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1.  Fecal lactoferrin in discriminating inflammatory bowel disease from Irritable bowel syndrome: a diagnostic meta-analysis 
BMC Gastroenterology  2014;14:121.
Background
To perform a meta-analysis evaluating the diagnostic ability of fecal lactoferrin (FL) to distinguish inflammatory bowel disease (IBD) from irritable bowel syndrome (IBS).
Methods
The Medline, EMBASE, Web of Science, Cochrane library and CNKI databases were systematically searched for studies that used FL concentrations to distinguish between IBD and IBS. The sensitivity, specificity, and other diagnostic indexes of FL were pooled using a random-effects model.
Results
Seven studies, involving 1012 patients, were eligible for inclusion. In distinguishing IBD from IBS, FL had a pooled sensitivity of 0.78 (95% confidence interval [CI]: 0.75, 0.82), a specificity of 0.94 (95% CI: 0.91, 0.96), a positive likelihood ratio of 12.31 (95% CI: 5.93, 29.15), and a negative likelihood ratio of 0.23 (95% CI: 0.18, 0.29). The area under the summary receiver-operating characteristic curve was 0.94 (95% CI: 0.90, 0.98) and the diagnostic odds ratio was 52.65 (95% CI: 25.69, 107.91).
Conclusions
FL, as a noninvasive and simple marker, is useful in differentiating between IBD and IBS.
doi:10.1186/1471-230X-14-121
PMCID: PMC4105129  PMID: 25002150
Fecal lactoferrin; Inflammatory bowel disease; Irritable bowel syndrome; Meta-analysis
2.  Zymomonas mobilis: a novel platform for future biorefineries 
Biosynthesis of liquid fuels and biomass-based building block chemicals from microorganisms have been regarded as a competitive alternative route to traditional. Zymomonas mobilis possesses a number of desirable characteristics for its special Entner-Doudoroff pathway, which makes it an ideal platform for both metabolic engineering and commercial-scale production of desirable bio-products as the same as Escherichia coli and Saccharomyces cerevisiae based on consideration of future biomass biorefinery. Z. mobilis has been studied extensively on both fundamental and applied level, which will provide a basis for industrial biotechnology in the future. Furthermore, metabolic engineering of Z. mobilis for enhancing bio-ethanol production from biomass resources has been significantly promoted by different methods (i.e. mutagenesis, adaptive laboratory evolution, specific gene knock-out, and metabolic engineering). In addition, the feasibility of representative metabolites, i.e. sorbitol, bionic acid, levan, succinic acid, isobutanol, and isobutanol produced by Z. mobilis and the strategies for strain improvements are also discussed or highlighted in this paper. Moreover, this review will present some guidelines for future developments in the bio-based chemical production using Z. mobilis as a novel industrial platform for future biofineries.
doi:10.1186/1754-6834-7-101
PMCID: PMC4094786  PMID: 25024744
Zymomonas mobilis; platform; biorefinery; biofuel; building block chemical
3.  Early Public Response to Influenza A(H7N9) Virus, Guangzhou, China, May 30–June 7, 2013 
Emerging Infectious Diseases  2014;20(7):1238-1240.
doi:10.3201/eid2007.131155
PMCID: PMC4073867  PMID: 24964006
public; influenza; influenza virus; influenza A(H7N9) virus; subtype H7N9; live poultry markets; China; Guangzhou; behaviors; attitudes; urban; semirural; viruses; chickens
4.  Optimization of Phenolics Extracted from Idesia polycarpa Defatted Fruit Residue and Its Antioxidant and Depigmenting Activity In Vitro and In Vivo 
Extraction of phenolics from Idesia polycarpa defatted fruit residue was optimized by the maximization of the yield in total phenolics, using the response surface methodology. The optimized conditions were 50% ethanol, 5 h extraction time, 1 : 40 liquid to solid ratio, and 80°C extraction temperature. The experimental average total phenolics yield was 54.49 ± 4.26 mg/g. These antioxidant properties of phenolics were comprehensively analyzed for the first time. All the extracts not only demonstrated the significant free radical scavenging activities and metal chelating activity but also inhibited lipid, lipoprotein peroxidation and revealed reducing power activity. Ethyl acetate extraction (EAE) also inhibited mushroom tyrosinase activity and significantly increased the average skin-whitening index (L value) of the skin of C57BL/6 mice, indicating its potential use for skin hyperpigmentation in humans. The results of cell experiments showed EAE could strongly inhibit cellular tyrosinase activity, which had led to the decrease of melanogenesis in B16 mouse melanoma cells. Overall, EAE is an excellent natural antioxidant and depigmenting agent, which can be developed as a new food additive, medicine, and cosmetic.
doi:10.1155/2014/931269
PMCID: PMC4087257  PMID: 25045392
5.  Basal stem cells contribute to squamous cell carcinomas in the oral cavity 
Carcinogenesis  2013;34(5):1158-1164.
