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1.  Deletion of arcD in Streptococcus pneumoniae D39 Impairs Its Capsule and Attenuates Virulence 
Infection and Immunity  2013;81(10):3903-3911.
The arginine deiminase system (ADS) is associated with arginine catabolism and plays a role in virulence of several pathogenic bacteria. In Streptococcus pneumoniae, the ADS genes exist as a locus consisting of arcABCDT. A recent genome-wide mutagenesis approach revealed that both arcD and arcT are potentially essential in a chinchilla otitis media (OM) model. In the present study, we generated ΔarcD, ΔarcT, and ΔarcDT mutants by homologous recombination and evaluated their infectivity. Our results showed that only arcD, and not arcT, of an OM isolate is required during chinchilla middle ear infection. Additionally, D39 ΔarcD exhibited enhanced nasopharyngeal colonization and was attenuated in both mouse pneumonia and bacteremia models. In vitro, D39 ΔarcD displayed enhanced adherence to A549 epithelial cells and increased phagocytosis by J774A.1 macrophages compared to those with the parental strain. This mutant also exhibited an impaired capsule, as detected using electron microscopy, immunofluorescence, and a capsule assay. We demonstrated that the capsule defect in the D39 ΔarcD mutant may not be associated with a deficiency in arginine but rather is likely caused by a loss of interaction between the capsule and the transmembrane protein ArcD.
doi:10.1128/IAI.00778-13
PMCID: PMC3811789  PMID: 23918778
2.  Alterations in HIV-1 gp120 V3 Region Are Necessary but Not Sufficient for Coreceptor Switching in CRF07_BC in China 
PLoS ONE  2014;9(3):e93426.
The most predominant HIV-1 strains in China's current epidemic is the Circulating Recombinant Form 07_BC (CRF07_BC). CRF07_BC is mainly considered as a CCR5-tropic (R5) virus, since CXCR4-tropic (X4) viruses have thus far not been found in this subtype, and the molecular determinants of coreceptor switching remain unknown. To investigate the mechanisms underlying coreceptor requirement in CRF07_BC viruses, we characterized a panel of pNL4-3-based chimeric viruses with mutated V3 loop regions derived from an HIV-1 CRF07_BC infectious clone pXJDC13. Among 17 chimeric viruses, seven were dual-tropic and induced syncytium formation in MT-2 cells. Two amino acid insertions between positions 13 and 14, as well as arginine substitution at position 11 or 16 (IG insertion and P16R mutation or MG insertion and S11R mutation), conferred the chimeric viruses CXCR4-tropic features, which were same as subtype C X4 viruses. Next, to construct CRF07_BC X4 variants, mutated V3 loops were cloned into the CRF07_BC infectious clone pXJDC13. These V3 loops, which in the pNL4-3 backbone conferred chimeric viruses with CXCR4-using ability, abrogated infectivity completely in the CRF07_BC pXJDC13 genetic background. Similarly, IG insertion or MG insertion and S11R mutation dramatically diminished or completely abolished viral infectivity in other envelopes of subtype C or CRF07_BC. These results suggest that the effects of IG insertion and P16R mutation or MG insertion and S11R mutation on CXCR4 usage are context dependent, and additional mutations elsewhere in the envelope are needed to compensate for these fitness-reducing alterations.
doi:10.1371/journal.pone.0093426
PMCID: PMC3968174  PMID: 24676404
3.  High-Density Lipoprotein Cholesterol Is a Favorable Prognostic Factor and Negatively Correlated with C-Reactive Protein Level in Non-Small Cell Lung Carcinoma 
PLoS ONE  2014;9(3):e91080.
Background
Although the alterations of lipid profile in lung cancer have been documented, the prognostic value of serum HDL-C level and its correlation with inflammation in NSCLC remain unknown.
Subjects and Methods
Levels of preoperative serum lipid concentrations (including HDL-C, LDL-C, TC, and TG) and the inflammatory biomarker C-reactive protein level (CRP) were retrospectively analyzed in 228 patients with NSCLC and in 300 healthy controls. The serum lipid levels in these two populations were compared. Univariate and multivariate cox hazards analyses were performed to investigate the prognostic value of serum lipid levels in NSCLC. The correlation between CRP and lipid profile were also analyzed.
Results
Compared with those in normal controls, the serum HDL-C, LDL-C, and TC levels were statistically decreased and the TG levels were significantly increased in 228 NSCLC patients. The patients with decreased levels of HDL-C had significantly lower 5-year survival rates than those with normal HDL-C, not only in the whole NSCLC cohort but also in the subgroups stratified according to the disease T, N classifications, and metastasis, whereas the other lipid components were not independent prognostic factors for NSCLC. Of the lipid components, a lower HDL-C level was observed more often in patients with a high CRP level than in those with a normal CRP level. Spearman’s rank correlation analysis revealed that the HDL-C level presented a negative correlation with the CRP level (r = −0.360, p<0.001).
