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1.  Expression of semaphorin 3A and neuropilin 1 with clinicopathological features and survival in human tongue cancer 
Objective: To investigate the association between semaphorin 3A (SEMA 3A) and its receptor neuropilin 1 (NRP1) and the clinicopathologic characteristics of patients with tongue cancer. Study Design: Forty-three tongue squamous cell carcinoma specimens were included. Immunohistochemical staining of SEMA3A and NRP1 was performed on 15 normal tongue epithelium specimens and the 43 tumour specimens. Immunoreactivity was evaluated based on the staining intensity and distribution score. Statistical analyses were performed using Chi-squared and Spearman tests and Kaplan-Meier analysis. Results: SEMA3A was significantly down-regulated in tongue cancer compared with normal tongue (P=0.025), while NRP1 was over-expressed in tumours (P<0.001). SEMA3A expression inversely correlated with nodal metastasis (P=0.017). NRP1 expression did not correlate with any clinicopathological characteristics. Higher SEMA3A expression strongly predicted longer survival (P=0.005). Scores for the NRP1/SEMA3A ratio of ≥1 predicted shorter survival (P=0.045). Conclusions: Aberrant expression of SEMA3A and its receptor NRP1 might be involved in the development of tongue cancer and might be useful prognostic markers in this tumour type.
Key words:Semaphorin 3A, neuropilin 1, tongue, squamous cell carcinoma.
doi:10.4317/medoral.18168
PMCID: PMC3505717  PMID: 22926477
2.  Expected estimating equations via EM for proportional hazards regression with covariate misclassification 
Biostatistics (Oxford, England)  2012;14(2):351-365.
In epidemiological and medical studies, covariate misclassification may occur when the observed categorical variables are not perfect measurements for an unobserved categorical latent predictor. It is well known that covariate measurement error in Cox regression may lead to biased estimation. Misclassification in covariates will cause bias, and adjustment for misclassification will be challenging when the gold standard variables are not available. In general, statistical modeling for misclassification is very different from that of the measurement error. In this paper, we investigate an approximate induced hazard estimator and propose an expected estimating equation estimator via an expectation–maximization algorithm to accommodate covariate misclassification when multiple surrogate variables are available. Finite sample performance is examined via simulation studies. The proposed method and other methods are applied to a human immunodeficiency virus clinical trial in which a few behavior variables from questionnaires are used as surrogates for a latent behavior variable.
doi:10.1093/biostatistics/kxs046
PMCID: PMC3590925  PMID: 23178735
EM algorithm; Estimating equation; Measurement error; Misclassification; Surrogate covariate
3.  Postweaning Exposure to Dietary Zearalenone, a Mycotoxin, Promotes Premature Onset of Puberty and Disrupts Early Pregnancy Events in Female Mice 
Toxicological Sciences  2013;132(2):431-442.
Zearalenone (ZEA) is a mycotoxin commonly found in contaminated livestock feed and human food with levels in the range of ppb and low ppm. It was hypothesized that ZEA, an endocrine disruptor, could affect puberty and early pregnancy. To test this hypothesis, newly weaned (3 weeks old) C57BL/6J female mice were exposed to 0, 0.002, 4, 10, and 40 ppm ZEA and 0.05 ppm diethylstilbestrol (positive control) in phytoestrogen-free AIN-93G diet. Females exposed to 10 and 40 ppm ZEA diets showed earlier onset of vaginal opening. Those treated with 40 ppm ZEA diet also had earlier first copulation plug and irregular estrous cyclicity. At 8 weeks old, all females were mated with untreated stud males on AIN-93G diet during mating. Treatment resumed upon identification of a vaginal plug on gestation day 0.5 (D0.5). Embryo implantation was assessed on D4.5. Exposure to 40 ppm ZEA diet resulted in reduced percentage of plugged mice with implantation sites, distended uterine appearance, and retained expression of progesterone receptor in D4.5 uterine epithelium. To determine the exposure timing and mechanisms of disrupted embryo implantation, four groups of females were fed with 0 or 40 ppm ZEA diets during premating (weaning to mating) and postmating (D0.5–D4.5), respectively. Premating exposure to 40 ppm ZEA diet reduced fertilization rate, whereas postmating exposure to 40 ppm ZEA diet delayed embryo transport and preimplantation embryo development, which subsequently affected embryo implantation. These data demonstrate that postweaning exposure to dietary ZEA can promote premature onset of puberty and disrupt early pregnancy events.
doi:10.1093/toxsci/kfs343
PMCID: PMC3595522  PMID: 23291560
zearalenone; vaginal opening; fertilization; embryo transport; embryo development; embryo implantation.
