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1.  Genomes of the rice pest brown planthopper and its endosymbionts reveal complex complementary contributions for host adaptation 
Genome Biology  2014;15(12):521.
The brown planthopper, Nilaparvata lugens, the most destructive pest of rice, is a typical monophagous herbivore that feeds exclusively on rice sap, which migrates over long distances. Outbreaks of it have re-occurred approximately every three years in Asia. It has also been used as a model system for ecological studies and for developing effective pest management. To better understand how a monophagous sap-sucking arthropod herbivore has adapted to its exclusive host selection and to provide insights to improve pest control, we analyzed the genomes of the brown planthopper and its two endosymbionts.
We describe the 1.14 gigabase planthopper draft genome and the genomes of two microbial endosymbionts that permit the planthopper to forage exclusively on rice fields. Only 40.8% of the 27,571 identified Nilaparvata protein coding genes have detectable shared homology with the proteomes of the other 14 arthropods included in this study, reflecting large-scale gene losses including in evolutionarily conserved gene families and biochemical pathways. These unique genomic features are functionally associated with the animal’s exclusive plant host selection. Genes missing from the insect in conserved biochemical pathways that are essential for its survival on the nutritionally imbalanced sap diet are present in the genomes of its microbial endosymbionts, which have evolved to complement the mutualistic nutritional needs of the host.
Our study reveals a series of complex adaptations of the brown planthopper involving a variety of biological processes, that result in its highly destructive impact on the exclusive host rice. All these findings highlight potential directions for effective pest control of the planthopper.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-014-0521-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4269174  PMID: 25609551
2.  Genotypic variants at 2q33 and risk of esophageal squamous cell carcinoma in China: a meta-analysis of genome-wide association studies 
Abnet, Christian C. | Wang, Zhaoming | Song, Xin | Hu, Nan | Zhou, Fu-You | Freedman, Neal D. | Li, Xue-Min | Yu, Kai | Shu, Xiao-Ou | Yuan, Jian-Min | Zheng, Wei | Dawsey, Sanford M. | Liao, Linda M. | Lee, Maxwell P. | Ding, Ti | Qiao, You-Lin | Gao, Yu-Tang | Koh, Woon-Puay | Xiang, Yong-Bing | Tang, Ze-Zhong | Fan, Jin-Hu | Chung, Charles C. | Wang, Chaoyu | Wheeler, William | Yeager, Meredith | Yuenger, Jeff | Hutchinson, Amy | Jacobs, Kevin B. | Giffen, Carol A. | Burdett, Laurie | Fraumeni, Joseph F. | Tucker, Margaret A. | Chow, Wong-Ho | Zhao, Xue-Ke | Li, Jiang-Man | Li, Ai-Li | Sun, Liang-Dan | Wei, Wu | Li, Ji-Lin | Zhang, Peng | Li, Hong-Lei | Cui, Wen-Yan | Wang, Wei-Peng | Liu, Zhi-Cai | Yang, Xia | Fu, Wen-Jing | Cui, Ji-Li | Lin, Hong-Li | Zhu, Wen-Liang | Liu, Min | Chen, Xi | Chen, Jie | Guo, Li | Han, Jing-Jing | Zhou, Sheng-Li | Huang, Jia | Wu, Yue | Yuan, Chao | Huang, Jing | Ji, Ai-Fang | Kul, Jian-Wei | Fan, Zhong-Min | Wang, Jian-Po | Zhang, Dong-Yun | Zhang, Lian-Qun | Zhang, Wei | Chen, Yuan-Fang | Ren, Jing-Li | Li, Xiu-Min | Dong, Jin-Cheng | Xing, Guo-Lan | Guo, Zhi-Gang | Yang, Jian-Xue | Mao, Yi-Ming | Yuan, Yuan | Guo, Er-Tao | Zhang, Wei | Hou, Zhi-Chao | Liu, Jing | Li, Yan | Tang, Sa | Chang, Jia | Peng, Xiu-Qin | Han, Min | Yin, Wan-Li | Liu, Ya-Li | Hu, Yan-Long | Liu, Yu | Yang, Liu-Qin | Zhu, Fu-Guo | Yang, Xiu-Feng | Feng, Xiao-Shan | Wang, Zhou | Li, Yin | Gao, She-Gan | Liu, Hai-Lin | Yuan, Ling | Jin, Yan | Zhang, Yan-Rui | Sheyhidin, Ilyar | Li, Feng | Chen, Bao-Ping | Ren, Shu-Wei | Liu, Bin | Li, Dan | Zhang, Gao-Fu | Yue, Wen-Bin | Feng, Chang-Wei | Qige, Qirenwang | Zhao, Jian-Ting | Yang, Wen-Jun | Lei, Guang-Yan | Chen, Long-Qi | Li, En-Min | Xu, Li-Yan | Wu, Zhi-Yong | Bao, Zhi-Qin | Chen, Ji-Li | Li, Xian-Chang | Zhuang, Xiang | Zhou, Ying-Fa | Zuo, Xian-Bo | Dong, Zi-Ming | Wang, Lu-Wen | Fan, Xue-Pin | Wang, Jin | Zhou, Qi | Ma, Guo-Shun | Zhang, Qin-Xian | Liu, Hai | Jian, Xin-Ying | Lian, Sin-Yong | Wang, Jin-Sheng | Chang, Fu-Bao | Lu, Chang-Dong | Miao, Jian-Jun | Chen, Zhi-Guo | Wang, Ran | Guo, Ming | Fan, Zeng-Lin | Tao, Ping | Liu, Tai-Jing | Wei, Jin-Chang | Kong, Qing-Peng | Fan, Lei | Wang, Xian-Zeng | Gao, Fu-Sheng | Wang, Tian-Yun | Xie, Dong | Wang, Li | Chen, Shu-Qing | Yang, Wan-Cai | Hong, Jun-Yan | Wang, Liang | Qiu, Song-Liang | Goldstein, Alisa M. | Yuan, Zhi-Qing | Chanock, Stephen J. | Zhang, Xue-Jun | Taylor, Philip R. | Wang, Li-Dong
Human Molecular Genetics  2012;21(9):2132-2141.
