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1.  Arabidopsis WRKY6 Transcription Factor Acts as a Positive Regulator of Abscisic Acid Signaling during Seed Germination and Early Seedling Development 
PLoS Genetics  2016;12(2):e1005833.
The phytohormone abscisic acid (ABA) plays important roles during seed germination and early seedling development. Here, we characterized the function of the Arabidopsis WRKY6 transcription factor in ABA signaling. The transcript of WRKY6 was repressed during seed germination and early seedling development, and induced by exogenous ABA. The wrky6-1 and wrky6-2 mutants were ABA insensitive, whereas WRKY6-overexpressing lines showed ABA-hypersensitive phenotypes during seed germination and early seedling development. The expression of RAV1 was suppressed in the WRKY6-overexpressing lines and elevated in the wrky6 mutants, and the expression of ABI3, ABI4, and ABI5, which was directly down-regulated by RAV1, was enhanced in the WRKY6-overexpressing lines and repressed in the wrky6 mutants. Electrophoretic mobility shift and chromatin immunoprecipitation assays showed that WRKY6 could bind to the RAV1 promoter in vitro and in vivo. Overexpression of RAV1 in WRKY6-overexpressing lines abolished their ABA-hypersensitive phenotypes, and the rav1 wrky6-2 double mutant showed an ABA-hypersensitive phenotype, similar to rav1 mutant. Together, the results demonstrated that the Arabidopsis WRKY6 transcription factor played important roles in ABA signaling by directly down-regulating RAV1 expression.
Author Summary
The WRKY6 protein is a WRKY transcription factor which plays important roles in plant pathogen defense, phosphate translocation, and arsenate resistance. This study demonstrated that the expression of WRKY6 was obviously repressed during seed germination and significantly induced by exogenous ABA. In the presence of exogenous ABA, the two wrky6 mutants showed ABA-insensitive phenotypes, whereas the WRKY6-overexpressing lines were hypersensitive to ABA. The WRKY6 transcription factor repressed RAV1 expression and enhanced the expression of ABI3, ABI4 and ABI5, which was down-regulated by RAV1. The WRKY6 protein could bind to the W-box motif within the RAV1 promoter, indicating that WRKY6 directly regulated RAV1 expression. Overexpression of RAV1 abolished the ABA-sensitivity of WRKY6-overexpressing lines, and repression of RAV1 impaired the ABA-insensitivity of wrky6 mutants. Our results reveal the important roles of WRKY6 in ABA signaling during seed germination and early seedling development.
doi:10.1371/journal.pgen.1005833
PMCID: PMC4734665  PMID: 26829043
2.  Relationship between Blood Pressure and Outcomes in Acute Ischemic Stroke Patients Administered Lytic Medication in the TIMS-China Study 
PLoS ONE  2016;11(2):e0144260.
Objective
Increased blood pressure (BP) management following acute ischemic stroke (AIS) remains controversial. This study aimed to identify the association between BP and clinical outcomes in AIS patients administered lytic medication in the TIMS-China (thrombolysis implementation and monitor of acute ischemic stroke in China) database.
Methods
The sample comprised 1128 patients hospitalized within 4.5 hours (h) of AIS for intravenous recombinant tissue plasminogen activator (i.v. rt-PA) thrombolysis. Systolic BP (SBP) and diastolic BP (DBP) at baseline, 2 h and 24 h after treatment, and changes from baseline were analyzed. The study outcomes comprised a favorable outcome (modified Rankin Scale 0–1 at 90 days) and symptomatic intracerebral hemorrhage (SICH), analyzed using logistic regression, with low BP as the reference group.
Results
Lower BP (baseline, 2 h, and 24 h) was beneficial in AIS patients and significantly related to a favorable outcome (P<0.05). A substantial BP decrease at 24 h after rt-PA thrombolysis was significantly associated with a favorable outcome compared with a moderate BP decrease (P = 0.0298). A SBP >160 mmHg 2 h after rt-PA thrombolysis was significantly associated with SICH compared with a SBP <140 mmHg (P = 0.0238). An increase or no change (>25 mmHg) in SBP was significantly associated with SICH (P = 0.002) compared with a small SBP decrease (1–9 mmHg).
Conclusions
This study provides novel evidence that lower BP within the first 24 h is associated with a more favorable outcome and less frequent SICH in AIS patients administered lytic medication. Routine BP-lowering treatment should be considered in AIS patients following lytic medication.
doi:10.1371/journal.pone.0144260
PMCID: PMC4735460  PMID: 26828609
3.  Neurodevelopmental Outcomes in Infants with Retinopathy of Prematurity and Bevacizumab Treatment 
PLoS ONE  2016;11(1):e0148019.
Purpose
The current study aims to investigate the neurodevelopment of premature infants after intravitreal injections of bevacizumab (IVB) for the treatment of retinopathy of prematurity (ROP) up to the age of 2 years.
Methods
The study design was retrospective observational case series conducted at an institutional referral center. Infants with type 1 ROP were classified into 3 groups: laser only, IVB only, and a combination of IVB and laser treatment. Main Outcome Measures were neurodevelopmental outcomes of the patients after treatment were assessed by Bayley Scales for Infant Development.
Results
Sixty-one patients who finished the neurodevelopmental survey were included. No detrimental effects on neurodevelopment were found in IVB group compared with the patients who received laser treatment only. The patients in the IVB + laser group had a higher incidence of significant mental (p = 0.028) and psychomotor (p = 0.002) impairment at 24 months than the patients in the laser group. The odds ratio of having severe psychomotor defects in the IVB + laser group was 5.3 compared with the laser group (p = 0.041). The causal source for the differences that were detected remained unknown due to lack of randomization in the study and accompanying bias in patient selection.
