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1.  An ABA-mimicking ligand that reduces water loss and promotes drought resistance in plants 
Cell Research  2013;23(8):1043-1054.
Abscisic acid (ABA) is the most important hormone for plants to resist drought and other abiotic stresses. ABA binds directly to the PYR/PYL family of ABA receptors, resulting in inhibition of type 2C phosphatases (PP2C) and activation of downstream ABA signaling. It is envisioned that intervention of ABA signaling by small molecules could help plants to overcome abiotic stresses such as drought, cold and soil salinity. However, chemical instability and rapid catabolism by plant enzymes limit the practical application of ABA itself. Here we report the identification of a small molecule ABA mimic (AM1) that acts as a potent activator of multiple members of the family of ABA receptors. In Arabidopsis, AM1 activates a gene network that is highly similar to that induced by ABA. Treatments with AM1 inhibit seed germination, prevent leaf water loss, and promote drought resistance. We solved the crystal structure of AM1 in complex with the PYL2 ABA receptor and the HAB1 PP2C, which revealed that AM1 mediates a gate-latch-lock interacting network, a structural feature that is conserved in the ABA-bound receptor/PP2C complex. Together, these results demonstrate that a single small molecule ABA mimic can activate multiple ABA receptors and protect plants from water loss and drought stress. Moreover, the AM1 complex crystal structure provides a structural basis for designing the next generation of ABA-mimicking small molecules.
doi:10.1038/cr.2013.95
PMCID: PMC3731570  PMID: 23835477
abscisic acid; plant hormone; drought resistance; crystal structure; ABA-mimicking ligand
2.  3-Bromo-4-dibenzyl­amino-5-methoxy­furan-2(5H)-one 
In the the title compound, C19H18BrNO3, the furan­one ring is almost planar [maximum atomic deviation = 0.019 (3) Å] and is nearly perpendicular to the two phenyl rings, making dihedral angles of 88.96 (17) and 87.71 (17)°. Inter­molecular C—H⋯O hydrogen bonding is present in the crystal structure.
doi:10.1107/S1600536810008007
PMCID: PMC2983877  PMID: 21580613
3.  N-{4-Bromo-2-[(S)-menth­yloxy]-5-oxo-2,5-dihydro-3-fur­yl}-l-valine 
The title compound, C19H30BrNO5, was obtained via a tandem asymmetric Michael addition–elimination reaction of 3,4-dibromo-5-[(S)-l-menth­yloxy]furan-2(5H)-one and l-valine in the presence of potassium hydroxide. The mol­ecular structure contains an approximately planar (r.m.s. deviation = 0.0204 Å) five-membered furan­one ring and a six-membered menth­yloxy ring adopting a chair conformation. The crystal packing is stabilized by inter­molecular O—H⋯O and N—H⋯O hydrogen bonding.
doi:10.1107/S1600536809026129
PMCID: PMC2977280  PMID: 21583539
4.  N-[(2S)-4-Chloro-2-(l-menth­yloxy)-5-oxo-2,5-dihydro­furan-3-yl]-l-valine 
The title compound, C19H30ClNO5, was obtained by the tandem asymmetric Michael addition–elimination reaction of (5S)-3,4-dichloro-5-(l-menth­yloxy)furan-2(5H)-one and l-valine in the presence of potassium hydroxide. The furan­one unit is approximately planar (r.m.s. deviation = 0.0204 Å) and the six-membered cyclo­hexane ring adopts a chair conformation. The crystal structure is stabilized by a network of O—H⋯O and N—H⋯O hydrogen bonds.
doi:10.1107/S1600536809022120
PMCID: PMC2969247  PMID: 21582860
5.  N-[(2S)-4-Chloro-2-(l-menthyloxy)-5-oxo-2,5-dihydro-3-furyl]-l-alanine 
The title compound, C17H26ClNO5, was prepared via a tandem asymmetric Michael addition–elimination reaction of (5S)-3,4-dichloro-5-(l-menth­yloxy)furan-2(5H)-­one and l-alanine in the presence of potassium hydroxide. The five-membered furan­one ring is approximately planar while the six-membered menth­yloxy ring adopts a chair conformation. The crystal packing is stabilized by inter­molecular O—H⋯O and N—H⋯O hydrogen bonds.
doi:10.1107/S1600536809012720
PMCID: PMC2977713  PMID: 21583849
6.  A genome-wide gene–environment interaction analysis for tobacco smoke and lung cancer susceptibility 
Carcinogenesis  2014;35(7):1528-1535.
