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1.  Functions of the lethal leaf-spot 1 gene in wheat cell death and disease tolerance to Puccinia striiformis  
Journal of Experimental Botany  2013;64(10):2955-2969.
Pheophorbide a oxygenase (PaO) is a key enzyme in chlorophyll catabolism that is known to suppress cell death in maize and Arabidopsis. The catalytic activity of PaO in chlorophyll degradation has been clearly demonstrated, but the function of PaO in the regulation of cell death and plant–microbe interactions is largely unknown. In this study, we characterized a PaO homologue in wheat of the lethal leaf-spot 1 gene, TaLls1, that was induced in leaves infected by Puccinia striiformis f.sp. tritici (Pst) and wounding treatment. The TaLls1 protein contains a conserved Rieske [2Fe-2S] motif and a mononuclear iron-binding site typical of PaOs. Silencing of TaLls1 by virus-induced gene silencing in wheat led to leaf cell death without pathogen attacks, possibly due to the accumulation of pheophorbide a (upstream substrate of PaO), indicating a suppressor role of TaLls1, while overexpression of TaLls1 also triggered cell death in both tobacco and wheat leaves, probably owing to the accumulation of the red chlorophyll catabolite (downstream product of PaO). Further deletion mutant analysis showed that the conserved Rieske domain, but not the iron-binding site, was essential for cell death induction. These results thus suggest a threshold for TaLls1 in maintaining cell homeostasis to adapt in various stresses, and shed new light on the role of TaLls1 in cell death regulation. Furthermore, silencing of TaLls1 in wheat did not change the disease symptoms but enhanced tolerance to Pst via an significant increase in H2O2 generation, elevated cell death occurrence, and upregulation of pathogenesis-related genes.
doi:10.1093/jxb/ert135
PMCID: PMC3697956  PMID: 23811695
cell death; disease resistance; pheophorbide a oxygenase; Puccinia striiformis f.sp. tritici; wheat.
2.  UNC1062, a new and potent Mer inhibitor 
Abnormal activation of Mer kinase has been implicated in the oncogenesis of many human cancers including acute lymphoblastic and myeloid leukemia, non-small cell lung cancer, and glioblastoma. We have discovered a new family of small molecule Mer inhibitors, pyrazolopyrimidine sulfonamides, that potently inhibit the kinase activity of Mer. Importantly, these compounds do not demonstrate significant hERG activity in the PatchXpress assay. Through structure-activity relationship studies, 35 (UNC1062) was identified as a potent (IC50 = 1.1 nM) and selective Mer inhibitor. When applied to live tumor cells, UNC1062 inhibited Mer phosphorylation and colony formation in soft agar. Given the potential of Mer as a therapeutic target, UNC1062 is a promising candidate for further drug development.
doi:10.1016/j.ejmech.2013.03.035
PMCID: PMC3720808  PMID: 23693152
Mer inhibitors; pyrazolopyrimidines; sulfonamides; leukemia; non-small cell lung cancer; glioblastoma
3.  Interfacial Free Energy Controlling Glass-Forming Ability of Cu-Zr Alloys 
Scientific Reports  2014;4:5167.
Glass is a freezing phase of a deeply supercooled liquid. Despite its simple definition, the origin of glass forming ability (GFA) is still ambiguous, even for binary Cu-Zr alloys. Here, we directly study the stability of the supercooled Cu-Zr liquids where we find that Cu64Zr36 at a supercooled temperature shows deeper undercoolability and longer persistence than other neighbouring compositions with an equivalent driving Gibbs free energy. This observation implies that the GFA of the Cu-Zr alloys is significantly affected by crystal-liquid interfacial free energy. In particular, the crystal-liquid interfacial free energy of Cu64Zr36 in our measurement was higher than that of other neighbouring liquids and, coincidently a molecular dynamics simulation reveals a larger glass-glass interfacial energy value at this composition, which reflects more distinct configuration difference between liquid and crystal phase. The present results demonstrate that the higher crystal-liquid interfacial free energy is a prerequisite of good GFA of the Cu-Zr alloys.
doi:10.1038/srep05167
PMCID: PMC4044622  PMID: 24893772
4.  Self-organized vanadium and nitrogen co-doped titania nanotube arrays with enhanced photocatalytic reduction of CO2 into CH4 
Nanoscale Research Letters  2014;9(1):272.
