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1.  The Microgeographical Patterns of Morphological and Molecular Variation of a Mixed Ploidy Population in the Species Complex Actinidia chinensis 
PLoS ONE  2015;10(2):e0117596.
Polyploidy and hybridization are thought to have significant impacts on both the evolution and diversification of the genus Actinidia, but the structure and patterns of morphology and molecular diversity relating to ploidy variation of wild Actinidia plants remain much less understood. Here, we examine the distribution of morphological variation and ploidy levels along geographic and environmental variables of a large mixed-ploidy population of the A. chinensis species complex. We then characterize the extent of both genetic and epigenetic diversity and differentiation exhibited between individuals of different ploidy levels. Our results showed that while there are three ploidy levels in this population, hexaploids were constituted the majority (70.3%). Individuals with different ploidy levels were microgeographically structured in relation to elevation and extent of niche disturbance. The morphological characters examined revealed clear difference between diploids and hexaploids, however tetraploids exhibited intermediate forms. Both genetic and epigenetic diversity were high but the differentiation among cytotypes was weak, suggesting extensive gene flow and/or shared ancestral variation occurred in this population even across ploidy levels. Epigenetic variation was clearly correlated with changes in altitudes, a trend of continuous genetic variation and gradual increase of epigenomic heterogeneities of individuals was also observed. Our results show that complex interactions between the locally microgeographical environment, ploidy and gene flow impact A. chinensis genetic and epigenetic variation. We posit that an increase in ploidy does not broaden the species habitat range, but rather permits A. chinensis adaptation to specific niches.
PMCID: PMC4319829  PMID: 25658107
2.  Maternal High-Salt Intake During Pregnancy Reprogrammed Renin–Angiotensin System-Mediated Cardiomyocyte Apoptosis in the Adult Offspring Heart 
Reproductive Sciences  2014;21(1):52-62.
Excess salt intake during pregnancy may alter fetal organ structures and functions leading to increased risks in the development of cardiovascular diseases in later life. The present study determined whether and how the prenatal high-salt (HS) diets affect renin–angiotensin system (RAS) that may mediate cardiac cell death.
Methods and Results:
Angiotensin II receptors, AT1 and AT2, protein expression was increased in the myocardium of the offspring exposed to prenatal HS; apoptotic cells appeared in the myocardium of the adult offspring. Mitochondrion was isolated in cell experiments, and the data showed cardiomyocyte apoptosis requiring cytochrome C release. Pretreating H9C2 cells with AT2 agonist CGP42112A induced cell apoptosis in DNA fragments and activated caspase 3. CGP42112A increased mitochondrion cytochrome C release and apoptosis in the cells.
Both in vitro and in vivo study demonstrated that cardiomyocyte apoptosis was related to AT2 activation. Prenatal HS diets may reprogram RAS that mediates apoptosis in the offspring myocardium, and AT2 may contribute to cardiomyocyte apoptosis via the cytochrome C release pathway.
PMCID: PMC3857761  PMID: 23690339
angiotensin receptors; high salt; apoptosis; offspring heart
3.  FOXM1 Promotes Lung Adenocarcinoma Invasion and Metastasis by Upregulating SNAIL 
The forkhead box M1 (FOXM1) transcription factor is one of the key genes inducing tumor invasion and metastasis by an unknown mechanism. In this study, we set out to investigate the effects of FOXM1 overexpression on metastatic human lung adenocarcinoma and the underlying mechanism. FOXM1 expression was analyzed in 78 frozen lung adenocarcinoma tissue samples using an Affymetrix microarray and a 155-paraffin-embedded lung adenocarcinoma tissue microarray with immunohistochemical detection. FOXM1 was found to be overexpressed in lung adenocarcinoma, particularly in metastatic patients, compared to non-metastatic patients. Knockdown of FOXM1 by a specific siRNA significantly suppressed EMT progression, migration and invasion of lung adenocarcinoma cells in vitro, and tumor growth and metastasis in vivo, whereas restored expression of FOXM1 had the opposite effect. FOXM1 binds directly to the SNAIL promoter through two specific binding sites and constitutively transactivates it. Collectively, our findings indicate that FOXM1 may play an important role in advancing lung adenocarcinoma progression. Aberrant FOXM1 expression directly and constitutively activates SNAIL, thereby promoting lung adenocarcinoma metastasis. Inhibition of FOXM1-SNAIL signaling may present an ideal target for future treatment.
PMCID: PMC4279094  PMID: 25561901
Lung adenocarcinoma; Invasion; Metastasis; FOXM1; SNAIL
4.  Increased number of negative lymph nodes is associated with improved cancer specific survival in pathological IIIB and IIIC rectal cancer treated with preoperative radiotherapy 
Oncotarget  2014;5(23):12459-12471.
