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author:("Liu, jinhua")
1.  Conditional Knockout of Telomerase Reverse Transcriptase in Mesenchymal Cells Impairs Mouse Pulmonary Fibrosis 
PLoS ONE  2015;10(11):e0142547.
Telomerase is typically expressed in cellular populations capable of extended replication, such as germ cells, tumor cells, and stem cells, but is also induced in tissue injury, repair and fibrosis. Its catalytic component, telomerase reverse transcriptase (TERT) is induced in lung fibroblasts from patients with fibrotic interstitial lung disease and in rodents with bleomycin-induced pulmonary fibrosis. To evaluate the fibroblast specific role of TERT in pulmonary fibrosis, transgenic mice bearing a floxed TERT allele were generated, and then crossed with an inducible collagen α2(I)-Cre mouse line to generate fibroblast specific TERT conditional knockout mice. TERT-specific deficiency in mesenchymal cells caused attenuation of pulmonary fibrosis as manifested by reduced lung hydroxyproline content, type I collagen and α-smooth muscle actin mRNA levels. The TERT-deficient mouse lung fibroblasts displayed decreased cell proliferative capacity and higher susceptibility to induced apoptosis compared with control cells. Additionally TERT deficiency was associated with heightened α-smooth muscle actin expression indicative of myofibroblast differentiation. However the impairment of cell proliferation and increased susceptibility to apoptosis would cause a reduction in the myofibroblast progenitor population necessary to mount a successful myofibroblast-dependent fibrotic response. These findings identified a key role for TERT in fibroblast proliferation and survival essential for pulmonary fibrosis.
doi:10.1371/journal.pone.0142547
PMCID: PMC4640706  PMID: 26555817
2.  Isolation and characterization of side population cells from the human ovarian cancer cell line SK-OV-3 
Ovarian cancer (OC) is the most malignant type of gynecological tumor due to its high recurrence rate following initial treatment. Previous studies have indicated that cancer stem cells (CSCs) may be a potential cause underlying the high proportion of recurrence. Side population (SP) cells isolated from cancer cell lines have been shown to exhibit characteristics associated with CSCs, but studies on SP cells in human ovarian SK-OV-3 cell line are limited. In the present study, the SP cell fraction (4.83% of the total cell population) was isolated using flow cytometry, and analyzed by immunocytochemical analysis and reverse transcription-quantitative polymerase chain reaction. The results showed that SP cells exhibited a high mean fluorescence intensity for CD44, a CSC marker, in addition to elevated expression of the CSCs-associated genes, ATP-binding cassette sub-family G member 2 and Nestin. These findings indicated the stem cell-like features of the SP cells. Furthermore, a colony formation test showed that the isolated SP cells possessed a marked capacity for self-regeneration and proliferation. In addition, a cell cycle assay involving cisplatin indicated that the SP cells were strongly resistant to chemotherapy. In conclusion, the present results suggested that SP cells isolated from the SK-OV-3 cell line exhibited properties typically associated with CSCs. Therefore, the isolated SP cells may be used to provide novel insight into potential therapies against OC.
doi:10.3892/etm.2015.2836
PMCID: PMC4665172  PMID: 26668597
human ovarian cancer; side population cells; cancer stem cells; SK-OV-3
3.  Late HIV Diagnosis: Proposed Common Definitions and Associations With Short-Term Mortality 
Medicine  2015;94(36):e1511.
Abstract
The aim of this study was to present a definition of late presentation according to different time periods between initial diagnosis of human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS) diagnosis which would reliably identify individuals with high risk of mortality within 1 year of diagnosis, and could be used as a suggested common definition.
Data of individuals diagnosed from 1994 to February 2012 in Wuhan, China were extracted retrospectively from the national HIV surveillance system. Four time periods (1, 3, 6, and 12 months) combined with the European consensus definition of advanced HIV disease (AHD) were compared. The predictive ability of each definition for identifying an individual who died within 1 year after HIV diagnosis was assessed.
A total of 980 patients were included, of whom 289 (29.49%), 324 (33.06%), 353 (36.02%), and 387 (39.49%) were defined as AHD according to the definition of a CD4 count <200 cells/μL or AIDS-defining event (ADE) within 1, 3, 6, and 12 months of HIV diagnosis, respectively. One hundred twenty-seven (12.96%) patients died within 1 year of diagnosis. The highest Youden's index and largest area under the curve were presented in time period within 3 months. Time period within 1 month presented the highest consistency rate, positive likelihood ratio, and kappa value. Longer time periods increased the sensitivity but decreased the specificity.
Given the European consensus definitions and the current results, we suggested that AHD could be defined as “a first-reported CD4 count <200 cells/μL or an ADE within 1 month after HIV diagnosis.” “Late presentation” could be defined as “a first-reported CD4 count <350 cells/μL or an ADE within 1 month after HIV diagnosis.”
doi:10.1097/MD.0000000000001511
PMCID: PMC4616627  PMID: 26356722
4.  Probing the coordination properties of glutathione with transition metal ions (Cr2+,Mn2+,Fe2+,Co2+, Ni2+,Cu2+,Zn2+,Cd2+,Hg2+) by density functional theory 
Journal of Biological Physics  2014;40(4):313-323.