Conclusions
Two years after laser and/or intravitreal injections of bevacizumab for infants with retinopathy of prematurity, no difference on neurodevelopment for those who received only bevacizumab versus only laser treatment were found. Those infants who required rescue therapy with laser or bevacizumab injection after initial, unsuccessful treatment showed some detrimental, neurodevelopmental effects.
doi:10.1371/journal.pone.0148019
PMCID: PMC4729687  PMID: 26815000
4.  Chromosomal copy number analysis on chorionic villus samples from early spontaneous miscarriages by high throughput genetic technology 
Background
About 10 –15 % of all clinically recognized pregnancies result in spontaneous miscarriages, and chromosomal abnormalities are the most common reason. The conventional karyotyping on chorionic villus samples (CVSs) is limited by cell culture and its resolution. This study aimed at evaluating the efficiency of the application of high throughput genetic technology, including array comparative genomic hybridization (array CGH) and next generation sequencing (NGS) on the chromosomal copy number analysis of CVSs from early spontaneous miscarriages.
Results
Four hundred and thirty-six CVSs from early spontaneous abortion were collected. Genomic DNA was extracted using a routine method, and the chromosomal copy number variants (CNVs) were analyzed by array CGH and NGS. Two hundred and twenty-five samples (51.6 %) with abnormal chromosomes were identified among 436 samples, of which 188 samples (41.3 %) were aneuploidy, 23 samples (5.3 %) were segmental deletion and/or duplication cases, and 14 samples (3.2 %) were triploid. Two of the three cases with small segmental deletion and duplication were validated to be transferred from their fathers who were carriers of submicroscopic reciprocal translocation.
Conclusion
A high chromosomal abnormality detection rate on CVSs from early spontaneous miscarriage was achieved by array CGH and NGS. Specifically, the detection of submicroscopic recombination, which is sometimes missed by conventional karyotyping, was important for genetic counseling for the couples that suffered from recurrent miscarriages.
doi:10.1186/s13039-015-0210-z
PMCID: PMC4728779  PMID: 26819630
Array comparative genomic hybridization; Next generation sequencing; Spontaneous miscarriage; Chorionic villus samples; Chromosome
5.  Common SNP in hsa-miR-196a-2 increases hsa-miR-196a-5p expression and predisposes to idiopathic male infertility in Chinese Han population 
Scientific Reports  2016;6:19825.
MicroRNA plays an important role in spermatogenesis. Whether pre-miRNAs polymorphisms are associated with idiopathic male infertility remains obscure. In this study, 1378 idiopathic infertile males and 486 fertile controls were included between 2006 and 2014. Genotype of three polymorphisms (hsa-mir-146a rs2910164, hsa-mir-196a-2 rs11614913, and hsa-mir-499 rs3746444) and expression of miRNA in seminal plasma were examined by TaqMan method. The role of hsa-miR-196a-5p in cell proliferation, apoptosis and cell cycle were also examined in GC-2 cells. Our results demonstrated that rs11614913 of hsa-miR-196a-2 was significantly associated with idiopathic infertility (TT vs. CT: P = 0.014; TT vs. CC: P = 0.005; TT vs. CT + CC: P = 0.003). In following stratified analysis, we found that rs11614913 exhibited a significantly higher risk of asthenospermia, oligozoospermia and azoospermia. However, no significant association was observed between the other two polymorphisms and idiopathic male infertility risk. In a genotype-expression correlation analysis, rs11614913 CC was significantly associated with elevated expression of hsa-miR-196a-5p (P < 0.05). Additionally, apoptosis levels were significantly increased in hsa-miR-196a-5p mimic treated GC-2 cells, while decreased in hsa-miR-196a-5p inhibitor treated GC-2 cells. Our data revealed a significant relationship between hsa-miR-196a-2 polymorphism and idiopathic male infertility.
doi:10.1038/srep19825
PMCID: PMC4726409  PMID: 26805933
6.  Analysis of bacterial diversity in two oil blocks from two low-permeability reservoirs with high salinities 
Scientific Reports  2016;6:19600.
The community diversities of two oil reservoirs with low permeability of 1.81 × 10−3 and 2.29 × 10−3 μm2 in Changqing, China, were investigated using a high throughput sequencing technique to analyze the influence of biostimulation with a nutrient activator on the bacterial communities. These two blocks differed significantly in salinity (average 17,500 vs 40,900 mg/L). A core simulation test was used to evaluate the effectiveness of indigenous microbial-enhanced oil recovery (MEOR). The results indicated that in the two high salinity oil reservoirs, one reservoir having relatively lower salinity level and a narrow salinity range had higher bacterial and phylogenetic diversity. The addition of the nutrient activator increased the diversity of the bacterial community structure and the diversity differences between the two blocks. The results of the core simulation test showed that the bacterial community in the reservoir with a salinity level of 17,500 mg/L did not show significant higher MEOR efficiency compared with the reservoir with 40,900 mg/L i.e. MEOR efficiency of 8.12% vs 6.56% (test p = 0.291 > 0.05). Therefore, salinity levels affected the bacterial diversities in the two low permeability oil blocks remarkably. But the influence of salinity for the MEOR recovery was slightly.
doi:10.1038/srep19600
PMCID: PMC4726302  PMID: 26786765
7.  ΔNp63α Transcriptionally Regulates the Expression of CTEN That Is Associated with Prostate Cell Adhesion 
PLoS ONE  2016;11(1):e0147542.