Genome-wide association studies have identified susceptibility loci for esophageal squamous cell carcinoma (ESCC). We conducted a meta-analysis of all single-nucleotide polymorphisms (SNPs) that showed nominally significant P-values in two previously published genome-wide scans that included a total of 2961 ESCC cases and 3400 controls. The meta-analysis revealed five SNPs at 2q33 with P< 5 × 10−8, and the strongest signal was rs13016963, with a combined odds ratio (95% confidence interval) of 1.29 (1.19–1.40) and P= 7.63 × 10−10. An imputation analysis of 4304 SNPs at 2q33 suggested a single association signal, and the strongest imputed SNP associations were similar to those from the genotyped SNPs. We conducted an ancestral recombination graph analysis with 53 SNPs to identify one or more haplotypes that harbor the variants directly responsible for the detected association signal. This showed that the five SNPs exist in a single haplotype along with 45 imputed SNPs in strong linkage disequilibrium, and the strongest candidate was rs10201587, one of the genotyped SNPs. Our meta-analysis found genome-wide significant SNPs at 2q33 that map to the CASP8/ALS2CR12/TRAK2 gene region. Variants in CASP8 have been extensively studied across a spectrum of cancers with mixed results. The locus we identified appears to be distinct from the widely studied rs3834129 and rs1045485 SNPs in CASP8. Future studies of esophageal and other cancers should focus on comprehensive sequencing of this 2q33 locus and functional analysis of rs13016963 and rs10201587 and other strongly correlated variants.
PMCID: PMC3315211  PMID: 22323360
3.  SPOCK1 as a potential cancer prognostic marker promotes the proliferation and metastasis of gallbladder cancer cells by activating the PI3K/AKT pathway 
Molecular Cancer  2015;14(1):12.
Gallbladder cancer (GBC) is a leading cause of cancer-related death worldwide, and its prognosis remains poor, with 5-year survival of approximately 5%. In this study, we analyzed the involvement of a novel proteoglycan, Sparc/osteonectin, cwcv, and kazal-like domains proteoglycan 1 (SPOCK1), in the tumor progression and prognosis of human GBC.
SPOCK1 expression levels were measured in fresh samples and stored specimens of GBC and adjacent nontumor tissues. The effect of SPOCK1 on cell growth, DNA replication, migration and invasion were explored by Cell Counting Kit-8, colony formation, EdU retention assay, wound healing, and transwell migration assays, flow cytometric analysis, western blotting, and in vivo tumorigenesis and metastasis in nude mice.
SPOCK1 mRNA and protein levels were increased in human GBC tissues compared with those in nontumor tissues. Immunohistochemical analysis indicated that SPOCK1 levels were increased in tumors that became metastatic, compared with those that did not, which was significantly associated with histological differentiation and patients with shorter overall survival periods. Knockdown of SPOCK1 expression by lentivirus-mediated shRNA transduction resulted in significant inhibition of GBC cell growth, colony formation, DNA replication, and invasion in vitro. The knockdown cells also formed smaller xenografted tumors than control GBC cells in nude mice. Overexpression of SPOCK1 had the opposite effects. In addition, SPOCK1 promoted cancer cell migration and epithelial-mesenchymal transition by regulating the expression of relevant genes. We found that activation of the PI3K/Akt pathway was involved in the oncogenic functions of SPOCK1 in GBC.
SPOCK1 activates PI3K/Akt signaling to block apoptosis and promote proliferation and metastasis by GBC cells in vitro and in vivo. Levels of SPOCK1 increase with the progression of human GBC. SPOCK1 acts as an oncogene and may be a prognostic factor or therapeutic target for patients with GBC.
Electronic supplementary material
The online version of this article (doi:10.1186/s12943-014-0276-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4320842  PMID: 25623055
Gallbladder cancer; SPOCK1; Tumor progression; RNA interference; Epithelial-mesenchymal transition
4.  Molecular Variation and Horizontal Gene Transfer of the Homocysteine Methyltransferase Gene mmuM and its Distribution in Clinical Pathogens 
The homocysteine methyltransferase encoded by mmuM is widely distributed among microbial organisms. It is the key enzyme that catalyzes the last step in methionine biosynthesis and plays an important role in the metabolism process. It also enables the microbial organisms to tolerate high concentrations of selenium in the environment. In this research, 533 mmuM gene sequences covering 70 genera of the bacteria were selected from GenBank database. The distribution frequency of mmuM is different in the investigated genera of bacteria. The mapping results of 160 mmuM reference sequences showed that the mmuM genes were found in 7 species of pathogen genomes sequenced in this work. The polymerase chain reaction products of one mmuM genotype (NC_013951 as the reference) were sequenced and the sequencing results confirmed the mapping results. Furthermore, 144 representative sequences were chosen for phylogenetic analysis and some mmuM genes from totally different genera (such as the genes between Escherichia and Klebsiella and between Enterobacter and Kosakonia) shared closer phylogenetic relationship than those from the same genus. Comparative genomic analysis of the mmuM encoding regions on plasmids and bacterial chromosomes showed that pKF3-140 and pIP1206 plasmids shared a 21 kb homology region and a 4.9 kb fragment in this region was in fact originated from the Escherichia coli chromosome. These results further suggested that mmuM gene did go through the gene horizontal transfer among different species or genera of bacteria. High-throughput sequencing combined with comparative genomics analysis would explore distribution and dissemination of the mmuM gene among bacteria and its evolution at a molecular level.
PMCID: PMC4278250  PMID: 25552925
comparative genomics; homocysteine methyltransferase gene; horizontal gene transfer; molecular variation
5.  One-dimensional CuO nanowire: synthesis, electrical, and optoelectronic devices application 
Nanoscale Research Letters  2014;9(1):637.
