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1.  Adaptation and Attenuation of Duck Tembusu Virus Strain Du/CH/LSD/110128 following Serial Passage in Chicken Embryos 
Duck Tembusu virus (DTMUV) is a newly emerging pathogenic flavivirus that has caused massive economic losses to the duck industry in China. In the current study, a virulent strain of DTMUV, designated Du/CH/LSD/110128, was isolated from the livers of diseased ducks and attenuated by serial passage in embryonated chicken eggs. The virus was partially attenuated after 50 and 70 passages and was fully attenuated after 90 passages, based on mortality and morbidity rates and viral loads in inoculated ducklings. Fourteen amino acid substitutions were observed in the capsid, prM, envelope, NS1, NS3, NS4A, NS4B, and NS5 proteins of the fully attenuated strain of Du/CH/LSD/110128, which might be responsible for the observed changes in replication and pathogenicity. A 72-nucleotide deletion was also observed in the 3′ untranslated region of the virus after 30 passages. The fully attenuated virus retained the immunogenicity of the parental strain, providing effective protection to challenge with virulent Du/CH/LSD/110128, and may represent a suitable candidate as a vaccine strain against DTMUV infection in ducks. Our results also lay the foundation for future studies on the replication and pathogenic mechanisms of DTMUV.
doi:10.1128/CVI.00154-14
PMCID: PMC4135909  PMID: 24872514
2.  Two-Dimensional Echocardiography in the Assessment of Long-Term Prognosis in Patients with Pulmonary Arterial Hypertension 
PLoS ONE  2014;9(12):e114443.
Objective
To investigate the relationship between cardiac diastolic dysfunction and outcomes in patients with pulmonary arterial hypertension (PAH) and to clarify the potential effect of two-dimensional echocardiography (2D-echo) on prognostic value in patients with PAH.
Methods
Patients diagnosed with PAH (as WSPH (World Symposia on Pulmonary Hypertension) classification I) confirmed by right heart catheterization (RHC), received targeted monotherapy or combination therapy. 2D-echo parameters, World Health Organization (WHO) functional classification and 6-minute walking distance (6MWD) were recorded. The clinical prognosis of patients was assessed by the correlation between echo parameters and clinical 6MWD using receiver operating characteristic (ROC) curve analysis.
Results
Fifty-eight patients were included. Left and right ventricular diastolic dysfunction (LVDD and RVDD) scores measured by 2D-echo had good correlation with 6MWD at baseline (rLVDD  = −0.699; rRVDD  = −0.818, both P<0.001) and at last follow-up (rLVDD  = −0.701; rRVDD  = −0.666, both P<0.001). Furthermore, bi-ventricular (LVDD+RVDD) scores measured by 2D-echo had a better correlation with 6MWD at baseline and last follow-up (r = −0.831; r = −0.771, both P<0.001). ROC curve analysis showed that the area under curves (AUCs) for LVDD score, RVDD score and (LVDD+RVDD) scores were 0.823 (P<0.0001), 0.737 (P = 0.0002), and 0.825 (P<0.0001), respectively. Compared with ROC analysis of other single parameters, cardiac diastolic function score was more accurate in predicting survival in patients with PAH.
Conclusion
LVDD score, RVDD score and (LVDD+RVDD) scores yielded a comprehensive quantitative assessment of LV and RV diastolic function that correlated moderately with clinical functional parameters and might be useful in the assessment of PAH.
doi:10.1371/journal.pone.0114443
PMCID: PMC4259339  PMID: 25485890
3.  Comparative study of bioactivity of collagen scaffolds coated with graphene oxide and reduced graphene oxide 
Background
Graphene oxide (GO) is a single layer carbon sheet with a thickness of less than 1 nm. GO has good dispersibility due to surface modifications with numerous functional groups. Reduced graphene oxide (RGO) is produced via the reduction of GO, and has lower dispersibility. We examined the bioactivity of GO and RGO films, and collagen scaffolds coated with GO and RGO.
Methods
GO and RGO films were fabricated on a culture dish. Some GO films were chemically reduced using either ascorbic acid or sodium hydrosulfite solution, resulting in preparation of RGO films. The biological properties of each film were evaluated by scanning electron microscopy (SEM), atomic force microscopy, calcium adsorption tests, and MC3T3-E1 cell seeding. Subsequently, GO- and RGO-coated collagen scaffolds were prepared and characterized by SEM and compression tests. Each scaffold was implanted into subcutaneous tissue on the backs of rats. Measurements of DNA content and cell ingrowth areas of implanted scaffolds were performed 10 days post-surgery.
Results
The results show that GO and RGO possess different biological properties. Calcium adsorption and alkaline phosphatase activity were strongly enhanced by RGO, suggesting that RGO is effective for osteogenic differentiation. SEM showed that RGO-modified collagen scaffolds have rough, irregular surfaces. The compressive strengths of GO- and RGO-coated scaffolds were approximately 1.7-fold and 2.7-fold greater, respectively, when compared with the non-coated scaffold. Tissue ingrowth rate was 39% in RGO-coated scaffolds, as compared to 20% in the GO-coated scaffold and 16% in the non-coated scaffold.