Conclusions
A decreased level of preoperative HDL-C was found to be associated with poor survival in patients with NSCLC. Serum HDL-C level may be a clinical prognosis factor for NSCLC patients. In addition, a negative correlation was present between the levels of HDL-C and CRP, the well-known inflammation biomarker.
doi:10.1371/journal.pone.0091080
PMCID: PMC3953329  PMID: 24625581
4.  Unique genome-wide map of TCF4 and STAT3 targets using ChIP-seq reveals their association with new molecular subtypes of glioblastoma 
Neuro-Oncology  2013;15(3):279-289.
Background
Aberrant activation of beta-catenin/TCF4 and STAT3 signaling in glioblastoma multiforme (GBM) has been reported. However, the molecular mechanisms related to this process are still poorly understood.
Methods
Genome-wide screening of the binding characteristics of the transcription factors TCF4 and STAT3 in GBM cells was performed by chromatin immunoprecipitation sequencing (ChIP-seq) assay. Hierarchical clustering was used to analyze the association of TCF4 and STAT3 coregulated genes with The Cancer Genome Atlas (TCGA) GBM subtypes (classical, mesenchymal, neural, and proneural). New molecular classification of GBM was proposed and validated in Western and Asian populations.
Results
We identified 1250 overlapping putative target genes that were coregulated by TCF4 and STAT3. Further, the coregulated genes had the potential to guide TCGA GBM subtypes. Finally, we proposed a new molecular classification of GBM into 2 subtypes (proneural-like and mesenchymal-like) and showed that the new classification could be applied to both Western and Asian populations. In addition, the GBM response to temozolomide therapy differed depending on its subtype; mesenchymal-like GBM benefited, while there was no benefit for proneural-like GBM.
Conclusions
This is the first comprehensive study to combine a ChIP-seq assay of TCF4 and STAT3 and data mining of patient cohorts to derive molecular subtypes of GBM.
doi:10.1093/neuonc/nos306
PMCID: PMC3578485  PMID: 23295773
ChIP-seq; glioblastoma; molecular subtype; STAT3; TCF4
5.  Alternative Polyadenylation in Glioblastoma Multiforme and Changes in Predicted RNA Binding Protein Profiles 
Abstract
Alternative polyadenylation (APA) is widely present in the human genome and plays a key role in carcinogenesis. We conducted a comprehensive analysis of the APA products in glioblastoma multiforme (GBM, one of the most lethal brain tumors) and normal brain tissues and further developed a computational pipeline, RNAelements (http://sysbio.zju.edu.cn/RNAelements/), using covariance model from known RNA binding protein (RBP) targets acquired by RNA Immunoprecipitation (RIP) analysis. We identified 4530 APA isoforms for 2733 genes in GBM, and found that 182 APA isoforms from 148 genes showed significant differential expression between normal and GBM brain tissues. We then focused on three genes with long and short APA isoforms that show inconsistent expression changes between normal and GBM brain tissues. These were myocyte enhancer factor 2D, heat shock factor binding protein 1, and polyhomeotic homolog 1 (Drosophila). Using the RNAelements program, we found that RBP binding sites were enriched in the alternative regions between the first and the last polyadenylation sites, which would result in the short APA forms escaping regulation from those RNA binding proteins. To the best of our knowledge, this report is the first comprehensive APA isoform dataset for GBM and normal brain tissues. Additionally, we demonstrated a putative novel APA-mediated mechanism for controlling RNA stability and translation for APA isoforms. These observations collectively lay a foundation for novel diagnostics and molecular mechanisms that can inform future therapeutic interventions for GBM.
doi:10.1089/omi.2012.0098
PMCID: PMC3603499  PMID: 23421905
6.  SELECTIVE INHIBITION OF THE WEST NILE VIRUS METHYLTRANSFERASE BY NUCLEOSIDE ANALOGS 
Antiviral research  2012;97(3):232-239.
The flavivirus methyltransferase (MTase) sequentially methylates the N7 and 2’-O positions of the viral RNA cap (GpppA-RNA→m7GpppA-RNA→m7GpppAm-RNA), using S-adenosyl-L-methionine (SAM) as a methyl donor. We report here the synthesis and biological evaluation of a series of novel nucleoside analogs. Two of these compounds can effectively and competitively inhibit the WNV MTase with IC50 values in micromolar range and, more importantly, do not inhibit human MTase. The compounds can also suppress the WNV replication in cell culture.
doi:10.1016/j.antiviral.2012.12.012
PMCID: PMC3608738  PMID: 23267828
Flavivirus NS5; RNA cap methylation; West Nile virus; methyltransferase; antiviral development
7.  Central Expression and Anorectic Effect of Brain-Derived Neurotrophic Factor Are Regulated by Circulating Estradiol Levels 
Hormones and behavior  2013;63(3):533-542.