Tobacco smoke is the major environmental risk factor underlying lung carcinogenesis. However, approximately one-tenth smokers develop lung cancer in their lifetime indicating there is significant individual variation in susceptibility to lung cancer. And, the reasons for this are largely unknown. In particular, the genetic variants discovered in genome-wide association studies (GWAS) account for only a small fraction of the phenotypic variations for lung cancer, and gene–environment interactions are thought to explain the missing fraction of disease heritability. The ability to identify smokers at high risk of developing cancer has substantial preventive implications. Thus, we undertook a gene–smoking interaction analysis in a GWAS of lung cancer in Han Chinese population using a two-phase designed case–control study. In the discovery phase, we evaluated all pair-wise (591 370) gene–smoking interactions in 5408 subjects (2331 cases and 3077 controls) using a logistic regression model with covariate adjustment. In the replication phase, promising interactions were validated in an independent population of 3023 subjects (1534 cases and 1489 controls). We identified interactions between two single nucleotide polymorphisms and smoking. The interaction P values are 6.73 × 10− 6 and 3.84 × 10− 6 for rs1316298 and rs4589502, respectively, in the combined dataset from the two phases. An antagonistic interaction (rs1316298–smoking) and a synergetic interaction (rs4589502–smoking) were observed. The two interactions identified in our study may help explain some of the missing heritability in lung cancer susceptibility and present strong evidence for further study of these gene–smoking interactions, which are benefit to intensive screening and smoking cessation interventions.
doi:10.1093/carcin/bgu076
PMCID: PMC4076813  PMID: 24658283
7.  Indentation experiments and simulation of ovine bone using a viscoelastic-plastic damage model 
Journal of materials research  2011;27(1):368-377.
Indentation methods have been widely used to study bone at the micro- and nanoscales. It has been shown that bone exhibits viscoelastic behavior with permanent deformation during indentation. At the same time, damage due to microcracks is induced due to the stresses beneath the indenter tip. In this work, a simplified viscoelastic-plastic damage model was developed to more closely simulate indentation creep data, and the effect of the model parameters on the indentation curve was investigated. Experimentally, baseline and 2-year postovariectomized (OVX-2) ovine (sheep) bone samples were prepared and indented. The damage model was then applied via finite element analysis to simulate the bone indentation data. The mechanical properties of yielding, viscosity, and damage parameter were obtained from the simulations. The results suggest that damage develops more quickly for OVX-2 samples under the same indentation load conditions as the baseline data.
doi:10.1557/jmr.2011.357
PMCID: PMC4484866  PMID: 26136623
8.  The role of the REG4 gene and its encoding product in ovarian epithelial carcinoma 
BMC Cancer  2015;15:471.
Background
Although its biological function remains poorly understood, REG4 is reported to be a potent activator of the EGFR/Akt/AP-1 signaling pathway in colon cancer cells and closely linked with the inhibition of apoptosis.
Methods
SKOV3 cells were transfected with a REG4-expressing plasmid or treated with recombinant REG4. We then analyzed proliferation, cell cycle, apoptosis, invasion and metastasis or expression of related molecules. REG4 expression was examined in normal ovarian tissue, benign and borderline tumors, and cancers by immunohistochemistry or real-time PCR.
Results
REG4 overexpression and the recombinant protein inhibited cell apoptosis, enhanced G2/S progression, proliferation, migration and invasion. Furthermore, expression of Wnt5a, p70s6k, survivin and VEGF expression was increased, while Bax expression was decreased at both the mRNA and protein levels compared to control or mock cells (P < 0.05). REG4 mRNA levels were higher in benign tumors and primary cancer compared to those in normal ovarian tissue (P < 0.05) while, REG4 protein expression was higher in all three tumor types than that in normal ovarian tissue (P < 0.05). Higher REG4 mRNA expression was observed in mucinous carcinomas than serous carcinomas (P < 0.05), and in well- and moderately-differentiated carcinomas than poorly-differentiated carcinomas (P < 0.05). Survival analysis revealed an inverse relationship between REG4 expression and cumulative or relapse-free survival rates of the patients with ovarian cancer as an independent factor (P < 0.05).
Conclusions
Our findings indicate that aberrant REG4 expression plays an essential role in early ovarian carcinogenesis and is closely linked to mucinous ovarian tumors, differentiation and adverse prognosis of ovarian cancer by modulating proliferation, apoptosis, migration and invasion.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1435-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s12885-015-1435-2
PMCID: PMC4469329  PMID: 26077911
Ovarian cancer; REG4; Aggressive phenotypes; Pathobiological behavior; Prognosis
9.  Parallelization of enumerating tree-like chemical compounds by breadth-first search order 
BMC Medical Genomics  2015;8(Suppl 2):S15.