p63 is a member of the p53 transcription factor family and a linchpin of epithelial development and homeostasis. p63 drives the expression of many target genes involved in cell survival, adhesion, migration and cancer. In this study, we identify C-terminal tensin-like (CTEN) molecule as a downstream target of ΔNp63α, the predominant p63 isoform expressed in epithelium. CTEN belongs to the tensin family and is mainly localized to focal adhesions, which mediate many biological events such as cell adhesion, migration, proliferation and gene expression. Our study demonstrate that ΔNp63 and CTEN are both highly expressed in normal prostate epithelial cells and are down-regulated in prostate cancer. In addition, reduced expression of CTEN and ΔNp63 is correlated with prostate cancer progression from primary tumors to metastatic lesions. Silencing of ΔNp63 leads to decreased mRNA and protein levels of CTEN. ΔNp63α induces transcriptional activity of the CTEN promoter and a 140-bp fragment upstream of the transcription initiation site is the minimal promoter region required for activation. A putative binding site for p63 is located between -61 and -36 within the CTEN promoter and mutations of the critical nucleotides in this region abolish ΔNp63α-induced promoter activity. The direct interaction of ΔNp63α with the CTEN promoter was demonstrated using a chromatin immunoprecipitation (ChIP) assay. Moreover, impaired cell adhesion caused by ΔNp63α depletion is rescued by over-expression of CTEN, suggesting that CTEN is a downstream effector of ΔNp63α-mediated cell adhesion. In summary, our findings demonstrate that ΔNp63α functions as a trans-activation factor of CTEN promoter and regulates cell adhesion through modulating CTEN. Our study further contributes to the potential regulatory mechanisms of CTEN in prostate cancer progression.
doi:10.1371/journal.pone.0147542
PMCID: PMC4718700  PMID: 26784942
8.  Polymorphisms in pre-miRNA genes and cooking oil fume exposure as well as their interaction on the risk of lung cancer in a Chinese nonsmoking female population 
OncoTargets and therapy  2016;9:395-401.
Background
MicroRNAs (miRNAs) are suggested to be very important in the development of lung cancer. This study assesses the association between polymorphisms in miRNA-related (miR)-26a-1, miR-605, and miR-16-1 genes and risk of lung cancer, as well as the effect of gene–environment interaction between miRNA polymorphisms and cooking fume exposure on lung cancer.
Methods
A case–control study including 268 diagnosed nonsmoking female lung cancer patients and 266 nonsmoking female controls was carried out. Three miRNA polymorphisms (miR-26a-1 rs7372209, miR-605 rs2043556, and miR-16-1 rs1022960) were analyzed. Both additive and multiplicative interactions were assessed.
Results
MiR-16-1 rs1022960 may be associated with the risk of lung cancer. Carriers with TT genotype of miR-16-1 rs1022960 were observed to have a decreased risk of lung cancer compared with CC and CT genotype carriers (odds ratio =0.550, 95% confidence interval =0.308–0.983, P=0.044). MiR-26a-1 rs7372209 and miR-605 rs2043556 showed no statistically significant associations with lung cancer risk. There were no significant associations between the three single nucleotide polymorphisms and lung adenocarcinoma. People with exposure to both risk genotypes of miR-26a-1 rs7372209 and cooking oil fumes were more likely to develop lung cancer than those with only genetic risk factor or cooking oil fumes (odds ratios were 2.136, 1.255, and 1.730, respectively). The measures of biological interaction and logistic models indicate that gene–environment interactions were not statistically significant on additive scale or multiplicative scale.
Conclusion
MiR-16-1 rs1022960 may be associated with the risk of lung cancer in a Chinese nonsmoking female population. The interactions between miRNA polymorphisms (miR-26a-1 rs7372209, miR-605 rs2043556, and miR-16-1 rs1022960) and cooking oil fumes were not statistically significant.
doi:10.2147/OTT.S96870
PMCID: PMC4727513  PMID: 26855588
lung cancer; microRNA; single nucleotide polymorphism; cooking oil fume; interaction
9.  Phylotranscriptomic Analysis Based on Coalescence was Less Influenced by the Evolving Rates and the Number of Genes: A Case Study in Ericales 
Evolutionary Bioinformatics Online  2016;11(Suppl 1):81-91.
Advances in high-throughput sequencing have generated a vast amount of transcriptomic data that are being increasingly used in phylogenetic reconstruction. However, processing the vast datasets for a huge number of genes and even identifying optimal analytical methodology are challenging. Through de novo sequenced and retrieved data from public databases, we identified 221 orthologous protein-coding genes to reconstruct the phylogeny of Ericales, an order characterized by rapid ancient radiation. Seven species representing different families in Ericales were used as in-groups. Both concatenation and coalescence methods yielded the same well-supported topology as previous studies, with only two nodes conflicting with previously reported relationships. The results revealed that a partitioning strategy could improve the traditional concatenation methodology. Rapidly evolving genes negatively affected the concatenation analysis, while slowly evolving genes slightly affected the coalescence analysis. The coalescence methods usually accommodated rate heterogeneity better and required fewer genes to yield well-supported topologies than the concatenation methods with both real and simulated data.
doi:10.4137/EBO.S22448
PMCID: PMC4718149  PMID: 26819541
Ericales; phylogenomics; coalescence methods; concatenation methods; evolving rates
10.  Selective Audiovisual Semantic Integration Enabled by Feature-Selective Attention 
Scientific Reports  2016;6:18914.