Estrogens potently suppress food intake. Compelling evidence suggests that estradiol, the primary form of estrogens, reduces food intake by facilitating other anorectic signals. Brain-derived neurotrophic factor (BDNF), like estradiol, appears to suppress food intake by affecting meal size. We hypothesized that estradiol modulates Bdnf expression and the anorectic effect of BDNF. The first goal was to determine whether Bdnf expression was regulated by endogenous estradiol of cycling rats and by cyclic estradiol treatment using ovariectomized rats. Bdnf expression within the ventromedial nucleus of hypothalamus (VMH) was temporally elevated at estrus following the estradiol peak, which coincided with the decline in feeding at this phase of the ovarian cycle. Additionally, food intake and body weight were increased following ovariectomy with a parallel decrease in Bdnf expression in the VMH. All of these alterations were reversed by cyclic estradiol treatment, suggesting that Bdnf expression within the VMH was regulated in an estradiol-dependent manner. The second goal was to determine whether estradiol modulates the anorectic effect of BDNF. Sham-operated estrous rats and ovariectomized rats cyclically treated with estradiol responded to a lower dose of central administration of BDNF to decrease food intake than male rats and oil-treated ovariectomized rats, implying that endogenous estradiol or cyclic estradiol replacement increased the sensitivity to anorectic effect of BDNF. These data indicate that Bdnf expression within the VMH and the anorectic effect of BDNF varied depending on plasma estradiol levels, suggesting that estradiol may regulate BDNF signaling to regulate feeding.
doi:10.1016/j.yhbeh.2013.01.009
PMCID: PMC3624754  PMID: 23376487
ovariectomy; ovarian cycle; food intake; ventromedial nucleus of hypothalamus
8.  Efficacy and safety of moxifloxacin in acute exacerbations of chronic bronchitis and COPD: a systematic review and meta-analysis 
Journal of Thoracic Disease  2014;6(3):221-229.
Purpose
To evaluate the efficacy and safety of moxifloxacin in acute exacerbations of chronic bronchitis (AECB) and chronic obstructive pulmonary disease (AECOPD).
Methods
We searched PubMed, EMBASE, and the Web of Science for relevant studies. Two reviewers extracted data and reviewed the quality of the studies independently. The primary outcome was clinical success at early follow-up. Study-level data were pooled using a random-effects model when I2 was >50% or a fixed-effects model when I2 was <50%.
Results
Eleven randomized controlled studies were considered. There was no difference between moxifloxacin and comparator agents with regard to treatment success in intention-to-treat (ITT) [odds ratio (OR) =1.18, 95% confidence interval (CI) 0.98-1.42], clinically evaluable (CE) (OR 1.13, 95% CI, 0.93-1.37) patients, or adverse effects in general (OR 1.00, 95% CI, 0.86-1.17). Moxifloxacin was associated with better microbiological success (OR 1.45; 95% CI, 1.14-1.85).
Conclusions
Moxifloxacin was as clinically equivalent and bacteriologically superior to the antibiotic regimens routinely used in patients with AECB and AECOPD. Moxifloxacin therapy may be a promising and safe alternative to empirical treatment for AECB and AECOPD.
doi:10.3978/j.issn.2072-1439.2013.11.12
PMCID: PMC3949192  PMID: 24624286
Moxifloxacin; chronic bronchitis; chronic obstructive pulmonary disease (COPD); meta-analysis; systematic review
9.  Molecular basis of host specificity in human pathogenic bacteria 
Pathogenic bacteria display various levels of host specificity or tropism. While many bacteria can infect a wide range of hosts, certain bacteria have strict host selectivity for humans as obligate human pathogens. Understanding the genetic and molecular basis of host specificity in pathogenic bacteria is important for understanding pathogenic mechanisms, developing better animal models and designing new strategies and therapeutics for the control of microbial diseases. The molecular mechanisms of bacterial host specificity are much less understood than those of viral pathogens, in part due to the complexity of the molecular composition and cellular structure of bacterial cells. However, important progress has been made in identifying and characterizing molecular determinants of bacterial host specificity in the last two decades. It is now clear that the host specificity of bacterial pathogens is determined by multiple molecular interactions between the pathogens and their hosts. Furthermore, certain basic principles regarding the host specificity of bacterial pathogens have emerged from the existing literature. This review focuses on selected human pathogenic bacteria and our current understanding of their host specificity.
doi:10.1038/emi.2014.23
PMCID: PMC3974339
host specificity; immune evasion; molecular mechanisms; pathogen–host interactions; pathogenic bacteria; tropism
10.  The Protective Effect of Stauntonia Chinensis Polysaccharide on CCl4-induced Acute Liver Injuries in Mice 
Objective:
To investigate the protective effect of Stauntonia chinensis polysaccharides (SCP) on carbon tetrachloride (CCl4) induced acute liver injuries in mice.
Methods:
Kunming mice were randomly divided into three groups: the control group, the pathological model group, and the SCP group. The SCP group was further divided into three subgroups based on SCP treatment: Low dosage (50 mg/kg), medium dosage (100 mg/kg) and high dosage (200 mg/kg). After being fed for 7 days, mixed-edible-oil solution was intraperitoneally injected into the control group, while the other two groups were injected with 0.15% CCl4 mixed with mixed-edible-oil. Sera were collected from mice 24 h later to determine the activity of serum alanine transaminase (ALT). Mice were then sacrificed to prepare liver homogenate. Levels of liver malondialdehyde (MDA), glutathione (GSH), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and nitric oxide (NO) were determined. Pathological changes in livers were also analyzed.
