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1.  microRNA-106a modulates cisplatin sensitivity by targeting PDCD4 in human ovarian cancer cells 
Oncology Letters  2013;7(1):183-188.
microRNAs (miRNAs/miRs) are a cluster of short non-protein coding RNAs that negatively regulate gene expression, which is involved in fundamental cellular processes, including the response of tumor cells to chemotherapeutic agents. The present study investigated the role of miR-106a in the development of drug resistance in ovarian cancer cells. The expression of miR-106a in the ovarian cancer OVCAR3 cell line and the cisplatin (CDDP)-resistant ovarian cancer OVCAR3/CIS cell line was detected using stem-loop quantitative (q)PCR. The OVCAR3 and OVCAR3/CIS cells were transfected with mimics or inhibitors of miR-106a or with negative control (NC) RNA using lipofectamine 2000. Luciferase reporter assays were used to determine whether PDCD4 was a direct target of miR-106a in the OVCAR3 cells. The expression levels of the PDCD4 proteins were assessed using qRT-PCR and western blotting, respectively. Drug sensitivity was analyzed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, while apoptosis was determined by fluorescence-activating cell sorting analysis. The expression levels of miR-106a were upregulated in the CDDP-resistant ovarian cancer OVCAR3/CIS cell line compared with the parental OVCAR3 cell line. However, the PDCD4 protein levels were decreased in the OVCAR3/CIS cells compared with the OVCAR3 cells. The luciferase reporter assays revealed that PDCD4 was a direct miR-106a target in the OVCAR3 cells. Transfection of the OVCAR3/CIS cells with inhibitors of miR-106a enhanced the sensitivity of the OVCAR3/CIS cells to CDDP and increased CDDP-induced apoptosis. The expression of the PDCD4 protein and the sensitivity to CDDP was decreased in the OVCAR3 cells that were transfected with the mimics of miR-106a. The knockdown of PDCD4 expression using PDCD4-specific siRNAs in the OVCAR3 cells demonstrated that PDCD4 is a key signaling molecule in OVCAR3 cell CDDP-induced resistance. miR-106a may be involved in the development of drug resistance and the regulation of PDCD4 expression, at least in part, by modulating CDDP-induced apoptosis in ovarian cancer cells.
doi:10.3892/ol.2013.1644
PMCID: PMC3861584  PMID: 24348845
microRNA-106a; drug resistance; PDCD4; ovarian cancer
2.  New Clustered Regularly Interspaced Short Palindromic Repeat Locus Spacer Pair Typing Method Based on the Newly Incorporated Spacer for Salmonella enterica 
Journal of Clinical Microbiology  2014;52(8):2955-2962.
A clustered regularly interspaced short palindromic repeat (CRISPR) typing method has recently been developed and used for typing and subtyping of Salmonella spp., but it is complicated and labor intensive because it has to analyze all spacers in two CRISPR loci. Here, we developed a more convenient and efficient method, namely, CRISPR locus spacer pair typing (CLSPT), which only needs to analyze the two newly incorporated spacers adjoining the leader array in the two CRISPR loci. We analyzed a CRISPR array of 82 strains belonging to 21 Salmonella serovars isolated from humans in different areas of China by using this new method. We also retrieved the newly incorporated spacers in each CRISPR locus of 537 Salmonella isolates which have definite serotypes in the Pasteur Institute's CRISPR Database to evaluate this method. Our findings showed that this new CLSPT method presents a high level of consistency (kappa = 0.9872, Matthew's correlation coefficient = 0.9712) with the results of traditional serotyping, and thus, it can also be used to predict serotypes of Salmonella spp. Moreover, this new method has a considerable discriminatory power (discriminatory index [DI] = 0.8145), comparable to those of multilocus sequence typing (DI = 0.8088) and conventional CRISPR typing (DI = 0.8684). Because CLSPT only costs about $5 to $10 per isolate, it is a much cheaper and more attractive method for subtyping of Salmonella isolates. In conclusion, this new method will provide considerable advantages over other molecular subtyping methods, and it may become a valuable epidemiologic tool for the surveillance of Salmonella infections.
doi:10.1128/JCM.00696-14
PMCID: PMC4136180  PMID: 24899040
3.  Novel recombinant chimeric virus-like particle is immunogenic and protective against both enterovirus 71 and coxsackievirus A16 in mice 
Scientific Reports  2015;5:7878.