The cells of origin of oral cavity squamous cell carcinoma (OCSCC) are unknown. We used a cell lineage tracing approach (adult K14-CreERTAM; ROSA26 mice transiently treated with tamoxifen) to identify and track normal epithelial stem cells (SCs) in mouse tongues by X-gal staining and to determine if these cells become neoplastically transformed by treatment with a carcinogen, 4-nitroquinoline 1-oxide (4-NQO). Here, we show that in normal tongue epithelia, X-gal(+) cells formed thin columns throughout the entire epithelium 12 weeks after tamoxifen treatment, indicating that the basal layer contains long-lived SCs that produce progeny by asymmetric division to maintain homeostasis. Carcinogen treatment results in a ~10-fold reduction in the total number of X-gal(+) clonal cell populations and horizontal expansion of X-gal(+) clonal cell columns, a pattern consistent with symmetric division of some SCs. Finally, X-gal(+) SCs are present in papillomas and invasive OCSCCs, and these long-lived X-gal(+) SCs are the cells of origin of these tumors. Moreover, the resulting 4-NQO-induced tumors are multiclonal. These findings provide insights into the identity of the initiating cells of oral cancer.
doi:10.1093/carcin/bgt021
PMCID: PMC3643419  PMID: 23358851
6.  Adipose-derived stem cells transfected with pEGFP-OSX enhance bone formation during distraction osteogenesis*  
This study was designed to investigate the effects of local delivery of adipose-derived stem cells (ADSCs) transfected with transcription factor osterix (OSX) on bone formation during distraction osteogenesis. New Zealand white rabbits (n=54) were randomly divided into three groups (18 rabbits per group). A directed cloning technique was used for the construction of recombinant plasmid pEGFP-OSX, where EGFP is the enhanced green fluorescence protein. After osteodistraction of the right mandible of all experimental rabbits, rabbits in group A were treated with ADSCs transfected with pEGFP-OSX, group B with ADSCs transfected with pEGFP-N1, and group C with physiological saline. Radiographic and histological examinations were processed after half of the animals within each group were humanely killed by injection of sodium pentothal at Week 2 or 6 after surgery. The distraction bone density was measured as its projectional bone mineral density (BMD). Three parameters were measured, namely, the thickness of new trabeculae (TNT), and the volumes of the newly generated cortical bone (NBV1) and the cancellous bone (NBV2) of the distracted regions. Good bone generation in the distraction areas was found in group A, which had the highest BMD, TNT, and NBV in the distraction zones among the groups. There was no significant difference in bone generation in the distraction areas between groups B and C. The results indicate that the transplantation of ADSCs transfected with pEGFP-OSX can effectively promote bone generation during distraction in vivo.
doi:10.1631/jzus.B1300203
PMCID: PMC4076605  PMID: 24793766
Adipose-derived stem cell (ADSC); Distraction osteogenesis; Transcription factor; Gene transfection
7.  Differentiation induction of mouse cardiac stem cells into sinus node-like cells by co-culturing with sinus node 
Sinus nodal cells can generate a diastolic or “pacemaker” depolarization at the end of an action potential driving the membrane potential slowly up to the threshold for firing the next action potential. It has been proved that adult cardiac stem cells (CSCs) can differentiate into sinus nodal cells by demethylating agent. However, there is no report about adult CSCs-derived sinus nodal cells with pacemaker current (the funny current, I f). In this study, we isolated the mouse adult CSCs from mouse hearts by the method of tissue explants adherence. The expression of c-kit protein indicated the isolation of CSCs. Then we co-cultured mouse CSCs with mouse sinus node tissue to induce the differentiation of these CSCs into sinus node-like cells, which was proved by identifying the enhanced expression of marker proteins cTnI, cTnT and α-Actinin with Immunofluorescence staining. At the same time, with whole-cell patch-clamp we detected the I f current, which can be blocked by CsCl, in these differentiated cells. In conclusion, by confirming specific I f current in the induced node-like cells, our work shows a method inducing differentiation of CSCs into sinus node-like cells, which can provide helpful information for the further research on sick sinus syndrome.
PMCID: PMC4069922  PMID: 24966897
Cardiac stem cells; If current; sinus node; co-culture
8.  Hydrogen Sulfide Inhibits Formaldehyde-Induced Endoplasmic Reticulum Stress in PC12 Cells by Upregulation of SIRT-1 
PLoS ONE  2014;9(2):e89856.
Background
Formaldehyde (FA), a well-known environmental pollutant, has been classified as a neurotoxic molecule. Our recent data demonstrate that hydrogen sulfide (H2S), the third gaseous transmitter, has a protective effect on the neurotoxicity of FA. However, the exact mechanisms underlying this protection remain largely unknown. Endoplasmic reticulum (ER) stress has been implicated in the neurotoxicity of FA. Silent mating type information regulator 2 homolog 1 (SIRT-1), a histone deacetylases, has various biological activities, including the extension of lifespan, the modulation of ER stress, and the neuroprotective action.
