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1.  Field-based evidence for consistent responses of bacterial communities to copper contamination in two contrasting agricultural soils 
Copper contamination on China's arable land could pose severe economic, ecological and healthy consequences in the coming decades. As the drivers in maintaining ecosystem functioning, the responses of soil microorganisms to long-term copper contamination in different soil ecosystems are still debated. This study investigated the impacts of copper gradients on soil bacterial communities in two agricultural fields with contrasting soil properties. Our results revealed consistent reduction in soil microbial biomass carbon (SMBC) with increasing copper levels in both soils, coupled by significant declines in bacterial abundance in most cases. Despite of contrasting bacterial community structures between the two soils, the bacterial diversity in the copper-contaminated soils showed considerably decreasing patterns when copper levels elevated. High-throughput sequencing revealed copper selection for major bacterial guilds, in particular, Actinobacteria showed tolerance, while Acidobacteria and Chloroflexi were highly sensitive to copper. The thresholds that bacterial communities changed sharply were 800 and 200 added copper mg kg−1 in the fluvo-aquic soil and red soil, respectively, which were similar to the toxicity thresholds (EC50 values) characterized by SMBC. Structural equation model (SEM) analysis ascertained that the shifts of bacterial community composition and diversity were closely related with the changes of SMBC in both soils. Our results provide field-based evidence that copper contamination exhibits consistently negative impacts on soil bacterial communities, and the shifts of bacterial communities could have largely determined the variations of the microbial biomass.
doi:10.3389/fmicb.2015.00031
PMCID: PMC4313605
copper contamination; soil bacterial community; diversity; abundance; community composition; soil microbial biomass carbon; field experiment
2.  Changes in the timing of departure and arrival of Irish migrant waterbirds 
PeerJ  2015;3:e726.
There have been many recent reports across Europe and North America of a change in the timing of arrival and departure of a range of migrant bird species to their breeding grounds. These studies have focused primarily on passerine birds and climate warming has been found to be one of the main drivers of earlier arrival and departure in spring. In Ireland, rising spring temperature has been shown to result in the earlier arrival of sub-Saharan passerine species and the early departure of the Whooper Swan. In order to investigate changes in spring arrival and departure dates of waterbirds to Ireland, we extracted latest dates as an indicator of the timing of departure of winter visitors (24 species) and earliest dates as an indicator of the timing of arrival of spring/summer migrants (2 species) from BirdWatch Ireland’s East Coast Bird reports (1980–2003). Three of the winter visitors showed evidence of later departure and one of earlier departure whereas one of the spring/summer visitors showed evidence of earlier arrival. In order to determine any influence of local temperature on these trends, we analysed data from two synoptic weather stations within the study area and found that spring (average February, March and April) air temperature significantly (P < 0.05) increased at a rate of 0.03 °C per year, which was strongly correlated with changes in latest and earliest records. We also tested the sensitivity of bird departure/arrival to temperature and found that Northern Pintail would leave 10 days earlier in response to a 1 °C increase in spring temperature. In addition, we investigated the impact of a large-scale circulation pattern, the North Atlantic Oscillation (NAO), on the timing of arrival and departure which correlated with both advances and delays in departure and arrival. We conclude that the impact of climate change on earliest and latest records of these birds is, as expected, species specific and that local temperature had less of an influence than large-scale circulation patterns.
doi:10.7717/peerj.726
PMCID: PMC4304860  PMID: 25653907
Spring arrival and departure; Temperature; Ireland; Waterbirds
3.  Differential Transcriptional Response in Macrophages Infected with Cell Wall Deficient versus Normal Mycobacterium Tuberculosis 
Host-pathogen interactions determine the outcome following infection by mycobacterium tuberculosis (Mtb). Under adverse circumstances, normal Mtb can form cell-wall deficient (CWD) variants within macrophages, which have been considered an adaptive strategy for facilitating bacterial survival inside macrophages. However, the molecular mechanism by which infection of macrophages with different phenotypic Mtb elicits distinct responses of macrophages is not fully understood. To explore the molecular events triggered upon Mtb infection of macrophages, differential transcriptional responses of RAW264.7 cells infected with two forms of Mtb, CWD-Mtb and normal Mtb, were studied by microarray analysis. Some of the differentially regulated genes were confirmed by RT-qPCR in both RAW264.7 cells and primary macrophages. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway was used to analyze functions of differentially expressed genes. Distinct gene expression patterns were observed between CWD-Mtb and normal Mtb group. Mapt was up-regulated, while NOS2 and IL-11 were down-regulated in CWD-Mtb infected RAW264.7 cells and primary macrophages compared with normal Mtb infected ones. Many deregulated genes were found to be related to macrophages activation, immune response, phagosome maturation, autophagy and lipid metabolism. KEGG analysis showed that the differentially expressed genes were mainly involved in MAPK signaling pathway, nitrogen metabolism, cytokine-cytokine receptor interaction and focal adhesion. Taken together, the present study showed that differential macrophage responses were induced by intracellular CWD-Mtb an normal Mtb infection, which suggested that interactions between macrophages and different phenotypic Mtb are very complex. The results provide evidence for further understanding of pathogenesis of CWD-Mtb and may help in improving strategies to eliminate intracellular CWD-Mtb.
doi:10.7150/ijbs.10217
PMCID: PMC4278251  PMID: 25552926
Mycobacterium tuberculosis; macrophage; bactericidal response; cytokine signaling; autophagy; lipid metabolism.
