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1.  Physical Activity, Body Mass Index, and Cardiorespiratory Fitness among School Children in Taiwan: A Cross-Sectional Study 
There is evidence that cardiorespiratory fitness and physical activity significantly reduce cardiovascular risks in adults. A better understanding of the association between cardiorespiratory fitness, physical activity, and childhood obesity is vital in assessing the benefits of interventions to prevent obesity. This study was to examine the relationship between physical activity, body mass index, and cardiorespiratory fitness levels in Taiwanese children. A cross-sectional study was designed. Study participants consisted of 2419 school children (1230 males and 1189 females) aged 12 years old living in a southern Taiwan county with one the highest countrywide rates of childhood obesity. The weight status of the participants was defined as underweight, normal, overweight, or obese according to specific criteria. Cardiorespiratory fitness was then assessed by an 800-m run. Participants were queried on their physical activity habits via a questionnaire survey. The overall prevalence of overweight/obesity was 29.6%. Normal, underweight and overweight boys and girls had an increased odds ratio of being categorized with higher cardiorespiratory fitness than obese one for both gender. A significantly higher level of cardiorespiratory fitness was found in children who engaged in regular physical activity than in children who engaged only in irregular physical activity. Obese children are more likely to lack cardiorespiratory fitness. Physically active children have significantly better cardiorespiratory fitness levels than inactive children. This study supports the conclusion that BMI and physical activity are significantly correlated with cardiorespiratory fitness levels. Findings may provide educational professionals with information to assist their developing effective health promotion programs to healthy weight and improving cardiorespiratory fitness for children.
PMCID: PMC4113875  PMID: 25032742
children; obesity; cardiorespiratory; health promotion; school nursing
2.  Preventive effect of Qianggan-Rongxian Decoction on rat liver fibrosis 
AIM: To study the preventive effects of Qianggan-Rongxian Decoction on liver fibrosis induced by dimethylnitrosamine (DMN) in rats.
METHODS: Male Wistar rats were randomly divided into hepatic fibrosis model group, control group and 3 treatment groups (12 rats in each group). Except for the normal control group, all the rats received 1% DMN (10 μL/kg body weight, i.p), 3 times a week for 4 wk. The rats in the 3 treatment groups including a high-dose DMN group (10 mL/kg), a medium-dose DMN group (7 mL/kg), and a low-dose DMN group (4 mL/kg) were daily gavaged with Qianggan-Rongxian Decoction, and the rats in the model and normal control groups were given saline vehicle. Enzyme-linked immunosorbent assay (ELISA) was used to determine the changes in serum hyaluronic acid (HA), laminin (LN), and type IV collagen levels. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured using routine laboratory methods. Pathologic changes, particularly fibrosis, were examined by hematoxylin and eosin (HE) and Sirius red staining. Hepatic stellate cells (HSC) were examined by transmission electron microscopy.
RESULTS: Compared with the model control group, the serum levels of HA, LN, type IV collagen, ALT and AST were decreased markedly in the other groups after treatment with Qianggan-Rongxian Decoction, especially in the medium-dose DMN group (P < 0.05). Moreover, the area-density percentage of collagen fibrosis was lower in the Qianggan-Rongxian Decoction treatment groups than in the model group, and a more significant drop was observed in the medium-dose DMN group (P < 0.05).
CONCLUSION: Qianggan-Rongxian Decoction can inhibit hepatic fibrosis due to chronic liver injury, delay the development of cirrhosis, and notably ameliorate liver function. It may be used as a safe and effective thera-peutic drug for patients with fibrosis.
PMCID: PMC2716622  PMID: 18567088
Liver fibrosis; Qianggan-Rongxian Decoction; Prevention; Rat model; Dimethylnitrosamine
3.  Localization of ANP-synthesizing cells in rat stomach 
AIM: To study the morphological positive expression of antrial natriuretic peptide (ANP)-synthesizing cells and ultrastructural localization and the relationship between ANP-synthesizing cells and microvessel density in the stomach of rats and to analyze the distribution of the three histologically distinct regions of ANP-synthesizing cells.
METHODS: Using immunohistochemical techniques, we studied positive expression of ANP-synthesizing cells in rat stomach. A postembedding immunogold microscopy technique was used for ultrastructural localization of ANP-synthesizing cells. Microvessel density in the rat stomach was estimated using tannic acid-ferric chloride (TAFC) method staining. Distribution of ANP-synthesizing cells were studied in different regions of rat stomach histochemically.
RESULTS: Positive expression of ANP-synthesizing cells were localized in the gastric mucosa of rats. Localization of ANP-synthesizing cells identified them to be enterochrochromaffin cells (EC) by using a postembedding immunogold electron microscopy technique. EC cells were in the basal third of the cardiac mucosa region. ANP-synthesizing cells existed in different regions of rat stomach and its density was largest in the gastric cardiac region, and the distribution order of ANP-synthesizing cells in density was cardiac region, pyloric region and fundic region in mucosa layer. We have also found a close relationship between ANP-synthesizing cells and microvessel density in gastric mucosa of rats using TAFC staining.
CONCLUSION: ANP-synthesizing cells are expressed in the gastric mucosa. EC synthesize ANP. There is a close relationship between ANP-synthesizing cells and microvessel density in gastric mucosa of rats.The distribution density of ANP-synthesizing cells is largest in the gastric cardiac region.
