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1.  Molecular mechanism of ERK dephosphorylation by striatal-enriched protein tyrosine phosphatase (STEP) 
Journal of neurochemistry  2013;128(2):315-329.
Striatal-enriched tyrosine phosphatase (STEP) is an important regulator of neuronal synaptic plasticity, and its abnormal level or activity contributes to cognitive disorders. One crucial downstream effector and direct substrate of STEP is extracellular signal-regulated protein kinase (ERK), which has important functions in spine stabilisation and action potential transmission. The inhibition of STEP activity toward phospho-ERK has the potential to treat neuronal diseases, but the detailed mechanism underlying the dephosphorylation of phospho-ERK by STEP is not known. Therefore, we examined STEP activity toward pNPP, phospho-tyrosine-containing peptides, and the full-length phospho-ERK protein using STEP mutants with different structural features. STEP was found to be a highly efficient ERK tyrosine phosphatase that required both its N-terminal regulatory region and key residues in its active site. Specifically, both KIM and KIS of STEP were required for ERK interaction. In addition to the N-terminal KIS region, S245, hydrophobic residues L249/L251, and basic residues R242/R243 located in the KIM region were important in controlling STEP activity toward phospho-ERK. Further kinetic experiments revealed subtle structural differences between STEP and HePTP that affected the interactions of their KIMs with ERK. Moreover, STEP recognised specific positions of a phospho-ERK peptide sequence through its active site, and the contact of STEP F311 with phospho-ERK V205 and T207 were crucial interactions. Taken together, our results not only provide the information for interactions between ERK and STEP, but will also help in the development of specific strategies to target STEP-ERK recognition, which could serve as a potential therapy for neurological disorders.
doi:10.1111/jnc.12463
PMCID: PMC3947313  PMID: 24117863
ERK; phosphorylation; phosphatase; synaptic plasticity; Striatal enriched tyrosine phosphatases (STEP); neurological disorders
2.  Genetic variants in antigen presentation-related genes influence susceptibility to hepatitis C virus and viral clearance: a case control study 
BMC Infectious Diseases  2014;14(1):3837.
Background
Genes related to antigen presentation pathway, which are in the non-classical class-II region of human leukocyte antigen (HLA), play a vital role during the infection of hepatitis C virus (HCV).
Methods
The current study determined the genotypes of 34 tagging-SNPs (single nucleotide polymorphisms) from 9 candidate genes (HLA-DMA, HLA-DMB, HLA-DOA, HLA-DOB, TAP1, TAP2, LMP2, LMP7, and tapasin) in a Chinese population of paid blood donors with high risk of HCV infection. The distributions of those SNPs were compared among the 1207 former paid blood donors with different HCV infection outcomes.
Results
HLA-DMA rs1063478 and HLA-DOA rs2284191 were independent factors of acquiring HCV infection. Carrying three favorable alleles of rs1063478-T and rs2284191-G offered the highest protective effect (odds ratio = 0.46, 95% confidence intervals = 0.27-0.78). HLA-DOB rs7383287 and LMP2 rs17587 were independent factors of infection chronicity. Subjects carrying two favorable alleles of rs7383287-G and rs17587-A had a decreased risk of HCV chronicity (odds ratio = 0.42, 95% confidence intervals = 0.26-0.66). The interaction analysis showed that experience of plasma donation interacted with the combined effects of rs1063478 and rs2284191 for HCV susceptibility, and the experience of whole blood donation interacted with the association of rs7383287 with HCV clearance.
Conclusions
Our results suggested that genetic variants in antigen presentation pathway had influence on susceptibility to HCV infection and viral clearance. HLA-DMA rs1063478, HLA-DOA rs2284191, and HLA-DOB rs7383287 were identified as novel loci in Chinese population that were involved in HCV infection.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-014-0716-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s12879-014-0716-8
PMCID: PMC4279674  PMID: 25528575
Hepatitis C; Genetic polymorphism; Human leukocyte antigen; Infection outcomes; Chinese population
3.  Research of shRNAmir inhibitory effects towards focal adhesion kinase expression in the treatment of gastric cancer 
Oncology Letters  2014;9(2):595-603.
Gastric cancer is the fourth most common type of malignant tumor, with a poor prognosis. Focal adhesion kinase (FAK) mediates the crosslink of intracellular signaling networks, playing a key role in cell migration and invasion. The aim of the present study was to investigate the effects of FAK interference on the proliferation ability, invasion and metastasis of gastric cancer cells. The FAK-RNAi lentiviral vector was infected into SGC7901 gastric cancer cells in order to observe the in vivo situations of tumor growth and metastasis before and after the FAK interference. The growth of SGC7901 gastric cancer cells in the interference group was significantly inhibited compared with that of the negative control (P<0.05) and the blank control groups (P<0.05), and the FAK expression significantly decreased (P<0.05). The in vitro invasion and metastasis experiments showed that the cell invasion and metastasis abilities of the interference group significantly decreased when compared with those of the negative control (P<0.05) and blank control groups (P<0.05). In the nude mouse subcutaneous tumor transplantation model, the mean ± standard deviation tumor weight of the interference group (1.474±0.9840 g) was lower than that of the negative control (3.134±0.3299 g) and blank control (2.68±0.12 g) groups (P<0.05). In the nude mice, the liver and peritoneal metastasis rates of the interference group were significantly lower than those of the negative control (P<0.05) and the blank control groups (P<0.05), and the FAK mRNA of the interference group significantly reduced (P<0.05). In conclusion, FAK interference could effectively suppress the proliferation, invasion and metastasis of transfected SGC7901 gastric cancer cells, and could inhibit the growth and distant metastasis of gastric cancer in nude mice.
