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1.  Fibroblast Growth Factor Receptor 2 (FGFR2) Is Required for Corneal Epithelial Cell Proliferation and Differentiation during Embryonic Development 
PLoS ONE  2015;10(1):e0117089.
Fibroblast growth factors (FGFs) play important roles in many aspects of embryonic development. During eye development, the lens and corneal epithelium are derived from the same surface ectodermal tissue. FGF receptor (FGFR)-signaling is essential for lens cell differentiation and survival, but its role in corneal development has not been fully investigated. In this study, we examined the corneal defects in Fgfr2 conditional knockout mice in which Cre expression is activated at lens induction stage by Pax6 P0 promoter. The cornea in LeCre, Fgfr2loxP/loxP mice (referred as Fgfr2CKO) was analyzed to assess changes in cell proliferation, differentiation and survival. We found that Fgfr2CKO cornea was much thinner in epithelial and stromal layer when compared to WT cornea. At embryonic day 12.5–13.5 (E12.5–13.5) shortly after the lens vesicle detaches from the overlying surface ectoderm, cell proliferation (judged by labeling indices of Ki-67, BrdU and phospho-histone H3) was significantly reduced in corneal epithelium in Fgfr2CKO mice. At later stage, cell differentiation markers for corneal epithelium and underlying stromal mesenchyme, keratin-12 and keratocan respectively, were not expressed in Fgfr2CKO cornea. Furthermore, Pax6, a transcription factor essential for eye development, was not present in the Fgfr2CKO mutant corneal epithelial at E16.5 but was expressed normally at E12.5, suggesting that FGFR2-signaling is required for maintaining Pax6 expression in this tissue. Interestingly, the role of FGFR2 in corneal epithelial development is independent of ERK1/2-signaling. In contrast to the lens, FGFR2 is not required for cell survival in cornea. This study demonstrates for the first time that FGFR2 plays an essential role in controlling cell proliferation and differentiation, and maintaining Pax6 levels in corneal epithelium via ERK-independent pathways during embryonic development.
doi:10.1371/journal.pone.0117089
PMCID: PMC4304804  PMID: 25615698
2.  Protection of Retina by Mini-αA in NaIO3-Induced Retinal Pigment Epithelium Degeneration Mice 
Background: Studies have shown that mini-αA can protect retinal pigment epithelium (RPE) cells from apoptosis. However, no in vivo study concerning the anti-apoptotic function of mini-αA has been conducted yet. Methods: MTT assay, HE staining and TUNEL assay were used to assess levels of cells, and an animal model was established to examine the protective effects of mini-αA against NaIO3-induced RPE cell apoptosis. Western blot analysis and RT-qPCR were performed to explore the possible mechanism of mini-αA’s protective function against NaIO3-induced RPE cell apoptosis. Results: Results from in vivo and animal experiments showed that mini-αA antagonized NaIO3-induced RPE cell apoptosis. Further investigation into how mini-αA provided protection against NaIO3-induced RPE cell apoptosis showed that mini-αA reduced NaIO3-induced RPE cell apoptosis and autophagy. In addition, unfolded protein response was also involved in the protective effects of mini-αA against NaIO3-induced RPE cell apoptosis. Conclusions: mini-αA can antagonize RPE cell apoptosis induced by NaIO3. A possible mechanism is by inhibition of apoptosis by repressing autophagy and endoplasmic reticulum stress.
doi:10.3390/ijms16011644
PMCID: PMC4307325  PMID: 25588217
mini-α; NaIO3-induced retinal pigment epithelium; cell apoptosis
3.  Red Cell Distribution Width Is Associated with Presence, Stage, and Grade in Patients with Renal Cell Carcinoma 
Disease Markers  2014;2014:860419.
It has been reported that red blood cell width (RDW) is a marker associated with the presence and adverse outcomes of various diseases. However, no data are available on the correlation of RDW with presence, stage, and grade in patients with renal cell carcinoma (RCC) yet. By retrospectively analyzing clinical and laboratory data at baseline of histologically confirmed RCC cases and controls, the present study demonstrated that the RDW values were significantly higher in patients with RCC than those in controls, and the baseline RDW value was independently associated with the presence of RCC. Besides, the data revealed a positive association between RCC stage and grade and the level of RDW. These findings may have important clinical implications due to future application using a RDW value in predicting RCC.
doi:10.1155/2014/860419
PMCID: PMC4280806  PMID: 25580051
4.  Recreational drug use and risks of HIV and sexually transmitted infections among Chinese men who have sex with men: Mediation through multiple sexual partnerships 
BMC Infectious Diseases  2014;14(1):642.