4.  Comparative Genomics Provide Insights into Evolution of Trichoderma Nutrition Style 
Genome Biology and Evolution  2014;6(2):379-390.
Saprotrophy on plant biomass is a recently developed nutrition strategy for Trichoderma. However, the physiology and evolution of this new nutrition strategy is still elusive. We report the deep sequencing and analysis of the genome of Trichoderma longibrachiatum, an efficient cellulase producer. The 31.7-Mb genome, smallest among the sequenced Trichoderma species, encodes fewer nutrition-related genes than saprotrophic T. reesei (Tr), including glycoside hydrolases and nonribosomal peptide synthetase–polyketide synthase. Homology and phylogenetic analyses suggest that a large number of nutrition-related genes, including GH18 chitinases, β-1,3/1,6-glucanases, cellulolytic enzymes, and hemicellulolytic enzymes, were lost in the common ancestor of T. longibrachiatum (Tl) and Tr. dN/dS (ω) calculation indicates that all the nutrition-related genes analyzed are under purifying selection. Cellulolytic enzymes, the key enzymes for saprotrophy on plant biomass, are under stronger purifying selection pressure in Tl and Tr than in mycoparasitic species, suggesting that development of the nutrition strategy of saprotrophy on plant biomass has increased the selection pressure. In addition, aspartic proteases, serine proteases, and metalloproteases are subject to stronger purifying selection pressure in Tl and Tr, suggesting that these enzymes may also play important roles in the nutrition. This study provides insights into the physiology and evolution of the nutrition strategy of Trichoderma.
doi:10.1093/gbe/evu018
PMCID: PMC3942035  PMID: 24482532
Trichoderma longibrachiatum; cellulolytic enzymes; carbohydrate-active enzymes; proteases; purifying selection; dN/dS
5.  Assessment of the AquaCrop Model for Use in Simulation of Irrigated Winter Wheat Canopy Cover, Biomass, and Grain Yield in the North China Plain 
PLoS ONE  2014;9(1):e86938.
Improving winter wheat water use efficiency in the North China Plain (NCP), China is essential in light of current irrigation water shortages. In this study, the AquaCrop model was used to calibrate, and validate winter wheat crop performance under various planting dates and irrigation application rates. All experiments were conducted at the Xiaotangshan experimental site in Beijing, China, during seasons of 2008/2009, 2009/2010, 2010/2011 and 2011/2012. This model was first calibrated using data from 2008/2009 and 2009/2010, and subsequently validated using data from 2010/2011 and 2011/2012. The results showed that the simulated canopy cover (CC), biomass yield (BY) and grain yield (GY) were consistent with the measured CC, BY and GY, with corresponding coefficients of determination (R2) of 0.93, 0.91 and 0.93, respectively. In addition, relationships between BY, GY and transpiration (T), (R2 = 0.57 and 0.71, respectively) was observed. These results suggest that frequent irrigation with a small amount of water significantly improved BY and GY. Collectively, these results indicate that the AquaCrop model can be used in the evaluation of various winter wheat irrigation strategies. The AquaCrop model predicted winter wheat CC, BY and GY with acceptable accuracy. Therefore, we concluded that AquaCrop is a useful decision-making tool for use in efforts to optimize wheat winter planting dates, and irrigation strategies.
doi:10.1371/journal.pone.0086938
PMCID: PMC3904961  PMID: 24489808
6.  Development of a genetic system for the deep-sea psychrophilic bacterium Pseudoalteromonas sp. SM9913 
Background
Pseudoalteromonas species are a group of marine gammaproteobacteria frequently found in deep-sea sediments, which may play important roles in deep-sea sediment ecosystem. Although genome sequence analysis of Pseudoalteromonas has revealed some specific features associated with adaptation to the extreme deep-sea environment, it is still difficult to study how Pseudoalteromonas adapt to the deep-sea environment due to the lack of a genetic manipulation system. The aim of this study is to develop a genetic system in the deep-sea sedimentary bacterium Pseudoalteromonas sp. SM9913, making it possible to perform gene mutation by homologous recombination.