doi:10.3892/ol.2014.2725
PMCID: PMC4301487  PMID: 25621028
focal adhesion kinase; gastric cancer; RNAi; invasion; metastasis; nude mouse
4.  Intravenous Remifentanil versus Epidural Ropivacaine with Sufentanil for Labour Analgesia: A Retrospective Study 
PLoS ONE  2014;9(11):e112283.
Remifentanil with appropriate pharmacological properties seems to be an ideal alternative to epidural analgesia during labour. A retrospective cohort study was undertaken to assess the efficacy and safety of remifentanil intravenous patient-controlled analgesia (IVPCA) compared with epidural analgesia. Medical records of 370 primiparas who received remifentanil IVPCA or epidural analgesia were reviewed. Pain and sedation scores, overall satisfaction, the extent of pain control, maternal side effects and neonatal outcome as primary observational indicators were collected. There was a significant decline of pain scores in both groups. Pain reduction was greater in the epidural group throughout the whole study period (0∼180 min) (P<0.0001), and pain scores in the remifentanil group showed an increasing trend one hour later. The remifentanil group had a lower SpO2 (P<0.0001) and a higher sedation score (P<0.0001) within 30 min after treatment. The epidural group had a higher overall satisfaction score (3.8±0.4 vs. 3.7±0.6, P = 0.007) and pain relief score (2.9±0.3 vs. 2.8±0.4, P<0.0001) compared with the remifentanil group. There was no significant difference on side effects between the two groups, except that a higher rate of dizziness (1% vs. 21.8%, P<0.0001) was observed during remifentanil analgesia. And logistic regression analysis demonstrated that nausea, vomiting were associated with oxytocin usage and instrumental delivery, and dizziness was associated to the type and duration of analgesia. Neonatal outcomes such as Apgar scores and umbilical-cord blood gas analysis were within the normal range, but umbilical pH and base excess of neonatus in the remifentanil group were significantly lower. Remifentanil IVPCA provides poorer efficacy on labor analgesia than epidural analgesia, with more sedation on parturients and a trend of newborn acidosis. Despite these adverse effects, remifentanil IVPCA can still be an alternative option for labor analgesia under the condition of one-to-one bedside care, continuous monitoring, oxygen supply and preparation for neonatal resuscitation.
doi:10.1371/journal.pone.0112283
PMCID: PMC4227805  PMID: 25386749
5.  Host genetic variations are associated with virological response to interferon therapy of chronic HCV in Han Chinese patients 
Journal of Biomedical Research  2014;28(6):476-483.
Abstract
Previous studies have suggested that host genetic polymorphisms may affect virological response to pegylated-interferon and ribavirin (PEG-IFN/ ribavirin) therapy in chronic HCV infection. IL28B and MxA are the most intensively studied genes in Chinese Han population. The current research is to summarize published data and evaluate the overall association of meaningful SNPs in these two genes with virological response to interferon-based therapy. Literature search was performed in online database and a systematic review was conducted based on the search results. Meaningful single nucleotide polymorphisms (SNPs) were summarized and analyzed for odds ratio (OR) and 95% confidence intervals (95% CI). Data manipulation and statistical analyses were performed by using STATA 12.0 and Review Manager version 5.1. Eighteen papers were included for final data analysis. Three SNPs of IL28B and two SNPs of MxA were found to be associated with higher sustained virological response (SVR) to interferon therapy. The ORs and 95% CIs of each variant were: IL28B rs8099917 TT (OR: 4.35, 95% CI: 3.10∼6.12), IL28B rs12979860 CC (OR: 5.37, 95% CI: 3.95∼7.31), IL28B rs7248668 CC (OR: 3.50, 95% CI: 2.30∼5.35), MxA rs2071430 GT (OR: 2.03, 95% CI: 1.31∼3.13), and MxA rs17000900 AC/AA (OR: 1.82, 95% CI: 1.17∼2.83). The genotypes of IL28B rs8099917, rs12979860, rs7248668, MxA rs2071430, and MxA rs17000900 were strong SVR predictors for PEG-IFN/ ribavirin -treated HCV patients in Han Chinese population. Our findings suggest that host genetic variations are associated with virological response to interferon therapy of chronic HCV in Han Chinese patients.
doi:10.7555/JBR.28.20130142
PMCID: PMC4250526  PMID: 25469117
hepatitis C virus; therapy; virological response; IL28B; MxA; meta-analysis
6.  Associations of IFN-γ rs2430561 T/A, IL28B rs12979860 C/T and ERα rs2077647 T/C polymorphisms with outcomes of hepatitis B virus infection: a meta-analysis 
Journal of Biomedical Research  2014;28(6):484-493.