Enumeration of chemical compounds greatly assists designing and finding new drugs, and determining chemical structures from mass spectrometry. In our previous study, we developed efficient algorithms, BfsSimEnum and BfsMulEnum for enumerating tree-like chemical compounds without and with multiple bonds, respectively. For many instances, our previously proposed algorithms were able to enumerate chemical structures faster than other existing methods.
Latest processors consist of multiple processing cores, and are able to execute many tasks at the same time. In this paper, we develop three parallelized algorithms BfsEnumP1-3 by modifying BfsSimEnum in simple manners to further reduce execution time. BfsSimEnum constructs a family tree in which each vertex denotes a molecular tree. BfsEnumP1-3 divide a set of vertices with some given depth of the family tree into several subsets, each of which is assigned to each processor.
For evaluation, we perform experiments for several instances with varying the division depth and the number of processors, and show that BfsEnumP1-3 are useful to reduce the execution time for enumeration of tree-like chemical compounds. In addition, we show that BfsEnumP3 achieves more than 80% parallelization efficiency using up to 11 processors, and reduce the execution time using 12 processors to about 1/10 of that by BfsSimEnum.
doi:10.1186/1755-8794-8-S2-S15
PMCID: PMC4460618  PMID: 26044861
10.  An embryo of protocells: The capsule of graphene with selective ion channels 
Scientific Reports  2015;5:10258.
The synthesis of artificial cell is a route for searching the origin of protocell. Here, we create a novel cell model of graphene capsules with selective ion channels, indicating that graphene might be an embryo of protocell membrane. Firstly, we found that the highly oxidized graphene and phospholipid-graphene oxide composite would curl into capsules under a strongly acidic saturated solution of heavy metallic salt solution at low temperature. Secondly, L-amino acids exhibited higher reactivity than D-amino acids on graphene oxides to form peptides, and the formed peptides in the influence of graphene would be transformed into a secondary structure, promoting the formation of left-handed proteins. Lastly, monolayer nanoporous graphene, prepared by unfocused 84Kr25+, has a high selectivity for permeation of the monovalent metal ions ( Rb+ > K+ > Cs+ > Na+ > Li+, based on permeation concentration), but does not allow Cl- go through. It is similar to K+ channels, which would cause an influx of K+ into capsule of graphene with the increase of pH in the primitive ocean, creating a suitable inner condition for the origin of life. Therefore, we built a model cell of graphene, which would provide a route for reproducing the origin of life.
doi:10.1038/srep10258
PMCID: PMC4437305  PMID: 25989440
11.  Intra-observer and inter-observer repeatability of ocular surface interferometer in measuring lipid layer thickness 
BMC Ophthalmology  2015;15:53.
Background
Tear lipid morphology is important for normal tear function. Recently, there have been clinical studies using interferometry to assess lipid layer thickness (LLT). The aim of the study is to examine the repeatability of a commercially available interferometer.
Methods
Two observers measured LLT in twenty Asian subjects (20 eyes) using an interferometer (LipiView® ocular surface interferometer, TearScience Inc, Morrisville, NC). Dry eye symptoms, tear break up time (TBUT) and corneal fluorescein staining were also prospectively evaluated.
Results
Data for 20 participants are presented for either right or left eye (randomly selected). The mean LLT ± standard deviation of these participants was 53.53 ± 14.59 nm. When a single observer repeated the imaging on the same day, the coefficient of repeatability was 16 nm and the 95 % limits of agreement were between −11 nm and 18 nm. When a different observer repeated the scan, the coefficient of repeatability was 13 nm and limits of agreement were −9 nm and 16 nm. LLT was not significantly associated with TBUT, presence of any corneal staining in any corneal zones, or symptomatic status.