Self-organized V-N co-doped TiO2 nanotube arrays (TNAs) with various doping amount were synthesized by anodizing in association with hydrothermal treatment. Impacts of V-N co-doping on the morphologies, phase structures, and photoelectrochemical properties of the TNAs films were thoroughly investigated. The co-doped TiO2 photocatalysts show remarkably enhanced photocatalytic activity for the CO2 photoreduction to methane under ultraviolet illumination. The mechanism of the enhanced photocatalytic activity is discussed in detail.
doi:10.1186/1556-276X-9-272
PMCID: PMC4050103  PMID: 24948893
TiO2; Photocatalytic; CO2; Nanotube; CH4
5.  Nanofabrication on monocrystalline silicon through friction-induced selective etching of Si3N4 mask 
Nanoscale Research Letters  2014;9(1):241.
A new fabrication method is proposed to produce nanostructures on monocrystalline silicon based on the friction-induced selective etching of its Si3N4 mask. With low-pressure chemical vapor deposition (LPCVD) Si3N4 film as etching mask on Si(100) surface, the fabrication can be realized by nanoscratching on the Si3N4 mask and post-etching in hydrofluoric acid (HF) and potassium hydroxide (KOH) solution in sequence. Scanning Auger nanoprobe analysis indicated that the HF solution could selectively etch the scratched Si3N4 mask and then provide the gap for post-etching of silicon substrate in KOH solution. Experimental results suggested that the fabrication depth increased with the increase of the scratching load or KOH etching period. Because of the excellent masking ability of the Si3N4 film, the maximum fabrication depth of nanostructure on silicon can reach several microns. Compared to the traditional friction-induced selective etching technique, the present method can fabricate structures with lesser damage and deeper depths. Since the proposed method has been demonstrated to be a less destructive and flexible way to fabricate a large-area texture structure, it will provide new opportunities for Si-based nanofabrication.
doi:10.1186/1556-276X-9-241
PMCID: PMC4036082  PMID: 24940174
Friction-induced selective etching; Si3N4 mask; Silicon
6.  A sequential Monte Carlo framework for haplotype inference in CNV/SNP genotype data 
Copy number variations (CNVs) are abundant in the human genome. They have been associated with complex traits in genome-wide association studies (GWAS) and expected to continue playing an important role in identifying the etiology of disease phenotypes. As a result of current high throughput whole-genome single-nucleotide polymorphism (SNP) arrays, we currently have datasets that simultaneously have integer copy numbers in CNV regions as well as SNP genotypes. At the same time, haplotypes that have been shown to offer advantages over genotypes in identifying disease traits even though available for SNP genotypes are largely not available for CNV/SNP data due to insufficient computational tools. We introduce a new framework for inferring haplotypes in CNV/SNP data using a sequential Monte Carlo sampling scheme ‘Tree-Based Deterministic Sampling CNV’ (TDSCNV). We compare our method with polyHap(v2.0), the only currently available software able to perform inference in CNV/SNP genotypes, on datasets of varying number of markers. We have found that both algorithms show similar accuracy but TDSCNV is an order of magnitude faster while scaling linearly with the number of markers and number of individuals and thus could be the method of choice for haplotype inference in such datasets. Our method is implemented in the TDSCNV package which is available for download at http://www.ee.columbia.edu/~anastas/tdscnv.
doi:10.1186/1687-4153-2014-7
PMCID: PMC4017783  PMID: 24868199
7.  A preliminary evaluation of efficacy and safety of Wharton’s jelly mesenchymal stem cell transplantation in patients with type 2 diabetes mellitus 
Introduction
Stem cell therapy has recently been introduced to treat patients with type 2 diabetes mellitus (T2DM). However, no data are available on the efficacy and safety of allogeneic Wharton’s Jelly-derived mesenchymal stem cell (WJ-MSC) transplantation in patients with T2DM. Here we performed a non-placebo controlled prospective phase I/II study to determine efficacy and safety of WJ-MSC transplantation in T2DM.
Methods
Twenty-two patients with T2DM were enrolled and received WJ-MSC transplantation through one intravenous injection and one intrapancreatic endovascular injection (catheterization). They were followed up for 12 months after transplantation. The primary endpoints were changes in the levels of glycated hemoglobin and C-peptide and the secondary endpoints included insulin dosage, fasting blood glucose (FBG), post-meal blood glucose (PBG), inflammatory markers and T lymphocyte counts.
Results
WJ-MSC transplantation significantly decreased the levels of glucose and glycated hemoglobin, improved C-peptide levels and beta cell function, and reduced markers of systemic inflammation and T lymphocyte counts. No major WJ-MSC transplantation-related adverse events occurred, but data suggest a temporary decrease in levels of C-peptide and beta cell function at one month after treatment, possibly related to intrapancreatic endovascular injection.
Conclusions
Our data demonstrate that treatment with WJ-MSCs can improve metabolic control and beta cell function in patients with T2DM. The therapeutic mechanism may involve improvements in systemic inflammation and/or immunological regulation.