Results:
SCP significantly reduced the ALT activity in the serum and inhibited the decrease of serum GSH, GSH-PX and SOD and rose the levels of MDA and NO (P<0.05-0.01). This lessened the pathological damage to the liver tissues.
Conclusion:
SCP protects against CCl4-induced acute liver injuries in mice.
PMCID: PMC3976442
Stauntonia chinensis polysaccharides; Liver injury; Antioxidation
11.  Expansion of Mesenchymal Stem Cells under Atmospheric Carbon Dioxide 
Biotechnology progress  2013;29(5):1298-1306.
Stem cells are needed for an increasing number of scientific applications, including both fundamental research and clinical disease treatment. To meet this rising demand, improved expansion methods to generate high quantities of high quality stem cells must be developed. Unfortunately, the bicarbonate buffering system – which relies upon an elevated CO2 environment – typically used to maintain pH in stem cell cultures introduces several unnecessary limitations in bioreactor systems. In addition to artificially high dissolved CO2 levels negatively affecting cell growth, but more importantly, the need to sparge CO2 into the system complicates the ability to control culture parameters. This control is especially important for stem cells, whose behavior and phenotype is highly sensitive to changes in culture conditions such as dissolved oxygen and pH. As a first step, this study developed a buffer to support expansion of mesenchymal stem cells (MSC) under an atmospheric CO2 environment in static cultures. MSC expanded under atmospheric CO2 with this buffer achieved equivalent growth rates without adaptation compared to those grown in standard conditions and also maintained a stem cell phenotype, self-renewal properties, and the ability to differentiate into multiple lineages after expansion.
doi:10.1002/btpr.1782
PMCID: PMC3902052  PMID: 23894049
Mesenchymal stem cell; Carbon dioxide independent medium; Bicarbonate buffer; Expansion
12.  Structural basis of conformational transitions in the active site and 80′s loop in the FK506-binding protein FKBP12 
Biochemical Journal  2014;458(Pt 3):525-536.
The extensive set of NMR doublings exhibited by the immunophilin FKBP12 (FK506-binding protein 12) arose from a slow transition to the cis-peptide configuration at Gly89 near the tip of the 80′s loop, the site for numerous protein-recognition interactions for both FKBP12 and other FKBP domain proteins. The 80′s loop also exhibited linebroadening, indicative of microsecond to millisecond conformational dynamics, but only in the trans-peptide state. The G89A variant shifted the trans–cis peptide equilibrium from 88:12 to 33:67, whereas a proline residue substitution induced fully the cis-peptide configuration. The 80′s loop conformation in the G89P crystal structure at 1.50 Å resolution differed from wild-type FKBP12 primarily at residues 88, 89 and 90, and it closely resembled that reported for FKBP52. Structure-based chemical-shift predictions indicated that the microsecond to millisecond dynamics in the 80′s loop probably arose from a concerted main chain (ψ88 and ϕ89) torsion angle transition. The indole side chain of Trp59 at the base of the active-site cleft was reoriented ~90o and the adjacent backbone was shifted in the G89P crystal structure. NOE analysis of wild-type FKBP12 demonstrated that this indole populates the perpendicular orientation at 20%. The 15N relaxation analysis was consistent with the indole reorientation occurring in the nanosecond timeframe. Recollection of the G89P crystal data at 1.20 Å resolution revealed a weaker wild-type-like orientation for the indole ring. Differences in the residues that underlie the Trp59 indole ring and altered interactions linking the 50′s loop to the active site suggested that reorientation of this ring may be disfavoured in the other six members of the FKBP domain family that bear this active-site tryptophan residue.
Extensive resonance doubling arises from a cis–trans peptide transition at Gly89, whereas linebroadening appears due to a concerted shift in the neighbouring torsion angles. The active site Trp59 ring adopts a perpendicular orientation at a population of 20%.
doi:10.1042/BJ20131429
PMCID: PMC3940039  PMID: 24405377
conformational dynamics; FK506-binding protein 12 (FKBP12); linebroadening analysis; NMR; slow exchange; X-ray structure; FKBP, FK506-binding protein; mTOR, mammalian target of rapamycin; RyR, ryanodine receptor
13.  Co-Circulation of Multiple Hemorrhagic Fever Diseases with Distinct Clinical Characteristics in Dandong, China 
PLoS ONE  2014;9(2):e89896.
Hemorrhagic fevers (HF) caused by viruses and bacteria are a major public health problem in China and characterized by variable clinical manifestations, such that it is often difficult to achieve accurate diagnosis and treatment. The causes of HF in 85 patients admitted to Dandong hospital, China, between 2011–2012 were determined by serological and PCR tests. Of these, 34 patients were diagnosed with Huaiyangshan hemorrhagic fever (HYSHF), 34 with Hemorrhagic Fever with Renal Syndrome (HFRS), one with murine typhus, and one with scrub typhus. Etiologic agents could not be determined in the 15 remaining patients. Phylogenetic analyses of recovered bacterial and viral sequences revealed that the causative infectious agents were closely related to those described in other geographical regions. As these diseases have no distinctive clinical features in their early stage, only 13 patients were initially accurately diagnosed. The distinctive clinical features of HFRS and HYSHF developed during disease progression. Enlarged lymph nodes, cough, sputum, and diarrhea were more common in HYSHF patients, while more HFRS cases presented with headache, sore throat, oliguria, percussion pain kidney area, and petechiae. Additionally, HYSHF patients displayed significantly lower levels of white blood cells (WBC), higher levels of creations kinase (CK) and alanine aminotransferase (ALT), while HFRS patients presented with an elevation of blood urea nitrogen (BUN) and creatinine (CREA). These clinical features will assist in the accurate diagnosis of both HYSHF and HFRS. Overall, our data reveal the complexity of pathogens causing HFs in a single Chinese hospital, and highlight the need for accurate early diagnosis and a better understanding of their distinctive clinical features.