Conclusion
In summary, these results suggest that GO and RGO coatings provide different biological properties to collagen scaffolds, and that RGO-coated scaffolds are more bioactive than GO-coated scaffolds.
doi:10.2147/IJN.S62342
PMCID: PMC4103921  PMID: 25050063
GO; RGO; tissue engineering; regenerative scaffold; cell ingrowth; biomaterials
4.  Clinical Malaria along the China–Myanmar Border, Yunnan Province, China, January 2011–August 2012 
Emerging Infectious Diseases  2014;20(4):675-678.
Passive surveillance for malaria cases was conducted in Yunnan Province, China, along the China–Myanmar border. Infection with Plasmodium vivax and P. falciparum protozoa accounted for 69% and 28% of the cases, respectively. Most patients were adult men. Cross-border travel into Myanmar was a key risk factor for P. falciparum malaria in China.
doi:10.3201/eid2004.130647
PMCID: PMC3966361  PMID: 24656298
Plasmodium falciparum; Plasmodium vivax; clinical malaria; age distribution; sex distribution; cross-border travel; Yunnan Province; China; Myanmar; malaria; vector-borne infections; China; parasite; protozoa
5.  The Membrane-Associated Transcription Factor NAC089 Controls ER-Stress-Induced Programmed Cell Death in Plants 
PLoS Genetics  2014;10(3):e1004243.
The unfolded protein response (UPR) is activated to sustain cell survival by reducing misfolded protein accumulation in the endoplasmic reticulum (ER). The UPR also promotes programmed cell death (PCD) when the ER stress is severe; however, the underlying molecular mechanisms are less understood, especially in plants. Previously, two membrane-associated transcriptions factors (MTFs), bZIP28 and bZIP60, were identified as the key regulators for cell survival in the plant ER stress response. Here, we report the identification of another MTF, NAC089, as an important PCD regulator in Arabidopsis (Arabidopsis thaliana) plants. NAC089 relocates from the ER membrane to the nucleus under ER stress conditions. Inducible expression of a truncated form of NAC089, in which the transmembrane domain is deleted, induces PCD with increased caspase 3/7-like activity and DNA fragmentation. Knock-down NAC089 in Arabidopsis confers ER stress tolerance and impairs ER-stress-induced caspase-like activity. Transcriptional regulation analysis and ChIP-qPCR reveal that NAC089 plays important role in regulating downstream genes involved in PCD, such as NAC094, MC5 and BAG6. Furthermore, NAC089 is up-regulated by ER stress, which is directly controlled by bZIP28 and bZIP60. These results show that nuclear relocation of NAC089 promotes ER-stress-induced PCD, and both pro-survival and pro-death signals are elicited by bZIP28 and bZIP60 during plant ER stress response.
Author Summary
Protein folding is fundamentally important for development and responses to environmental stresses in eukaryotes. When excess misfolded proteins are accumulated in the endoplasmic reticulum (ER), the unfolded protein response (UPR) is triggered to promote cell survival through optimizing protein folding, and also promote programmed cell death (PCD) when the stress is severe. However, the link from ER-stress-sensing to PCD is largely unknown. Here, we report the identification of one membrane-associated transcription factor NAC089 as an important regulator of ER stress-induced PCD in plants. We have established a previously unrecognized molecular connection between ER stress sensors and PCD regulators. We have shown that organelle-to-organelle translocation of a transcription factor is important for its function in transcriptional regulation. Our results have provided novel insights into the molecular mechanisms of PCD in plants, especially under ER stress conditions.
doi:10.1371/journal.pgen.1004243
PMCID: PMC3967986  PMID: 24675811
6.  Mst1 and Mst2 Are Essential Regulators of Trophoblast Differentiation and Placenta Morphogenesis 
PLoS ONE  2014;9(3):e90701.
The placenta is essential for survival and growth of the fetus because it promotes the delivery of nutrients and oxygen from the maternal circulation as well as fetal waste disposal. Mst1 and Mst2 (Mst1/2), key components of the mammalian hpo/Mst signaling pathway, encode two highly conserved Ser/Thr kinases and play important roles in the prevention of tumorigenesis and autoimmunity, control of T cell development and trafficking, and embryonic development. However, their functions in placental development are not fully understood, and the underlying cellular and molecular mechanisms remain elusive. Here, we investigated the functions of Mst1/2 in mouse placental development using both conventional and conditional (endothelial) Mst1/2 double knockout mice. We found that the number of trophoblast giant cells dramatically increased while spongiotrophoblast cells almost completely disappeared in Mst1/2 deficient placentas. We showed that Mst1/2 deficiency down regulated the expression of Mash2, which is required for suppressing the differentiation of trophoblast giant cells. Furthermore, we demonstrated that endothelial-specific deletion of Mst1/2 led to impaired placental labyrinthine vasculature and embryonic lethality at E11.5, but neither affected vasculature in yolk sac and embryo proper nor endocardium development. Collectively, our findings suggest that Mst1/2 regulate placental development by control of trophoblast cell differentiation and labyrinthine vasculature at midgestation and Mst1/2 control labyrinth morphogenesis in trophoblast- and fetal endothelial-dependent manners. Thus, our studies have defined novel roles of Mst1/2 in mouse placental development.
doi:10.1371/journal.pone.0090701
PMCID: PMC3942462  PMID: 24595170
7.  Design and Validation of a Novel Bioreactor to Subject Aortic Valve Leaflets to Side-Specific Shear Stress 
Annals of biomedical engineering  2011;39(8):2174-2185.