Objective
We hypothesize that the protection of H2S against FA-induced neurotoxicity involves in inhibiting ER stress by upregulation of SIRT-1. The present study attempted to investigate the protective effect of H2S on FA-induced ER stress in PC12 cells and the contribution of SIRT-1 to the protection of H2S against FA-induced injuries, including ER stress, cytotoxicity and apoptosis.
Principal Findings
We found that exogenous application of sodium hydrosulfide (NaHS; an H2S donor) significantly attenuated FA-induced ER stress responses, including the upregulated levels of glucose-regulated protein 78, C/EBP homologous protein, and cleaved caspase-12 expression. We showed that NaHS upregulates the expression of SIRT-1 in PC12 cells. Moreover, the protective effects of H2S on FA-elicited ER stress, cytotoxicity and apoptosis were reversed by Sirtinol, a specific inhibitor of SIRT-1.
Conclusion/Significance
These data indicate that H2S exerts its protection against the neurotoxicity of FA through overcoming ER stress via upregulation of SIRT-1. Our findings provide novel insights into the protective mechanisms of H2S against FA-induced neurotoxicity.
doi:10.1371/journal.pone.0089856
PMCID: PMC3938548  PMID: 24587076
9.  The rhythmic expression of clock genes attenuated in human plaque-derived vascular smooth muscle cells 
Background
Acute myocardial infarction and stroke are more likely to occur in the early morning. Circadian pacemakers are considered to be involved in the process. Many peripheral tissues and cells also contain clock systems. In this study, we examined whether the primary cultured human plaque-derived vascular smooth muscle cells (VSMCs) process circadian rhythmicity; furthermore, we investigated the expression difference of clock genes between normal human carotid VSMCs and human plaque-derived VSMCs.
Methods
Fifty-six human carotid plaques provided the atherosclerotic tissue, and 21 samples yielded viable cultured primary VSMCs. The normal carotid VSMCs were cultured from donors’ normal carotids. The mRNA levels of the target genes were measured by Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR).
Results
After serum shock, both types of cells showed clear circadian expressions of Bmal1, Cry1, Cry2, Per1, Per2, Per3 and Rev-erbα mRNA; meanwhile the Clock mRNA show a rhythmic expression in plaque-derived SMCs but not in normal carotid VSMCs. The expression levels of these main clock genes were significantly attenuated in human plaque-derived VSMCs compared with normal human carotid VSMCs. The rhythm of Bmal1 mRNA in plaque-derived VSMCs was changed.
Conclusion
The present results demonstrate that the human plaque-derived VSMCs possess different circadian rhythmicity from that of normal carotid VSMCs. The rhythm changes of clock genes in plaque-derived VSMCs may be involved in the process of atherosclerosis and finally promote the rupture of plaque.
doi:10.1186/1476-511X-13-14
PMCID: PMC4077102  PMID: 24418196
Circadian rhythm; Primary cell culture; Human vascular smooth muscle cells; Atherosclerosis; Plaque rupture
10.  Effects of Acupuncture on CCL2 and CXCL8 Expression and the Subset of uNK Cells in Rats with Embryo Implantation Failure 
The present study was designed to investigate the efficacy and mechanism of acupuncture treatment on embryo implantation failure in rats. The pregnant rats were randomized into normal group (N), implantation failure group (M), acupuncture treatment group (A), and progestin treatment group (W). The embryo implantation failure model was established by mifepristone. Efficacy of acupuncture treatment was evaluated by the number of implanted embryos. The expression of CCL2 and CXCL8 and the subset of uterine natural killer cells in the endometrium were detected. We demonstrated that the number of implanted embryos was dramatically reduced after mifepristone (M group) treatment, while the acupuncture (A group) and progestin (W group) treatments significantly rescued impaired embryo implantation. The protein and mRNA expressions of CCL2 and CXCL8 were significantly reduced by mifepristone treatment, but the attenuated expression of CCL2 and CXCL8 was markedly reversed by acupuncture or progestin treatment. More importantly, acupuncture and progestin could markedly increase the subset of uNK cells in rats with embryo implantation failure. These evidences suggest that acupuncture is able to modulate the endometrial immune microenvironment and thus improve embryo implantation in pregnant rats, which provides solid experimental evidence for the curative effect of acupuncture treatment on infertility.
doi:10.1155/2013/678390
PMCID: PMC3874941  PMID: 24396391
11.  Comparative transcriptome analysis of tomato (Solanum lycopersicum) in response to exogenous abscisic acid 
BMC Genomics  2013;14(1):841.
Background
Abscisic acid (ABA) can regulate the expressions of many stress-responsive genes in plants. However, in defense responses to pathogens, mounting evidence suggests that ABA plays variable roles. Little information exists about genome-wide gene expression in ABA responses in tomato (Solanum lycopersicum L.), a model fruit crop plant.