In this work, we presented a surface mechanical attrition treatment (SMAT)-assisted approach to the synthesis of one-dimensional copper oxide nanowires (CuO NWs) for nanodevices applications. The as-prepared CuO NWs have diameter and the length of 50 ~ 200 nm and 5 ~ 20 μm, respectively, with a preferential growth orientation along [1 1¯ 0] direction. Interestingly, nanofield-effect transistor (nanoFET) based on individual CuO NW exhibited typical p-type electrical conduction, with a hole mobility of 0.129 cm2V-1 s-1 and hole concentration of 1.34 × 1018 cm-3, respectively. According to first-principle calculations, such a p-type electrical conduction behavior was related to the oxygen vacancies in CuO NWs. What is more, the CuO NW device was sensitive to visible light illumination with peak sensitivity at 600 nm. The responsitivity, conductive gain, and detectivity are estimated to be 2.0 × 102 A W-1, 3.95 × 102 and 6.38 × 1011 cm Hz1/2 W-1, respectively, which are better than the devices composed of other materials. Further study showed that nanophotodetectors assembled on flexible polyethylene terephthalate (PET) substrate can work under different bending conditions with good reproducibility. The totality of the above results suggests that the present CuO NWs are potential building blocks for assembling high-performance optoelectronic devices.
PMCID: PMC4256975  PMID: 25489288
Surface mechanical attrition treatment (SMAT); Semiconductor nanostructures; The first-principle calculation; Metal oxide; Flexible photodetector
6.  Abnormal percolative transport and colossal electroresistance induced by anisotropic strain in (011)-Pr0.7(Ca0.6Sr0.4)0.3MnO3/PMN-PT heterostructure 
Scientific Reports  2014;4:7075.
Abnormal percolative transport in inhomogeneous systems has drawn increasing interests due to its deviation from the conventional percolation picture. However, its nature is still ambiguous partly due to the difficulty in obtaining controllable abnormal percolative transport behaviors. Here, we report the first observation of electric-field-controlled abnormal percolative transport in (011)-Pr0.7(Ca0.6Sr0.4)0.3MnO3/0.7Pb(Mg1/3Nb2/3)O3-0.3PbTiO3 heterostructure. By introducing an electric-field-induced in-plane anisotropic strain-field in a phase separated PCSMO film, we stimulate a significant inverse thermal hysteresis (~ -17.5 K) and positive colossal electroresistance (~11460%), which is found to be crucially orientation-dependent and completely inconsistent with the well accepted conventional percolation picture. Further investigations reveal that such abnormal inverse hysteresis is strongly related to the preferential formation of ferromagnetic metallic domains caused by in-plane anisotropic strain-field. Meanwhile, it is found that the positive colossal electroresistance should be ascribed to the coactions between the anisotropic strain and the polarization effect from the poling of the substrate which leads to orientation and bias-polarity dependencies for the colossal electroresistance. This work unambiguously evidences the indispensable role of the anisotropic strain-field in driving the abnormal percolative transport and provides a new perspective for well understanding the percolation mechanism in inhomogeneous systems.
PMCID: PMC4233337  PMID: 25399635
7.  Current Models of Mammalian Target of Rapamycin Complex 1 (mTORC1) Activation by Growth Factors and Amino Acids 
Mammalian target of rapamycin (mTOR), which is now referred to as mechanistic target of rapamycin, integrates many signals, including those from growth factors, energy status, stress, and amino acids, to regulate cell growth and proliferation, protein synthesis, protein degradation, and other physiological and biochemical processes. The mTOR-Rheb-TSC-TBC complex co-localizes to the lysosome and the phosphorylation of TSC-TBC effects the dissociation of the complex from the lysosome and activates Rheb. GTP-bound Rheb potentiates the catalytic activity of mTORC1. Under conditions with growth factors and amino acids, v-ATPase, Ragulator, Rag GTPase, Rheb, hVps34, PLD1, and PA have important but disparate effects on mTORC1 activation. In this review, we introduce five models of mTORC1 activation by growth factors and amino acids to provide a comprehensive theoretical foundation for future research.
PMCID: PMC4264194  PMID: 25402640
mTORC1; Rheb; Ragulator; Rag GTPases; hVps34; PA
8.  Successful treatment of a case with pancreatic neuroendocrine carcinoma with focal hepatoid differentiation: a case report and literature review 
A 33-year-old Chinese woman was admitted to our hospital because of an elevated serum alpha-fetoprotein (AFP) level (300 ng/mL) found in a regular medical checkup. Computed tomography imaging of the abdomen revealed a 1.6 × 2.2 cm low-attenuation mass in the head of the pancreas, with no enlarged lymph nodes and no metastatic liver nodules, and a pancreaticoduodenectomy was performed and the tumor was completely removed. The tumor was solid, unencapsulated and poorly demarcated, measuring 2 × 1.4 × 1.8 cm, and the cut surface was grey-yellowish. Histologically, most of the areas of the tumor were composed of small monotonous and round shaped neuroendocrine cells, and approximately 20% of the areas were cells with indistinct cytoplasmic borders, large oval nuclei, prominent nucleoli and abundant eosinophilic cytoplasm, resembling the appearance of HCC. Immunohistochemical stains revealed that the neuroendocrine areas were diffusely positive for chromogranin, and the hepatoid areas showed diffuse and strong positive reaction to AFP. After surgery the AFP level reduced to normal. She received six cycles of postoperative chemotherapy and three years after the surgery was found to have an elevated serum AFP level again which gave rise to the suspicion of tumor recurrence, and a positron emission tomography-computed tomography confirmed the speculation by showing a hypermetabolic lymph node behind the body of the pancreas. She then underwent radiotherapy and the AFP level reduced to normal. Up till now she has survived 46 months since the initial diagnosis. This case and previous cases suggest that the serum AFP could be a useful marker for early detection of the disease, but careful differential diagnosis should be performed, and AFP could also be a marker for evaluation of therapeutic response and recurrence of the AFP-producing hepatoid carcinomas of pancreas.
