State Key Laboratory of Biotherapy

Chengdu, China

State Key Laboratory of Biotherapy

Chengdu, China
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Yang X.-G.,Sichuan University | Wei L.V.,Sichuan University | Chen Y.U.-Z.,State Key Laboratory of Biotherapy | Chen Y.U.-Z.,National University of Singapore | And 2 more authors.
Journal of Computational Chemistry | Year: 2010

γ-Secretase inhibitors have been explored for the prevention and treatment of Alzheimer's disease (AD). Methods for prediction and screening of γ-secretase inhibitors are highly desired for facilitating the design of novel therapeutic agents against AD, especially when incomplete knowledge about the mechanism and three-dimensional structure of γ-secretase. We explored two machine learning methods, support vector machine (SVM) and random forest (RF), to develop models for predicting γ-secretase inhibitors of diverse structures. Quantitative analysis of the receiver operating characteristic (ROC) curve was performed to further examine and optimize the models. Especially, the Youden index (YI) was initially introduced into the ROC curve of RF so as to obtain an optimal threshold of probability for prediction. The developed models were validated by an external testing set with the prediction accuracies of SVM and RF 96.48 and 98.83% for γ-secretase inhibitors and 98.18 and 99.27% for noninhibitors, respectively. The different feature selection methods were used to extract the physicochemical features most relevant to γ-secretase .inhibition. To the best of our knowledge, the RF model developed in this work is the first model with a broad applicability domain, based on which the virtual screening of γ-secretase inhibitors against the ZINC database was performed, resulting in 368 potential hit candidates. © 2009 Wiley Periodicals, Inc.

Wang X.,University of Sichuan | Wang X.,State Key Laboratory of Biotherapy | Chen T.,Xindu District Peoples Hospital | Yu R.,State Key Laboratory of Biotherapy | And 3 more authors.
Diagnostic Microbiology and Infectious Disease | Year: 2013

Among 82 clinical isolates of the Acinetobacter calcoaceticus-baumannii complex recovered in 13 hospitals of Sichuan, China, in 2011, 13 were Acinetobacter pittii and 2 were Acinetobacter nosocomialis. Multilocus sequence typing revealed a novel sequence type (ST) of A. nosocomialis and 7 novel STs of A. pittii. Most isolates were hospital-acquired and colonized in the respiratory tract, while 6 cases with pneumonia due to A. pittii were identified. This study provided a snapshot of the local incidence of A. pittii and A. nosocomialis. © 2013 Elsevier Inc.

Xia J.,Key Laboratory of Transplant Engineering and Immunology | Xia J.,State Key Laboratory of Biotherapy | Zhou Y.,Key Laboratory of Transplant Engineering and Immunology | Ji H.,Key Laboratory of Transplant Engineering and Immunology | And 10 more authors.
Hepatology | Year: 2013

Histone deacetylases 1 and 2 (HDAC1 and HDAC2) are ubiquitously expressed in tissues, including the liver, and play critical roles in numerous physiopathological processes. Little is known regarding the role of HDAC1 and HDAC2 in liver regeneration. In this study we generated mice in which Hdac1, Hdac2 or both genes were selectively knocked out in hepatocytes to investigate the role of these genes in liver regeneration following hepatic injury induced by partial hepatectomy or carbon tetrachloride administration. The loss of HDAC1 and/or HDAC2 (HDAC1/2) protein resulted in impaired liver regeneration. HDAC1/2 inactivation did not decrease hepatocytic 5-bromo-2-deoxyuridine uptake or the expression of proliferating cell nuclear antigen, cyclins, or cyclin-dependent kinases. However, the levels of Ki67, a mitotic marker that is expressed from the mid-G1 phase to the end of mitosis and is closely involved in the regulation of mitotic progression, were greatly decreased, and abnormal mitosis lacking Ki67 expression was frequently observed in HDAC1/2-deficient livers. The down-regulation of either HDAC1/2 or Ki67 in the mouse liver cancer cell line Hepa1-6 resulted in similar mitotic defects. Finally, both HDAC1 and HDAC2 proteins were associated with the Ki67 gene mediated by CCAAT/enhancer-binding protein β. Conclusion: Both HDAC1 and HDAC2 play crucial roles in the regulation of liver regeneration. The loss of HDAC1/2 inhibits Ki67 expression and results in defective hepatocyte mitosis and impaired liver regeneration. © 2013 by the American Association for the Study of Liver Diseases.

