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1.  Proline Metabolism Increases katG Expression and Oxidative Stress Resistance in Escherichia coli 
Journal of Bacteriology  2014;197(3):431-440.
The oxidation of l-proline to glutamate in Gram-negative bacteria is catalyzed by the proline utilization A (PutA) flavoenzyme, which contains proline dehydrogenase (PRODH) and Δ1-pyrroline-5-carboxylate (P5C) dehydrogenase domains in a single polypeptide. Previous studies have suggested that aside from providing energy, proline metabolism influences oxidative stress resistance in different organisms. To explore this potential role and the mechanism, we characterized the oxidative stress resistance of wild-type and putA mutant strains of Escherichia coli. Initial stress assays revealed that the putA mutant strain was significantly more sensitive to oxidative stress than the parental wild-type strain. Expression of PutA in the putA mutant strain restored oxidative stress resistance, confirming that depletion of PutA was responsible for the oxidative stress phenotype. Treatment of wild-type cells with proline significantly increased hydroperoxidase I (encoded by katG) expression and activity. Furthermore, the ΔkatG strain failed to respond to proline, indicating a critical role for hydroperoxidase I in the mechanism of proline protection. The global regulator OxyR activates the expression of katG along with several other genes involved in oxidative stress defense. In addition to katG, proline increased the expression of grxA (glutaredoxin 1) and trxC (thioredoxin 2) of the OxyR regulon, implicating OxyR in proline protection. Proline oxidative metabolism was shown to generate hydrogen peroxide, indicating that proline increases oxidative stress tolerance in E. coli via a preadaptive effect involving endogenous hydrogen peroxide production and enhanced catalase-peroxidase activity.
doi:10.1128/JB.02282-14
PMCID: PMC4285992  PMID: 25384482
2.  A Murine Myh6MerCreMer Knock-In Allele Specifically Mediates Temporal Genetic Deletion in Cardiomyocytes after Tamoxifen Induction 
PLoS ONE  2015;10(7):e0133472.
A mouse model that mediates temporal, specific, and efficient myocardial deletion with Cre-LoxP technology will be a valuable tool to determine the function of genes during heart formation. Mhy6 encodes a cardiac muscle specific protein: alpha-myosin heavy chain. Here, we generated a new Myh6-MerCreMer (Myh6MerCreMer/+) inducible Cre knock-in mouse by inserting a MerCreMer cassette into the Myh6 start codon. By crossing knock-in mice with Rosa26 reporter lines, we found the Myh6MerCreMer/+ mice mediate complete Cre-LoxP recombination in cardiomyocytes after tamoxifen induction. X-gal staining and immunohistochemistry analysis revealed that Myh6-driven Cre recombinase was specifically activated in cardiomyocytes at embryonic and adult stages. Furthermore, echocardiography showed that Myh6MerCreMer/+ mice maintained normal cardiac structure and function before and after tamoxifen administration. These results suggest that the new Myh6MerCreMer/+ mouse can serve as a robust tool to dissect the roles of genes in heart development and function. Additionally, myocardial progeny during heart development and after cardiac injury can be traced using this mouse line.
doi:10.1371/journal.pone.0133472
PMCID: PMC4512710  PMID: 26204265
3.  Structural Model of RNA Polymerase II Elongation Complex with Complete Transcription Bubble Reveals NTP Entry Routes 
PLoS Computational Biology  2015;11(7):e1004354.
The RNA polymerase II (Pol II) is a eukaryotic enzyme that catalyzes the synthesis of the messenger RNA using a DNA template. Despite numerous biochemical and biophysical studies, it remains elusive whether the “secondary channel” is the only route for NTP to reach the active site of the enzyme or if the “main channel” could be an alternative. On this regard, crystallographic structures of Pol II have been extremely useful to understand the structural basis of transcription, however, the conformation of the unpaired non-template DNA part of the full transcription bubble (TB) is still unknown. Since diffusion routes of the nucleoside triphosphate (NTP) substrate through the main channel might overlap with the TB region, gaining structural information of the full TB is critical for a complete understanding of Pol II transcription process. In this study, we have built a structural model of Pol II with a complete transcription bubble based on multiple sources of existing structural data and used Molecular Dynamics (MD) simulations together with structural analysis to shed light on NTP entry pathways. Interestingly, we found that although both channels have enough space to allow NTP loading, the percentage of MD conformations containing enough space for NTP loading through the secondary channel is twice higher than that of the main channel. Further energetic study based on MD simulations with NTP loaded in the channels has revealed that the diffusion of the NTP through the main channel is greatly disfavored by electrostatic repulsion between the NTP and the highly negatively charged backbones of nucleotides in the non-template DNA strand. Taken together, our results suggest that the secondary channel is the major route for NTP entry during Pol II transcription.