PMCID: PMC4238550  PMID: 25419403
Pancreas; hepatoid carcinoma; endocrine carcinoma; alpha-fetoprotein
9.  An improved alignment-free model for dna sequence similarity metric 
BMC Bioinformatics  2014;15(1):321.
DNA Clustering is an important technology to automatically find the inherent relationships on a large scale of DNA sequences. But the DNA clustering quality can still be improved greatly. The DNA sequences similarity metric is one of the key points of clustering. The alignment-free methodology is a very popular way to calculate DNA sequence similarity. It normally converts a sequence into a feature space based on words’ probability distribution rather than directly matches strings. Existing alignment-free models, e.g. k-tuple, merely employ word frequency information and ignore many types of useful information contained in the DNA sequence, such as classifications of nucleotide bases, position and the like. It is believed that the better data mining results can be achieved with compounded information. Therefore, we present a new alignment-free model that employs compounded information to improve the DNA clustering quality.
This paper proposes a Category-Position-Frequency (CPF) model, which utilizes the word frequency, position and classification information of nucleotide bases from DNA sequences. The CPF model converts a DNA sequence into three sequences according to the categories of nucleotide bases, and then yields a 12-dimension feature vector. The feature values are computed by an entropy based model that takes both local word frequency and position information into account. We conduct DNA clustering experiments on several datasets and compare with some mainstream alignment-free models for evaluation, including k-tuple, DMk, TSM, AMI and CV. The experiments show that CPF model is superior to other models in terms of the clustering results and optimal settings.
The following conclusions can be drawn from the experiments. (1) The hybrid information model is better than the model based on word frequency only. (2) For DNA sequences no more than 5000 characters, the preferred size of sliding windows for CPF is two which provides a great advantage to promote system performance. (3) The CPF model is able to obtain an efficient stable performance and broad generalization.
PMCID: PMC4261891  PMID: 25261973
DNA sequence similarity; Clustering; Alignment-free model; Classifications of nucleotide bases
10.  MiR-506 suppresses proliferation of hepatoma cells through targeting YAP mRNA 3′UTR 
Acta Pharmacologica Sinica  2014;35(9):1207-1214.
MiR-506 is a miRNA involved in carcinogenesis of several kinds of cancer. In this study, we explored whether miR-506 played a critical role in hepatocellular carcinoma (HCC).
Twenty HCC and adjacent normal liver tissue samples were collected. Human hepatoma cell lines HepG2 and H7402 were used for in vitro studies. The expression of miR-506 and transcriptional co-activator YAP was examined using qRT-PCR. Western blot analysis was used to measure the expression of YAP and its target genes. Luciferase reporter gene assay was used to identify YAP as a target gene of miR-506. MTT and EdU assays were carried out for functional analysis.
The expression of miR-506 was significantly lower in HCC than in adjacent normal liver tissues. Bioinformatics analysis revealed that YAP mRNA might be one of the targets of miR-506, and miR-506 in HCC tissues was found to be negatively correlated with YAP (r=−0.605). In both HepG2 and H7402 cells, miR-506 dose-dependently down-regulated YAP and its target genes c-Myc and the connective tissue growth factor (CTGF). Luciferase reporter gene assays demonstrated that miR-506 targeted the wild type 3′UTR of YAP mRNA, but not a 3′UTR with a mutant seed site. Furthermore, miR-506 significantly inhibited the proliferation of HepG2 and H7402 cells, while anti-miR-506 enhanced the cell proliferation, which was blocked by YAP siRNA.
MiR-506 suppresses the proliferation of hepatoma cells by targeting YAP mRNA.
PMCID: PMC4155531  PMID: 25087998
microRNA; miR-506; hepatocellular carcinoma; cell proliferation; YAP; c-Myc; connective tissue growth factor
11.  Analysis of horse genomes provides insight into the diversification and adaptive evolution of karyotype 
Scientific Reports  2014;4:4958.
Karyotypic diversification is more prominent in Equus species than in other mammals. Here, using next generation sequencing technology, we generated and de novo assembled quality genomes sequences for a male wild horse (Przewalski's horse) and a male domestic horse (Mongolian horse), with about 93-fold and 91-fold coverage, respectively. Portion of Y chromosome from wild horse assemblies (3 M bp) and Mongolian horse (2 M bp) were also sequenced and de novo assembled. We confirmed a Robertsonian translocation event through the wild horse's chromosomes 23 and 24, which contained sequences that were highly homologous with those on the domestic horse's chromosome 5. The four main types of rearrangement, insertion of unknown origin, inserted duplication, inversion, and relocation, are not evenly distributed on all the chromosomes, and some chromosomes, such as the X chromosome, contain more rearrangements than others, and the number of inversions is far less than the number of insertions and relocations in the horse genome. Furthermore, we discovered the percentages of LINE_L1 and LTR_ERV1 are significantly increased in rearrangement regions. The analysis results of the two representative Equus species genomes improved our knowledge of Equus chromosome rearrangement and karyotype evolution.
PMCID: PMC4021364  PMID: 24828444
12.  The influence of lentivirus-mediated CXCR4 RNA interference on hepatic metastasis of colorectal cancer 
International Journal of Oncology  2014;44(6):1861-1869.