PMCID: PMC4088169  PMID: 17007021
Antrial natriuretic peptide-synthesizing cells; Microvessel density; Close relationship; Gastric cardiac region
4.  Global transcriptome and gene regulation network for secondary metabolite biosynthesis of tea plant (Camellia sinensis) 
BMC Genomics  2015;16(1):560.
Major secondary metabolites, including flavonoids, caffeine, and theanine, are important components of tea products and are closely related to the taste, flavor, and health benefits of tea. Secondary metabolite biosynthesis in Camellia sinensis is differentially regulated in different tissues during growth and development. Until now, little was known about the expression patterns of genes involved in secondary metabolic pathways or their regulatory mechanisms. This study aimed to generate expression profiles for C. sinensis tissues and to build a gene regulation model of the secondary metabolic pathways.
RNA sequencing was performed on 13 different tissue samples from various organs and developmental stages of tea plants, including buds and leaves of different ages, stems, flowers, seeds, and roots. A total of 43.7 Gbp of raw sequencing data were generated, from which 347,827 unigenes were assembled and annotated. There were 46,693, 8446, 3814, 10,206, and 4948 unigenes specifically expressed in the buds and leaves, stems, flowers, seeds, and roots, respectively. In total, 1719 unigenes were identified as being involved in the secondary metabolic pathways in C. sinensis, and the expression patterns of the genes involved in flavonoid, caffeine, and theanine biosynthesis were characterized, revealing the dynamic nature of their regulation during plant growth and development. The possible transcription factor regulation network for the biosynthesis of flavonoid, caffeine, and theanine was built, encompassing 339 transcription factors from 35 families, namely bHLH, MYB, and NAC, among others. Remarkably, not only did the data reveal the possible critical check points in the flavonoid, caffeine, and theanine biosynthesis pathways, but also implicated the key transcription factors and related mechanisms in the regulation of secondary metabolite biosynthesis.
Our study generated gene expression profiles for different tissues at different developmental stages in tea plants. The gene network responsible for the regulation of the secondary metabolic pathways was analyzed. Our work elucidated the possible cross talk in gene regulation between the secondary metabolite biosynthetic pathways in C. sinensis. The results increase our understanding of how secondary metabolic pathways are regulated during plant development and growth cycles, and help pave the way for genetic selection and engineering for germplasm improvement.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1773-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4518527  PMID: 26220550
Tea plant; Camellia sinensis; RNA-seq; Secondary metabolite; Transcription factor; Regulation network
5.  Ki-67 as a prognostic marker in early-stage non-small cell lung cancer in Asian patients: a meta-analysis of published studies involving 32 studies 
BMC Cancer  2015;15:520.
Despite the large number of published papers analyzing the prognostic role of Ki-67 in NSCLC, it is still not considered an established factor for routine use in clinical practice. The present meta-analysis summarizes and analyses the associations between Ki-67 expression and clinical outcome in NSCLC patients.
PubMed, Cochrane, and Embase databases were searched systematically using identical search strategies. The impacts of Ki-67 expression on survival in patients with NSCLC and NSCLC subtypes were evaluated. Furthermore, the association between Ki-67 expression and the clinicopathological features of NSCLC were evaluated.
In total, 32 studies from 30 articles met the inclusion criteria, involving 5600 patients. Meta-analysis results suggested that high Ki-67 expression was negatively associated with overall survival (OS; HR = 1.59, 95 % CI 1.35-1.88, P < 0.001) and disease-free survival (DFS; HR = 2.21, 95 % CI 1.43-3.42, P < 0.001) in NSCLC patients. Analysis of the different subgroups of NSCLC suggested that the negative association between high Ki-67 expression and OS and DFS in Asian NSCLC patients was stronger than that in non-Asian NSCLC patients, particularly in early-stage (Stage I-II) adenocarcinoma (ADC) patients. Additionally, while high expression was more common in males, smokers, and those with poorer differentiation, there was no correlation between high Ki-67 expression and age or lymph node status. Importantly, significant correlations between high Ki-67 expression and clinicopathological features (males, higher tumor stage, poor differentiation) were seen only in Asian NSCLC patients.
The present meta-analysis indicated that elevated Ki-67 expression was associated with a poorer outcome in NSCLC patients, particularly in early-stage Asian ADC patients. Studies with larger numbers of patients are needed to validate our findings.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1524-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4502553  PMID: 26174366
Ki-67; Meta-analysis; Non-small cell lung cancer; Prognostic value
6.  Extracellular protein analysis of activated sludge and their functions in wastewater treatment plant by shotgun proteomics 
Scientific Reports  2015;5:12041.
In this work, proteins in extracellular polymeric substances extracted from anaerobic, anoxic and aerobic sludges of wastewater treatment plant (WWTP) were analyzed to probe their origins and functions. Extracellular proteins in WWTP sludges were identified using shotgun proteomics, and 130, 108 and 114 proteins in anaerobic, anoxic and aerobic samples were classified, respectively. Most proteins originated from cell and cell part, and their most major molecular functions were catalytic activity and binding activity. The results exhibited that the main roles of extracellular proteins in activated sludges were multivalence cations and organic molecules binding, as well as in catalysis and degradation. The catalytic activity proteins were more widespread in anaerobic sludge compared with those in anoxic and aerobic sludges. The structure difference between anaerobic and aerobic sludges could be associated with their catalytic activities proteins. The results also put forward a relation between the macro characteristics of activated sludges and micro functions of extracellular proteins in biological wastewater treatment process.