Zong Z.,University of Sichuan | Zong Z.,State Key Laboratory of Biotherapy | Lu X.,University of Sichuan
PLoS ONE | Year: 2010

Background: Many SCCmec elements of coagulase-negative staphylococci (CoNS) could not be typed using multiplex PCR. Such a 'non-typable' SCCmec was encountered in a Staphylococcus cohnii isolate. Methodology/Principal Findings: The SCCmec type of methicillin-resistant S. cohnii clinical isolate WC28 could not be assigned using multiplex PCR. Newly-designed primers were used to amplify ccrA and ccrB genes. The whole SCCmec was obtained by three overlapping long-range PCR, targeting regions from left-hand inverted repeat (IRL) to ccrA/B, from ccrA/B to mecA and from mecA to orfX. The region abutting IRL was identified using inverse PCR with self-ligated enzyme-restricted WC28 fragments as the template. WC28 SCCmec had a class A mec gene complex (mecI-mecR1-mecA). The ccrA and ccrB genes were closest (89.7% identity) to ccrASHP of Staphylococcus haemolyticus strain H9 and to ccrB3 (90% identity) of Staphylococcus pseudintermedius strain KM241, respectively. Two new genes potentially encoding AAA-type ATPase were found in J1 region and a ΨTn554 transposon was present in J2 region, while J3 region was the same as many SCCmec of Staphylococcus aureus. WC28 SCCmec abutted an incomplete SCC element with a novel allotype of ccrC, which was closest (82% identity) to ccrC1 allele 9 in Staphylococcus saprophyticus strain ATCC 15305. Only two direct target repeat sequences, one close to the 39-end of orfX and the other abutting the left end of WC28 SCCmec, could be detected. Conclusions/Significance: A new 35-kb SCCmec was characterized in a S. cohnii isolate, carrying a class A mec gene complex, new variants of ccrA5 and ccrB3 and two novel genes in the J1 region. This element is flanked by 8-bp perfect inverted repeats and is similar to type III SCCmec in S. aureus and a SCCmec in S. pseudintermedius but with different J1 and J3 regions. WC28 SCCmec was arranged in tandem with an additional SCC element with ccrC, SCC WC28, but the two elements might have integrated independently rather than constituted a composite. This study adds new evidence of the diversity of SCCmec in CoNS and highlights the need for characterizing the 'non-typable' SCCmec to reveal the gene pool associated with mecA. © 2010 Zong, Lü.

Feng Y.,University of Sichuan | Feng Y.,State Key Laboratory of Biotherapy | Yang P.,University of Sichuan | Yang P.,State Key Laboratory of Biotherapy | And 4 more authors.
Journal of Antimicrobial Chemotherapy | Year: 2016

Objectives: To obtain the complete genome sequence of an Acinetobacter johnsonii isolate, which encodes the NDM-1 and OXA-58 carbapenemases. Methods: Genome sequencing was performed using the 454 and HiSeq 2000 platforms. Reads were assembled into scaffolds and gaps between scaffolds were filled by PCR and Sanger sequencing. Phylogenetic analyses of A. johnsonii isolates and their intrinsic blaOXA genes were performed using Harvest and MEGA. The context of blaaOXA-58 was analysed in detail. Results: Isolate XBB1 has one 3.5 Mb chromosome (38.5% GC content) and nine plasmids in the range 3.9-398.9 kb. Isolate XBB1 appears to be distinct from other A. johnsonii isolates. Five of the nine plasmids contained genes encoding for mobilization. The largest contains four XerC/XerD-like binding sites and five Re27 regions. Alignment revealed that Re27 regions are variants of XerC/XerD-like sites. Besides blaNDM-1 and blaOXA-58, isolate XBB1 has an ESBL gene blaPER-1 and a few other genes conferring resistance to aminoglycosides, chloramphenicol, rifampicin, sulphonamides and tetracycline. blaOXA-58 is located in a Russian doll-type structure, as it is flanked by ISAba3, then by two copies of a newly identified element ISAjo2 and bracketed by a pair of Re27 regions. The intrinsic blaOXA of XBB1 is a new variant, blaOXA-311, which is most closely related to blaOXA-333 in an Australian A. johnsonii isolate. Conclusions: We present the first completely assembled genome sequence of A. johnsonii. The ability of A. johnsonii to harbour nine plasmids suggests this species could generate various platforms to mediate the dissemination of antimicrobial resistance. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.