Complexes formed by reduced glutathione (GSH) with metal cations (Cr2+, Mn2+,Fe2+,Co2+,Ni2+,Cu2+,Zn2+,Cd2+,Hg2+) were systematically investigated by the density functional theory (DFT). The results showed that the interactions of the metal cations with GSH resulted in nine different stable complexes and many factors had an effect on the binding energy. Generally, for the same period of metal ions, the binding energies ranked in the order of Cu2+>Ni2+>Co2+>Fe2+>Cr2+>Zn2+>Mn2+; and for the same group of metal ions, the general trend of binding energies was Zn2+>Hg2+>Cd2+. Moreover, the amounts of charge transferred from S or N to transition metal cations are greater than that of O atoms. For Fe2+,Co2+,Ni2+,Cu2+,Zn2+,Cd2+ and Hg2+ complexes, the values of the Wiberg bond indices (WBIs) of M-S (M denotes metal cations) were larger than that of M-N and M-O; for Cr2+ complexes, most of the WBIs of M-O in complexes were higher than that of M-S and M-N. Furthermore, the changes in the electron configuration of the metal cations before and after chelate reaction revealed that Cu2+, Ni2+,Co2+ and Hg2+ had obvious tendencies to be reduced to Cu+,Ni+,Co+ and Hg+ during the coordination process.
Electronic supplementary material
The online version of this article (doi:10.1007/s10867-014-9350-3) contains supplementary material, which is available to authorized users.
doi:10.1007/s10867-014-9350-3
PMCID: PMC4119187  PMID: 24923419
Glutathione; Metal complex; Density functional theory NBO analysis
5.  Transcriptomic analysis of a moderately growing subisolate Botryococcus braunii 779 (Chlorophyta) in response to nitrogen deprivation 
Background
The colonial microalga Botryococcus braunii has been brought to people’s attention for its conspicuous ability to accumulate a variety of lipids including hydrocarbons. B. braunii strains are classified into 3 races based on the types of hydrocarbons. A and B races are known to accumulate high level of lipids. However, their extreme slow growth rate has impeded its application for renewable biofuel production.
Results
In this study, we report the transcriptomic response of a moderately growing subisolate from the culture of Botryococcus sp. CCALA-779 upon nitrogen deprivation (ND). We show that the subisolate has an average growth rate of 0.52 g l−1 day−1 under photoautotrophic growth conditions and lipid content is enhanced to 75 % of CDW upon ND. Both rDNA sequence and hydrocarbon composition analyses indicate that the subisolate belongs to A race B. braunii. Hence, it is designated as B. braunii 779. We show that B. braunii 779 transcriptome shares homology to majority of the A race but not B race B. braunii ESTs, suggesting that transcriptomes of A race differ from that of B race. We found that many homologous ESTs between A races 779 and Bot-88 are unknown sequences, implying that A race contains many unknown genes. Pathway-based transcriptomic analysis indicates that energy metabolisms are among the top expressed functions in log-phase cells, indicating that the slow growth rate is a result that energy flow is directed to lipid biosynthesis but not population growth. Upon ND, reconfiguration of metabolisms for reducing power is apparent, suggesting that B. braunii 779 is rapidly adapting under ND condition by transcriptomic reprogramming.
Conclusions
Taken together, our result shows that the subisolate B. braunii 779, similar to the Gottingen strain, is useful for biofuel production. Difference between transcriptomes of A and B races implies that different races of B. braunii strains belong to different sub-species. Furthermore, there are many novel genes that are unique to A race, suggesting that sequences of many enzymes involved in hydrocarbon biosynthesis are not currently known. We propose that B. braunii transcriptomes provide a rich source for discovery of novel genes involved in hydrocarbon biosynthesis.
Electronic supplementary material
The online version of this article (doi:10.1186/s13068-015-0307-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s13068-015-0307-y
PMCID: PMC4552190  PMID: 26322124
Botryococcus braunii; Green microalgae; Hydrocarbon; Transcriptome; Response to nitrogen deprivation
6.  The Use of Unidirectional Barbed Suture for Urethrovesical Anastomosis during Robot-Assisted Radical Prostatectomy: A Systematic Review and Meta-Analysis of Efficacy and Safety 
PLoS ONE  2015;10(7):e0131167.
Background
Unidirectional barbed suture (UBS) has been widely used for surgery in recent years, especially for urethrovesical anastomosis (UVA) during robot-assisted radical prostatectomy (RARP). However, the efficacy and safety comparing it with conventional non-barbed suture (CS) for UVA is still controversial.
Aims
The objective of this study is to assess the current evidence regarding the efficacy and safety of UBS compared with CS for UVA during RARP.
Methods
We comprehensively searched PubMed, Embase, The Cochrane Library, SinoMed (Chinese) and other databases on Oct. 9, 2014 to conduct a systematic review and meta-analysis of all randomized controlled trials (RCTs) and other comparative studies evaluating these two types of suture. The outcome measures included anastomosis time operative time, posterior reconstruction (PR) time, postoperative leakage (PL) rate and continence rates at different time points (4-6 weeks, 3 months, 6-12 months) after surgery. Secondary outcomes included estimated blood loss (EBL) and length of catheterization (LOC).
