapeutic activity of anticancer drugs against melanoma.

  E Shaheen , F Zanca , F Sisini , G Zhang , J Jacobs and H. Bosmans
 

Digital breast tomosynthesis is a new three-dimensional (3D) breast-imaging modality that produces images of cross-sectional planes parallel to the detector plane from a limited number of X-ray projections over a limited angular range. Several technical and clinical parameters have not yet been completely optimised. Some of the open questions could be addressed experimentally; other parameter settings cannot be easily realised in practice and the associated optimisation process requires therefore a theoretical approach. Rather than simulating the complete 3D imaging chain, it is hypothesised that the simulation of small lesions into clinical (or test object) images can be of help in the optimisation process. In the present study, small 3D objects have been simulated into real projection images. Subsequently, these hybrid projection images are reconstructed using the routine clinical reconstruction tools. In this study, the validation of this simulation framework is reported through the comparison between simulated and real objects in reconstructed planes. The results confirm that there is no statistically significant difference between the simulated and the real objects. This suggests that other small mathematical or physiological objects could be simulated with the same approach.

  K. L Sens , S Zhang , P Jin , R Duan , G Zhang , F Luo , L Parachini and E. H. Chen
 

Recent studies in Drosophila have implicated actin cytoskeletal remodeling in myoblast fusion, but the cellular mechanisms underlying this process remain poorly understood. Here we show that actin polymerization occurs in an asymmetric and cell type–specific manner between a muscle founder cell and a fusion-competent myoblast (FCM). In the FCM, a dense F-actin–enriched focus forms at the site of fusion, whereas a thin sheath of F-actin is induced along the apposing founder cell membrane. The FCM-specific actin focus invades the apposing founder cell with multiple finger-like protrusions, leading to the formation of a single-channel macro fusion pore between the two muscle cells. Two actin nucleation–promoting factors of the Arp2/3 complex, WASP and Scar, are required for the formation of the F-actin foci, whereas WASP but not Scar promotes efficient foci invasion. Our studies uncover a novel invasive podosome-like structure (PLS) in a developing tissue and reveal a previously unrecognized function of PLSs in facilitating cell membrane juxtaposition and fusion.

 
 
 
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