Results
Global transcriptome profiles of tomato leaf responses to exogenous ABA were generated using Illumina RNA-sequencing. More than 173 million base pair reads were mapped onto the tomato reference genome and the expression pattern differences between treated and control leaves were assessed. In total, 50,616 transcripts were generated. Among them, 42,583 were functionally annotated in the NCBI non-redundant database and 47,877 in the tomato genome reference. Additionally, 31,107 transcripts were categorized into 57 functional groups based on Gene Ontology terms, and 14,371 were assigned to 310 Kyoto Encyclopedia of Genes and Genomes pathways. In both the ABA treatment and control samples, 39,671 transcripts were available to analyze their expressions, of which 21,712 (54.73%) responded to exogenous ABA. Of these transcripts, 2,787 were significantly differently expressed genes (DEGs). Many known and novel ABA-induced and -repressed genes were found. Exogenous ABA can influence the ABA signaling pathway with PYR/PYL/RCARs-PP2Cs-SnRK2s as the center. Eighteen PYL genes were detected. A large number of genes related to various transcription factors, heat shock proteins, pathogen resistance, and the salicylic acid, jasmonic acid, and ethylene signaling pathways were up-regulated by exogenous ABA.
Conclusions
The results indicated that ABA has the potential to improve pathogen-resistance and abiotic stress tolerance in tomato. This study presents the global expression analysis of ABA-regulated transcripts in tomato and provides a robust database for investigating the functions of genes induced by ABA.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-14-841) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2164-14-841
PMCID: PMC4046761  PMID: 24289302
Tomato; Exogenous ABA; RNA-Seq; ABA signaling pathway; Transcription factors; Heat shock proteins; Pathogen-related proteins; ROS scavenging enzymes
12.  Harnessing the Potential of Halogenated Natural Product Biosynthesis by Mangrove-Derived Actinomycetes 
Marine Drugs  2013;11(10):3875-3890.
Mangrove-derived actinomycetes are promising sources of bioactive natural products. In this study, using homologous screening of the biosynthetic genes and anti-microorganism/tumor assaying, 163 strains of actinomycetes isolated from mangrove sediments were investigated for their potential to produce halogenated metabolites. The FADH2-dependent halogenase genes, identified in PCR-screening, were clustered in distinct clades in the phylogenetic analysis. The coexistence of either polyketide synthase (PKS) or nonribosomal peptide synthetase (NRPS) as the backbone synthetases in the strains harboring the halogenase indicated that these strains had the potential to produce structurally diversified antibiotics. As a validation, a new enduracidin producer, Streptomyces atrovirens MGR140, was identified and confirmed by gene disruption and HPLC analysis. Moreover, a putative ansamycin biosynthesis gene cluster was detected in Streptomyces albogriseolus MGR072. Our results highlight that combined genome mining is an efficient technique to tap promising sources of halogenated natural products synthesized by mangrove-derived actinomycetes.
doi:10.3390/md11103875
PMCID: PMC3826140  PMID: 24129229
mangrove-derived actinomycetes; genome mining; halogenase; enduracidin; ansamycin
13.  Calcium-permeable AMPA receptors in neonatal hypoxic-ischemic encephalopathy (Review) 
Biomedical Reports  2013;1(6):828-832.
Hypoxic-ischemic encephalopathy (HIE) is an important cause of brain injury in the newborn and may result in long-term devastating consequences. Excessive stimulation of glutamate receptors (GluRs) is a pivotal mechanism underlying ischemia-induced selective and delayed neuronal death. Although initial studies focused on N-methyl-D-aspartic acid (NMDA) receptors as critical mediators in HIE, subsequent studies supported a more central role for α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPARs), particularly Ca2+-permeable AMPARs, in brain damage associated with hypoxia-ischemia. This study reviewed the important role of Ca2+-permeable AMPARs in HIE and the future potential neuroprotective strategies associated with Ca2+-permeable AMPARs.
doi:10.3892/br.2013.154
PMCID: PMC3916971  PMID: 24649036
hypoxic-ischemic encephalopathy; neonate; Ca2+-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors; glutamate receptors 2
14.  Treatment of stage IIIb/IV non-small cell lung cancer with Pemetrexed plus Oxaliplatin after failure of Erlotinib as second-line treatment 
To determine the efficacy and toxicity of Pemetrexed plus Oxaliplatin in patients suffering from stage IIIb or IV lung adenocarcinoma and being treated with Erlotinib as second-line treatment, a total of 45 patients were randomly divided into two groups. One group was treated with 500 mg/m2 Pemetrexed plus 100 mg/m2 Oxaliplatin, and the other was treated with 500 mg/m2 Pemetrexed plus 75 mg/m2 Cisplatin. All drugs were administered on day one of a 21-day cycle. In the Oxaliplatin group, 3 patients (13.6 %) experienced partial response (PR), 9 patients (41.0 %) showed stable disease (SD), and 10 patients (45.5 %) had progressive disease (PD). In the Cisplatin group, 2 patients (8.7 %) experienced PR, 7 patients (30.4 %) showed SD, and 14 patients (60.9 %) had PD. The PFS of the Oxaliplatin group and the Cisplatin group was 4.45 months (95 % CI 4.10–4.80) and 3.96 months (95 % CI 3.68–4.24) (P = 0.03), respectively. The median overall survival (OS) was 10.8 months (95 % CI 10.2–11.5) and 10.7 months (95 % CI 10.2–11.3) (P = 0.72), respectively. There was no statistically significant difference in the occurrence rate of grades 3 and 4 myelotoxicity between the two groups. However, there was a significant difference in the occurrence rate of grades 3 and 4 gastrointestinal reactions and peripheral neurotoxicity between the two groups (P < 0.05). A regime combining Pemetrexed and Oxaliplatin was marginally effective and well tolerated in patients with stage IIIb or IV lung adenocarcinoma who have received Erlotinib as second-line treatment.
