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1.  Non-Contrast Enhanced MR Angiography of the Foot: Initial Experience of Using Flow Sensitive Dephasing (FSD) Prepared Steady-State Free Precession in Patients with Diabetes 
Radiology  2014;272(3):885-894.
To assess image quality and diagnostic performance of non-contrast enhanced MR angiography (NCE-MRA) using flow-sensitive dephasing (FSD) prepared steady-state free precession (SSFP) for the foot arteries in patients with diabetes.
Materials and Methods
This prospective study was approved by institutional review board and informed consent was obtained from all subjects. Thirty-two healthy volunteers and 38 diabetic patients who had been scheduled for lower extremity contrast-enhanced MRA (CE-MRA) were recruited for the NCE-MRA study on a 1.5T MR system. Image quality and diagnostic accuracy of NCE-MRA for detecting significant arterial stenosis (≥50%) were assessed by two independent reviewers using CE-MRA as reference standard. The difference of the percentage of diagnostic arterial segments on NCE-MRA between healthy volunteers and diabetic patient was evaluated using McNemar test and Generalized Estimating Equation (GEE) for correlated data. Signal-to-noise ratio (SNR) and artery-to-muscle contrast-to-noise ratio (CNR) of pedal arteries were measured and compared between the two MRA techniques using paired t-test.
All subjects successfully underwent NCE-MRA of the foot. NCE-MRA yielded a high percentage of diagnostic arterial segments obtained in both healthy volunteers (303/320=95%) and patients (341/370=92%) and there was no difference in the percentage between the two populations (p=0.195). In patients, the average SNR, and CNR on NCE-MRA was higher than those on CE-MRA (90.7± 38.1 vs. 81.7± 34.7, p=0.023, and 85.2 ± 33.2 vs. 76.6 ± 33.5, p=0.013, respectively.). The average sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of NCE-MRA were 35/40=88%, 107/115=93%, 35/43=81%, 107/112=96%, and 142/155=92%, respectively. Interobserver agreement between the two readers for diagnostic accuracy was good (k = 0.83).
NCE-MRA using FSD-prepared SSFP allows clear depiction of the foot arterial tree and accurate detection of significant arterial stenosis. The technique has the potential to be a safe and reliable screening tool for the assessment of foot arteries in diabetic patients without using gadolinium-based contrast agent.
PMCID: PMC4154940  PMID: 24758556
MR angiography; non-contrast enhanced; diabetes; foot arteries; steady-state free precession; flow-sensitive dephasing
2.  TLR3 Signaling in Macrophages Is Indispensable for the Protective Immunity of Invariant Natural Killer T Cells against Enterovirus 71 Infection 
PLoS Pathogens  2015;11(1):e1004613.
Enterovirus 71 (EV71) is the most virulent pathogen among enteroviruses that cause hand, foot and mouth disease in children but rarely in adults. The mechanisms that determine the age-dependent susceptibility remain largely unclear. Here, we found that the paucity of invariant natural killer T (iNKT) cells together with immaturity of the immune system was related to the susceptibility of neonatal mice to EV71 infection. iNKT cells were crucial antiviral effector cells to protect young mice from EV71 infection before their adaptive immune systems were fully mature. EV71 infection led to activation of iNKT cells depending on signaling through TLR3 but not other TLRs. Surprisingly, iNKT cell activation during EV71 infection required TLR3 signaling in macrophages, but not in dendritic cells (DCs). Mechanistically, interleukin (IL)-12 and endogenous CD1d-restricted antigens were both required for full activation of iNKT cells. Furthermore, CD1d-deficiency led to dramatically increased viral loads in central nervous system and more severe disease in EV71-infected mice. Altogether, our results suggest that iNKT cells may be involved in controlling EV71 infection in children when their adaptive immune systems are not fully developed, and also imply that iNKT cells might be an intervention target for treating EV71-infected patients.
Author Summary
Enterovirus 71 (EV71) is a major causative pathogen of hand, foot and mouth disease. EV71 infection occurs mainly in children but rarely in adults. The factors that determine the susceptibility of children to EV71 infection remain elusive. Here, we found that the paucity of invariant natural killer T (iNKT) cells in new-born mice was associated with their susceptibility to EV71 infection. Furthermore, iNKT cells played a critical role in protecting older young mice from EV71 infection before their adaptive immune systems were fully developed. Mechanistically, TLR3 signaling in macrophages, but not in dendritic cells, was essentially required for iNKT cell activation during EV71 infection. Both interleukin (IL)-12 production and endogenous lipid antigens presented by macrophages were required for full iNKT cell activation. iNKT cells tended to prevent the dissemination of EV71 into central nervous system. Taken together, our findings provide a new insight into the susceptibility of children to EV71 infection, and imply that the manipulation of iNKT cells might represent a potential therapeutic strategy for HFMD and other viral infectious diseases in children.
PMCID: PMC4304831  PMID: 25615690
3.  Parameterizing the Morse Potential for Coarse-Grained Modeling of Blood Plasma 
Journal of computational physics  2014;257(Pt A):726-736.