Results
Three RCTs and six observational studies including 786 cases were identified. Meta-analysis of extractable data showed that use of UBS could significantly reduce anastomosis time (weighted mean difference [WMD]:-3.98min; 95% confidence interval [CI], -6.02 -1.95; p = 0.0001), operative time (WMD:-10.06min; 95% CI, -15.45–-4.67; p = 0.0003) and PR time (WMD:-0.93min; 95% CI, -1.52–-0.34; p = 0.002). No significant difference was found in PL rate, EBL, LOC, or continence rates at 4-6 weeks, 3 months and 6–12 months after surgery.
Conclusions
Our meta-analysis indicates that UBS appears to be safe and efficient as CS for UVA during RARP with not only shorter anastomosis time, operative time, PR time, but also equivalent PL rate, EBL, LOC, and continence rates at 4-6 weeks, 3 months and 6-12 months after surgery. For the inherent limitations of the eligible studies, future more persuasive RCTs are needed to confirm and update our findings.
doi:10.1371/journal.pone.0131167
PMCID: PMC4489906  PMID: 26135310
7.  Morphological study of the posterior osseous structures of subaxial cervical spine in a population from northeastern China 
Background
Laminar screws and lateral mass screws have been increasingly used in the treatment of cervical diseases. The purpose of this study is to determine the morphological characteristics of the posterior anatomical structures of the subaxial cervical vertebrae in a northeastern Chinese population.
Methods
Sixty-one consecutive patients underwent cervical spine computed tomography (CT). We analyzed a total of 610 axial images and 61 sagittal images. The following parameters were measured: lamina outer width (LOW), lamina inner width (LIW), lamina axis length (LAL), lamina transverse angle (LTA), lateral mass longitudinal diameter (LMLD), lateral mass transverse diameter (LMTD), sagittal spinous process length (SSPL), axial spinous process length (ASPL), spinal canal transverse diameter (SCTD), spinal canal longitudinal diameter (SCLD), osseous spinal canal area (OSCA), and Pavlov ratio (PR). The participants were classified into male and female groups and developmental canal stenosis (DCS; PR ≤0.75) and non-DCS (NDCS; PR >0.75) groups.
Results
Significant differences were observed among the different vertebral levels for almost all evaluated parameters, except for LTA and OSCA. Statistical differences were found between the right and left sides in all parameters, except for LIW and LOW. All linear parameters, except for SCLD and the angular parameter LTA, significantly differed between the sexes. Significant differences were found between the DCS and NDCS groups in terms of all parameters, except for SCTD.
Conclusions
Various measurements of the posterior structures of subaxial cervical vertebrae differed between the left and right sides, females and males, and the DCS and NDCS groups. Different techniques for lateral mass screw insertion should be used according to different vertebral level. Only C7 laminar may be able to safely accommodate a 2.5-mm translaminar screw. The study data can help doctors to make better surgical decisions and develop more appropriate implants for northeastern Chinese patients.
doi:10.1186/s13018-015-0194-8
PMCID: PMC4409703  PMID: 25896074
Northeastern Chinese; Subaxial cervical spine; Lateral mass; Lamina; Spinous process; Spinal canal
8.  Epidemiology of Hepatitis E Virus in China: Results from the Third National Viral Hepatitis Prevalence Survey, 2005–2006 
PLoS ONE  2014;9(10):e110837.
In China, hepatitis E virus (HEV) is prevalent and causes disease, but its epidemiological profile is not well understood. We used a commercial enzyme-linked immunosorbent assay to detect total antibodies to hepatitis E virus in 15,862 serum samples collected during the Third National Viral Hepatitis Prevalence Survey. The results were analyzed to calculate estimates of HEV seroprevalence and to examine the effects of some putative risk factors. The seroprevalence of HEV in the general Chinese population during the period from 2005 through 2006 was 23.46% (95% confidence interval [CI], 18.41%–28.50%). The farming population, the age group of 15–60 year olds, and those living in the Midwest or Mideast region and in Xinjiang province had the highest seroprevalence estimates. The prevalence of HEV is high in China. The seroprevalence rate of HEV shows an unbalanced distribution among areas with different geographic location and economic development levels. The characteristics of the distribution associated may be due to the route of HEV transmission (via contaminated water or animal reservoirs). Within the same region, the seroprevalence of HEV is generally increased with age.
doi:10.1371/journal.pone.0110837
PMCID: PMC4215996  PMID: 25360522
9.  Characterization of the Medium- and Long-Chain n-Alkanes Degrading Pseudomonas aeruginosa Strain SJTD-1 and Its Alkane Hydroxylase Genes 
PLoS ONE  2014;9(8):e105506.
A gram-negative aliphatic hydrocarbon-degrading bacterium SJTD-1 isolated from oil-contaminated soil was identified as Pseudomonas aeruginosa by comparative analyses of the 16S rRNA sequence, phenotype, and physiological features. SJTD-1 could efficiently mineralize medium- and long-chain n-alkanes (C12-C30) as its sole carbon source within seven days, showing the most optimal growth on n-hexadecane, followed by n-octadecane, and n-eicosane. In 36 h, 500 mg/L of tetradecane, hexadecane, and octadecane were transformed completely; and 2 g/L n-hexadecane was degraded to undetectable levels within 72 h. Two putative alkane-degrading genes (gene 3623 and gene 4712) were characterized and our results indicated that their gene products were rate-limiting enzymes involved in the synergetic catabolism of C12–C16 alkanes. On the basis of bioinformatics and transcriptional analysis, two P450 monooxygenases, along with a putative AlmA-like oxygenase, were examined. Genetically defective mutants lacking the characteristic alkane hydroxylase failed to degrade n-octadecane, thereby suggesting a different catalytic mechanism for the microbial transformation of alkanes with chain lengths over C18.
doi:10.1371/journal.pone.0105506
PMCID: PMC4148322  PMID: 25165808
10.  Transthyretin as a potential biomarker for the differential diagnosis between lung cancer and lung infection 
Biomedical Reports  2014;2(5):765-769.