Abstract
Several studies investigated associations of IFN-γ rs2430561 T/A, IL28B rs12979860 C/T and ERα rs2077647 T/C gene polymorphisms with outcomes of hepatitis B virus (HBV) infection, but the results were controversial. Therefore, we performed a meta-analysis of all published observational studies to address this inconsistency. Literature was searched in online database and a systematic review was conducted based on the search results. A total of 24 studies were included and dichotomous data were presented as odds ratio (OR) with a 95% confidence interval (CI). The rs2430561 T allele was associated with reduced persistent HBV infection risk (T vs. A: OR, 0.690; 95% CI, [0.490, 0.971]), while the rs2077647 T allele significantly increased the risk of persistent HBV infection (T vs. C: OR, 1.678; 95% CI, [1.212, 2.323]). Rs 2077647 CC might play a role in protecting individuals against HBV persistence (TT vs. CC: OR, 4.109; 95% CI, [2.609, 6.473]). Furthermore, carriers of the rs2430561 TT genotype were more likely to clear HBV spontaneously compared with those of the AA genotype (TT vs. AA: OR, 0.555; 95% CI, [0.359, 0.856]). For rs12979860 C/T polymorphism, no significant correlation with HBV infection outcomes was found. In subgroup analyses, the results were similar to those of overall analysis. However, for rs2077647 TT vs. TC+CC, significantly increased risks were observed in the Asian and hospital-based population, but not in the overall analysis. IFN-γ rs2430561 T/A and ERα rs2077647 T/C genetic polymorphisms were associated with outcomes of HBV infection, but no association was found between IL28B rs12979860 C/T and HBV infection.
doi:10.7555/JBR.28.20130162
PMCID: PMC4250527  PMID: 25469118
meta-analysis; single nucleotide polymorphism; IFN-γ rs2430561 T/A; IL28B rs12979860 C/T; ERα rs2077647 T/C; hepatitis B virus
7.  Association between Helicobacter pylori infection and migraine: A meta-analysis 
World Journal of Gastroenterology : WJG  2014;20(40):14965-14972.
AIM: To quantify the association between Helicobacter pylori (H. pylori) infection and migraine.
METHODS: A systematic literature search of PubMed and EMBASE was conducted from inception to December 2013. Studies that provided data dealing with H. pylori infection in patients with migraine, as well as healthy controls, were selected. Meta-analysis was carried out using the odds ratio (OR) with a fixed or random effects model, and a 95%CI for the OR was calculated. An unconditional logistic regression model was used to analyze potential parameters related to H. pylori prevalence. Subgroup analyses were conducted as methods of detection and evidence grade.
RESULTS: Five case-control studies published between 2000 and 2013 were finally identified, involving 903 patients, with a total H. pylori infection rate of 39.31%. The prevalence of H. pylori infection was significantly greater in migraineurs than in controls (44.97% vs 33.26%, OR = 1.92, 95%CI: 1.05-3.51, P = 0.001). A sensitivity test indicated that no single study dominated the combined results. Univariate regression analysis found that publication year, geographical distribution and evidence grade were relevant to the results and were the main reason for the heterogeneity. Subgroup analysis found a significantly greater infection rate of H. pylori in Asian patients with migraine, but no statistically significant infection rate in European patients. The ORs were 3.48 (95%CI: 2.09-5.81, P = 0.000) and 1.19 (95%CI: 0.86-1.65, P = 0.288), respectively.
CONCLUSION: The pooled data suggest a trend of more frequent H. pylori infections in patients with migraine.
doi:10.3748/wjg.v20.i40.14965
PMCID: PMC4209561  PMID: 25356058
Helicobacter pylori; Migraine; Meta-analysis; Odds ratio; Subgroup analysis
8.  ECM-incorporated hydrogels crosslinked 1 via native chemical ligation to engineer stem cell microenvironments 
Biomacromolecules  2013;14(9):10.1021/bm400728e.
Limiting the precise study of the biochemical impact of whole molecule extracellular matrix (ECM) proteins on stem cell differentiation is the lack of 3D in vitro models that can accommodate many different types of ECM. Here we sought to generate such a system while maintaining consistent mechanical properties and supporting stem cell survival. To this end, we used native chemical ligation to crosslink poly(ethylene glycol) macromonomers under mild conditions while entrapping ECM proteins (termed ECM composites) and stem cells. Sufficiently low concentrations of ECM were used to maintain constant storage moduli and pore size. Viability of stem cells in composites was maintained over multiple weeks. ECM of composites encompassed stem cells and directed the formation of distinct structures dependent on ECM type. Thus, we introduce a powerful approach to study the biochemical impact of multiple ECM proteins (either alone or in combination) on stem cell behavior.
doi:10.1021/bm400728e
PMCID: PMC3880157  PMID: 23875943
stem cells; extracellular matrix; native chemical ligation; differentiation; poly(ethylene glycol) hydrogel
9.  Any detectable thyroglobulin in lymph node biopsy washouts suggests local recurrence in differentiated thyroid cancer 
Endocrine Connections  2014;3(4):150-155.