Multiscale simulations of fluids such as blood represent a major computational challenge of coupling the disparate spatiotemporal scales between molecular and macroscopic transport phenomena characterizing such complex fluids. In this paper, a coarse-grained (CG) particle model is developed for simulating blood flow by modifying the Morse potential, traditionally used in Molecular Dynamics for modeling vibrating structures. The modified Morse potential is parameterized with effective mass scales for reproducing blood viscous flow properties, including density, pressure, viscosity, compressibility and characteristic flow dynamics of human blood plasma fluid. The parameterization follows a standard inverse-problem approach in which the optimal micro parameters are systematically searched, by gradually decoupling loosely correlated parameter spaces, to match the macro physical quantities of viscous blood flow. The predictions of this particle based multiscale model compare favorably to classic viscous flow solutions such as Counter-Poiseuille and Couette flows. It demonstrates that such coarse grained particle model can be applied to replicate the dynamics of viscous blood flow, with the advantage of bridging the gap between macroscopic flow scales and the cellular scales characterizing blood flow that continuum based models fail to handle adequately.
PMCID: PMC4045626  PMID: 24910470
Morse potential; inverse problems; coarse-grained; blood plasma fluid
4.  Trends in HIV infection in the First Affiliated Hospital of Harbin, China 
BMC Infectious Diseases  2014;14:605.
Major hospitals in most Chinese cities have the capability to perform HIV testing. However, it is not a routine test for all patients and, as a result, many patients are not aware of their HIV status. To understand the rate of HIV infection and the factors associated with infection, we tested serum to determine HIV status and analyzed factors associated with HIV infection.
We collected blood samples from 348,151 patients who visited the First Affiliated Hospital of Harbin Medical University from 1 January 2007 to 31 December 2012. Serum was screened with an ELISA. If the test was positive, we conducted two additional ELISAs: a repeat with the initial kit and one with another kit. If there was a positive result with either of these two ELISA kits, western blotting was performed at Harbin Centers for Disease Control and Prevention.
The HIV positivity rate of inpatients significantly increased during the course of this study. HIV infection in patients appeared to differ by sex, age, occupation, marital status, educational level, and route of infection. HIV was more prevalent in men than in women. More than 80% of HIV-positive patients had not received higher (>12 years) education. From 2007 to 2012, HIV-positive patients were mainly infected through sexual transmission. For sexually acquired infections, the rate of HIV infections through homosexual contact has increased rapidly in recent years, and ranged from 36.4% to 65.1%.
The number of patients diagnosed as HIV positive has increased in recent years. Offering routine HIV testing in hospitals is feasible and can increase linkage to HIV care and treatment for many individuals.
PMCID: PMC4245807  PMID: 25422121
HIV testing; Early diagnosis; Inpatients; Hospital; China
5.  Identification and Expression Profiling of MicroRNAs in the Brain, Liver and Gonads of Marine Medaka (Oryzias melastigma) and in Response to Hypoxia 
PLoS ONE  2014;9(10):e110698.
The marine medaka (Oryzias melastigma) has been increasingly used as a fish model for detecting environmental stresses and chemical contaminants in the marine environment. Recent mammalian studies have shown that environmental stresses can alter the expression profiles of microRNAs (miRNAs), leading to transgenerational effects. Here, we use high-throughput Illumina RNA sequencing (RNA-Seq) for miRNA transcriptome analysis of brain, liver, and gonads from sexually mature male and female marine medaka. A total of 128,883,806 filtered sequence reads were generated from six small RNA libraries, identifying a total of 2,125,663 non-redundant sequences. These sequences were aligned and annotated to known animal miRNAs (miRBase) using the BLAST method. A total of 223 distinct miRNA types were identified, with the greatest number expressed in brain tissue. Our data suggested that 55 miRNA types from 34 families are common to all tested tissues, while some of the miRNAs are tissue-enriched or sex-enriched. Quantitative real-time PCR analysis further demonstrated that let-7a, miR-122, and miR-9-3p were downregulated in hypoxic female medaka, while miR-2184 was specifically upregulated in the testis of hypoxic male fish. This is the first study to identify miRNAs in O. melastigma using small RNA deep sequencing technology. Because miRNA expression is highly conserved between marine medaka and other vertebrates, marine medaka may serve as a good model for studies on the functional roles of miRNAs in hypoxia stress response and signaling in marine fish.
PMCID: PMC4211694  PMID: 25350659
6.  Phase transition and phase separation in multiferroic orthorhombic Dy1−xHoxMnO3 (0 ≤ x ≤ 1) 
Scientific Reports  2014;4:6506.