An audiovisual object may contain multiple semantic features, such as the gender and emotional features of the speaker. Feature-selective attention and audiovisual semantic integration are two brain functions involved in the recognition of audiovisual objects. Humans often selectively attend to one or several features while ignoring the other features of an audiovisual object. Meanwhile, the human brain integrates semantic information from the visual and auditory modalities. However, how these two brain functions correlate with each other remains to be elucidated. In this functional magnetic resonance imaging (fMRI) study, we explored the neural mechanism by which feature-selective attention modulates audiovisual semantic integration. During the fMRI experiment, the subjects were presented with visual-only, auditory-only, or audiovisual dynamical facial stimuli and performed several feature-selective attention tasks. Our results revealed that a distribution of areas, including heteromodal areas and brain areas encoding attended features, may be involved in audiovisual semantic integration. Through feature-selective attention, the human brain may selectively integrate audiovisual semantic information from attended features by enhancing functional connectivity and thus regulating information flows from heteromodal areas to brain areas encoding the attended features.
doi:10.1038/srep18914
PMCID: PMC4725371  PMID: 26759193
11.  Administration of Glucocorticoids to Ovarian Cancer Patients Is Associated with Expression of the Anti-apoptotic Genes SGK1 and MKP1/DUSP1 in Ovarian Tissues 
Purpose
To prevent chemotherapy-related side effects, synthetic glucocorticoids, for example, dexamethasone, are routinely administered to patients with ovarian cancer. However, preclinical data implicate glucocorticoids in suppressing chemotherapy-mediated apoptosis in epithelial tumors. The anti-apoptotic mechanisms underlying this increased survival have been shown to require up-regulation of prosurvival genes, including serum and glucocorticoid-regulated kinase 1 (SGK1) and map kinase phosphatase 1 (MKP1)/dual specificity phosphatase 1 (DUSP1). Despite abundant preclinical data, there are no correlative studies in patients. We therefore evaluated anti-apoptotic gene expression in tumor samples from patients randomized to dexamethasone or normal saline.
Experimental Design
Eighteen patients were randomized before exploratory laparotomy for suspected ovarian cancer. Dexamethasone or normal saline was administered i.v. following anesthesia. Ovarian and omental tumor samples were collected intra-operatively before and after infusion. Samples were analyzed for histology and glucocorticoid receptor expression by immunohistochemistry. SGK1 and MKP1/DUSP1 mRNA levels were determined using quantitative real-time PCR.
Results
Ten patients were evaluable. At 30 min postinfusion, tumor samples from five patients receiving dexamethasone revealed an average SGK1 mRNA induction of 6.1-fold (SEM, ±2.6) compared with only 1.5-fold (SEM, ±0.4) in tumor samples from five patients receiving normal saline (P = 0.028). Average MKP1/DUSP1 mRNA expression was increased by 8.2-fold (SEM, ±2.9) following dexamethasone versus 1.1-fold (SEM, ±0.4) following normal saline (P = 0.009). All samples expressed glucocorticoid receptor.
Conclusion
Glucocorticoid administration to patients is associated with rapid up-regulation of SGK1 and MKP1 expression in ovarian tumors. This finding supports the hypothesis that pharmacologic doses of glucocorticoids may decrease chemotherapy effectiveness in ovarian cancer patients through increased anti-apoptotic gene expression.
doi:10.1158/1078-0432.CCR-08-2131
PMCID: PMC4707040  PMID: 19383827
12.  Local recurrence of small cell lung cancer following radiofrequency ablation is induced by HIF-1α expression in the transition zone 
Oncology Reports  2015;35(3):1297-1308.
Local recurrence of lung cancer following radiofrequency ablation (RFA) treatment is common. The aims of the present study were to assess how RFA treatment affects the growth of small cell lung cancer (SCLC) micrometastases in the transition zone (TZ) surrounding the ablated region and in the reference zones (RZs) of the ablated or unablated lobes and to identify the molecular mechanism(s) of lung cancer recurrence following RFA treatment. After lung micrometastases of human SCLCs had formed, RFA treatment was applied to the right upper lobe (RUL) of the lung in nude mice. Hypoxia inducible factor (HIF)-1α expression, proliferation and angiogenesis potential both in the TZ and RZ were evaluated over time. Separately, at day 1, 7 and 14 following RFA treatment, the growth of micrometastases showed an ~2-fold increase in the TZ compared to the RZ of the unablated lobe, as the right lower lobe (RLL) and the growth of micrometastases in the RZ of the RUL was also induced by RFA. In addition, accelerated tumor growth in the TZ was induced by HIF-1α, but was not associated with tissue angiogenesis potential. We concluded that local recurrences of SCLCs caused by overproliferation of micrometastases following RFA treatment were driven by HIF-1α, although angiogenesis was not the driving force in the TZ.
doi:10.3892/or.2015.4541
PMCID: PMC4750745  PMID: 26750332
radiofrequency ablation; small cell lung cancers; transition zone; reference zones; tumor overproliferation
13.  Clinical comparison of laparoscopy vs open surgery in a radical operation for rectal cancer: A retrospective case-control study 
World Journal of Gastroenterology  2015;21(48):13532-13541.
AIM: To assess the diverse immediate and long-term clinical outcomes, a retrospective comparison between laparoscopic and conventional operation was performed.
METHODS: A total number of 916 clinical cases, from January 2006 to December 2013 in our hospital, were analyzed which covered 492 patients underwent the laparoscopy in radical resection (LRR) and 424 cases in open radical resection (ORR). A retrospective analysis was proceeded by comparing the general information, surgery performance, pathologic data, postoperative recovery and complications as well as long-term survival to investigate the diversity of immediate and long-term clinical outcomes of laparoscopic radical operation.
RESULTS: There were no statistically significance differences between gender, age, height, weight, body mass index (BMI), tumor loci, tumor node metastasis stages, cell differentiation degree or American Society of Anesthesiologists scores of the patients (P > 0.05). In contrast to the ORR group, the LRR group experienced less operating time (P < 0.001), a lower blood loss (P < 0.001), and had a 2.44% probability of conversion to open surgery. Postoperative bowel function recovered more quickly, analgesic usage and the average hospital stay (P < 0.001) were reduced after LRR. Lymph node dissection during LRR appeared to be slightly more than in ORR (P = 0.338). There were no obvious differences in the lengths and margins (P = 0.182). And the occurrence rate in the two groups was similar (P = 0.081). Overall survival rate of ORR and LRR for 1, 3 and 5 years were 94.0% and 93.6% (P = 0.534), 78.1% and 80.9% (P = 0.284) and 75.2% and 77.0% (P = 0.416), respectively.