Conclusion
With the repeatability of measurements being known, the significance of LLT changes measured by this interferometer may be better interpreted. In this small Asian study, the LLT was lower than previously reported studies.
doi:10.1186/s12886-015-0036-9
PMCID: PMC4462010  PMID: 25975974
Imaging; Human; Clinical study; Cornea; Lipid; Tear
12.  Current evidence on the relationship between two common polymorphisms in NPAS2 gene and cancer risk 
The relationship between neuronal PAS domain protein 2 (NPAS2) gene polymorphisms and cancer risk has been widely investigated. However, the results are conflicting. We performed this meta-analysis to derive a more precise estimation on the relationship. We searched Pubmed, and Web of Knowledge databases until Dec, 2014 to identify eligible studies. Case-control studies containing available genotype frequencies of the NPAS2 polymorphisms were chosen. The odds ratios (ORs) with 95% confidence interval (CI) were used to assess the strength of association. Eight independent case-control studies with 3,857 cancer patients and 4,525 cancer-free controls were selected for this meta-analysis. Two NPAS2 gene polymorphisms were identified (rs2305160 and rs17024926). The results showed statistically significant associations of rs2305160 with cancer risk (AA+GA vs. GG: OR = 0.84, 95% CI = 0.72-0.98, P = 0.02; AG vs. GG: OR = 0.81, 95% CI = 0.68-0.96, P = 0.02). Stratified analysis by cancer type indicated that rs2305160 may decrease the risk of breast cancer (A vs. G: OR = 0.87, 95% CI = 0.76-0.96, P = 0.006; AA+GA vs. GG: OR = 0.77, 95% CI = 0.67-0.88, P<0.001; AG vs. GG: OR = 0.74, 95% CI = 0.64-0.86, P<0.001), whereas negative results were obtained for prostate cancer. For rs17024926 polymorphism, there was no significant association in any genetic model. This meta-analysis suggests that NPAS2 rs2305160 polymorphism may reduce cancer susceptibility, especially in breast cancer.
PMCID: PMC4509201  PMID: 26221256
NPAS2; polymorphism; cancer risk; meta-analysis
13.  Evolutionary and Expression Analysis of miR-#-5p and miR-#-3p at the miRNAs/isomiRs Levels 
BioMed Research International  2015;2015:168358.
We mainly discussed miR-#-5p and miR-#-3p under three aspects: (1) primary evolutionary analysis of human miRNAs; (2) evolutionary analysis of miRNAs from different arms across the typical 10 vertebrates; (3) expression pattern analysis of miRNAs at the miRNA/isomiR levels using public small RNA sequencing datasets. We found that no bias can be detected between the numbers of 5p-miRNA and 3p-miRNA, while miRNAs from miR-#-5p and miR-#-3p show variable nucleotide compositions. IsomiR expression profiles from the two arms are always stable, but isomiR expressions in diseased samples are prone to show larger degree of dispersion. miR-#-5p and miR-#-3p have relative independent evolution/expression patterns and datasets of target mRNAs, which might also contribute to the phenomena of arm selection and/or arm switching. Simultaneously, miRNA/isomiR expression profiles may be regulated via arm selection and/or arm switching, and the dynamic miRNAome and isomiRome will adapt to functional and/or evolutionary pressures. A comprehensive analysis and further experimental study at the miRNA/isomiR levels are quite necessary for miRNA study.
doi:10.1155/2015/168358
PMCID: PMC4436453  PMID: 26075215
14.  A new species of the brown lacewing genus Zachobiella Banks from China (Neuroptera, Hemerobiidae) with a key to species 
ZooKeys  2015;27-37.
The genus Zachobiella Banks, 1920 is reviewed and a new species Zachobiella yunanica sp. n. described from China. All species found in China are redescribed, and Zachobiella submarginata Esben-Petersen, 1929 is recorded from China for the first time. A key to the adults of Zachobiella is provided.
doi:10.3897/zookeys.502.9251
PMCID: PMC4443588  PMID: 26019662
Notiobiellinae; Zachobiella; China
15.  Invasive Adenocarcinoma of the Lung is Associated with the Upper Lung Regions 
Objectives
We postulated that ventilation-perfusion (V/Q) relationships within the lung might influence where lung cancer occurs. To address this hypothesis we evaluated the location of lung adenocarcinoma, by both tumor lobe and superior-inferior regional distribution, and associated variables such as emphysema.
Materials and Methods
One hundred fifty-nine cases of invasive adenocarcinoma and adenocarcinoma with lepidic features were visually evaluated to identify lobar or regional tumor location. Regions were determined by automated division of the lungs into three equal volumes: (upper region, middle region, or lower region). Automated densitometry was used to measure radiographic emphysema.