Hemodynamic stresses are presumed to play an important role in the development of calcific aortic valve disease (CAVD). The elucidation of the shear stress mechanisms involved in the pathogenesis of CAVD has been hampered by the complexity of the native unsteady and side-specific valvular flow environment. To address this gap, this article describes the design and validation of a novel device to expose leaflet samples to time-dependent side-specific shear stress. The device built on a double cone-and-plate geometry was dimensioned based on our previous single-sided shear stress device that minimizes secondary flow effects inherent to this geometry. A fluid–structure interaction (FSI) model was designed to predict the actual shear stress produced on a tissue sample mounted in the new device. Staining was performed on porcine leaflets conditioned in the new bioreactor to assess endothelial integrity and cellular apoptosis. The FSI results demonstrated good agreement between the target (native) and the actual side-specific shear stress produced on a tissue sample. No significant difference in endothelial integrity and cellular apoptosis was detected between samples conditioned for 96 h and fresh controls. This new device will enable the investigation of valvular response to normal and pathologic hemodynamics and the potential mechano-etiology of CAVD.
doi:10.1007/s10439-011-0305-6
PMCID: PMC3899241  PMID: 21455792
Mechanobiology; Signal transduction; Hemodynamics; Flow; Remodeling; Inflammation
8.  Defining the Role of Fluid Shear Stress in the Expression of Early Signaling Markers for Calcific Aortic Valve Disease 
PLoS ONE  2013;8(12):e84433.
Calcific aortic valve disease (CAVD) is an active process presumably triggered by interplays between cardiovascular risk factors, molecular signaling networks and hemodynamic cues. While earlier studies demonstrated that alterations in fluid shear stress (FSS) on the fibrosa could trigger inflammation, the mechanisms of CAVD pathogenesis secondary to side-specific FSS abnormalities are poorly understood. This knowledge could be critical to the elucidation of key CAVD risk factors such as congenital valve defects, aging and hypertension, which are known to generate FSS disturbances. The objective of this study was to characterize ex vivo the contribution of isolated and combined abnormalities in FSS magnitude and frequency to early valvular pathogenesis. The ventricularis and fibrosa of porcine aortic valve leaflets were exposed simultaneously to different combinations of sub-physiologic/physiologic/supra-physiologic levels of FSS magnitude and frequency for 24, 48 and 72 hours in a double cone-and-plate device. Endothelial activation and paracrine signaling were investigated by measuring cell-adhesion molecule (ICAM-1, VCAM-1) and cytokine (BMP-4, TGF-β1) expressions, respectively. Extracellular matrix (ECM) degradation was characterized by measuring the expression and activity of the proteases MMP-2, MMP-9, cathepsin L and cathepsin S. The effect of the FSS treatment yielding the most significant pathological response was examined over a 72-hour period to characterize the time-dependence of FSS mechano-transduction. While cytokine expression was stimulated under elevated FSS magnitude at normal frequency, ECM degradation was stimulated under both elevated FSS magnitude at normal frequency and physiologic FSS magnitude at abnormal frequency. In contrast, combined FSS magnitude and frequency abnormalities essentially maintained valvular homeostasis. The pathological response under supra-physiologic FSS magnitude peaked at 48 hours but was then maintained until the 72-hour time point. This study confirms the sensitivity of valve leaflets to both FSS magnitude and frequency and suggests the ability of supra-physiologic FSS levels or abnormal FSS frequencies to initiate CAVD mechanisms.
doi:10.1371/journal.pone.0084433
PMCID: PMC3871675  PMID: 24376809
9.  Histone demethylase GASC1, a potential prognostic and predictive marker in esophageal squamous cell carcinoma 
Gene amplified in squamous cell carcinoma 1 (GASC1) is a member of Jumonji C-domain containing histone demethylases that play an essential role in affecting chromatin architecture and gene expression. The purpose of this study was to determine the expression features and the clinical significance of GASC1 in esophageal squamous cell carcinoma (ESCC). GASC1 expression was detected on tissue microarrays of ESCC samples in 185 cases using immunohistochemical staining. Strong nuclear staining for GASC1 was observed in a subset of ESCC samples. The nuclear expression of GASC1 was significantly associated with lymph node metastasis (P=0.030) and tumor-node metastasis stages (P=0.013). Kaplan-Meier survival analysis showed a tendency that high expression of GASC1 in the nucleus was associated with poor survival of ESCC patients, with a 5-year survival rate of 26.5%, as compared to 43.7% for patients with GASC1-negative/low expression. Furthermore, multivariate analysis revealed that high expression of GASC1 likely acts as a predictive factor for overall survival of ESCC patients, despite the P-value failing to reach significance (P=0.059). The findings indicate that histone demethylase GASC1 may play an important role in promoting cancer metastasis, and shed new light on the importance of targeting GASC1 to suppress metastatic disease in various tumor types, including ESCC.