Background
Recreational drug use (RDU) may result in sexual disinhibition and higher risk for HIV and other sexually transmitted infections (STIs) among men who have sex with men (MSM) in China. We assessed whether RDU was associated with HIV, syphilis, and herpes simplex virus type 2 (HSV-2) within the context of multiple sexual partnerships and unprotected sex.
Methods
We conducted a cross-sectional study among sexually-active MSM in six Chinese cities (Kunming, Jinan, Changsha, Zhengzhou, Nanjing, and Shanghai) in 2012–2013. We interviewed participants regarding RDU and sexual activity and drew blood for HIV, syphilis, and HSV-2. We fit multiple logistic regression models to assess associations of drug use and HIV, syphilis and HSV-2 infections, controlling for number of sexual partners and unprotected sex.
Results
Of 3830 participants, 28% reported ever using ≥1 of these drugs in the past 6 months: popper (alkyl nitrites), ecstasy, ice (methamphetamine), amphetamine, tramadol, and ketamine. In the past six months, 62% of MSM reported ≥2 sexual partners and 76% did not use condoms at last sexual encounter. HIV, syphilis and HSV-2 prevalences were 9.2%, 12.2%, and 10.3%, respectively.RDU was associated with HIV infection (aOR = 1.67; 95% CI, 1.31-2.13). Men with RDU were more likely to report multiple sexual partners (OR = 1.69; 95% CI, 1.44-1.98) and unprotected sex (aOR = 1.25; 95% CI, 1.05-1.49). The RDU-HIV association persisted (aOR = 1.58; 95% CI = 1.23-2.02) after adjusting for numbers of partners.
Conclusions
RDU was associated with multiple sexual partnerships, unprotected sex, and HIV among Chinese MSM. It is plausible that RDU is a driver of increased sexual/HIV risk and/or may be an associated behavior with sexually risky lifestyles. Community engagement is needed.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-014-0642-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s12879-014-0642-9
PMCID: PMC4272794  PMID: 25443542
Men who have sex with men; Multiple sexual partners; Unprotected sex; HIV; Syphilis; HSV-2; Recreational drug use; Substance use; China
5.  The Protective Effects of IGF-1 on Different Subpopulations of DRG Neurons with Neurotoxicity Induced by gp120 and Dideoxycytidine In Vitro 
Biomolecules & Therapeutics  2014;22(6):532-539.
Peripheral neuropathy induced by human immunodeficiency virus (HIV) infection and antiretroviral therapy is not only difficult to distinguish in clinical practice, but also difficult to relieve the pain symptoms by analgesics because of the severity of the disease at the later stage. Hence, to explore the mechanisms of HIV-related neuropathy and find new therapeutic options are particularly important for relieving neuropathic pain symptoms of the patients. In the present study, primary cultured embryonic rat dorsal root ganglion (DRG) neurons were used to determine the neurotoxic effects of HIV-gp120 protein and/or antiretroviral drug dideoxycytidine (ddC) and the therapeutic actions of insulin-like growth factor-1 (IGF-1) on gp120- or ddC-induced neurotoxicity. DRG neurons were exposed to gp120 (500 pmol/L), ddC (50 μmol/L), gp120 (500 pmol/L) plus ddC (50 μmol/L), gp120 (500 pmol/L) plus IGF-1 (20 nmol/L), ddC (50 μmol/L) plus IGF-1 (20 nmol/L), gp120 (500 pmol/L) plus ddC (50 μmol/L) plus IGF-1 (20 nmol/L), respectively, for 72 hours. The results showed that gp120 and/or ddC caused neurotoxicity of primary cultured DRG neurons. Interestingly, the severity of neurotoxicity induced by gp120 and ddC was different in different subpopulation of DRG neurons. gp120 mainly affected large diameter DRG neurons (>25 μm), whereas ddC mainly affected small diameter DRG neurons (≤25 μm). IGF-1 could reverse the neurotoxicity induced by gp120 and/or ddC on small, but not large, DRG neurons. These data provide new insights in elucidating the pathogenesis of HIV infection- or antiretroviral therapy-related peripheral neuropathy and facilitating the development of novel treatment strategies.