We report on structural, magnetic, ferroelectric, and thermodynamic properties of polycrystalline orthorhombic manganites Dy1−xHoxMnO3 for Ho substitution levels 0 ≤ x ≤ 1. This system offers a possibility to systemically modulate the multiferroicity of RMnO3 via tuning the A-site ionic radii as well as the A-site magnetism. The successive transition of the multiferroic ground state is traced from the bc-cycloidal (DyMnO3) to the E-type antiferromagnetic phase (HoMnO3). In the middle substitution range 0.4 < x < 0.5, the phase separation is prominent, which's residual may survive in an even wider range. Accompanied with the phase transition and phase separation, obvious enhancement of both the polarization and magnetoelectric response is observed. Our experimental study also confirmed that the rare earth (Dy/Ho)-Mn exchange striction is a crucial role in deciding the multiferroicity of manganites.
PMCID: PMC4179129  PMID: 25266322
7.  Responses to crizotinib in a patient with c-ros oncogene 1, receptor tyrosine kinase-positive advanced lung adenocarcinoma: A case report 
Oncology Letters  2014;8(6):2624-2626.
Rearrangements to the c-ros oncogene 1, receptor tyrosine kinase (ROS1) gene are reported in 1–2% of lung adenocarcinomas. These rearrangements are associated with a response to the small-molecule tyrosine kinase inhibitor crizotinib. ROS1 rearrangements can be detected using fluorescence in situ hybridization (FISH), which is considered the gold standard technique in detecting ROS1 rearrangements, and determining whether a patient would respond well to crizotinib treatment. However, FISH is an expensive and time-consuming assay, requiring specialized microscopy equipment and some level of technical expertise. The present report describes the case of a patient with advanced lung adenocarcinoma, who was identified to be negative for ROS-1 rearrangements by FISH, but positive by immunohistochemistry (IHC). The health of the patient improved following treatment with crizotinib. These results indicate that IHC assay could be an alternative option for the detection of ROS1 gene rearrangements.
PMCID: PMC4214434  PMID: 25364439
non-small cell lung cancer; gene rearrangements; receptor tyrosine kinase 1; immunohistochemistry; crizotinib; partial responses
8.  Monitoring the kinetics of the pH driven transition of the anthrax toxin prepore to the pore by biolayer interferometry and surface plasmon resonance 
Biochemistry  2013;52(37):6335-6347.
Domain 2 of the anthrax protective antigen (PA) prepore heptamer unfolds and refolds during endosome acidification to generate an extended 100 Å beta barrel pore that inserts into the endosomal membrane. The PA pore facilitates the pH dependent unfolding and translocation of bound toxin enzymic components, lethal factor (LF) and/or edema factor (EF), from the endosome into the cytoplasm. We constructed immobilized complexes of the prepore with the PA-binding domain of LF (LFN) to monitor the real-time prepore to pore kinetic transition using surface plasmon resonance (SPR) and bio-layer interferometry (BLI). The kinetics of this transition increased as the solution pH was decreased from pH 7.5 to pH 5.0, mirroring acidification of the endosome. Once transitioned, the LFN-PA pore complex was removed from the BLI biosensor tip and deposited onto EM grids, where the PA pore formation was confirmed by negative stain electron microscopy. When the soluble receptor domain (ANTRX2/CMG2) binds the immobilized PA prepore, the transition to the pore state was observed only after the pH was lowered to early or late endosomal pH conditions (5.5 to 5.0 respectively). Once the pore formed, the soluble receptor readily dissociated from the PA pore. Separate binding experiments with immobilized PA pores and soluble receptor indicate that the receptor has a weakened propensity to bind to the transitioned pore. This immobilized anthrax toxin platform can be used to identify or validate potential antimicrobial lead compounds capable of regulating and/or inhibiting anthrax toxin complex formation or pore transitions.
PMCID: PMC3790466  PMID: 23964683
9.  Genomic Analysis of the Pacific Oyster (Crassostrea gigas) Reveals Possible Conservation of Vertebrate Sex Determination in a Mollusc 
G3: Genes|Genomes|Genetics  2014;4(11):2207-2217.
Despite the prevalence of sex in animal kingdom, we have only limited understanding of how sex is determined and evolved in many taxa. The mollusc Pacific oyster Crassostrea gigas exhibits complex modes of sexual reproduction that consists of protandric dioecy, sex change, and occasional hermaphroditism. This complex system is controlled by both environmental and genetic factors through unknown molecular mechanisms. In this study, we investigated genes related to sex-determining pathways in C. gigas through transcriptome sequencing and analysis of female and male gonads. Our analysis identified or confirmed novel homologs in the oyster of key sex-determining genes (SoxH or Sry-like and FoxL2) that were thought to be vertebrate-specific. Their expression profile in C. gigas is consistent with conserved roles in sex determination, under a proposed model where a novel testis-determining CgSoxH may serve as a primary regulator, directly or indirectly interacting with a testis-promoting CgDsx and an ovary-promoting CgFoxL2. Our findings plus previous results suggest that key vertebrate sex-determining genes such as Sry and FoxL2 may not be inventions of vertebrates. The presence of such genes in a mollusc with expression profiles consistent with expected roles in sex determination suggest that sex determination may be deeply conserved in animals, despite rapid evolution of the regulatory pathways that in C. gigas may involve both genetic and environmental factors.