Hand-foot-and-mouth disease (HFMD) has been recognized as an important global public health issue, which is predominantly caused by enterovirus 71 (EV-A71) and coxsackievirus A16 (CVA16). There is no available vaccine against HFMD. An ideal HFMD vaccine should be bivalent against both EV-A71 and CVA16. Here, a novel strategy to produce bivalent HFMD vaccine based on chimeric EV-A71 virus-like particles (ChiEV-A71 VLPs) was proposed and illustrated. The neutralizing epitope SP70 within the capsid protein VP1 of EV-A71 was replaced with that of CVA16 in ChiEV-A71 VLPs. Structural modeling revealed that the replaced CVA16-SP70 epitope is well exposed on the surface of ChiEV-A71 VLPs. These VLPs produced in Saccharomyces cerevisiae exhibited similarity in both protein composition and morphology as naive EV-A71 VLPs. Immunization with ChiEV-A71 VLPs in mice elicited robust Th1/Th2 dependent immune responses against EV-A71 and CVA16. Furthermore, passive immunization with anti-ChiEV-A71 VLPs sera conferred full protection against lethal challenge of both EV-A71 and CVA16 infection in neonatal mice. These results suggested that this chimeric vaccine, ChiEV-A71 might have the potential to be further developed as a bivalent HFMD vaccine in the near future. Such chimeric enterovirus VLPs provide an alternative platform for bivalent HFMD vaccine development.
doi:10.1038/srep07878
PMCID: PMC4297979  PMID: 25597595
4.  IL-23 Promotes TCR-mediated Negative Selection of Thymocytes through the Upregulation of IL-23 Receptor and RORγt 
Nature communications  2014;5:4259.
Summary
Transient thymic involution is frequently found during inflammation, yet the mode of action of inflammatory cytokines is not well defined. Here we report that interleukin-23 (IL-23) production by the thymic dendritic cells (DCs) promotes apoptosis of the CD4hiCD8hi double positive (DP) thymocytes. A deficiency in IL-23 signaling interferes with negative selection in the male Db/H-Y T-cell receptor (TCR) transgenic mice. IL-23 plus TCR signaling results in significant up-regulation of IL-23 receptor (IL-23R) expressed predominantly on CD4hiCD8hiCD3+αβTCR+ DP thymocytes, and leads to RORγt dependent apoptosis. These results extend the action of IL-23 beyond its peripheral effects to a unique role in TCR mediated negative selection including elimination of natural T regulatory cells in the thymus.
doi:10.1038/ncomms5259
PMCID: PMC4136447  PMID: 25001511
5.  Emergence and Prevalence of Non-H2S-Producing Salmonella enterica Serovar Senftenberg Isolates Belonging to Novel Sequence Type 1751 in China 
Journal of Clinical Microbiology  2014;52(7):2557-2565.
Salmonella enterica serovar Senftenberg is a common nontyphoidal Salmonella serotype which causes human Salmonella infections worldwide. In this study, 182 S. Senftenberg isolates, including 17 atypical non-hydrogen sulfide (H2S)-producing isolates, were detected in China from 2005 to 2011. The microbiological and genetic characteristics of the non-H2S-producing and selected H2S-producing isolates were determined by using pulsed-field gel electrophoresis (PFGE), multilocus sequence typing (MLST), and clustered regularly interspaced short palindromic repeat (CRISPR) analysis. The phs operons were amplified and sequenced. The 17 non-H2S-producing and 36 H2S-producing isolates belonged to 7 sequence types (STs), including 3 new STs, ST1751, ST1757, and ST1758. Fourteen of the 17 non-H2S-producing isolates belonged to ST1751 and had very similar PFGE patterns. All 17 non-H2S-producing isolates had a nonsense mutation at position 1621 of phsA. H2S-producing and non-H2S-producing S. Senftenberg isolates were isolated from the same stool sample from three patients; isolates from the same patients displayed the same antimicrobial susceptibility, ST, and PFGE pattern but could be discriminated based on CRISPR spacers. Non-H2S-producing S. Senftenberg isolates belonging to ST1751 have been prevalent in Shanghai, China. It is possible that these emerging organisms will disseminate further, because they are difficult to detect. Thus, we should strengthen the surveillance for the spread of this atypical S. Senftenberg variant.
doi:10.1128/JCM.00377-14
PMCID: PMC4097678  PMID: 24829240
6.  Aqueous Ionic Liquids and Deep Eutectic Solvents for Cellulosic Biomass Pretreatment and Saccharification 
RSC advances  2013;4(21):10586-10596.
Ionic liquids (ILs) have proven effective solvents for pretreating lignocellulose, leading to the fast saccharification of cellulose and hemicellulose. However, the high current cost of most ILs remains a major barrier to commercializing this recent approach at a practical scale. As a strategic detour, aqueous solutions of ILs are also being explored as less costly alternatives to neat ILs for cellulose pretreatment. However, limited studies on a few select IL systems are known and there remains no systematic survey of various ILs, eluding an in-depth understanding of pretreatment mechanisms afforded by aqueous IL systems. As a step toward filling this gap, this study presents results for Avicel cellulose pretreatment by neat and aqueous solutions (1.0 and 2.0 M) of 20 different ILs and three deep eutectic solvents, correlating enzymatic hydrolysis rates of pretreated cellulose with various IL properties such as hydrogen-bond basicity, polarity, Hofmeister ranking, and hydrophobicity. The pretreatment efficiencies of neat ILs may be loosely correlated to the hydrogen-bond basicity of the constituent anion and IL polarity; however, the pretreatment efficacies for aqueous ILs are more complicated and cannot be simply related to any single IL property. Several aqueous IL systems have been identified as effective alternatives to neat ILs in lignocellulose pretreatment. In particular, this study reveals that aqueous solutions of 1-butyl-3-methylimidazolium methanesulfonate ([BMIM][MeSO3]) are effective for pretreating switchgrass (Panicum virgatum), resulting in fast saccharification of both cellulose and hemicellulose. An integrated analysis afforded by X-ray diffraction, scanning electron microscopy, thermogravimetric analysis and cellulase adsorption isotherm of lignocellulose samples is further used to deliver a more complete view of the structural changes attending aqueous IL pretreatment.