PMCID: PMC4498230  PMID: 26160685
7.  IGF-1 decreases portal vein endotoxin via regulating intestinal tight junctions and plays a role in attenuating portal hypertension of cirrhotic rats 
BMC Gastroenterology  2015;15:77.
Intestinal barrier dysfunction is not only the consequence of liver cirrhosis, but also an active participant in the development of liver cirrhosis. Previous studies showed that external administration of insulin-like growth factor 1 (IGF-1) improved intestinal barrier function in liver cirrhosis. However, the mechanism of IGF-1 on intestinal barrier in liver cirrhosis is not fully elucidated. The present study aims to investigate the mechanisms of IGF-1 improving intestinal barrier function via regulating tight junctions in intestines.
We used carbon tetrachloride induced liver cirrhotic rats to investigate the effect of IGF-1 on intestinal claudin-1 and occludin expressions, serum alanine transaminase (ALT) and aspartate transaminase (AST) levels, severity of liver fibrosis, portal pressures, enterocytic apoptosis and lipopolysaccharides (LPS) levels in portal vein. The changes of IGF-1 in serum during the development of rat liver cirrhosis were also evaluated. Additionally, we assessed the effect of IGF-1 on claudin-1 and occludin expressions, changes of transepithelial electrical resistance (TEER) and apoptosis in Caco-2 cells to confirm in vivo findings.
Serum IGF-1 levels were decreased in the development of rat liver cirrhosis, and external administration of IGF-1 restored serum IGF-1 levels. External administration of IGF-1 reduced serum ALT and AST levels, severity of liver fibrosis, LPS levels in portal vein, enterocytic apoptosis and portal pressure in cirrhotic rats. External administration of IGF-1 increased the expressions of claudin-1 and occludin in enterocytes, and attenuated tight junction dysfunction in intestines of cirrhotic rats. LPS decreased TEER in Caco-2 cell monolayer. LPS also decreased claudin-1 and occludin expressions and increased apoptosis in Caco-2 cells. Furthermore, IGF-1 attenuated the effect of LPS on TEER, claudin-1 expression, occludin expression and apoptosis in Caco-2 cells.
Tight junction dysfunction develops during the development of liver cirrhosis, and endotoxemia will develop subsequently. Correspondingly, increased endotoxin in portal system worsens tight junction dysfunction via decreasing intestinal occludin and claudin-1 expressions and increasing enterocytic apoptosis. Endotoxemia and intestinal barrier dysfunction form a vicious circle. External administration of IGF-1 breaks this vicious circle. Improvement of tight junctions might be one possible mechanism of the restoration of intestinal barrier function mediated by IGF-1.
PMCID: PMC4495682  PMID: 26152281
Liver cirrhosis; IGF-1; Tight junction; Intestinal barrier; Apoptosis
8.  A Macro-to-Micro Interface for the Control of Cellular Organization 
The spatial organization of cellular communities plays a fundamental role in determining intercellular communication and emergent behavior. However, few tools exist to modulate tissue organization at the scale of individual cells, particularly in the case of dynamic manipulation. Micromechanical reconfigurable culture achieves dynamic control of tissue organization by culturing adherent cells on microfabricated plates that can be shifted to reorganize the arrangement of the cells. While biological studies utilizing this approach have been previously reported, this paper focuses on the engineering of the device, including the mechanism for translating manual manipulation to precise microscale position control, fault-tolerant design for manufacture, and the synthetic-to-living interface.
PMCID: PMC4495972  PMID: 26167106
Biological cells; Micromechanical devices; Tissue engineering
9.  MetaDiff: differential isoform expression analysis using random-effects meta-regression 
BMC Bioinformatics  2015;16(1):208.
RNA sequencing (RNA-Seq) allows an unbiased survey of the entire transcriptome in a high-throughput manner. A major application of RNA-Seq is to detect differential isoform expression across experimental conditions, which is of great biological interest due to its direct relevance to protein function and disease pathogenesis. Detection of differential isoform expression is challenging because of uncertainty in isoform expression estimation owing to ambiguous reads and variability in precision of the estimates across samples. It is desirable to have a method that can account for these issues and is flexible enough to allow adjustment for covariates.
In this paper, we present MetaDiff, a random-effects meta-regression model that naturally fits for the above purposes. Through extensive simulations and analysis of an RNA-Seq dataset on human heart failure, we show that the random-effects meta-regression approach is computationally fast, reliable, and can improve the power of differential expression analysis while controlling for false positives due to the effect of covariates or confounding variables. In contrast, several existing methods either fail to control false discovery rate or have reduced power in the presence of covariates or confounding variables. The source code, compiled JAR package and documentation of MetaDiff are freely available at
Our results indicate that random-effects meta-regression offers a flexible framework for differential expression analysis of isoforms, particularly when gene expression is influenced by other variables.