doi:10.4062/biomolther.2014.036
PMCID: PMC4256033  PMID: 25489421
gp120; Dideoxycytidine; Neurotoxicity; Insulin-like growth factor-1; Neuron; Dorsal root ganglion
6.  Association of cholesteryl ester transfer protein (CETP) gene polymorphism, high density lipoprotein cholesterol and risk of coronary artery disease: a meta-analysis using a Mendelian randomization approach 
BMC Medical Genetics  2014;15(1):118.
Background
Recent randomized controlled trials have challenged the concept that increased high density lipoprotein cholesterol (HDL-C) levels are associated with coronary artery disease (CAD) risk reduction. The causal role of HDL-C in the development of atherosclerosis remains unclear. To increase precision and to minimize residual confounding, we exploited the cholesteryl ester transfer protein (CETP)-TaqIB polymorphism as an instrument based on Mendelian randomization.
Methods
The Mendelian randomization analysis was performed by two steps. First, we conducted a meta-analysis of 47 studies, including 23,928 cases and 27,068 controls, to quantify the relationship between the TaqIB polymorphism and the CAD risk. Next, the association between the TaqIB polymorphism and HDL-C was assessed among 5,929 Caucasians. We further employed Mendelian randomization to evaluate the causal effect of HDL-C on CAD based on the findings from the meta-analysis.
Results
The overall comparison of the B2 allele with the B1 allele yielded a significant risk reduction of CAD (P < 0.0001; OR = 0.88; 95% CI: 0.84–0.92) with substantial between-study heterogeneity (I2 = 55.2%; Pheterogeneity <0.0001). The result was not materially changed after excluding the Hardy-Weinberg Equilibrium (HWE)-violation studies. Compared with B1B1 homozygotes, Caucasian carriers of the B2 allele had a 0.25 mmol/L increase in HDL-C level (95% CI: 0.20–0.31; P <0.0001; I2 = 0; Pheterogeneity =0.87). However, a 1 standard deviation (SD) elevation in HDL-C levels due to the TaqIB polymorphism, was marginal associated with CAD risk (OR =0.79; 95% CI: 0.54–1.03; P =0.08).
Conclusions
Taken together, our results lend support to the concept that increased HDL-C cannot be translated into a reduction in CAD risk.
Electronic supplementary material
The online version of this article (doi:10.1186/s12881-014-0118-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s12881-014-0118-1
PMCID: PMC4258818  PMID: 25366166
Coronary artery disease; High density lipoprotein cholesterol; Polymorphism; Mendelian randomization
7.  Copy number variation of the Lipoprotein(a) (LPA) gene is associated with coronary artery disease in a southern Han Chinese population 
Copy number variations (CNVs), genomic duplication or deletion events occurring at larger than 1 kb scale, contribute to the complex diseases substantially. Lipoprotein(a) [Lp(a)] is a major inherited risk factor for atherosclerosis and coronary artery disease (CAD). We investigated the association between a CNV of the Lp(a) (LPA) gene and CAD. The case-control study included 271 CAD patients and 207 controls diagnosed by coronary angiography. A taqman real-time fluorescence PCR based technique was developed according to the 2 × 2-ΔΔCt±SD calculation method. We detected LPA CNVs with a range of 1, 2 and 3. The 1 copy number carriers had a significantly reduced risk of CAD compared with those with 2 copy number after adjusting for the confounding factors (P < 0.001, OR = 0.38, 95% CI 0.23-0.64). Further stratified analyses suggested a significant protective effect of the 1 copy number in the elderly population (P = 0.008), females (P = 0.007) as well as in populations with non-hyperlipidemia (P = 0.003), hypertension (P = 0.001), non-smoking (P < 0.001) and high Lp(a) (≥ 0.3 g/L) levels (P = 0.001). The 1 copy number of the LPA gene may be an independent protective factor of CAD in a southern Han Chinese population, particularly in females and the elderly.