Preoperative radiation significantly decreases the number of retrieved lymph nodes (LNs) in rectal cancer, but little is known with respect to the prognostic significance of negative LN (NLN) counts under these circumstances. In this study, Surveillance, Epidemiology, and End Results Program (SEER)-registered ypIII stage rectal cancer patients, and patients from Fudan University Shanghai Cancer Center (FDSCC) were combined and analyzed. The results showed that the survival rate of patients with n (cutoff) or more NLNs increased gradually when n ranged from two to nine. After n reached 10 or greater, survival rates were approximately equivalent. Furthermore, the optimal cutoff value of 10 was validated as an independent prognostic factor in stage ypIIIB and ypIIIC patients by both univariate and multivariate analysis (P < 0.001); the number of NLNs could also stratify the prognosis of ypN(+) patients in more detail. Patients in the FDSCC set validated these findings and confirmed that NLN count was not decreased in the good tumor regression group relative to the poor tumor regression group. These results suggest that NLN count is an independent prognostic factor for ypIIIB and ypIIIC rectal cancer patients, and, together with the number of positive LNs, this will provide better prognostic information than the number of positive LNs alone.
PMCID: PMC4323013  PMID: 25514596
Rectal cancer; negative lymph nodes; prognosis; SEER
5.  Expression of Aquaporin 4 and Breakdown of the Blood-Brain Barrier after Hypoglycemia-Induced Brain Edema in Rats 
PLoS ONE  2014;9(9):e107022.
Hypoglycemia-induced brain edema is a severe clinical event that often results in death. The mechanisms by which hypoglycemia induces brain edema are unclear.
In a hypoglycemic injury model established in adult rats, brain edema was verified by measuring brain water content and visualizing water accumulation using hematoxylin and eosin staining. Temporal expression of aquaporin 4 (AQP4) and the integrity of the blood-brain barrier (BBB) were evaluated. We assessed the distribution and expression of AQP4 following glucose deprivation in astrocyte cultures.
Brain edema was induced immediately after severe hypoglycemia but continued to progress even after recovery from hypoglycemia. Upregulation of AQP4 expression and moderate breakdown of the BBB were observed 24 h after recovery. In vitro, significant redistribution of AQP4 to the plasma membrane was induced following 6 h glucose deprivation.
Hypoglycemia-induced brain edema is caused by cytotoxic and vasogenic factors. Changes in AQP4 location and expression may play a protective role in edema resolution.
PMCID: PMC4180270  PMID: 25264602
7.  Relating gene expression evolution with CpG content changes 
BMC Genomics  2014;15(1):693.
Previous studies have shown that CpG dinucleotides are enriched in a subset of promoters and the CpG content of promoters is positively correlated with gene expression levels. But the relationship between divergence of CpG content and gene expression evolution has not been investigated. Here we calculate the normalized CpG (nCpG) content in DNA regions around transcription start site (TSS) and transcription terminal site (TTS) of genes in nine organisms, and relate them with expression levels measured by RNA-seq.
The nCpG content of TSS shows a bimodal distribution in all organisms except platypus, whereas the nCpG content of TTS only has a single peak. When the nCpG contents are compared between different organisms, we observe a different evolution pattern between TSS and TTS: compared with TTS, TSS exhibits a faster divergence rate between closely related species but are more conserved between distant species. More importantly, we demonstrate the link between gene expression evolution and nCpG content changes: up-/down- regulation of genes in an organism is accompanied by the nCpG content increase/decrease in their TSS and TTS proximal regions.
Our results suggest that gene expression changes between different organisms are correlated with the alterations in normalized CpG contents of promoters. Our analyses provide evidences for the impact of nCpG content on gene expression evolution.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-693) contains supplementary material, which is available to authorized users.
PMCID: PMC4148958  PMID: 25142157
8.  Multi-Cultural Association of the Serotonin Transporter Gene (SLC6A4) with Substance Use Disorder 
Neuropsychopharmacology  2013;38(9):1737-1747.
A number of studies have reported associations between the serotonin transporter gene (SLC6A4) and alcohol, heroin, cocaine, or methamphetamine abuse. Other studies have yielded contrary results. There are a number of reasons for non-replication, including inadequate statistical power, population stratification, and poor phenotype definition. This study was to test the association using a meta-analytic approach across a variety of racial and ethnic populations. Using the genotype data of 55 studies (7999 cases, 8264 controls, and 676 families or parent-offspring trios) published in the past 15 years, we have conducted comprehensive meta-analyses to examine the associations of the 5-HTTLPR and STin2 polymorphisms with substance use disorder. The meta-analyses support the associations of 5-HTTLPR with alcohol, heroin, cocaine, and methamphetamine dependence and abuse (eg, the smallest P-values were 0.0058 with odds ratio (OR)=0.54 (0.35, 0.84); 0.0024 with OR=0.77 (0.66, 0.91); 0.018 with OR=1.38 (1.06, 1.81); and 0.028 with OR=0.46 (0.23, 0.92) for alcohol, heroin, cocaine, and methamphetamine dependence/abuse, respectively). When all the phenotypes are combined, the P-value was 0.0006 with OR=0.86 (0.78, 0.94) in the combined European, Asian, and Mexican populations and P-value was 0.0028 with OR=1.41 (1.13, 1.78) in the African populations. Evidence of significant associations was also identified in other subgroup analyses regarding differently combined substance and populations. The effect sizes of 5-HTTLPR were comparable among the European, Asian, and Mexican populations, however, the risk allele was more frequent in Asians than in Europeans and Mexicans. The opposite directions of risk allele in African population might be driven by the opposite directions of risk allele in cocaine dependence. This meta-analysis supports that the association of the SLC6A4 gene with substance use disorder varies depending on substances with different risk allele frequencies in the multi-cultural populations. Further studies using larger sample size are warranted.