The aim of this study was to construct a lentiviral vector of CXCR4-siRNA (Lenti-CXCR4-siRNA) and investigate whether the vector can inhibit the growth, migration, invasion and hepatic metastasis of colorectal cancer (CRC). RT-PCR and western blotting were employed to identify the ideal RNA interference sequence. Lenti-CXCR4-siRNA was constructed and transfected into the SW480 cell line. We used RT-PCR and western blotting to measure the expression of CXCR4 RNA and protein, respectively; the MTS assay to assess the proliferation of SW480 cells; transwell chambers to estimate the inhibitory effect on migration and invasion; and the Balb/c nude mouse model of CRC to examine the inhibition of hepatic metastasis. The relative expression of the CXCR4 gene and protein was 5.4 and 18.95%, respectively, in the siCXCR4 group. The genes in the expression plasmid pLenti-CXCR4-siRNA were in the correct order. In the SW480, nonsense control (NC) and the Lenti-CXCR4-siRNA groups CXCR4 RNA levels were, respectively, 0.54±0.06, 1.00±0.03 and 0.11±0.04 (P=0.0001); CXCR4 protein levels were 0.60±0.03, 0.72±0.03 and 0.18±0.02 (P=0.0001); the OD value was 1.38±0.04 (P=0.0050), 1.28±0.05 (P=0.0256) and 0.92±0.06; SW480 cell number in migration test was 32±6.85, 32.63±1.69 and 0.75±0.71 (P=0.0000); SW480 cell number in the invasion test was 29.13±10.3, 30.38±6.09 and 0.63±0.74 (P=0.0000); hepatic metastasis number was 7.10±3.98 (P=0.034), 7.50±4.09 (P=0.019) and (3.50±2.51); hepatic metastasis mean weight (in g) was 2.25±2.51 (P=0.000), 2.11±2.38 (P=0.000) and 1.45±2.07. Lenti-CXCR4-siRNA constructs were correctly constructed and effectively inhibit the expression of CXCR4 RNA and protein, reducing the proliferation, migration, invasion capacity of SW480 cells and hepatic metastasis of CRC.
PMCID: PMC4063541  PMID: 24647809
CXCR4; RNA interference; lentivirus; SW480 cell; hepatic metastasis
13.  Human Antibody Neutralizes Severe Fever with Thrombocytopenia Syndrome Virus, an Emerging Hemorrhagic Fever Virus 
Severe fever with thrombocytopenia syndrome virus (SFTSV), a newly discovered member of the Bunyaviridae family, is the causative agent of an emerging hemorrhagic fever, SFTS, in China. Currently, there are no vaccines or effective therapies against SFTS. In this study, a combinatorial human antibody library was constructed from the peripheral lymphocytes of 5 patients who had recovered from SFTS. The library was screened against purified virions for the production of single-chain variable-region fragments (ScFv). Of the 6 positive clones, one clone (monoclonal antibody [MAb] 4-5) showed neutralizing activity against SFTSV infection in Vero cells. MAb 4-5 was found to effectively neutralize all of the clinical isolates of SFTSV tested, which were isolated from patients in China from 2010 to 2012. MAb 4-5 was found to bind a linear epitope in the ectodomain of glycoprotein Gn. Its neutralizing activity is attributed to blockage of the interactions between the Gn protein and the cellular receptor, indicating that inhibition of virus-cell attachment is its main mechanism. These data suggest that MAb 4-5 can be used as a promising candidate molecule for immunotherapy against SFTSV infection.
PMCID: PMC3889583  PMID: 23863504
14.  Ultrasonic Elastography Features of Phyllodes Tumors of the Breast: A Clinical Research 
PLoS ONE  2014;9(1):e85257.
The purpose of this study was to analyze the ultrasonic elastography features of phyllodes tumors of the breast comparing with fibroadenomas. A retrospective database was queried for the patients diagnosed as phyllodes tumors and fibroadenomas at Sun Yat-sen Memorial Hospital from January 2008 to August 2012. Three hundred and fifty lesions from 323 consecutive patients were included in the study. All the cases were examined by conventional ultrasonography and ultrasound elastography. Ultrasound elastography was used to calculate strain ratio of the lesions with bilateral breast tissue at the same depth as reference. There were 36 phyllodes tumors (27 benign, 8 borderline, 1 malignant) and 314 fibroadenomas (158 the pericanalicular type, 103 the intracanalicular type, 53 other special types). The strain ratio for phyllodes tumors (3.19±2.33) was significantly higher than for fibroadenomas (1.69±0.88) (p<0.05). The Spearman.s correlation coefficient between strain ratio of ultrasound elastography and pathological groups was significant, with a value of 0.17 (p<0.05). Ultrasound elastography could provide additional information to differentiate phyllodes tumors from fibroadenoma in breast.
PMCID: PMC3893177  PMID: 24454830
15.  Resiquimod and polyinosinic–polycytidylic acid formulation with aluminum hydroxide as an adjuvant for foot-and-mouth disease vaccine 
Toll-like receptor (TLR) agonists reportedly have potent antiviral and antitumor activities and may be a new kind of adjuvant for enhancing immune efficacy. Resiquimod (R848) is an imidazoquinoline compound with potent antiviral activity and functions through the TLR7/TLR8 MyD88-dependent signaling pathway. Polyinosinic-polycytidylic acid [poly(I:C)] is a synthetic analog of double-stranded RNA that induces the production of pro-inflammatory cytokines by the activation of NF-κB through TLR3. This study investigated the potential of R848 and poly(I:C) as an adjuvant 146S foot-and-mouth disease virus (FMDV) vaccine formulated with aluminum hydroxide (Al(OH)3).
Antibody titers to FMDV and CD8+ T cells were markedly enhanced in mice immunized to 146S FMDV + Al(OH)3 + R848 + poly(I:C) compared with mice immunized to FMDV + ISA206. IFN-γ secretion substantially increased compared with IL-4 secretion by splenic T cells stimulated with FMDV antigens in vitro, suggesting that R848, poly(I:C), and with Al(OH)3 together biased the immune response toward a Th1-type direction.
These results indicated that the R848 and poly(I:C) together with Al(OH)3 enhanced humoral and cellular immune responses to immunization with 146S FMDV antigens. Thus, this new vaccine formulation can be used for FMDV prevention.