PMCID: PMC3816970  PMID: 24224128
Histone demethylase; GASC1; lymph node metastasis; immunohistochemistry; esophageal squamous cell carcinoma
10.  Theranostic Protein Targeting ErbB2 for Bioluminescence Imaging and Therapy for Cancer 
PLoS ONE  2013;8(9):e75288.
A combination of molecular-targeted cancer imaging and therapy is an emerging strategy to improve cancer diagnosis and minimize the side effects of conventional treatments. Here, we generated a recombinant protein, EC1-GLuc-p53C, by fusing EC1 peptide, an artificial ligand of ErbB2, with Gaussia luciferase (GLuc) and a p53-activating peptide, p53C. EC1-GLuc-p53C was expressed and purified from E. coli BL21. In vitro experiments showed that EC1-GLuc-p53c was stable in luminescent activity and selectively targeted ErbB2-overexpressing BT474 cells for bioluminescence imaging. Moreover, the internalized EC1-GLuc-p53C in BT474 cells exerted its function to reactivate p53 and significantly inhibited cellular proliferation. In tumor-bearing mice, the ErbB2-targeted bioluminescence imaging and therapeutic effect of EC1-GLuc-p53C were also observed specifically in BT474 tumors but not in MCF7 tumors, which does not overexpress ErbB2. Thus, the present study demonstrates EC1-GLuc-p53C to be an effective theranostic reagent targeting ErbB2 for bioluminescence imaging and cancer therapy.
doi:10.1371/journal.pone.0075288
PMCID: PMC3775930  PMID: 24069396
11.  Regulation of Tumor Necrosis Factor-related Apoptosis-inducing Ligand Expression in Primary Acute Leukemic Cells by Chemotherapeutics 
Turkish Journal of Hematology  2013;30(3):263-268.
Objective: The expression of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) protein and its regulation by chemotherapeutics were analyzed in primary acute leukemic cells.
Materials and Methods: Peripheral blood was collected from 16 patients with acute leukemia on days 0, 1, 3, and 5 of chemotherapy. The mononuclear cells were separated from the peripheral blood, and TRAIL expression was assessed by flow cytometry. The bone marrow mononuclear cells of patients with acute leukemia were separated before chemotherapy and cultured in vitro with VP-16 and/or interferon (IFN). The TRAIL expression level was detected after the cell culture.
Results: TRAIL expression in the mononuclear cells of peripheral blood was significantly upregulated on day 1 (p<0.05) and then significantly decreased on day 5 after chemotherapy (p<0.05). Results from the in vitro culture revealed that VP-16 upregulated TRAIL expression in the bone marrow mononuclear cells of patients with acute leukemia, but the binding of VP-16 to IFN did not enhance TRAIL expression as compared with VP-16 alone (p>0.05).
onclusion: OA single chemotherapy mechanism for leukemia may suffice to induce TRAIL expression and promote the apoptosis of leukemic cells.
Conflict of interest:None declared.
doi:10.4274/Tjh.2013.0027
PMCID: PMC3878528  PMID: 24385805
TRAIL; Acute leukemia; chemotherapeutics
12.  Global Analysis of Fission Yeast Mating Genes Reveals New Autophagy Factors 
PLoS Genetics  2013;9(8):e1003715.
Macroautophagy (autophagy) is crucial for cell survival during starvation and plays important roles in animal development and human diseases. Molecular understanding of autophagy has mainly come from the budding yeast Saccharomyces cerevisiae, and it remains unclear to what extent the mechanisms are the same in other organisms. Here, through screening the mating phenotype of a genome-wide deletion collection of the fission yeast Schizosaccharomyces pombe, we obtained a comprehensive catalog of autophagy genes in this highly tractable organism, including genes encoding three heretofore unidentified core Atg proteins, Atg10, Atg14, and Atg16, and two novel factors, Ctl1 and Fsc1. We systematically examined the subcellular localization of fission yeast autophagy factors for the first time and characterized the phenotypes of their mutants, thereby uncovering both similarities and differences between the two yeasts. Unlike budding yeast, all three Atg18/WIPI proteins in fission yeast are essential for autophagy, and we found that they play different roles, with Atg18a uniquely required for the targeting of the Atg12–Atg5·Atg16 complex. Our investigation of the two novel factors revealed unforeseen autophagy mechanisms. The choline transporter-like protein Ctl1 interacts with Atg9 and is required for autophagosome formation. The fasciclin domain protein Fsc1 localizes to the vacuole membrane and is required for autophagosome-vacuole fusion but not other vacuolar fusion events. Our study sheds new light on the evolutionary diversity of the autophagy machinery and establishes the fission yeast as a useful model for dissecting the mechanisms of autophagy.