doi:10.1371/journal.pone.0089896
PMCID: PMC3937409  PMID: 24587107
14.  pRB and E2F4 play distinct cell-intrinsic roles in fetal erythropoiesis 
Cell cycle (Georgetown, Tex.)  2010;9(2):371-376.
The retinoblastoma tumor suppressor protein pRB functions, at least in part, by directly binding to and modulating the activity of the E2F transcription factors. Previous studies have shown that both E2F4 and pRB play important roles in fetal erythropoiesis. Given that these two proteins interact directly we investigated the overlap of E2F4 and pRB function in this process by analyzing E2f4−/−, conditional Rb knockout (Rb1lox/1lox), and compound E2f4−/−;Rb1lox/1lox embryos. At E15.5 E2f4−/− and Rb1lox/1lox fetal erythroid cells display distinct abnormalities in their differentiation profiles. When cultured in vitro, both E2f4−/− and Rb1lox/1lox erythroid cells show defects in cell cycle progression. Surprisingly, analysis of cell cycle profiling suggests that E2F4 and pRB control cell cycle exit through different mechanisms. Moreover, only pRB, but not E2F4, promotes cell survival in erythroid cells. We observed an additive rather than a synergistic impact upon the erythroid defects in the compound E2f4−/−;Rb1lox/1lox embryos. We further found that fetal liver macrophage development is largely normal regardless of genotype. Taken together, our results show that E2F4 and pRB play independent cell-intrinsic roles in fetal erythropoiesis.
PMCID: PMC3931422  PMID: 20023434
retinoblastoma; pRB; E2F4; erythroid differentiation; cell cycle
15.  Prevalence and Predictors of HIV among Chinese Tuberculosis Patients by Provider-Initiated HIV Testing and Counselling (PITC): A Multisite Study in South Central of China 
PLoS ONE  2014;9(2):e89723.
Background
Tuberculosis (TB) and HIV are two worldwide public health concerns. Co-infection of these two diseases has been considered to be a major obstacle for the global efforts in reaching the goals for the prevention of HIV and TB.
Method
A comprehensive cross-sectional study was conducted to recruit TB patients in three provinces (Guangxi, Henan and Sichuan) of China between April 1 and September 30, 2010.
Results
A total of 1,032 consenting TB patients attended this survey during the study period. Among the participants, 3.30% were HIV positive; about one quarter had opportunistic infections. Nearly half of the participants were 50 years or older, the majority were male and about one third were from minority ethnic groups. After adjusting for site, gender and areas of residence (using the partial/selective Model 1), former commercial plasma donors (adjusted OR [aOR] = 33.71) and injecting drug users(aOR = 15.86) were found to have significantly higher risk of being HIV-positivity. In addition, having extramarital sexual relationship (aOR = 307.16), being engaged in commercial sex (aOR = 252.37), suffering from opportunistic infections in the past six months (aOR = 2.79), losing 10% or more of the body weight in the past six months (aOR = 5.90) and having abnormal chest X-ray findings (aOR = 20.40) were all significantly associated with HIV seropositivity (each p<0.05).
Conclusions
HIV prevalence among TB patients was high in the study areas of China. To control the dual epidemic, intervention strategies targeting socio-demographic and behavioral factors associated with higher risk of TB-HIV co-infection are urgently called for.
doi:10.1371/journal.pone.0089723
PMCID: PMC3931821  PMID: 24586987
16.  Inferring consistent functional interaction patterns from natural stimulus FMRI data 
NeuroImage  2012;61(4):987-999.
There has been increasing interest in how the human brain responds to natural stimulus such as video watching in the neuroimaging field. Along this direction, this paper presents our effort in inferring consistent and reproducible functional interaction patterns under natural stimulus of video watching among known functional brain regions identified by task-based fMRI. Then, we applied and compared four statistical approaches, including Bayesian network modeling with searching algorithms: greedy equivalence search (GES), Peter and Clark (PC) analysis, independent multiple greedy equivalence search (IMaGES), and the commonly used Granger causality analysis (GCA), to infer consistent and reproducible functional interaction patterns among these brain regions. It is interesting that a number of reliable and consistent functional interaction patterns were identified by the GES, PC and IMaGES algorithms in different participating subjects when they watched multiple video shots of the same semantic category. These interaction patterns are meaningful given current neuroscience knowledge and are reasonably reproducible across different brains and video shots. In particular, these consistent functional interaction patterns are supported by structural connections derived from diffusion tensor imaging (DTI) data, suggesting the structural underpinnings of consistent functional interactions. Our work demonstrates that specific consistent patterns of functional interactions among relevant brain regions might reflect the brain's fundamental mechanisms of online processing and comprehension of video messages.
doi:10.1016/j.neuroimage.2012.01.142
PMCID: PMC3929522  PMID: 22440644
Natural stimulus fMRI; DTI; Functional interaction
17.  The Flavivirus Protease As a Target for Drug Discovery 
Virologica Sinica  2013;28(6):326-336.