PMCID: PMC3892093  PMID: 24386990
R848; Poly(I:C); Aluminum hydroxide; FMDV
16.  Role of Tomato Lipoxygenase D in Wound-Induced Jasmonate Biosynthesis and Plant Immunity to Insect Herbivores 
PLoS Genetics  2013;9(12):e1003964.
In response to insect attack and mechanical wounding, plants activate the expression of genes involved in various defense-related processes. A fascinating feature of these inducible defenses is their occurrence both locally at the wounding site and systemically in undamaged leaves throughout the plant. Wound-inducible proteinase inhibitors (PIs) in tomato (Solanum lycopersicum) provide an attractive model to understand the signal transduction events leading from localized injury to the systemic expression of defense-related genes. Among the identified intercellular molecules in regulating systemic wound response of tomato are the peptide signal systemin and the oxylipin signal jasmonic acid (JA). The systemin/JA signaling pathway provides a unique opportunity to investigate, in a single experimental system, the mechanism by which peptide and oxylipin signals interact to coordinate plant systemic immunity. Here we describe the characterization of the tomato suppressor of prosystemin-mediated responses8 (spr8) mutant, which was isolated as a suppressor of (pro)systemin-mediated signaling. spr8 plants exhibit a series of JA-dependent immune deficiencies, including the inability to express wound-responsive genes, abnormal development of glandular trichomes, and severely compromised resistance to cotton bollworm (Helicoverpa armigera) and Botrytis cinerea. Map-based cloning studies demonstrate that the spr8 mutant phenotype results from a point mutation in the catalytic domain of TomLoxD, a chloroplast-localized lipoxygenase involved in JA biosynthesis. We present evidence that overexpression of TomLoxD leads to elevated wound-induced JA biosynthesis, increased expression of wound-responsive genes and, therefore, enhanced resistance to insect herbivory attack and necrotrophic pathogen infection. These results indicate that TomLoxD is involved in wound-induced JA biosynthesis and highlight the application potential of this gene for crop protection against insects and pathogens.
Author Summary
Plants have evolved sophisticated strategies to defend themselves against insect attack. Wound-inducible proteinase inhibitors (PIs) in tomato (Solanum lycopersicum) provide an attractive model to understand the signal transduction events leading from localized injury to the systemic expression of defense-related genes. A wealth of evidence indicates that the peptide signal systemin and the phytohormone jasmonic acid (JA) work together in the same signaling pathway to activate the expression of PIs and other defense-related genes. We have been using a genetic approach to dissect the systemin/JA signaling pathway and to discover important genes that can be used for crop protection. Here we report the characterization of the suppressor of prosystemin-mediated responses8 (spr8) mutant, which is defective in wound-induced defense gene expression and therefore is more susceptible to insect attack. We demonstrate that spr8 defines the TomLoxD gene, which encodes a chloroplast-localized lipoxygenase involved in wound-induced JA biosynthesis. Further, we demonstrate that genetic manipulation of Spr8/TomLoxD leads to increased plant resistance against insect attack and pathogen infection.
PMCID: PMC3861047  PMID: 24348260
17.  Cardioprotection by systemic dosing of thymosin beta four following ischemic myocardial injury 
Thymosin beta 4 (Tβ4) was previously shown to reduce infarct size and improve contractile performance in chronic myocardial ischemic injury via two phases of action: an acute phase, just after injury, when Tβ4 preserves ischemic myocardium via antiapoptotic or anti-inflammatory mechanisms; and a chronic phase, when Tβ4 activates the growth of vascular or cardiac progenitor cells. In order to differentiate between the effects of Tβ4 during the acute and during the chronic phases, and also in order to obtain detailed hemodynamic and biomarker data on the effects of Tβ4 treatment suitable for use in clinical studies, we tested Tβ4 in a rat model of chronic myocardial ischemia using two dosing regimens: short term dosing (Tβ4 administered only during the first 3 days following injury), and long term dosing (Tβ4 administered during the first 3 days following injury and also every third day until the end of the study). Tβ4 administered throughout the study reduced infarct size and resulted in significant improvements in hemodynamic performance; however, chamber volumes and ejection fractions were not significantly improved. Tβ4 administered only during the first 3 days following injury tended to reduce infarct size, chamber volumes and improve hemodynamic performance. Plasma biomarkers of myocyte injury were significantly reduced by Tβ4 treatment during the acute injury period, and plasma ANP levels were significantly reduced in both dosing groups. Surprisingly, neither acute nor chronic Tβ4 treatment significantly increased blood vessel density in peri-infarct regions. These results suggest the following: repeated dosing may be required to achieve clinically measureable improvements in cardiac function post-myocardial infarction (MI); improvement in cardiac function may be observed in the absence of a high degree of angiogenesis; and that plasma biomarkers of cardiac function and myocardial injury are sensitive pharmacodynamic biomarkers of the effects of Tβ4.
PMCID: PMC3843122  PMID: 24348421
thymosin beta four; myocardial ischemia; ischemia/reperfusion; angiogenesis
18.  Thiol-functionalized magnetite/graphene oxide hybrid as a reusable adsorbent for Hg2+ removal 
Nanoscale Research Letters  2013;8(1):486.
A thiol-functionalized magnetite/graphene oxide (MGO) hybrid as an adsorbent of Hg2+ was successfully synthesized by a two-step reaction. It exhibited a higher adsorption capacity compared to the bare graphene oxide and MGO due to the combined adsorption of thiol groups and magnetite nanocrystals. Its capacity reached 289.9 mg g-1 in a solution with an initial Hg2+ concentration of 100 mg l-1. After being exchanged with H+, the adsorbent could be reused. The adsorption of Hg2+ by the thiol-functionalized MGO fits well with the Freundlich isotherm model and followed pseudo-second-order kinetics.