PMCID: PMC4232546  PMID: 25213692
sex determination; doublesex; Sry; FoxL2; oyster; Mollusca
10.  Function of SREBP1 in the Milk Fat Synthesis of Dairy Cow Mammary Epithelial Cells 
Sterol regulatory element-binding proteins (SREBPs) belong to a family of nuclear transcription factors. The question of which is the most important positive regulator in milk fat synthesis in dairy cow mammary epithelial cells (DCMECs) between SREBPs or other nuclear transcription factors, such as peroxisome proliferator-activated receptor γ (PPARγ), remains a controversial one. Recent studies have found that mTORC1 (the mammalian target of rapamycin C1) regulates SREBP1 to promote fat synthesis. Thus far, however, the interaction between the SREBP1 and mTOR (the mammalian target of rapamycin) pathways in the regulation of milk fat synthesis remains poorly understood. This study aimed to identify the function of SREBP1 in milk fat synthesis and to characterize the relationship between SREBP1 and mTOR in DCMECs. The effects of SREBP1 overexpression and gene silencing on milk fat synthesis and the effects of stearic acid and serum on SREBP1 expression in the upregulation of milk fat synthesis were investigated in DCMECs using immunostaining, Western blotting, real-time quantitative PCR, lipid droplet staining, and detection kits for triglyceride content. SREBP1 was found to be a positive regulator of milk fat synthesis and was shown to be regulated by stearic acid and serum. These findings indicate that SREBP1 is the key positive regulator in milk fat synthesis.
PMCID: PMC4200870  PMID: 25250914
SREBPs; mTOR; dairy cow mammary epithelial cells; milk fat synthesis
11.  Melatonin promotes ripening and improves quality of tomato fruit during postharvest life 
Journal of Experimental Botany  2014;66(3):657-668.
Tomato fruits were treated by exogenous melatonin. The effect of melatonin on ethylene biosynthesis, ethylene perception, and ethylene signalling may contribute to fruit ripening and quality improvement in tomato.
In this study, the effect of melatonin on the postharvest ripening and quality improvement of tomato fruit was carried out. The tomatoes were immersed in exogenous melatonin for 2h, and then the related physiological indicators and the expression of genes during post-harvest life were evaluated. Compared with control check (CK), the 50 µM melatonin treatment significantly increased lycopene levels by 5.8-fold. Meanwhile, the key genes involved in fruit colour development, including phytoene synthase1 (PSY1) and carotenoid isomerase (CRTISO), showed a 2-fold increase in expression levels. The rate of water loss from tomato fruit also increased 8.3%, and the expression of aquaporin genes, such as SlPIP12Q, SlPIPQ, SlPIP21Q, and SlPIP22, was up-regulated 2- to 3-fold under 50 µM melatonin treatment. In addition, 50 µM melatonin treatment enhanced fruit softening, increased water-soluble pectin by 22.5%, and decreased protopectin by 19.5%. The expression of the cell wall modifying proteins polygalacturonase (PG), pectin esterase1 (PE1), β-galactosidase (TBG4), and expansin1 (Exp1) was up-regulated under 50 µM melatonin treatment. Melatonin increased ethylene production by 27.1%, accelerated the climacteric phase, and influenced the ethylene signalling pathway. Alteration of ethylene production correlated with altered 1-aminocyclopropane-1-carboxylic acid (ACC) synthase (ACS4) expression. The expression of ethylene signal transduction-related genes such as NR, SlETR4, SlEIL1, SlEIL3, and SlERF2, was enhanced by 50 µM melatonin. The effect of melatonin on ethylene biosynthesis, ethylene perception, and ethylene signalling may contribute to fruit ripening and quality improvement in tomato. This research may promote the application of melatonin on postharvest ripening and quality improvement of tomato fruit as well as other horticultural productions in the future.
PMCID: PMC4321535  PMID: 25147270
Ethylene; gene expression; melatonin; postharvest; ripening; tomato.
12.  Grey Situation Group Decision-Making Method Based on Prospect Theory 
The Scientific World Journal  2014;2014:703597.
This paper puts forward a grey situation group decision-making method on the basis of prospect theory, in view of the grey situation group decision-making problems that decisions are often made by multiple decision experts and those experts have risk preferences. The method takes the positive and negative ideal situation distance as reference points, defines positive and negative prospect value function, and introduces decision experts' risk preference into grey situation decision-making to make the final decision be more in line with decision experts' psychological behavior. Based on TOPSIS method, this paper determines the weight of each decision expert, sets up comprehensive prospect value matrix for decision experts' evaluation, and finally determines the optimal situation. At last, this paper verifies the effectiveness and feasibility of the method by means of a specific example.
PMCID: PMC4146360  PMID: 25197706
13.  The Influence of Precipitation Regimes and Elevated CO2 on Photosynthesis and Biomass Accumulation and Partitioning in Seedlings of the Rhizomatous Perennial Grass Leymus chinensis 
PLoS ONE  2014;9(8):e103633.