4.  Combination of extracorporeal membrane oxygenation and continuous renal replacement therapy in critically ill patients: a systematic review 
Critical Care  2014;18(6):675.
Introduction
Extracorporeal membrane oxygenation (ECMO) is used in critically ill patients presenting acute cardiac and/or pulmonary dysfunctions, who are at high risk of developing acute kidney injury and fluid overload. Continuous renal replacement therapy (CRRT) is commonly used in intensive care units (ICU) to provide renal replacement and fluid management. We conducted a review to assess the feasibility, efficacy and safety of the combination of ECMO and CRRT and to illustrate the indications and methodology of providing renal replacement therapy during the ECMO procedure.
Method
We searched for all published reports of a randomized controlled trial (RCT), quasi-RCT, or other comparative study design, conducted in patients undergoing ECMO plus CRRT. Two reviewers independently selected potential studies and extracted data. We used the modified Jadad scale and the Newcastle-Ottawa for quality assessment of RCTs and non-RCTs, respectively. Statistical analyses were performed using RevMan 5.2.
Results
We identified 19 studies meeting the eligibility criteria (seven cohort, six case control, one historically controlled trial and five studies of technical aspects). There are three major methods for performing CRRT during ECMO: ‘independent CRRT access’, ‘introduction of a hemofiltration filter into the ECMO circuit (in-line hemofilter)’ and ‘introduction of a CRRT device into the ECMO circuit’. We conducted a review with limited data synthesis rather than a formal meta-analysis because there could be greater heterogeneity in a systematic review of non-randomized studies than that of randomized trials. For ECMO survivors receiving CRRT, overall fluid balance was less than that in non-CRRT survivors. There was a higher mortality and a longer ECMO duration when CRRT was added, which may reflect a relatively higher severity of illness in patients who received ECMO plus CRRT.
Conclusions
The combination of ECMO and CRRT in a variety of methods appears to be a safe and effective technique that improves fluid balance and electrolyte disturbances. Prospective studies would be beneficial in determining the potential of this technique to improve the outcome in critically ill patients.
Electronic supplementary material
The online version of this article (doi:10.1186/s13054-014-0675-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s13054-014-0675-x
PMCID: PMC4277651  PMID: 25482187
5.  Synbindin in Extracellular Signal-Regulated Protein Kinase Spatial Regulation and Gastric Cancer Aggressiveness 
Background
The molecular mechanisms that control the aggressiveness of gastric cancer (GC) remain poorly defined. Here we show that synbindin contributes to the aggressiveness of GC by activating extracellular signal-regulated protein kinase (ERK) signaling on the Golgi apparatus.
Methods
Expression of synbindin was examined in normal gastric mucosa (n = 44), intestinal metaplastic gastric mucosa (n = 66), and GC tissues (n=52), and the biological effects of synbindin on tumor growth and ERK signaling were detected in cultured cells, nude mice, and human tissue samples. The interaction between synbindin and mitogen-activated protein kinase kinase (MEK1)/ERK was determined by immunofluorescence and fluorescence resonance energy transfer assays. The transactivation of synbindin by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) was detected using luciferase reporter assay and chromatin immunoprecipitation.
Results
High expression of synbindin was associated with larger tumor size (120.8 vs 44.8cm3; P = .01), advanced tumor node metastasis (TNM) stage (P = .003), and shorter patient survival (hazard ratio = 1.51; 95% confidence interval [CI] = 1.01 to 2.27; P = .046). Synbindin promotes cell proliferation and invasion by activating ERK2 on the Golgi apparatus, and synbindin is directly transactivated by NF-κB. Synbindin expression level was statistically significantly higher in human GCs with activated ERK2 than those with low ERK2 activity (intensity score of 11.5, 95% CI = 10.4 to 12.4 vs intensity score of 4.6, 95% CI 3.9 to 5.3; P < .001). Targeting synbindin in xenograft tumors decreased ERK2 phosphorylation and statistically significantly reduced tumor volume (451.2mm3, 95% CI = 328.3 to 574.1 vs 726.1mm3, 95% CI = 544.2 to 908.2; P = .01).
Conclusions
Synbindin contributes to malignant phenotypes of GC by activating ERK on the Golgi, and synbindin is a potential biomarker and therapeutic target for GC.
doi:10.1093/jnci/djt271
PMCID: PMC4042874  PMID: 24104608
6.  An organ boundary-enriched gene regulatory network uncovers regulatory hierarchies underlying axillary meristem initiation 
Molecular Systems Biology  2014;10(10):1-2.