The sensitivity of local recurrence detection in differentiated thyroid cancer (DTC) is increased by measuring thyroglobulin in needle washouts from lymph node fine-needle aspiration biopsies (FNA-Tg). Recent studies have proposed minimum diagnostic threshold values for FNA-Tg and have reported interference from Tg antibodies (Tg Ab), leading to low or false-negative results. The aim of this study was to assess the utility of FNA-Tg in the diagnosis of local DTC recurrence in patients referred to a single pathology service used by our tertiary teaching hospital, the first such study in an Australian cohort. Data were collected from the pathology service database for FNA-Tg over an 18-month period, and the results of 69 FNA-Tg samples from 57 patients were obtained. FNA-Tg findings were compared with cytology and histology when patients proceeded to surgery. Using the functional sensitivity as the cut-off, detectable FNA-Tg (≥0.9 μg/l) had a sensitivity of 95.7%, specificity of 50% and positive predictive value of 95.7%. Our results suggest that detectable FNA-Tg leads to histological confirmation of local nodal DTC recurrence and would support a decision to proceed to surgery. Serum Tg Ab can, however, interfere with FNA-Tg measurements. Thus, we now recommend routine use of FNA-Tg washouts in all lymph node FNA biopsies for the detection of DTC recurrence.
doi:10.1530/EC-14-0071
PMCID: PMC4165034  PMID: 25125556
thyroglobulin; lymph node; differentiated thyroid cancer; local recurrence; washout
10.  Surface Functionalization of Gold Nanoparticles with Red Blood Cell Membranes 
doi:10.1002/adma.201300638
PMCID: PMC4138311  PMID: 23712782
gold nanoparticles; red blood cells; functionalization; biomimetic; nanomedicine
11.  Tandem RNA Chimeras Contribute to Transcriptome Diversity in Human Population and Are Associated with Intronic Genetic Variants 
PLoS ONE  2014;9(8):e104567.
Chimeric RNAs originating from two or more different genes are known to exist not only in cancer, but also in normal tissues, where they can play a role in human evolution. However, the exact mechanism of their formation is unknown. Here, we use RNA sequencing data from 462 healthy individuals representing 5 human populations to systematically identify and in depth characterize 81 RNA tandem chimeric transcripts, 13 of which are novel. We observe that 6 out of these 81 chimeras have been regarded as cancer-specific. Moreover, we show that a prevalence of long introns at the fusion breakpoint is associated with the chimeric transcripts formation. We also find that tandem RNA chimeras have lower abundances as compared to their partner genes. Finally, by combining our results with genomic data from the same individuals we uncover intronic genetic variants associated with the chimeric RNA formation. Taken together our findings provide an important insight into the chimeric transcripts formation and open new avenues of research into the role of intronic genetic variants in post-transcriptional processing events.
doi:10.1371/journal.pone.0104567
PMCID: PMC4136775  PMID: 25133550
12.  Bcl-2 Family Proteins Are Involved in the Signal Crosstalk between Endoplasmic Reticulum Stress and Mitochondrial Dysfunction in Tumor Chemotherapy Resistance 
BioMed Research International  2014;2014:234370.
Tumor cells overexpress antiapoptotic proteins of the Bcl-2 (B-cell leukemia/lymphoma-2) family, which can lead to both escape from cell death and resistance to chemotherapeutic drugs. Recent studies suggest that the endoplasmic reticulum (ER) can produce proapoptotic signals, amplifying the apoptotic signaling cascade. The crosstalk between mitochondria and ER plays a decisive role in many cellular events but especially in cell death. Bcl-2 family proteins located in the ER and mitochondria can influence not only the function of the two organelles but also the interaction between them. Therefore, the Bcl-2 family of proteins may also be involved in the mechanism of tumor chemotherapy resistance by influencing crosstalk between the ER and mitochondria. In this review we will briefly discuss evidence to support this concept.
doi:10.1155/2014/234370
PMCID: PMC4142381  PMID: 25177684
13.  Selenite reduction by the obligate aerobic bacterium Comamonas testosteroni S44 isolated from a metal-contaminated soil 
BMC Microbiology  2014;14:204.
Background
Selenium (Se) is an essential trace element in most organisms but has to be carefully handled since there is a thin line between beneficial and toxic concentrations. Many bacteria have the ability to reduce selenite (Se(IV)) and (or) selenate (Se(VI)) to red elemental selenium that is less toxic.