Leymus chinensis is a dominant, rhizomatous perennial C3 species in the grasslands of Songnen Plain of Northern China, and its productivity has decreased year by year. To determine how productivity of this species responds to different precipitation regimes, elevated CO2 and their interaction in future, we measured photosynthetic parameters, along with the accumulation and partitioning of biomass. Plants were subjected to combinations of three precipitation gradients (normal precipitation, versus normal ± 40%) and two CO2 levels (380±20 µmol mol-1,760±20 µmol mol-1) in controlled-environment chambers. The net photosynthetic rate, and above-ground and total biomass increased due to both elevated CO2 and increasing precipitation, but not significantly so when precipitation increased from the normal to high level under CO2 enrichment. Water use efficiency and the ratio of root: total biomass increased significantly when precipitation was low, but decreased when it was high under CO2 enrichment. Moreover, high precipitation at the elevated level of CO2 increased the ratio between stem biomass and total biomass. The effect of elevated CO2 on photosynthesis and biomass accumulation was higher at the low level of precipitation than with normal or high precipitation. The results suggest that at ambient CO2 levels, the net photosynthetic rate and biomass of L. chinensis increase with precipitation, but those measures are not further affected by additional precipitation when CO2 is elevated. Furthermore, CO2 may partly compensate for the negative effect of low precipitation on the growth and development of L. chinensis.
PMCID: PMC4122356  PMID: 25093814
14.  The association of PTPN22 rs2476601 polymorphism and CTLA-4 rs231775 polymorphism with LADA risks: a systematic review and meta-analysis 
Acta Diabetologica  2014;51(5):691-703.
Although the polymorphisms of PTPN22 and the variants of CTLA-4 have been reported to be the susceptibility genes, which increased risk of latent autoimmune diabetes in adults (LADA), the results remained inconclusive. The aim of this meta-analysis was to evaluate the association between the polymorphisms of two genes and LADA. We performed a systematic review by identifying relevant studies and applied meta-analysis to pool gene effects. Data from ten studies published between 2001 and 2013 were pooled for two polymorphisms: rs2476601 in the PTPN22 gene and rs231775 in the CTLA-4 gene. Data extraction and assessments for risk of bias were independently performed by two reviewers. Fixed-effect model and random-effect model were used to pool the odds ratios; meanwhile, heterogeneity test, publication bias and sensitive analysis were explored. The minor T allele at rs2476601 and the minor G at rs231775 carried estimated relative risks (odds ratio) of 1.52 (95 % CI 1.29–1.79) and 1.39 (95 % CI 1.11–1.74), respectively. These alleles contributed to an absolute lowering of the risk of all LADA by 4.88 and 14.93 % when individuals do not carry these alleles. The estimated lambdas were 0.49 and 0.63, suggesting a codominant model of effects was most likely for two genes. In summary, our systematic review has demonstrated that PTPN22 rs2476601 and CTLA-4 rs231775 are potential risk factors for LADA. An updated meta-analysis is required when more studies are published to increase the power of these polymorphisms and LADA.
Electronic supplementary material
The online version of this article (doi:10.1007/s00592-014-0613-z) contains supplementary material, which is available to authorized users.
PMCID: PMC4176954  PMID: 25005490
PTPN22; CTLA-4; Polymorphism; LADA; Systematic review; Meta-analysis
15.  Effects of dimethyl sulfoxide on asymmetric division and cytokinesis in mouse oocytes 
Dimethyl sulfoxide (DMSO) is used extensively as a permeable cryoprotectant and is a common solvent utilized for several water-insoluble substances. DMSO has various biological and pharmacological activities; however, the effect of DMSO on mouse oocyte meiotic maturation remains unknown.
In DMSO-treated oocytes, we observed abnormal MII oocytes that contained large polar bodies, including 2-cell–like MII oocytes, during in vitro maturation. Oocyte polarization did not occur, due to the absence of actin cap formation and spindle migration. These features are among the primary causes of abnormal symmetric division; however, analysis of the mRNA expression levels of genes related to asymmetric division revealed no significant difference in the expression of these factors between the 3% DMSO-treated group and the control group. After each “blastomere” of the 2-cell–like MII stage oocytes was injected by one sperm head respectively, the oocytes still possessed the ability to extrude the second polar body from each “blastomere” and to begin cleavage. However, MII oocytes with large polar bodies developed to the blastocyst stage after intracytoplasmic sperm injection (ICSI). Furthermore, other permeable cryoprotectants, such as ethylene glycol and glycerol, also caused asymmetric division failure.
Permeable cryoprotectants, such as DMSO, ethylene glycol, and glycerol, affect asymmetric division. DMSO disrupts cytokinesis completion by inhibiting cortical reorganization and polarization. Oocytes that undergo symmetric division maintain the ability to begin cleavage after ICSI.