doi:10.1007/s12032-013-0550-7
PMCID: PMC3667368  PMID: 23576138
Lung adenocarcinoma; Oxaliplatin; Pemetrexed; Erlotinib as second-line treatment
15.  The expressions of MIF and CXCR4 protein in tumor microenvironment are adverse prognostic factors in patients with esophageal squamous cell carcinoma 
Background
Tumor-derived cytokines and their receptors usually take important roles in the disease progression and prognosis of cancer patients. In this survey, we aimed to detect the expression levels of MIF and CXCR4 in different cell populations of tumor microenvironments and their association with survivals of patients with esophageal squamous cell carcinoma (ESCC).
Methods
MIF and CXCR4 levels were measured by immunochemistry in tumor specimens from 136 resected ESCC. Correlation analyses and independent prognostic outcomes were determined using Pearson’s chi-square test and Cox regression analysis.
Results
The expression of CXCR4 in tumor cells was positively associated with tumor status (P = 0.045) and clinical stage (P = 0.044); whereas the expression of CXCR4 in tumor-infiltrating lymphocytes (TILs) and the expression of MIF in tumor cells and in TILs were not associated with clinical parameters of ESCC patients. High MIF expression in tumor cells or in TILs or high CXCR4 expression in tumor cells was significantly related to poor survival of ESCC patients (P < 0.05). Multivariate analysis showed that the expression of MIF or CXCR4 in tumor cells and the expression of MIF in TILs were adverse independent factors for disease-free survival (DFS) and overall survival (OS) in the whole cohort of patients (P < 0.05). Furthermore, the expression of MIF and CXCR4 in tumor cells were independent factors for reduced DFS and OS in metastatic/recurrent ESCC patients (P < 0.05). Interestingly, the expressions of MIF and CXCR4 in tumor cells and in TILs were significantly positively correlated (P < 0.05), and the combined MIF and CXCR4 expression in tumor cells was an independent adverse predictive factor for DFS and OS (P < 0.05).
Conclusion
The expressions of MIF and CXCR4 proteins in tumor cells and TILs have different clinically predictive values in ESCC.
doi:10.1186/1479-5876-11-60
PMCID: PMC3623724  PMID: 23497377
Esophageal squamous cell carcinoma; Tumor microenvironment; MIF; CXCR4; Prognosis
16.  A Novel Mechanism of Formaldehyde Neurotoxicity: Inhibition of Hydrogen Sulfide Generation by Promoting Overproduction of Nitric Oxide 
PLoS ONE  2013;8(1):e54829.
Background
Formaldehyde (FA) induces neurotoxicity by overproduction of intracellular reactive oxygen species (ROS). Increasing studies have shown that hydrogen sulfide (H2S), an endogenous gastransmitter, protects nerve cells against oxidative stress by its antioxidant effect. It has been shown that overproduction of nitric oxide (NO) inhibits the activity of cystathionine-beta-synthase (CBS), the predominant H2S-generating enzyme in the central nervous system.
Objective
We hypothesize that FA-caused neurotoxicity involves the deficiency of this endogenous protective antioxidant gas, which results from excessive generation of NO. The aim of this study is to evaluate whether FA disturbs H2S synthesis in PC12 cells, and whether this disturbance is associated with overproduction of NO.
Principal Findings
We showed that exposure of PC12 cells to FA causes reduction of viability, inhibition of CBS expression, decrease of endogenous H2S production, and NO production. CBS silencing deteriorates FA-induced decreases in endogenous H2S generation, neurotoxicity, and intracellular ROS accumulation in PC12 cells; while ADMA, a specific inhibitor of NOS significantly attenuates FA-induced decreases in endogenous H2S generation, neurotoxicity, and intracellular ROS accumulation in PC12 cells.
Conclusion/Significance
Our data indicate that FA induces neurotoxicity by inhibiting the generation of H2S through excess of NO and suggest that strategies to manipulate endogenous H2S could open a suitable novel therapeutic avenue for FA-induced neurotoxicity.
doi:10.1371/journal.pone.0054829
PMCID: PMC3554621  PMID: 23359814
17.  Reduced Airway Surface pH Impairs Bacterial Killing in the Porcine Cystic Fibrosis Lung 
Nature  2012;487(7405):109-113.