Author Summary
Autophagy is a eukaryotic cellular process that transports cytoplasmic contents into lysosomes/vacuoles for degradation. It has been linked to multiple human diseases, including cancer and neurodegenerative disorders. The molecular machinery of autophagy was first identified and has been best characterized in the budding yeast Saccharomyces cerevisiae, but little is known about the autophagy machinery in another important unicellular model organism, the fission yeast Schizosaccharomyces pombe. In this study, we performed an unbiased and comprehensive screening of the fission yeast autophagy genes by profiling the mating phenotypes of nearly 3000 deletion strains. Following up on the screening results, we systematically characterized both previously known and newly identified fission yeast autophagy factors by examining their localization and the phenotype of their mutants. Our analysis increased the number of experimentally defined fission yeast autophagy factors from 14 to 23, including two novel factors that act in ways different from all previously known autophagy proteins. Together, our data reveal unexpected evolutionary divergence of autophagy mechanisms and establish a new model system for unraveling the molecular details of the autophagy process.
doi:10.1371/journal.pgen.1003715
PMCID: PMC3738441  PMID: 23950735
13.  Conductivity of individual particles measured by a microscopic four-point-probe method 
Scientific Reports  2013;3:1991.
We introduce a technique for measuring the conductivity of individual hybrid metal, semiconducting core-shell and full-metal conducting particles by a microscopic four-point probe (μ-4PP) method. The four-point probe geometry allows for minimizing contact resistances between electrodes and particles. By using a focused ion beam we fabricate platinum nanoleads between four microelectrodes on a silicon chip and an individual particle, and determine the particle's conductivity via sensitive current and voltage measurements. Up to sixteen particles can be taken up by each chip, which allows for multiple conductivity measurements by simply multiplexing the electric contacts connected to a multimeter. Although, for demonstration, we used full Au (conducting) and Ag-coated latex particles (semiconducting) of a few micrometers in diameter, the method can be applied to other types of conducting or semiconducting particles of different diameters.
doi:10.1038/srep01991
PMCID: PMC3683700  PMID: 23771149
14.  Transcriptomic Analysis of Cadmium Stress Response in the Heavy Metal Hyperaccumulator Sedum alfredii Hance 
PLoS ONE  2013;8(6):e64643.
The Sedum alfredii Hance hyperaccumulating ecotype (HE) has the ability to hyperaccumulate cadmium (Cd), as well as zinc (Zn) and lead (Pb) in above-ground tissues. Although many physiological studies have been conducted with these plants, the molecular mechanisms underlying their hyper-tolerance to heavy metals are largely unknown. Here we report on the generation of 9.4 gigabases of adaptor-trimmed raw sequences and the assembly of 57,162 transcript contigs in S. alfredii Hance (HE) shoots by the combination of Roche 454 and Illumina/Solexa deep sequencing technologies. We also have functionally annotated the transcriptome and analyzed the transcriptome changes upon Cd hyperaccumulation in S. alfredii Hance (HE) shoots. There are 110 contigs and 123 contigs that were up-regulated (Fold Change ≧2.0) and down-regulated (Fold Change ≦0.5) by chronic Cd treatment in S. alfredii Hance (HE) at q-value cutoff of 0.005, respectively. Quantitative RT-PCR was employed to compare gene expression patterns between S. alfredii Hance (HE) and non-hyperaccumulating ecotype (NHE). Our results demonstrated that several genes involved in cell wall modification, metal translocation and remobilization were more induced or constitutively expressed at higher levels in HE shoots than that in NHE shoots in response to Cd exposure. Together, our study provides large-scale expressed sequence information and genome-wide transcriptome profiling of Cd responses in S. alfredii Hance (HE) shoots.
doi:10.1371/journal.pone.0064643
PMCID: PMC3670878  PMID: 23755133
15.  Differential roles of Kras and Pten in murine leukemogenesis 
Leukemia  2012;27(5):1210-1214.
doi:10.1038/leu.2012.316
PMCID: PMC3650112  PMID: 23183424
Kras; Pten; Murine model; T-ALL
16.  Understanding the Pathogenesis of Kawasaki Disease by Network and Pathway Analysis 
Kawasaki disease (KD) is a complex disease, leading to the damage of multisystems. The pathogen that triggers this sophisticated disease is still unknown since it was first reported in 1967. To increase our knowledge on the effects of genes in KD, we extracted statistically significant genes so far associated with this mysterious illness from candidate gene studies and genome-wide association studies. These genes contributed to susceptibility to KD, coronary artery lesions, resistance to initial IVIG treatment, incomplete KD, and so on. Gene ontology category and pathways were analyzed for relationships among these statistically significant genes. These genes were represented in a variety of functional categories, including immune response, inflammatory response, and cellular calcium ion homeostasis. They were mainly enriched in the pathway of immune response. We further highlighted the compelling immune pathway of NF-AT signal and leukocyte interactions combined with another transcription factor NF-κB in the pathogenesis of KD. STRING analysis, a network analysis focusing on protein interactions, validated close contact between these genes and implied the importance of this pathway. This data will contribute to understanding pathogenesis of KD.