Results
A strictly aerobic bacterium, Comamonas testosteroni S44, previously isolated from metal(loid)-contaminated soil in southern China, reduced Se(IV) to red selenium nanoparticles (SeNPs) with sizes ranging from 100 to 200 nm. Both energy dispersive X-ray Spectroscopy (EDX or EDS) and EDS Elemental Mapping showed no element Se and SeNPs were produced inside cells whereas Se(IV) was reduced to red-colored selenium in the cytoplasmic fraction in presence of NADPH. Tungstate inhibited Se(VI) but not Se(IV) reduction, indicating the Se(IV)-reducing determinant does not contain molybdenum as co-factor. Strain S44 was resistant to multiple heavy and transition metal(loid)s such as Se(IV), As(III), Cu(II), and Cd(II) with minimal inhibitory concentrations (MIC) of 100 mM, 20 mM, 4 mM, and 0.5 mM, respectively. Disruption of iscR encoding a transcriptional regulator negatively impacted cellular growth and subsequent resistance to multiple heavy metal(loid)s.
Conclusions
C. testosteroni S44 could be very useful for bioremediation in heavy metal(loid) polluted soils due to the ability to both reduce toxic Se(VI) and Se(IV) to non-toxic Se (0) under aerobic conditions and to tolerate multiple heavy and transition metals. IscR appears to be an activator to regulate genes involved in resistance to heavy or transition metal(loid)s but not for genes responsible for Se(IV) reduction.
doi:10.1186/s12866-014-0204-8
PMCID: PMC4236595  PMID: 25098921
Se(IV) reduction; Selenium nanoparticles (SeNPs); Resistance to heavy metals and metalloids; iscR; Se(VI) reduction
14.  Potassium transport of Salmonella is important for type III secretion and pathogenesis 
Microbiology  2013;159(Pt 8):1705-1719.
Intracellular cations are essential for the physiology of all living organisms including bacteria. Cations such as potassium ion (K+), sodium ion (Na+) and proton (H+) are involved in nearly all aspects of bacterial growth and survival. K+ is the most abundant cation and its homeostasis in Escherichia coli and Salmonella is regulated by three major K+ transporters: high affinity transporter Kdp and low affinity transporters Kup and Trk. Previous studies have demonstrated the roles of cations and cation transport in the physiology of Escherichia coli; their roles in the virulence and physiology of pathogenic bacteria are not well characterized. We have previously reported that the Salmonella K+ transporter Trk is important for the secretion of effector proteins of the type III secretion system (TTSS) of Salmonella pathogenicity island 1 (SPI-1). Here we further explore the role of Salmonella cation transport in virulence in vitro and pathogenesis in animal models. Impairment of K+ transport through deletion of K+ transporters or exposure to the chemical modulators of cation transport, gramicidin and valinomycin, results in a severe defect in the TTSS of SPI-1, and this defect in the TTSS was not due to a failure to regulate intrabacterial pH or ATP. Our results also show that K+ transporters are critical to the pathogenesis of Salmonella in mice and chicks and are involved in multiple growth and virulence characteristics in vitro, including protein secretion, motility and invasion of epithelial cells. These results suggest that cation transport of the pathogenic bacterium Salmonella, especially K+ transport, contributes to its virulence in addition to previously characterized roles in maintaining homeostasis of bacteria.
doi:10.1099/mic.0.068700-0
PMCID: PMC4089031  PMID: 23728623
15.  Modeling Cell–Cell Interactions in Regulating Multiple Myeloma Initiating Cell Fate 
Cancer initiating cells have been documented in multiple myeloma and believed to be a key factor that initiates and drives tumor growth, differentiation, metastasis, and recurrence of the diseases. Although myeloma initiating cells (MICs) are likely to share many properties of normal stem cells, the underlying mechanisms regulating the fate of MICs are largely unknown. Studies designed to explore such communication are urgently needed to enhance our ability to predict the fate decisions of MICs (self-renewal, differentiation, and proliferation). In this study, we developed a novel system to understand the intercellular communication between MICs and their niche by seamlessly integrating experimental data and mathematical model. We first designed dynamic cell culture experiments and collected three types of cells (side population cells, progenitor cells, and mature myeloma cells) under various cultural conditions with flow cytometry. Then we developed a lineage model with ordinary differential equations by considering secreted factors, self-renewal, differentiation, and other biological functions of those cells, to model the cell–cell interactions among the three cell types. Particle swarm optimization was employed to estimate the model parameters by fitting the experimental data to the lineage model. The theoretical results show that the correlation coefficient analysis can reflect the feedback loops among the three cell types, the intercellular feedback signaling can regulate cell population dynamics, and the culture strategies can decide cell growth. This study provides a basic framework of studying cell–cell interactions in regulating MICs fate.
doi:10.1109/JBHI.2013.2281774
PMCID: PMC4104531  PMID: 24058033
Cancer initiating cell; lineage model; mathematical modeling; multiple myeloma (MM); parameter estimation
16.  Integrating Genomics and Proteomics Data to Predict Drug Effects Using Binary Linear Programming 
PLoS ONE  2014;9(7):e102798.