PMCID: PMC4074394  PMID: 24953160
Dimethyl sulfoxide (DMSO); Asymmetric division; Actin cap; Spindle migration; Oocyte maturation
16.  TC-1 Overexpression Promotes Cell Proliferation in Human Non-Small Cell Lung Cancer that Can Be Inhibited by PD173074 
PLoS ONE  2014;9(6):e100075.
Thyroid cancer-1 (TC-1), a natively disordered protein, is widely expressed in vertebrates and overexpressed in many kinds of tumors. However, its exact role and regulation mechanism in human non-small cell lung cancer (NSCLC) are still unclear. In the present study, we found that TC-1 is highly expressed in NSCLC and that its aberrant expression is strongly associated with NSCLC cell proliferation. Exogenous TC-1 overexpression promotes cell proliferation, accelerates the cell G1-to-S-phase transition, and reduces apoptosis in NSCLC. The knockdown of TC-1, however, inhibits NSCLC cell proliferation, cycle transition, and apoptosis resistance. Furthermore, we also demonstrated that PD173074, which functions as an inhibitor of the TC-1 in NSCLC, decreases the expression of TC-1 and inhibits TC-1 overexpression mediated cell proliferation in vitro and in vivo. Nevertheless, the inhibition function of PD173074 on NSCLC cell proliferation was eliminated in cells with TC-1 knockdown. These results suggest that PD173074 plays a significant role in TC-1 overexpression mediated NSCLC cell proliferation and may be a potential intervention target for the prevention of cell proliferation in NSCLC.
PMCID: PMC4062440  PMID: 24941347
17.  Selection and Expression Profiles of Reference Genes in Mouse Preimplantation Embryos of Different Ploidies at Various Developmental Stages 
PLoS ONE  2014;9(6):e98956.
Real-time reverse transcription quantitative polymerase chain reaction (qPCR) has become the most frequently used system for studies of gene expression. Manystudies have provided reliable evidence that the transcription levels of reference genes are not constant at different developmental stages and in different experimental conditions. However, suitable reference genes which are stably expressed in polyploid preimplantation embryos of different developmental stages have not yet been identified. Therefore, it is critical to verify candidate reference genes to analyze gene expression accurately in both diploid and polyploid embryos. We examined the expression levels of 12 candidate reference genes in preimplantation embryos of four different ploidies at six developmental stages. Stability analysis of the reference genes was performed by four independent software programs, and the stability of three genes was evaluated by comparison with the Oct4 expression level during preimplantation development in diploid embryos. The expression levels of most genes in the polyploid embryos were higher than that in the diploid embryos, but the increasing degree were disproportionate with the ploidies. There were no significant difference in reference gene expressions among embryos of different ploidies when they reached the morula stage, and the expression level remained flat until the blastocyst stage. Ubc, Ppia, and Pgk1 were the three most stable reference genes in diploid and polyploid embryos.
PMCID: PMC4057156  PMID: 24927500
18.  Preclinical studies of N3-O-toluyl-fluorouracil-loaded lipid-based nanosuspensions in H22-bearing mice 
N3-O-toluyl-fluorouracil (TFU) is a potential antitumor prodrug of 5-fluorouracil (5-FU), but its poor solubility has limited its use in clinic. This study aimed to improve the bioavailability of TFU by preparing TFU-loaded lipid-based nanosuspensions (TFU-LNS) and perform a preclinical evaluation.
TFU-LNS were prepared through high-pressure homogenization and were lyophilized afterwards. For in vitro test, the physicochemical properties and cytotoxicity against HegG2 cells were conducted. For in vivo evaluation, the pharmacokinetics, tissue distribution, and antitumor efficacy were investigated in H22-bearing Kunming mice.
TFU showed different degradability in four media; in particular, nearly all of it converted to an equimolar amount of 5-FU in blank plasma of Wistar rats. The lyophilized TFU-LNS had a mean particle size of 180.03±3.11 nm and zeta potential of −8.02±1.43 mV and showed no discernible changes after storage at 4°C for 3 months. In the in vivo antitumor study, the antitumor efficacy of TFU-LNS was consistent with that of 5-FU injection. Furthermore, TFU-LNS released a lower concentration of 5-FU in heart and kidney throughout the tissue distribution studies.
TFU-LNS exhibited convincing antitumor activity and easy scale-up opportunity, which suggests that TFU-LNS might be a promising drug delivery system for cancer therapy.
PMCID: PMC4045086  PMID: 24920908
5-fluorouracil; high-pressure homogenization; cytotoxicity; cancer therapy
19.  A Three-Stage Birandom Program for Unit Commitment with Wind Power Uncertainty 
The Scientific World Journal  2014;2014:583157.