CONCLUSION: Laparoscopy as a radical operation for rectal cancer was safe, produced better immediate outcomes. Long-term survival of laparoscopy revealed that it was similar to the open operation.
doi:10.3748/wjg.v21.i48.13532
PMCID: PMC4690183  PMID: 26730165
Laparoscopic; Open surgery; Short-term outcomes; Long-term outcomes; Rectal cancer
14.  Spatial Temperature Mapping within Polymer Nanocomposites Undergoing Ultrafast Photothermal Heating via Gold Nanorods 
Nanoscale  2014;6(24):15236-15247.
Heat emanates from gold nanorods (GNRs) under ultrafast optical excitation of the localized surface plasmon resonance. The steady state nanoscale temperature distribution formed within a polymer matrix embedded with GNRs undergoing pulsed femtosecond photothermal heating is determined experimentally using two independent ensemble optical techniques. Physical rotation of the nanorods reveals the average local temperature of the polymer melt in the immediate spatial volume surrounding them while fluorescence of homogeneously-distributed perylene molecules monitors temperature over sample regions at larger distances from the GNRs. Polarization-sensitive fluorescence measurements of the perylene probes provide an estimate of the average size of the quasi-molten region surrounding each nanorod (that is, the boundary between softened polymer and solid material as the temperature decreases radially away from each particle) and distinguishes the steady state temperature in the solid and melt regions. Combining these separate methods enables nanoscale spatial mapping of the average steady state temperature distribution caused by ultrafast excitation of the GNRs. These observations definitively demonstrate the presence of a steady-state temperature gradient and indicate that localized heating via the photothermal effect within materials enables nanoscale thermal manipulations without significantly altering the bulk sample temperature in these systems. These quantitative results are further verified by reorienting nanorods within a solid polymer nanofiber without inducing any morphological changes to the highly temperature-sensitive nanofiber surface. Temperature differences of 70 – 90 °C were observed over a distances of ~100 nm.
doi:10.1039/c4nr05179c
PMCID: PMC4488066  PMID: 25379775
gold nanorods; photothermal heating; polymer nanocomposites; polymer nanofibers; optical temperature sensing
15.  Assessment of White Matter Loss Using Bond-Selective Photoacoustic Imaging in a Rat Model of Contusive Spinal Cord Injury 
Journal of Neurotrauma  2014;31(24):1998-2002.
Abstract
White matter (WM) loss is a critical event after spinal cord injury (SCI). Conventionally, such loss has been measured with histological and histochemical approaches, although the procedures are complex and may cause artifact. Recently, coherent Raman microscopy has been proven to be an emerging technology to study de- and remyelination of the injured spinal cord; however, limited penetration depth and small imaging field prevent it from comprehensive assessments of large areas of damaged tissues. Here, we report the use of bond-selective photoacoustic (PA) imaging with 1730-nm excitation, where the first overtone vibration of CH2 bond is located, to assess WM loss after a contusive SCI in adult rats. By employing the first overtone vibration of CH2 bond as the contrast, the mapping of the WM in an intact spinal cord was achieved in a label-free three-dimensional manner, and the physiological change of the spinal cord before and after injury was observed. Moreover, the recovery of the spinal cord from contusive injury with the treatment of a neuroprotective nanomedicine ferulic-acid–conjugated glycol chitosan (FA-GC) was also observed. Our study suggests that bond-selective PA imaging is a valuable tool to assess the progression of WM pathology after SCI as well as neuroprotective therapeutics in a label-free manner.
doi:10.1089/neu.2014.3349
PMCID: PMC4245875  PMID: 24850066
deep tissue imaging; photoacoustic imaging; spinal cord injury; white matter loss
16.  Gene Expression in Relation to Exhaled Nitric Oxide Identifies Novel Asthma Phenotypes with Unique Biomolecular Pathways 
Rationale
Although asthma is recognized as a heterogeneous disease associated with clinical phenotypes, the molecular basis of these phenotypes remains poorly understood. Although genomic studies have successfully broadened our understanding in diseases such as cancer, they have not been widely used in asthma studies.
Objectives
To link gene expression patterns to clinical asthma phenotypes.
Methods
We used a microarray platform to analyze bronchial airway epithelial cell gene expression in relation to the asthma biomarker fractional exhaled nitric oxide (FeNO) in 155 subjects with asthma and healthy control subjects from the Severe Asthma Research Program (SARP).
Measurements and Main Results
We first identified a diverse set of 549 genes whose expression correlated with FeNO. We used k-means to cluster the patient samples according to the expression of these genes, identifying five asthma clusters/phenotypes with distinct clinical, physiological, cellular, and gene transcription characteristics—termed “subject clusters” (SCs). To then investigate differences in gene expression between SCs, a total of 1,384 genes were identified that highly differentiated the SCs at an unadjusted P value < 10−6. Hierarchical clustering of these 1,384 genes identified nine gene clusters or “biclusters,” whose coexpression suggested biological characteristics unique to each SC. Although genes related to type 2 inflammation were present, novel pathways, including those related to neuronal function, WNT pathways, and actin cytoskeleton, were noted.