Author Summary
In eukaryotic cells, the RNA polymerase II (Pol II) is a central enzyme that reads the genetic information encoded in the DNA template to synthetize a messenger RNA. To perform its function, Pol II needs to have the substrate nucleoside triphosphate (NTP) diffuse into its deeply buried active site. Despite numerous efforts, the NTP entry routes remain elusive: NTP could diffuse only through the secondary channel, or also via the main channel. The structural information of the transcription bubble is essential to study this process, however, the unpaired non-template DNA of the transcription bubble is absent in the available X-ray crystal structures. In this regard, we have built a structural model of the Pol II elongation complex with reconstructed transcription bubble using existing experimental data. We then performed Molecular Dynamics (MD) simulations and applied structural analysis to study the routes of NTP diffusion. We found that sterically the probability of NTP loading through the secondary channel is more than twice that of the main channel. Further analysis of the non-bonded energetic contributions to NTP diffusion suggests that NTP diffusion through the main channel is greatly disfavored by the electrostatic repulsion between the substrate and negatively charged backbones of nucleotides in the non-template strand of the transcription bubble. Altogether, our findings suggest that the secondary channel is the more favorable NTP diffusion route for Pol II transcription elongation.
doi:10.1371/journal.pcbi.1004354
PMCID: PMC4489626  PMID: 26134169
4.  Curcumin Improves Amyloid β-Peptide (1-42) Induced Spatial Memory Deficits through BDNF-ERK Signaling Pathway 
PLoS ONE  2015;10(6):e0131525.
Curcumin, the most active component of turmeric, has various beneficial properties, such as antioxidant, anti-inflammatory, and antitumor effects. Previous studies have suggested that curcumin reduces the levels of amyloid and oxidized proteins and prevents memory deficits and thus is beneficial to patients with Alzheimer’s disease (AD). However, the molecular mechanisms underlying curcumin’s effect on cognitive functions are not well-understood. In the present study, we examined the working memory and spatial reference memory in rats that received a ventricular injection of amyloid-β1-42 (Aβ1-42), representing a rodent model of Alzheimer’s disease (AD). The rats treated with Aβ1-42 exhibited obvious cognitive deficits in behavioral tasks. Chronic (seven consecutive days, once per day) but not acute (once a day) curcumin treatments (50, 100, and 200 mg/kg) improved the cognitive functions in a dose-dependent manner. In addition, the beneficial effect of curcumin is accompanied by increased BDNF levels and elevated levels of phosphorylated ERK in the hippocampus. Furthermore, the cognition enhancement effect of curcumin could be mimicked by the overexpression of BDNF in the hippocampus and blocked by either bilateral hippocampal injections with lentiviruses that express BDNF shRNA or a microinjection of ERK inhibitor. These findings suggest that chronic curcumin ameliorates AD-related cognitive deficits and that upregulated BDNF-ERK signaling in the hippocampus may underlie the cognitive improvement produced by curcumin.
doi:10.1371/journal.pone.0131525
PMCID: PMC4482657  PMID: 26114940
5.  Incidence of and Risk Factors for Mastoiditis after Intensity Modulated Radiotherapy in Nasopharyngeal Carcinoma 
PLoS ONE  2015;10(6):e0131284.
Purpose
To report the incidence of and risk factors for mastoiditis after intensity-modulated radiotherapy (IMRT) in nasopharyngeal carcinoma (NPC).
Patients and Methods
Retrospective analysis of pretreatment and follow-up magnetic resonance imaging (MRI) data for 451 patients with NPC treated with IMRT at a single institution. The diagnosis of mastoiditis was based on MRI; otomastoid opacification was rated as Grade 0 (none), 1 (mild), 2 (moderate) or 3 (severe) by radiologists blinded to clinical outcome. This study mainly focused on severe mastoiditis; patients were divided into three groups: the G0M (Grade 0 mastoiditis before treatment) group, G1-2M (Grade 1 to 2 mastoiditis before treatment) group and G3M (Grade 3 mastoiditis before treatment) group. The software SAS9.3 program was used to analyze the data.
Results
For the entire cohort, the incidence of Grade 3 mastoiditis was 20% before treatment and 31%, 19% and 17% at 3, 12 and 24 months after radiotherapy, respectively. In the G0M group, the incidence of severe mastoiditis was 0% before treatment and 23%, 15% and 13% at 3, 12 and 24 months after radiotherapy, respectively. Multivariate analysis revealed T category (OR=0.68, 95% CI = 0.469 to 0.984), time (OR=0.668, 95% CI = 0.59 to 0.757) and chemotherapy (OR=0.598, 95% CI = 0.343 to 0.934) were independent factors associated with severe mastoiditis in the G0M group after treatment.
Conclusions
Mastoiditis, as diagnosed by MRI, occurs as a progressive process that regresses and resolves over time in patients with NPC treated using IMRT.
doi:10.1371/journal.pone.0131284
PMCID: PMC4483256  PMID: 26114761
6.  Microfluidic Synthesis of Rigid Nanovesicles for Hydrophilic Reagents Delivery** 
We present a hollow-structured rigid nanovesicle (RNV) fabricated by a multi-stage microfluidic chip in one step, to effectively entrap various hydrophilic reagents inside, without complicated synthesis, extensive use of emulsifiers and stabilizers, and laborious purification procedures. The RNV contains a hollow water core, a rigid poly (lactic-co-glycolic acid) (PLGA) shell, and an outermost lipid layer. The formation mechanism of the RNV is investigated by dissipative particle dynamics (DPD) simulations. The entrapment efficiency of hydrophilic reagents such as calcein, rhodamine B and siRNA inside the hollow water core of RNV is ≈90 %. In comparison with the combination of free Dox and siRNA, RNV that co-encapsulate siRNA and doxorubicin (Dox) reveals a significantly enhanced anti-tumor effect for a multi-drug resistant tumor model.
doi:10.1002/anie.201500096
PMCID: PMC4471572  PMID: 25704675
drug delivery; hydrophilic reagents; microfluidics; nanoparticles; vesicles
7.  Mesodermal Nkx2.5 is necessary and sufficient for early second heart field development 
Developmental biology  2014;390(1):68-79.