Trial registration
Chinese Clinical Trial Register ChiCTR-ONC-10000985. Registered 23 September 2010
doi:10.1186/scrt446
PMCID: PMC4055092  PMID: 24759263
8.  Rare giant bilateral calvarial hyperostosis across the superior sagittal sinus secondary to brain meningioma: A case report 
Oncology Letters  2014;8(1):281-284.
The current study presents a case of a 43-year-old female with giant bilateral calvarial hyperostosis across the superior sagittal sinus, secondary to brain meningioma. The patient presented with a huge mass in the bilateral calvarial region, and diagnoses of huge skull hyperplasia and meningioma were strongly suggested by computed tomography and magnetic resonance imaging examination. In addition, digital subtraction angiography demonstrated that the left middle meningeal artery and branches of the left superficial temporal artery were the major sources of blood supply to the tumor, with the little involvement of the right middle meningeal artery and branches of the right superficial temporal artery. The patient successfully underwent simultaneous embolization of the tumor-supplying vessels, total resection of the giant calvarial hyperostosis and intracranial tumor and skull cranioplasty. Additionally, histological study of the mass revealed a meningioma. The management of such a case presents a surgical challenge, however, the current study provides a good reference for the future treatment of similar diseases.
doi:10.3892/ol.2014.2074
PMCID: PMC4063660  PMID: 24959261
hyperostosis; parasagittal meningioma; tumor invasion
9.  Pseudo Cyclization through Intramolecular Hydrogen Bond Enables Discovery of Pyridine Substituted Pyrimidines as New Mer Kinase Inhibitors 
Journal of medicinal chemistry  2013;56(23):9683-9692.
Abnormal activation or overexpression of Mer receptor tyrosine kinase has been implicated in survival signaling and chemoresistance in many human cancers. Consequently, Mer is a promising novel cancer therapeutic target. A structure-based drug design approach using a pseudo-ring replacement strategy was developed and validated to discover a new family of pyridinepyrimidine analogs as potent Mer inhibitors. Through SAR studies, 10 (UNC2250) was identified as the lead compound for further investigation based on high selectivity against other kinases and good pharmacokinetic properties. When applied to live cells, 10 inhibited steady-state phosphorylation of endogenous Mer with an IC50 of 9.8 nM and blocked ligand-stimulated activation of a chimeric EGFR-Mer protein. Treatment with 10 also resulted in decreased colony-forming potential in rhabdoid and NSCLC tumor cells, thereby demonstrating functional anti-tumor activity. The results provide a rationale for further investigation of this compound for therapeutic application in patients with cancer.
doi:10.1021/jm401387j
PMCID: PMC3980660  PMID: 24195762
Mer inhibitors; leukemia; solid tumor; NSCLC; pyridinepyrimidine; pseudo-ring replacement
10.  Regularized EM algorithm for sparse parameter estimation in nonlinear dynamic systems with application to gene regulatory network inference 
Parameter estimation in dynamic systems finds applications in various disciplines, including system biology. The well-known expectation-maximization (EM) algorithm is a popular method and has been widely used to solve system identification and parameter estimation problems. However, the conventional EM algorithm cannot exploit the sparsity. On the other hand, in gene regulatory network inference problems, the parameters to be estimated often exhibit sparse structure. In this paper, a regularized expectation-maximization (rEM) algorithm for sparse parameter estimation in nonlinear dynamic systems is proposed that is based on the maximum a posteriori (MAP) estimation and can incorporate the sparse prior. The expectation step involves the forward Gaussian approximation filtering and the backward Gaussian approximation smoothing. The maximization step employs a re-weighted iterative thresholding method. The proposed algorithm is then applied to gene regulatory network inference. Results based on both synthetic and real data show the effectiveness of the proposed algorithm.
doi:10.1186/1687-4153-2014-5
PMCID: PMC3998071  PMID: 24708632
Nonlinear dynamic system; Parameter estimation; Sparsity; Expectation-maximization; Forward-backward recursion; Gaussian approximation; Gene regulatory network
11.  Risk Factors for HIV/Syphilis Infection and Male Circumcision Practices and Preferences among Men Who Have Sex with Men in China 
BioMed Research International  2014;2014:498987.