doi:10.1039/C3RA46149A
PMCID: PMC3979586  PMID: 24729865
ionic liquid; cellulose; pretreatment; enzymatic hydrolysis; cellulosic ethanol
7.  Allospecific rejection of MHC class I-deficient bone marrow by CD8 T cells 
Avoidance of long-term immunosuppression is a desired goal in organ transplantation. Mixed chimerism offers a promising approach to tolerance induction, and we have aimed to develop low-toxicity, non-immunodepleting approaches to achieve this outcome. In a mouse model achieving fully MHC-mismatched allogeneic bone marrow engraftment with minimal conditioning (3 Gy total body irradiation followed by anti-CD154 and T cell-depleted allogeneic bone marrow cells), CD4 T cells in the recipient are required to promote tolerance of pre-existing alloreactive recipient CD8 T cells and thereby permit chimerism induction. We now demonstrate that mice devoid of CD4 T cells and NK cells reject MHC class-I deficient and class I/class II-deficient marrow in a CD8 T cell-dependent manner. This rejection is specific for donor alloantigens, since recipient hematopoiesis is not affected by donor marrow rejection and MHC class-I deficient bone marrow that is syngeneic to the recipient is not rejected. Recipient CD8 T cells are activated and develop cytotoxicity against MHC class I-deficient donor cells in association with rejection. These data implicate a novel CD8 T cell-dependent bone marrow rejection pathway, wherein recipient CD8 T cells indirectly activated by donor alloantigens promote direct killing, in a TCR-independent manner, of class I-deficient donor cells.
doi:10.1111/ajt.12525
PMCID: PMC4045013  PMID: 24304495
Bone marrow transplantation; indirect alloreactivity; tolerance; CD8 T cells
8.  Evaluation Models for Soil Nutrient Based on Support Vector Machine and Artificial Neural Networks 
The Scientific World Journal  2014;2014:478569.
Soil nutrient is an important aspect that contributes to the soil fertility and environmental effects. Traditional evaluation approaches of soil nutrient are quite hard to operate, making great difficulties in practical applications. In this paper, we present a series of comprehensive evaluation models for soil nutrient by using support vector machine (SVM), multiple linear regression (MLR), and artificial neural networks (ANNs), respectively. We took the content of organic matter, total nitrogen, alkali-hydrolysable nitrogen, rapidly available phosphorus, and rapidly available potassium as independent variables, while the evaluation level of soil nutrient content was taken as dependent variable. Results show that the average prediction accuracies of SVM models are 77.87% and 83.00%, respectively, while the general regression neural network (GRNN) model's average prediction accuracy is 92.86%, indicating that SVM and GRNN models can be used effectively to assess the levels of soil nutrient with suitable dependent variables. In practical applications, both SVM and GRNN models can be used for determining the levels of soil nutrient.
doi:10.1155/2014/478569
PMCID: PMC4273551  PMID: 25548781
9.  Fundus Camera Guided Photoacoustic Ophthalmoscopy 
Current eye research  2013;38(12):1229-1234.
Purpose
To demonstrate the feasibility of fundus camera guided photoacoustic ophthalmoscopy (PAOM) system and its multimodal imaging capabilities.
Methods
We integrated PAOM and a fundus camera consisting of a white-light illuminator and a high-sensitivity, high-speed CCD. The fundus camera captures both retinal anatomy and PAOM illumination at the same time to provide a real-time feedback when we position the PAOM illuminating light. We applied the integrated system to image rat eyes in vivo and used full-spectrum, visible (VIS), and near infrared (NIR) illuminations in fundus photography.
Results
Both albino and pigmented rat eyes were imaged in vivo. During alignment, different trajectories of PAOM laser scanning were successfully visualized by the fundus camera, which reduced the PAOM alignment time from several minutes to 30 s. In albino eyes, in addition to retinal vessels, main choroidal vessels were observed using VIS-illumination, which is similar to PAOM images. In pigmented eyes, the radial striations of retinal nerve fiber layer were visualized by fundus photography using full-spectrum illumination; meanwhile, PAOM imaged both retinal vessels and the retinal pigmented epithelium melanin distribution.