Summary
The vertebrate heart develops from mesoderm and requires inductive signals secreted from early endoderm. During embryogenesis, Nkx2.5 acts as a key transcription factor and plays essential roles for heart formation from Drosophila to human. In mice, Nkx2.5 is expressed in the early first heart field, second heart field pharyngeal mesoderm, as well as pharyngeal endodermal cells underlying the second heart field. Currently, the specific requirements for Nkx2.5 in the endoderm versus mesoderm with regard to early heart formation are incompletely understood. Here, we performed tissue-specific deletion in mice to dissect the roles of Nkx2.5 in the pharyngeal endoderm and mesoderm. We found that heart development appeared normal after endodermal deletion of Nkx2.5 whereas mesodermal deletion engendered cardiac defects almost identical to those observed on Nkx2.5 null embryos (Nkx2.5−/−). Furthermore, re-expression of Nkx2.5 in the mesoderm rescued Nkx2.5−/− heart defects. Our findings reveal that Nkx2.5 in the mesoderm is essential while endodermal expression is dispensable for early heart formation in mammals.
doi:10.1016/j.ydbio.2014.02.023
PMCID: PMC4461860  PMID: 24613616
Nkx2.5; pharyngeal endoderm; pharyngeal mesoderm; second heart field; heart development
8.  Polymorphisms in the Perilipin Gene May Affect Carcass Traits of Chinese Meat-type Chickens 
Improved meat quality and greater muscle yield are highly sought after in high-quality chicken breeding programs. Past studies indicated that polymorphisms of the Perilipin gene (PLIN1) are highly associated with adiposity in mammals and are potential molecular markers for improving meat quality and carcass traits in chickens. In the present study, we screened single nucleotide polymorphisms (SNPs) in all exons of the PLIN1 gene with a direct sequencing method in six populations with different genetic backgrounds (total 240 individuals). We evaluated the association between the polymorphisms and carcass and meat quality traits. We identified three SNPs, located on the 5′ flanking region and exon 1 of PLIN1 on chromosome 10 (rs315831750, rs313726543, and rs80724063, respectively). Eight main haplotypes were constructed based on these SNPs. We calculated the allelic and genotypic frequencies, and genetic diversity parameters of the three SNPs. The polymorphism information content (PIC) ranged from 0.2768 to 0.3750, which reflected an intermediate genetic diversity for all chickens. The CC, CT, and TT genotypes influenced the percentage of breast muscle (PBM), percentage of leg muscle (PLM) and percentage of abdominal fat at rs315831750 (p<0.05). Diplotypes (haplotype pairs) affected the percentage of eviscerated weight (PEW) and PBM (p<0.05). Compared with chickens carrying other diplotypes, H3H7 had the greatest PEW and H2H2 had the greatest PBM, and those with diplotype H7H7 had the smallest PEW and PBM. We conclude that PLIN1 gene polymorphisms may affect broiler carcass and breast muscle yields, and diplotypes H3H7 and H2H2 could be positive molecular markers to enhance PEW and PBM in chickens.
doi:10.5713/ajas.14.0554
PMCID: PMC4412972  PMID: 25925053
Chickens; Perilipin Gene; Polymorphism; Carcass Traits; Association Analysis
9.  Synergistic anti-tumor effects of combined gemcitabine and cisplatin nanoparticles in a stroma-rich bladder carcinoma model 
Tumors grown in a stroma-rich mouse model resembling clinically advanced bladder carcinoma with UMUC3 and NIH 3T3 cells have high levels of fibroblasts and an accelerated tumor growth rate. We used this model to investigate the synergistic effect of combined gemcitabine monophosphate (GMP) nanoparticles and Cisplatin nanoparticles (Combo NP) on tumor-associated fibroblasts (TAFs). A single injection of Combo NP had synergistic anti-tumor effects while the same molar ratio of combined GMP and Cisplatin delivered as free drug (Combo Free) fell outside of the synergistic range. Combo NP nearly halted tumor growth with little evidence of general toxicity while Combo Free had only a modest inhibitory effect at 16 mg/kg GMP and 1.6 mg/kg Cisplatin. Combo NP increased levels of apoptosis within the tumor by approximately 1.3 fold (TUNEL analysis) and decreased α-SMA-positive fibroblast recruitment by more than 87% (immunofluorescence) after multiple injections compared with Combo Free, GMP NP or Cisplatin NP alone. The TAF-targeting capability of Combo NP was evaluated by double staining for TUNEL and α-SMA at various time points after a single injection. On day one after injection, 57% of the TUNEL-positive cells were identified as α-SMA-positive fibroblasts. By day four, tumor stroma was 85% depleted and 87% of the remaining TAFs were TUNEL-positive. Combo NP-treated tumors became 2.75 fold more permeable than those treated with Combo Free as measured by Evans Blue. We conclude that the antineoplastic effect of Combo NP works by first targeting TAFs and is more effective as an anti-tumor therapy than Combo Free, GMP NP or Cisplatin NP alone.