PMCID: PMC3717550  PMID: 23518607
addiction & substance abuse; alcohol & alcoholism; behavioral science; genetic association; meta-analysis; serotonin; meta-analysis; association; serotonin transporter; addiction; common genetic risk
9.  GACT: a Genome build and Allele definition Conversion Tool for SNP imputation and meta-analysis in genetic association studies 
BMC Genomics  2014;15:610.
Genome-wide association studies (GWAS) have successfully identified genes associated with complex human diseases. Although much of the heritability remains unexplained, combining single nucleotide polymorphism (SNP) genotypes from multiple studies for meta-analysis will increase the statistical power to identify new disease-associated variants. Meta-analysis requires same allele definition (nomenclature) and genome build among individual studies. Similarly, imputation, commonly-used prior to meta-analysis, requires the same consistency. However, the genotypes from various GWAS are generated using different genotyping platforms, arrays or SNP-calling approaches, resulting in use of different genome builds and allele definitions. Incorrect assumptions of identical allele definition among combined GWAS lead to a large portion of discarded genotypes or incorrect association findings. There is no published tool that predicts and converts among all major allele definitions.
In this study, we have developed a tool, GACT, which stands for Genome build and Allele definition Conversion Tool, that predicts and inter-converts between any of the common SNP allele definitions and between the major genome builds. In addition, we assessed several factors that may affect imputation quality, and our results indicated that inclusion of singletons in the reference had detrimental effects while ambiguous SNPs had no measurable effect. Unexpectedly, exclusion of genotypes with missing rate > 0.001 (40% of study SNPs) showed no significant decrease of imputation quality (even significantly higher when compared to the imputation with singletons in the reference), especially for rare SNPs.
GACT is a new, powerful, and user-friendly tool with both command-line and interactive online versions that can accurately predict, and convert between any of the common allele definitions and between genome builds for genome-wide meta-analysis and imputation of genotypes from SNP-arrays or deep-sequencing, particularly for data from the dbGaP and other public databases.
GACT software
PMCID: PMC4223508  PMID: 25038819
Allele definition (nomenclature); Genome build; Genome-wide association study (GWAS); Imputation; Meta-analysis
10.  Associations of the 5-hydroxytryptamine (Serotonin) Receptor 1B Gene (HTR1B) with Alcohol, Cocaine, and Heroin Abuse 
Abnormal serotonergic pathways are implicated in numerous neuropsychiatric disorders including alcohol and drug dependence (abuse). The human 5-hydroxytryptamine (serotonin) receptor 1B, encoded by the HTR1B (5-HT1B) gene, is a presynaptic serotonin autoreceptor that plays an important role in regulating serotonin synthesis and release. Although there was evidence of associations of the HTR1B gene variants in the etiologies of substance use disorders, negative findings were also reported. To clarify the roles of commonly-reported single nucleotide polymorphisms (SNPs) of the HTR1B gene underlying alcohol and drug dependence (abuse), we performed a meta-analysis based on the available genotype data from individual candidate gene-based association studies. Evidence of association was found between the functional SNP -161A>T (rs130058) and alcohol, cocaine, and heroin dependence (e.g., P = 0.03 and odds ratio = 1.2 (1.02, 1.42) in the combined European, Asian, African, and Hispanic populations). SNP -261T>G (rs11568817) also showed evidence of association but with different directions in Europeans and non-Europeans (e.g., P = 0.0018 with odds ratio = 1.42 (1.14, 1.76) and P = 0.01 with odds ratio = 0.5 (0.3, 0.85), respectively). This meta-analysis supports the associations of HTR1B -261T>G and -161A>T with alcohol and drug abuse and further investigations are warranted in larger samples.
PMCID: PMC4089973  PMID: 23335468
Substance Use Disorder; Addiction; Meta-analysis; Association; Linkage Disequilibrium
11.  Pathological Features and Survival Outcomes of Young Patients with Operable Colon Cancer: Are They Homogeneous? 
PLoS ONE  2014;9(7):e102004.
To compare the pathological features and survival outcomes at different age subgroups of young patients with colon cancer.
Using Surveillance, Epidemiology, and End Results (SEER) population-based data, we identified 2,861 young patients with colon cancer diagnosed between 1988 and 2005 treated with surgery. Patients were divided into four groups: group 1 (below 25 years), group 2 (26–30 years), group 3 (31–35 years) and group 4 (36–40 years). Five-year cancer specific survival data were obtained. Kaplan-Meier methods were adopted and multivariable Cox regression models were built for the analysis of long-term survival outcomes and risk factors.