Zong Z.,University of Sichuan | Zong Z.,State Key Laboratory of Biotherapy | Peng C.,University of Sichuan | Peng C.,Peoples Hospital of Guizhou Province | Lu X.,University of Sichuan
PLoS ONE | Year: 2011

Background: Methicillin-resistant coagulase-negative staphylococci (MR-CoNS) are opportunistic pathogens and serve as a large reservoir of staphylococcal cassette chromosome mec (SCCmec). Characterization of SCCmec in MR-CoNS can generate useful information on the mobilization and evolution of this element. Methodology/Principal Findings: Non-repetitive MR-CoNS clinical isolates (n = 84; 39 S. epidermidis, 19 S. haemolyticus, 9 S. hominis, 6 S. capitis, 4 S. warneri, 2 S. cohnii, 2 S. saprophyticus, 1 S. kloosii, 1 S. simulans and 1 S. massiliensis) were collected. All isolates could grow on plates with 4 mg/L cefoxitin and all had mecA as detected by PCR. Strain typing using RAPD and ERIC-PCR revealed that almost all isolates were of different strains. SCCmec typing was performed using multiplex PCR published previously. For isolates in which SCCmec could not be typed, the mec complex classes were determined by additional PCR and the ccr genes were amplified with published or newly-designed primers and then sequenced. SCCmec types were assigned for 63 isolates by multiplex PCR and were assigned for 14 other isolates by PCR targeting mec and ccr. Among 77 isolates with determined SCCmec types, 54 had a single type, including type III (n = 19), IV (n = 14), V (n = 10), II (n = 2), I (n = 1), VIII (n = 1) and five unnamed types (n = 7), while 23 isolates had two types, III+V (n = 12), II+V (n = 8), II+IV (n = 2) or IV+V (n = 1). The five unnamed types were assigned UT1 (class A mec, ccrA1/ccrB4), UT2 (class C1 mec, ccrA4/ccrB4), UT3 (class A mec, ccrA5/ccrB3), UT4 (class C2 mec, ccrA2/ccrB2 plus ccrC1) and UT5 (class A mec, ccrA1/ccrB1 plus ccrC1). Conclusions/Significance: SCCmec types III, IV and V were prevalent in MR-CoNS and many isolates could harbor more than one type. Several new types of SCCmec were identified, highlighting the great genetic diversity and the need of developing classification schemes for SCCmec in MR-CoNS. © 2011 Zong et al.

Wang X.,University of Sichuan | Wang X.,State Key Laboratory of Biotherapy | Qiao F.,University of Sichuan | Yu R.,University of Sichuan | And 5 more authors.
BMC Microbiology | Year: 2013