The Library of Integrated Network-Based Cellular Signatures (LINCS) project aims to create a network-based understanding of biology by cataloging changes in gene expression and signal transduction that occur when cells are exposed to a variety of perturbations. It is helpful for understanding cell pathways and facilitating drug discovery. Here, we developed a novel approach to infer cell-specific pathways and identify a compound's effects using gene expression and phosphoproteomics data under treatments with different compounds. Gene expression data were employed to infer potential targets of compounds and create a generic pathway map. Binary linear programming (BLP) was then developed to optimize the generic pathway topology based on the mid-stage signaling response of phosphorylation. To demonstrate effectiveness of this approach, we built a generic pathway map for the MCF7 breast cancer cell line and inferred the cell-specific pathways by BLP. The first group of 11 compounds was utilized to optimize the generic pathways, and then 4 compounds were used to identify effects based on the inferred cell-specific pathways. Cross-validation indicated that the cell-specific pathways reliably predicted a compound's effects. Finally, we applied BLP to re-optimize the cell-specific pathways to predict the effects of 4 compounds (trichostatin A, MS-275, staurosporine, and digoxigenin) according to compound-induced topological alterations. Trichostatin A and MS-275 (both HDAC inhibitors) inhibited the downstream pathway of HDAC1 and caused cell growth arrest via activation of p53 and p21; the effects of digoxigenin were totally opposite. Staurosporine blocked the cell cycle via p53 and p21, but also promoted cell growth via activated HDAC1 and its downstream pathway. Our approach was also applied to the PC3 prostate cancer cell line, and the cross-validation analysis showed very good accuracy in predicting effects of 4 compounds. In summary, our computational model can be used to elucidate potential mechanisms of a compound's efficacy.
doi:10.1371/journal.pone.0102798
PMCID: PMC4103865  PMID: 25036040
17.  TCF7L2 is a master regulator of insulin production and processing 
Human Molecular Genetics  2014;23(24):6419-6431.
Genome-wide association studies have revealed >60 loci associated with type 2 diabetes (T2D), but the underlying causal variants and functional mechanisms remain largely elusive. Although variants in TCF7L2 confer the strongest risk of T2D among common variants by presumed effects on islet function, the molecular mechanisms are not yet well understood. Using RNA-sequencing, we have identified a TCF7L2-regulated transcriptional network responsible for its effect on insulin secretion in rodent and human pancreatic islets. ISL1 is a primary target of TCF7L2 and regulates proinsulin production and processing via MAFA, PDX1, NKX6.1, PCSK1, PCSK2 and SLC30A8, thereby providing evidence for a coordinated regulation of insulin production and processing. The risk T-allele of rs7903146 was associated with increased TCF7L2 expression, and decreased insulin content and secretion. Using gene expression profiles of 66 human pancreatic islets donors’, we also show that the identified TCF7L2-ISL1 transcriptional network is regulated in a genotype-dependent manner. Taken together, these results demonstrate that not only synthesis of proinsulin is regulated by TCF7L2 but also processing and possibly clearance of proinsulin and insulin. These multiple targets in key pathways may explain why TCF7L2 has emerged as the gene showing one of the strongest associations with T2D.
doi:10.1093/hmg/ddu359
PMCID: PMC4240194  PMID: 25015099
18.  Decreased miR-204 in H. pylori-Associated Gastric Cancer Promotes Cancer Cell Proliferation and Invasion by Targeting SOX4 
PLoS ONE  2014;9(7):e101457.
Background
The molecular mechanism between Helicobacter pylori (H. pylori) infection and gastric cancer remained largely unknown. In this study, we determined the role of miRNA in H. pylori induced gastric cancer.
Methods and Results
We found that miR-204 was decreased in H. pylori positive tissues by qRT-PCR. Knockdown of miR-204 enhanced the invasion and proliferation ability of gastric cancer cells in vitro. Luciferase assay revealed that SOX4 was target gene of miR-204, which was found up-regulated in H. pylori positive tissues. Down-regulation of miR-204 and over-expression of SOX4 promoted epithelial-mesenchymal transition process.
Conclusion
Taken together, our findings demonstrated that miR-204 may act as a tumor suppressor in H. pylori induced gastric cancer by targeting SOX4.
doi:10.1371/journal.pone.0101457
PMCID: PMC4077842  PMID: 24984017
19.  Fluoride and Arsenic Exposure Impairs Learning and Memory and Decreases mGluR5 Expression in the Hippocampus and Cortex in Rats 
PLoS ONE  2014;9(4):e96041.