Gene regulatory networks (GRNs) control development via cell type-specific gene expression and interactions between transcription factors (TFs) and regulatory promoter regions. Plant organ boundaries separate lateral organs from the apical meristem and harbor axillary meristems (AMs). AMs, as stem cell niches, make the shoot a ramifying system. Although AMs have important functions in plant development, our knowledge of organ boundary and AM formation remains rudimentary. Here, we generated a cellular-resolution genomewide gene expression map for low-abundance Arabidopsis thaliana organ boundary cells and constructed a genomewide protein–DNA interaction map focusing on genes affecting boundary and AM formation. The resulting GRN uncovers transcriptional signatures, predicts cellular functions, and identifies promoter hub regions that are bound by many TFs. Importantly, further experimental studies determined the regulatory effects of many TFs on their targets, identifying regulators and regulatory relationships in AM initiation. This systems biology approach thus enhances our understanding of a key developmental process.
doi:10.15252/msb.20145470
PMCID: PMC4299377  PMID: 25358340
axillary meristem; gene regulatory network; organ boundary
7.  Procalcitonin as a predictor of moderate to severe acute respiratory distress syndrome after cardiac surgery with cardiopulmonary bypass: a study protocol for a prospective cohort study 
BMJ Open  2014;4(10):e006344.
Introduction
Procalcitonin (PCT) is activated during cardiopulmonary bypass (CPB) and may be a predictor of acute respiratory distress syndrome (ARDS). The objective of this study is to determine whether patients with different serum PCT concentrations exhibit different rates of developing moderate to severe ARDS.
Methods and analysis
This is a prospective, single centre, observational cohort study. All patients admitted to the cardiosurgery department for cardiac surgery with CPB were screened for study eligibility. All eligible patients received a CPB procedure. Blood samples were obtained to determine white cell counts as well as N-terminal pro-B-type natriuretic peptide, C reactive protein and PCT levels. Patients were assigned to the PCT elevated cohort or the control cohort based on serum PCT concentrations on the first postoperative day with a cut-off value of 7.0 ng/mL. Data, including baseline, perioperative and outcome data, were collected daily for 7 days. The primary end point was the incidence of moderate to severe ARDS, which was diagnosed according to the Berlin definition.
Ethics and dissemination
The study was approved by the Institutional Review Board of Fujian Provincial Hospital. Study findings are disseminated through peer-reviewed publications and conference presentations.
Study registration
Chinese Clinical Trial Registry (ChiCTR-OCH-14005076).
doi:10.1136/bmjopen-2014-006344
PMCID: PMC4216854  PMID: 25354826
8.  P16INK4a overexpression and survival in osteosarcoma patients: a meta analysis 
Osteosarcoma is one of the most common primary bone malignancies. Although there is a significant improvement of survival on osteosarcoma patients in the past decades, treatment of osteosarcoma is still unsatisfactory for the development of pulmonary metastasis. The potential prognostic value of p16INK4a in osteosarcoma has been investigated, however, the results from different studies were somewhat controversial. To elucidate whether p16INK4a is indeed a prognostic factor of osteosarcoma, we conducted a meta-analysis of the published literatures to provide a comprehensive evaluation of the significance of p16INK4a expression in patients with osteosarcoma. Eight studies with a total of 354 patients with osteosarcoma were examined. The pooled odds ratio (OR) with corresponding 95% confidence interval (95% CI) was calculated to evaluate the effect of p16INK4a expression on overall survival. Meta-analysis showed that patients with high p16INK4a expression were significantly associated with favourable overall survival when compared to their counterparts with low or undetectable p16INK4a expression (OR = 0.270, 95% CI 0.162-0.451, P < 0.001). Sensitivity analysis suggested the pooled OR was stable and not significantly changed when a single study was removed. In conclusion, the results from this meta-analysis highlight that p16INK4a is an effective biomarker of survival in patients with osteosarcoma.
PMCID: PMC4203227  PMID: 25337256
Osteosarcoma P16INK4a expression; survival; meta-analysis
9.  A Comparison of Loop-Mediated Isothermal Amplification (LAMP) with Other Surveillance Tools for Echinococcus granulosus Diagnosis in Canine Definitive Hosts 
PLoS ONE  2014;9(7):e100877.
Background
Cystic echinococcosis is highly prevalent in northwest China. A cost-effective, easy to operate diagnostic tool with high sensitivity and specificity would greatly facilitate the monitoring of Echinococcus infections in canine definitive hosts.
Methods
The primers used in the LAMP assay were based on the mitochondrial nad5 gene of E. granulosus sensu stricto (E. granulosus s.s., or E.g.s.s.) and were designed using Primer Explorer V4 software. The developed LAMP assay was compared with a conventional PCR method, copro-ELISA and microscopy, using the faeces of dogs experimentally infected with E.g.s.s., and field-collected faeces of domestic dogs including 190 from Qinghai province highly endemic for E.g.s.s. and 30 controls from an area in Gansu, where a domestic dog de-worming program was in operation.