Background: Acinetobacter baumannii is a notorious opportunistic pathogen mainly associated with hospital-acquired infections. Studies on the clonal relatedness of isolates could lay the foundation for effective infection control. A snapshot study was performed to investigate the clonal relatedness of A. baumannii clinical isolates in our local settings. Results: Among 82 non-repetitive Acinetobacter spp. clinical isolates that were recovered during a period of four days in 13 hospitals in Sichuan, Southwest China, 67 isolates were identified as A. baumannii. Half of the 67 A. baumannii isolates were non-susceptible to carbapenems. bla OXA-23 was the only acquired carbapenemase gene detected, present in 40 isolates including five carbapenem-susceptible ones. The isolates belonged to 62 pulsotypes determined by PFGE and 31 sequence types (ST) by multi-locus sequence typing. Forty-three isolates belonged to the globally-disseminated clonal complex 92, among which ST75, ST92 and ST208 were the most common sequence types. Conclusions: Clinical isolates of A. baumannii were diverse in clonality in this snapshot study. However, most of the isolates belonged to the globally-distributed clonal complex CC92. ST75, ST92 and ST208 were the most common types in our region. In particular, ST208 might be an emerging lineage carrying bla OXA-23. © 2013 Wang et al.; licensee BioMed Central Ltd.

Li X.,State Key Laboratory of Biotherapy | Du J.-R.,State Key Laboratory of Biotherapy | Yu Y.,State Key Laboratory of Biotherapy | Bai B.,State Key Laboratory of Biotherapy | Zheng X.-Y.,State Key Laboratory of Biotherapy
Journal of Ethnopharmacology | Year: 2010

Aim of the study: To investigate the effect of tashinone IIA (TA) on intimal hyperplasia in a rat model of carotid artery balloon injury and on the proliferation of cultured vascular smooth muscle cells (VSMCs) induced by fetal bovine serum (FBS) and its underlying mechanisms. Materials and methods: Carotid artery injury was induced in rats by balloon dilatation and they were treated with TA or vehicle for 2 weeks until killed for assessment of neointimal formation and lumen area. VSMC was cultured in vitro and proliferation was assessed by determining cell number, bromodeoxyuridine (BrdU) incorporation and cell cycle analysis. The extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and c-fos expression were assessed by Western blot and reverse transcription-polymerase chain reaction (RT-PCR) respectively. Results: TA could significantly decrease intimal thickening, suppress cell proliferation and BrdU incorporation into DNA, block cell cycle in G0/G1 phase, inhibit ERK1/2 phosphorylation and c-fos expression. Conclusions: TA abolishes VSMC proliferation and reduces intimal hyperplasia through inhibition of mitogen-activated protein kinase (MAPK) signaling pathway and down-regulation of c-fos expression. © 2010 Elsevier Ireland Ltd.

Zong Z.,University of Sichuan | Zong Z.,State Key Laboratory of Biotherapy
Antonie van Leeuwenhoek, International Journal of General and Molecular Microbiology | Year: 2012

Staphylococcus massiliensis is a newly-recognized species but its ecological niche and its role in infection remained unclear. Clinical isolate WCG21 recovered from a wound sample was initially identified as Staphylococcus simulans by the WalkAway automated system but was subsequently identified as S. massiliensis by partially sequencing the 16S rRNA and dnaJ genes. Strain WCG21 was probably a contaminant rather than a pathogen. The 16S rRNA gene sequences of several bacterial clones from human skin were also identical or near identical to that of S. massiliensis, suggesting that this species is part of human skin microflora. Although strain WCG21 was susceptible to a wide range of antimicrobials, it harbored a type V staphylococcal cassette chromosome mec. © 2011 Springer Science+Business Media B.V.

Yang P.,University of Sichuan | Yang P.,State Key Laboratory of Biotherapy | Xie B.Y.,University of Sichuan | Feng P.,University of Sichuan | And 2 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2014

blaNDM-5was found in Escherichia coli strain 0215 from a Chinese patient without travel history. Genomic sequencing and conjugation experiments were performed. Strain 0215 belonged to sequence type 167 (ST167) and had other resistance determinants, including blaTEM-135, blaCTX-M-14, and aac(6=)-Ib. blaNDM-5was carried by a 47-kb self-transmissible IncX3 plasmid and was in a complex genetic context similar to that of blaNDM-1 on IncX3 plasmids. IncX3 plasmids might have emerged as a common vehicle mediating the spread of blaNDM. © 2014 American Society for Microbiology. All Rights Reserved.

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