Conclusions
The results demonstrated that PAOM can be well-integrated with fundus camera without affecting its functionality. The fundus camera guidance is faster and easier comparing with our previous work. The integrated system also set the stage for the next-step verification between oximetry methods based on PAOM and fundus photography.
doi:10.3109/02713683.2013.815219
PMCID: PMC3986591  PMID: 24131226
Fundus camera; multimodal imaging; photoacoustic ophthalmoscopy; retina; retinal imaging
10.  Identification of Salt-Stress-Induced Genes from the RNA-Seq Data of Reaumuria trigyna Using Differential-Display Reverse Transcription PCR 
Next generation sequencing (NGS) technologies have been used to generate huge amounts of sequencing data from many organisms. However, the correct choice of candidate genes and prevention of false-positive results computed from digital gene expression (DGE) of RNA-seq data are vital when using these genetic resources. We indirectly identified 18 salt-stress-induced Reaumuria trigyna transcripts from the transcriptome sequencing data using differential-display reverse transcription PCR (DDRT-PCR) combined with local BLAST searches. Highly consistent with the DGE results, the quantitative real-time PCR expression patterns of these transcripts showed strong upregulation by salt stress, suggesting that these genes may play important roles in R. trigyna's survival under high-salt environments. The method presented here successfully identified responsive genes from the massive amount of RNA-seq data. Thus, we suggest that DDRT-PCR could be employed to mine NGS data in a wide range of applications in transcriptomic studies. In addition, the genes identified in the present study are promising candidates for further elucidation of the salt tolerance mechanisms in R. trigyna.
doi:10.1155/2014/381501
PMCID: PMC4322826
11.  Web-based tool for dynamic functional outcome after acute ischemic stroke and comparison with existing models 
BMC Neurology  2014;14(1):214.
Background
Acute ischemic stroke (AIS) is one of the leading causes of death and adult disability worldwide. In the present study, we aimed to develop a web-based risk model for predicting dynamic functional status at discharge, 3-month, 6-month, and 1-year after acute ischemic stroke (Dynamic Functional Status after Acute Ischemic Stroke, DFS-AIS).
Methods
The DFS-AIS was developed based on the China National Stroke Registry (CNSR), in which eligible patients were randomly divided into derivation (60%) and validation (40%) cohorts. Good functional outcome was defined as modified Rankin Scale (mRS) score ≤ 2 at discharge, 3-month, 6-month, and 1-year after AIS, respectively. Independent predictors of each outcome measure were obtained using multivariable logistic regression. The area under the receiver operating characteristic curve (AUROC) and plot of observed and predicted risk were used to assess model discrimination and calibration.
Results
A total of 12,026 patients were included and the median age was 67 (interquartile range: 57–75). The proportion of patients with good functional outcome at discharge, 3-month, 6-month, and 1-year after AIS was 67.9%, 66.5%, 66.9% and 66.9%, respectively. Age, gender, medical history of diabetes mellitus, stroke or transient ischemic attack, current smoking and atrial fibrillation, pre-stroke dependence, pre-stroke statins using, admission National Institutes of Health Stroke Scale score, admission blood glucose were identified as independent predictors of functional outcome at different time points after AIS. The DFS-AIS was developed from sets of predictors of mRS ≤ 2 at different time points following AIS. The DFS-AIS demonstrated good discrimination in the derivation and validation cohorts (AUROC range: 0.837-0.845). Plots of observed versus predicted likelihood showed excellent calibration in the derivation and validation cohorts (all r = 0.99, P < 0.001). When compared to 8 existing models, the DFS-AIS showed significantly better discrimination for good functional outcome and mortality at discharge, 3-month, 6-month, and 1-year after AIS (all P < 0.0001).
Conclusion
The DFS-AIS is a valid risk model to predict functional outcome at discharge, 3-month, 6-month, and 1-year after AIS.
Electronic supplementary material
The online version of this article (doi:10.1186/s12883-014-0214-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s12883-014-0214-z
PMCID: PMC4255632
Acute ischemic stroke; Prognosis; Risk model
12.  Expression of human DNA mismatch-repair protein, hMSH2, in patients with oral lichen planus 
hMSH2 is one of the human DNA mismatch repair genes that plays an important role in reducing mutations and maintaining genomic stability. The aim of the present study was to detect the expression and significance of hMSH2 protein in patients with oral lichen planus (OLP). The expression levels of hMSH2 in the OLP group (n=51) and control group with normal oral mucosa (NM; n=40) were detected using an immunohistochemical method and subsequently assessed. The positive rate of hMSH2 expression in the OLP group was 52.94%, while the rate was 80% in the control group, exhibiting a statistically significant difference (χ2=7.1993; P<0.05). However, the expression of hMSH2 in the OLP tissues was not shown to significantly correlate with the patient gender, age and type of OLP (P>0.05). In conclusion, the protein expression levels of hMSH2 in the OLP tissues were significantly reduced as compared with that in the NM tissues, indicating that hMSH2 plays a role in the development of OLP. Therefore, hMSH2 may be used as a biomarker for evaluating the cancer risk of patients with OLP.