Results
The majority of invasive adenocarcinomas occurred in the upper lobes (69%), with 94% of upper lobe adenocarcinomas occurring in the upper region of the lung. The distribution of adenocarcinoma, when classified as upper or lower lobe, was not different between invasive adenocarcinoma and adenocarcinoma with lepidic features (formerly bronchioloalveolar cell carcinoma, P=0.08). Regional distribution of tumor was significantly different between invasive adenocarcinoma and adenocarcinoma with lepidic features (P = 0.001). Logistic regression analysis with the outcome of invasive adenocarcinoma histology was used to adjust for confounders. Tumor region continued to be a significant predictor (OR 8.5, P=0.008, compared to lower region), whereas lobar location of tumor was not (P=0.09). In stratified analysis, smoking was not associated with region of invasive adenocarcinoma occurrence (p=0.089). There was no difference in total emphysema scores between invasive adenocarcinoma cases occurring in each of the three regions (P=0.155). There was also no difference in the distribution of region of adenocarcinoma occurrence between quartiles of emphysema (P=0.217).
Conclusion
Invasive adenocarcinoma of the lung is highly associated with the upper lung regions. This association is not related to smoking, history of COPD, or total emphysema. The regional distribution of invasive adenocarcinoma may be due to V/Q relationships or other local factors.
doi:10.1016/j.lungcan.2014.02.002
PMCID: PMC4004700  PMID: 24598367
Non-small cell lung cancer; tumor location; emphysema
16.  Inhibition of Ovarian Epithelial Carcinoma Tumorigenesis and Progression by microRNA 106b Mediated through the RhoC Pathway 
PLoS ONE  2015;10(5):e0125714.
Epithelial ovarian cancer (EOC) is the most lethal of the gynecological malignancies. Exploring the molecular mechanisms and major factors of invasion and metastasis could have great significance for the treatment and prognosis of EOC. Studies have demonstrated that microRNA 106b (miR-106b) may be a promising therapeutic target for inhibiting breast cancer bone metastasis, but the role of miR-106b in EOC is largely unknown. In this work, miRNA-106b expression was quantified in various ovarian tissues and tumors. Ovarian carcinoma cell lines were transfected with miR-106b, after which, cell phenotype and expression of relevant molecules was assayed. Dual-luciferase reporter assays and xenograft mouse models were also used to investigate miR-106b and its target gene. MiR-106b mRNA expression was found to be significantly higher in normal ovarian tissues and benign tumors than in ovarian carcinomas and borderline tumors (p < 0.01), and was negatively associated with differentiation (Well vs. Por & Mod) and the International Federation of Gynecology and Obstetrics (FIGO) staging (stage I/II vs. stage III/IV) in ovarian carcinoma (p < 0.05). MiR-106b transfection reduced cell proliferation; promoted G1 or S arrest and apoptosis (p < 0.05); suppressed cell migration and invasion (p < 0.05); reduced Ras homolog gene family member C (RhoC), P70 ribosomal S6 kinase (P70S6K), Bcl-xL, Matrix metallopeptidase 2 (MMP2), MMP9 mRNA and protein expression; and induced p53 expression (p < 0.05). Dual-luciferase reporter assays indicated that miR-106b directly targets RhoC by binding its 3’UTR. MiR-106b transfection also suppressed tumor development and RhoC expression in vivo in xenograft mouse models. This is the first demonstration that miR-106b may inhibit tumorigenesis and progression of EOC by targeting RhoC. The involvement of miR-106b-mediated RhoC downregulation in EOC aggression may give extended insights into molecular mechanisms underlying cancer aggression. Approaches aimed at overexpressing miR-106b may serve as promising therapeutic strategies for treating EOC patients.
doi:10.1371/journal.pone.0125714
PMCID: PMC4416747  PMID: 25933027
17.  Microfluidic Impedance Flow Cytometry Enabling High-Throughput Single-Cell Electrical Property Characterization 
This article reviews recent developments in microfluidic impedance flow cytometry for high-throughput electrical property characterization of single cells. Four major perspectives of microfluidic impedance flow cytometry for single-cell characterization are included in this review: (1) early developments of microfluidic impedance flow cytometry for single-cell electrical property characterization; (2) microfluidic impedance flow cytometry with enhanced sensitivity; (3) microfluidic impedance and optical flow cytometry for single-cell analysis and (4) integrated point of care system based on microfluidic impedance flow cytometry. We examine the advantages and limitations of each technique and discuss future research opportunities from the perspectives of both technical innovation and clinical applications.
doi:10.3390/ijms16059804
PMCID: PMC4463619  PMID: 25938973
microfluidics; single-cell electrical property analysis; impedance flow cytometry; high throughput
18.  Relationship between apurinic endonuclease 1 Asp148Glu polymorphism and gastrointestinal cancer risk: An updated meta-analysis 
AIM: To evaluate the relationship between apurinic endonuclease 1 (APE1) Asp148Glu polymorphism and the susceptibility to gastrointestinal (GI) cancers.