Cystic fibrosis (CF) is a life-shortening disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene 1. Although bacterial lung infection and the resulting inflammation cause most of the morbidity and mortality, how loss of CFTR first disrupts airway host defense has remained uncertain 2–6. We asked what abnormalities impair eradication when a bacterium lands on the pristine surface of a newborn CF airway? To investigate these defects, we interrogated the viability of individual bacteria immobilized on solid grids and placed on the airway surface. As a model we studied CF pigs, which spontaneously develop hallmark features of CF lung disease 7,8. At birth, their lungs lack infection and inflammation, but have a reduced ability to eradicate bacteria 8. Here we show that in newborn wild-type pigs, the thin layer of airway surface liquid (ASL) rapidly killed bacteria in vivo, when removed from the lung, and in primary epithelial cultures. Lack of CFTR reduced bacterial killing. We found that ASL pH was more acidic in CF, and reducing pH inhibited the antimicrobial activity of ASL. Reducing ASL pH diminished bacterial killing in wild-type pigs, and increasing ASL pH rescued killing in CF pigs. These results directly link the initial host defense defect to loss of CFTR, an anion channel that facilitates HCO3− transport 9–13. Without CFTR, airway epithelial HCO3− secretion is defective, ASL pH falls and inhibits antimicrobial function, and thereby impairs killing of bacteria that enter the newborn lung. These findings suggest that increasing ASL pH might prevent the initial infection in patients with CF and that assaying bacterial killing could report on the benefit of therapeutic interventions.
doi:10.1038/nature11130
PMCID: PMC3390761  PMID: 22763554
18.  Mutations and Down-Regulation of CDX1 in Children with Anorectal Malformations 
Background: Anorectal malformations (ARMs) represent a variety of congenital disorders that involve abnormal termination of the anorectum. This study was to reveal relation between CDX1 and human ARMs phenotypes.
Methods: 108 Chinese patients and 120 Chinese controls were included in this study. We analyzed the relation between two by PCR, qRT-PCR, western blot and immunofluorescence.
Results: Four heterozygous mutations in CDX1 gene were identified in ARMs patients (3.7%, 4/108), no found in controls. CDX1 protein expression was significantly decreased in the ARMs compared with the control anorectum. All samples analyzed in ARMs group exhibited down-regulated CDX1 mRNA expression in comparison to matched normal group, demonstrated significant differences statistically.
Conclusion: The findings represented the relation between CDX1 mutations and CDX1 genotype. Furthermore, it was suggested that the downregulation of CDX1 might be related to the development of ARMs.
doi:10.7150/ijms.4929
PMCID: PMC3547218  PMID: 23329892
Anorectal malformations; CDX1; mutation; children
19.  Insights into the Maturation of Hyperthermophilic Pyrolysin and the Roles of Its N-Terminal Propeptide and Long C-Terminal Extension 
Applied and Environmental Microbiology  2012;78(12):4233-4241.
Pyrolysin-like proteases from hyperthermophiles are characterized by large insertions and long C-terminal extensions (CTEs). However, little is known about the roles of these extra structural elements or the maturation of these enzymes. Here, the recombinant proform of Pyrococcus furiosus pyrolysin (Pls) and several N- and C-terminal deletion mutants were successfully expressed in Escherichia coli. Pls was converted to mature enzyme (mPls) at high temperatures via autoprocessing of both the N-terminal propeptide and the C-terminal portion of the long CTE, indicating that the long CTE actually consists of the C-terminal propeptide and the C-terminal extension (CTEm), which remains attached to the catalytic domain in the mature enzyme. Although the N-terminal propeptide deletion mutant PlsΔN displayed weak activity, this mutant was highly susceptible to autoproteolysis and/or thermogenic hydrolysis. The N-terminal propeptide acts as an intramolecular chaperone to assist the folding of pyrolysin into its thermostable conformation. In contrast, the C-terminal propeptide deletion mutant PlsΔC199 was converted to a mature form (mPlsΔC199), which is the same size as but less stable than mPls, suggesting that the C-terminal propeptide is not essential for folding but is important for pyrolysin hyperthermostability. Characterization of the full-length (mPls) and CTEm deletion (mPlsΔC740) mature forms demonstrated that CTEm not only confers additional stability to the enzyme but also improves its catalytic efficiency for both proteineous and small synthetic peptide substrates. Our results may provide important clues about the roles of propeptides and CTEs in the adaptation of hyperthermophilic proteases to hyperthermal environments.