Satisfactory biomarkers for screening and early diagnosis of lung cancer remain scarce and require further investigation. The aim of the present study was to examine the changes of the biochemical and protein composition in the serum and pleural effusion from lung cancer and lung infection (bacterial pneumonia) patients. A total of 92 patients with lung cancer, 38 with bacterial pneumonia and 42 healthy controls were enrolled in the study. The serum levels of cholesterol, apolipoprotein A and transthyretin (TTR) in the lung cancer patients were higher than that of the lung infection patients (P<0.05). The levels of TTR were higher, whereas the activity of adenosine deaminase (ADA) was lower in the pleural effusion from the lung cancer patients compared to the lung infection patients (P<0.05). Furthermore, the pleural effusion/serum TTR ratios in the lung cancer patients were higher, whereas the ratios of ADA were lower (P<0.05). By matrix-assisted laser desorption/ionization time-of-flight mass spectrometry analysis, four major peaks corresponding to native TTR, Sul-TTR, Cys-TTR and Cysgly-TTR were observed in the serum of the lung cancer and lung infection patients. A significant increase was found in the proportion of Cysgly-TTR in the pleural effusion from the patients with lung cancer. The data indicated that a combination of pleural effusion/serum TTR ratios and modified TTR may be beneficial for the differential diagnosis between lung cancer and lung infection.
doi:10.3892/br.2014.313
PMCID: PMC4106510  PMID: 25054025
transthyretin; lung cancer; lung infection; pleural effusion; matrix-assisted laser desorption/ionization time-of-flight mass spectrometry
11.  A Game-Theoretic Response Strategy for Coordinator Attack in Wireless Sensor Networks 
The Scientific World Journal  2014;2014:950618.
The coordinator is a specific node that controls the whole network and has a significant impact on the performance in cooperative multihop ZigBee wireless sensor networks (ZWSNs). However, the malicious node attacks coordinator nodes in an effort to waste the resources and disrupt the operation of the network. Attacking leads to a failure of one round of communication between the source nodes and destination nodes. Coordinator selection is a technique that can considerably defend against attack and reduce the data delivery delay, and increase network performance of cooperative communications. In this paper, we propose an adaptive coordinator selection algorithm using game and fuzzy logic aiming at both minimizing the average number of hops and maximizing network lifetime. The proposed game model consists of two interrelated formulations: a stochastic game for dynamic defense and a best response policy using evolutionary game formulation for coordinator selection. The stable equilibrium best policy to response defense is obtained from this game model. It is shown that the proposed scheme can improve reliability and save energy during the network lifetime with respect to security.
doi:10.1155/2014/950618
PMCID: PMC4102080  PMID: 25105171
12.  FIZZ2/RELM-β Induction and Role in Pulmonary Fibrosis 
Found in inflammatory zone (FIZZ) 2, also known as resistin-like molecule (RELM)-β, belongs to a novel cysteine-rich secreted protein family named FIZZ/RELM. Its function is unclear, but a closely related family member, FIZZ1, has profibrotic activities. The human ortholog of rodent FIZZ1 has not been identified, but human FIZZ2 has significant sequence homology to both rodent FIZZ2 (59%) and FIZZ1 (50%). Given the greater homology to rodent FIZZ2, analyzing the role of FIZZ2 in a rodent model of bleomycin-induced pulmonary fibrosis would be of greater potential relevance to human fibrotic lung disease. The results showed that FIZZ2 was highly induced in lungs of rodents with bleomycin-induced pulmonary fibrosis and of human patients with idiopathic pulmonary fibrosis. FIZZ2 expression was induced in rodent and human lung epithelial cells by Th2 cytokines, which was mediated via STAT6 signaling. The FIZZ2 induction in murine lungs was found to be essential for pulmonary fibrosis, as FIZZ2 deficiency significantly suppressed pulmonary fibrosis and associated enhanced extracellular matrix and cytokine gene expression. In vitro analysis indicated that FIZZ2 could stimulate type I collagen and α-smooth muscle actin expression in lung fibroblasts. Furthermore, FIZZ2 was shown to have chemoattractant activity for bone marrow (BM) cells, especially BM-derived CD11c+ dendritic cells. Notably, lung recruitment of BM-derived cells was impaired in FIZZ2 knockout mice. These findings suggest that FIZZ2 is a Th2-associated multifunctional mediator with potentially important roles in the pathogenesis of fibrotic lung diseases.
doi:10.4049/jimmunol.1000964
PMCID: PMC4030639  PMID: 21602491
13.  Hemostatic Effects of Microbubble-Enhanced Low-Intensity Ultrasound in a Liver Avulsion Injury Model 
PLoS ONE  2014;9(5):e95589.