Objective. To investigate factors associated with HIV infection and the frequency and willingness of male circumcision among men who have sex with men (MSM) in Chengdu city, China. Methods. A cross-sectional survey provided information on participants' demographics, risk behaviors, circumcision, and uptake of HIV prevention services. Results. Of 570 participants, 13.3% were infected with HIV and 15.9% with syphilis. An estimated 43.0% of respondents reported having unprotected receptive anal intercourse, and 58.9% reported having ≥2 male sexual partners in the past 6 months. Multivariable logistic regression revealed that syphilis, more male sex partners, predominantly receptive anal intercourse, and exclusively receptive male sex were associated with HIV infection. Higher level of education and peer education service were inversely associated with HIV infection. Nearly a fifth (18.0%) of participants were circumcised. More than half of uncircumcised participants expressed willingness to be circumcised. Conclusion. This study reveals a high prevalence of HIV and syphilis among MSM in Chengdu province of China. The frequency of unprotected receptive anal intercourse and multiple male sexual partnerships highlight the urgency for an effective comprehensive HIV prevention strategy. Although the willingness to accept male circumcision (MC) is high, further research is needed to assess the protective effective of MC among MSM.
doi:10.1155/2014/498987
PMCID: PMC3985172  PMID: 24795883
12.  Discovery of Mer Specific Tyrosine Kinase Inhibitors for the Treatment and Prevention of Thrombosis 
Journal of medicinal chemistry  2013;56(23):9693-9700.
The role of Mer kinase in regulating the second phase of platelet activation generates an opportunity to use Mer inhibitors for preventing thrombosis with diminished likelihood for bleeding as compared to current therapies. Toward this end, we have discovered a novel, Mer kinase specific substituted-pyrimidine scaffold using a structure-based drug design and a pseudo-ring replacement strategy. The co-crystal structure of Mer with two compounds (7 & 22) possessing distinct activity have been determined. Subsequent SAR studies identified compound 23 (UNC2881) as a lead compound for in vivo evaluation. When applied to live cells, 23 inhibits steady-state Mer kinase phosphorylation with an IC50 value of 22 nM. Treatment with 23 is also sufficient to block EGF-mediated stimulation of a chimeric receptor containing the intracellular domain of Mer fused to the extracellular domain of EGFR. In addition, 23 potently inhibits collagen-induced platelet aggregation, suggesting that this class of inhibitors may have utility for prevention and/or treatment of pathologic thrombosis.
doi:10.1021/jm4013888
PMCID: PMC3962266  PMID: 24219778
Mer inhibitors; TAM RTK; platelet aggregation; thrombosis; pyrimidines; pseudo-ring replacement
13.  Multifactorial Comparative Proteomic Study of Cytochrome P450 2E1 Function in Chronic Alcohol Administration 
PLoS ONE  2014;9(3):e92504.
With the use of iTRAQ technique, a multifactorial comparative proteomic study can be performed. In this study, to obtain an overview of ethanol, CYP2E1 and gender effects on liver injury and gain more insight into the underlying molecular mechanism, mouse liver proteomes were quantitatively analyzed using iTRAQ under eight conditions including mice of different genders, wild type versus CYP2E1 knockout, and normal versus alcohol diet. A series of statistical and bioinformatic analyses were explored to simplify and clarify multifactorial comparative proteomic data. First, with the Principle Component analysis, six proteins, CYP2E1, FAM25, CA3, BHMT, HIBADH and ECHS1, involved in oxidation reduction, energy and lipid metabolism and amino acid metabolism, were identified as the most differentially expressed gene products across all of the experimental conditions of our chronic alcoholism model. Second, hierarchical clustering analysis showed CYP2E1 knockout played a primary role in the overall differential protein expression compared with ethanol and gender factors. Furthermore, pair-wise multiple comparisons have revealed that the only significant expression difference lied in wild-type and CYP2E1 knockout mice both treated with ethanol. Third, K-mean clustering analysis indicated that the CYP2E1 knockout had the reverse effect on ethanol induced oxidative stress and lipid oxidation. More importantly, IPA analysis of proteomic data inferred that the gene expressions of two upstream regulators, NRF2 and PPARα, regulated by chronic alcohol feeding and CYP2E1 knockout, are involved in ethanol induced oxidative stress and lipid oxidation. The present study provides an effectively comprehensive data analysis strategy to compare multiple biological factors, contributing to biochemical effects of alcohol on the liver. The mass spectrometry proteomics data have been deposited to the ProteomeXchange with data set identifier of PXD000635.
doi:10.1371/journal.pone.0092504
PMCID: PMC3962406  PMID: 24658151
14.  A Prolyl-isomerase Mediates Dopamine-dependent Plasticity and Cocaine Motor Sensitization 
Cell  2013;154(3):637-650.