The integration of large-scale wind power adds a significant uncertainty to power system planning and operating. The wind forecast error is decreased with the forecast horizon, particularly when it is from one day to several hours ahead. Integrating intraday unit commitment (UC) adjustment process based on updated ultra-short term wind forecast information is one way to improve the dispatching results. A novel three-stage UC decision method, in which the day-ahead UC decisions are determined in the first stage, the intraday UC adjustment decisions of subfast start units are determined in the second stage, and the UC decisions of fast-start units and dispatching decisions are determined in the third stage is presented. Accordingly, a three-stage birandom UC model is presented, in which the intraday hours-ahead forecasted wind power is formulated as a birandom variable, and the intraday UC adjustment event is formulated as a birandom event. The equilibrium chance constraint is employed to ensure the reliability requirement. A birandom simulation based hybrid genetic algorithm is designed to solve the proposed model. Some computational results indicate that the proposed model provides UC decisions with lower expected total costs.
PMCID: PMC4060537  PMID: 24987739
20.  The Influence of Education on Chinese Version of Montreal Cognitive Assessment in Detecting Amnesic Mild Cognitive Impairment among Older People in a Beijing Rural Community 
The Scientific World Journal  2014;2014:689456.
To assess the influence of education on the performance of Chinese version of Montreal cognitive assessment (C-MoCA) in relation to the mini-mental state examination (MMSE) in detecting amnesic mild cognitive impairment (aMCI) among rural-dwelling older people C-MoCA and MMSE was administered and diagnostic interviews were conducted among community-dwelling elderly in two villages in Beijing. The performance of C-MoCA and MMSE in detecting aMCI was evaluated by the area under the ROC curve (AUC). Effect size of education on variations in C-MoCA scores was estimated with general linear model. Among 172 study participants (24 cases of aMCI and 148 normal controls), the AUC of C-MoCA was 0.72 (95% CI = 0.62–0.81, cutoff = 20/21), compared to AUC of MMSE of 0.74 (95% CI = 0.64–0.84, cutoff = 26/27). The performance of both C-MoCA and MMSE was especially poorer among those with low (0–6 years) education. After controlling for gender and age, education (η2 = 0.204) had a surpassing effect over aMCI diagnosis (η2 = 0.052) on variations in C-MoCA scores. Among rural older people, the MoCA showed modest accuracy and was no better than MMSE in detecting aMCI, especially in those with low education, due to the overwhelming effect of education relative to aMCI diagnosis on variations in C-MoCA performance.
PMCID: PMC4058117  PMID: 24982978
21.  The negative interplay between Aurora A/B and BRCA1/2 controls cancer cell growth and tumorigenesis via distinct regulation of cell cycle progression, cytokinesis, and tetraploidy 
Molecular Cancer  2014;13:94.
It is well known that the activation of Aurora A/B (Aur A/B) or inactivation of BRCA1/2 induces tumor formation. Others and we have reported that the mutual suppression between Aur A/B and BRCA1/2 may manipulate cancer cell growth and tumorigenesis, however, the interactive regulation and mechanism between these molecules are still elusive. In this study, by consecutive silencing of Aur A/B or/and BRCA1/2 with specific shRNAs, we showed that, in BRCA2-deficient pancreatic cancer cell line Capan-1 and in ovarian cancer cell line OVCA433, Aur A/B and BRCA1/2 inversely regulated the expression of each other likely through proteasome-mediated proteolysis but not through gene transcription. Aur A/B and BRCA1/2 conversely regulated cell cycle progression mainly through control of p53 and cyclin A. Moreover, the disruption of Aur A/B blocked abnormal cytokinesis and decreased cell multinuclearity and chromosome tetraploidy, whereas the deprivation of BRCA1/2 promoted the abnormal cytokinesis and enhanced the cell multinuclearity and tetraploidy. Furthermore, we showed by animal assays that the depletion of Aur A/B inhibited tumor growth of both cell lines, while the knockdown of BRCA1/2 promoted the tumor growth. However, the concurrent silencing of Aur A/B and BRCA1/2 diminished the effects of these molecules on the regulation of cell cycle, cytokinesis, and tetraploidy, leading to the burdened tumor sizes similar to those induced by scrambled shRNA-treated control cells. In summary, our study revealed that the negative interplay between Aur A/B and BRCA1/2 inversely controls the cell proliferation, cell cycle progression, cell multinuclearity, and tetraploidization to modulate tumorigenesis.
PMCID: PMC4028103  PMID: 24775809
Aurora A/B; BRCA1/2; Cell cycle; Cytokinesis; Tetraploidy; Tumorigenesis
22.  Effects of Chinese Medicine Tong xinluo on Diabetic Nephropathy via Inhibiting TGF-β1-Induced Epithelial-to-Mesenchymal Transition 
Diabetic nephropathy (DN) is a major cause of chronic kidney failure and characterized by interstitial and glomeruli fibrosis. Epithelial-to-mesenchymal transition (EMT) plays an important role in the pathogenesis of DN. Tong xinluo (TXL), a Chinese herbal compound, has been used in China with established therapeutic efficacy in patients with DN. To investigate the molecular mechanism of TXL improving DN, KK-Ay mice were selected as models for the evaluation of pathogenesis and treatment in DN. In vitro, TGF-β1 was used to induce EMT. Western blot (WB), immunofluorescence staining, and real-time polymerase chain reaction (RT-PCR) were applied to detect the changes of EMT markers in vivo and in vitro, respectively. Results showed the expressions of TGF-β1 and its downstream proteins smad3/p-smad3 were greatly reduced in TXL group; meantime, TXL restored the expression of smad7. As a result, the expressions of collagen IV (Col IV) and fibronectin (FN) were significantly decreased in TXL group. In vivo, 24 h-UAER (24-hour urine albumin excretion ratio) and BUN (blood urea nitrogen) were decreased and Ccr (creatinine clearance ratio) was increased in TXL group compared with DN group. In summary, the present study demonstrates that TXL successfully inhibits TGF-β1-induced epithelial-to-mesenchymal transition in DN, which may account for the therapeutic efficacy in TXL-mediated renoprotection.
