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1.  Breakthrough cancer medicine and its impact on novel drug development in China: report of the US Chinese Anti-Cancer Association (USCACA) and Chinese Society of Clinical Oncology (CSCO) Joint Session at the 17th CSCO Annual Meeting 
Chinese Journal of Cancer  2014;33(12):620-624.
The US Chinese Anti-Cancer Association (USCACA) teamed up with Chinese Society of Clinical Oncology (CSCO) to host a joint session at the17th CSCO Annual Meeting on September 20th, 2014 in Xiamen, China. With a focus on breakthrough cancer medicines, the session featured innovative approaches to evaluate breakthrough agents and established a platform to interactively share successful experiences from case studies of 6 novel agents from both the United States and China. The goal of the session is to inspire scientific and practical considerations for clinical trial design and strategy to expedite cancer drug development in China. A panel discussion further provided in-depth advice on advancing both early and full development of novel cancer medicines in China.
PMCID: PMC4308658  PMID: 25418191
Breakthrough; clinical trial; cancer medicine
2.  A randomized, controlled, blinded study of the safety and immunogenicity of Haemophilus influenzae type b conjugate vaccine injected at different intramuscular sites in Chinese infants 
Human Vaccines & Immunotherapeutics  2013;9(11):2311-2315.
To compare the safety and immunogenicity of Haemophilus influenzae type b (Hib) conjugate vaccine administered via the vastus lateralis and deltoid muscles, 320 healthy Chinese infants <12 mo of age were enrolled in a randomized, controlled, blinded study and divided into 2 age groups: 2–5 mo and 6–12 mo. Each age group was then randomized (1:1) to either the vastus lateralis (experimental) group who received Hib vaccination into this muscle 2 or 3 times at monthly intervals, or the deltoid (control) group who received Hib vaccination into this muscle either 3 times (2–5 mo group) or twice (6–12 mo group) at monthly intervals. Local and systemic adverse reactions after each vaccine dose were recorded, and Hib-PRP antibody concentrations were determined by ELISA at 28 d after completion of the immunization schedule. There were no significant differences in the proportions of subjects with post-immunization Hib-PRP antibody concentrations ≥1.0 μg/mL or ≥0.15 μg/mL with the two injection sites for either age group, or in the post-immunization Hib-PRP antibody concentrations achieved (P > 0.05). In addition, there were no significant differences in the rates of local and systemic reactions after the first and second vaccinations between the 2 injection sites for either age group (P > 0.05), but the rate of systemic reactions in the 2–5 mo group after the third vaccination via the vastus lateralis muscle was significantly lower than after deltoid vaccination (0% vs 8.57%; P < 0.05). Thus, administration via the vastus lateralis muscle is worth considering for Hib vaccination.
PMCID: PMC3981838  PMID: 23842003
Haemophilus influenzae type b vaccine; vaccination site; vastus lateralis; deltoid; safety; immunogenicity
3.  Isolation, Identification and Characteristics of an Endophytic Quinclorac Degrading Bacterium Bacillus megaterium Q3 
PLoS ONE  2014;9(9):e108012.
In this study, we isolated an endophytic quinclorac-degrading bacterium strain Q3 from the root of tobacco grown in quinclorac contaminated soil. Based on morphological characteristics, Biolog identification, and 16S rDNA sequence analysis, we identified strain Q3 as Bacillus megaterium. We investigated the effects of temperature, pH, inoculation size, and initial quinclorac concentration on growth and degrading efficiency of Q3. Under the optimal degrading condition, Q3 could degrade 93% of quinclorac from the initial concentration of 20 mg/L in seven days. We analyzed the degradation products of quinclorac using liquid chromatography–tandem mass spectrometry (LC-MS/MS). The major degradation products by Q3 were different from those of previously identified quinclorac degrading strains, which suggests that Q3 may employ new pathways for quinclorac degradation. Our indoor pot experiments demonstrated that Q3 can effectively alleviate the quinclorac phytotoxicity in tobacco. As the first endophytic microbial that is capable of degrading quinclorac, Q3 can be a good bioremediation bacterium for quinclorac phytotoxicity.
PMCID: PMC4171507  PMID: 25244184
4.  Immunogenicity and safety of three 2010–2011 seasonal trivalent influenza vaccines in Chinese toddlers, children and older adults 
Human Vaccines & Immunotherapeutics  2013;9(8):1725-1734.