doi:10.3892/etm.2014.2053
PMCID: PMC4247292  PMID: 25452803
oral lichen planus; mismatch repair genes; hMSH2; immunohistochemistry
13.  Robust Optimization Model and Algorithm for Railway Freight Center Location Problem in Uncertain Environment 
Railway freight center location problem is an important issue in railway freight transport programming. This paper focuses on the railway freight center location problem in uncertain environment. Seeing that the expected value model ignores the negative influence of disadvantageous scenarios, a robust optimization model was proposed. The robust optimization model takes expected cost and deviation value of the scenarios as the objective. A cloud adaptive clonal selection algorithm (C-ACSA) was presented. It combines adaptive clonal selection algorithm with Cloud Model which can improve the convergence rate. Design of the code and progress of the algorithm were proposed. Result of the example demonstrates the model and algorithm are effective. Compared with the expected value cases, the amount of disadvantageous scenarios in robust model reduces from 163 to 21, which prove the result of robust model is more reliable.
doi:10.1155/2014/607159
PMCID: PMC4236974  PMID: 25435867
14.  Decreased expression of microRNA-21 correlates with the imbalance of Th17 and Treg cells in patients with rheumatoid arthritis 
The imbalance of Th17/Treg cell populations has been suggested to be involved in the regulation of rheumatoid arthritis (RA) pathogenesis; however, the mechanism behind this phenomenon remains unclear. Recent studies have shown how microRNAs (miRNAs) are important regulators of immune responses and are involved in the development of a variety of inflammatory diseases, including RA. In this study, we demonstrated that the frequencies of CD3+CD4+IL-17+Th17 cells were significantly higher, and CD4+CD25+FOXP3+ Treg cells significantly lower in peripheral blood mononuclear cells from RA patients. Detection of cytokines from RA patients revealed an elevated panel of pro-inflammatory cytokines, including IL-17, IL-6, IL-1β, TNF-α and IL-22, which carry the inflammatory signature of RA and are crucial in the differentiation and maintenance of pathogenic Th17 cells and dysfunction of Treg cells. However, the level of miR-21 was significantly lower in RA patients, accompanied by the increase in STAT3 expression and activation, and decrease in STAT5/pSTAT5 protein and Foxp3 mRNA levels. Furthermore, lipopolysaccharide stimulation up-regulated miR-21 expression from healthy controls, but down-regulated miR-21 expression from RA patients. Therefore, we speculate that miR-21 may be part of a negative feedback loop in the normal setting. However, miR-21 levels decrease significantly in RA patients, suggesting that this feedback loop is dysregulated and may contribute to the imbalance of Th17 and Treg cells. MiR-21 may thus serve as a novel regulator in T-cell differentiation and homoeostasis, and provides a new therapeutic target for the treatment of RA.
doi:10.1111/jcmm.12353
PMCID: PMC4224555  PMID: 25164131
rheumatoid arthritis; Treg; Th17; miRNA; pro-inflammatory cytokine
15.  Large-scale transcriptome comparison reveals distinct gene activations in wheat responding to stripe rust and powdery mildew 
BMC Genomics  2014;15(1):898.
Background
Stripe rust (Puccinia striiformis f. sp. tritici; Pst) and powdery mildew (Blumeria graminis f. sp. tritici; Bgt) are important diseases of wheat (Triticum aestivum) worldwide. Similar mechanisms and gene transcripts are assumed to be involved in the host defense response because both pathogens are biotrophic fungi. The main objective of our study was to identify co-regulated mRNAs that show a change in expression pattern after inoculation with Pst or Bgt, and to identify mRNAs specific to the fungal stress response.
Results
The transcriptome of the hexaploid wheat line N9134 inoculated with the Chinese Pst race CYR 31 was compared with that of the same line inoculated with Bgt race E09 at 1, 2, and 3 days post-inoculation. Infection by Pst and Bgt affected transcription of 23.8% of all T. aestivum genes. Infection by Bgt triggered a more robust alteration in gene expression in N9134 compared with the response to Pst infection. An array of overlapping gene clusters with distinctive expression patterns provided insight into the regulatory differences in the responses to Bgt and Pst infection. The differentially expressed genes were grouped into seven enriched Kyoto Encyclopedia of Genes and Genomes pathways in Bgt-infected leaves and four pathways in Pst-infected leaves, while only two pathways overlapped. In the plant–pathogen interaction pathway, N9134 activated a higher number of genes and pathways in response to Bgt infection than in response to Pst invasion. Genomic analysis revealed that the wheat genome shared some microbial genetic fragments, which were specifically induced in response to Bgt and Pst infection.
Conclusions
Taken together, our findings indicate that the responses of wheat N9134 to infection by Bgt and Pst shows differences in the pathways and genes activated. The mass sequence data for wheat–fungus interaction generated in this study provides a powerful platform for future functional and molecular research on wheat–fungus interactions.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-898) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2164-15-898
PMCID: PMC4201691  PMID: 25318379
Bread wheat; Stripe rust; Powdery mildew; RNA-Seq; Gene expression
16.  Mitochondrial Dysfunction in Obesity-Associated Nonalcoholic Fatty Liver Disease: The Protective Effects of Pomegranate with Its Active Component Punicalagin 
Antioxidants & Redox Signaling  2014;21(11):1557-1570.