Electronic supplementary material
The online version of this article (doi:10.1186/s12859-015-0623-z) contains supplementary material, which is available to authorized users.
PMCID: PMC4489045  PMID: 26134005
RNA-Seq; Isoform; Differential expression; Random-effects meta-regression
10.  Chansu inhibits the expression of cortactin in colon cancer cell lines in vitro and in vivo 
Chansu is a transitional Chinese medicine that has been used for centuries as therapy for inflammation, anaesthesia and arrhythmia in China and other Asian countries. Recently, it has also been used for anti-cancer purposes. We have previously shown that Chansu has a huge pro-apoptotic potential on colon cancer cells, but to date the detailed mechanism of this action is not well understood.
One of the major components of Chansu, Cinobufagin (CBF) was used to treat cancer cells. The expressions of levels of cortactin, an important factor in tumour progression and cancer invasion, were assessed in in vitro and in vivo experiments. Additional analyses were performed in subcellular protein fractions and immune-fluorescent staining was used to define cortactin protein expression and the changes of location in CBF-treated cells.
CBF strongly inhibited the expression of cortactin in HCT116 cells. There were reductions of both mRNA transcription and protein synthesis, which were more significant in the absence of oxygen in vitro. In addition, nuclear translocation of cortactin was observed in HCT116 cells post CBF exposure but not in the negative control, indicating that CBF is likely to interrupt co-localisation of cortactin to cytoskeletal proteins. Most importantly, CBF could diminish the expression of cortactin in human HCT116 xenograft tumours in nude mouse in vivo.
CBF inhibits cortactin expression and nuclear translocation in colon cancer cells in vitro and in mouse models bearing human colon tumour in vivo, suggesting it might disrupt actin-regulated cell movement. Thus, CBF or Chansu could be developed as an effective anti-cancer therapy to stop local invasion and metastasis.
PMCID: PMC4489352  PMID: 26134506
Apoptosis; Chansu; Cinobufagin; Cortactin and xenograft
11.  Anticancer drug sensitivity prediction in cell lines from baseline gene expression through recursive feature selection 
BMC Cancer  2015;15:489.
An enduring challenge in personalized medicine is to select right drug for individual patients. Testing drugs on patients in large clinical trials is one way to assess their efficacy and toxicity, but it is impractical to test hundreds of drugs currently under development. Therefore the preclinical prediction model is highly expected as it enables prediction of drug response to hundreds of cell lines in parallel.
Recently, two large-scale pharmacogenomic studies screened multiple anticancer drugs on over 1000 cell lines in an effort to elucidate the response mechanism of anticancer drugs. To this aim, we here used gene expression features and drug sensitivity data in Cancer Cell Line Encyclopedia (CCLE) to build a predictor based on Support Vector Machine (SVM) and a recursive feature selection tool. Robustness of our model was validated by cross-validation and an independent dataset, the Cancer Genome Project (CGP).
Our model achieved good cross validation performance for most drugs in the Cancer Cell Line Encyclopedia (≥80 % accuracy for 10 drugs, ≥ 75 % accuracy for 19 drugs). Independent tests on eleven common drugs between CCLE and CGP achieved satisfactory performance for three of them, i.e., AZD6244, Erlotinib and PD-0325901, using expression levels of only twelve, six and seven genes, respectively.
These results suggest that drug response could be effectively predicted from genomic features. Our model could be applied to predict drug response for some certain drugs and potentially play a complementary role in personalized medicine.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1492-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4485860  PMID: 26121976
Drug sensitivity prediction; Feature selection; Recursive feature elimination
12.  Phase and composition controllable synthesis of cobalt manganese spinel nanoparticles towards efficient oxygen electrocatalysis 
Nature Communications  2015;6:7345.
Spinel-type oxides are technologically important in many fields, including electronics, magnetism, catalysis and electrochemical energy storage and conversion. Typically, these materials are prepared by conventional ceramic routes that are energy consuming and offer limited control over shape and size. Moreover, for mixed-metal oxide spinels (for example, CoxMn3−xO4), the crystallographic phase sensitively correlates with the metal ratio, posing great challenges to synthesize active product with simultaneously tuned phase and composition. Here we report a general synthesis of ultrasmall cobalt manganese spinels with tailored structural symmetry and composition through facile solution-based oxidation–precipitation and insertion–crystallization process at modest condition. As an example application, the nanocrystalline spinels catalyse the oxygen reduction/evolution reactions, showing phase and composition co-dependent performance. Furthermore, the mild synthetic strategy allows the formation of homogeneous and strongly coupled spinel/carbon nanocomposites, which exhibit comparable activity but superior durability to Pt/C and serve as efficient catalysts to build rechargeable Zn–air and Li–air batteries.
It is challenging to synthesize cobalt manganese spinels with controlled phase and composition. Here the authors present a solution-based synthesis method for the spinels, which show potential in catalysing oxygen reduction reactions.