Many flaviviruses are significant human pathogens causing considerable disease burdens, including encephalitis and hemorrhagic fever, in the regions in which they are endemic. A paucity of treatments for flaviviral infections has driven interest in drug development targeting proteins essential to flavivirus replication, such as the viral protease. During viral replication, the flavivirus genome is translated as a single polyprotein precursor, which must be cleaved into individual proteins by a complex of the viral protease, NS3, and its cofactor, NS2B. Because this cleavage is an obligate step of the viral life-cycle, the flavivirus protease is an attractive target for antiviral drug development. In this review, we will survey recent drug development studies targeting the NS3 active site, as well as studies targeting an NS2B/NS3 interaction site determined from flavivirus protease crystal structures.
doi:10.1007/s12250-013-3390-x
PMCID: PMC3927373  PMID: 24242363
Flavivirus; Inhibitor; Protease
18.  Association of liver X receptor α (LXRα) gene polymorphism and coronary heart disease, serum lipids and glucose levels 
Background
To explore the relationship between the liver X receptor α gene (LXRα) rsl2221497 polymorphism and the susceptibility of coronary heart disease (CHD) and serum lipids and glucose levels.
Methods
The single fluorescently labeled probes technique was used to detect the genotype of rsl2221497 in LXRα gene in 240 CHD patients and 250 healthy control subjects. The difference of genotype distribution between the two groups was analyzed using of Chi-square test. The serum lipids and glucose levels between the different genotypes were also compared.
Results
The risk of CHD in carriers with (AA + GA) genotype was 1.76 times as that in the GG genotype carriers (OR = 1.76, 95% CI: 1.18-2.87, P <0.05), and the risk of CHD in carriers with A allele increased 0.88 times compared to that in G allele carriers (OR = 1.88, 95% CI:1.21-3.43, P <0.01). Logistic regression analysis showed that after adjusting for other confounding factors, A allele was an independent risk for CHD. However, there were no differences in serum lipids and glucose levels between each genotype.
Conclusions
The rsl2221497 polymorphism in LXRα gene was associated with susceptibility of CHD in Han population.
doi:10.1186/1476-511X-13-34
PMCID: PMC3975963  PMID: 24533572
Liver X receptor α; Gene; Coronary heart disease; Polymorphism
19.  Detecting and understanding genetic and structural features in HIV-1 B subtype V3 underlying HIV-1 co-receptor usage 
Bioinformatics  2013;29(4):451-460.
Motivation: To define V3 genetic elements and structural features underlying different HIV-1 co-receptor usage in vivo.
Results: By probabilistically modeling mutations in the viruses isolated from HIV-1 B subtype patients, we present a unique statistical procedure that would first identify V3 determinants associated with the usage of different co-receptors cooperatively or independently, and then delineate the complicated interactions among mutations functioning cooperatively. We built a model based on dual usage of CXCR4 and CCR5 co-receptors. The molecular basis of our statistical predictions is further confirmed by phenotypic and molecular modeling analyses. Our results provide new insights on molecular basis of different HIV-1 co-receptor usage. This is critical to optimize the use of genotypic tropism testing in clinical practice and to obtain molecular-implication for design of vaccine and new entry-inhibitors.
Contact: jing.zhang.jz349@yale.edu or cf.perno@uniroma2.it
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btt002
PMCID: PMC3570207  PMID: 23297034
20.  Advances in serous tubal intraepithelial carcinoma: correlation with high grade serous carcinoma and ovarian carcinogenesis 
Early serous carcinoma in fallopian tube or serous tubal intraepithelial carcinoma (STIC), an early lesion limited to the epithelium of the fallopian tube and firstly identified from specimen obtained by prophylactic salpingo-oophorectomy, has provided insight into pelvic high grade serous carcinoma (HGSC). Increasing evidence indicates that STIC is a likely precursor for HGSC and several studies have focused on this lesion and its clinical significance. This review addresses recent advances in recognizing STIC and its correlation with HGSC and ovarian carcinogenesis. It also describes evidence regarding the fallopian tube as a source of some HGSCs, the protocol for optimizing histological evaluation of the tubes, the spectrum of tubal lesions from benign to noninvasive carcinoma, changes in diagnostic criteria from purely morphologic characteristics to a combination of morphologic features and molecular biomarkers, and new studies about potential biomarkers. However, the direct evidence regarding STIC as the precursor of HGSC is still tantalizing due to other possibilities that may also explain the origin of pelvic HGSC. Further molecular genetic studies are required to address this important question.