doi:10.1016/j.jconrel.2014.03.016
PMCID: PMC4009696  PMID: 24637468
bladder cancer; stroma; gemcitabine; Cisplatin; tumor-associated fibroblasts
10.  A Novel and Simple Method for Rapid Generation of Recombinant Porcine Adenoviral Vectors for Transgene Expression 
PLoS ONE  2015;10(5):e0127958.
Many human (different serotypes) and nonhuman adenovirus vectors are being used for gene delivery. However, the current system for isolating recombinant adenoviral vectors is either time-consuming or expensive, especially for the generation of recombinant non-human adenoviral vectors. We herein report a new and simple cloning approach for the rapid generation of a porcine adenovirus (PAdV-3) vector which shows promise for gene transfer to human cells and evasion of human adenovirus type 5 (HAdV-5) immunity. Based on the final cloning plasmid, pFPAV3-CcdB-Cm, and our modified SLiCE strategy (SLiCE cloning and lethal CcdB screening), the process for generating recombinant PAdV-3 plasmids required only one step in 3 days, with a cloning efficiency as high as 620±49.56 clones/ng and zero background (100% accuracy). The recombinant PAdV-3 plasmids could be successfully rescued in porcine retinal pigment epithelium cells (VR1BL), which constitutively express the HAdV-5 E1 and PAdV-3 E1B 55k genes, and the foreign genes were highly expressed at 24 h after transduction into swine testicle (ST) cells. In conclusion, this strategy for generating recombinant PAdV-3 vectors based on our modified SLiCE cloning system was rapid and cost-efficient, which could be used as universal cloning method for modification the other regions of PAdV-3 genome as well as other adenoviral genomes.
doi:10.1371/journal.pone.0127958
PMCID: PMC4444375  PMID: 26011074
11.  Umbilical Cord-Derived Mesenchymal Stem Cells Inhibit Cadherin-11 Expression by Fibroblast-Like Synoviocytes in Rheumatoid Arthritis 
Journal of Immunology Research  2015;2015:137695.
This study aimed to determine whether umbilical cord-derived mesenchymal stem cells (UCMSC) regulate Cadherin-11 (CDH11) expression by fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA). FLS were isolated from the synovium of RA and osteoarthritis (OA) patients. FLS from RA patients were cocultured with UCMSC in a transwell system. CDH11 mRNA levels in FLS were tested, and levels of soluble factors expressed by UCMSC, such as indoleamine 2,3-dioxygenase (IDO), hepatocyte growth factor (HGF), and interleukin- (IL-) 10, were determined. IDO, HGF, and IL-10 were upregulated in cocultures, so that appropriate inhibitors were added before determination of CDH11 expression. The effects of UCMSC on arthritis were investigated in the collagen-induced arthritis (CIA) model in Wistar rats. FLS from RA patients expressed higher CDH11 levels than those from OA patients, and this effect was suppressed by UCMSC. The inhibitory effect of UCMSC on CDH11 expression by FLS was abolished by suppression of IL-10 activity. CDH11 expression in synovial tissues was higher in the context of CIA than under basal conditions, and this effect was prevented by UCMSC administration. IL-10 mediates the inhibitory effect of UCMSC on CDH11 expression by FLS, and this mechanism might be targeted to ameliorate arthritis.
doi:10.1155/2015/137695
PMCID: PMC4451296  PMID: 26090476
12.  The effect of PDIA3 gene knockout on the mucosal immune function in IBS rats 
Objective: To observe the changes of intestinal inflammation on PDIA3 gene knockout IBS rats and its effect on immune function. Methods: 36 SD rats were randomly divided into four groups: the control group (n = 8); IBS- empty virus group (IBS-GFP, which); IBS-PDIA3 knockout group (n = 12); IBS- the control group (n = 12). After modeling, colon and ileocecal tissue pathology in each group were observed separately. Changes of immune and inflammatory markers were measured. At the same time, ultrastructural changes in each group were observed by electron microscopy. Results: Compared with the IBS control group, inflammation was reduced significantly in IBS-PDIA3 knockout group. IgE, IL-4 and IL-9 and the level of intestinal trypsin type were decreased significantly. Furthermore, mast cell degranulation and PAR 2 receptor reduced significantly. Conclusion: PDIA3 may play an important role in the development of IBS by mediating through immune responses of mucosal abnormalities. However, the mechanism needs to be confirmed in further study.