PMCID: PMC4468846  PMID: 26040417
13.  Eye Acupuncture Treatment for Stroke: A Systematic Review and Meta-Analysis 
There were applications of eye acupuncture for stroke patients. Unfortunately, similar to many other Traditional Chinese Medicine (TCM) treatments, it lacks comprehensive evaluation and system review for its effect and safety. Objective. This study is a systematic review to appraise the safety and effectiveness of eye acupuncture for stroke. Methods. “Eye acupuncture therapy” in eleven databases was searched by randomized controlled trials and quasi-randomized controlled trials. The search activity was ended in April 2014. The data were extracted and assessed by three independent authors. Rev Man 5.0 software was used for data analysis with effect estimate presented as relative risk (RR) and mean difference (MD) with a 95% confidence interval. Results. Sixteen trials (1120 patients) were involved with generally poor methodological quality. The study indicated that when eye acupuncture was combined with western medicine compared to western medicine, there was a significant difference in the areas of mental state, swallow function, and NDS. When eye acupuncture was combined with western medicine and rehabilitation compared to western medicine and rehabilitation, there was significant difference in the changes of SSS, FMA, and constipation symptoms evaluation. No adverse events or side effects have been reported. Conclusions. The current evidence is insufficient and the rigorously designed trials are warranted.
PMCID: PMC4486759  PMID: 26161127
14.  The effect of red light and far-red light conditions on secondary metabolism in Agarwood 
BMC Plant Biology  2015;15:139.
Agarwood, a heartwood derived from Aquilaria trees, is a valuable commodity that has seen prevalent use among many cultures. In particular, it is widely used in herbal medicine and many compounds in agarwood are known to exhibit medicinal properties. Although there exists much research into medicinal herbs and extraction of high value compounds, few have focused on increasing the quantity of target compounds through stimulation of its related pathways in this species.
In this study, we observed that cucurbitacin yield can be increased through the use of different light conditions to stimulate related pathways and conducted three types of high-throughput sequencing experiments in order to study the effect of light conditions on secondary metabolism in agarwood. We constructed genome-wide profiles of RNA expression, small RNA, and DNA methylation under red light and far-red light conditions. With these profiles, we identified a set of small RNA which potentially regulates gene expression via the RNA-directed DNA methylation pathway.
We demonstrate that light conditions can be used to stimulate pathways related to secondary metabolism, increasing the yield of cucurbitacins. The genome-wide expression and methylation profiles from our study provide insight into the effect of light on gene expression for secondary metabolism in agarwood and provide compelling new candidates towards the study of functional secondary metabolic components.
Electronic supplementary material
The online version of this article (doi:10.1186/s12870-015-0537-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4464252  PMID: 26067652
Agarwood; Aquilaria agallocha; Genome; Secondary metabolism; Red light; Cucurbitacin
15.  Relationship between insecticide resistance and kdr mutations in the dengue vector Aedes aegypti in Southern China 
Parasites & Vectors  2015;8:325.
Aedes aegypti is an important vector for dengue virus and thus has been targeted with pyrethroid insecticides in many areas of the world. As such, resistance has been detected to several of these insecticides, including in China, but the mechanisms of the resistance are not well understood in this country.
Using the World Health Organization larval mosquito bioassay, five field populations of Aedes aegypti from Southern China were characterized for their resistance to cypermethrin and cyhalothrin. RNA extraction with PCR amplification, cloning and sequencing of the sodium channel gene was followed by comparisons of susceptible and wild mosquito strains Additionally, genomic DNA was used for Allele-specific PCR (AS-PCR) genotyping of the sodium channel genes to detect S989P, V1016G and F1534C mutations and allow for correlation analysis of resistance expression for the different mutations.
All wild strains expressed resistance to cypermethrin and cyhalothrin and the resistance expression between the two insecticides was highly correlated suggesting cross-resistance between these two pyrethroids. The AS-PCR technique effectively distinguished individual genotypes for all three mutations. Among the five wild strains tested, two strains carried all three mutations. Although the S989P and V1016G mutations were positively correlated to resistance expression of both pyrethroids, the F1534C mutation was negatively correlated.
Our methodology proved highly reliable and will aid future detection of kdr mutations. The three sodium channel mutations were common in the Ae. aegypti strains sampled from Southern China. The V1016G mutation appears to be the most important kdr mutation in Ae. aegypti strains in Southern China.
PMCID: PMC4475621  PMID: 26068925
Aedes aegypti; kdr mutation; China
16.  Comparative transcriptomics analysis reveals difference of key gene expression between banana and plantain in response to cold stress 
BMC Genomics  2015;16(1):446.
Banana and plantain (Musa spp.) comprise an important part of diets for millions of people around the globe. Low temperature is one of the key environmental stresses which greatly affects the global banana production. To understand the molecular mechanism of the cold-tolerance in plantain we used RNA-Seq based comparative transcriptomics analyses for both cold-sensitive banana and cold-tolerant plantain subjected to the cold stress for 0, 3 and 6 h.
The cold-response genes at early stage are identified and grouped in both species by GO analysis. The results show that 10 and 68 differentially expressed genes (DEGs) are identified for 3 and 6 h of cold stress respectively in plantain, while 40 and 238 DEGs are identified respectively in banana. GO classification analyses show that the majority of DEGs identified in both banana and plantain belong to 11 categories including regulation of transcription, response to stress signal transduction, etc. A similar profile for 28 DEGs was found in both banana and plantain for 6 h of cold stress, suggesting both share some common adaptation processes in response to cold stress. There are 17 DEGs found uniquely in cold-tolerance plantain, which were involved in signal transduction, abiotic stress, copper ion equilibrium, photosynthesis and photorespiration, sugar stimulation, protein modifications etc. Twelve early responsive genes including ICE1 and MYBS3 were selected and further assessed and confirmed by qPCR in the extended time course experiments (0, 3, 6, 24 and 48 h), which revealed significant expression difference of key genes in response to cold stress, especially ICE1 and MYBS3 between cold-sensitive banana and cold-tolerant plantain.