Results
The positivity rates obtained for the field-collected faecal samples were 12.6%, 1.6% and 2.1% by the LAMP, PCR and copro-ELISA assays, respectively. All samples obtained from the control dogs were negative. Compared with the conventional PCR, the LAMP assay provided 88.8% specificity and 100% sensitivity. The higher sensitivity of the LAMP method was also shown by the fact that it could detect the presence of laboratory challenge dog infections of E. granulsous s.s. four days earlier than the PCR method. Three copro-samples shown positive by the commercial copro-ELISA were all negative by LAMP, PCR and microscopy, which suggests these samples may have originated from another infection rather than E. granulsous s.s., possibly E. shiquicus or E. Canadensis, which is also present in China.
Conclusions
We have developed a potentially useful surveillance tool for determining the prevalence of canine E. granulosus s.s. infections in the field. The LAMP assay may lead to a more cost-effective and practicable way of tracking Echinococcus infections in canids, especially when combined with the copro-ELISA.
doi:10.1371/journal.pone.0100877
PMCID: PMC4089910  PMID: 25007051
10.  Biodegradation of high concentrations of halomethanes by a fermentative enrichment culture 
AMB Express  2014;4:48.
A fermentative enrichment culture (designated DHM-1) that grows on corn syrup was evaluated for its ability to cometabolically biodegrade high concentrations of chloroform (CF), carbon tetrachloride (CT), and trichlorofluoromethane (CFC-11). When provided with corn syrup and vitamin B12 (0.03 mol B12 per mol CF), DHM-1 grew and biodegraded up to 2,000 mg/L of CF in 180 days, with only minor transient accumulation of dichloromethane and chloromethane. CT (15 mg/L) and CFC-11 (25 mg/L) were also biodegraded without significant accumulation of halomethane daughter products. The rate of CF biodegradation followed a Michaelis-Menten-like pattern with respect to the B12 concentration; one-half the maximum rate (66 mg CF/L/d) occurred at 0.005 mol B12 per mol CF. DHM-1 was able to biodegrade 500 mg/L of CF at an inoculum level as low as 10−8 mg protein/L. The highest rate of CF biodegradation occurred at pH 7.7; activity decreased substantially below pH 6.0. DHM-1 biodegraded mixtures of CT, CFC-11, and CF, although CFC-11 inhibited CF biodegradation. Evidence for compete defluorination of CFC-11 was obtained based on a fluoride mass balance. Overall, the results suggest that DHM-1 may be effective for bioaugmentation in source zones contaminated with thousands of milligrams per liter of CF and tens of milligrams per liter of CT and CFC-11.
doi:10.1186/s13568-014-0048-5
PMCID: PMC4230812  PMID: 25401061
Chloroform; Carbon tetrachloride; Trichlorofluoromethane; Vitamin B12; Bioremediation
11.  Berberine-induced apoptotic and autophagic death of HepG2 cells requires AMPK activation 
Background
Hepatocellular carcinoma (HCC), the primary liver cancer, is one of the most malignant human tumors with extremely poor prognosis. The aim of this study was to investigate the anti-cancer effect of berberine in a human hepatocellular carcinoma cell line (HepG2), and to study the underlying mechanisms by focusing on the AMP-activated protein kinase (AMPK) signaling cascade.
Results
We found that berberine induced both apoptotic and autophagic death of HepG2 cells, which was associated with a significant activation of AMPK and an increased expression of the inactive form of acetyl-CoA carboxylase (ACC). Inhibition of AMPK by RNA interference (RNAi) or by its inhibitor compound C suppressed berberine-induced caspase-3 cleavage, apoptosis and autophagy in HepG2 cells, while AICAR, the AMPK activator, possessed strong cytotoxic effects. In HepG2 cells, mammalian target of rapamycin complex 1 (mTORC1) activation was important for cell survival, and berberine inhibited mTORC1 via AMPK activation.
Conclusions
Together, these results suggested that berberine-induced both apoptotic and autophagic death requires AMPK activation in HepG2 cells.
doi:10.1186/1475-2867-14-49
PMCID: PMC4079188  PMID: 24991192
Hepatocellular carcinoma; Berberine; AMPK; Apoptosis; Autophagy and mTOR
12.  Long-term results of single-procedure catheter ablation for atrial fibrillationin pre- and post-menopausal women 
Objectives
To address whether menopause affects outcome of catheter ablation (CA) for atrial fibrillation (AF) by comparing the safety and long-term outcome of a single-procedure in pre- and post-menopausal women.
Methods
A total of 743 female patients who underwent a single CA procedure of drug-refractory AF were retrospectively analyzed. The differences in clinical presentation and outcomes of CA for AF between the pre-menopausal women (PreM group, 94 patients, 12.7%) and the post-menopausal women (PostM group, 649 patients, 87.3%) were assessed.