Summary
Synaptic plasticity induced by cocaine and other drugs underlies addiction. Here we elucidate molecular events at synapses that cause this plasticity and the resulting behavioral response to cocaine in mice. In response to D1 dopamine receptor signaling that is induced by drug administration, the glutamate receptor protein mGluR5 is phosphorylated by MAP kinase, which we show potentiates Pin1-mediated prolyl isomerization of mGluR5 in instances where the product of an activity-dependent gene, Homer1a, is present to enable Pin1-mGluR5 interaction. These biochemical events potentiate NMDA receptor-mediated currents that underlie synaptic plasticity and cocaine-evoked motor sensitization as tested in mice with relevant mutations. The findings elucidate how a coincidence of signals from the nucleus and the synapse can render mGluR5 accessible to activation with consequences for drug-induced dopamine responses, and point to depotentiation at corticostriatal synapses as a possible therapeutic target for treating addiction.
doi:10.1016/j.cell.2013.07.001
PMCID: PMC3785238  PMID: 23911326
15.  A comparative study between Embosphere® and conventional transcatheter arterial chemoembolization for treatment of unresectable liver metastasis from GIST 
Objective
Transcatheter arterial chemoembolization (TACE) is a standard treatment for hepatocellular carcinoma (HCC) and/or some unresectable liver metastasis tumors. Hypervascular liver metastatic lesions such as metastasis from gastrointestinal stromal tumor (GIST) are an indication for transcatheter arterial embolization (TAE). The purpose of this study was to evaluate the efficacy and safety of Embosphere®-TAE (Embo-TAE) in comparison with conventional TACE (cTACE) for the treatment of liver metastasis from GIST.
Methods
A total of 45 patients who underwent TACE between Aug 2008 and Feb 2013 were enrolled. Patients with GIST who underwent TAE with Embosphere® (n=19) were compared with controls who received cTACE (n=26). The primary end points were treatment response and treatment-related adverse events. The secondary end points were progression-free survival (PFS) and overall survival (OS).
Results
The treatment response of Embo-TAE group was significantly higher than that of the cTACE group (P<0.001). The PFS was significantly better in the Embosphere®-group than in the cTACE group (56.6 and 42.1 weeks, respectively; P=0.003). However, there was no statistically significant difference in liver toxicity between the two groups (P>0.05). The median OS in the Embo-TAE group was longer than that in the cTACE group (74.0 weeks, 95% CI: 68.2-79.8 vs. 61.7 weeks, 95% CI: 56.2-67.2 weeks) (unadjusted P=0.045). The use of Embo-TAE significantly reduced the risk of death in patients with GIST with liver metastases according to the Cox proportional hazards regression model [hazard ratio (HR): 0.149; 95% CI: 0.064-0.475].
Conclusions
TAE with Embosphere® showed better treatment response and delayed tumor progression compared with cTACE. There was no significant difference in treatment-related hepatic toxicities. Embo-TAE thus appears to be a feasible and promising approach in the treatment of liver metastasis from GIST.
doi:10.3978/j.issn.1000-9604.2014.02.11
PMCID: PMC3937743  PMID: 24653635
Transcatheter arterial chemoembolization (TACE); gastrointestinal stromal tumor (GIST); embolization
16.  Peli1 promotes microglia-mediated CNS inflammation by regulating Traf3 degradation 
Nature medicine  2013;19(5):595-602.
Microglia are crucial for the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). Here, we show that the E3 ubiquitin ligase Peli1 is abundantly expressed in microglia and serves as a pivotal mediator of microglial activation during the course of EAE induction. Peli1 mediates the induction of chemokines and proinflammatory cytokines in microglia and, thereby, promotes recruitment of T cells into the central nervous system. Peli1-deficient mice are refractory to EAE induction despite their competent production of inflammatory T cells in the peripheral lymphoid organs. Notably, Peli1 regulates a novel signaling axis of the toll-like receptor pathway that mediates degradation of Traf3, a potent inhibitor of MAP kinase activation and gene induction. Ablation of Traf3 restores the microglial activation and EAE sensitivity of Peli1-deficient mice. These findings establish Peli1 as a microglia-specific mediator of autoimmune neuroinflammation and suggest a novel signaling mechanism of Peli1 function.
doi:10.1038/nm.3111
PMCID: PMC3899792  PMID: 23603814
Peli1; Ubiquitination; CNS inflammation; EAE; Traf3; c-IAP
17.  An Efficient Solution-Phase Synthesis of 4,5,7-Trisubstituted Pyrrolo[3,2-d]pyrimidines 
ACS combinatorial science  2012;15(1):10-19.
We have developed an efficient and robust route to synthesize 4,5,7-trisubstituted pyrrolo[3,2-d]pyrimidines as potent kinase inhibitors. This solution-phase synthesis features a SNAr substitution reaction, cross-coupling reaction, one-pot reduction/reductive amination and N-alkylation reaction. These reactions occur rapidly with high yields and have broad substrate scopes. A variety of groups can be selectively introduced into the N5 and C7 positions of 4,5,7-trisubstituted pyrrolopyrimidines at a late stage of the synthesis, thereby providing a highly efficient approach to explore the structure-activity relationships of pyrrolopyrimidine derivatives. Four synthetic analogs have been profiled against a panel of 48 kinases and a new and selective FLT3 inhibitor 9 is identified.
doi:10.1021/co300106f
PMCID: PMC3724770  PMID: 23181516
Pyrrolopyrimidine; SNAr displacement; Coupling reaction; Reductive amination; N-alkylation
18.  MMP9 regulates the cellular response to inflammation after skeletal injury 
Bone  2012;52(1):111-119.