Abstract
Aims: Punicalagin (PU) is one of the major ellagitannins found in the pomegranate (Punica granatum), which is a popular fruit with several health benefits. So far, no studies have evaluated the effects of PU on nonalcoholic fatty liver disease (NAFLD). Our work aims at studying the effect of PU-enriched pomegranate extract (PE) on high fat diet (HFD)-induced NAFLD. Results: PE administration at a dosage of 150 mg/kg/day significantly inhibited HFD-induced hyperlipidemia and hepatic lipid deposition. As major contributors to NAFLD, increased expression of pro-inflammatory cytokines such as tumor necrosis factor-alpha, interleukins 1, 4, and 6 as well as augmented oxidative stress in hepatocytes followed by nuclear factor (erythroid-derived-2)-like 2 (Nrf2) activation were normalized through PE supplementation. In addition, PE treatment reduced uncoupling protein 2 (UCP2) expression, restored ATP content, suppressed mitochondrial protein oxidation, and improved mitochondrial complex activity in the liver. In contrast, mitochondrial content was not affected despite increased peroxisomal proliferator-activated receptor–gamma coactivator-1α (PGC-1α) and elevated expression of genes related to mitochondrial beta-oxidation after PE treatment. Finally, PU was identified as the predominant active component of PE with regard to the lowering of triglyceride and cholesterol content in HepG2 cells, and both PU- and PE-protected cells from palmitate induced mitochondrial dysfunction and insulin resistance. Innovation: Our work presents the beneficial effects of PE on obesity-associated NAFLD and multiple risk factors. PU was proposed to be the major active component. Conclusions: By promoting mitochondrial function, eliminating oxidative stress and inflammation, PU may be a useful nutrient for the treatment of NAFLD. Antioxid. Redox Signal. 21, 1557–1570.
doi:10.1089/ars.2013.5538
PMCID: PMC4175030  PMID: 24393106
17.  Minimally invasive surgery treatment for the patients with spontaneous supratentorial intracerebral hemorrhage (MISTICH): protocol of a multi-center randomized controlled trial 
BMC Neurology  2014;14(1):206.
Background
The choice of surgical or conservative treatment for patients with spontaneous intracerebral hemorrhage is controversial. Some minimally invasive treatments have been applied to hematoma evacuation and could improve prognosis to some extent. Up to now, studies on minimally invasive surgery for patients with spontaneous intracerebral hemorrhage are still insufficient.
Design
The MISTICH is a multi-center, prospective, randomized, assessor-blinded, parallel group, controlled clinical trial. 2448 eligible patients will be assigned to neuroendoscopy group, stereotactic aspiration group and craniotomy group randomly. Patients will receive the corresponding surgery based on the result of randomization. Surgeries will be performed by well-trained surgeons and standard medical treatment will be given to all patients. Patients will be followed up at 7 days, 30 days, and 6 months. The primary outcome of this study is unfavorable outcome at 6 months. Secondary outcomes include: mortality at 30 days and 6 months after surgery; neurological functional status of 6 months after surgery; complications including rebleeding, ischemic stroke and intracranial infection; days of hospitalization.
Discussion
The MISTICH trial is a randomized controlled trial designed to determine whether minimally invasive surgeries could improve the prognosis for patients with spontaneous intracerebral hemorrhage compared with craniotomy. (ChiCTR-TRC-12002026. Registered 23 March 2012).
doi:10.1186/s12883-014-0206-z
PMCID: PMC4194378  PMID: 25300611
Intracerebral hemorrhage; Minimally invasive surgical treatment; Craniotomy; Neuroendoscope; Stereotactic aspiration
18.  Dynamic Characterization of Growth and Gene Expression Using High-throughput Automated Flow cytometry 
Nature methods  2014;11(4):443-448.
Cells adjust to changes in environmental conditions using complex regulatory programs. These cellular programs are the result of an intricate interplay between gene expression, cellular growth rate, and protein degradation fluxes. New technologies that enable simultaneous and time-resolved measurements of these variables are necessary to dissect cellular homeostatic strategies. Here, we report the development of a novel automated flow-cytometry robotic setup that enables real-time measurement of precise and simultaneous relative growth and protein synthesis rates of multiplexed microbial populations across many conditions. These measurements generate quantitative profiles of dynamically-evolving protein synthesis and degradation rates. We demonstrate this setup in the context of gene regulation of the unfolded protein response (UPR) and uncover a dynamic and complex landscape of gene expression, growth dynamics, and proteolysis following perturbations.
doi:10.1038/nmeth.2879
PMCID: PMC4016179  PMID: 24608180
19.  Research of dose-effect relationship parameters of percutaneous microwave ablation for uterine leiomyomas - a quantitative study 
Scientific Reports  2014;4:6469.