Conclusions
These findings show that bronchial epithelial cell gene expression, as related to the asthma biomarker FeNO, can identify distinct asthma phenotypes, while also suggesting the presence of underlying novel gene pathways relevant to these phenotypes.
doi:10.1164/rccm.201406-1099OC
PMCID: PMC4294630  PMID: 25338189
exhaled nitric oxide; clustering; severe asthma
17.  Anti-inflammatory and anti-apoptotic effects of oxysophoridine on lipopolysaccharide-induced acute lung injury in mice 
Oxysophoridine (OSR) is an alkaloid with multiple pharmacological activities. This study aimed to investigate the protective effects and underlying mechanisms of OSR on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. Here, we found that OSR treatment markedly mitigated LPS-induced body weight loss and significant lung injury characterized by the deterioration of histopathology, histologic scores, wet-to-dry ratio, exduate volume, and protein leakage. OSR dramatically attenuated LPS-induced lung inflammation, as evidenced by the reduced levels of total cells, neutrophils, lymphocytes, and macrophages and pro-inflammatory cytokines (i.e., tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and monocyte chemoattractant protein-1) in bronchoalveolar lavage fluid and of their mRNA expression in lung tissues. OSR also inhibited LPS-induced expression and activation of nuclear factor-κB p65 in pulmonary tissue. Additionally, OSR administration markedly prevented LPS-induced pulmonary cell apoptosis in mice, as reflected by the decrease in expression of procaspase-8, procaspase-3, cleaved caspase-8, and cleaved caspase-3, and Bcl-2-associated X/B-cell lymphoma 2 ratio. These results indicate that OSR is a potential therapeutic drug for treating LPS-induced ALI.
PMCID: PMC4731665  PMID: 26885265
Acute lung injury; lipopolysaccharide; oxysophoridine; inflammation; apoptosis
18.  The Salford Lung Study protocol: a pragmatic, randomised phase III real-world effectiveness trial in asthma 
BMC Pulmonary Medicine  2015;15:160.
Background
Novel therapies need to be evaluated in normal clinical practice to allow a true representation of the treatment effectiveness in real-world settings.
Methods/design
The Salford Lung Study is a pragmatic randomised controlled trial in adult asthma, evaluating the clinical effectiveness and safety of once-daily fluticasone furoate (100 μg or 200 μg)/vilanterol 25 μg in a novel dry-powder inhaler, versus existing asthma maintenance therapy. The study was initiated before this investigational treatment was licensed and conducted in real-world clinical practice to consider adherence, co-morbidities, polypharmacy, and real-world factors. Primary endpoint: Asthma Control Test at week 24; safety endpoints include the incidence of serious pneumonias. The study utilises the Salford electronic medical record, which allows near to real-time collection and monitoring of safety data.
Discussion
The Salford Lung Study is the world’s first pragmatic randomised controlled trial of a pre-licensed medication in asthma. Use of patients’ linked electronic health records to collect clinical endpoints offers minimal disruption to patients and investigators, and also ensures patient safety. This highly innovative study will complement standard double-blind randomised controlled trials in order to improve our understanding of the risk/benefit profile of fluticasone furoate/vilanterol in patients with asthma in real-world settings.
Trial registration
Clinicaltrials.gov, NCT01706198; 04 October 2012.
doi:10.1186/s12890-015-0150-8
PMCID: PMC4676141  PMID: 26651333
Asthma; Electronic medical record; Fluticasone furoate/vilanterol; Inhaled corticosteroid/long-acting β2-agonist; Pragmatic randomised controlled trial; Real-world evidence
19.  Functional redundancy of transcription factors explains why most binding targets of a transcription factor are not affected when the transcription factor is knocked out 
BMC Systems Biology  2015;9(Suppl 6):S2.
Background
Biologists are puzzled by the extremely low percentage (3%) of the binding targets of a yeast transcription factor (TF) affected when the TF is knocked out, a phenomenon observed by comparing the TF binding dataset and TF knockout effect dataset.
Results
This study gives a plausible biological explanation of this counterintuitive phenomenon. Our analyses find that TFs with high functional redundancy show significantly lower percentage than do TFs with low functional redundancy. This suggests that functional redundancy may lead to one TF compensating for another, thus masking the TF knockout effect on the binding targets of the knocked-out TF. In addition, we show that seven classes of genes (lowly expressed genes, TATA box-less genes, genes containing a nucleosome-free region immediately upstream of the transcriptional start site (TSS), genes with low transcriptional plasticity, genes with a low number of bound TFs, genes with a low number of TFBSs, and genes with a short average distance of TFBSs to the TSS) are insensitive to the knockout of their promoter-binding TFs, providing clues for finding other biological explanations of the surprisingly low percentage of the binding targets of a TF affected when the TF is knocked out.
Conclusions
This study shows that one property of TFs (functional redundancy) and seven properties of genes (expression level, TATA box, nucleosome, transcriptional plasticity, the number of bound TFs, the number of TFBSs, and the average distance of TFBSs to the TSS) may be useful for explaining a counterintuitive phenomenon: most binding targets of a yeast transcription factor are not affected when the transcription factor is knocked out.
doi:10.1186/1752-0509-9-S6-S2
PMCID: PMC4674858  PMID: 26678747
20.  Investigation of microRNAs in mouse macrophage responses to lipopolysaccharide-stimulation by combining gene expression with microRNA-target information 
BMC Genomics  2015;16(Suppl 12):S13.
Background
Toll-like receptors, which stimulated by pathogen-associated molecular patterns such as lipopolysaccharides (LPS), induces the releasing of many kinds of proinflammatory cytokines to activate subsequent immune responses. Plenty of studies have also indicated the importance of TLR-signalling on the avoidance of excessive inflammation, tissue repairing and the return to homeostasis after infection and tissue injury. The significance of TLR-signalling attracts many attentions on the regulatory mechanisms since several years ago. However, as newly discovered regulators, how and how many different microRNAs (miRNAs) regulate TLR-signalling pathway are still unclear.