PMCID: PMC4238520  PMID: 25419416
Lipoprotein(a); copy number variation; coronary artery disease
8.  Association of natriuretic peptide polymorphisms with left ventricular dysfunction in southern Han Chinese coronary artery disease patients 
Background: Left ventricular dysfunction (LVD) occurs with myocardial ischemia and coronary artery disease (CAD). The natriuretic peptide system has compensatory vasodilatory, natriuretic and paracrine effects on LVD and subsequent heart failure. The aim of this study was to investigate the relationship between natriuretic peptide polymorphisms and risk of LVD in CAD patients. Methods: We recruited 747 consecutive Southern Han Chinese patients with angiographically confirmed CAD, 201 had a reduced left ventricle ejection fraction (LVEF ≤45%, LVD group) and 546 had a preserved left ventricle ejection fraction (LVEF >45%). The reduced and preserved LVEF groups were matched by gender and age. Taqman assays were performed to identify five polymorphisms in the NPPA-NPPB locus (rs5065, rs5063, rs632793, rs198388 and rs198389). Results: Single-locus analyses found no significant difference in the allele and genotype frequencies of the reduced and preserved LVEF group, even after adjusting for confounding factors. Subgroup analyses performed by hyperlipidemia (HLP) demonstrated 3 polymorphisms, rs632793 (OR = 0.31, 95% CI 0.1-0.93, P = 0.04), rs198388 (OR = 0.26, 95% CI 0.09-0.79, P = 0.02) and rs198389 (OR = 0.26, 95% CI 0.09-0.80, P = 0.02) were associated with the reduced risk of LVD. No CAD-susceptible haplotypes were identified. Multifactor dimensionality reduction analysis did not detect any gene-to-gene interactions among the five loci. Three loci (rs5063, rs632793 and rs198388) formed the best model with the maximum testing accuracy (39.89%) and cross-validation consistency (10/10). Conclusion: Three NPPA-NPPB polymorphisms (rs632793, rs198388 and rs198389) were associated with reduced risk of LVD in CAD patients with HLP.
PMCID: PMC4230134  PMID: 25400811
Left ventricular dysfunction; coronary artery disease; natriuretic peptide; polymorphism; heart failure
9.  Prediction of S-Nitrosylation Modification Sites Based on Kernel Sparse Representation Classification and mRMR Algorithm 
BioMed Research International  2014;2014:438341.
Protein S-nitrosylation plays a very important role in a wide variety of cellular biological activities. Hitherto, accurate prediction of S-nitrosylation sites is still of great challenge. In this paper, we presented a framework to computationally predict S-nitrosylation sites based on kernel sparse representation classification and minimum Redundancy Maximum Relevance algorithm. As much as 666 features derived from five categories of amino acid properties and one protein structure feature are used for numerical representation of proteins. A total of 529 protein sequences collected from the open-access databases and published literatures are used to train and test our predictor. Computational results show that our predictor achieves Matthews' correlation coefficients of 0.1634 and 0.2919 for the training set and the testing set, respectively, which are better than those of k-nearest neighbor algorithm, random forest algorithm, and sparse representation classification algorithm. The experimental results also indicate that 134 optimal features can better represent the peptides of protein S-nitrosylation than the original 666 redundant features. Furthermore, we constructed an independent testing set of 113 protein sequences to evaluate the robustness of our predictor. Experimental result showed that our predictor also yielded good performance on the independent testing set with Matthews' correlation coefficients of 0.2239.
doi:10.1155/2014/438341
PMCID: PMC4145740  PMID: 25184139
10.  Differential Expression of Heat Shock Transcription Factors and Heat Shock Proteins after Acute and Chronic Heat Stress in Laying Chickens (Gallus gallus) 
PLoS ONE  2014;9(7):e102204.