Results
The patients in the PreM group were younger (P < 0.001) and less likely to have hypertension (P < 0.001) and diabetes (P = 0.005) than those in the PostM group. The two groups were similar with regards to the proportion of concomitant mitral valve regurgitation coronary artery disease, left atrium dimensions, and left ventricular ejection fraction. The overall rate of complications related to AF ablation was similar in both groups (P = 0.385). After 43 (16–108) months of follow-up, the success rate of ablation was 54.3% in the PreM group and 54.2% in the PostM group (P = 0.842). The overall freedom from atrial tachyarrhythmia recurrence was similar in both groups. Menopause was not found to be an independent predictive factor of the recurrence of atrial tachyarrhythmia.
Conclusions
The long-term outcomes of single-procedure CA for AF are similar in pre- and post-menopausal women. Results indicated that CA of AF appears to be as safe and effective in pre-menopausal women as in post-menopausal women.
doi:10.3969/j.issn.1671-5411.2014.02.005
PMCID: PMC4076451  PMID: 25009561
Atrial fibrillation; Catheter ablation; Follow-up; Menopausal woman
13.  Synthesis of l-Ascorbic Acid Lactone Derivatives 
A small focused library which comprised of l-AA lactone derivatives was built with a facile method. This reported method was optimized by modifying the acidity of the solvent. As a result, 12 l-AA lactones were synthesized. Among these lactones, lactones 8–12 were new compounds. The cytotoxicity of these synthetic compounds were investigated.
doi:10.1007/s13659-014-0022-6
PMCID: PMC4050306  PMID: 24955300
l-Ascorbic acid lactone; Cytotoxicity; Focused library
14.  Synthesis of l-Ascorbic Acid Lactone Derivatives 
A small focused library which comprised of l-AA lactone derivatives was built with a facile method. This reported method was optimized by modifying the acidity of the solvent. As a result, 12 l-AA lactones were synthesized. Among these lactones, lactones 8–12 were new compounds. The cytotoxicity of these synthetic compounds were investigated.
doi:10.1007/s13659-014-0022-6
PMCID: PMC4050306  PMID: 24955300
l-Ascorbic acid lactone; Cytotoxicity; Focused library
15.  The predictive value of anti-mullerian hormone on embryo quality, blastocyst development, and pregnancy rate following in vitro fertilization-embryo transfer (IVF-ET) 
Purpose
The objective of this study was to investigate the predictive value of anti-Mullerian hormone (AMH) on fertilization rate (FR), blastocyst development, embryo quality, the outcome of the pregnancy and the live birth rate (LBR) following in vitro fertilization-embryo transfer (IVF-ET)/intracytoplasmic sperm injection (ICSI).
Method
In this prospective study outcomes were followed in 83 women undergoing cycles of IVF/ICSI within a university hospital. Basal serum AMH, follicle stimulating hormone (FSH), luteinizing hormone (LH) and antral follicle count (AFC) were measured on Day 3. Serum AMH (Gn6 AMH ) level was measured on Day 6 after the administration of gonadotrophin (Gn). AMH was measured in follicle fluid (FF AMH) on the day of ovum pick-up (dOPU). The numbers of retrieved and fertilized oocytes, good quality embryos and blastocysts were counted. Secondary outcome variables included clinical pregnancy rate (CPR) and LBR.
Results
Spearman correlation analysis indicated that the numbers of oocytes, good quality embryos and blastocysts were associated with AMH (P < 0.05) and that LBR was correlated with FF AMH (r = 0.495, P < 0.05). No associations were found between FR and AMH (P > 0.05). Receiver operating characteristic analysis showed that the sensitivity of FF AMH at predicting CPR was 91.2 %; the specificity was 86.5 % and ROCAUC was 0.893 (P < 0.0001).
Conclusion
AMH parameters were correlated with good quality embryos and blastocysts, but only FF AMH showed a significant correlation with LBR and CPR.
doi:10.1007/s10815-013-9973-5
PMCID: PMC3663964  PMID: 23504440
Anti-Mullerian hormone; Fertilization; Blastocyte; Live birth rate; Pregnancy
16.  Analysis of the Microbial Community Structure by Monitoring an Hg Methylation Gene (hgcA) in Paddy Soils along an Hg Gradient 
Knowledge of the diversity of mercury (Hg)-methylating microbes in the environment is limited due to a lack of available molecular biomarkers. Here, we developed novel degenerate PCR primers for a key Hg-methylating gene (hgcA) and amplified successfully the targeted genes from 48 paddy soil samples along an Hg concentration gradient in the Wanshan Hg mining area of China. A significant positive correlation was observed between hgcA gene abundance and methylmercury (MeHg) concentrations, suggesting that microbes containing the genes contribute to Hg methylation in the sampled soils. Canonical correspondence analysis (CCA) showed that the hgcA gene diversity in microbial community structures from paddy soils was high and was influenced by the contents of total Hg, SO42−, NH4+, and organic matter. Phylogenetic analysis showed that hgcA microbes in the sampled soils likely were related to Deltaproteobacteria, Firmicutes, Chloroflexi, Euryarchaeota, and two unclassified groups. This is a novel report of hgcA diversity in paddy habitats, and results here suggest a link between Hg-methylating microbes and MeHg contamination in situ, which would be useful for monitoring and mediating MeHg synthesis in soils.