There were significant different among four groups in pathological grading, histological type, AJCC stage, current standard (≥12 lymph nodes retrieval), mean number of lymph nodes examined and positive lymph nodes (p<0.001). The 5-year cause specific survival was 71.0% in group 1, 75.1% in group 2, 80.6% in group 3 and 82.5% in group 4, which had significant difference in both univariate (P = 0.002) and multivariate analysis (P = 0.041).
Young patients with colon cancer at age 18–40 years are essentially a heterogeneous group. Patients at age 31–35, 36–40 subgroups have more favorable clinicopathologic characteristics and better cancer specific survival than below 30 years.
PMCID: PMC4087023  PMID: 25003760
12.  Low expression of novel lncRNA RP11-462C24.1 suggests a biomarker of poor prognosis in colorectal cancer 
Long noncoding RNAs (lncRNAs) have recently emerged as a major class of regulatory molecules, which were involved in a broad range of biological processes and complex diseases. Research on lncRNAs may shed light on tumorigenesis and progression of colorectal cancer (CRC). The purpose of the present study was to identify lncRNAs correlated with CRC and then investigate their potential functions. We selected 92 patients for this prospective study and then collected the tumor samples and clinical records. First, the global lncRNA expression profiles in tumor and adjacent normal tissues of patients with non-metastatic CRC and patients with metastatic CRC were measured by microarray assay. Then, a noteworthy lncRNAs RP11-462C24.1 whose function was previously unknown was explored in detail on the aspect of the association of its expression level and clinicopathological features of CRC and patients’ survival. We found that RP11-462C24.1 expression level was lower in cancer tissues compared with adjacent normal samples (P < 0.001). Furthermore, its expression level was lower in CRC patients with metastasis than those without metastasis (P = 0.049). That is, RP11-462C24.1 expression level decreased as the malignant degree of CRC increased. In addition, low expression of RP11-462C24.1 significantly correlated with more distant metastasis (P = 0.011). The areas under ROC curves were 0.78 and 0.65 for RP11-462C24.1, distinguishing CRC from normal tissue and distinguishing CRC without metastasis from CRC with metastasis, respectively. Multivariate analysis identified that RP11-462C24.1 was an independent predictor for patients prognosis (P = 0.005). Furthermore, Kaplan–Meier analysis showed that patients with low expression of RP11-462C24.1 had a poor disease-free survival (P < 0.001). This is the first study that correlates RP11-462C24.1 expression profile with malignancy grade in human CRC. Our results showed that RP11-462C24.1 could be a potential novel prognostic marker for CRC, and thus, provided a new strategy for CRC diagnosis. Meanwhile, our findings indicated the potential roles of RP11-462C24.1 in tumorigenesis and progression of CRC, which gave a clue for future studies.
Electronic supplementary material
The online version of this article (doi:10.1007/s12032-014-0031-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4079943  PMID: 24908062
Colorectal cancer; Long noncoding RNAs; Microarray; RP11-462C24.1; Survival
13.  Stereopsis impairment is associated with decreased color perception and worse motor performance in Parkinson’s disease 
We conducted this study is to investigate the correlation between stereopsis dysfunction and color perception, as well as whether stereopsis impairment is associated with motor dysfunction in patients with Parkinson’s disease (PD).
Our present study included 45 PD patients and 50 non-PD control patients attending the Movement Disorder Center at Xuanwu Hospital Capital Medical University in Beijing from July 2011 to November 2011. Neurologic evaluations and visual function assessments were conducted, and the results between two groups of patients were compared.
We found that the total error scores (TESs) and partial error scores (PESs) for red, green, blue and purple were all significantly higher in PD patients than in control patients. The limited grade on the FLY Stereo Acuity Test with LEA Symbols was significantly lower in PD patients than in control patients (P = 0.0001), whereas the percentage of abnormal stereopsis in PD patients was significantly higher than in control patients (42.2% vs. 12%; P = 0.001). Multiple linear regression analysis showed that PD patients with higher Hoehn and Yahr Scale stage, and those with decreased stereopsis had higher Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores and worse motor function. Furthermore, our study demonstrates that the UPDRS motor scores and total average number of the Purdue Pegboard Test scores of PD patients were significantly improved when they had taken their medications, and the TESs and PESs for green were lower in when they were off their medications.
Our results provide more information on the underlying mechanisms of vision, motor and stereopsis impairments in PD patients.
PMCID: PMC4046158  PMID: 24886673
Color perception; Parkinson’s disease; Stereopsis
14.  Solitary lymph node metastasis is a distinct subset of colon cancer associated with good survival: a retrospective study of surveillance, epidemiology, and end-results population-based data 
BMC Cancer  2014;14:368.
Colon cancer with lymph node metastases has been considered as advanced stage and to have poor survival. We postulated that patients with solitary lymph node metastasis are a distinct subset with better colon cancer-specific survival than those with multiple lymph node metastases.