doi:10.1155/2013/989307
PMCID: PMC3606754  PMID: 23533546
17.  Ex Vivo Evidence for the Contribution of Hemodynamic Shear Stress Abnormalities to the Early Pathogenesis of Calcific Bicuspid Aortic Valve Disease 
PLoS ONE  2012;7(10):e48843.
The bicuspid aortic valve (BAV) is the most common congenital cardiac anomaly and is frequently associated with calcific aortic valve disease (CAVD). The most prevalent type-I morphology, which results from left-/right-coronary cusp fusion, generates different hemodynamics than a tricuspid aortic valve (TAV). While valvular calcification has been linked to genetic and atherogenic predispositions, hemodynamic abnormalities are increasingly pointed as potential pathogenic contributors. In particular, the wall shear stress (WSS) produced by blood flow on the leaflets regulates homeostasis in the TAV. In contrast, WSS alterations cause valve dysfunction and disease. While such observations support the existence of synergies between valvular hemodynamics and biology, the role played by BAV WSS in valvular calcification remains unknown. The objective of this study was to isolate the acute effects of native BAV WSS abnormalities on CAVD pathogenesis. Porcine aortic valve leaflets were subjected ex vivo to the native WSS experienced by TAV and type-I BAV leaflets for 48 hours. Immunostaining, immunoblotting and zymography were performed to characterize endothelial activation, pro-inflammatory paracrine signaling, extracellular matrix remodeling and markers involved in valvular interstitial cell activation and osteogenesis. While TAV and non-coronary BAV leaflet WSS essentially maintained valvular homeostasis, fused BAV leaflet WSS promoted fibrosa endothelial activation, paracrine signaling (2.4-fold and 3.7-fold increase in BMP-4 and TGF-β1, respectively, relative to fresh controls), catabolic enzyme secretion (6.3-fold, 16.8-fold, 11.7-fold, 16.7-fold and 5.5-fold increase in MMP-2, MMP-9, cathepsin L, cathepsin S and TIMP-2, respectively) and activity (1.7-fold and 2.4-fold increase in MMP-2 and MMP-9 activity, respectively), and bone matrix synthesis (5-fold increase in osteocalcin). In contrast, BAV WSS did not significantly affect α-SMA and Runx2 expressions and TIMP/MMP ratio. This study demonstrates the key role played by BAV hemodynamic abnormalities in CAVD pathogenesis and suggests the dependence of BAV vulnerability to calcification on the local degree of WSS abnormality.
doi:10.1371/journal.pone.0048843
PMCID: PMC3485349  PMID: 23119099
18.  Polyoxygenated Sterols from the South China Sea Soft Coral Sinularia sp 
Marine Drugs  2012;10(7):1422-1432.
Chemical investigation of the ethanol extract of soft coral Sinularia sp. collected from the South China Sea led to the isolation of three new polyoxygenated sterols, (3S,23R,24S)-ergost-5-ene-3β,23α,25-triol (1), (24S)-ergostane-6-acetate-3β,5α,6β,25-tetraol (2), (24S)-ergostane-6-acetate-3β,6β,12β,25-tetraol (3) together with three known ones (4–6). The structures, including relative configurations of the new compounds (1–3), were elucidated by detailed analysis of spectroscopic data (IR, UV, NMR, MS) and by comparison with related reported compounds. The absolute configuration of 1 was further determined by modified Mosher’s method. Compound 5 exhibited moderate cytotoxicity against K562 cell line with an IC50 value of 3.18 μM, but also displayed strong lethality toward the brine shrimp Artemia salina with a LC50 value of 0.96 μM.
doi:10.3390/md10071422
PMCID: PMC3407921  PMID: 22851916
soft coral; Sinularia sp.; polyoxygenated sterols; cytotoxicity
19.  Protein Phosphatase Pph3 and Its Regulatory Subunit Psy2 Regulate Rad53 Dephosphorylation and Cell Morphogenesis during Recovery from DNA Damage in Candida albicans ▿ 
Eukaryotic Cell  2011;10(11):1565-1573.