METHODS: We searched PubMed, ISI Web of Knowledge, and Chinese National Knowledge Infrastructure (CNKI) databases updated on July 15, 2014 for relevant studies. Only case-control studies comparing APE1 Asp148Glu polymorphism and GI cancer risk were included. We excluded studies reporting only standardized incidence ratios without control groups and those without detailed genotyping data. Meta-analysis was performed on 17 studies involving 4856 cancer patients and 6136 cancer-free controls. Review Manager version 5.1 was used to perform the meta-analysis. The pooled odds ratios (ORs) and 95% confidence intervals (CIs) were estimated under the allele contrast, homozygous, heterozygous, dominant and recessive genetic models. We also conducted subgroup analyses stratified by ethnicity and cancer type. Publication bias was evaluated using Begg’s test.
RESULTS: The meta-analysis showed a significant association between APE1 Asp148Glu polymorphism and GI cancer risk in three genetic models in the overall population (G vs T: OR = 1.18; 95%CI: 1.05-1.32; TG vs TT: OR = 1.28; 95%CI: 1.08-1.52; TG + GG vs TT: OR = 1.32; 95%CI: 1.10-1.57). Stratified analysis by ethnicity revealed a statistically increased GI cancer risk in Asians (G vs T: OR = 1.27; 95%CI: 1.07-1.51; GG vs TT: OR = 1.58; 95%CI: 1.05-2.38; TG vs TT: OR = 1.30; 95%CI, 1.01- 1.67; and TG + GG vs TT: OR = 1.38; 95%CI: 1.07-1.78), but not in Caucasians. Further subgroup analysis by cancer type indicated that APE1 Asp148Glu polymorphism may contribute to gastric cancer risk. However, Asp148Glu has no significant association with colorectal or esophageal cancer risk in any genetic model.
CONCLUSION: This meta-analysis suggests that the APE1 Asp148Glu polymorphism G allele is associated with an increased GI cancer risk, especially in gastric cancer.
doi:10.3748/wjg.v21.i16.5081
PMCID: PMC4408483  PMID: 25945024
Apurinic endonuclease 1; Single nucleotide polymorphism; Gastrointestinal cancers; Cancer risk; Meta-analysis
20.  HPLC-DAD-ELSD Combined Pharmacodynamics and Serum Medicinal Chemistry for Quality Assessment of Huangqi Granule 
PLoS ONE  2015;10(4):e0123176.
Objective
To more scientifically and reasonably control the quality of Huangqi Granules, preliminary studies on the pharmacodynamics and serum pharmacochemistry of this medicine were performed. DPPH and MTT experiments showed that water extracts of Huangqi Granules had good antioxidant activity and increased immunity. Timed blood samples collected 5 min, 15 min, and 30 min after oral administration of a set amount of Huangqi Granules were collected and tested using UPLC-ESI-MS/MS. As a result, calycosin-7-O-β-D-glucoside, ononin, calycosin, astragaloside IV, and formononetin were found to exist in rat blood after dosing, indicating that the five chemical compounds might have pharmacological activity, and based on this result, they were designated biomarkers for quality control of Huangqi Granules. Consequently, a simple, rapid and efficient method was developed in the present study for the simultaneous determination of the five characteristic compounds in Huangqi Granules using HPLC-DAD-ELSD.
Materials and Methods
The separation was performed using an Agilent Hypersil ODS column (4.6 × 250 mm, 5 μm) at 30 ℃. The mobile phase was composed of water (solvent A) and acetonitrile (solvent B) with a flow rate of 1 mL/min. The drift tube temperature of the ELSD system was set to 85 ℃, and the nitrogen pressure was 3.5 bar.
Results
All five characteristic compounds had good linear behavior with r2 values greater than 0.9972. The recoveries varied from 96.31% to 101.22%. Subsequently, the developed method was applied to evaluate the quality of Huangqi Granules from different batches, and hierarchical clustering analysis (HCA) was used to analyze the classification of the samples based on the values of the five compounds.
Conclusion
The established HPLC method combined with HCA proved to be effective to evaluate the quality of Huangqi Granules.
doi:10.1371/journal.pone.0123176
PMCID: PMC4411121  PMID: 25915040
21.  Grammar-based compression approach to extraction of common rules among multiple trees of glycans and RNAs 
BMC Bioinformatics  2015;16(1):128.