Objectives
Microbubble-enhanced therapeutic ultrasound (MEUS) can block the blood flow in the organs. The aim of this study was to evaluate the hemostatic effect of microbubble-enhanced pulsed, low-intensity ultrasound in a New Zealand White rabbit model of avulsion trauma of the liver. The therapeutic ultrasound (TUS) transducer was operated with the frequency of 1.2 MHz and an acoustic pressure of 3.4 MPa. Microbubble-(MB) enhanced ultrasound (MEUS) (n = 6) was delivered to the distal part of the liver where the avulsion was created. Livers were treated by TUS only (n = 4) or MB only (n = 4) which served as controls. Bleeding rates were measured and contrast enhanced ultrasound (CEUS) was performed to assess the hemostatic effect, and liver hemoperfusion before and after treatment. Generally, bleeding rates decreased more than 10-fold after the treatment with MEUS compared with those of the control group (P<0.05). CEUS showed significant declines in perfusion. The peak intensity value and the area under the curve also decreased after insonation compared with those of the control group (P<0.05). Histological examination showed cloudy and swollen hepatocytes, dilated hepatic sinusoids, perisinusoidal spaces with erythrocyte accumulation in small blood vessels, obvious hemorrhage around portal areas and scattered necrosis in liver tissues within the insonation area of MEUS Group. In addition, necrosis was found in liver tissue 48 h after insonation. We conclude that MEUS might provide an effective hemostatic therapy for serious organ trauma such as liver avulsion injury.
doi:10.1371/journal.pone.0095589
PMCID: PMC4006836  PMID: 24788757
14.  Rapamycin Inhibition of Polyposis and Progression to Dysplasia in a Mouse Model 
PLoS ONE  2014;9(4):e96023.
Familial adenomatous polyposis (FAP) is often due to adenomatous polyposis coli (APC) gene germline mutations. Somatic APC defects are found in about 80% of colorectal cancers (CRCs) and adenomas. Rapamycin inhibits mammalian target of rapamycin (mTOR) protein, which is often expressed in human adenomas and CRCs. We sought to assess the effects of rapamycin in a mouse polyposis model in which both Apc alleles were conditionally inactivated in colon epithelium. Two days after inactivating Apc, mice were given rapamycin or vehicle in cycles of two weeks on and two weeks off. Polyps were scored endoscopically. Mice were euthanized at time points or when moribund, and tissue analyses were performed. In other studies, mice with demonstrable Apc-defective colon polyps were given rapamycin, followed by analysis of their colon tissues. The median survival of mice receiving rapamycin treatment cycles was 21.5 versus 6.5 weeks in control mice (p = 0.03), and rapamycin-treated mice had a significantly lower percentage of their colon covered with polyps (4.3+/− 2 vs 56.5+/− 10.8 percent, p = 0.001). Mice with Apc-deficient colon tissues that developed high grade dysplasia treated with rapamycin underwent treatment for significantly longer than mice treated with vehicle (15.8 vs 5.1 weeks, p = 0.003). In Apc-defective colon tissues, rapamycin treatment was linked to decreased levels of β-catenin and Sox9 at 7 weeks. Other effects of rapamycin in Apc-defectivecolon tissues included decreased proliferation and increased numbers of differentiated goblet cells at 7 weeks. Rapamycin did not affect β-catenin-regulated gene expression in cultured intestinal epithelial cells. Rapamycin has potent inhibitory effects in a mouse colon polyposis model, and mTOR inhibition is linked to decreased proliferation and increased expression of differentiation markers in Apc-mutant colon epithelium and delays development of dysplasia. Our findings highlight the possibility that mTOR inhibitors may have relevance for polyposis inhibition approaches in FAP patients.
doi:10.1371/journal.pone.0096023
PMCID: PMC3999114  PMID: 24763434
15.  The In Vivo Fibrotic Role of FIZZ1 in Pulmonary Fibrosis 
PLoS ONE  2014;9(2):e88362.
FIZZ (found in inflammatory zone) 1, a member of a cysteine-rich secreted protein family, is highly induced in lung allergic inflammation and bleomycin induced lung fibrosis, and primarily expressed by airway and type II alveolar epithelial cells. This novel mediator is known to stimulate α-smooth muscle actin and collagen expression in lung fibroblasts. The objective of this study was to investigate the in vivo effects of FIZZ1 on the development of lung fibrosis by evaluating bleomycin-induced pulmonary fibrosis in FIZZ1 deficient mice. FIZZ1 knockout mice exhibited no detectable abnormality. When these mice were treated with bleomycin they exhibited significantly impaired pulmonary fibrosis relative to wild type mice, along with impaired proinflammatory cytokine/chemokine expression. Deficient lung fibroblast activation was also noted in the FIZZ1 knockout mice. Moreover, recruitment of bone marrow-derived cells to injured lung was deficient in FIZZ1 knockout mice. Interestingly in vitro FIZZ1 was shown to have chemoattractant activity for bone marrow cells, including bone marrow-derived dendritic cells. Finally, overexpression of FIZZ1 exacerbated fibrosis. These findings suggested that FIZZ1 exhibited profibrogenic properties essential for bleomycin induced pulmonary fibrosis, as reflected by its ability to induce myofibroblast differentiation and recruit bone marrow-derived cells.