The 2009 influenza A(H1N1) pandemic strain was for the first time included in the 2010–2011 seasonal trivalent influenza vaccine (TIV). We conducted a double-blind, randomized trial in Chinese population to assess the immunogenicity and safety of the 2010–2011 TIV manufactured by GlaxoSmithKline and compared it with the counterpart vaccines manufactured by Sanofi Pasteur and Sinovac Biotech. Healthy toddlers (6–36 mo), children (6–12 y) and older adults (≥60 y) with 300 participants in each age group were enrolled to randomly receive two doses (toddlers, 28 d apart) or one dose (children and older adults). The immunogenicity was assessed by hemagglutination-inhibition (HI) assay. The solicited injection-site and systemic adverse events (AEs) were collected within 7 d after vaccination. All the three TIVs were well-tolerated with 15.1% of participants reporting AEs, most of which were mild. No serious AEs and unusual AEs were reported. Fever and pain were the most common systemic and injection-site AEs, respectively. The three TIVs showed good immunogenicity. The seroprotection rates against both H1N1 and H3N2 strains were more than 87% in toddlers after two doses and more than 95% in children and more than 86% in older adults after one dose. The seroprotection rates against B strain were 68–71% in toddlers after two doses, 70–74% in children and 69–72% in older adults after one dose. In conclusion, the three 2010–2011 TIVs had good immunogenicity and safety in Chinese toddlers, children and older adults and were generally comparable in immunogenicity and reactogenicity.
PMCID: PMC3906273  PMID: 23896581
influenza; vaccine; seasonal trivalent influenza vaccine; influenza A (H1N1); immunogenicity; safety
5.  Treatment of nasopharyngeal carcinoma with pulmonary tuberculosis and gout: A case report 
Oncology Letters  2014;8(2):753-757.
In China, the incidence of nasopharyngeal carcinoma (NPC) and tuberculosis remains high. Additionally, there has been a marked increase in the prevalence of gout. In recent years, there has been an increase in the number of co-existing diseases. To the best of our knowledge, there have been no previous cases reported in the literature with regard to patients suffering from NPC complicated with pulmonary tuberculosis and gout. The present study describes the case of a 59-year-old male with this condition. The patient received a combination of anti-tumor, anti-tuberculosis and anti-gout therapies, and experienced no severe adverse reactions during treatment. At present, the patient’s Eastern Cooperative Oncology Group performance status is good, there has been no local recurrence or distant metastasis of the NPC, and the pulmonary tuberculosis and gout are well controlled. The aim of this study was to provide insight into the treatment of patients suffering from co-existing conditions.
PMCID: PMC4081372  PMID: 25013497
combination treatment; gout; nasopharyngeal carcinoma; pulmonary tuberculosis
6.  MiRNA-125a-5p: a regulator and predictor of gefitinib’s effect on nasopharyngeal carcinoma 
Nasopharyngeal carcinoma (NPC) is a common malignancy in China and Southeast Asia. Radiotherapy is the major treatment modality for patients with NPC, but does not always achieve fully satisfactory outcomes. Studies have shown that epidermal growth factor receptor (EGFR) is highly expressed in NPC, and EGFR-targeted treatment is expected to be a new strategy for NPC. Recently, clinical trials have shown that NPC patients have different responses to gefitinib. Thus, the identification of indicators that can regulate and predict the sensitivity of NPC to gefitinib is very valuable. MiRNAs (MicroRNAs) are closely related to cancer development. We studied miRNAs in NPC cell lines to identify those that can regulate and predict the effectiveness of gefitinib on NPC.
CCK8, Annexin V-FITC assays and animal models were carried out to evaluate the inhibitory effect of gefitinib on NPC cell lines HNE-1 and HK-1. MiRNA microarrays were used to detect and compare the miRNAs expression levels in the two cells with gefitinib or not, and qRT-PCR was used to evaluate miR-125a-5p expression in NPC cells and in serum of the tumor animal models. Loss-of-function and gain-of-function experiments were taken to evaluate the effect of miR-125a-5p on gefitinib effectiveness. Western blots were used to evaluate the effect of miR-125a-5p on p53 and Her2 in HNE-1 and HK-1 cells.
Gefitinib inhibited two NPC cell lines proliferation in vitro and in vivo,and HNE-1 cells were less sensitive than HK-1 cells to gefitinib.MiR-125a-5p expression levels were increased by geftinib in the two cell lines and in the serum of NPC tumor bearing-mice. This phenomenon was weak in HNE-1 cells and strong in HK-1 cells. MiR-125a-5p over expression improved anti-proliferative and pro-apoptotic effects of gefitinib on the NPC cells and that miR-125a-5p down-regulation decreased those effects. MiR-125a-5p also increased p53 protein expression in HNE-1 cells, and decreased Her2 protein expression in HNE-1 and HK-1 cells.