In this retrospective study, we searched Surveillance, Epidemiology, and End-Results (SEER) population-based data and identified 86,674 patients who had been diagnosed with colon cancer without distant metastases and with less than three metastatic nodes between 1991 and 2005. We divided lymph node status into three subgroups: pN0, pN1a, and pN1b and obtained 5-year colon cancer-specific survival for each pT stage. We used Kaplan–Meier and multivariate Cox regression models to assess correlations between risk factors and survival outcomes.
Analysis of SEER data confirmed that patients with solitary lymph node metastases had better 5-year cancer-specific survival than pN1b according to both univariate and multivariate analysis. This finding was confirmed by further analyses in five pT subgroups. Cancer-specific survival of patients with pT1-2N1a was comparable to that of those with pIIA but higher than those with pIIB. In addition, survival of patients with pT3-4aN1a was better than those with pIIC.
Colon cancer patients with solitary lymph node metastasis are a distinct subset with a favorable prognosis; full consideration should be given to this in clinical practice.
PMCID: PMC4070651  PMID: 24885443
Colon Cancer; Lymph node metastasis; Surgery; Survival analysis
15.  Small-molecule inhibitors of acetyltransferase p300 identified by high-throughput screening are potent anticancer agents 
Molecular cancer therapeutics  2013;12(5):610-620.
Acetyltransferase p300 (KAT3B) plays key roles in signaling cascades that support cancer cell survival and sustained proliferation. Thus, p300 represents a potential anticancer therapeutic target. To discover novel anticancer agents that target p300, we conducted a high-throughput screening campaign. A library of 622,079 compounds was assayed for cytotoxicity to the triple-negative breast cancer (TNBC) cell line MDA-MB-231 but not to the human mammary epithelial cells. The resulting compounds were tested in a biochemical assay for inhibiting the enzymatic activity of p300. One compound (L002, NSC764414) displayed an IC50 of 1.98 μM against p300 in vitro, inhibited acetylation of histones and p53, and suppressed STAT3 activation in cell-based assays. L002 could be docked to the active site of the p300 catalytic domain. Biochemical tests of a series of related compounds revealed functional groups that may impact inhibitory potency of L002 against p300. Interestingly, these analogs showed inhibitory activities against CBP (the cellular paralog of p300), PCAF and GCN5, but not to other acetyltransferases (KAT5, KAT6B and KAT7), histone deacetylases (HDACs) and histone methyltransferases. Among the NCI-60 panel of cancer cell lines, leukemia and lymphoma cell lines were extremely sensitive to L002, whereas it is toxic to only a limited number of cell lines derived from solid tumors. Notably, breast cancer cell lines, especially those derived from TNBC, were highly susceptible to L002. In vivo, it potently suppressed tumor growth and histone acetylation of MDA-MB-468 xenografts. Thus, these new acetyltransferase inhibitors are potential anticancer therapeutics.
PMCID: PMC3651759  PMID: 23625935
16.  Better Long-Term Survival in Young Patients with Non-Metastatic Colorectal Cancer after Surgery, an Analysis of 69,835 Patients in SEER Database 
PLoS ONE  2014;9(4):e93756.
To compare the long-term survival of colorectal cancer (CRC) in young patients with elderly ones.
Using Surveillance, Epidemiology, and End Results (SEER) population-based data, we identified 69,835 patients with non-metastatic colorectal cancer diagnosed between January 1, 1988 and December 31, 2003 treated with surgery. Patients were divided into young (40 years and under) and elderly groups (over 40 years of age). Five-year cancer specific survival data were obtained. Kaplan-Meier methods were adopted and multivariable Cox regression models were built for the analysis of long-term survival outcomes and risk factors.
Young patients showed significantly higher pathological grading (p<0.001), more cases of mucinous and signet-ring histological type (p<0.001), later AJCC stage (p<0.001), more lymph nodes (≥12 nodes) dissected (p<0.001) and higher metastatic lymph node ratio (p<0.001). The 5-year colorectal cancer specific survival rates were 78.6% in young group and 75.3% in elderly group, which had significant difference in both univariate and multivariate analysis (P<0.001). Further analysis showed this significant difference only existed in stage II and III patients.
Compared with elderly patients, young patients with colorectal cancer treated with surgery appear to have unique characteristics and a higher cancer specific survival rate although they presented with higher proportions of unfavorable biological behavior as well as advanced stage disease.
PMCID: PMC3974782  PMID: 24699879
17.  A catechol biosensor based on electrospun carbon nanofibers 
Carbon nanofibers (CNFs) were prepared by combining electrospinning with a high-temperature carbonization technique. And a polyphenol biosensor was fabricated by blending the obtained CNFs with laccase and Nafion. Raman spectroscopy, Fourier transform infrared spectroscopy (FTIR) and field emission scanning electron microscope (FE-SEM) were, respectively, employed to investigate the structures and morphologies of the CNFs and of the mixtures. Cyclic voltammetry and chronoamperometry were employed to study the electrocatalysis of the catechol biosensor. The results indicated that the sensitivity of the biosensor was 41 µA·mM−1, the detection limit was 0.63 µM, the linear range was 1–1310 µM and the response time was within 2 seconds, which excelled most other laccase-based biosensor reported. Furthermore, the biosensor showed good repeatability, reproducibility, stability and tolerance to interferences. This novel biosensor also demonstrated its promising application in detecting catechol in real water samples.