doi:10.1371/journal.pone.0088362
PMCID: PMC3916640  PMID: 24516640
16.  Needle-knife therapy improves the clinical symptoms of knee osteoarthritis by inhibiting the expression of inflammatory cytokines 
Knee osteoarthritis (KOA) is a degenerative joint disease that occurs mainly in the elderly population. However, there are currently no effective treatments for treating this condition. In this study, the efficacy of needle-knife therapy, a technique of traditional Chinese medicine that has been widely used to treat KOA was investigated. Patients (n=170) with KOA were randomly divided for needle-knife therapy (treatment group) and acupuncture therapy (control group). Outcome evaluation included stiffness, pain, physiological function, overall changes, total symptom score, clinical curative effects and the concentrations of interleukin (IL)-1β, IL-6 and tumor necrosis factor-α (TNF-α) in the synovial fluid. The trial was completed in 151 patients (233 knees) from a total of 170 patients (264 knees); the treatment group comprised 76 patients (117 knees) who completed the trial and 9 patients (14 knees) who were removed from the study, and the control group comprised 75 patients (116 knees) who completed the trial and 10 patients (17 knees) who were removed from the study. The symptom scores of KOA in stages I–IV were reduced significantly in the treatment group and those of stages I–III were decreased significantly in the control group. The effective rate of the KOA therapy in the patients of stages III and IV in the treatment group was significantly higher than that in the control group. After treatment, the decrements of IL-1β, IL-6 and TNF-α in the treatment group were greater than those in the control group. These results showed that the use of needle-knife therapy to treat KOA effectively improved the clinical symptoms by inhibiting the expression of inflammatory cytokines.
doi:10.3892/etm.2014.1516
PMCID: PMC3961116  PMID: 24669238
needle-knife therapy; osteoarthritis; knee joint; acupuncture
17.  De novo transcriptome profiling uncovers a drastic downregulation of photosynthesis upon nitrogen deprivation in the nonmodel green alga Botryosphaerella sudeticus 
BMC Genomics  2013;14(1):715.
Background
Neutral lipid storage is enhanced by nitrogen deprivation (ND) in numbers of green microalgal species. However, little is known about the metabolic pathways whose transcription levels are most significantly altered following ND in green microalgae, especially the nonmodel species.
Results
To start gaining knowledge on this, we performed transcriptome profiling of the nonmodel green microalga Botryosphaerella sudeticus cells in response to ND. Transcriptome of B. sudeticus is de novo assembled based on millions of HiSEQ short sequence reads using CLC Genomics Workbench software. The resulting non-redundant ESTs are annotated based on the best hits generated from the BLASTX homology comparison against the “best” proteins in the model microalgae Chlamydomonas reinhardtii and Chlorella variabilis. By using a pathway-based approach according to KEGG databases, we show that ESTs encoding ribosomal proteins and photosynthetic functions are the most abundantly expressed ESTs in the rapidly growing B. sudeticus cells. We find that ESTs encoding photosynthetic function but not the ribosomal proteins are most drastically downregulated upon ND. Notably, ESTs encoding lipid metabolic pathways are not significantly upregulated. Further analyses indicate that chlorophyll content is markedly decreased by 3-fold and total lipid content is only slightly increased by 50%, consistent with the transcriptional profiling. On the other hand, carbon content and photosynthesis efficiency are only marginally decreased by 7% and 20%, respectively, indicating that photosynthesis is only slightly reduced upon drastic downregulation of photosynthetic ESTs and chlorophyll content upon ND. In addition, TAG content is found to be greatly increased by 50-fold, though total lipid content is only slightly increased by 1.5-fold.
Conclusions
Taken together, our results suggest that light-harvesting proteins and chlorophylls are in excess in B. sudeticus. Degradation of excess photosynthesis proteins is most likely a mechanism for recycling of nitrogen-rich molecules to synthesize new proteins for preparation of gametogenesis and zygospore formation in adaptation and survival upon ND. Furthermore, our analyses indicate that TAG accumulation is largely attributed to the modification of other pre-existing lipid molecules, rather than de novo synthesis. We propose that this is likely an evolutionarily conserved mechanism in many green microalgae species.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-14-715) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2164-14-715
PMCID: PMC4050207  PMID: 24138407
Next-generation sequencing; De novo assembly; Transcriptome profiling; Metabolic pathways; B. sudeticus UTEX2629
18.  Hsp70-Hsp40 Chaperone Complex Functions in Controlling Polarized Growth by Repressing Hsf1-Driven Heat Stress-Associated Transcription 
PLoS Genetics  2013;9(10):e1003886.
How the molecular mechanisms of stress response are integrated at the cellular level remains obscure. Here we show that the cellular polarity machinery in the fission yeast Schizosaccharomyces pombe undergoes dynamic adaptation to thermal stress resulting in a period of decreased Cdc42 activity and altered, monopolar growth. Cells where the heat stress-associated transcription was genetically upregulated exhibit similar growth patterning in the absence of temperature insults. We identify the Ssa2-Mas5/Hsp70-Hsp40 chaperone complex as repressor of the heat shock transcription factor Hsf1. Cells lacking this chaperone activity constitutively activate the heat-stress-associated transcriptional program. Interestingly, they also exhibit intermittent monopolar growth within a physiological temperature range and are unable to adapt to heat stress. We propose that by negatively regulating the heat stress-associated transcription, the Ssa2-Mas5 chaperone system could optimize cellular growth under different temperature regiments.