PMCID: PMC3971287
Serous tubal intraepithelial carcinoma; fallopian tube; high grade serous carcinoma; ovarian cancer; carcinogenesis
21.  Protective role of hydrogen-rich water on aspirin-induced gastric mucosal damage in rats 
AIM: To investigate the role of the hydrogen-rich water (HRW) in the prevention of aspirin-induced gastric mucosal injury in rats.
METHODS: Forty male rats were allocated into four groups: normal control group, HRW group, aspirin group, and HRW plus aspirin group. The protective efficacy was tested by determining the gastric mucosal damage score. Malondialdehyde (MDA), superoxide dismutase (SOD), myeloperoxidase (MPO), interleukin (IL)-06 and tumor necrosis factor (TNF)-α in gastric tissues were evaluated. The serum levels of IL-1β and TNF-α were also detected. Histopathology of gastric tissues and localization of Cyclooxygenase 2 (COX-2) were detected using hematoxylin and eosin staining and immunohistochemistry, respectively.
RESULTS: Pretreatment with HRW obviously reduced aspirin-induced gastric damage scores (4.04 ± 0.492 vs 2.10 ± 0.437, P < 0.05). The oxidative stress levels of MDA and MPO in the gastric tissues increased significantly in the aspirin-treated group compared with the HRW group (2.43 ± 0.145 vs 1.79 ± 0.116 nmol/mg prot, P < 0.05 and 2.53 ± 0.238 vs 1.40 ± 0.208 U/g tissue, P < 0.05, respectively). HRW could obviously elevated the SOD levels in the gastric tissues (37.94 ± 8.44 vs 59.55 ± 9.02 nmol/mg prot, P < 0.05). Pretreatment with HRW significantly reduced IL-06 and TNF-α in the gastric tissues (46.65 ± 5.50 vs 32.15 ± 4.83 pg/mg, P < 0.05 and 1305.08 ± 101.23 vs 855.96 ± 93.22 pg/mg, P < 0.05), and IL-1β and TNF-α in the serum (505.38 ± 32.97 vs 343.37 ± 25.09 pg/mL, P < 0.05 and 264.53 ± 28.63 vs 114.96 ± 21.79 pg/mL, P < 0.05) compared to treatment with aspirin alone. HRW could significantly decrease the COX-2 expression in the gastric tissues (staining score: 8.4 ± 2.1 vs 2.9 ± 1.5, P < 0.05).
CONCLUSION: HRW pretreatment alleviated the aspirin-induced gastric lesions by inhibiting the oxidative stress, inflammatory reaction and reducing the COX-2 in the gastric tissues.
doi:10.3748/wjg.v20.i6.1614
PMCID: PMC3925872  PMID: 24587639
Hydrogen; Aspirin; Gastric lesion; Oxidative stress; Cytokines; Cyclooxygenase 2
22.  Network Meta-Analysis of Erlotinib, Gefitinib, Afatinib and Icotinib in Patients with Advanced Non-Small-Cell Lung Cancer Harboring EGFR Mutations 
PLoS ONE  2014;9(2):e85245.
Background
Several EGFR-tyrosine kinase inhibitors (EGFR-TKIs) including erlotinib, gefitinib, afatinib and icotinib are currently available as treatment for patients with advanced non-small-cell lung cancer (NSCLC) who harbor EGFR mutations. However, no head to head trials between these TKIs in mutated populations have been reported, which provides room for indirect and integrated comparisons.
Methods
We searched electronic databases for eligible literatures. Pooled data on objective response rate (ORR), progression free survival (PFS), overall survival (OS) were calculated. Appropriate networks for different outcomes were established to incorporate all evidences. Multiple-treatments comparisons (MTCs) based on Bayesian network integrated the efficacy and specific toxicities of all included treatments.
Results
Twelve phase III RCTs that investigated EGFR-TKIs involving 1821 participants with EGFR mutation were included. For mutant patients, the weighted pooled ORR and 1-year PFS of EGFR-TKIs were significant superior to that of standard chemotherapy (ORR: 66.6% vs. 30.9%, OR 5.46, 95%CI 3.59 to 8.30, P<0.00001; 1-year PFS: 42.9% vs. 9.7%, OR 7.83, 95%CI 4.50 to 13.61; P<0.00001) through direct meta-analysis. In the network meta-analyses, no statistically significant differences in efficacy were found between these four TKIs with respect to all outcome measures. Trend analyses of rank probabilities revealed that the cumulative probabilities of being the most efficacious treatments were (ORR, 1-year PFS, 1-year OS, 2-year OS): erlotinib (51%, 38%, 14%, 19%), gefitinib (1%, 6%, 5%, 16%), afatinib (29%, 27%, 30%, 27%) and icotinib (19%, 29%, NA, NA), respectively. However, afatinib and erlotinib showed significant severer rash and diarrhea compared with gefitinib and icotinib.