We found that the cold-tolerance pathway appears selectively activated by regulation of ICE1 and MYBS3 expression in plantain under different stages of cold stress. We conclude that the rapid activation and selective induction of ICE1 and MYBS3 cold tolerance pathways in plantain, along with expression of other cold-specific genes, may be one of the main reasons that plantain has higher cold resistance than banana.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1551-z) contains supplementary material, which is available to authorized users.
PMCID: PMC4461995  PMID: 26059100
Comparative transcriptome analysis; Cold tolerance; Banana; Plantain; ICE1; MYBS3 pathways
17.  Leveraging Identity-by-Descent for Accurate Genotype Inference in Family Sequencing Data 
PLoS Genetics  2015;11(6):e1005271.
Sequencing family DNA samples provides an attractive alternative to population based designs to identify rare variants associated with human disease due to the enrichment of causal variants in pedigrees. Previous studies showed that genotype calling accuracy can be improved by modeling family relatedness compared to standard calling algorithms. Current family-based variant calling methods use sequencing data on single variants and ignore the identity-by-descent (IBD) sharing along the genome. In this study we describe a new computational framework to accurately estimate the IBD sharing from the sequencing data, and to utilize the inferred IBD among family members to jointly call genotypes in pedigrees. Through simulations and application to real data, we showed that IBD can be reliably estimated across the genome, even at very low coverage (e.g. 2X), and genotype accuracy can be dramatically improved. Moreover, the improvement is more pronounced for variants with low frequencies, especially at low to intermediate coverage (e.g. 10X to 20X), making our approach effective in studying rare variants in cost-effective whole genome sequencing in pedigrees. We hope that our tool is useful to the research community for identifying rare variants for human disease through family-based sequencing.
Author Summary
To identify disease variants that occur less frequently in population, sequencing families in which multiple individuals are affected is more powerful due to the enrichment of causal variants. An important step in such studies is to infer individual genotypes from sequencing data. Existing methods do not utilize full familial transmission information and therefore result in reduced accuracy of inferred genotypes. In this study we describe a new method that infers shared genetic materials among family members and then incorporate the shared genomic information in a novel algorithm that can accurately infer genotypes. Our method is particularly advantageous when inferring low frequency variants with fewer sequence data, making it effective in analyzing genome-wide sequence data. We implemented the algorithm in a computationally efficient tool to facilitate cost-effective sequencing in families for identifying disease genetic variants.
PMCID: PMC4456389  PMID: 26043085
18.  Large-Scale SNP Discovery and Genotyping for Constructing a High-Density Genetic Map of Tea Plant Using Specific-Locus Amplified Fragment Sequencing (SLAF-seq) 
PLoS ONE  2015;10(6):e0128798.
Genetic maps are important tools in plant genomics and breeding. The present study reports the large-scale discovery of single nucleotide polymorphisms (SNPs) for genetic map construction in tea plant. We developed a total of 6,042 valid SNP markers using specific-locus amplified fragment sequencing (SLAF-seq), and subsequently mapped them into the previous framework map. The final map contained 6,448 molecular markers, distributing on fifteen linkage groups corresponding to the number of tea plant chromosomes. The total map length was 3,965 cM, with an average inter-locus distance of 1.0 cM. This map is the first SNP-based reference map of tea plant, as well as the most saturated one developed to date. The SNP markers and map resources generated in this study provide a wealth of genetic information that can serve as a foundation for downstream genetic analyses, such as the fine mapping of quantitative trait loci (QTL), map-based cloning, marker-assisted selection, and anchoring of scaffolds to facilitate the process of whole genome sequencing projects for tea plant.
PMCID: PMC4452719  PMID: 26035838
19.  Gambogic acid induces apoptosis and inhibits colorectal tumor growth via mitochondrial pathways 
AIM: To investigate the effect of gambogic acid (GA) on apoptosis in the HT-29 human colon cancer cell line.
METHODS: H-29 cells were used for in vitro experiments in this study. Relative cell viability was assessed using MTT assays. Cell apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling and Hoechst 33342 staining, and quantified by flow cytometry. Cellular ultrastructure was observed by transmission electron microscopy. Real-time PCR and Western blot analyses were used to evaluate gene and protein expression levels. For in vivo experiments, BALB/c nude mice received subcutaneous injections of HT-29 cells in the right armpit. When well-established xenografts were palpable with a tumor size of 75 mm3, mice were randomly assigned to a vehicle (negative) control, positive control or GA treatment group (n = 6 each). The animals in the treatment group received one of three dosages of GA (in saline; 5, 10 or 20 mg/kg) via the caudal vein twice weekly, whereas animals in the negative and positive control groups were given equal volumes of 0.9% saline or 10 mg/kg docetaxel, respectively, via the caudal vein once weekly.