PMCID: PMC3842736  PMID: 24252617
Mercury ion; Magnetite; Adsorption capacity; Graphene oxide; Hybrid
19.  Effect of topiramate on interleukin 6 expression in the hippocampus of amygdala-kindled epileptic rats 
The objective of this study was to analyze the changes in expression and the possible functions of interleukin-6 (IL-6) in electrical kindling of the basolateral amygdala (BLA) in epileptic rats. Bipolar electrodes were implanted into the BLA of Sprague-Dawley rats, and the rats were then subjected to chronic electrical stimulation through the electrodes to induce kindling. The seizure characteristics and behavioral changes of the rats were observed, and electroencephalograms were recorded during and following kindling. The IL-6 mRNA expression in the hippocampi of the rats was analyzed using semi-quantitative reverse transcription-polymerase chain reaction, and control and topiramate (TPM)-treated groups were compared. The mean time-period required for kindling was 13.50±3.99 days, and the afterdischarge duration (ADD) measured between 21,450 and 119,720 msec. The expression of IL-6 mRNA was significantly upregulated in the kindled rats. TPM was able to depress the seizures and decrease the IL-6 level in the kindled rats. In conclusion, IL-6 mRNA was upregulated in the hippocampi of epileptic rats, and IL-6 may have participated in the process of kindling.
PMCID: PMC3860984  PMID: 24348794
interleukin-6; epilepsy; kindling; rat; basolateral amygdale; topiramate
20.  Targeting CSC-Related miRNAs for Cancer Therapy by Natural Agents 
Current drug targets  2012;13(14):1858-1868.
The theory of cancer stem cells (CSCs) has provided evidence on fundamental clinical implications because of the involvement of CSCs in cell migration, invasion, metastasis, and treatment resistance, which leads to the poor clinical outcome of cancer patients. Therefore, targeting CSCs will provide a novel therapeutic strategy for the treatment and/or prevention of tumors. However, the regulation of CSCs and its signaling pathways during tumorigenesis are not well understood. MicroRNAs (miRNAs) have been proved to act as key regulators of the post-transcriptional regulation of genes, which involve in a wide array of biological processes including tumorigenesis. The altered expressions of miRNAs are associated with poor clinical outcome of patients diagnosed with a variety of tumors. Therefore, emerging evidence strongly suggest that miRMAs play critical roles in tumor development and progression. Emerging evidence also suggest that miRNAs participate in the regulation of tumor cell growth, migration, invasion, angiogenesis, drug resistance, and metastasis. Moreover, miRNAs such as let-7, miR-21, miR-22, miR-34, miR-101, miR-146a, and miR-200 have been found to be associated with CSC phenotype and function mediated through targeting oncogenic signaling pathways. In this article, we will discuss the role of miRNAs in the regulation of CSC phenotype and function during tumor development and progression. We will also discuss the potential role of naturally occurring agents (nutraceuticals) as potent anti-tumor agents that are believed to function by targeting CSC-related miRNAs.
PMCID: PMC3792656  PMID: 23140295
CSCs; miRNAs; natural agents
21.  Higher expression of circulating miR-182 as a novel biomarker for breast cancer 
Oncology Letters  2013;6(6):1681-1686.
MicroRNAs (miRNAs), present in the serum in a stable and reproducible manner, may be used as biomarkers for various diseases. Few studies have previously investigated circulating miRNAs in the peripheral blood of breast cancer (BC) patients. To identify the role of serum miR-182 levels in BC, the present study detected miR-182 levels in the serum of 46 BC patients and 58 controls, by quantitative PCR. The results showed that the serum miR-182 levels in BC patients were significantly higher compared with the serum of healthy controls (P<0.01). The miR-182 was also overexpressed in the BC tissues compared with the para-carcinoma tissues. Furthermore, the serum levels of miR-182 in the estrogen receptor (ER)-positive patients were considerably lower compared with those in the ER-negative patients. The serum levels of miR-182 in the progesterone receptor (PR)-positive patients were also found to be lower compared with those in the PR-negative patients. The current study highlights results consistent with miR-182 as a novel and valuable biomarker for the diagnosis of BC.
PMCID: PMC3834356  PMID: 24260062
miR-182; circulating miRNAs; breast cancer; diagnosis; gene expression
22.  Palliative treatment for incurable malignant colorectal obstructions: A meta-analysis 
AIM: To perform a meta-analysis of palliative stent placement vs palliative surgical decompression for management of incurable malignant colorectal obstructions.
METHODS: The databases of Medline, Web of Science, Embase, and the Cochrane Central Register of Controlled Trials were searched from their inception to July 2012 for studies (prospective, retrospective, randomized controlled trials, and case-control trials) designed as comparative analyses of patients with incurable malignant colorectal obstructions treated by self-expanding metallic stents (SEMS) or palliative surgery. No language restrictions were imposed. The main outcome measures were hospital stay, intensive care unit admission, clinical success rate, 30-d mortality, stoma formation, complications, and overall survival time. The data extraction was conducted by two investigators working independently and using a standardized form. The Mantel-Haenszel χ2 method was used to estimate the pooled risk ratios with 95%CI under a fixed-effects model; when statistical heterogeneity existed in the pooled data (as evaluated by Q test and I2 statistics, where P < 0.10 and I2 < 25% indicated heterogeneity), a random-effects model was used.
RESULTS: Thirteen relevant articles, representing 837 patients (SEMS group, n = 404; surgery group, n = 433), were selected for analysis. Compared to the surgery group, the SEMS group showed lower clinical success (99.8% vs 93.1%, P = 0.0009) but shorter durations of hospital stay (18.84 d vs 9.55 d, P < 0.00001) and time to initiation of chemotherapy (33.36 d vs 15.53 d, P < 0.00001), and lower rate of stoma formation (54.0% vs 12.7%, P < 0.00001). Additionally, the SEMS group experienced a significantly lower rate of 30-d mortality (4.2% vs 10.5%, P = 0.01). Stent-related complications were not uncommon and included perforation (10.1%), migration (9.2%), and occlusion (18.3%). Surgery-related complications were slightly less common and included wound infection (5.0%) and anastomotic leak (4.7%). The rate of total complications was similar between these two groups (SEMS: 34.0% vs surgery: 38.1%, P = 0.60), but the surgery-related complications occurred earlier than stent-related complications (rate of early complications: 33.7% vs 13.7%, P = 0.03; rate of late complications: 32.3% vs 12.7%, P < 0.0001). The overall survival time of SEMS- and surgery-treated patients was not significantly different (7.64 mo vs 7.88 mo).