Results
By integrating several microarray datasets and miRNA-target information datasets, we identified 431 miRNAs and 498 differentially expressed target genes in bone marrow-derived macrophages (BMDMs) with LPS-stimulation. Cooperative miRNA network were constructed by calculating targets overlap scores, and a sub-network finding algorithm was used to identify cooperative miRNA modules. Finally, 17 and 8 modules are identified in the cooperative miRNA networks composed of miRNAs up-regulate and down-regulate genes, respectively.
Conclusions
We used gene expression data of mouse macrophage stimulated by LPS and miRNA-target information to infer the regulatory mechanism of miRNAs on LPS-induced signalling pathway. Also, our results suggest that miRNAs can be important regulators of LPS-induced innate immune response in BMDMs.
doi:10.1186/1471-2164-16-S12-S13
PMCID: PMC4682375  PMID: 26680554
microRNA; macrophage; inflammation; immune system; toll-like receptor; lipopolysaccharide
21.  PCTFPeval: a web tool for benchmarking newly developed algorithms for predicting cooperative transcription factor pairs in yeast 
BMC Bioinformatics  2015;16(Suppl 18):S2.
Background
Computational identification of cooperative transcription factor (TF) pairs helps understand the combinatorial regulation of gene expression in eukaryotic cells. Many advanced algorithms have been proposed to predict cooperative TF pairs in yeast. However, it is still difficult to conduct a comprehensive and objective performance comparison of different algorithms because of lacking sufficient performance indices and adequate overall performance scores. To solve this problem, in our previous study (published in BMC Systems Biology 2014), we adopted/proposed eight performance indices and designed two overall performance scores to compare the performance of 14 existing algorithms for predicting cooperative TF pairs in yeast. Most importantly, our performance comparison framework can be applied to comprehensively and objectively evaluate the performance of a newly developed algorithm. However, to use our framework, researchers have to put a lot of effort to construct it first. To save researchers time and effort, here we develop a web tool to implement our performance comparison framework, featuring fast data processing, a comprehensive performance comparison and an easy-to-use web interface.
Results
The developed tool is called PCTFPeval (Predicted Cooperative TF Pair evaluator), written in PHP and Python programming languages. The friendly web interface allows users to input a list of predicted cooperative TF pairs from their algorithm and select (i) the compared algorithms among the 15 existing algorithms, (ii) the performance indices among the eight existing indices, and (iii) the overall performance scores from two possible choices. The comprehensive performance comparison results are then generated in tens of seconds and shown as both bar charts and tables. The original comparison results of each compared algorithm and each selected performance index can be downloaded as text files for further analyses.
Conclusions
Allowing users to select eight existing performance indices and 15 existing algorithms for comparison, our web tool benefits researchers who are eager to comprehensively and objectively evaluate the performance of their newly developed algorithm. Thus, our tool greatly expedites the progress in the research of computational identification of cooperative TF pairs.
doi:10.1186/1471-2105-16-S18-S2
PMCID: PMC4682397  PMID: 26677932
Web tool; Cooperative transcription factor pairs; Performance index; Performance comparison; Algorithm
22.  Properly defining the targets of a transcription factor significantly improves the computational identification of cooperative transcription factor pairs in yeast 
BMC Genomics  2015;16(Suppl 12):S10.
Background
Transcriptional regulation of gene expression in eukaryotes is usually accomplished by cooperative transcription factors (TFs). Computational identification of cooperative TF pairs has become a hot research topic and many algorithms have been proposed in the literature. A typical algorithm for predicting cooperative TF pairs has two steps. (Step 1) Define the targets of each TF under study. (Step 2) Design a measure for calculating the cooperativity of a TF pair based on the targets of these two TFs. While different algorithms have distinct sophisticated cooperativity measures, the targets of a TF are usually defined using ChIP-chip data. However, there is an inherent weakness in using ChIP-chip data to define the targets of a TF. ChIP-chip analysis can only identify the binding targets of a TF but it cannot distinguish the true regulatory from the binding but non-regulatory targets of a TF.
Results
This work is the first study which aims to investigate whether the performance of computational identification of cooperative TF pairs could be improved by using a more biologically relevant way to define the targets of a TF. For this purpose, we propose four simple algorithms, all of which consist of two steps. (Step 1) Define the targets of a TF using (i) ChIP-chip data in the first algorithm, (ii) TF binding data in the second algorithm, (iii) TF perturbation data in the third algorithm, and (iv) the intersection of TF binding and TF perturbation data in the fourth algorithm. Compared with the first three algorithms, the fourth algorithm uses a more biologically relevant way to define the targets of a TF. (Step 2) Measure the cooperativity of a TF pair by the statistical significance of the overlap of the targets of these two TFs using the hypergeometric test. By adopting four existing performance indices, we show that the fourth proposed algorithm (PA4) significantly out performs the other three proposed algorithms. This suggests that the computational identification of cooperative TF pairs is indeed improved when using a more biologically relevant way to define the targets of a TF. Strikingly, the prediction results of our simple PA4 are more biologically meaningful than those of the 12 existing sophisticated algorithms in the literature, all of which used ChIP-chip data to define the targets of a TF. This suggests that properly defining the targets of a TF may be more important than designing sophisticated cooperativity measures. In addition, our PA4 has the power to predict several experimentally validated cooperative TF pairs, which have not been successfully predicted by any existing algorithms in the literature.