RESULTS: The cell viability assay showed that GA inhibited proliferation of HT-29 cells in a dose- and time-dependent manner after treatment with GA (0.00, 0.31, 0.62, 1.25, 2.50, 5.00 or 10.00 μmol/L) for 24, 48 or 72 h. After 48 h, the percentage of apoptotic cells in cells treated with 0.00, 1.25, 2.50 and 5.00 μmol/L GA was 1.4% ± 0.3%, 9.8% ± 1.2%, 25.7% ± 3.3% and 49.3% ± 5.8%, respectively. Ultrastructural analysis of HT-29 cells treated for 48 h with 2.5μmol/L GA revealed apoptotic bodies and condensed and fragmented nuclei. Levels of caspase-8, -9 and -3 mRNAs were significantly increased after treatment with GA (1.25, 2.50 or 5.00 μmol/L) for 48 h (P < 0.05 for all). Protein levels of apoptosis-related factors Fas, FasL, FADD, cytochrome c, and Apaf-1 were increased in GA-treated cells, whereas levels of pro-caspase-8, -9 and -3 were significantly decreased (P < 0.05 for all). Furthermore, GA significantly and dose-dependently inhibited the growth of HT-29 tumors in a mouse xenograft model (P < 0.05).
CONCLUSION: GA inhibits HT-29 proliferation via induction of apoptosis. The anti-cancer effects are likely mediated by death receptor (extrinsic) and mitochondrial (intrinsic) pathways.
PMCID: PMC4445096  PMID: 26034354
Apoptosis; Death receptor pathway; Flow cytometry; Gambogic acid; Hoechst 33342; HT-29 cells; Mitochondrial pathway; MTT; Terminal deoxynucleotidyl transferase dUTP nick end labeling
20.  A Powerful Association Test of Multiple Genetic Variants Using a Random-Effects Model 
Statistics in medicine  2013;33(11):1816-1827.
There is an emerging interest in sequencing-based association studies of multiple rare variants. Most association tests suggested in the literature involve collapsing rare variants with or without weighting. Recently, a variance-component score test, SKAT, was proposed to address the limitations of collapsing method. Although SKAT was shown to outperform most of the alternative tests, its applications and power might be restricted and influenced by missing genotypes. In this paper, we suggest a new method based on testing whether the fraction of causal variants in a region is zero. The new association test, TREM, is derived from a random-effects model, allows for missing genotypes and the choice of weighting function is not required when common and rare variants are analyzed simultaneously. We performed simulations to study the type I error rates and power of four competing tests under various conditions on the sample size, genotype missing rate, variant frequency, effect directionality, and the number of non-causal rare variant and/or causal common variant. The simulation results showed that TREM was a valid test and less sensitive to the inclusion of non-causal rare variants and/or low effect common variants, or to the presence of missing genotypes. When the effects were more consistent in the same direction, TREM also had better power performance. Finally, an application to the Shanghai breast cancer study showed that rare causal variants at the FGFR2 gene were detected by TREM and SKAT, but TREM produced more consistent results for different sets of rare and common variants.
PMCID: PMC4008649  PMID: 24338936
association test; random-effects model; rare variant; sequencing-based study
21.  Triptolide Attenuates Podocyte Injury by Regulating Expression of miRNA-344b-3p and miRNA-30b-3p in Rats with Adriamycin-Induced Nephropathy 
Objectives. We investigated the action of triptolide in rats with adriamycin-induced nephropathy and evaluated the possible mechanisms underlying its protective effect against podocyte injury. Methods. In total, 30 healthy male Sprague-Dawley rats were randomized into three groups (normal group, model group, and triptolide group). On days 7, 28, 42, and 56, 24 h urine samples were collected. All rats were sacrificed on day 56, and their blood and renal tissues were collected for determination of biochemical and molecular biological parameters. Expression of miRNAs in the renal cortex was analyzed by a biochip assay and RT-PCR was used to confirm observed differences in miRNA levels. Results. Triptolide decreased proteinuria, improved renal function without apparent adverse effects on the liver, and alleviated renal pathological lesions. Triptolide also elevated the nephrin protein level. Furthermore, levels of miR-344b-3p and miR-30b-3p were elevated in rats with adriamycin-induced nephropathy, while triptolide treatment reversed the increase in the expression of these two miRNAs. Conclusions. These results suggest that triptolide may attenuate podocyte injury in rats with adriamycin-induced nephropathy by regulating expression of miRNA-344b-3p and miRNA-30b-3p.