CONCLUSION: SEMS is less effective than surgery for palliation of incurable malignant colorectal obstructions, but is associated with a shorter time to chemotherapy and lower 30-d mortality.
PMCID: PMC3761112  PMID: 24023502
Self-expandable metal stents; Palliative surgery; Incurable malignant colorectal obstruction; Large-bowel obstruction; Treatment outcomes
23.  A retrospective study of posterior malleolus fractures 
International Orthopaedics  2012;36(9):1929-1936.
In this retrospective study, we evaluated the treatment effect of ankle joint fracture surgery involving the posterior malleolus, and discuss relevant factors influencing the occurrence of traumatic arthritis of the ankle joint.
A total of 102 cases of ankle joint fractures involving the posterior malleolus in five large-scale skeletal trauma centres in China, from January 2000 to July 2009, were retrospectively analysed in terms of surgical treatment and complete follow-up. Ankle joint mobility, posterior malleolus fragment size, articular surface evenness, Ankle-Hindfoot Scale of the American Orthopedic Foot and Ankle Society (AOFAS) score, and imaging scale score for arthritis were recorded. The degree of fracture pain during rest, active movement, and weight-bearing walking, and satisfaction with treatment were evaluated using a visual analogue scale (VAS).
The average AOFAS score was 95.9, excellence rate was 92.2 %, and average VAS scores for degree of fracture pain during rest, active movement, and weight-bearing walking were 0.15, 0.31, and 0.68, respectively. Thirty-six cases showed arthritic manifestations. Ankle joint mobility along all directions on the injured side was lower than that on the unaffected side. There was no obvious difference in treatment effect between the fixed and unfixed posterior malleolus fragment groups for all and for fragment size of <25 %; between fixing the posterior malleolus fragment from front to back or from back to front; or between elderly patients (≥60 years old) and young patients (<60 years old). There was a distinct difference in the treatment effect between articular surface evenness and unevenness for all and for fragment size of ≥25 %.
For all 102 cases of ankle joint fracture involving the posterior malleolus, the treatment effect was satisfactory. Restoration of an even articular surface, especially when fragment size ≥25 %, should be attempted during treatment.
PMCID: PMC3427438  PMID: 22777382
24.  Control Costs, Enhance Quality, and Increase Revenue in Three Top General Public Hospitals in Beijing, China 
PLoS ONE  2013;8(8):e72166.
With market-oriented economic and health-care reform, public hospitals in China have received unprecedented pressures from governmental regulations, public opinions, and financial demands. To adapt the changing environment and keep pace of modernizing healthcare delivery system, public hospitals in China are expanding clinical services and improving delivery efficiency, while controlling costs. Recent experiences are valuable lessons for guiding future healthcare reform. Here we carefully study three teaching hospitals, to exemplify their experiences during this period.
We performed a systematic analysis on hospitalization costs, health-care quality and delivery efficiencies from 2006 to 2010 in three teaching hospitals in Beijing, China. The analysis measured temporal changes of inpatient cost per stay (CPS), cost per day (CPD), inpatient mortality rate (IMR), and length of stay (LOS), using a generalized additive model.
There were 651,559 hospitalizations during the period analyzed. Averaged CPS was stable over time, while averaged CPD steadily increased by 41.7% (P<0.001), from CNY 1,531 in 2006 to CNY 2,169 in 2010. The increasing CPD seemed synchronous with the steady rising of the national annual income per capita. Surgical cost was the main contributor to the temporal change of CPD, while medicine and examination costs tended to be stable over time. From 2006 and 2010, IMR decreased by 36%, while LOS reduced by 25%. Increasing hospitalizations with higher costs, along with an overall stable CPS, reduced IMR, and shorter LOS, appear to be the major characteristics of these three hospitals at present.
These three teaching hospitals have gained some success in controlling costs, improving cares, adopting modern medical technologies, and increasing hospital revenues. Effective hospital governance and physicians' professional capacity plus government regulations and supervisions may have played a role. However, purely market-oriented health-care reform could also misguide future healthcare reform.
PMCID: PMC3745407  PMID: 23977243
25.  64-Slice spiral CT perfusion combined with vascular imaging of acute ischemic stroke for assessment of infarct core and penumbra 
The aim of this study was to determine the value of computed tomography perfusion (CTP) parameters, including cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT) and time-to-peak (TP), in a clinical study of patients with stroke. Additionally, we determined which parameter or combination of parameters are reliable in detecting the presence of an infarct and penumbra. CTP was performed within 24 h of the onset of symptoms in 20 patients with possible stroke. Magnetic resonance imaging (MRI) was performed 3-7 days later and the threshold of the CTP was adjusted according to the results to provide CT images that correlated with the MRI; the MRI results were taken as the gold standard. CBV, CBF and TP contrast agent enhancement were calculated using the CT results. The CTP results were compared with the MRI findings. All CTP parameters were reliable in detecting the penumbra (P<0.001). In these parameters, changes of MTT were the most useful. CTP revealed various changes in CBF, CBV, MTT and TP in ischemic areas. CTP parameters were also reliable in detecting the infarct core (P<0.001). We determined that when detecting the penumbra, all CTP parameters are reliable, and when detecting cerebral ischemia, a combination of parameters should be used.
PMCID: PMC3735805  PMID: 23935734
computed tomography; perfusion; penumbra; stroke

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