Results
The sensitivity of Pseudoalteromonas sp. SM9913 to antibiotic was investigated and the erythromycin resistance gene was chosen as the selective marker. A shuttle vector pOriT-4Em was constructed and transferred into Pseudoalteromonas sp. SM9913 through intergeneric conjugation with an efficiency of 1.8 × 10-3, which is high enough to perform the gene knockout assay. A suicide vector pMT was constructed using pOriT-4Em as the bone vector and sacB gene as the counterselective marker. The epsT gene encoding the UDP-glucose lipid carrier transferase was selected as the target gene for inactivation by in-frame deletion. The epsT was in-frame deleted using a two-step integration–segregation strategy after transferring the suicide vector pMT into Pseudoalteromonas sp. SM9913. The ΔepsT mutant showed approximately 73% decrease in the yield of exopolysaccharides, indicating that epsT is an important gene involved in the EPS production of SM9913.
Conclusions
A conjugal transfer system was constructed in Pseudoalteromonas sp. SM9913 with a wide temperature range for selection and a high transfer efficiency, which will lay the foundation of genetic manipulation in this strain. The epsT gene of SM9913 was successfully deleted with no selective marker left in the chromosome of the host, which thus make it possible to knock out other genes in the same host. The construction of a gene knockout system for Pseudoalteromonas sp. SM9913 will contribute to the understanding of the molecular mechanism of how Pseudoalteromonas adapt to the deep-sea environment.
doi:10.1186/1475-2859-13-13
PMCID: PMC3930924  PMID: 24450434
7.  Minimally invasive plate osteosynthesis for distal radius fractures 
Indian Journal of Orthopaedics  2014;48(1):20-24.
Background:
Fractures of distal radius are common injury in all age groups. Cast treatment with or without close reduction is a viable option. However, the results are often unsatisfactory with restricted function. The open reduction and internal fixation often results in extensive soft tissue dissection and associated high rates of infect and delayed/nonunion. The distractor/external fixator have reported good functional and anatomical results but the incidence of pin traction infection nerve injury and cosmedic deformity are high. We introduced a modified operative technique for minimally invasive plate osteosynthesis (MIPO) for distal radial fracture and evaluated the functional outcomes and complications.
Materials and Methods:
22 distal radial fractures (10 left, 12 right) were treated using the MIPO technique and two small incisions with a palmar locking plate from August 2009 to August 2010. The wrist function was assessed according to Dienst wrist rating system, and postoperative complications were recorded.
Results:
According to Dienst wrist rating system, 13 patients showed excellent results, 6 cases showed good results and 3 patients had moderate results. No patient had poor results. Thus, the excellent and good rate was 86.4%. One patient had anesthesia in the thenar eminence and this symptom disappeared after 3 months. One patient had delayed healing in the proximal wrist crease. Two patients had mild pain on the ulnar side of the wrist and two patients had limited wrist joint function.
Conclusion:
The MIPO technique by using two small palmar incisions is safe and effective for treatment of distal radial fractures.
doi:10.4103/0019-5413.125483
PMCID: PMC3931148  PMID: 24600058
Distal radius fracture; minimally invasive plate fixation; palmar locking plate
8.  A Vaccine That Co-Targets Tumor Cells and Cancer Associated Fibroblasts Results in Enhanced Antitumor Activity by Inducing Antigen Spreading 
PLoS ONE  2013;8(12):e82658.
Dendritic cell (DC) vaccines targeting only cancer cells have produced limited antitumor activity in most clinical studies. Targeting cancer-associated fibroblasts (CAFs) in addition to cancer cells may enhance antitumor effects, since CAFs, the central component of the tumor stroma, directly support tumor growth and contribute to the immunosuppressive tumor microenvironment. To co-target CAFs and tumor cells we developed a new compound DC vaccine that encodes an A20-specific shRNA to enhance DC function, and targets fibroblast activation protein (FAP) expressed in CAFs and the tumor antigen tyrosine-related protein (TRP)2 (DC-shA20-FAP-TRP2). DC-shA20-FAP-TRP2 vaccination induced robust FAP- and TRP2-specific T-cell responses, resulting in greater antitumor activity in the B16 melanoma model in comparison to monovalent vaccines or a vaccine encoding antigens and a control shRNA. DC-shA20-FAP-TRP2 vaccination enhanced tumor infiltration of CD8-positive T cells, and induced antigen-spreading resulting in potent antitumor activity. Thus, co-targeting of tumor cells and CAFs results in the induction of broad-based tumor-specific T-cell responses and has the potential to improve current vaccine approaches for cancer.
doi:10.1371/journal.pone.0082658
PMCID: PMC3861387  PMID: 24349329
9.  Nonparametric ROC Based Evaluation for Survival Outcomes 
Statistics in medicine  2012;31(23):2660-2675.