Our results indicate that gefitinib sensitivity and some miRNAs expressions varied in NPC cell lines. The miR-125a-5p is a possible candidate that can regulate and predict the effect of gefitinib on NPC.
PMCID: PMC3973965  PMID: 24602316
miRNA; miR-125a-5p; Nasopharyngeal carcinoma; Gefitinib
7.  Correction: A High Density Consensus Genetic Map of Tetraploid Cotton That Integrates Multiple Component Maps through Molecular Marker Redundancy Check 
PLoS ONE  2014;9(1):10.1371/annotation/d2b10915-daa3-4ed7-ad95-3a6d50b26fea.
PMCID: PMC3899042
8.  Mesoporous Magnetic Gold “Nanoclusters” as Theranostic Carrier for Chemo-Photothermal Co-therapy of Breast Cancer 
Theranostics  2014;4(7):678-692.
Photothermal therapy (PTT) is proved to be an efficient manner for superficial tumor therapy in preclinical studying. The tumor suppression of chemotherapy can be enhanced by combining with PTT. In this study, we reported a mesoporous magnetic gold “nanoclusters” (MMGNCs) structure as theranostic carrier for chemo-photothermal co-therapy. MMGNCs were successfully prepared and they exhibited efficient photo-thermal effect for PTT. The mesoporous structure provided MMGNCs with high drug loading capacity. By in vitro cytotoxicity testing, we revealed that the combination of PTT and chemotherapy could cause more damage than chemotherapy or PTT did alone. By topically targeting mediated by the extra-magnetic field (MF), MMGNCs can be targeted to the tumor site efficiently. In vivo chemo-photothermal co-therapy of 4T1 breast cancer, under the combinational treatments of chemo-photothermal co-therapy and extra-MF targeting, the tumor growth has been efficiently inhibited, and the pulmonary and mediastinal metastasis have also been prevented. The survival of the cancer bearing mice was prolonged. The bio-imaging applications of this system and the mechanism of the metastasis prevention are ongoing.
PMCID: PMC4038750  PMID: 24883118
Multifunctional nanoparticles; Photothermal Therapy; Multidrug Resistance; Co-therapy.
9.  Synthesis, Characterization, and Acute Oral Toxicity Evaluation of pH-Sensitive Hydrogel Based on MPEG, Poly(ε-caprolactone), and Itaconic Acid 
BioMed Research International  2013;2013:239838.
A kind of chemically cross-linked pH-sensitive hydrogels based on methoxyl poly(ethylene glycol)-poly(caprolactone)-acryloyl chloride (MPEG-PCL-AC, PECA), poly(ethylene glycol) methyl ether methacrylate (MPEGMA, MEG), N,N-methylenebisacrylamide (BIS), and itaconic acid (IA) were prepared without using any organic solvent by heat-initiated free radical method. The obtained macromonomers and hydrogels were characterized by 1H NMR and FT-IR, respectively. Morphology study of hydrogels was also investigated in this paper, and it showed that the hydrogels had good pH-sensitivity. The acute toxicity test and histopathological study were conducted in BALB/c mice. The results indicated that the maximum tolerance dose of the hydrogel was higher than 10000 mg/kg body weight. No morality or signs of toxicity were observed during the whole 7-day observation period. Compared to the control groups, there were no important adverse effects in the variables of hematology routine test and serum chemistry analysis both in male or female treatment group. Histopathological study also did not show any significant lesions, including heart, liver, lung, spleen, kidney, stomach, intestine, and testis. All the results demonstrated that this hydrogel was nontoxic after gavage. Thus, the hydrogel might be the biocompatible potential candidate for oral drug delivery system.
PMCID: PMC3864077  PMID: 24364030
10.  A quantitative structure–activity relationship (QSAR) study on glycan array data to determine the specificities of glycan-binding proteins 
Glycobiology  2011;22(4):552-560.
Advances in glycan array technology have provided opportunities to automatically and systematically characterize the binding specificities of glycan-binding proteins. However, there is still a lack of robust methods for such analyses. In this study, we developed a novel quantitative structure–activity relationship (QSAR) method to analyze glycan array data. We first decomposed glycan chains into mono-, di-, tri- or tetrasaccharide subtrees. The bond information was incorporated into subtrees to help distinguish glycan chain structures. Then, we performed partial least-squares (PLS) regression on glycan array data using the subtrees as features. The application of QSAR to the glycan array data of different glycan-binding proteins demonstrated that PLS regression using subtree features can obtain higher R2 values and a higher percentage of variance explained in glycan array intensities. Based on the regression coefficients of PLS, we were able to effectively identify subtrees that indicate the binding specificities of a glycan-binding protein. Our approach will facilitate the glycan-binding specificity analysis using the glycan array. A user-friendly web tool of the QSAR method is available at
PMCID: PMC3409798  PMID: 22156918
glycan array; PLS; QSAR
11.  Correction: A High Density Consensus Genetic Map of Tetraploid Cotton That Integrates Multiple Component Maps through Molecular Marker Redundancy Check 
PLoS ONE  2013;8(3):10.1371/annotation/ab8211a0-53a5-4765-a7cb-4b613ffb1b09.