PMCID: PMC4509169  PMID: 26221224
PDIA3; knockout; irritable bowel syndrome; immune response; colon
13.  Construction of interference vector targeting Ep-CAM gene and its effects on colorectal cancer cell proliferation 
Background
Prior study indicates that abnormal protein expression and functional changes in the development and progression of colorectal cancer is related to gene expression. The aim of this study was to construct an interference plasmid targeting the Ep-CAM gene and to investigate its effects on the proliferation of colorectal cancer cells.
Methods
In this study, HT-29 and HCT-116 colorectal cancer cell lines were selected as cell models. The double-stranded micro (mi)RNA oligo was inserted into the pcDNATM6.2-GW/EmGFPmiR vector, which is an expression of miRNA. Lipofectamine™ 2000 was used to transfer plasmid into the empty plasmid group (transfected pcDNATM6.2-GW/EmGFPmiR-neg) and the interference group (transfected pcDNATM6.2-GW/EmGFPmiR-Ep-CAM-1), respectively. Meanwhile, the nontransferred HT-29 and HCT-116 acts as the blank control group. Reverse transcription polymerase chain reaction (RT-PCR) was used to detect the transfection efficiency. Western blot was used to detect Ep-CAM protein expression. The cell proliferation in each group was detected by using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay.
Results
The results indicated that the Ep-CAM messenger (m)RNA expression in the interference group was lower significantly compared with that of the empty plasmid group and control group (P<0.01). Western blot analysis results showed that Ep-CAM protein expression was significantly lower in interference group compared with that of the empty plasmid group and the control group (P<0.01). MTT assay results demonstrated that the proliferation ability of cells in the interference group was significantly inhibited compared with the two other groups (P<0.05).
Conclusion
Silencing of Ep-CAM can significantly inhibit the proliferation of colorectal cancer cells.
doi:10.2147/DDDT.S82917
PMCID: PMC4440878  PMID: 26028961
epidermal growth factor; Ep-CAM; colorectal cancer; vector construction
14.  HaploShare: identification of extended haplotypes shared by cases and evaluation against controls 
Genome Biology  2015;16(1):92.
Recent founder mutations may play important roles in complex diseases and Mendelian disorders. Detecting shared haplotypes that are identical by descent (IBD) could facilitate discovery of these mutations. Several programs address this, but are usually limited to detecting pair-wise shared haplotypes and not providing a comparison of cases and controls. We present a novel algorithm and software package, HaploShare, which detects extended haplotypes that are shared by multiple individuals, and allows comparisons between cases and controls. Testing on simulated and real cases demonstrated significant improvements in detection power and reduction of false positive rate by HaploShare relative to other programs.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-015-0662-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s13059-015-0662-9
PMCID: PMC4432975  PMID: 25956955
15.  The prevalence, incidence, management and risks of atrial fibrillation in an elderly Chinese population: a prospective study 
Background
There is limited information on prevalent and incident atrial fibrillation in Chinese. We aimed to investigate the prevalence, incidence, management and risks of atrial fibrillation in an elderly Chinese population.
Methods
In a population—based prospective study in elderly (≥60 years) Chinese, we performed cardiovascular health examinations including a 12-lead electrocardiogram at baseline in 3,922 participants and biennially during follow-up in 2,017 participants. We collected information on vital status during the whole follow-up period.
Results
The baseline prevalence of atrial fibrillation was 2.0 % (n = 34) in 1718 men and 1.6 % (n = 36) in 2204 women. During a median 3.8 years of follow-up, the incidence rate of atrial fibrillation (n = 34) was 4.9 per 1000 person-years (95 % confidence interval [CI], 3.4–6.9). In univariate analysis, both the prevalence and incidence of atrial fibrillation were higher with age advancing (P < 0.0001) and in the presence of coronary heart disease (P ≤ 0.02). Of the 104 prevalent and incident cases of atrial fibrillation, only 1 (1.0 %) received anticoagulant therapy (warfarin). These patients with atrial fibrillation, compared with those with sinus rhythm, had significantly higher risks of all-cause (n = 261, hazard ratio [HR] 1.87, 95 % CI, 1.09–3.20, P = 0.02), cardiovascular (n = 136, HR 3.78, 95 % CI 2.17–6.58, P < 0.0001) and stroke mortality (n = 44, HR 6.31, 95 % CI 2.81–14.19, P = 0.0003).
Conclusions
Atrial fibrillation was relatively frequent in elderly Chinese, poorly managed and associated with higher risks of mortality.
doi:10.1186/s12872-015-0023-3
PMCID: PMC4427946  PMID: 25953603
Atrial fibrillation; Epidemiology; Elderly Chinese; Mortality
16.  Optimal designs of an HA-based DNA vaccine against H7 subtype influenza viruses 
Human Vaccines & Immunotherapeutics  2014;10(7):1949-1958.