PMCID: PMC4452866  PMID: 26078766
22.  Snail promotes epithelial-mesenchymal transition and invasiveness in human ovarian cancer cells 
There are limited reports with respect to the study on the epithelium-mesenchymal transformation (EMT) mediated by Snail in the ovarian cancer. This study detected the expression of Snail and related EMT markers in the ovarian cancer tissues, and explored the possible molecular mechanism of EMT mediated by Snail in the metastasis of ovarian cancer. The patients diagnosed with ovarian cancer according to the pathology were recruited in this study during 2010-2014. The carcinoma tissue and normal tissue adjacent to carcinoma were surgically obtained from patients. The genes of E-cadherin, β-catenin, Fibronectin and N-cadherin were detected using the RT-PCR. The 64 patients were recruited and diagnosed as ovarian cancer by pathological examination. The expression levels of Snail, Fibronectin and N-cadherin in the stage III and IV were higher than those in the stage I and II, respectively (all P < 0.05). However, the expression levels of E-cadherin and β-catenin decreased along with the stage developed (trend test, both P < 0.05), respectively. The expression of Snail was positively correlated with the expression of Fibronectin, N-cadherin, but negatively correlated with the expression of E-cadherin and β-catenin. The number of A2780 cells entering into the lower compartment in the group of carcinoma tissue were significantly higher than that in the group of normal tissue after transfected with Snail expression vector. While, the invasion ability of A2780 significantly reduced after RNAi-Snail. The correlation between Snail and invasion and metastasis of ovarian cancer and epithelial-mesenchymal transition based on tissue and cell levels, and to some extent explored the molecular mechanism of the EMT process mediated by Snail.
PMCID: PMC4509225  PMID: 26221280
Snail; epithelium-mesenchymal transformation; molecular mechanism; ovarian cancer
23.  Clinical characteristics of acute lymphoblastic leukemia in male and female patients: A retrospective analysis of 705 patients 
Oncology Letters  2015;10(1):453-458.
The aim of the present study was to compare the clinical characteristics of acute lymphoblastic leukemia (ALL) that occurred in male and female patients at one institution in Southern China. The medical electronic records of Nanfang Hospital, affiliated to Southern Medical University, were searched for patients with a definite diagnosis of ALL that were diagnosed between January 1, 2001 and December 31, 2012. The clinical data of the patients were collected and analyzed. A total of 705 eligible patients were identified. The gender ratio of male to female patients was 1.84:1. The average ages at the time of diagnosis were 16.43 and 19.54 years for male and female patients, respectively (P=0.007). No significant differences were identified in the seasonal occurrence distribution, blood group distribution or ratio for the presence of the Ph chromosome between males and females. However, a higher incidence of T-cell type ALL was identified in males (P=0.023). The present study reveals that ALL demonstrates a male predominance, but similar clinical characteristics of ALL are present in males and females in Southern China.
PMCID: PMC4487153  PMID: 26171050
acute lymphoblastic leukemia; clinical characteristics; retrospective analysis
24.  The mitochondrial Na+/Ca2+ exchanger may reduce high glucose-induced oxidative stress and nucleotide-binding oligomerization domain receptor 3 inflammasome activation in endothelial cells 
The mitochondrial Na+/Ca2+ exchanger, NCLX, plays an important role in the balance between Ca2+ influx and efflux across the mitochondrial inner membrane in endothelial cells. Mitochondrial metabolism is likely to be affected by the activity of NCLX because Ca2+ activates several enzymes of the Krebs cycle. It is currently believed that mitochondria are not only centers of energy production but are also important sites of reactive oxygen species (ROS) generation and nucleotide-binding oligomerization domain receptor 3 (NLRP3) inflammasome activation.
Methods & Results
This study focused on NCLX function, in rat aortic endothelial cells (RAECs), induced by glucose. First, we detected an increase in NCLX expression in the endothelia of rats with diabetes mellitus, which was induced by an injection of streptozotocin. Next, colocalization of NCLX expression and mitochondria was detected using confocal analysis. Suppression of NCLX expression, using an siRNA construct (siNCLX), enhanced mitochondrial Ca2+ influx and blocked efflux induced by glucose. Unexpectedly, silencing of NCLX expression induced increased ROS generation and NLRP3 inflammasome activation.
These findings suggest that NCLX affects glucose-dependent mitochondrial Ca2+ signaling, thereby regulating ROS generation and NLRP3 inflammasome activation in high glucose conditions. In the early stages of high glucose stimulation, NCLX expression increases to compensate in order to self-protect mitochondrial maintenance, stability, and function in endothelial cells.
PMCID: PMC4460171  PMID: 26089852
Calcium ion; NCLX; Mitochondria; NLRP3 inflammasome; Reactive oxygen species
25.  Valproic acid promotes radiosensitization in meningioma stem-like cells 
Oncotarget  2015;6(12):9959-9969.
Although meningioma stem-like cells have been isolated and characterized, their therapeutic targeting remains a challenge. Meningioma sphere cells (MgSCs) with cancer stem cells properties show chemo- and radioresistance in comparison with meningioma adherent cells (MgACs). We tested the effect of valproic acid (VPA), a commonly used anti-epileptic drug, which passes the blood brain barrier, on cultured MgSCs. VPA reduced the viability of MgSCs and MgACs. In MgSCs, treatment with VPA increased radio-sensitivity, expression of p-cdc2, p-H2AX and cleaved caspase-3 and PARP. Anchorage-independent growth (AIG) was reduced by VPA. AIG was further reduced by combined treatment with irradiation. Expression of a stem cell marker, Oct4, was reduced by VPA. Oct4 was further decreased by combined treatment with irradiation. These results suggest that VPA may be a potential treatment for meningioma through targeting meningioma stem-like cells.
PMCID: PMC4496410  PMID: 25895030
meningioma; tumor stem-like cells; radiosensitization; valproic acid; Oct4

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