SUMMARY
For censored survival outcomes, it can be of great interest to evaluate the predictive power of individual markers or their functions. Compared with alternative evaluation approaches, the time-dependent ROC (receiver operating characteristics) based approaches rely on much weaker assumptions, can be more robust, and hence are preferred. In this article, we examine evaluation of markers’ predictive power using the time-dependent ROC curve and a concordance measure which can be viewed as a weighted area under the time-dependent AUC (area under the ROC curve) profile. This study significantly advances from existing time-dependent ROC studies by developing nonparametric estimators of the summary indexes and, more importantly, rigorously establishing their asymptotic properties. It reinforces the statistical foundation of the time-dependent ROC based evaluation approaches for censored survival outcomes. Numerical studies, including simulations and application to an HIV clinical trial, demonstrate the satisfactory finite-sample performance of the proposed approaches.
doi:10.1002/sim.5386
PMCID: PMC3743052  PMID: 22987578
time-dependent ROC; concordance measure; inverse-probability-of-censoring weighting; marker evaluation; survival outcomes
10.  Cancer-associated fibroblasts as targets for immunotherapy 
Immunotherapy  2012;4(11):1129-1138.
Immunotherapy for solid tumors has shown promise in preclinical as well as early clinical studies. However, its efficacy remains limited. The hindrance to achieving objective, long-lasting therapeutic responses in solid tumors is, in part, mediated by the dynamic nature of the tumor and its complex microenvironment. Tumor-directed therapies fail to eliminate components of the microenvironment, which can reinstate a tumorigenic milieu and contribute to recurrence. Cancer-associated fibroblasts (CAFs) form the most preponderant cell type in the solid tumor microenvironment. Given their pervasive role in facilitating tumor growth and metastatic dissemination, CAFs have emerged as attractive therapeutic targets in the tumor microenvironment. In this article, we highlight the cross-talk between CAFs and cancer cells, and discuss how targeting CAFs has the potential to improve current immunotherapy approaches for cancer.
doi:10.2217/imt.12.112
PMCID: PMC3568630  PMID: 23194363
cancer-associated fibroblasts; FAP-directed therapies; fibroblast activation protein; immunotherapy; tumor microenvironment
11.  On Weak Exponential Expansiveness of Evolution Families in Banach Spaces 
The Scientific World Journal  2013;2013:284630.
The aim of this paper is to give several characterizations for the property of weak exponential expansiveness for evolution families in Banach spaces. Variants for weak exponential expansiveness of some well-known results in stability theory (Datko (1973), Rolewicz (1986), Ichikawa (1984), and Megan et al. (2003)) are obtained.
doi:10.1155/2013/284630
PMCID: PMC3745963  PMID: 23983627
12.  An Effective Vaccination Approach Augments anti-HIV Systemic and Vaginal Immunity in Mice with Decreased HIV-1 Susceptible α4β7high CD4+ T Cells 
Current HIV research  2013;11(1):56-66.
HIV-1 preferentially infects activated CD4+ T cells expressing α4β7 integrin and conventional vaccination approaches non-selectively induce immune responses including α4β7high CD4+ T cells, suggesting that current candidate AIDS vaccines may produce more target cells for HIV-1 and paradoxically enhance HIV-1 infection. Thus it remains a challenge to selectively induce robust anti-HIV immunity without the unwanted HIV-1 susceptible α4β7high CD4+ T cells. Here we describe a vaccination strategy that targets ALDH1a2, a retinoic acid producing enzyme in dendritic cells (DCs). Silencing ALDH1a2 in DCs enhanced the maturation and production of proinflammatory cytokines of DCs and promoted Th1/Th2 differentiation while suppressing Treg. ALDH1a2-silenced DCs effectively downregulated the expression of guthoming receptors α4β7 and CCR9 on activated T and B lymphocytes. Consequently, intranasal immunization of a lentiviral vaccine encoding ALDH1a2 shRNA and HIV-1 gp140 redirected gp140-specific mucosal T cell and antibody responses from the gut to the vaginal tract, while dramatically enhancing systemic gp140-specific immune responses. We further demonstrated that silencing ALDH1a2 in human DCs resulted in downregulation of β7 expression on activated autologous CD4+ T cells. Hence this study provides a unique and effective strategy to induce α4β7low anti-HIV immune responses.
PMCID: PMC3717605  PMID: 23157585
ALDH1a2; α4β7; CCR9; CD4+ T cell; dendritic cell; HIV-1 Vaccine; shRNA
13.  The Combination of SMAD4 Expression and Histological Grade of Dysplasia Is a Better Predictor for the Malignant Transformation of Oral Leukoplakia 
PLoS ONE  2013;8(6):e66794.