Background
Many tree structures are found in nature and organisms. Such trees are believed to be constructed on the basis of certain rules. We have previously developed grammar-based compression methods for ordered and unordered single trees, based on bisection-type tree grammars. Here, these methods find construction rules for one single tree. On the other hand, specified construction rules can be utilized to generate multiple similar trees.
Results
Therefore, in this paper, we develop novel methods to discover common rules for the construction of multiple distinct trees, by improving and extending the previous methods using integer programming. We apply our proposed methods to several sets of glycans and RNA secondary structures, which play important roles in cellular systems, and can be regarded as tree structures. The results suggest that our method can be successfully applied to determining the minimum grammar and several common rules among glycans and RNAs.
Conclusions
We propose integer programming-based methods MinSEOTGMul and MinSEUTGMul for the determination of the minimum grammars constructing multiple ordered and unordered trees, respectively. The proposed methods can provide clues for the determination of hierarchical structures contained in tree-structured biological data, beyond the extraction of frequent patterns.
Electronic supplementary material
The online version of this article (doi:10.1186/s12859-015-0558-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s12859-015-0558-4
PMCID: PMC4419412  PMID: 25907438
Grammar-based compression; Bisection-type tree grammar; Glycan; RNA secondary structure
22.  Permutation-based variance component test in generalized linear mixed model with application to multilocus genetic association study 
Background
In many medical studies the likelihood ratio test (LRT) has been widely applied to examine whether the random effects variance component is zero within the mixed effects models framework; whereas little work about likelihood-ratio based variance component test has been done in the generalized linear mixed models (GLMM), where the response is discrete and the log-likelihood cannot be computed exactly. Before applying the LRT for variance component in GLMM, several difficulties need to be overcome, including the computation of the log-likelihood, the parameter estimation and the derivation of the null distribution for the LRT statistic.
Methods
To overcome these problems, in this paper we make use of the penalized quasi-likelihood algorithm and calculate the LRT statistic based on the resulting working response and the quasi-likelihood. The permutation procedure is used to obtain the null distribution of the LRT statistic. We evaluate the permutation-based LRT via simulations and compare it with the score-based variance component test and the tests based on the mixture of chi-square distributions. Finally we apply the permutation-based LRT to multilocus association analysis in the case–control study, where the problem can be investigated under the framework of logistic mixed effects model.
Results
The simulations show that the permutation-based LRT can effectively control the type I error rate, while the score test is sometimes slightly conservative and the tests based on mixtures cannot maintain the type I error rate. Our studies also show that the permutation-based LRT has higher power than these existing tests and still maintains a reasonably high power even when the random effects do not follow a normal distribution. The application to GAW17 data also demonstrates that the proposed LRT has a higher probability to identify the association signals than the score test and the tests based on mixtures.
Conclusions
In the present paper the permutation-based LRT was developed for variance component in GLMM. The LRT outperforms existing tests and has a reasonably higher power under various scenarios; additionally, it is conceptually simple and easy to implement.
doi:10.1186/s12874-015-0030-1
PMCID: PMC4410500  PMID: 25897803
Likelihood ratio test; Permutation procedure; Variance component; Multilocus association analysis; Working response; Penalized quasi-likelihood algorithm; Generalized linear mixed model; Logistic mixed effects model
23.  Macrophages promote benzopyrene-induced tumor transformation of human bronchial epithelial cells by activation of NF-κB and STAT3 signaling in a bionic airway chip culture and in animal models 
Oncotarget  2015;6(11):8900-8913.
We investigated the role of macrophages in promoting benzopyrene (BaP)-induced malignant transformation of human bronchial epithelial cells using a BaP-induced tumor transformation model with a bionic airway chip in vitro and in animal models. The bionic airway chip culture data showed that macrophages promoted BaP-induced malignant transformation of human bronchial epithelial cells, which was mediated by nuclear factor (NF)-κB and STAT3 pathways to induce cell proliferation, colony formation in chip culture, and tumorigenicity in nude mice. Blockage of interleukin (IL)-6 or tumor necrosis factor (TNF)-α signaling or inhibition of NF-κB, STAT3, or cyclinD1 expression abrogated the effect of macrophages on malignant transformation in the bionic airway chip culture. In vivo, macrophages promoted lung tumorigenesis in a carcinogen-induced animal model. Similarly, blockage of NF-κB, STAT3, or cyclinD1 using siRNA transfection decreased the carcinogen-induced tumorigenesis in rats. We demonstrated that macrophages are critical in promoting lung tumorigenesis and that the macrophage-initiated TNF-α/NF-κB/cyclinD1 and IL-6/STAT3/cyclinD1 pathways are primarily responsible for promoting lung tumorigenesis.