doi:10.1128/AEM.04225-13
PMCID: PMC3993304  PMID: 24584244
17.  Analysis on the Relevance of Asthma Susceptibility with the Alteration of Integrin β 4 Expression 
PLoS ONE  2014;9(4):e95533.
Accumulated research has suggested the importance of the adhesion molecules modulation as therapeutic approach for bronchial asthma. Adhesion molecules expression alteration contributes to the pathogenesis of asthma. In order to probe the roles of expression imbalance of adhesion molecules in asthma pathogenesis, expression profiling of adhesion molecules was performed using cDNA microarray assay. The results showed that the expression pattern of adhesion molecules was altered in peripheral blood leucocytes of asthma patients. In this study, we focused on one of the abnormally expressed molecule, integrin β4, which was down-regulated in all asthma patients, to analyze the relevance of asthma susceptibility with the alteration of integrin β4 expressions. Real time PCR was used to verify the down-regulation of integrin β4 in additional 38 asthma patients. Next, the 5′flanking region of integrin β4 DNA were amplified, sequenced and site-directed mutagenesis technology in correspondent variation sites were carried out. Among 4 variation sites found in 5′ flanking region of integrin β4, 3 were related to asthma susceptibility: -nt1029 G/A, -nt 1051 G/A, and -nt 1164 G/C. A reduction of human integrin β4 promoter activity was observed at mutants of these sites. This study demonstrates that various adhesion molecules in asthma patients are abnormally expressed. Mutations in 5′ flanking region result in reduced integrin β4 expression, which is related to increased risk of asthma.
doi:10.1371/journal.pone.0095533
PMCID: PMC3989341  PMID: 24740264
18.  An Agomir of miR-144-3p Accelerates Plaque Formation through Impairing Reverse Cholesterol Transport and Promoting Pro-Inflammatory Cytokine Production 
PLoS ONE  2014;9(4):e94997.
Aims
ATP-binding cassette transporter A1 (ABCA1) mediates the efflux of cholesterol and phospholipids to lipid-poor apolipoproteins, which then form nascent HDL, a key step in the mechanism of reverse cholesterol transport (RCT). While a series of microRNAs (miRNAs) have been identified as potent post-transcriptional regulators of lipid metabolism, their effects on ABCA1 function and associated mechanisms remain unclear.
Methods and Results
ABCA1 was identified as a potential target of miR-144-3p, based on the results of bioinformatic analysis and the luciferase reporter assay, and downregulated after transfection of cells with miR-144-3p mimics, as observed with real-time PCR and western blot. Moreover, miR-144-3p mimics (agomir) enhanced the expression of inflammatory factors, including IL-1β, IL-6 and TNF-α, in vivo and in vitro, inhibited cholesterol efflux in THP-1 macrophage-derived foam cells, decreased HDL-C circulation and impaired RCT in vivo, resulting in accelerated pathological progression of atherosclerosis in apoE−/− mice. Clinical studies additionally revealed a positive correlation of circulating miR-144-3p with serum CK, CK-MB, LDH and AST in subjects with AMI.
Conclusions
Our findings clearly indicate that miR-144-3p is essential for the regulation of cholesterol homeostasis and inflammatory reactions, supporting its utility as a potential therapeutic target of atherosclerosis and a promising diagnostic biomarker of AMI.
doi:10.1371/journal.pone.0094997
PMCID: PMC3986368  PMID: 24733347
19.  MicroRNA-222 Expression and Its Prognostic Potential in Non-Small Cell Lung Cancer 
The Scientific World Journal  2014;2014:908326.
Overexpression of miR-222 has been found in several types of cancers; however, the expression of miR-222 in non-small cell lung cancer (NSCLC) and its prognostic values are unclear. This study aimed to investigate whether the miR-222 expression level is related to clinicopathological factors and prognosis of NSCLC. Through a prospective study, 100 pairs of NSCLC tissues and adjacent normal tissues were examined by quantitative reverse-transcription polymerase chain reaction. The correlation between miR-222 expression and clinicopathological features was analyzed, and the significance of miR-222 as a prognostic factor and its relationship with survival were determined. Results showed that the expression levels of miR-222 were significantly elevated in the NSCLC tissue compared with that in adjacent normal tissue. In addition, Cox's proportional hazards model analysis confirmed that miR-222 high expression level was an independent predictor of poor prognosis. In conclusion, miR-222 overexpression is involved in the poor prognosis of NSCLC and can be used as a biomarker for selection of cases requiring especial attention.
doi:10.1155/2014/908326
PMCID: PMC4009118  PMID: 24955421
20.  Evolution of light-induced vapor generation at a liquid-immersed metallic nanoparticle 
Nano letters  2013;13(4):1736-1742.