Oral leukoplakia (OL) is the most common premalignancy in the oral cavity and can progress to oral squamous cell carcinoma (OSCC). SMAD4 is a tumor suppressor implicated in multiple cancer types including OSCC. To assess the role of SMAD4 in oral leukoplakia malignant transformation, the authors investigated SMAD4 expression patterns in OL and OSCC using a highly specific antibody and correlated the patterns with the risk of malignant transformation oral leukoplakia. Immunohistochemistry and a quantitative imaging system were used to measure SMAD4 expression in OL from 88 OL patients, including 22 who later went through malignant transformation, and their OSCC counterpart. Forty-three (48.9%) of the 88 OL patients had strong SMAD4 expression. SMAD4 expression had no significant correlation with patients' clinicopathological parameters. Interestingly, 17 (39.5%) of the 43 OL lesions with strong SMAD4 expression went through malignant transformation whereas only 5 (11.1%) of the 45 OL lesions with weak SMAD4 expression did so (p = 0.002). The SMAD4 expression in OL was much higher than that in their OSCC counterpart. Kaplan-Meier analysis revealed that the combination of SMAD4 expression and histological grade of dysplasia (p = 0.007) is a better predictor for the malignant transformation of oral leukoplakia. In the multivariate analysis, both SMAD4 expression and grade of dysplasia were identified as independent factors for OL malignant transformation risk (p = 0.013 and 0.021, respectively). It was concluded that high SMAD4 expression may be indicative of an early carcinogenic process in OL and serve as an independent biomarker in assessing malignant transformation risk in patients with OL, and the combination of SMAD4 expression and histological grade of dysplasia is a better predictor for the malignant transformation of oral leukoplakia.
doi:10.1371/journal.pone.0066794
PMCID: PMC3691281  PMID: 23826135
14.  A20 Is an Antigen Presentation Attenuator and Its Inhibition Supersedes Regulatory T Cell-Mediated Suppression 
Nature medicine  2008;14(3):258-265.
Regulatory T cells (Treg) suppress autoreactive immune responses and limit the efficacy of tumor vaccines; however, it remains a challenge to selectively eliminate or inhibit Treg. In this study, A20, a negative regulator of the TLR and TNFR signaling pathways, was found to play a critical role in controlling the maturation, cytokine production, and immunostimulatory potency of dendritic cells (DC). A20-silenced DCs with the spontaneous and enhanced expression of costimulatory molecules and proinflammatory cytokines have contrary effects on T cell subsets: inhibiting Treg and hyperactivating cytotoxic T lymphocytes and T-helpers that produced IL-6 and TNFα, infiltrated tumors, and were refractory to Treg-mediated suppression. Hence, this study not only identifies A20 as a critical antigen presentation attenuator in control of antitumor immune responses during both the priming and effector phases, but also provides a novel strategy to supersede Treg-mediated suppression in an antigen-specific manner, reducing the need to directly target Treg.
doi:10.1038/nm1721
PMCID: PMC3684168  PMID: 18311150
15.  Topological insulator bismuth selenide as a theranostic platform for simultaneous cancer imaging and therapy 
Scientific Reports  2013;3:1998.
Employing theranostic nanoparticles, which combine both therapeutic and diagnostic capabilities in one dose, has promise to propel the biomedical field toward personalized medicine. Here we investigate the theranostic properties of topological insulator bismuth selenide (Bi2Se3) in in vivo and in vitro system for the first time. We show that Bi2Se3 nanoplates can absorb near-infrared (NIR) laser light and effectively convert laser energy into heat. Such photothermal conversion property may be due to the unique physical properties of topological insulators. Furthermore, localized and irreversible photothermal ablation of tumors in the mouse model is successfully achieved by using Bi2Se3 nanoplates and NIR laser irradiation. In addition, we also demonstrate that Bi2Se3 nanoplates exhibit strong X-ray attenuation and can be utilized for enhanced X-ray computed tomography imaging of tumor tissue in vivo. This study highlights Bi2Se3 nanoplates could serve as a promising platform for cancer diagnosis and therapy.
doi:10.1038/srep01998
PMCID: PMC3683666  PMID: 23770650
16.  catena-Poly[[(tri­phenyl­phosphane-κP)silver(I)]-μ-4,4′-bi­pyridine-κ2 N:N′-[(tri­phenyl­phosphane-κP)silver(I)]-di-μ-chlorido] 
In the title coordination polymer, [Ag2Cl2(C10H8N2)(C18H15P)2]n, the AgI cation is coordinated by a 4,4′-bi­pyridine N atom, a tri­phenyl­phosphane P atom and two Cl− anions in a distorted tetra­hedral geometry. The 4,4-bi­pyridine and Cl− anions bridge the AgI cations, forming polymeric chains running along [21-1]. In the crystal, weak C—H⋯Cl inter­actions link the polymeric chains into a three-dimensiona supra­molecular architecture.
doi:10.1107/S160053681301413X
PMCID: PMC3684900  PMID: 23795002
17.  Gene Cloning, Expression and Characterization of a Novel Xylanase from the Marine Bacterium, Glaciecola mesophila KMM241 
Marine Drugs  2013;11(4):1173-1187.