PMCID: PMC3600078
12.  Massive-Scale Gene Co-Expression Network Construction and Robustness Testing Using Random Matrix Theory 
PLoS ONE  2013;8(2):e55871.
The study of gene relationships and their effect on biological function and phenotype is a focal point in systems biology. Gene co-expression networks built using microarray expression profiles are one technique for discovering and interpreting gene relationships. A knowledge-independent thresholding technique, such as Random Matrix Theory (RMT), is useful for identifying meaningful relationships. Highly connected genes in the thresholded network are then grouped into modules that provide insight into their collective functionality. While it has been shown that co-expression networks are biologically relevant, it has not been determined to what extent any given network is functionally robust given perturbations in the input sample set. For such a test, hundreds of networks are needed and hence a tool to rapidly construct these networks. To examine functional robustness of networks with varying input, we enhanced an existing RMT implementation for improved scalability and tested functional robustness of human (Homo sapiens), rice (Oryza sativa) and budding yeast (Saccharomyces cerevisiae). We demonstrate dramatic decrease in network construction time and computational requirements and show that despite some variation in global properties between networks, functional similarity remains high. Moreover, the biological function captured by co-expression networks thresholded by RMT is highly robust.
PMCID: PMC3567026  PMID: 23409071
13.  A High Density Consensus Genetic Map of Tetraploid Cotton That Integrates Multiple Component Maps through Molecular Marker Redundancy Check 
PLoS ONE  2012;7(9):e45739.
A consensus genetic map of tetraploid cotton was constructed using six high-density maps and after the integration of a sequence-based marker redundancy check. Public cotton SSR libraries (17,343 markers) were curated for sequence redundancy using 90% as a similarity cutoff. As a result, 20% of the markers (3,410) could be considered as redundant with some other markers. The marker redundancy information had been a crucial part of the map integration process, in which the six most informative interspecific Gossypium hirsutum×G. barbadense genetic maps were used for assembling a high density consensus (HDC) map for tetraploid cotton. With redundant markers being removed, the HDC map could be constructed thanks to the sufficient number of collinear non-redundant markers in common between the component maps. The HDC map consists of 8,254 loci, originating from 6,669 markers, and spans 4,070 cM, with an average of 2 loci per cM. The HDC map presents a high rate of locus duplications, as 1,292 markers among the 6,669 were mapped in more than one locus. Two thirds of the duplications are bridging homoeologous AT and DT chromosomes constitutive of allopolyploid cotton genome, with an average of 64 duplications per AT/DT chromosome pair. Sequences of 4,744 mapped markers were used for a mutual blast alignment (BBMH) with the 13 major scaffolds of the recently released Gossypium raimondii genome indicating high level of homology between the diploid D genome and the tetraploid cotton genetic map, with only a few minor possible structural rearrangements. Overall, the HDC map will serve as a valuable resource for trait QTL comparative mapping, map-based cloning of important genes, and better understanding of the genome structure and evolution of tetraploid cotton.
PMCID: PMC3454346  PMID: 23029214
14.  Conserved Non-Coding Regulatory Signatures in Arabidopsis Co-Expressed Gene Modules 
PLoS ONE  2012;7(9):e45041.
Complex traits and other polygenic processes require coordinated gene expression. Co-expression networks model mRNA co-expression: the product of gene regulatory networks. To identify regulatory mechanisms underlying coordinated gene expression in a tissue-enriched context, ten Arabidopsis thaliana co-expression networks were constructed after manually sorting 4,566 RNA profiling datasets into aerial, flower, leaf, root, rosette, seedling, seed, shoot, whole plant, and global (all samples combined) groups. Collectively, the ten networks contained 30% of the measurable genes of Arabidopsis and were circumscribed into 5,491 modules. Modules were scrutinized for cis regulatory mechanisms putatively encoded in conserved non-coding sequences (CNSs) previously identified as remnants of a whole genome duplication event. We determined the non-random association of 1,361 unique CNSs to 1,904 co-expression network gene modules. Furthermore, the CNS elements were placed in the context of known gene regulatory networks (GRNs) by connecting 250 CNS motifs with known GRN cis elements. Our results provide support for a regulatory role of some CNS elements and suggest the functional consequences of CNS activation of co-expression in specific gene sets dispersed throughout the genome.