PMCID: PMC4496191  PMID: 25823926
Macrophages; malignant transformation; NF-κB; STAT3; microfluidic chip
24.  Lower gastrointestinal bleeding: Role of 64-row computed tomographic angiography in diagnosis and therapeutic planning 
AIM: To determine the value of computed tomographic angiography (CTA) for diagnosis and therapeutic planning in lower gastrointestinal (GI) bleeding.
METHODS: Sixty-three consecutive patients with acute lower GI bleeding underwent CTA before endovascular or surgical treatment. CTA was used to determine whether the lower GI bleeding was suitable for endovascular treatment, surgical resection, or conservative treatment in each patient. Treatment planning with CTA was compared with actual treatment decisions or endovascular or surgical treatment that had been carried out in each patient based on CTA findings.
RESULTS: 64-row CTA detected active extravasation of contrast material in 57 patients and six patients had no demonstrable active bleeding, resulting in an accuracy of 90.5% in the detection of acute GI bleeding (57 of 63). In three of the six patients with no demonstrable active bleeding, active lower GI bleeding recurred within one week after CTA, and angiography revealed acute bleeding. The overall location-based accuracy, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for the detection of GI bleeding by 64-row CTA were 98.8% (249 of 252), 95.0% (57 of 60), 100% (192 of 192), 100% (57 of 57), and 98.5% (192 of 195), respectively. Treatment planning was correctly established on the basis of 64-row CTA with an accuracy, sensitivity, specificity, PPV and NPV of 98.4% (248 of 252), 93.3% (56 of 60), 100% (192 of 192), 100% (56 of 56), and 97.5% (192 of 196), respectively, in a location-based evaluation.
CONCLUSION: 64-row CTA is safe and effective in making decisions regarding treatment, without performing digital subtraction angiography or surgery, in the majority of patients with lower GI bleeding.
doi:10.3748/wjg.v21.i13.4030
PMCID: PMC4385553  PMID: 25852291
Gastrointestinal bleeding; Digital subtraction angiography; Surgical resection; Computed tomography angiography; Embolization
25.  Functional Roles of Three Cutin Biosynthetic Acyltransferases in Cytokinin Responses and Skotomorphogenesis 
PLoS ONE  2015;10(3):e0121943.
Cytokinins (CKs) regulate plant development and growth via a two-component signaling pathway. By forward genetic screening, we isolated an Arabidopsis mutant named grow fast on cytokinins 1 (gfc1), whose seedlings grew larger aerial parts on MS medium with CK. gfc1 is allelic to a previously reported cutin mutant defective in cuticular ridges (dcr). GFC1/DCR encodes a soluble BAHD acyltransferase (a name based on the first four enzymes characterized in this family: Benzylalcohol O-acetyltransferase, Anthocyanin O-hydroxycinnamoyltransferase, anthranilate N-hydroxycinnamoyl/benzoyltransferase and Deacetylvindoline 4-O-acetyltransferase) with diacylglycerol acyltransferase (DGAT) activity in vitro and is necessary for normal cuticle formation on epidermis in vivo. Here we show that gfc1 was a CK-insensitive mutant, as revealed by its low regeneration frequency in vitro and resistance to CK in adventitious root formation and dark-grown hypocotyl inhibition assays. In addition, gfc1 had de-etiolated phenotypes in darkness and was therefore defective in skotomorphogenesis. The background expression levels of most type-A Arabidopsis Response Regulator (ARR) genes were higher in the gfc1 mutant. The gfc1-associated phenotypes were also observed in the cutin-deficient glycerol-3-phosphate acyltransferase 4/8 (gpat4/8) double mutant [defective in glycerol-3-phosphate (G3P) acyltransferase enzymes GPAT4 and GPAT8, which redundantly catalyze the acylation of G3P by hydroxyl fatty acid (OH-FA)], but not in the cutin-deficient mutant cytochrome p450, family 86, subfamily A, polypeptide 2/aberrant induction of type three 1 (cyp86A2/att1), which affects the biosynthesis of some OH-FAs. Our results indicate that some acyltransferases associated with cutin formation are involved in CK responses and skotomorphogenesis in Arabidopsis.
doi:10.1371/journal.pone.0121943
PMCID: PMC4372371  PMID: 25803274

Results 1-25 (243)