Fluoride and arsenic are two common inorganic contaminants in drinking water that are associated with impairment in child development and retarded intelligence. The present study was conducted to explore the effects on spatial learning, memory, glutamate levels, and group I metabotropic glutamate receptors (mGluRs) expression in the hippocampus and cortex after subchronic exposure to fluoride, arsenic, and a fluoride and arsenic combination in rats. Weaned male Sprague-Dawley rats were assigned to four groups. The control rats drank tap water. Rats in the three exposure groups drank water with sodium fluoride (120 mg/L), sodium arsenite (70 mg/L), and a sodium fluoride (120 mg/L) and sodium arsenite (70 mg/L) combination for 3 months. Spatial learning and memory was measured in Morris water maze. mGluR1 and mGluR5 mRNA and protein expression in the hippocampus and cortex was detected using RT-PCR and Western blot, respectively. Compared with controls, learning and memory ability declined in rats that were exposed to fluoride and arsenic both alone and combined. Combined fluoride and arsenic exposure did not have a more pronounced effect on spatial learning and memory compared with arsenic and fluoride exposure alone. Compared with controls, glutamate levels decreased in the hippocampus and cortex of rats exposed to fluoride and combined fluoride and arsenic, and in cortex of arsenic-exposed rats. mGluR5 mRNA and protein expressions in the hippocampus and mGluR5 protein expression in the cortex decreased in rats exposed to arsenic alone. Interestingly, compared with fluoride and arsenic exposure alone, fluoride and arsenic combination decreased mGluR5 mRNA expression in the cortex and protein expression in the hippocampus, suggesting a synergistic effect of fluoride and arsenic. These data indicate that fluoride and arsenic, either alone or combined, can decrease learning and memory ability in rats. The mechanism may be associated with changes of glutamate level and mGluR5 expression in cortex and hippocampus.
doi:10.1371/journal.pone.0096041
PMCID: PMC3997496  PMID: 24759735
20.  Discovery of Novel Wall Teichoic Acid Inhibitors as Effective anti-MRSA β-lactam Combination Agents 
Chemistry & biology  2013;20(2):272-284.
Summary
Innovative strategies are needed to combat drug resistance associated with methicillin-resistant Staphylococcus aureus (MRSA). Here, we investigate the potential of wall teichoic acid (WTA) biosynthesis inhibitors as combination agents to restore β-lactam efficacy against MRSA. Performing a whole cell pathway-based screen we identified a series of WTA inhibitors (WTAIs) targeting the WTA transporter protein, TarG. Whole genome sequencing of WTAI resistant isolates across two methicillin-resistant Staphylococci spp. revealed TarG as their common target, as well as a broad assortment of drug resistant bypass mutants mapping to earlier steps of WTA biosynthesis. Extensive in vitro microbiological analysis and animal infection studies provide strong genetic and pharmacological evidence of the potential effectiveness of WTAIs as anti-MRSA β-lactam combination agents. This work also highlights the emerging role of whole genome sequencing in antibiotic mode-of-action and resistance studies.
doi:10.1016/j.chembiol.2012.11.013
PMCID: PMC3762323  PMID: 23438756
Staphylococcus aureus; MRSA; MRSE; imipenem; wall teichoic acid; antibiotic resistance; β-lactam potentiation; combination agent; chemical biology; Next Generation Sequencing
21.  Targeting the Biophysical Properties of the Myeloma Initiating Cell Niches: A Pharmaceutical Synergism Analysis Using Multi-Scale Agent-Based Modeling 
PLoS ONE  2014;9(1):e85059.
Multiple myeloma, the second most common hematological cancer, is currently incurable due to refractory disease relapse and development of multiple drug resistance. We and others recently established the biophysical model that myeloma initiating (stem) cells (MICs) trigger the stiffening of their niches via SDF-1/CXCR4 paracrine; The stiffened niches then promote the colonogenesis of MICs and protect them from drug treatment. In this work we examined in silico the pharmaceutical potential of targeting MIC niche stiffness to facilitate cytotoxic chemotherapies. We first established a multi-scale agent-based model using the Markov Chain Monte Carlo approach to recapitulate the niche stiffness centric, pro-oncogenetic positive feedback loop between MICs and myeloma-associated bone marrow stromal cells (MBMSCs), and investigated the effects of such intercellular chemo-physical communications on myeloma development. Then we used AMD3100 (to interrupt the interactions between MICs and their stroma) and Bortezomib (a recently developed novel therapeutic agent) as representative drugs to examine if the biophysical properties of myeloma niches are drugable. Results showed that our model recaptured the key experimental observation that the MBMSCs were more sensitive to SDF-1 secreted by MICs, and provided stiffer niches for these initiating cells and promoted their proliferation and drug resistance. Drug synergism analysis suggested that AMD3100 treatment undermined the capability of MICs to modulate the bone marrow microenvironment, and thus re-sensitized myeloma to Bortezomib treatments. This work is also the first attempt to virtually visualize in 3D the dynamics of the bone marrow stiffness during myeloma development. In summary, we established a multi-scale model to facilitate the translation of the niche-stiffness centric myeloma model as well as experimental observations to possible clinical applications. We concluded that targeting the biophysical properties of stem cell niches is of high clinical potential since it may re-sensitize tumor initiating cells to chemotherapies and reduce risks of cancer relapse.
doi:10.1371/journal.pone.0085059
PMCID: PMC3903473  PMID: 24475036
22.  CASME II: An Improved Spontaneous Micro-Expression Database and the Baseline Evaluation 
PLoS ONE  2014;9(1):e86041.