PMCID: PMC3999850  PMID: 24778958
biosensor; carbon nanofibers; catechol; electrospinning; laccase
18.  Complete Resequencing of 40 Genomes Reveals Domestication Events and Genes in Silkworm (Bombyx) 
Science (New York, N.Y.)  2009;326(5951):433-436.
A single–base pair resolution silkworm genetic variation map was constructed from 40 domesticated and wild silkworms, each sequenced to approximately threefold coverage, representing 99.88% of the genome. We identified ∼16 million single-nucleotide polymorphisms, many indels, and structural variations. We find that the domesticated silkworms are clearly genetically differentiated from the wild ones, but they have maintained large levels of genetic variability, suggesting a short domestication event involving a large number of individuals. We also identified signals of selection at 354 candidate genes that may have been important during domestication, some of which have enriched expression in the silk gland, midgut, and testis. These data add to our understanding of the domestication processes and may have applications in devising pest control strategies and advancing the use of silkworms as efficient bioreactors.
PMCID: PMC3951477  PMID: 19713493
19.  The sequence and de novo assembly of the giant panda genome 
Li, Ruiqiang | Fan, Wei | Tian, Geng | Zhu, Hongmei | He, Lin | Cai, Jing | Huang, Quanfei | Cai, Qingle | Li, Bo | Bai, Yinqi | Zhang, Zhihe | Zhang, Yaping | Wang, Wen | Li, Jun | Wei, Fuwen | Li, Heng | Jian, Min | Li, Jianwen | Zhang, Zhaolei | Nielsen, Rasmus | Li, Dawei | Gu, Wanjun | Yang, Zhentao | Xuan, Zhaoling | Ryder, Oliver A. | Leung, Frederick Chi-Ching | Zhou, Yan | Cao, Jianjun | Sun, Xiao | Fu, Yonggui | Fang, Xiaodong | Guo, Xiaosen | Wang, Bo | Hou, Rong | Shen, Fujun | Mu, Bo | Ni, Peixiang | Lin, Runmao | Qian, Wubin | Wang, Guodong | Yu, Chang | Nie, Wenhui | Wang, Jinhuan | Wu, Zhigang | Liang, Huiqing | Min, Jiumeng | Wu, Qi | Cheng, Shifeng | Ruan, Jue | Wang, Mingwei | Shi, Zhongbin | Wen, Ming | Liu, Binghang | Ren, Xiaoli | Zheng, Huisong | Dong, Dong | Cook, Kathleen | Shan, Gao | Zhang, Hao | Kosiol, Carolin | Xie, Xueying | Lu, Zuhong | Zheng, Hancheng | Li, Yingrui | Steiner, Cynthia C. | Lam, Tommy Tsan-Yuk | Lin, Siyuan | Zhang, Qinghui | Li, Guoqing | Tian, Jing | Gong, Timing | Liu, Hongde | Zhang, Dejin | Fang, Lin | Ye, Chen | Zhang, Juanbin | Hu, Wenbo | Xu, Anlong | Ren, Yuanyuan | Zhang, Guojie | Bruford, Michael W. | Li, Qibin | Ma, Lijia | Guo, Yiran | An, Na | Hu, Yujie | Zheng, Yang | Shi, Yongyong | Li, Zhiqiang | Liu, Qing | Chen, Yanling | Zhao, Jing | Qu, Ning | Zhao, Shancen | Tian, Feng | Wang, Xiaoling | Wang, Haiyin | Xu, Lizhi | Liu, Xiao | Vinar, Tomas | Wang, Yajun | Lam, Tak-Wah | Yiu, Siu-Ming | Liu, Shiping | Zhang, Hemin | Li, Desheng | Huang, Yan | Wang, Xia | Yang, Guohua | Jiang, Zhi | Wang, Junyi | Qin, Nan | Li, Li | Li, Jingxiang | Bolund, Lars | Kristiansen, Karsten | Wong, Gane Ka-Shu | Olson, Maynard | Zhang, Xiuqing | Li, Songgang | Yang, Huanming | Wang, Jian | Wang, Jun
Nature  2009;463(7279):311-317.
Using next-generation sequencing technology alone, we have successfully generated and assembled a draft sequence of the giant panda genome. The assembled contigs (2.25 gigabases (Gb)) cover approximately 94% of the whole genome, and the remaining gaps (0.05 Gb) seem to contain carnivore-specific repeats and tandem repeats. Comparisons with the dog and human showed that the panda genome has a lower divergence rate. The assessment of panda genes potentially underlying some of its unique traits indicated that its bamboo diet might be more dependent on its gut microbiome than its own genetic composition. We also identified more than 2.7 million heterozygous single nucleotide polymorphisms in the diploid genome. Our data and analyses provide a foundation for promoting mammalian genetic research, and demonstrate the feasibility for using next-generation sequencing technologies for accurate, cost-effective and rapid de novo assembly of large eukaryotic genomes.