doi:10.1128/AEM.00548-12
PMCID: PMC3370559  PMID: 22504813
20.  Adaptive prospective ECG-triggered sequence coronary angiography in dual-source CT without heart rate control: Image quality and diagnostic performance 
The aim of this study was to evaluate the accuracy of using second generation dual-source CT (DSCT) to obtain high quality images and diagnostic performance and to reduce the radiation dose in adaptive prospective electrocardiography (ECG)-triggered sequence (CorAdSeq) CT coronary angiography (CTCA) without heart rate control. No prescan β-blockers were administered. Un-enhanced CT and CTCA with adaptive prospective CorAdSeq scanning without heart rate control were performed in 683 consecutive patients divided into two body mass index (BMI) groups: BMI <25 kg/m2 (group A, n=412) and BMI ≥25 kg/m2 (group B, n=271). The image quality and quantitative stenosis of all coronary segments with a diameter ≥1 mm were assessed. The mean heart rate (MHR), heart rate variability (HRV) and radiation dose values were recorded. In 426 cases, the diagnostic performance was evaluated using quantitative conventional coronary angiography as the reference standard. Diagnostic image quality was obtained in 98.5% of segments in group A and in 98.8% of segments in group B, with no significant differences between the groups. No correlations were observed between the image quality score and MHR or HRV (P=0.492, P=0.564, respectively). The effective radiation doses in groups A and B were 2.57±1.01 mSv and 6.36±1.88 mSv, respectively. The sensitivities and specificities of diagnosing coronary heart disease per patient were 99.6% and 97.8% in group A and 99.5% and 97.5% in group B, respectively (P>0.05). Adaptive prospective CorAdSeq scanning, without heart rate control, by second generation DSCT had a high image quality and diagnostic performance for coronary artery stenosis with lower radiation doses.
doi:10.3892/etm.2012.828
PMCID: PMC3570094  PMID: 23403952
dual-source computed tomography; non-invasive coronary angiography; coronary angiography; heart rate
21.  trans-Iodido(pyrazinyl-κC 2)bis­(triphenyl­phosphane-κP)palladium(II) 
There are two independent mol­ecules with similar configurations in the asymmetric unit of the title complex, [Pd(C4H3N2)I(C18H15P)2]. In each mol­ecule, the geometry around the Pd atom is distorted square-planar, with the Pd atom displaced by 0.0549 (12) and 0.0734 (13) Å from the least-squares plane of the I—P—P—C atoms. The PPh3 ligands are in trans positions, with P—Pd—P angles of 173.12 (4) and 170.29 (4)°, while the pyrazinyl ligands and I atoms, also trans to each other, form C—Pd—I angles of 179.38 (12) and 178.44 (12)°. In the crystal, C—H⋯π inter­actions occur, resulting in a three-dimensional supramolecular architecture.
doi:10.1107/S1600536812043589
PMCID: PMC3515155  PMID: 23284382
22.  Transcriptome profiling of Zymomonas mobilis under ethanol stress 
Background
High tolerance to ethanol is a desirable characteristics for ethanologenic strains used in industrial ethanol fermentation. A deeper understanding of the molecular mechanisms underlying ethanologenic strains tolerance of ethanol stress may guide the design of rational strategies to increase process performance in industrial alcoholic production. Many extensive studies have been performed in Saccharomyces cerevisiae and Escherichia coli. However, the physiological basis and genetic mechanisms involved in ethanol tolerance for Zymomonas mobilis are poorly understood on genomic level. To identify the genes required for tolerance to ethanol, microarray technology was used to investigate the transcriptome profiling of the ethanologenic Z. mobilis in response to ethanol stress.
Results
We successfully identified 127 genes which were differentially expressed in response to ethanol. Ethanol up- or down-regulated genes related to cell wall/membrane biogenesis, metabolism, and transcription. These genes were classified as being involved in a wide range of cellular processes including carbohydrate metabolism, cell wall/membrane biogenesis, respiratory chain, terpenoid biosynthesis, DNA replication, DNA recombination, DNA repair, transport, transcriptional regulation, some universal stress response, etc.
Conclusion
In this study, genome-wide transcriptional responses to ethanol were investigated for the first time in Z. mobilis using microarray analysis.Our results revealed that ethanol had effects on multiple aspects of cellular metabolism at the transcriptional level and that membrane might play important roles in response to ethanol. Although the molecular mechanism involved in tolerance and adaptation of ethanologenic strains to ethanol is still unclear, this research has provided insights into molecular response to ethanol in Z. mobilis. These data will also be helpful to construct more ethanol resistant strains for cellulosic ethanol production in the future.
doi:10.1186/1754-6834-5-75
PMCID: PMC3495753  PMID: 23057803
23.  The Complete Genome Sequence of Natrinema sp. J7-2, a Haloarchaeon Capable of Growth on Synthetic Media without Amino Acid Supplements 
PLoS ONE  2012;7(7):e41621.
Natrinema sp. J7-2 is an extreme haloarchaeon capable of growing on synthetic media without amino acid supplements. Here we report the complete genome sequence of Natrinema sp. J7-2 which is composed of a 3,697,626-bp chromosome and a 95,989-bp plasmid pJ7-I. This is the first complete genome sequence of a member of the genus Natrinema. We demonstrate that Natrinema sp. J7-2 can use gluconate, glycerol, or acetate as the sole carbon source and that its genome encodes complete metabolic pathways for assimilating these substrates. The biosynthetic pathways for all 20 amino acids have been reconstructed, and we discuss a possible evolutionary relationship between the haloarchaeal arginine synthetic pathway and the bacterial lysine synthetic pathway. The genome harbors the genes for assimilation of ammonium and nitrite, but not nitrate, and has a denitrification pathway to reduce nitrite to N2O. Comparative genomic analysis suggests that most sequenced haloarchaea employ the TrkAH system, rather than the Kdp system, to actively uptake potassium. The genomic analysis also reveals that one of the three CRISPR loci in the Natrinema sp. J7-2 chromosome is located in an integrative genetic element and is probably propagated via horizontal gene transfer (HGT). Finally, our phylogenetic analysis of haloarchaeal genomes provides clues about evolutionary relationships of haloarchaea.