Like other tissue injuries, bone fracture triggers an inflammatory response, which plays an important role in skeletal repair. Inflammation is believed to have both positive and negative effects on bone repair, but the underlying cellular mechanisms are not well understood. To assess the role of inflammation on skeletal cell differentiation, we used mouse models of fracture repair that stimulate either intramembranous or endochondral ossification. In the first model, fractures are rigidly stabilized leading to direct bone formation, while in the second model, fracture instability causes cartilage and bone formation. We compared the inflammatory response in these two mechanical environments and found changes in the expression patterns of inflammatory genes and in the recruitment of inflammatory cells and osteoclasts. These results suggested that the inflammatory response could influence skeletal cell differentiation after fracture. We then exploited matrix metalloproteinase 9 (MMP9) that is expressed in inflammatory cells and osteoclasts, and which we previously showed is a potential regulator of cell fate decisions during fracture repair. Mmp9-/- mice heal stabilized fractures via endochondral ossification, while wild type mice heal via intramembranous ossification. In parallel, we observed increases in macrophages and T cells in the callus of Mmp9-/- compared to wild type mice. To assess the link between the profile of inflammatory cells and skeletal cell fate functionally, we transplanted Mmp9-/- mice with wild type bone marrow, to reconstitute a wild type hematopoietic lineage in interaction with the Mmp9-/- stroma and periosteum. Following transplantation, Mmp9-/- mice healed stabilized fractures via intramembranous ossification and exhibited a normal profile of inflammatory cells. Moreover, Mmp9-/- periosteal grafts healed via intramembranous ossification in wild type hosts, but healed via endochondral ossification in Mmp9-/- hosts. We observed that macrophages accumulated at the periosteal surface in Mmp9-/- mice, suggesting that cell differentiation in the periosteum is influenced by factors such as BMP2 that are produced locally by inflammatory cells. Taken together, these results show that MMP9 mediates indirect effects on skeletal cell differentiation by regulating the inflammatory response and the distribution of inflammatory cells, leading to the local regulation of periosteal cell differentiation.
doi:10.1016/j.bone.2012.09.018
PMCID: PMC3513654  PMID: 23010105
19.  Fatty Acid Synthase Mediates the Epithelial-Mesenchymal Transition of Breast Cancer Cells 
This study aimed to investigate the role of fatty acid synthase (FASN) in the epithelial-mesenchymal transition (EMT) of breast cancer cells. MCF-7 cells and MCF-7 cells overexpressing mitogen-activated protein kinase 5 (MCF-7-MEK5) were used in this study. MCF-7-MEK5 cells showed stable EMT characterized by increased vimentin and decreased E-cadherin expression. An In vivo animal model was established using the orthotopic injection of MCF-7 or MCF-7-MEK5 cells. Real-time quantitative PCR and western blotting were used to detect the expression levels of FASN and its downstream proteins liver fatty acid-binding protein (L-FABP) and VEGF/VEGFR-2 in both in vitro and in vivo models (nude mouse tumor tissues). In MCF-7-MEK5 cells, significantly increased expression of FASN was associated with increased levels of L-FABP and VEGF/VEGFR-2. Cerulenin inhibited MCF-7-MEK5 cell migration and EMT, and reduced FASN expression and down-stream proteins L-FABP, VEGF, and VEGFR-2. MCF-7-MEK5 cells showed higher sensitivity to Cerulenin than MCF-7 cells. Immunofluorescence revealed an increase of co-localization of FASN with VEGF on the cell membrane and with L-FABP within MCF-7-MEK5 cells. Immunohistochemistry further showed that increased percentage of FASN-positive cells in the tumor tissue was associated with increased percentages of L-FABP- and VEGF-positive cells and the Cerulenin treatment could reverse the effect. Altogether, our results suggest that FASN is essential to EMT possibly through regulating L-FABP, VEGF and VEGFR-2. This study provides a theoretical basis and potential strategy for effective suppression of malignant cells with EMT.
doi:10.7150/ijbs.7357
PMCID: PMC3920172  PMID: 24520215
EMT; FASN; L-FABP; VEGF; Breast cancer.
20.  Comparative analysis of curative effect of CT-guided stem cell transplantation and open surgical transplantation for sequelae of spinal cord injury 
Background
This study compared the clinical efficacies, advantages and disadvantages of two transplantation approaches for treating spinal cord injury: open surgical exploration combined with local stem cell transplantation (referred to as open surgical transplantation) and local stem cell transplantation by CT-guided puncture (referred to as CT-guided transplantation).