PMCID: PMC3443200  PMID: 23024789
15.  Implication of the env Gene of the Human Endogenous Retrovirus W Family in the Expression of BDNF and DRD3 and Development of Recent-Onset Schizophrenia 
Schizophrenia Bulletin  2010;37(5):988-1000.
Objective: Retrovirus has been suggested as one of agents involved in the development of schizophrenia. In the present study, we examined the role of the human endogenous retrovirus W family (HERV-W) env gene in the etiopathogenesis of recent-onset schizophrenia, using molecular and epidemiological approaches. Methods: Nested RT-PCR was used to detect the messenger RNA (mRNA) of the HERV-w env gene in plasmas. Quantitative real-time polymerase chain reaction (PCR) was employed to detect the viral reverse transcriptase activity in human sera. Human U251 glioma cells were used to study the potential role of the HERV-W env gene in the etiopathogenesis of recent-onset schizophrenia. Results: We identified genes with mRNA sequences homologous to HERV-W env gene from plasmas of 42 out of 118 individuals with recent-onset schizophrenia but not from any of 106 normal persons (P < .01, t test). Quantitative real-time PCR showed a significantly increase in the reverse transcriptase activity in the sera of patients (by 35.59%) compared with controls (by 2.83%) (P < .05, t test). Overexpression of HERV-w env in human U251 glioma cells upregulated brain-derived neurotrophic factor (BDNF), an important schizophrenia-associated gene, neurotrophic tyrosine kinase receptor type 2 (NTRK2, also called TrkB), and dopamine receptor D3 and increased the phosphorylation of cyclic adenosine monophosphate response element–binding (CREB) protein. BDNF promoter reporter gene assays showed that the HERV-W env triggers BDNF production in human U251 glioma cells. Using gene knockdown, we found that CREB is required for the expression of BDNF that is regulated by env. Conclusion: Our data revealed that the transcriptional activation of HERV is associated with the development of schizophrenia in some patients and indicated that HERV-W env regulates the expression of schizophrenia-associated genes. This report is the first to elucidate the signaling pathway responsible for the upregulation of HERV-W env–triggered BDNF. Our study provides new evidence for the involvement of HERV-W in the central nervous system, which will benefit the diagnosis and treatment of the devastating schizophrenia and related disorders.
PMCID: PMC3160218  PMID: 20100784
schizophrenia; HERV-W; env; Human U251 glioma cells; DRD3; BDNF; siRNA
16.  Predicting synthetic lethal genetic interactions in Saccharomyces cerevisiae using short polypeptide clusters 
Proteome Science  2012;10(Suppl 1):S4.
Protein synthetic lethal genetic interactions are useful to define functional relationships between proteins and pathways. However, the molecular mechanism of synthetic lethal genetic interactions remains unclear.
In this study we used the clusters of short polypeptide sequences, which are typically shorter than the classically defined protein domains, to characterize the functionalities of proteins. We developed a framework to identify significant short polypeptide clusters from yeast protein sequences, and then used these short polypeptide clusters as features to predict yeast synthetic lethal genetic interactions. The short polypeptide clusters based approach provides much higher coverage for predicting yeast synthetic lethal genetic interactions. Evaluation using experimental data sets showed that the short polypeptide clusters based approach is superior to the previous protein domain based one.
We were able to achieve higher performance in yeast synthetic lethal genetic interactions prediction using short polypeptide clusters as features. Our study suggests that the short polypeptide cluster may help better understand the functionalities of proteins.
PMCID: PMC3380729  PMID: 22759581
17.  Whole-Genome Association Study on Tissue Tropism Phenotypes in Group A Streptococcus▿# 
Journal of Bacteriology  2011;193(23):6651-6663.
Group A Streptococcus (GAS) has a rich evolutionary history of horizontal transfer among its core genes. Yet, despite extensive genetic mixing, GAS strains have discrete ecological phenotypes. To further our understanding of the molecular basis for ecological phenotypes, comparative genomic hybridization of a set of 97 diverse strains to a GAS pangenome microarray was undertaken, and the association of accessory genes with emm genotypes that define tissue tropisms for infection was determined. Of the 22 nonprophage accessory gene regions (AGRs) identified, only 3 account for all statistically significant linkage disequilibrium among strains having the genotypic biomarkers for throat versus skin infection specialists. Networked evolution and population structure analyses of loci representing each of the AGRs reveal that most strains with the skin specialist and generalist biomarkers form discrete clusters, whereas strains with the throat specialist biomarker are highly diverse. To identify coinherited and coselected accessory genes, the strength of genetic associations was determined for all possible pairwise combinations of accessory genes among the 97 GAS strains. Accessory genes showing very strong associations provide the basis for an evolutionary model, which reveals that a major transition between many throat and skin specialist haplotypes correlates with the gain or loss of genes encoding fibronectin-binding proteins. This study employs a novel synthesis of tools to help delineate the major genetic changes associated with key adaptive shifts in an extensively recombined bacterial species.