The outbreak of a novel H7N9 influenza virus in 2013 has raised serious concerns for the potential of another avian-source pandemic influenza. Effective vaccines against H7N9 virus are important in the prevention and control of any major outbreak. Novel vaccination technologies are useful additions to existing approaches. In the current report, DNA vaccine studies were conducted to identify the optimal design of an H7 HA antigen using the HA gene from a previously reported H7N7 virus that is lethal in humans as the model antigen. New Zealand White rabbits were immunized with DNA vaccines expressing 1 of 3 forms of H7 HA antigen inserts encoding the HA gene from the same H7N7 virus. High-level H7 HA-specific IgG was detected by ELISA, and functional antibodies were confirmed by hemagglutination inhibition assay and pseudotyped virus-based neutralization assay against viruses expressing HA antigens from either the previous H7N7 virus or the novel H7N9 virus. HA antigen design under the tissue plasminogen activator leader (tPA) was the most immunogenic. The data presented in the current report confirm the immunogenicity of the H7 HA antigen and provide useful guidance to prepare for an optimized H7 HA DNA vaccine to help to control the emerging H7N9 virus if and when it is needed.
doi:10.4161/hv.28795
PMCID: PMC4186056  PMID: 25424804
influenza infection; H7N7; H7N9; antibody; neutralizing antibody; cross protection; vaccine
17.  Locational Determinants of Emissions from Pollution-Intensive Firms in Urban Areas 
PLoS ONE  2015;10(4):e0125348.
Industrial pollution has remained as one of the most daunting challenges for many regions around the world. Characterizing the determinants of industrial pollution should provide important management implications. Unfortunately, due to the absence of high-quality data, rather few studies have systematically examined the locational determinants using a geographical approach. This paper aimed to fill the gap by accessing the pollution source census dataset, which recorded the quantity of discharged wastes (waste water and solid waste) from 717 pollution-intensive firms within Huzhou City, China. Spatial exploratory analysis was applied to analyze the spatial dependency and local clusters of waste emissions. Results demonstrated that waste emissions presented significantly positive autocorrelation in space. The high-high hotspots generally concentrated towards the city boundary, while the low-low clusters approached the Taihu Lake. Their locational determinants were identified by spatial regression. In particular, firms near the city boundary and county road were prone to discharge more wastes. Lower waste emissions were more likely to be observed from firms with high proximity to freight transfer stations or the Taihu Lake. Dense populous districts saw more likelihood of solid waste emissions. Firms in the neighborhood of rivers exhibited higher waste water emissions. Besides, the control variables (firm size, ownership, operation time and industrial type) also exerted significant influence. The present methodology can be applicable to other areas, and further inform the industrial pollution control practices. Our study advanced the knowledge of determinants of emissions from pollution-intensive firms in urban areas.
doi:10.1371/journal.pone.0125348
PMCID: PMC4416044  PMID: 25927438
18.  Influences of Different Land Use Spatial Control Schemes on Farmland Conversion and Urban Development 
PLoS ONE  2015;10(4):e0125008.
Land use planning is always officially implemented as an effective tool to control urban development and protect farmland. However, its impact on land use change remains untested in China. Using a case study of Hang-Jia-Hu region, the main objective of this paper was to investigate the influence of different land use spatial control schemes on farmland conversion and urban development. Comparisons of farmland conversion and urban development patterns between the urban planning area and the non-urban planning area were characterized by using remote sensing, geographical information systems, and landscape metrics. Results indicated that farmland conversion in the non-urban planning area was more intensive than that in the urban planning area, and that farmland patterns was more fragmented in the non-urban planning area. Built-up land patterns in the non-urban planning area showed a trend of aggregation, while those in the urban planning area had a dual trend of fragmentation and aggregation. Existing built-up areas had less influence on built-up land sprawl in the non-urban planning area than that in the urban planning area. Built-up land sprawl in the form of continuous development in the urban planning area led to farmland conversion; and in the non-urban planning area, built-up land sprawl in the form of leapfrogging development resulted in farmland areal declines and fragmentation. We argued that it is a basic requirement to integrate land use plans in urban and non-urban planning areas for land use planning and management.
doi:10.1371/journal.pone.0125008
PMCID: PMC4411046  PMID: 25915897
19.  Sphenopalatine ganglion stimulation with one acupuncture needle for moderate-severe persistent allergic rhinitis: study protocol for a multicenter randomized controlled trial 
Trials  2015;16:183.
Background
Allergic rhinitis is a symptomatic allergic disease of the nose that affects 10 to 20% of the global population. Chinese otolaryngologists use one acupuncture needle to stimulate the sphenopalatine ganglion because of its potential advantages for treating moderate-severe persistent allergic rhinitis compared with traditional Chinese acupuncture (verum acupuncture); however, little evidence is available to support the wide clinical use thus far. Therefore, we propose a protocol for a parallel, multicenter, assessor-blinded, randomized controlled trial to evaluate sphenopalatine ganglion stimulation with one acupuncture needle compared to verum acupuncture for treatment of moderate-severe persistent allergic rhinitis.