Conclusions
This study shows that the performance of computational identification of cooperative TF pairs could be improved by using a more biologically relevant way to define the targets of a TF. The main contribution of this study is not to propose another new algorithm but to provide a new thinking for the research of computational identification of cooperative TF pairs. Researchers should put more effort on properly defining the targets of a TF (i.e. Step 1) rather than totally focus on designing sophisticated cooperativity measures (i.e. Step 2). The lists of TF target genes, the Matlab codes and the prediction results of the four proposed algorithms could be downloaded from our companion website http://cosbi3.ee.ncku.edu.tw/TFI/
doi:10.1186/1471-2164-16-S12-S10
PMCID: PMC4682405  PMID: 26679776
23.  YAGM: a web tool for mining associated genes in yeast based on diverse biological associations 
BMC Systems Biology  2015;9(Suppl 6):S1.
Background
Investigating association between genes can be used in understanding the relations of genes in biological processes. STRING and GeneMANIA are two well-known web tools which can provide a list of associated genes of a query gene based on diverse biological associations such as co-expression, co-localization, co-citation and so on. However, the transcriptional regulation association and mutant phenotype association have not been used in these two web tools. Since the comprehensive transcription factor (TF)-gene binding data, TF-gene regulation data and mutant phenotype data are available in yeast, we developed a web tool called YAGM (Yeast Associated Genes Miner) which constructed the transcriptional regulation association, mutant phenotype association and five commonly used biological associations to mine a list of associated genes of a query yeast gene.
Description
In YAGM, we collected seven kinds of datasets including TF-gene binding (TFB) data, TF-gene regulation (TFR) data, mutant phenotype (MP) data, functional annotation (FA) data, physical interaction (PI) data, genetic interaction (GI) data, and literature evidence (LE) data. Then by using the hypergeometric test to calculate the association scores of all gene pairs in yeast, we constructed seven biological associations including two transcriptional regulation associations (TFB association and TFR association), MP association, FA association, PI association, GI association, and LE association. Moreover, the expression profile association from SPELL database was also included in YAGM. When using YAGM, users can input a query gene and choose any possible subsets of the eight biological associations, then a list of associated genes of the query gene will be returned based on the chosen biological associations.
Conclusions
In this study, we presented the YAGM which provides eight biological associations for mining associated genes of a query gene in yeast. Among the eight biological associations constructed in YAGM, three (TFB association, TFR association, and MP association) are novel ones. By comparing the query results of two well-known web tools (STRING and GeneMANIA), we found that YAGM can find out distinct associated genes of a query gene. That is, YAGM can provide alternative candidates of associated genes for biologists to do further experimental investigation. We believe that YAGM will be a useful web tool for yeast biologists. YAGM is available online at http://cosbi3.ee.ncku.edu.tw/yagm/.
doi:10.1186/1752-0509-9-S6-S1
PMCID: PMC4674844  PMID: 26678566
24.  Chemosensitization of HepG2 cells by suppression of NF-κB/p65 gene transcription with specific-siRNA 
World Journal of Gastroenterology  2015;21(45):12814-12821.
AIM: To investigate small interfering RNA (siRNA)-mediated inhibition of nuclear factor-kappa B (NF-κB) activation and multidrug-resistant (MDR) phenotype formation in human HepG2 cells.
METHODS: Total RNA was extracted from human HepG2 or LO2 cells. NF-κB/p65 mRNA was amplified by nested reverse transcription polymerase chain reaction and confirmed by sequencing. NF-κB/p65 was analyzed by immunohistochemistry. Specific-siRNA was transfected to HepG2 cells to knock down NF-κB/p65 expression. The effects on cell proliferation, survival, and apoptosis were assessed, and the level of NF-κB/p65 or P-glycoprotein (P-gp) was quantitatively analyzed by enzyme-linked immunosorbent assay.
RESULTS: HepG2 cells express NF-κB/p65 and express relatively less phosphorylated p65 (P-p65) and little P-gp. After treatment of HepG2 cells with different doses of doxorubicin, the expression of NF-κB/p65, P-p65, and especially P-gp were dose-dependently upregulated. After HepG2 cells were transfected with NF-κB/p65 siRNA (100 nmol/L), the expression of NF-κB/p65, P-p65, and P-gp were downregulated significantly and dose-dependently. The viability of HepG2 cells was decreased to 23% in the combination NF-κB/p65 siRNA (100 nmol/L) and doxorubicin (0.5 μmol/L) group and 47% in the doxorubicin (0.5 μmol/L) group (t = 7.043, P < 0.001).
CONCLUSION: Knockdown of NF-κB/p65 with siRNA is an effective strategy for inhibiting HepG2 cell growth by downregulating P-gp expression associated chemosensitization and apoptosis induction.
doi:10.3748/wjg.v21.i45.12814
PMCID: PMC4671036  PMID: 26668505
Hepatocellular carcinoma; Nuclear factor-κB; Multidrug-resistant; Chemosensitization; Small interference RNA; P-glycoprotein
25.  Formation of Carbonized Polystyrene Sphere/hemisphere Shell Arrays by Ion Beam Irradiation and Subsequent Annealing or Chloroform Treatment 
Scientific Reports  2015;5:17529.
Heat-resistant two-dimensional (2D) sphere/hemisphere shell array is significant for the fabrication of novel nanostructures. Here large-area, well-ordered arrays of carbonized polystyrene (PS) hollow sphere/hemisphere with controlled size and morphology are prepared by combining the nanosphere self-assembly, kV Ag ion beam modification, and subsequent annealing or chloroform treatment. Potential mechanisms for the formation and evolution of the heat-resistant carbonized PS spherical shell with increasing ion fluence and energy are discussed. Combined with noble metal or semiconductor, these modified PS sphere arrays should open up new possibilities for high-performance nanoscale optical sensors or photoelectric devices.
doi:10.1038/srep17529
PMCID: PMC4670998  PMID: 26640125

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