Eighty eight patients with 91 uterine leiomyomas who underwent ultrasound-guided percutaneous microwave ablation (PMWA) treatment were prospectively included in the study in order to study the dose-effect relationship parameters (DERP) of PMWA for uterine leiomyomas and its relationship with T2-weighted MR imaging (T2WI). Based on the signal intensity of T2WI, uterine leiomyomas were classified as hypointense, isointense, and hyperintense. During ablation, leiomyomas were treated with quantitative microwave ablation (QMWA) energy of 50 w × 300 s or 60 w × 300 s. After QMWA, contrast-enhanced ultrasound (CEUS) was performed to evaluate DERP. No matter under 50 w × 300 s or 60 w × 300 s, quantitative microwave ablation volume (QMAV) of hyperintense leiomyoma was smaller than that of hypointense and isointense leiomyoma (P<0.016). For hypointense and isointense leiomyoma, QMAV of 60 w × 300 s was larger than that of 50 w × 300 s (P<0.05). DERPs obtained by T2WI can be used to guide the treatment of uterine leiomyoma by PMWA.
doi:10.1038/srep06469
PMCID: PMC4179463  PMID: 25267154
20.  Acat1 Gene Ablation in Mice Increases Hematopoietic Progenitor Cell Proliferation in Bone Marrow and Causes Leukocytosis 
Arteriosclerosis, thrombosis, and vascular biology  2013;33(9):10.1161/ATVBAHA.112.301080.
Objective
To investigate the role of acyl-CoA:cholesterol acyltransferase 1 (ACAT1) in hematopoiesis.
Approach and Results
ACAT1 converts cellular cholesterol to cholesteryl esters for storage in multiple cell types and is a potential drug target for human diseases. In mouse models for atherosclerosis, global Acat1 knockout causes increased lesion size; bone marrow (BM) transplantation experiments suggest that the increased lesion size might be caused by ACAT1 deficiency in macrophages. However, BM contains hematopoietic stem cells (HSCs) which give rise to cells in myeloid and lymphoid lineages; these cell types affect atherosclerosis at various stages. Here, we test the hypothesis that global Acat1-/- may affect hematopoiesis, rather than affecting macrophage function only, and show that Acat1-/- mice contain significantly higher numbers of myeloid cells and other cells than wild type mice. Detailed analysis of BM cells demonstrated that Acat1-/- causes a higher proportion of the stem cell-enriched LSK population (Lin-Sca1+ckit+) to proliferate, resulting in higher numbers of myeloid progenitor cells. In addition, we show that Acat1-/- causes higher monocytosis in Apoe-/- mouse during atherosclerosis development.
Conclusion
ACAT1 plays important roles in hematopoiesis in normal mouse and in Apoe-/- mouse during atherosclerosis development.
doi:10.1161/ATVBAHA.112.301080
PMCID: PMC3882116  PMID: 23846496
ACAT1; Leukocytosis; LSK cell; Monocytosis; Atherosclerosis
21.  Molecular Epidemiology of Reemergent Rabies in Yunnan Province, Southwestern China 
Emerging Infectious Diseases  2014;20(9):1433-1442.
This province is a focal point for spread of rabies between Southeast Asia and China.
Yunnan Province in China borders 3 countries (Vietnam, Laos, and Myanmar) in Southeast Asia. In the 1980s, a large-scale rabies epidemic occurred in this province, which subsided by the late 1990s. However, 3 human cases of rabies in 2000 indicated reemergence of the disease in 1 county. In 2012, rabies was detected in 77 counties; 663 persons died of rabies during this new epidemic. Fifty two rabies virus strains obtained during 2008–2012 were identified and analyzed phylogenetically by sequencing the nucleoprotein gene. Of the 4 clades identified, clades YN-A and YN-C were closely related to strains from neighboring provinces, and clade YN-B was closely related to strains from Southeast Asia, but formed a distinct branch. Rabies virus diversity might be attributed to dog movements among counties, provinces, and neighboring countries. These findings suggest that Yunnan Province is a focal point for spread of rabies between Southeast Asia and China.
doi:10.3201/eid2009.130440
PMCID: PMC4178403  PMID: 25144604
rabies; rabies virus; viruses; molecular epidemiology; endemic disease; public health; nucleoprotein; homology; phylogenetic analysis; dogs; China
22.  Inhibition of Fucosylation Reshapes Inflammatory Macrophages and Suppresses Type II Collagen-Induced Arthritis 
Objective
Fucosylation catalyzed by fucosyltransferases (FUTs) is an important post-translational modification involved in a variety of biological processes. The purpose of the current study is to determine the roles of fucosylation in rheumatoid arthritis (RA) and the efficacy of reestablishing the immune homeostasis by using 2-Deoxy-D-galactose (2-D-gal), a fucosylation inhibitor.
Methods
Q-PCR was performed to determine the expression of fucosyltransferases (FUTs) in RA and osteoarthritis (OA) synovial tissues and FACS sorted cells from RA synovial fluids. The in vivo inhibitory effect of 2-D-gal was evaluated in a collagen-induced arthritis (CIA) model. The in vitro effects of 2-D-gal on inflammatory macrophage differentiation, cytokine production, antigen uptake, processing, and presenting functions were analyzed.