Heat stress due to high environmental temperature negatively influences animal performances. To better understand the biological impact of heat stress, laying broiler breeder chickens were subjected either to acute (step-wisely increasing temperature from 21 to 35°C within 24 hours) or chronic (32°C for 8 weeks) high temperature exposure. High temperature challenges significantly elevated body temperature of experimental birds (P<0.05). However, oxidation status of lipid and protein and expression of heat shock transcription factors (HSFs) and heat shock proteins (HSPs) 70 and 90 were differently affected by acute and chronic treatment. Tissue-specific responses to thermal challenge were also found among heart, liver and muscle. In the heart, acute heat challenge affected lipid oxidation (P = 0.05) and gene expression of all 4 HSF gene expression was upregulated (P<0.05). During chronic heat treatment, the HSP 70 mRNA level was increased (P<0.05) and HSP 90 mRNA (P<0.05) was decreased. In the liver, oxidation of protein was alleviated during acute heat challenge (P<0.05), however, gene expression HSF2, 3 and 4 and HSP 70 were highly induced (P<0.05). HSP90 expression was increased by chronic thermal treatment (P<0.05). In the muscle, both types of heat stress increased protein oxidation, but HSFs and HSPs gene expression remained unaltered. Only tendencies to increase were observed in HSP 70 (P = 0.052) and 90 (P = 0.054) gene expression after acute heat stress. The differential expressions of HSF and HSP genes in different tissues of laying broiler breeder chickens suggested that anti-heat stress mechanisms might be provoked more profoundly in the heart, by which the muscle was least protected during heat stress. In addition to HSP, HSFs gene expression could be used as a marker during acute heat stress.
doi:10.1371/journal.pone.0102204
PMCID: PMC4114549  PMID: 25072282
11.  Predictable Chronic Mild Stress in Adolescence Increases Resilience in Adulthood 
Neuropsychopharmacology  2013;38(8):1387-1400.
Stress in adolescence has been widely demonstrated to have a lasting impact in humans and animal models. Developmental risk and protective factors play an important role in the responses to stress in adulthood. Mild-to-moderate stress in adolescence may resist the negative impacts of adverse events in adulthood. However, little research on resilience has been conducted. In this study, we used a predictable chronic mild stress (PCMS) procedure (5 min of daily restraint stress for 28 days) in adolescent rats (postnatal days (PNDs) 28–55) to test the resilience effect of PCMS on depressive-like behavior in the sucrose preference test and forced swim test and anxiety-like behavior in the novelty-suppressed feeding test and elevated plus maze in adulthood. We also investigated the role of mammalian target of rapamycin (mTOR) signaling in the brain during the PCMS procedure in adolescence. Moreover, we investigated the effect of PCMS in adolescence on subsequent responses to chronic unpredictable stress (CUS; PNDs 63–83) in adulthood. The results demonstrated that PCMS during adolescence produced antidepressant- and anxiolytic-like effects and increased mTOR signaling activity in the prefrontal cortex in early adulthood. Either systemic administration or intra-PFC infusion of the mTOR inhibitor rapamycin completely blocked the behavioral effects produced by PCMS in adolescence. PCMS during adolescence resisted depressive- and anxiety-like behavior caused by CUS in adulthood. These findings indicate that PCMS in adolescence can contribute to resilience against depression and anxiety caused by stress in adulthood.
doi:10.1038/npp.2013.67
PMCID: PMC3682155  PMID: 23478858
adolescence; behavioral science; depression; development/developmental disorders; molecular & cellular neurobiology; mood/anxiety/stress disorders; mTOR; predictable chronic mild stress; resilience; adolescence; depression; mTOR; predictable chronic mild stress; resilience
12.  Identification and Characterization of a Novel HIV-1 Circulating Recombinant Form (CRF59_01B) Identified among Men-Who-Have-Sex-with-Men in China 
PLoS ONE  2014;9(6):e99693.