Author Summary
Heat stress, caused by fluctuations in ambient temperature, occurs frequently in nature. How organisms adapt and maintain regular patterns of growth over a range of environmental conditions remain poorly understood. Our work in the simple unicellular yeast Schizosaccharomyces pombe suggests that the heat stress-associated transcription must be repressed by the evolutionary conserved Hsp70-Hsp40 chaperone complex to allow cells to adapt the polarized growth machinery to elevated temperature.
doi:10.1371/journal.pgen.1003886
PMCID: PMC3798271  PMID: 24146635
19.  Genetic variations of E6 and long control region of human papillomavirus type 16 from patients with cervical lesion in Liaoning, China 
BMC Cancer  2013;13:459.
Background
High-risk human papillomavirus type 16 (HPV16) is a risk factor for cervical cancer. Previous studies suggest that polymorphisms in the E6 gene or the long control region(LCR)of HPV16 may alter the oncogenic potential of the virus. The aims of this study were to investigate the genetic variations of HPV16 E6 gene and LCR in isolates from Chinese population and correlation of the E6 and LCR polymorphisms with disease status of infected patients.
Methods
HPV16 positive endocervical specimens were collected from 304 women living in Northeast of China. Sequences of E6 gene and LCR were analyzed by PCR-sequencing.
Results
Two lineages were found in the populations, including EUR lineage and As lineage. Based on the HPV16 prototype, the most frequent variation in the E6 gene was T178A/G (48.7%), followed by mutations of G94A (12.2%) and T350G (9.9%). The rank orders of incidence of E6 variations in amino acid were as follows: D25E (46.3%), L83V (9.9%) and H78Y (4.3%). Nucleotide variations in LCR were found in all the 304 isolates from HPV16 positive cervical samples. The most commonly observed LCR variations were the transition replacement G7193T, 7434CIns, G7521A and 7863ADel (100%). The As lineage was associated with HPV persistent infections and with disease status of ≥CIN2,3. The EUR lineage variants showed a negative trend of association with the severity of ≥CIN2,3. Among 41 variations found in LCR, 25 (61.0%) were located at the binding sites for transcription factors. Occurrence of ≥CIN2,3 was significantly associated with the mutations of R10G/L83V in E6 and the C7294T co-variation in LCR, after adjusting for ages of infected patients.
Conclusions
Associations between As lineage and HPV persistent infections, and with disease status of ≥CIN2,3, and an association between the EUR lineage and negative trend of association with the severity of ≥CIN2,3 were found in this study. An association between a co-variation of R10G/L83V in E6 and C7294T in LCR and an increased risk for developing CIN-2,3 was found in a HPV16 infected population of Chinese women. These findings indicate that HPV16 polymorphism influences development of CIN-2,3.
doi:10.1186/1471-2407-13-459
PMCID: PMC3852402  PMID: 24099556
HPV16; E6; LCR; Cervical lesion
20.  The Condition-Dependent Transcriptional Landscape of Burkholderia pseudomallei 
PLoS Genetics  2013;9(9):e1003795.
Burkholderia pseudomallei (Bp), the causative agent of the often-deadly infectious disease melioidosis, contains one of the largest prokaryotic genomes sequenced to date, at 7.2 Mb with two large circular chromosomes (1 and 2). To comprehensively delineate the Bp transcriptome, we integrated whole-genome tiling array expression data of Bp exposed to >80 diverse physical, chemical, and biological conditions. Our results provide direct experimental support for the strand-specific expression of 5,467 Sanger protein-coding genes, 1,041 operons, and 766 non-coding RNAs. A large proportion of these transcripts displayed condition-dependent expression, consistent with them playing functional roles. The two Bp chromosomes exhibited dramatically different transcriptional landscapes — Chr 1 genes were highly and constitutively expressed, while Chr 2 genes exhibited mosaic expression where distinct subsets were expressed in a strongly condition-dependent manner. We identified dozens of cis-regulatory motifs associated with specific condition-dependent expression programs, and used the condition compendium to elucidate key biological processes associated with two complex pathogen phenotypes — quorum sensing and in vivo infection. Our results demonstrate the utility of a Bp condition-compendium as a community resource for biological discovery. Moreover, the observation that significant portions of the Bp virulence machinery can be activated by specific in vitro cues provides insights into Bp's capacity as an “accidental pathogen”, where genetic pathways used by the bacterium to survive in environmental niches may have also facilitated its ability to colonize human hosts.
Author Summary
Bacterial transcriptomes are dynamic, context-specific and condition-dependent. Infection by the soil bacterium, Burkholderia pseudomallei, causes melioidosis, an often fatal infectious disease of humans and animals. Possessing a large multi-chromosomal genome, B. pseudomallei is able to persist and survive in a multitude of environments. To obtain a comprehensive overview of B. pseudomallei expressed transcripts, we initiated whole-genome transcriptome profiling covering a broad spectrum of conditions and exposures — a so-called “condition compendium”. Using the compendium, we confirmed many previously-annotated genes and operons, and also identified hundreds of novel transcripts including anti-sense transcripts and non-coding RNAs. By systematically examining genes exhibiting highly similar expression patterns, we ascribed putative functions to previously uncharacterized genes, and identified novel regulatory elements controlling these expression patterns. We also used the compendium to elucidate candidate virulence pathways associated with quorum-sensing and infection in mice. Our study showcases the power of a B. pseudomallei condition compendium as a valuable resource for understanding microbial physiology and the pathogenesis of melioidosis.