Results
FUTs that are involved in terminal or sub-terminal, but not core or O-fucosylation, were upregulated in RA, compared to OA synovial tissues. The expression of terminal FUTs was highly positively correlated with that of TNF encoding for tumor necrosis factor α. Terminal FUTs were predominately expressed in M1 macrophages. In vivo, 2-D-gal treatment precluded CIA development with reduced inflammatory macrophages and Th17 in draining lymph nodes, decreased TNF-α, IL-6 and antibodies to type II collagen in the serum. In vitro, 2-D-gal skewed the differentiation of M1 macrophages to IL-10 producing M2 macrophages. Furthermore, 2-D-gal significantly inhibited antigen presenting function of M1 macrophages.
Conclusion
Terminal fucosylation is a novel hallmark of inflammatory macrophages. Inhibition of terminal FUTs reshapes the differentiation and functions M1 macrophages, leading to resolution of inflammation in arthritis.
doi:10.1002/art.38711
PMCID: PMC4146698  PMID: 24838610
23.  Visual Learning Alters the Spontaneous Activity of the Resting Human Brain: An fNIRS Study 
BioMed Research International  2014;2014:631425.
Resting-state functional connectivity (RSFC) has been widely used to investigate spontaneous brain activity that exhibits correlated fluctuations. RSFC has been found to be changed along the developmental course and after learning. Here, we investigated whether and how visual learning modified the resting oxygenated hemoglobin (HbO) functional brain connectivity by using functional near-infrared spectroscopy (fNIRS). We demonstrate that after five days of training on an orientation discrimination task constrained to the right visual field, resting HbO functional connectivity and directed mutual interaction between high-level visual cortex and frontal/central areas involved in the top-down control were significantly modified. Moreover, these changes, which correlated with the degree of perceptual learning, were not limited to the trained left visual cortex. We conclude that the resting oxygenated hemoglobin functional connectivity could be used as a predictor of visual learning, supporting the involvement of high-level visual cortex and the involvement of frontal/central cortex during visual perceptual learning.
doi:10.1155/2014/631425
PMCID: PMC4163468  PMID: 25243168
24.  Dysregulated Cytokine Production by Dendritic Cells Modulates B Cell Responses in the NZM2410 Mouse Model of Lupus 
PLoS ONE  2014;9(8):e102151.
The breakdown in tolerance of autoreactive B cells in the lupus-prone NZM2410-derived B6.Sle1.Sle2.Sle3 (TC) mice results in the secretion of autoantibodies. TC dendritic cells (DCs) enhance B cell proliferation and antibody secretion in a cytokine-dependent manner. However, the specific cytokine milieu by which TC DCs activate B cells was not known. In this study, we compared TC and C57BL/6 (B6) control for the distribution of DC subsets and for their production of cytokines affecting B cell responses. We show that TC DCs enhanced B cell proliferation through the production of IL-6 and IFN-γ, while antibody secretion was only dependent on IL-6. Pre-disease TC mice showed an expanded PDCA1+ cells prior to disease onset that was localized to the marginal zone and further expanded with age. The presence of PDCA1+ cells in the marginal zone correlated with a Type I Interferon (IFN) signature in marginal zone B cells, and this response was higher in TC than B6 mice. In vivo administration of anti-chromatin immune complexes upregulated IL-6 and IFN-γ production by splenic DCs from TC but not B6 mice. The production of BAFF and APRIL was decreased upon TC DC stimulation both in vitro and in vivo, indicating that these B cell survival factors do not play a role in B cell modulation by TC DCs. Finally, TC B cells were defective at downregulating IL-6 expression in response to anti-inflammatory apoptotic cell exposure. Overall, these results show that the TC autoimmune genetic background induces the production of B cell-modulating inflammatory cytokines by DCs, which are regulated by the microenvironment as well as the interplay between DC.
doi:10.1371/journal.pone.0102151
PMCID: PMC4122346  PMID: 25093822
25.  Malignant intraventricular meningioma with craniospinal dissemination and concurrent pulmonary metastasis 
Background
Malignant intraventricular meningiomas are quite rare and may spread along the craniospinal axis or extraneurally. However, simultaneous cerebrospinal dissemination and distal extraneural metastasis has seldom been reported.
Case presentation
A 51-year-old woman presented with recurrent anaplastic meningioma in the trigone of right lateral ventricle over a 1.5-year period. Suggested radiotherapy was refused after each operation. The patient showed a local relapse and dissemination around the previous tumoral cavity and along the spinal canal during the last recurrence. Left pulmonary metastasis was also found. She died despite multiple lesion resections.
Conclusions
Malignant intraventricular meningiomas are an uncommon subset of intracranial meningiomas, and have a great potential for intraneural and extraneural metastasis. Systemic investigation for metastasis is required after surgery, especially for those without adjuvant therapies.
doi:10.1186/1477-7819-12-238
PMCID: PMC4126346  PMID: 25073808
CSF dissemination; extraneural metastasis; intraventricular meningioma; malignant

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