When an Au nanoparticle in a liquid medium is illuminated with resonant light of sufficient intensity, a nanometer scale envelope of vapor -a “nanobubble”- surrounding the particle, is formed. This is the nanoscale onset of the well-known process of liquid boiling, occurring at a single nanoparticle nucleation site, resulting from the photothermal response of the nanoparticle. Here we examine bubble formation at an individual metallic nanoparticle in detail. Incipient nanobubble formation is observed by monitoring the plasmon resonance shift of an individual, illuminated Au nanoparticle, when its local environment changes from liquid to vapor. The temperature on the nanoparticle surface is monitored during this process, where a dramatic temperature jump is observed as the nanoscale vapor layer thermally decouples the nanoparticle from the surrounding liquid. By increasing the intensity of the incident light or decreasing the interparticle separation, we observe the formation of micron sized bubbles resulting from the coalescence of nanoparticle-“bound” vapor envelopes. These studies provide the first direct and quantitative analysis of the evolution of light-induced steam generation by nanoparticles from the nanoscale to the macroscale, a process that is of fundamental interest for a growing number of applications.
doi:10.1021/nl4003238
PMCID: PMC3888228  PMID: 23517407
Plasmonic heating; Au Nanoparticle; LSPR; Nanobubble; Microbubble
21.  The structural basis of transferrin sequestration by transferrin-binding protein B 
Neisseria meningitidis, the causative agent of bacterial meningitis, acquires the essential element iron from the host glycoprotein transferrin (Tf) during infection via a surface Tf receptor system composed of proteins TbpA and TbpB. Here in we present the crystal structures of TbpB from N. meningitidis, in its apo form and in complex with human Tf (hTf). The structure reveals how TbpB sequesters hTf and initiates iron release from hTf.
doi:10.1038/nsmb.2251
PMCID: PMC3981719  PMID: 22343719 CAMSID: cams4091
22.  The has-miR-526b Binding-Site rs8506G>A Polymorphism in the lincRNA-NR_024015 Exon Identified by GWASs Predispose to Non-Cardia Gastric Cancer Risk 
PLoS ONE  2014;9(3):e90008.
Gastric cancer including the cardia and non-cardia types is the second frequent cause of cancer-related deaths worldwide. A subset of non-cardia gastric cancer genetic susceptibility loci have been addressed among Asian through genome-wide association studies (GWASs). This study was to evaluate the effects of single nucleotide polymorphisms (SNPs) of long intergenic non-coding RNAs (lincRNAs) on non-cardia gastric cancer susceptibility in Chinese populations. We selected long intergenic noncoding RNAs (lincRNAs) located in non-cardia gastric cancer risk-related loci and identified 10 SNPs located within lincRNA exonic regions. We examined whether genetic polymorphisms in lincRNAs exons are associated with non-cardia gastric cancer risk in 438 non-cardia gastric cancer patients and 727 control subjects in Chinese populations using logistic regression. Functional relevance was further examined by biochemical assays. We found that lincRNA-NR_024015 rs8506AA carrier was significantly associated with risk of non-cardia gastric cancer (adjusted odds ratio [OR] = 1.56, 95%CI = 1.03–2.39, compared with the rs8506 AG or GG genotype. Further stratification analysis showed that the risk effect was more pronounced in subgroups of smokers (P = 0.001). Biochemical analysis demonstrated that the G to A base change at rs8506G>A disrupts the binding site for has-miR-526b, thereby influencing the transcriptional activity of lincRNA-NR_024015 and affecting cell proliferation. Our present study established a robust association between the rs8506G>A polymorphism in the lincRNA-NR_024015 exon and the risk of non-cardia gastric cancer.
doi:10.1371/journal.pone.0090008
PMCID: PMC3942390  PMID: 24595048
23.  Comparisons of the effects of long-acting and short-acting GnRH agonists on embryo quality, endometrial thickness and pregnancy rate in human in vitro fertilization 
Archives of Medical Science : AMS  2014;10(1):161-166.
Introduction
The aim was to compare the efficacy of long-acting and short-acting gonadotropin-releasing hormone (GnRH) agonists by long protocol on embryo quality, endometrial thickness and pregnancy rate in in vitro fertilization.
Material and methods
In this retrospective study, long-term pituitary downregulation, achieved with long- and short-acting GnRH agonists (GnRHa), was performed for patients undergoing in vitro fertilization (n = 175).