PMCID: PMC3232895  PMID: 21949075
18.  Glycogen Synthase Kinase 3β Inhibitor (2'Z,3'E)-6-Bromo-indirubin- 3'-Oxime Enhances Drug Resistance to 5-Fluorouracil Chemotherapy in Colon Cancer Cells 
To explore the effects and mechanism of glycogen synthase kinase 3β (GSK-3β) inhibitor (2'Z,3'E)-6-bromo-indirubin-3'-oxime (BIO) on drug resistance in colon cancer cells.
The colon cancer SW480 and SW620 cells were treated with BIO, 5-fluorouracil (5-FU) and BIO/5-FU, separately. Cell cycle distribution, apoptosis level and efflux ability of rhodamine 123 (Rh123) were detected by flow cytometry. The protein expressions of P-glycoprotein (P-gp), multidrug resistance protein 2 (MRP2), thymidylate synthase (TS), β-catenin, E2F-1 and Bcl-2 were detected by Western blot. β-catenin and P-gp were stained with double immunofluorescence and observed under a confocal microscope.
BIO up-regulated β-catenin, P-gp, MRP2 and TS, enhanced the efflux ability of Rh123, decreased Bcl-2 protein and gave the opposite effect to E2F-1 protein in SW480 and SW620 cells. Furthermore, BIO significantly inhibited cell apoptosis, increased S and G2/M phase cells, and reduced the cell apoptosis induced by 5-FU in SW480 cells, whereas the effects were slight or not obvious in SW620 cells.
GSK-3β was involved in drug resistance regulation, and activation of β-catenin and inhibition of E2F-1 may be the most responsible for the enhancement of 5-FU chemotherapy resistance induced by GSK-3β inhibitor BIO in colon cancer.
PMCID: PMC3555271  PMID: 23359767
Colorectal neoplasms; Drug resistance; Glycogen synthase kinase 3β; Fluorouracil; β-catenin; E2F-1
19.  Molecular ecological network analyses 
BMC Bioinformatics  2012;13:113.
Understanding the interaction among different species within a community and their responses to environmental changes is a central goal in ecology. However, defining the network structure in a microbial community is very challenging due to their extremely high diversity and as-yet uncultivated status. Although recent advance of metagenomic technologies, such as high throughout sequencing and functional gene arrays, provide revolutionary tools for analyzing microbial community structure, it is still difficult to examine network interactions in a microbial community based on high-throughput metagenomics data.
Here, we describe a novel mathematical and bioinformatics framework to construct ecological association networks named molecular ecological networks (MENs) through Random Matrix Theory (RMT)-based methods. Compared to other network construction methods, this approach is remarkable in that the network is automatically defined and robust to noise, thus providing excellent solutions to several common issues associated with high-throughput metagenomics data. We applied it to determine the network structure of microbial communities subjected to long-term experimental warming based on pyrosequencing data of 16 S rRNA genes. We showed that the constructed MENs under both warming and unwarming conditions exhibited topological features of scale free, small world and modularity, which were consistent with previously described molecular ecological networks. Eigengene analysis indicated that the eigengenes represented the module profiles relatively well. In consistency with many other studies, several major environmental traits including temperature and soil pH were found to be important in determining network interactions in the microbial communities examined. To facilitate its application by the scientific community, all these methods and statistical tools have been integrated into a comprehensive Molecular Ecological Network Analysis Pipeline (MENAP), which is open-accessible now (
The RMT-based molecular ecological network analysis provides powerful tools to elucidate network interactions in microbial communities and their responses to environmental changes, which are fundamentally important for research in microbial ecology and environmental microbiology.
PMCID: PMC3428680  PMID: 22646978
Ecological network; Random Matrix Theory; Microbial community; Microbiological ecology; Network interaction; Environmental changes
20.  Self-assembled mPEG–PCL-g–PEI micelles for simultaneous codelivery of chemotherapeutic drugs and DNA: synthesis and characterization in vitro 
In this paper, a series of amphiphilic triblock copolymers based on polyethylene glycol–poly ɛ-caprolactone–polyethylenimine (mPEG–PCL-g–PEI) were successfully synthesized, and their application for codelivery of chemotherapeutic drugs and DNA simultaneously was investigated.