Methods
The patients were divided into the following three groups to perform a retrospective controlled study: Group A included nine patients who underwent open surgical transplantation, Group B included nine patients who underwent CT-guided transplantation, and Group C included nine patients who did not receive stem cell transplantation. The Abbreviated Injury Scale (AIS), the American Spinal Injury Association (ASIA) score and the motor evoked potentials (MEP) examination were utilized to compare the differences in the clinical efficacies. The advantages and disadvantages of the two transplantation approaches were also compared, including the surgical risks, the possibility of repeating the operation, the interval between surgery and rehabilitation exercises and the scope of conditions suitable for the operation.
Results
Whether evaluated by the AIS grading scale, the ASIA score or the MEP results, there were significant differences in the clinical efficacy among the three patient groups. Group B exhibited the best clinical outcome, followed by Group A, and Group C fared the worst. The CT-guided transplantation had the advantages of lower surgical risk, the potential to repeat the operations within a short time-frame and a short interval between surgery and rehabilitation exercise compared with the open surgical transplantation. The conditions that are suitable for CT-guided transplantation versus the conditions suitable for open surgical transplantation are not identical. The application scopes for the two approaches had their respective strengths.
Conclusions
CT-guided stem cell transplantation was confirmed as a safe and effective approach to treat sequelae of spinal cord injury with the advantages of simpler operation, minimal invasion, less adverse reaction and quicker recovery.
Trial registration
Clinical trials registration number: ChiCTR-TNRC-12002477.
doi:10.1186/1479-5876-11-315
PMCID: PMC3878170  PMID: 24355001
Mesenchymal stem cells; Spinal cord injury; CT-guided puncture; Cell transplantation
21.  Gene regulatory network inference by point-based Gaussian approximation filters incorporating the prior information 
The extended Kalman filter (EKF) has been applied to inferring gene regulatory networks. However, it is well known that the EKF becomes less accurate when the system exhibits high nonlinearity. In addition, certain prior information about the gene regulatory network exists in practice, and no systematic approach has been developed to incorporate such prior information into the Kalman-type filter for inferring the structure of the gene regulatory network. In this paper, an inference framework based on point-based Gaussian approximation filters that can exploit the prior information is developed to solve the gene regulatory network inference problem. Different point-based Gaussian approximation filters, including the unscented Kalman filter (UKF), the third-degree cubature Kalman filter (CKF3), and the fifth-degree cubature Kalman filter (CKF5) are employed. Several types of network prior information, including the existing network structure information, sparsity assumption, and the range constraint of parameters, are considered, and the corresponding filters incorporating the prior information are developed. Experiments on a synthetic network of eight genes and the yeast protein synthesis network of five genes are carried out to demonstrate the performance of the proposed framework. The results show that the proposed methods provide more accurate inference results than existing methods, such as the EKF and the traditional UKF.
doi:10.1186/1687-4153-2013-16
PMCID: PMC3977693  PMID: 24341668
Gene regulatory network; Point-based Gaussian approximation filters; Network prior information; Sparsity; Iterative thresholding
22.  Identification of QTLs Associated with Oil Content in a High-Oil Brassica napus Cultivar and Construction of a High-Density Consensus Map for QTLs Comparison in B. napus 
PLoS ONE  2013;8(12):e80569.
Increasing seed oil content is one of the most important goals in breeding of rapeseed (B. napus L.). To dissect the genetic basis of oil content in B. napus, a large and new double haploid (DH) population containing 348 lines was obtained from a cross between ‘KenC-8’ and ‘N53-2’, two varieties with >10% difference in seed oil content, and this population was named the KN DH population. A genetic linkage map consisting of 403 markers was constructed, which covered a total length of 1783.9 cM with an average marker interval of 4.4 cM. The KN DH population was phenotyped in eight natural environments and subjected to quantitative trait loci (QTL) analysis for oil content. A total of 63 identified QTLs explaining 2.64–17.88% of the phenotypic variation were identified, and these QTLs were further integrated into 24 consensus QTLs located on 11 chromosomes using meta-analysis. A high-density consensus map with 1335 marker loci was constructed by combining the KN DH map with seven other published maps based on the common markers. Of the 24 consensus QTLs in the KN DH population, 14 were new QTLs including five new QTLs in A genome and nine in C genome. The analysis revealed that a larger population with significant differences in oil content gave a higher power detecting new QTLs for oil content, and the construction of the consensus map provided a new clue for comparing the QTLs detected in different populations. These findings enriched our knowledge of QTLs for oil content and should be a potential in marker-assisted breeding of B. napus.
doi:10.1371/journal.pone.0080569
PMCID: PMC3846612  PMID: 24312482
23.  Neuroendoscopic Surgery versus External Ventricular Drainage Alone or with Intraventricular Fibrinolysis for Intraventricular Hemorrhage Secondary to Spontaneous Supratentorial Hemorrhage: A Systematic Review and Meta-Analysis  
PLoS ONE  2013;8(11):e80599.