A robust automatic micro-expression recognition system would have broad applications in national safety, police interrogation, and clinical diagnosis. Developing such a system requires high quality databases with sufficient training samples which are currently not available. We reviewed the previously developed micro-expression databases and built an improved one (CASME II), with higher temporal resolution (200 fps) and spatial resolution (about 280×340 pixels on facial area). We elicited participants' facial expressions in a well-controlled laboratory environment and proper illumination (such as removing light flickering). Among nearly 3000 facial movements, 247 micro-expressions were selected for the database with action units (AUs) and emotions labeled. For baseline evaluation, LBP-TOP and SVM were employed respectively for feature extraction and classifier with the leave-one-subject-out cross-validation method. The best performance is 63.41% for 5-class classification.
doi:10.1371/journal.pone.0086041
PMCID: PMC3903513  PMID: 24475068
23.  Risk Factors and Prevalence of Helicobacter pylori Infection in Persistent High Incidence Area of Gastric Carcinoma in Yangzhong City 
Aim. The aim of this study was to investigate the prevalence and risk factors of H. pylori infection in areas with high prevalence of gastric cancer in Jiangsu Province, China. Methods. A prospective epidemiologic survey of H. pylori infection was accomplished in a natural population of 5417 individuals in Yangzhong city. Questionnaires and 13C-urea breath test for H. pylori infection were performed. Results. Among 5417 subjects who completed questionnaires and 13C-urea breath test, 3435 (63.41%) were H. pylori positive. The prevalence reached a peak at the age of 30–39 years (90.82%). There was significant difference between sexes and women had a higher infection rate than men. The prevalence of H. pylori infection was also associated with eating kipper food and fried food. No association between H. pylori prevalence and smoking or drinking was found. Compared to healthy individuals, people with dyspeptic diseases (peptic ulcer, gastroenteritis) presented a high prevalence of H. pylori infection. Using multivariate logistic regression analysis, age and history of peptic ulcer and gastroenteritis were the independent predictors for H. pylori infection. Conclusions. Yangzhong city had a high prevalence of H. pylori infection and was related to several risk factors. The underlying mechanisms are needed to be further investigated.
doi:10.1155/2014/481365
PMCID: PMC3914443  PMID: 24550981
24.  An Attenuated Coxsackievirus B3 Vector: A Potential Tool for Viral Tracking Study and Gene Delivery 
PLoS ONE  2013;8(12):e83753.
Cardiomyocytes are quite resistant to gene transfer using standard techniques. We developed an expression vector carrying an attenuated but infectious and replicative coxsackievirus B3 (CVB3) genome, and unique ClaI-StuI cloning sites for an exogenous gene, whose product can be released from the nascent viral polyprotein by 2Apro cleavage. This vector was tested as an expression vehicle for green fluorescent protein (GFP). The vector transiently expressed GFP in cell cultures for at least ten passages and delivered functional GFP to the infected cardiomyocytes for at least 6 days. Moreover, the recombinant viruses showed virulence attenuation in vitro and in vivo. The findings suggest that the recombinant CVB3 vector could be a useful tool for viral tracking study and delivering exogenous proteins to cardiomyocytes.
doi:10.1371/journal.pone.0083753
PMCID: PMC3875476  PMID: 24386270
25.  Contradictory imaging and EEG results in resection surgery of bitemporal lobe epilepsy: A case report 
The present study describes the case of a 27-year-old, right-handed female with bilateral mesial temporal lobe epilepsy. Electroencephalogram (EEG) monitoring from implanted electrodes displayed two different and independent onsets on the two sides of the mesial temporal structures, which specifically included clinical generalized tonic clonic seizure (GTCS) discharges originating from the left mesial temporal lobe, as well as complex partial seizure (CPS) discharges arising from the right mesial region. However, fluid-attenuated inversion recovery magnetic resonance imaging (FLAIR MRI) showed a unilateral abnormality, as in right mesial temporal lobe sclerosis. A decision was made to resect one side of the mesial temporal lobe, in order to avoid memory function impairment, and, relying on the MRI results, the right side was selected. However, surgery did not leave the patient seizure-free. The CPSs gradually eased, while the GTCSs originating from the left side became severely aggravated. In describing this case, the drawbacks of current epileptic diagnostic methods and surgical strategies for bitemporal lobe epilepsy are discussed, and the requirement for more treatment options is emphasized.
doi:10.3892/etm.2013.1462
PMCID: PMC3919855  PMID: 24520276
epilepsy; bitemporal lobe epilepsy; epileptic surgery

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