Methods and results
These copolymers could self-assemble into micelles with positive charges. The size and zeta potential of the micelles was measured, and the results indicate that temperature had a large effect on the micelles obtained. In vitro gene transfection evaluation in cancer cells indicated that the self-assembled micelles could serve as potential gene delivery vectors. In addition, hydrophobic drug entrapment efficiency and codelivery with the gene was also studied in vitro. The self-assembled micelles could load doxorubicin efficiently and increase cellular uptake in vitro, while maintaining high gene transfection efficiency.
The triblock copolymer mPEG–PCL-g–PEI could be a novel vector for codelivery of drug and gene therapy.
PMCID: PMC3356179  PMID: 22619525
self-assembly; triblock copolymer; DNA; drug codelivery; gene transfection
21.  Accelerating drug discovery for Alzheimer's disease: best practices for preclinical animal studies 
Animal models have contributed significantly to our understanding of the underlying biological mechanisms of Alzheimer's disease (AD). As a result, over 300 interventions have been investigated and reported to mitigate pathological phenotypes or improve behavior in AD animal models or both. To date, however, very few of these findings have resulted in target validation in humans or successful translation to disease-modifying therapies. Challenges in translating preclinical studies to clinical trials include the inability of animal models to recapitulate the human disease, variations in breeding and colony maintenance, lack of standards in design, conduct and analysis of animal trials, and publication bias due to under-reporting of negative results in the scientific literature. The quality of animal model research on novel therapeutics can be improved by bringing the rigor of human clinical trials to animal studies. Research communities in several disease areas have developed recommendations for the conduct and reporting of preclinical studies in order to increase their validity, reproducibility, and predictive value. To address these issues in the AD community, the Alzheimer's Drug Discovery Foundation partnered with Charles River Discovery Services (Morrisville, NC, USA) and Cerebricon Ltd. (Kuopio, Finland) to convene an expert advisory panel of academic, industry, and government scientists to make recommendations on best practices for animal studies testing investigational AD therapies. The panel produced recommendations regarding the measurement, analysis, and reporting of relevant AD targets, th choice of animal model, quality control measures for breeding and colony maintenance, and preclinical animal study design. Major considerations to incorporate into preclinical study design include a priori hypotheses, pharmacokinetics-pharmacodynamics studies prior to proof-of-concept testing, biomarker measurements, sample size determination, and power analysis. The panel also recommended distinguishing between pilot 'exploratory' animal studies and more extensive 'therapeutic' studies to guide interpretation. Finally, the panel proposed infrastructure and resource development, such as the establishment of a public data repository in which both positive animal studies and negative ones could be reported. By promoting best practices, these recommendations can improve the methodological quality and predictive value of AD animal studies and make the translation to human clinical trials more efficient and reliable.
PMCID: PMC3218805  PMID: 21943025
22.  Preventing postoperative abdominal adhesions in a rat model with PEG-PCL-PEG hydrogel 
Poly (ethylene glycol)-poly (ɛ-caprolactone)-poly (ethylene glycol) (PEG-PCL-PEG, PECE) hydrogel has been demonstrated to be biocompatible and thermosensitive. In this study, its potential efficacy and mechanisms of preventing postsurgical abdominal adhesions were investigated.
PECE hydrogel was transformed into gel state from sol state in less than 20 seconds at 37°C. None of the animals treated with the hydrogel (n = 15) developed adhesions. In contrast, all untreated animals (n = 15) had adhesions that could only be separated by sharp dissection (P < 0.001). The hydrogel adhered to the peritoneal wounds, gradually disappeared from the wounds within 7 days, and transformed into viscous fluid, being completely absorbed within 12 days. The parietal and visceral peritoneum were remesothelialized in about 5 and 9 days, respectively. The hydrogel prevented the formation of fibrinous adhesion and the invasion of fibroblasts. Also, along with the hydrogel degradation, a temporary inflammatory cell barrier was formed which could effectively delay the invasion of fibroblasts during the critical period of mesothelial regeneration.
The results suggested that PECE hydrogel could effectively prevent postsurgical intra-abdominal adhesions, which possibly result from the prevention of the fibrinous adhesion formation and the fibroblast invasion, the promotion of the remesothelialization, and the hydroflotation effect.
PMCID: PMC3277435  PMID: 22346350
anti-adhesion; thermosensitive; barrier; biocompatible
23.  Determining Thermal Inactivation of Escherichia coli O157:H7 in Fresh Compost by Simulating Early Phases of the Composting Process ▿  
Applied and Environmental Microbiology  2011;77(12):4126-4135.