PMCID: PMC3951497  PMID: 20010809
20.  Laccase Biosensor Based on Electrospun Copper/Carbon Composite Nanofibers for Catechol Detection 
Sensors (Basel, Switzerland)  2014;14(2):3543-3556.
The study compared the biosensing properties of laccase biosensors based on carbon nanofibers (CNFs) and copper/carbon composite nanofibers (Cu/CNFs). The two kinds of nanofibers were prepared by electrospinning and carbonization under the same conditions. Scanning electron microscopy (SEM), X-ray diffraction (XRD) and Raman spectroscopy were employed to investigate the morphologies and structures of CNFs and Cu/CNFs. The amperometric results indicated that the Cu/CNFs/laccase(Lac)/Nafion/glass carbon electrode (GCE) possessed reliable analytical performance for the detection of catechol. The sensitivity of the Cu/CNFs/Lac/Nafion/GCE reached 33.1 μA/mM, larger than that of CNFs/Lac/Nafion/GCE. Meanwhile, Cu/CNFs/Lac/Nafion/GCE had a wider linear range from 9.95 × 10−6 to 9.76 × 10−3 M and a lower detection limit of 1.18 μM than CNFs/Lac/Nafion/GCE. Moreover, it exhibited a good repeatability, reproducibility, selectivity and long-term stability, revealing that electrospun Cu/CNFs have great potential in biosensing.
PMCID: PMC3958252  PMID: 24561403
electrospinning; copper/carbon composite nanofibers; laccase biosensor; catechol detection; electrochemical properties
21.  Deep Sequencing–Based Transcriptome Profiling Reveals Comprehensive Insights into the Responses of Nicotiana benthamiana to Beet necrotic yellow vein virus Infections Containing or Lacking RNA4 
PLoS ONE  2014;9(1):e85284.
Beet necrotic yellow vein virus (BNYVV), encodes either four or five plus-sense single stranded RNAs and is the causal agent of sugar beet rhizomania disease, which is widely distributed in most regions of the world. BNYVV can also infect Nicotiana benthamiana systemically, and causes severe curling and stunting symptoms in the presence of RNA4 or mild symptoms in the absence of RNA4.
Confocal laser scanning microscopy (CLSM) analyses showed that the RNA4-encoded p31 protein fused to the red fluorescent protein (RFP) accumulated mainly in the nuclei of N. benthamiana epidermal cells. This suggested that severe RNA4-induced symptoms might result from p31-dependent modifications of the transcriptome. Therefore, we used next-generation sequencing technologies to analyze the transcriptome profile of N. benthamiana in response to infection with different isolates of BNYVV. Comparisons of the transcriptomes of mock, BN3 (RNAs 1+2+3), and BN34 (RNAs 1+2+3+4) infected plants identified 3,016 differentially expressed transcripts, which provided a list of candidate genes that potentially are elicited in response to virus infection. Our data indicate that modifications in the expression of genes involved in RNA silencing, ubiquitin-proteasome pathway, cellulose synthesis, and metabolism of the plant hormone gibberellin may contribute to the severe symptoms induced by RNA4 from BNYVV.
These results expand our understanding of the genetic architecture of N. benthamiana as well as provide valuable clues to identify genes potentially involved in resistance to BNYVV infection. Our global survey of gene expression changes in infected plants reveals new insights into the complicated molecular mechanisms underlying symptom development, and aids research into new strategies to protect crops against viruses.
PMCID: PMC3887015  PMID: 24416380
22.  Estimating Working Memory Capacity for Lists of Nonverbal Sounds 
Working memory (WM) capacity limit has been extensively studied in the domains of visual and verbal stimuli. Previous studies have suggested a fixed WM capacity of typically about 3 or 4 items, based on the number of items in working memory reaching a plateau after several items as the set size increases. However, the fixed WM capacity estimate appears to rely on categorical information in the stimulus set (Olsson & Poom, 2005). We designed a series of experiments to investigate nonverbal auditory WM capacity and its dependence on categorical information. Experiments 1 and 2 used simple tones and revealed capacity limit of up to 2 tones following a 6-s retention interval. Importantly, performance was significantly higher at set sizes 2, 3, and 4 when the frequency difference between target and test tones was relatively large. In Experiment 3, we added categorical information to the simple tones, and the effect of tone change magnitude decreased. Maximal capacity for each individual was just over 3 sounds, in the range of typical visual procedures. We propose that two types of information, categorical and detailed acoustic information, are kept in WM, and that categorical information is critical for high WM performance.
PMCID: PMC3527657  PMID: 23143913
23.  TPX2 is a novel prognostic marker for the growth and metastasis of colon cancer 
We have previously demonstrated an aberrant overexpression of the microtubule-associated protein TPX2 in colon cancer using a genome-wide gene expression profiling analysis. Here, we aim to investigate its expression pattern, clinical significance, and biological function in colon cancer.