doi:10.1371/journal.pone.0041621
PMCID: PMC3402447  PMID: 22911826
24.  Short term effects of different omega-3 fatty acid formulation on lipid metabolism in mice fed high or low fat diet 
Background
Bioactivities of Docosahexaenoic acid (DHA) and Eicosapentaenoic acid (EPA) depend on their chemical forms. The present study was to investigate short term effects of triglyceride (TG), ethyl ester (EE), free fatty acid (FFA) and phospholipid (PL) forms of omega-3 fatty acid (FA) on lipid metabolism in mice, fed high fat or low fat diet.
Method
Male Balb/c mice were fed with 0.7% different Omega-3 fatty acid formulation: DHA bound free fatty acid (DHA-FFA), DHA bound triglyceride (DHA-TG), DHA bound ethyl ester (DHA-EE) and DHA bound phospholipid (DHA-PL) for 1 week, with dietary fat levels at 5% and 22.5%. Serum and hepatic lipid concentrations were analyzed, as well as the fatty acid composition of liver and brain.
Result
At low fat level, serum total cholesterol (TC) level in mice fed diets with DHA-FFA, DHA-EE and DHA-PL were significantly lower than that in the control group (P < 0.05). Hepatic TG level decreased significantly in mice fed diets with DHA-TG (P < 0.05), DHA-EE (P < 0.05) and DHA-PL (P < 0.05), while TC level in liver was significantly lower in mice fed diets with TG and EE compared with the control group (P < 0.05). At high fat level, mice fed diets with DHA-EE and DHA-PL had significantly lower hepatic TC level compared with the control diet (P < 0.05). Hepatic PL concentration experienced a significant increase in mice fed the diet with PL at high fat level (P < 0.05). Furthermore, both at low and high fat levels, hepatic DHA level significantly increased and AA level significantly decreased in all forms of DHA groups (P < 0.05), compared to control groups at two different fat levels, respectively. Additionally, cerebral DHA level in mice fed diets with DHA-FFA, DHA-EE and DHA-PL significantly increased compared with the control at high fat level (P < 0.05), but no significant differences were observed among dietary treatments for mice fed diets with low fat level.
Conclusion
The present study suggested that not only total dietary fat content but also the molecular forms of omega-3 fatty acids contributed to lipid metabolism in mice. DHA-PL showed effective bioactivity in decreasing hepatic and serum TC, TG levels and increasing omega-3 concentration in liver and brain.
doi:10.1186/1476-511X-11-70
PMCID: PMC3393618  PMID: 22676394
Omega-3 fatty acid; DHA; EPA; Lipid metabolism; Triglycerides; Ethyl ester; Phospholipids
25.  Ex vivo expansion of tumor-infiltrating lymphocytes from nasopharyngeal carcinoma patients for adoptive immunotherapy 
Chinese Journal of Cancer  2012;31(6):287-294.
Establishing Epstein-Barr virus (EBV)-specific cytolytic T lymphocytes (EBV-CTLs) from peripheral blood mononuclear cells (PBMCs) for adoptive immunotherapy has been reported in EBV-associated malignancies including Hodgkin's lymphoma and nasopharyngeal carcinoma (NPC). In the current study, we performed ex vivo expansion of tumor-infiltrating lymphocytes (TILs) obtained from NPC biopsy specimens with a rapid expansion protocol using anti-CD3 monoclonal antibody (OKT3), recombinant human interleukin (IL)-2, and irradiated PBMCs from healthy donors to initiate the growth of TILs. Young TIL cultures comprised of more than 90% of CD3+ T cells, a variable percentage of CD3+CD8+ and CD3+ CD4+ T cells, and less than 10% of CD3−CD16+ natural killer cells, a similar phenotype of EBV-CTL cultures from PBMCs. Interestingly, TIL cultures secreted high levels of the Th1 cytokines, interferon gamma (IFNγ) and tumor necrosis factor-alpha (TNF-α), and low levels of the Th2 cytokines, IL-4 and IL-10. Moreover, young TILs could recognize autologous EBV-transformed B lymphoblast cell lines, but not autologous EBV-negative blast cells or allogeneic EBV-negative tumor cells. Taken together, these data suggest that ex vivo expansion of TILs from NPC biopsy tissue is an appealing alternative method to establish T cell-based immunotherapy for NPC.
doi:10.5732/cjc.011.10376
PMCID: PMC3777488  PMID: 22257383
Tumor-infiltrating lymphocytes; immunotherapy; nasopharyngeal carcinoma

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