Conclusions
The current study indicated that erlotinib, gefitinib, afatinib and icotinib shared equivalent efficacy but presented different efficacy-toxicity pattern for EGFR-mutated patients. Erlotinib and afatinib revealed potentially better efficacy but significant higher toxicities compared with gefitinib and icotinib.
doi:10.1371/journal.pone.0085245
PMCID: PMC3922700  PMID: 24533047
23.  Individual Differences in Automatic Emotion Regulation Affect the Asymmetry of the LPP Component 
PLoS ONE  2014;9(2):e88261.
The main goal of this study was to investigate how automatic emotion regulation altered the hemispheric asymmetry of ERPs elicited by emotion processing. We examined the effect of individual differences in automatic emotion regulation on the late positive potential (LPP) when participants were viewing blocks of positive high arousal, positive low arousal, negative high arousal and negative low arousal pictures from International affect picture system (IAPS). Two participant groups were categorized by the Emotion Regulation-Implicit Association Test which has been used in previous research to identify two groups of participants with automatic emotion control and with automatic emotion express. The main finding was that automatic emotion express group showed a right dominance of the LPP component at posterior electrodes, especially in high arousal conditions. But no right dominance of the LPP component was observed for automatic emotion control group. We also found the group with automatic emotion control showed no differences in the right posterior LPP amplitude between high- and low-arousal emotion conditions, while the participants with automatic emotion express showed larger LPP amplitude in the right posterior in high-arousal conditions compared to low-arousal conditions. This result suggested that AER (Automatic emotion regulation) modulated the hemispheric asymmetry of LPP on posterior electrodes and supported the right hemisphere hypothesis.
doi:10.1371/journal.pone.0088261
PMCID: PMC3921131  PMID: 24523881
24.  The IRP1-HIF-2α Axis Coordinates Iron and Oxygen Sensing with Erythropoiesis and Iron Absorption 
Cell metabolism  2013;17(2):282-290.
SUMMARY
Red blood cell production is a finely tuned process that requires coordinated oxygen- and iron-dependent regulation of cell differentiation and iron metabolism. Here we show that translational regulation of HIF-2α synthesis by IRP1 is critical for controlling erythrocyte number. IRP1 null mice (Irp1−/−) display a marked transient polycythemia. HIF-2α mRNA is derepressed in kidney of Irp1−/− but not Irp2−/− mice leading to increased renal erythropoietin (Epo) mRNA and inappropriately elevated serum Epo levels. Expression of the iron transport genes DCytb, DMT1 and ferroportin as well as other HIF-2α targets is enhanced in IRP1−/− duodenum. Analysis of mRNA translation state in liver revealed IRP1-dependent dysregulation of HIF-2α mRNA translation while IRP2 deficiency derepressed translation of all other known 5′ IRE-containing mRNAs expressed in liver. These results uncover separable physiological roles of each IRP and identify IRP1 as a therapeutic target for manipulating HIF-2α action in hematologic, oncologic and other disorders.
doi:10.1016/j.cmet.2013.01.007
PMCID: PMC3612289  PMID: 23395174
25.  Inhibition of Angiogenesis, Fibrosis and Thrombosis by Tetramethylpyrazine: Mechanisms Contributing to the SDF-1/CXCR4 Axis 
PLoS ONE  2014;9(2):e88176.
Background
Tetramethylpyrazine (TMP) is one of the active ingredients extracted from the Chinese herb Chuanxiong, which has been used to treat cerebrovascular and cardiovascular diseases, pulmonary diseases and cancer. However, the molecular mechanisms underlying the actions of TMP have not been fully elucidated. In a previous study we showed that TMP-mediated glioma suppression and neural protection involves the inhibition of CXCR4 expression. The SDF-1/CXCR4 axis plays a fundamental role in many physiological and pathological processes. In this study, we further investigated whether the regulation of the SDF-1/CXCR4 pathway is also involved in the TMP-mediated inhibition of neovascularization or fibrosis and improvement of microcirculation.
Methodology/Principal Findings
Using a scratch-wound assay, we demonstrated that TMP significantly suppressed the migration and tubule formation of the human umbilical vein endothelial cell line ECV304 in vitro. The expression of CXCR4 in ECV304 cells is notably down-regulated after TMP treatment. In addition, TMP significantly suppresses corneal neovascularization in a rat model of corneal alkali burn injury. The expression of CXCR4 on days 1, 3 and 7 post-injury was determined through RT-PCR analysis. Consistent with our hypotheses, the expression of CXCR4 in the rat cornea is significantly increased with alkali burn and dramatically down-regulated with TMP treatment. Moreover, TMP treatment significantly attenuates bleomycin-induced rat pulmonary fibrosis, while immunofluorescence shows a notably decreased amount of CXCR4-positive cells in the TMP-treated group. Furthermore, TMP significantly down-regulates the expression of CXCR4 in platelets, lymphocytes and red blood cells. Whole-blood viscosity and platelet aggregation in rats are significantly decreased by TMP treatment.
Conclusions
These results show that TMP exerts potent effects in inhibiting neovascularization, fibrosis and thrombosis under pathological conditions; thus, the underlying mechanism of TMP might partially contribute to the down-regulation of CXCR4.
doi:10.1371/journal.pone.0088176
PMCID: PMC3914919  PMID: 24505417

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