The ability of the pathogenic fungus Candida albicans to switch cellular morphologies is important for infection and virulence. Recent studies have revealed that C. albicans yeast cells can switch to filamentous growth under genotoxic stress in a manner dependent on the DNA replication/damage checkpoint. Here, we have investigated the functions of Pph3 (orf19.4378) and Psy2 (orf19.3685), whose orthologues in Saccharomyces cerevisiae mediate the dephosphorylation of the DNA damage checkpoint kinase Rad53 and the histone variant H2AX during recovery from DNA damage. Deleting PPH3 or PSY2 causes hypersensitivity to DNA-damaging agents, including cisplatin, methylmethane sulfonate (MMS), and UV light. In addition, pph3Δ and psy2Δ cells exhibit strong filamentous growth under genotoxic stress. Flow cytometry analysis shows that the mutant cells have lost the ability to adapt to genotoxic stress and remain arrested even after the stress is withdrawn. Furthermore, we show that Pph3 and Psy2 are required for the dephosphorylation of Rad53, but not H2AX, during DNA damage recovery. Taken together, these results show that C. albicans Pph3 and Psy2 have important roles in mediating genotoxin-induced filamentous growth and regulating Rad53 dephosphorylation.
doi:10.1128/EC.05042-11
PMCID: PMC3209060  PMID: 21890819
20.  Roles of Pro- and Anti-Inflammatory Cytokines in the Pathogenesis of SLE  
SLE is an autoimmune inflammatory disease in which various pro- and anti-inflammatory cytokines, including TGF-β, IL-10, BAFF, IL-6, IFN-α, IFN-γ, IL-17, and IL-23, play crucial pathogenic roles. Virtually, all these cytokines can be generated by both innate and adaptive immune cells and exert different effects depending on specific local microenvironment. They can also interact with each other, forming a complex network to maintain delicate immune homeostasis. In this paper, we elaborate on the abnormal secretion and functions of these cytokines in SLE, analyze their potential pathogenic roles, and probe into the possibility of them being utilized as targets for therapy.
doi:10.1155/2012/347141
PMCID: PMC3303597  PMID: 22500087
21.  The impact of educational status on the clinical features of major depressive disorder among Chinese women 
Journal of Affective Disorders  2012;136(3):988-992.
Background
Years of education are inversely related to the prevalence of major depressive disorder (MDD), but the relationship between the clinical features of MDD and educational status is poorly understood. We investigated this in 1970 Chinese women with recurrent MDD identified in a clinical setting.
Methods
Clinical and demographic features were obtained from 1970 Han Chinese women with DSM-IV major depression between 30 and 60 years of age across China. Analysis of linear, logistic and multiple logistic regression models were used to determine the association between educational level and clinical features of MDD.
Results
Subjects with more years of education are more likely to have MDD, with an odds ratio of 1.14 for those with more than ten years. Low educational status is not associated with an increase in the number of episodes, nor with increased rates of co-morbidity with anxiety disorders. Education impacts differentially on the symptoms of depression: lower educational attainment is associated with more biological symptoms and increased suicidal ideation and plans to commit suicide.
Limitations
Findings may not generalize to males or to other patient populations. Since the threshold for treatment seeking differs as a function of education there may an ascertainment bias in the sample.
Conclusions
The relationship between symptoms of MDD and educational status in Chinese women is unexpectedly complex. Our findings are inconsistent with the simple hypothesis from European and US reports that low levels of educational attainment increase the risk and severity of MDD.
doi:10.1016/j.jad.2011.06.046
PMCID: PMC3314924  PMID: 21824664
Major depressive disorder; Education; Socio-economic status; Symptom
22.  A meta-analysis on the effect of corticosteroid therapy in Kawasaki disease 
European Journal of Pediatrics  2011;171(3):571-578.
The current recommended therapy for Kawasaki disease (KD) is the combination of intravenous immunoglobulin (IVIG) and aspirin. However, the role of corticosteroid therapy in KD remains controversial. Using meta-analysis, this study aimed to investigate the efficacy of corticosteroid therapy in KD by comparing it with standard IVIG and aspirin therapy. We included all related randomized and quasi-randomized controlled trials by searching Medline, the Cochrane Central Register of Controlled Trials, EMBASE, Pub Med, Chinese BioMedical Literature Database, China National Knowledge Infrastructure, and the Japanese database (Japan Science and Technology) as well as hand searches of selected references. Data collection and meta-analysis were performed to evaluate the effect of corticosteroids. Our search yielded 11 studies; 7 of which evaluated the effect of corticosteroid for primary therapy in KD, and 4 investigated the effect of corticosteroid therapy in IVIG-resistant patients. Meta-analysis of these studies revealed a significant reduction in the rates of initial treatment failure among patients who received corticosteroid therapy in combination with IVIG compared to IVIG alone (odds ratio (OR) = 0.50; 95% CI, 0.32~0.79; p = 0.003). Furthermore, the use of corticosteroids reduced the duration of fever and the time required for C-reactive protein to return to normal. Our data did not show any significant increase in the incidence of coronary artery lesions or coronary aneurysms (OR = 0.67; 95% CI, 0.35~1.28; p = 0.23) in the corticosteroid group. Conclusion. Corticosteroid combined with IVIG in primary treatment or as treatment of IVIG-resistant patients improved clinical course without increasing coronary artery lesions in children with acute KD.
doi:10.1007/s00431-011-1585-4
PMCID: PMC3284666  PMID: 22057683
Kawasaki disease; Coronary artery lesions; Coronary artery aneurysm; Corticosteroids; Meta-analysis
23.  Survival trends in gastric cancer patients of Northeast China 
AIM: To describe survival trends in patients in Northeast China diagnosed as gastric cancer.