Background and Purpose
Although neuroendoscopy (NE) has been applied to many cerebral diseases, the effect of NE for intraventricular hemorrhage (IVH) secondary to spontaneous supratentorial hemorrhage remains controversial. The purpose of this study was to analyze the effect of NE compared with external ventricular drainage (EVD) alone or with intraventricular fibrinolysis (IVF) on the management of IVH secondary to spontaneous supratentorial hemorrhage.
Methodology/ Principal Findings
A systematic search of electronic databases (PubMed, EMBASE, OVID, Web of Science, The Cochrane Library, CBM, VIP, CNKI, and Wan Fang database) was performed to identify related studies published from 1970 to 2013. Randomized controlled trials (RCTs) or observational studies (OS) comparing NE with EVD alone or with IVF for the treatment of IVH were included. The quality of the included trials was assessed by Jaded scale and the Newcastle-Ottawa Scale (NOS). RevMan 5.1 software was used to conduct the meta-analysis.
Results
Eleven trials (5 RCTs and 6 ORs) involving 680 patients were included. The odds ratio (OR) showed a statistically significant difference between the NE + EVD and EVD + IVF groups in terms of mortality (OR, 0.31; 95% CI, 0.16-0.59; P=0.0004), effective hematoma evacuation rate (OR, 25.50, 95%CI; 14.30, 45.45; P<0.00001), good functional outcome (GFO) (OR, 4.51; (95%CI, 2.81-7.72; P<0.00001), and the ventriculo-peritoneal (VP) shunt dependence rate (OR, 0.16; 95%CI; 0.06, 0.40; P<0.0001).
Conclusion
Applying neuroendoscopic approach with EVD may be a better management for IVH secondary to spontaneous supratentorial hemorrhage than NE + IVF. However, there is still no concluive evidence regarding the preference of NE vs. EVD alone in the case of IVH, because insufficient data has been published thus far. This study suggests that the NE approach with EVD could become an alternative to EVD + IVF for IVH in the future.
doi:10.1371/journal.pone.0080599
PMCID: PMC3827437  PMID: 24232672
24.  Transcriptome Analysis of Leaf Tissue of Raphanus sativus by RNA Sequencing 
PLoS ONE  2013;8(11):e80350.
Raphanus sativus is not only a popular edible vegetable but also an important source of medicinal compounds. However, the paucity of knowledge about the transcriptome of R. sativus greatly impedes better understanding of the functional genomics and medicinal potential of R. sativus. In this study, the transcriptome sequencing of leaf tissues in R. sativus was performed for the first time. Approximately 22 million clean reads were generated and used for transcriptome assembly. The generated unigenes were subsequently annotated against gene ontology (GO) database. KEGG analysis further revealed two important pathways in the bolting stage of R.sativus including spliceosome assembly and alkaloid synthesis. In addition, a total of 6,295 simple sequence repeats (SSRs) with various motifs were identified in the unigene library of R. sativus. Finally, four unigenes of R. sativus were selected for alignment with their homologs from other plants, and phylogenetic trees for each of the genes were constructed. Taken together, this study will provide a platform to facilitate gene discovery and advance functional genomic research of R. sativus.
doi:10.1371/journal.pone.0080350
PMCID: PMC3827192  PMID: 24265813
25.  WormBase 2014: new views of curated biology 
Nucleic Acids Research  2013;42(D1):D789-D793.
WormBase (http://www.wormbase.org/) is a highly curated resource dedicated to supporting research using the model organism Caenorhabditis elegans. With an electronic history predating the World Wide Web, WormBase contains information ranging from the sequence and phenotype of individual alleles to genome-wide studies generated using next-generation sequencing technologies. In recent years, we have expanded the contents to include data on additional nematodes of agricultural and medical significance, bringing the knowledge of C. elegans to bear on these systems and providing support for underserved research communities. Manual curation of the primary literature remains a central focus of the WormBase project, providing users with reliable, up-to-date and highly cross-linked information. In this update, we describe efforts to organize the original atomized and highly contextualized curated data into integrated syntheses of discrete biological topics. Next, we discuss our experiences coping with the vast increase in available genome sequences made possible through next-generation sequencing platforms. Finally, we describe some of the features and tools of the new WormBase Web site that help users better find and explore data of interest.
doi:10.1093/nar/gkt1063
PMCID: PMC3965043  PMID: 24194605

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