A three-strain mixture of Escherichia coli O157:H7 was inoculated into fresh dairy compost (ca. 107 CFU/g) with 40 or 50% moisture and was placed in an environmental chamber (ca. 70% humidity) that was programmed to ramp from room temperature to selected composting temperatures in 2 and 5 days to simulate the early composting phase. The surviving E. coli O157:H7 population was analyzed by direct plating and enrichment. Optimal and suboptimal compost mixes, with carbon/nitrogen (C/N) ratios of 25:1 and 16:1, respectively, were compared in this study. In the optimal compost mix, E. coli O157:H7 survived for 72, 48, and 24 h in compost with 40% moisture and for 72, 24, and 24 h with 50% moisture at 50, 55, and 60°C, respectively, following 2 days of come-up time (rate of heating up). However, in the suboptimal compost mix, the pathogen survived for 288, 72, and 48 h in compost with 40% moisture and for 240, 72, 24 h in compost with 50% moisture at the same temperatures, respectively. Pathogen survival was longer, with 5 days of come-up time compared with 2 days of come-up. Overall, E. coli O157:H7 was inactivated faster in the compost with 50% moisture than in the compost with 40% at 55 and 60°C. Both moisture and come-up time were significant factors affecting Weibull model parameters. Our results suggest that slow come-up time at the beginning of composting can extend pathogen survival during composting. Additionally, both the C/N ratio and the initial moisture level in the compost mix affect the rate of pathogen inactivation as well.
PMCID: PMC3131655  PMID: 21498743
24.  Preparation of poly(ethylene glycol)/polylactide hybrid fibrous scaffolds for bone tissue engineering 
Polylactide (PLA) electrospun fibers have been reported as a scaffold for bone tissue engineering application, however, the great hydrophobicity limits its broad application. In this study, the hybrid amphiphilic poly(ethylene glycol) (PEG)/hydrophobic PLA fibrous scaffolds exhibited improved morphology with regular and continuous fibers compared to corresponding blank PLA fiber mats. The prepared PEG/PLA fibrous scaffolds favored mesenchymal stem cell (MSC) attachment and proliferation by providing an interconnected porous extracellular environment. Meanwhile, MSCs can penetrate into the fibrous scaffold through the interstitial pores and integrate well with the surrounding fibers, which is very important for favorable application in tissue engineering. More importantly, the electrospun hybrid PEG/PLA fibrous scaffolds can enhance MSCs to differentiate into bone-associated cells by comprehensively evaluating the representative markers of the osteogenic procedure with messenger ribonucleic acid quantitation and protein analysis. MSCs on the PEG/PLA fibrous scaffolds presented better differentiation potential with higher messenger ribonucleic acid expression of the earliest osteogenic marker Cbfa-1 and mid-stage osteogenic marker Col I. The significantly higher alkaline phosphatase activity of the PEG/PLA fibrous scaffolds indicated that these can enhance the differentiation of MSCs into osteoblast-like cells. Furthermore, the higher messenger ribonucleic acid level of the late osteogenic differentiation markers OCN (osteocalcin) and OPN (osteopontin), accompanied by the positive Alizarin red S staining, showed better maturation of osteogenic induction on the PEG/PLA fibrous scaffolds at the mineralization stage of differentiation. After transplantation into the thigh muscle pouches of rats, and evaluating the inflammatory cells surrounding the scaffolds and the physiological characteristics of the surrounding tissues, the PEG/PLA scaffolds presented good biocompatibility. Based on the good cellular response and excellent osteogenic potential in vitro, as well as the biocompatibility with the surrounding tissues in vivo, the electrospun PEG/PLA fibrous scaffolds could be one of the most promising candidates in bone tissue engineering.
PMCID: PMC3235027  PMID: 22163160
electrospinning; fibrous scaffolds; poly(ethylene glycol)/polylactide; mesenchymal stem cells; bone tissue engineering
25.  N-[4-(4-Fluoro­phen­yl)-5-hy­droxy­methyl-6-isopropyl­pyrimidin-2-yl]-N-methyl­methane­sulfonamide 
In the title compound, C16H20FN3O3S, the pyrimidine and benzene rings are oriented at a dihedral angle of 38.8 (3)°. An intra­molecular C—H⋯O hydrogen bond occurs. The crystal structure is stabilized by O—H⋯N hydrogen bonds. In addition, C—H⋯O inter­actions are also present.
PMCID: PMC3239065  PMID: 22199913

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