METHODS: A review of all inpatient and outpatient records of gastric cancer patients was conducted in the First Affiliated Hospital of China Medical University. All the gastric cancer patients who satisfied the inclusion criteria from January 1, 1980 through December 31, 2003 were included in the study. The main outcomes were based on median survival and 3-year and 5-year survival rates, by decade of diagnosis.
RESULTS: From 1980 through 2003, the median survival for patients with gastric cancer (n = 1604) increased from 33 mo to 49 mo. The decade of diagnosis was not significantly associated with patient survival for gastric cancer (P = 0.084 for overall survival, and P = 0.150 for 5-year survival); however, the survival rate of the 2000s was remarkably higher than that of the 1980s (P = 0.019 for overall survival, and P = 0.027 for 5-year survival).
CONCLUSION: There was no significant difference of survival among each period; however, the survival rate of the 2000s was remarkably higher than that of the 1980s.
doi:10.3748/wjg.v17.i27.3257
PMCID: PMC3158403  PMID: 21912476
Survival trends; Gastric cancer; Northeast China
24.  Crystal structures of cytochrome P450 2B4 in complex with the inhibitor 1-biphenyl-4-methyl-1H–imidazole: ligand induced structural response through α-helical repositioning†‡ 
Biochemistry  2009;48(22):4762-4771.
Two different ligand occupancy structures of cytochrome P450 2B4 (CYP2B4) in complex with 1-biphenyl-4-methyl-1H–imidazole (1-PBI) have been solved by x-ray crystallography. 1-PBI belongs to a series of tight binding, imidazole-based CYP2B4 inhibitors. 1-PBI binding to CYP2B4 yields a type II spectrum with a Ks value of 0.23 µM and inhibits enzyme activity with an IC50 value of 0.035 µM. Previous CYP2B4 structures have shown a large degree of structural movement in response to ligand size. With two phenyl rings, 1-PBI is larger than 1-(4-chlorophenyl)imidazole (1-CPI) and 4-(4-chlorophenyl)imidazole (4-CPI) but smaller than bifonazole, which is branched and contains three phenyl rings. The CYP2B4:1-PBI complex is a structural intermediate to the closed CPI and the open bifonazole structures. The B/C loop reorganizes itself to include two short partial helices while closing one side of the active site. The F-G helix cassette pivots over the I-helix in direct response to the size of the ligand in the active site. A cluster of Phe residues at the fulcrum of this pivot point allows for dramatic repositioning of the cassette with only a relatively small amount of secondary structure rearrangement. Comparisons of ligand bound CYP2B4 structures reveal trends in plastic region mobility that could allow for predictions of their position in future structures based on ligand shape and size.
doi:10.1021/bi9003765
PMCID: PMC2764533  PMID: 19397311
cytochrome P450 2B4; 1-biphenyl-4-methyl-1H–imidazole; 1-PBI; x-ray crystallography; plastic regions; F-G helix cassette
25.  Development of a database system for mapping insertional mutations onto the mouse genome with large-scale experimental data 
BMC Genomics  2009;10(Suppl 3):S7.
Background
Insertional mutagenesis is an effective method for functional genomic studies in various organisms. It can rapidly generate easily tractable mutations. A large-scale insertional mutagenesis with the piggyBac (PB) transposon is currently performed in mice at the Institute of Developmental Biology and Molecular Medicine (IDM), Fudan University in Shanghai, China. This project is carried out via collaborations among multiple groups overseeing interconnected experimental steps and generates a large volume of experimental data continuously. Therefore, the project calls for an efficient database system for recording, management, statistical analysis, and information exchange.
Results
This paper presents a database application called MP-PBmice (insertional mutation mapping system of PB Mutagenesis Information Center), which is developed to serve the on-going large-scale PB insertional mutagenesis project. A lightweight enterprise-level development framework Struts-Spring-Hibernate is used here to ensure constructive and flexible support to the application. The MP-PBmice database system has three major features: strict access-control, efficient workflow control, and good expandability. It supports the collaboration among different groups that enter data and exchange information on daily basis, and is capable of providing real time progress reports for the whole project. MP-PBmice can be easily adapted for other large-scale insertional mutation mapping projects and the source code of this software is freely available at http://www.idmshanghai.cn/PBmice.
Conclusion
MP-PBmice is a web-based application for large-scale insertional mutation mapping onto the mouse genome, implemented with the widely used framework Struts-Spring-Hibernate. This system is already in use by the on-going genome-wide PB insertional mutation mapping project at IDM, Fudan University.
doi:10.1186/1471-2164-10-S3-S7
PMCID: PMC2788394  PMID: 19958505

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