Results
There were no significant differences between the long and short-acting GnRH group (63.16% vs. 66.26%, p > 0.05), and the secondary and primary infertility group (63.47% vs. 66.86%, p > 0.05) in embryo quality. Logistic regression analysis showed that type of infertility and endometrial thickness were significantly associated with pregnancy outcome. Patients in the long-acting GnRHa group had a thicker endometrium on the day of human chorionic gonadotrophin (hCG) administration (10.79 ±2.62 mm vs. 9.64 ±1.97 mm, p < 0.01), lower serum luteinizing hormone (LH) concentration (1.21 ±1.13 vs. 2.53 ±3.39) and a higher pregnancy rate (59.60% vs. 43.42%, p < 0.05) than those of patients in the short-acting GnRHa group.
Conclusions
This work suggests that types of agonist protocol and infertility may not affect embryo quality. Type of infertility and endometrial thickness may be positive predictors for clinical pregnancy, but the key finding is that the long-acting GnRHa protocol may be an effective method of improving endometrial thickness, endometrial receptivity and pregnancy rate in in vitro fertilization.
doi:10.5114/aoms.2014.40743
PMCID: PMC3953985  PMID: 24701229
embryo quality; endometrial thickness; fragmentation; GnRH agonist; pregnancy
24.  Feasibility of omitting clinical target volume for limited-disease small cell lung cancer treated with chemotherapy and intensity-modulated radiotherapy 
Purpose
To analyze the feasibility of omitting clinical target volume (CTV) for limited small cell lung cancer treated with chemotherapy and intensity modulated radiotherapy.
Methods and materials
89 patients were treated from January 1, 2008 to August 31, 2011, 54 cases were irradiated with target volume without CTV, and 35 cases were irradiated with CTV. Both arms were irradiated post chemotherapy tumor extent and omitted elective nodal irradiation; dose prescription was 95% PTV56-63 Gy/28-35 F/5.6-7 weeks.
Results
In the arm without CTV and arm with CTV, the local relapse rates were 16.7% and 17.1% (p = 0.586) respectively. In the arm without CTV, of the 9 patients with local relapse, 6 recurred in-field, 2 recurred in margin, 1 recurred out of field. In the arm with CTV, of the 6 patients with local relapse, 4 recurred in-field, 1 recurred in margin, 1 recurred out of field. The distant metastases rates were 42.6% and 51.4% (p = 0.274) respectively. Grade 3-4 hematological toxicity and radiation esophagitis had no statistically significant, but grade 3-4 radiation pneumonia was observed in only 7.4% in the arm without CTV, compared 22.9% in the arm with CTV (p = 0.040). The median survival in the arm without CTV had not reached, compared with 38 months in the with CTV arm. The l- years, 2- years, 3- years survival rates of the arm without CTV and the arm with CTV were 81.0%, 66.2%, 61.5% and 88.6%, 61.7%, 56.6% (p = 0.517). The multivariate analysis indicated that the distant metastases (p = 0.000) and PCI factor (p = 0.004) were significantly related to overall survival.
Conclusions
Target delineation omitting CTV for limited-disease small cell lung cancer received IMRT was feasible. The distant metastases and PCI factor were significantly related to overall survival.
doi:10.1186/1748-717X-9-17
PMCID: PMC4006522  PMID: 24410971
Radiotherapy; Lung cancer; Limited-disease small cell lung cancer; Clinical target volume; Local relapse; Intensity-modulated radiotherapy; Radiation pneumonia
25.  Genome-wide analysis of light-regulated alternative splicing mediated by photoreceptors in Physcomitrella patens 
Genome Biology  2014;15(1):R10.
Background
Light is one of the most important factors regulating plant growth and development. Light-sensing photoreceptors tightly regulate gene expression to control photomorphogenic responses. Although many levels of gene expression are modulated by photoreceptors, regulation at the mRNA splicing step remains unclear.
Results
We performed high-throughput mRNA sequencing to analyze light-responsive changes in alternative splicing in the moss Physcomitrella patens, and found that a large number of alternative splicing events were induced by light in the moss protonema. Light-responsive intron retention preferentially occurred in transcripts involved in photosynthesis and translation. Many of the alternatively spliced transcripts were expressed from genes with a function relating to splicing or light signaling, suggesting a potential impact on pre-mRNA splicing and photomorphogenic gene regulation in response to light. Moreover, most light-regulated intron retention was induced immediately upon light exposure, while motif analysis identified a repetitive GAA motif that may function as an exonic regulatory cis element in light-mediated alternative splicing. Further analysis in gene-disrupted mutants was consistent with a function for multiple red-light photoreceptors in the upstream regulation of light-responsive alternative splicing.
Conclusions
Our results indicate that intensive alternative splicing occurs in non-vascular plants and that, during photomorphogenesis, light regulates alternative splicing with transcript selectivity. We further suggest that alternative splicing is rapidly fine-tuned by light to modulate gene expression and reorganize metabolic processes, and that pre-mRNA cis elements are involved in photoreceptor-mediated splicing regulation.
doi:10.1186/gb-2014-15-1-r10
PMCID: PMC4054894  PMID: 24398233

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