Marine xylanases are rather less studied compared to terrestrial xylanases. In this study, a new xylanase gene, xynB, was cloned from the marine bacterium, Glaciecola mesophila KMM241, and expressed in Escherichia coli. xynB encodes a multi-domain xylanase XynB of glycoside hydrolase (GH) family 8. The recombinant XynB comprises an N-terminal domain (NTD) with unknown function and a catalytic domain, which is structurally novel among the characterized xylanases of GH family 8. XynB has the highest identity (38%) to rXyn8 among the characterized xylanases. The recombinant XynB showed maximal activity at pH 6–7 and 35 °C. It is thermolabile and salt-tolerant. XynB is an endo-xylanase that demands at least five sugar moieties for effective cleavage and to hydrolyze xylohexaose and xylopentaose into xylotetraose, xylotriose and xylobiose. NTD was expressed in Escherichia coli to analyze its function. The recombinant NTD exhibited a high binding ability to insoluble xylan and avicel and little binding ability to chitosan and chitin. Since the NTD shows no obvious homology to any known carbohydrate-binding module (CBM) sequence in public databases, XynB may contain a new type of CBM.
doi:10.3390/md11041173
PMCID: PMC3705397  PMID: 23567318
xylanase; XynB; cold-active; Glaciecola mesophila KMM241; carbohydrate-binding module
18.  Modulation of Inflammatory Response in a Cirrhotic Rat Model with Induced Bacterial Peritonitis 
PLoS ONE  2013;8(3):e59692.
Bacterial peritonitis is a severe complication in patients with cirrhosis and ascites and despite antibiotic treatment, the inflammatory response to infection may induce renal dysfunction leading to death. This investigation evaluated the effect of TNF-α blockade on the inflammatory response and mortality in cirrhotic rats with induced bacterial peritonitis treated or not with antibiotics. Sprague-Dawley rats with carbon-tetrachloride-induced cirrhosis were treated with an intraperitoneal injection of 109 CFU of Escherichia coli diluted in 20 mL of sterile water to induce bacterial peritonitis and randomized to receive subcutaneously-administered placebo, ceftriaxone, anti-TNF-α mAb and ceftriaxone, or anti-TNF-α mAb alone. No differences were observed between groups at baseline in respect to renal function, liver hepatic tests, serum levels of nitrite/nitrate and TNF-α. Treatment with ceftriaxone reduced mortality (73.3%) but differences did not reach statistical significance as compared to placebo. Mortality in rats treated with ceftriaxone and anti-TNF-α mAb was significantly lower than in animals receiving placebo (53% vs. 100%, p<0.01). Serum TNF-α decreased significantly in surviving rats treated with ceftriaxone plus anti-TNF-α mAb but not in treated with antibiotics alone. Additional studies including more animals are required to assess if the association of antibiotic therapy and TNF-α blockade might be a possible approach to reduce mortality in cirrhotic patients with bacterial peritonitis.
doi:10.1371/journal.pone.0059692
PMCID: PMC3603865  PMID: 23527251
19.  Allelic Variation of the MMP3 Promoter Affects Transcription Activity through the Transcription Factor C-MYB in Human Brain Arteriovenous Malformations 
PLoS ONE  2013;8(3):e57958.
MMPs comprise a family of proteolytic enzymes that degrade pericellular substances, which may result in the destabilization of vessels and related to the development of brain arteriovenous malformations (BAVM). MMP3 is a key member of this family, overexpressed in BAVM tissues, and a single nucleotide polymorphism within MMP3, −709A>G (rs522616), is significantly associated with the risk of BAVM. In this study, we aimed to investigate the mechanism through which the polymorphism rs522616 regulates the expression of MMP3. Our results showed that −709A led to a over 2-fold higher transcriptional activity compared with the G allele (P<0.05) and this transcriptional activity can be depressed by co-transfecting cells with competitive DNA fragments containing −709A but not −709G. Bioinformatics analyses suggested that the transcription factor C-MYB might bind to the area around rs522616. Overexpressed C-MYB significantly increased the transcriptional activity of −709A compared with −709G or controls that did not overexpress c-myb (P<0.01) in HEK293 and HUVEC cells. ChIP assays indicated that C-MYB bound to the SNP region in the two cell lines and three BAVM tissue samples. Together, these data indicated that C-MYB can bind to the −709A allele of the MMP3 promoter, activate its transcription and lead to a higher expression of this gene. This novel hypothesis, supported by molecular evidence, explains how this SNP affects MMP3 promoter function and results in a risk of BAVM development.