PMCID: PMC4016864  PMID: 24864150
23.  Identification of adipophilin as a potential diagnostic tumor marker for lung adenocarcinoma 
In our previous study, the upregulation of adipophilin in lung adenocarcinoma were identified compared with normal lung tissues by quantitative proteomics. In this study, our aim was to verify the result from quantitative proteomics, further investigate the relationship between adipophilin expression and clinicopathologic factors of lung cancer patients. The expression levels of adipophilin were examined in 10 pairs of lung adenocarcinoma and normal lung tissues using western blotting and the expression and cellular distribution of adipophilin were determined by IHC in 62 formalin-fixed and paraffin embedded primary lung cancer specimens. Adipophilin expression was significantly higher in lung adenocarcinoma specimens than in normal tissues and lung squamous cell carcinomas (P<0.05). There were no significant difference of adipophilin expression between lung squamous cell carcinomas and normal lung tissues. The expression of adipophilin in lung cancer did not correlate with any clinicopathologic factors such as lymph node metastasis, patients’ age, gender, tumor size, grade, and TNM stage. In Conclusion, Adipophilin was upregulated in lung adenocarcinoma, suggesting that adipophilin play an important role in tumorigenesis of lung adenocarcinoma and may serve as a potential marker for lung adenocarcinoma.
PMCID: PMC4057887  PMID: 24955208
Adipophilin; lung cancer; western blotting; immunohistochemistry
24.  Development of a Proficiency Testing Program for the HIV-1 BED Incidence Assay in China 
Scientific Reports  2014;4:4512.
The HIV-1 BED incidence assay was adopted in China in 2005 for HIV-1 incidence surveillance. A proficiency testing (PT) program was established in 2006 to provide quality assurance services. The BED PT program consisted of two components, an international program provided by the U.S. Centers for Disease Control and Prevention from 2006 and a domestic program started by the National HIV/HCV Reference Laboratory in 2011. Each PT panel consisted of eight coded specimens distributed to participating laboratories semi-annually, and testing results were collected and analyzed. The number of participating laboratories increased progressively from 2006 to 2012. The Chinese HIV-1 incidence laboratory network performed satisfactorily both in international and domestic PT programs. We also demonstrated that the BED assay was highly reproducible among participating laboratories. Our success and lessons learned can be readily replicated in other countries or regions contemplating the establishment of a PT program for assay-based HIV incidence estimation.
PMCID: PMC3968539  PMID: 24676229
25.  Arabidopsis Transcriptome Analysis Reveals Key Roles of Melatonin in Plant Defense Systems 
PLoS ONE  2014;9(3):e93462.
Melatonin is a ubiquitous molecule and exists across kingdoms including plant species. Studies on melatonin in plants have mainly focused on its physiological influence on growth and development, and on its biosynthesis. Much less attention has been drawn to its affect on genome-wide gene expression. To comprehensively investigate the role(s) of melatonin at the genomics level, we utilized mRNA-seq technology to analyze Arabidopsis plants subjected to a 16-hour 100 pM (low) and 1 mM (high) melatonin treatment. The expression profiles were analyzed to identify differentially expressed genes. 100 pM melatonin treatment significantly affected the expression of only 81 genes with 51 down-regulated and 30 up-regulated. However, 1 mM melatonin significantly altered 1308 genes with 566 up-regulated and 742 down-regulated. Not all genes altered by low melatonin were affected by high melatonin, indicating different roles of melatonin in regulation of plant growth and development under low and high concentrations. Furthermore, a large number of genes altered by melatonin were involved in plant stress defense. Transcript levels for many stress receptors, kinases, and stress-associated calcium signals were up-regulated. The majority of transcription factors identified were also involved in plant stress defense. Additionally, most identified genes in ABA, ET, SA and JA pathways were up-regulated, while genes pertaining to auxin responses and signaling, peroxidases, and those associated with cell wall synthesis and modifications were mostly down-regulated. Our results indicate critical roles of melatonin in plant defense against various environmental stresses, and provide a framework for functional analysis of genes in melatonin-mediated signaling pathways.
PMCID: PMC3969325  PMID: 24682084

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