TPX2 expression was analyzed in human colon cancer cell lines and tumor samples. The effect of TPX2 on cell proliferation, tumorigenesis, and metastasis was examined in vitro and in vivo.
TPX2 was overexpressed in 129 of the 203 (60.8%) colon cancer metastatic lesions, with the expression being significantly higher than that in primary cancerous tissue and normal colon mucosa. Overexpression of TPX2 was significantly associated with clinical staging, vessel invasion, and metastasis. In survival analyses, patients with TPX2 overexpression had worse overall survival and metastasis free survival, suggesting that deregulation of TPX2 may contribute to the metastasis of colon cancer. Consistent with this, suppression of TPX2 expression inhibited proliferation and tumorigenicity of colon cancer cells both in vitro and in vivo. Strikingly, we found that TPX2 knockdown significantly attenuated the migration and invasion ability of colon cancer cells, which was further shown to be mechanistically associated with AKT-mediated MMP2 activity.
These findings suggest that TPX2 plays an important role in promoting tumorigenesis and metastasis of human colon cancer, and may represent a novel prognostic biomarker and therapeutic target for the disease.
PMCID: PMC3878622  PMID: 24341487
TPX2; Colon cancer; Tumorigenesis; Metastasis
24.  New dammarane-type triterpenoids from the leaves of Panax notoginseng and their protein tyrosine phosphatase 1B inhibitory activity 
Journal of Ginseng Research  2013;38(1):28-33.
Panax notoginseng has been used as a general tonic agent to invigorate human body for millennia in China and continued to be used until present.
Some chromatographic methods were performed to isolate pure triterpenoids, and their structures were determined by nuclear magnetic resonance (NMR) experiments. Anti-diabetes activities of isolated compounds were evaluated through their inhibitory activity of protein tyrosine phosphatase 1B (PTP1B) enzyme.
Results and Conclusion
Three new dammarane-type triterpenoids, notoginsenoside-LX (1), notoginsenoside-LY (2), and notoginsenoside-FZ (3) together with eighteen known compounds were isolated from the Panax notoginseng leaves. The structure-activity relationship of the compounds with dammarane-type triterpenoids and their PTP1B inhibitory activity were also reported. Results showed that compounds 2, 15, 20, and 21 can significantly inhibit the enzyme activity of PTP1B in a dose-dependent manner, with inhibitory concentration 50 (IC50) values of 29.08 μM, 21.27 μM, 28.12 μM, and 26.59 μM, respectively. The results suggested that Panax notoginseng leaves might have potential as a new therapeutic agent for the treatment of diabetes.
PMCID: PMC3915329  PMID: 24558307
notoginsenoside-FZ; notoginsenoside-LX; notoginsenoside-LY; Panax notoginseng; protein tyrosine phosphatase 1B
25.  p53 SUMOylation promotes its nuclear export by facilitating its release from the nuclear export receptor CRM1 
Molecular Biology of the Cell  2013;24(17):2739-2752.
p53 SUMOylation promotes its nuclear export. The SIM-binding groove of a SUMO moiety linked to p53 and a SIM in CRM1 regulates their interaction. CRM1 binds to tetrameric p53 with a properly folded core domain, and CRM1 with a mutated SIM in the HEAT9 loop accumulates with SUMOylated p53 at NPCs and cytoplasmic aggregates.
Chromosomal region maintenance 1 (CRM1) mediates p53 nuclear export. Although p53 SUMOylation promotes its nuclear export, the underlying mechanism is unclear. Here we show that tethering of a small, ubiquitin-like modifier (SUMO) moiety to p53 markedly increases its cytoplasmic localization. SUMO attachment to p53 does not affect its oligomerization, suggesting that subunit dissociation required for exposing p53’s nuclear export signal (NES) is unnecessary for p53 nuclear export. Surprisingly, SUMO-mediated p53 nuclear export depends on the SUMO-interacting motif (SIM)-binding pocket of SUMO-1. The CRM1 C-terminal domain lacking the NES-binding groove interacts with tetrameric p53, and the proper folding of the p53 core domain, rather than the presence of the N- or C-terminal tails, appears to be important for p53–CRM1 interaction. The CRM1 Huntington, EF3, a subunit of PP2A, and TOR1 9 (HEAT9) loop, which regulates GTP-binding nuclear protein Ran binding and cargo release, contains a prototypical SIM. Remarkably, disruption of this SIM in conjunction with a mutated SIM-binding groove of SUMO-1 markedly enhances the binding of CRM1 to p53-SUMO-1 and their accumulation in the nuclear pore complexes (NPCs), as well as their persistent association in the cytoplasm. We propose that SUMOylation of a CRM1 cargo such as p53 at the NPCs unlocks the HEAT9 loop of CRM1 to facilitate the disassembly of the transporting complex and cargo release to the cytoplasm.
PMCID: PMC3756925  PMID: 23825024

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