doi:10.1371/journal.pone.0057958
PMCID: PMC3587415  PMID: 23483952
20.  Description of Pella maoershanensis sp. n. (Coleoptera, Staphylinidae, Aleocharinae) associated with Lasius spathepus from Guangxi, South China 
ZooKeys  2013;17-21.
Pellamaoershanensis Song & Li, sp. n., collected from a colony of Lasius (Dendrolasius) spathepus in Maoershan Natural Reserve, Guangxi, is diagnosed, described and illustrated. The discovery represents the first record of the genus in South China.
doi:10.3897/zookeys.275.4449
PMCID: PMC3677325  PMID: 23794809
Coleoptera; Staphylinidae; Aleocharinae; Pella; South China; myrmecophilous
21.  TNFα is a therapeutic target for impaired cutaneous wound healing 
Wound Repair and Regeneration  2011;20(1):38-49.
Impaired wound healing states lead to substantial morbidity and cost with treatment resulting in an expenditure of billions of dollars per annum in the USA alone. Both chronic wounds and impaired acute wounds are characterized by excessive inflammation, enhanced proteolysis, and reduced matrix deposition. These confounding factors are exacerbated in the elderly, in part, as we report here, related to increased local and systemic tumor necrosis factor alpha(TNFα) levels. Moreover, we have used a secretory leukocyte protease inhibitor(SLPI) null mouse model of severely impaired wound healing and excessive inflammation, comparable to age-related delayed human healing, to demonstrate that topical application of anti-TNFα neutralizing antibodies blunts leukocyte recruitment and NFκB activation, alters the balance between M1 and M2 macrophages, and accelerates wound healing. Following antagonism of TNFα, matrix synthesis is enhanced, associated with suppression of both inflammatory parameters and NFκB binding activity. Our data suggest that inhibiting TNFα is a critical event in reversing the severely impaired healing response associated with the absence of SLPI, and may be applicable to prophylaxis and/or treatment of impaired wound healing states in humans.
doi:10.1111/j.1524-475X.2011.00748.x
PMCID: PMC3287056  PMID: 22151742
wound healing; inflammation; SLPI; TNFα; macrophage
22.  Fine Mapping of a Region of Chromosome 11q23.3 Reveals Independent Locus Associated with Risk of Glioma 
PLoS ONE  2012;7(12):e52864.
Background
A single nucleotide polymorphism (SNP) at locus 11q23.3 (rs498872) in the near 5′-UTR of the PHLDB1 gene was recently implicated as a risk factor for gliomas in a genome-wide association study, and this involvement was confirmed in three additional studies.
Methodology/Principal Findings
To identify possible causal variants in the region, the authors genotyped 15 tagging SNPs in the 200 kb genomic region at 11q23.3 locus in a Chinese Han population-based case-control study with 983 cases and 1024 controls. We found evidence for an association between two independent loci (both the PHLDB1 and the ACRN1 genes) and a predisposition for gliomas. Among the multiple significant SNPs in the PHLDB1 gene region, the rs17749 SNP was the most significant [P = 1.31×10−6 in a recessive genetic model]. Additionally, two novel SNPs (rs2236661 and rs494560) that were independent of rs17749 were significantly associated with glioma risk in a recessive genetic model [P = 1.31×10−5 and P = 3.32×10−5, respectively]. The second novel locus was within the ARCN1 gene, and it was associated with a significantly reduced risk for glioma.