Methods
In the trial, 96 patients previously diagnosed with moderate-severe persistent allergic rhinitis and meeting all inclusion criteria will be allocated to one of two equal therapeutic groups by using a computer-generated randomization list. The interventional group will receive sphenopalatine ganglion stimulation with one acupuncture needle for 4 weeks (once or twice weekly, total four to eight sessions); attending physicians will decide whether the second session is required in a week by examining signs and symptoms. The control group will receive individualized verum acupuncture for 4 weeks (twice weekly, total eight sessions). Follow-up evaluations will be performed 1 month later. The primary outcome measure is the change in the total nasal symptom score from the baseline to week 4. The secondary outcome measures include onset time and duration of effectiveness in every session, change in number of days with moderate-severe persistent allergic rhinitis from the baseline to week 8, change in total immunoglobulin E level and eosinophil count in venous blood from the baseline to week 4, change in Rhinoconjunctivitis Quality of Life Questionnaire score from the baseline to week 4, and clinical waiting time.
Discussion
The trial should provide evidence for the benefits of sphenopalatine ganglion stimulation with one acupuncture needle for treating moderate-severe persistent allergic rhinitis, including better change in total nasal symptom score, faster onset time, longer duration of effectiveness, and shorter treatment time.
Trial registration
Current Controlled Trials: ISRCTN21980724 (registered on 27 March 2014).
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-015-0707-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s13063-015-0707-0
PMCID: PMC4426638  PMID: 25899566
Study protocol; Randomized controlled trial; Sphenopalatine ganglion; Persistent allergic rhinitis; Acupuncture; Traditional Chinese medicine
20.  Single photon detector with high polarization sensitivity 
Scientific Reports  2015;5:9616.
Polarization is one of the key parameters of light. Most optical detectors are intensity detectors that are insensitive to the polarization of light. A superconducting nanowire single photon detector (SNSPD) is naturally sensitive to polarization due to its nanowire structure. Previous studies focused on producing a polarization-insensitive SNSPD. In this study, by adjusting the width and pitch of the nanowire, we systematically investigate the preparation of an SNSPD with high polarization sensitivity. Subsequently, an SNSPD with a system detection efficiency of 12% and a polarization extinction ratio of 22 was successfully prepared.
doi:10.1038/srep09616
PMCID: PMC4397915  PMID: 25875225
21.  Elevated High-Sensitivity C-Reactive Protein Levels Predict Decreased Survival for Nasopharyngeal Carcinoma Patients in the Intensity-Modulated Radiotherapy Era 
PLoS ONE  2015;10(4):e0122965.
Purpose
This study aimed to clarify the prognostic utility of high-sensitivity C-reactive protein (hs-CRP) in nasopharyngeal carcinoma (NPC) patients in the Intensity-Modulated Radiotherapy (IMRT) era.
Patients and Methods
In this observational study, 1,589 non-metastatic NPC patients treated with IMRT were recruited. Blood samples were collected before treatment for examination of hs-CRP levels. We evaluated the association of pretreatment hs-CRP levels with overall survival rate (OS), progression free survival rate (PFS), locoregional relapse free survival rate (LRFS) and distant metastasis free survival rate (DMFS).
Results
Baseline hs-CRP levels were correlated with sex, clinical stage, body mass index, smoking status, and EBV DNA level. Multivariate analysis showed that hs-CRP had significant association with OS (HR:1.723; 95%CI:1.238–2.398; p = 0.001), PFS (HR:1.621; 95%CI:1.273–2.064; p<0.001) and DMFS (HR:1.879; 95%CI:1.394–2.531; p<0.001). In subgroups such as advanced-stage group, low EBV DNA group and high EBV DNA group, elevated hs-CRP levels still predicted poor clinical outcomes. Furthermore, in patients with chronic HBV infection, decreased 4-year survival was observed in the cohort of high hs-CRP levels, with 87.4% vs. 94.9% (p = 0.023) for OS, 65.2% vs. 90.8% (p<0.001) for PFS, and 67.6% vs. 95.0% (p<0.001) for DMFS. A similar finding was observed for patients with cardiovascular disease, with 79.1% vs. 90.2% (p = 0.020) for PFS, and 71.4% vs. 97.6% (p = 0.002) for DMFS.
Conclusion
Elevated serum hs-CRP levels were correlated with poor survival for NPC patients in the IMRT era, playing a complementary role to TNM stage and EBV DNA. In addition, elevated hs-CRP level was still an effective indicator for patients with chronic HBV infection and cardiovascular disease.
doi:10.1371/journal.pone.0122965
PMCID: PMC4395211  PMID: 25874450
22.  Brain-Derived Neurotrophic Factor Ameliorates Learning Deficits in a Rat Model of Alzheimer's Disease Induced by Aβ1-42 
PLoS ONE  2015;10(4):e0122415.