doi:10.1371/journal.pgen.1003795
PMCID: PMC3772027  PMID: 24068961
21.  Primary Pericardial Mesothelioma: A Rare Entity 
Primary pericardial malignant mesothelioma is an extremely rare neoplasm that arises from the pericardial mesothelial cell layers. Clinical symptoms and signs are frequently nonspecific, and the diagnosis is usually made after surgery or at autopsy. There is no standard treatment for pericardial mesothelioma; nonetheless, radical surgery is the mainstay of therapy for localized disease. The neoplasm is highly aggressive and carries a dismal prognosis with an overall survival of less than six months. This paper presents a case study of a 68-year-old patient with a primary pericardial malignant mesothelioma. Radiologic evaluation revealed a small nodule in the posterior pericardium with pericardial and bilateral pleural effusions. The diagnosis was established after surgery by histological and immunohistochemical studies. The patient remained alive and free of disease for about 24 months; however, due to rapid local recurrence, the patient died 27 months after the surgical treatment.
doi:10.1155/2013/283601
PMCID: PMC3697233  PMID: 23840993
22.  Aberrant expression of DNA damage response proteins is associated with breast cancer subtype and clinical features 
Landmark studies of the status of DNA damage checkpoints and associated repair functions in preneoplastic and neoplastic cells has focused attention on importance of these pathways in cancer development, and inhibitors of repair pathways are in clinical trials for treatment of triple negative breast cancer. Cancer heterogeneity suggests that specific cancer subtypes will have distinct mechanisms of DNA damage survival, dependent on biological context. In this study, status of DNA damage response (DDR)-associated proteins was examined in breast cancer subtypes in association with clinical features; 479 breast cancers were examined for expression of DDR proteins γH2AX, BRCA1, pChk2, and p53, DNA damage-sensitive tumor suppressors Fhit and Wwox, and Wwox-interacting proteins Ap2α, Ap2γ, ErbB4, and correlations among proteins, tumor subtypes, and clinical features were assessed. In a multivariable model, triple negative cancers showed significantly reduced Fhit and Wwox, increased p53 and Ap2γ protein expression, and were significantly more likely than other subtype tumors to exhibit aberrant expression of two or more DDR-associated proteins. Disease-free survival was associated with subtype, Fhit and membrane ErbB4 expression level and aberrant expression of multiple DDR-associated proteins. These results suggest that definition of specific DNA repair and checkpoint defects in subgroups of triple negative cancer might identify new treatment targets. Expression of Wwox and its interactor, ErbB4, was highly significantly reduced in metastatic tissues vs. matched primary tissues, suggesting that Wwox signal pathway loss contributes to lymph node metastasis, perhaps by allowing survival of tumor cells that have detached from basement membranes, as proposed for the role of Wwox in ovarian cancer spread.
doi:10.1007/s10549-010-1248-6
PMCID: PMC3677189  PMID: 21069451
Triple negative breast cancer; DNA damage response proteins; Lymph node metastases; Fhit; Wwox; Tissue microarrays
23.  Genome Sequence of Pseudomonas putida Strain SJTE-1, a Bacterium Capable of Degrading Estrogens and Persistent Organic Pollutants 
Journal of Bacteriology  2012;194(17):4781-4782.
Pseudomonas putida strain SJTE-1 can utilize 17β-estradiol and other environmental estrogens/toxicants, such as estrone, and naphthalene as sole carbon sources. We report the draft genome sequence of strain SJTE-1 (5,551,505 bp, with a GC content of 62.25%) and major findings from its annotation, which could provide insights into its biodegradation mechanisms.
doi:10.1128/JB.01060-12
PMCID: PMC3415482  PMID: 22887678
24.  Genome Sequence of Pseudomonas aeruginosa Strain SJTD-1, a Bacterium Capable of Degrading Long-Chain Alkanes and Crude Oil 
Journal of Bacteriology  2012;194(17):4783-4784.
Pseudomonas aeruginosa strain SJTD-1 can utilize long-chain alkanes, diesel oil, and crude oil as sole carbon sources. We report the draft genome sequence of strain SJTD-1 (6,074,058 bp, with a GC content of 66.83%) and major findings from its annotation, which could provide insights into its petroleum biodegradation mechanism.
doi:10.1128/JB.01061-12
PMCID: PMC3415508  PMID: 22887679
25.  The Neural Pathway of Reflex Regulation of Electroacupuncture at Orofacial Acupoints on Gastric Functions in Rats 
Acupuncture has a reflex regulation in gastrointestinal functions, which is characterized with segment. In the present study, the neural pathway of electroacupuncture (EA) at orofacial acupoints (ST2) on gastric myoelectric activity (GMA) in rats was investigated. The results indicated that EA at ST2 facilitated spike bursts of GMA, which is similar to EA at limbs and opposite to EA at abdomen. The excitatory effect was abolished by the transaction of infraorbital nerves, dorsal vagal complex lesion, and vagotomy, respectively. In addition, microinjection of L-glutamate into the nucleus of the solitary tract (NTS) attenuated the excitatory effect. All these data suggest that the dorsal vagal complex is involved in the reflex regulation of EA at orofacial acupoints on gastric functions and NTS-dorsal motor nucleus of the vagus (DMV) inhibitory connections may be essential for it.
doi:10.1155/2012/753264
PMCID: PMC3549401  PMID: 23346213

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