Conclusions/Significance
Our data strongly support PHLDB1 as a susceptibility gene for glioma, also shedding light on a new potentially candidate gene, ARCN1.
doi:10.1371/journal.pone.0052864
PMCID: PMC3534108  PMID: 23300798
23.  Preimplantation exposure to bisphenol A (BPA) affects embryo transport, preimplantation embryo development, and uterine receptivity in mice 
To investigate the effects of bisphenol A (BPA) on embryo and uterine factors in embryo implantation, timed pregnant C57BL6 females were treated subcutaneously with 0, 0.025, 0.5, 10, 40, and 100 mg/kg/day BPA from gestation days 0.5 to 3.5. In 100 mg/kg/day BPA-treated females, no implantation sites were detected on day 4.5 but retention of embryos in the oviduct and delayed embryo development were detected on day 3.5. When untreated healthy embryos were transferred to pseudopregnant females treated with 100 mg/kg/day BPA, no implantation sites were detected on day 4.5. In 40 mg/kg/day BPA-treated females, delayed implantation and increased perinatal lethality of their offspring were observed. Implantation seemed normal in the rest BPA-treated groups or the female offspring from 40 mg/kg/day BPA-treated group. These data demonstrate the adverse effects of high doses of BPA on processes critical for embryo implantation: embryo transport, preimplantation embryo development, and establishment of uterine receptivity.
doi:10.1016/j.reprotox.2011.08.010
PMCID: PMC3225705  PMID: 21907787
Bisphenol A; embryo implantation; embryo transport; preimplantation embryo development; uterine receptivity; progesterone receptor
24.  Comparative pharmacokinetic studies of borneol in mouse plasma and brain by different administrations*  
Borneol, a monoterpenoid alcohol, is used widely, particularly in combined formulas for preventing and curing cardiovascular and cerebrovascular diseases in traditional Chinese medicine. In order to understand the blood and brain pharmacokinetics after intravenous, intranasal, or oral administration and to investigate the superiority and feasibility of intranasal administration, a simple gas chromatographic (GC) method with flame ionization detection (FID) was developed for the quantification of borneol. Blood samples and brain were collected from mice at 1, 3, 5, 10, 20, 30, 60, 90, and 120 min after intravenous, intranasal, or oral administration of borneol at a dosage of 30.0 mg/kg. Sample preparations were carried out by liquid-liquid extraction with an internal standard solution of octadecane. The pharmacokinetic parameters were calculated by the software of Kinetica. The calibration curves were linear in the range of 0.11–84.24 μg/ml and 0.16–63.18 μg/g for borneol in plasma and brain, respectively. The methodological and extraction recoveries were both in the range of 85%–115%. The intra-day and inter-day variabilities for plasma and brain samples were ≤5.00% relative standard deviation (RSD). The absolute bioavailabilities F of intranasal and oral administrations were 90.68% and 42.99%. The relative brain targeted coefficients Re of intranasal and oral administrations were 68.37% and 38.40%. The GC-FID method developed could be applied to determination and pharmacokinetic study. The borneol from injection was distributed and metabolized fast without absorption process. The borneol from oral administration was distributed more slowly and had the lowest absolute bioavailability. Nasal administration of borneol was quickly absorbed into the blood and brain, was easy to use and had a greater safety than infection, which makes it worthy of further development as an administration route for encephalopathy treatment.
doi:10.1631/jzus.B1200142
PMCID: PMC3520453  PMID: 23225854
Borneol; Intravenous administration; Intranasal administration; Oral administration; Pharmacokinetics
25.  Pollen Analysis of Natural Honeys from the Central Region of Shanxi, North China 
PLoS ONE  2012;7(11):e49545.
Based on qualitative and quantitative melissopalynological analyses, 19 Chinese honeys were classified by botanical origin to determine their floral sources. The honey samples were collected during 2010–2011 from the central region of Shanxi Province, North China. A diverse spectrum of 61 pollen types from 37 families was identified. Fourteen samples were classified as unifloral, whereas the remaining samples were multifloral. Bee-favoured families (occurring in more than 50% of the samples) included Caprifoliaceae (found in 10 samples), Laminaceae (10), Brassicaceae (12), Rosaceae (12), Moraceae (13), Rhamnaceae (15), Asteraceae (17), and Fabaceae (19). In the unifloral honeys, the predominant pollen types were Ziziphus jujuba (in 5 samples), Robinia pseudoacacia (3), Vitex negundo var. heterophylla (2), Sophora japonica (1), Ailanthus altissima (1), Asteraceae type (1), and Fabaceae type (1). The absolute pollen count (i.e., the number of pollen grains per 10 g honey sample) suggested that 13 samples belonged to Group I (<20,000 pollen grains), 4 to Group II (20,000–100,000), and 2 to Group III (100,000–500,000). The dominance of unifloral honeys without toxic pollen grains and the low value of the HDE/P ratio (i.e., honey dew elements/pollen grains from nectariferous plants) indicated that the honey samples are of good quality and suitable for human consumption.
doi:10.1371/journal.pone.0049545
PMCID: PMC3504156  PMID: 23185358

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