An emerging body of data suggests that the early onset of Alzheimer’s disease (AD) is associated with decreased brain-derived neurotrophic factor (BDNF). Because BDNF plays a critical role in the regulation of high-frequency synaptic transmission and long-term potentiation in the hippocampus, the up-regulation of BDNF may rescue cognitive impairments and learning deficits in AD. In the present study, we investigated the effects of hippocampal BDNF in a rat model of AD produced by a ventricle injection of amyloid-β1-42 (Aβ1-42). We found that a ventricle injection of Aβ1-42 caused learning deficits in rats subjected to the Morris water maze and decreased BDNF expression in the hippocampus. Chronic intra-hippocampal BDNF administration rescued learning deficits in the water maze, whereas infusions of NGF and NT-3 did not influence the behavioral performance of rats injected with Aβ1-42. Furthermore, the BDNF-related improvement in learning was ERK-dependent because the inhibition of ERK, but not JNK or p38, blocked the effects of BDNF on cognitive improvement in rats injected with Aβ1-42. Together, our data suggest that the up-regulation of BDNF in the hippocampus via activation of the ERK signaling pathway can ameliorate Aβ1-42-induced learning deficits, thus identifying a novel pathway through which BDNF protects against AD-related cognitive impairments. The results of this research may shed light on a feasible therapeutic approach to control the progression of AD.
doi:10.1371/journal.pone.0122415
PMCID: PMC4388634  PMID: 25849905
23.  Signs Analysis and Clinical Assessment: Phase-Contrast Computed Tomography of Human Breast Tumours 
PLoS ONE  2015;10(4):e0124143.
Purpose
To analyse the diagnostic signs present in slices of human breast tumour specimens using synchrotron radiation phase-contrast imaging computed tomography (PCI-CT) for the first time and assess the feasibility of this technique for clinical applications.
Materials and Methods
The ethics committee of our university and relevant clinical hospital approved this prospective study, and written informed consent was obtained from all patients. PCI-CT of human breast tumour specimens with synchrotron radiation was performed at the Shanghai Synchrotron Radiation Facility (SSRF). A total of 14 specimens of early-stage carcinomas and 8 specimens of adenomas were enrolled. Based on raw data reconstruction, the diagnostic signs present in the slices were analysed and correlated with histopathology. We proposed a criterion for clinical diagnosis according to the evaluated signs and the Breast Imaging Reporting and Data System (BI-RADS) for reference. The criterion was then assessed by clinicians in a double-blind method. Finally, descriptive statistics were evaluated, depending on the assessment results.
Results
The 14 carcinoma specimens and 8 adenoma specimens were diagnosed as malignant and benign tumours, respectively. The total coincidence rate was 100%.
Conclusion
Our study results demonstrate that the X-ray diagnostic signs observed in the specimen slices and the criterion used for clinical diagnosis were accurate and reliable. The criterion based on signs analysis can be used to differentiate early-stage benign or malignant tumours. As a promising imaging method, PCI-CT can serve as a possible and feasible supplement to BI-RADS in the future.
doi:10.1371/journal.pone.0124143
PMCID: PMC4386813  PMID: 25844722
24.  Induction of autophagy-dependent cell death by the survivin suppressant YM155 in salivary adenoid cystic carcinoma 
Adenoid cystic carcinoma (ACC) is one of the most common malignancies of the major and minor salivary glands. However, the molecular mechanism underlying the aggressive growth of human salivary ACC remains unclear. In the present study, we showed that survivin, which belongs to the family of inhibitors of apoptosis, is closely related to the high expression of CDK4 and cyclin D1 in human ACC specimens. By employing the smallmolecule drug YM155, we found that the inhibition of survivin in ACC cells caused significant cell death and induced autophagy. Chloroquine, an autophagy inhibitor, prevented cell death induced by YM155, suggesting YM155-induced autophagy contributed to the cell death effects in ACC cells. More importantly, evidence obtained from a xenograft model using ACC-2 cells proved the occurrence of YM155-induced autophagy and cell death in vivo was correlated with the suppression of Erk1/2 and S6 activation as well as increased TFEB nuclear translocation. Taken together, our results indicate YM155 is a novel inducer of autophagy-dependent cell death and possesses therapeutic potential in ACC.
doi:10.1007/s10495-013-0960-1
PMCID: PMC4211076  PMID: 24370995
Survivin; Adenoid cystic carcinoma; YM155; Apoptosis; Autophagy
25.  Consumption and Sources of Dietary Salt in Family Members in Beijing 
Nutrients  2015;7(4):2719-2730.
In China, few people are aware of the amount and source of their salt intake. We conducted a survey to investigate the consumption and sources of dietary salt using the “one-week salt estimation method” by weighing cooking salt and major salt-containing food, and estimating salt intake during dining out based on established evidence. Nine hundred and three families (1981 adults and 971 children) with students in eight primary or junior high schools in urban and suburban Beijing were recruited. On average, the daily dietary salt intake of family members in Beijing was 11.0 (standard deviation: 6.2) g for children and adolescents (under 18 years old), 15.2 (9.1) g for adults (18 to 59 years old), and 10.2 (4.8) g for senior citizens (60 years old and over), respectively. Overall, 60.5% of dietary salt was consumed at home, and 39.5% consumed outside the home. Approximately 90% of the salt intake came from cooking (household cooking and cafeteria or restaurant cooking), while less than 10% came from processed food. In conclusion, the dietary salt intake in Beijing families far surpassed the recommended amounts by World Health Organization, with both household cooking and dining-out as main sources of salt consumption. More targeted interventions, especially education about major sources of salt and corresponding methods for salt reduction should be taken to reduce the risks associated with a high salt diet.
doi:10.3390/nu7042719
PMCID: PMC4425169  PMID: 25867952
salt intake; salt sources

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