The HIV-1 epidemic among men-who-have-sex-with-men (MSM) continues to expand in China. A large-scale national survey we conducted on HIV-1 strains among MSM in 11 provinces in China from 2008 to 2013 (n = 920) identified a novel transmission cluster consisting of six strains (0.7%) that belonged to a new circulating recombinant form (designated CRF59_01B). CRF59_01B contains two subtype B segments of U.S.-European origin (in the pol and vpu-env regions) in a CRF01_AE backbone. CRF59_01B is the second CRF (after CRF55_01B) circulating primarily among MSM in China. CRF59_01B occurs at a low frequency (less than 1%), but it was detected in four different provinces/regions in China: Liaoning (northeast China) (n = 3); Hunan (central China) (n = 1); Guangdong (south China) (n = 1); Yunnan (southwest China) (n = 1). One additional recombinant strain was detected in a heterosexual individual in Liaoning province but is not the focus of this paper. Bayesian molecular clock analyses indicate that CRF59_01B emerged as a result of recombination between CRF01_AE and subtype B around the year 2001. The emergence of multiple forms of recombinants and CRFs reflects the ever-increasing contribution of homosexual transmission in China's HIV epidemic and indicates an active HIV transmission network among MSM in China.
doi:10.1371/journal.pone.0099693
PMCID: PMC4076182  PMID: 24978029
13.  Glycation of Apoprotein A-I Is Associated With Coronary Artery Plaque Progression in Type 2 Diabetic Patients 
Diabetes Care  2013;36(5):1312-1320.
OBJECTIVE
To investigate whether glycation level of apoprotein (apo)A-I is associated with coronary artery disease (CAD) and plaque progression in patients with type 2 diabetes.
RESEARCH DESIGN AND METHODS
Among 375 consecutive type 2 diabetic patients undergoing quantitative coronary angiography (QCA) and intravascular ultrasound (IVUS), 82 patients with nonsignificant stenosis (luminal diameter narrowing <30% [group I]) and 190 patients with significant CAD (luminal diameter stenosis ≥70% [group II]) were included for analysis of apoA-I glycation level and serum activity of lecithin: cholesterol acyltransferase (LCAT). The control group had 136 healthy subjects. At the 1-year follow-up, angiography and IVUS were repeated mainly in group II patients for plaque progression assessment.
RESULTS
Relative intensity of apoA-I glycation by densitometry was increased, and serum LCAT activity was decreased stepwise across groups control, I, and II. These two measurements were associated with the number of diseased coronary arteries and extent index in group II. During 1-year follow-up, QCA detected 45 patients with plaque progression in 159 subjects, and IVUS found 38 patients with plaque progression in 127 subjects. Baseline relative intensity of apoA-I glycation was significantly increased in patients with plaque progression compared with those without, with values associated with changes in QCA and IVUS measurements. Multivariable regression analysis revealed that baseline relative intensity of apoA-I glycation was an independent determinant of CAD and plaque progression in type 2 diabetic patients.
CONCLUSIONS
ApoA-I glycation level is associated with the severity of CAD and coronary artery plaque progression in type 2 diabetic patients.
doi:10.2337/dc12-1411
PMCID: PMC3631856  PMID: 23230102
14.  Toll-Like Receptor 4 Mediates Inflammatory Cytokine Secretion in Smooth Muscle Cells Induced by Oxidized Low-Density Lipoprotein 
PLoS ONE  2014;9(4):e95935.
Oxidized low-density lipoprotein (oxLDL)-regulated secretion of inflammatory cytokines in smooth muscle cells (SMCs) is regarded as an important step in the progression of atherosclerosis; however, its underlying mechanism remains unclear. This study investigated the role of toll-like receptor 4 (TLR4) in oxLDL-induced expression of inflammatory cytokines in SMCs both in vivo and in vitro. We found that the levels of TLR4, interleukin 1-β (IL1-β), tumor necrosis factor-α (TNFα), monocyte chemoattractant protein 1 (MCP-1) and matrix metalloproteinase-2 (MMP-2) expression were increased in the SMCs of atherosclerotic plaques in patients with femoral artery stenosis. In cultured primary arterial SMCs from wild type mice, oxLDL caused dose- and time-dependent increase in the expression levels of TLR4 and cytokines. These effects were significantly weakened in arterial SMCs derived from TLR4 knockout mice (TLR4−/−). Moreover, the secretion of inflammatory cytokines was blocked by TLR4-specific antibodies in primary SMCs. Ox-LDL induced activation of p38 and NFκB was also inhibited in TLR4−/− primary SMCs or when treated with TLR4-specific antibodies. These results demonstrated that TLR4 is a crucial mediator in oxLDL-induced inflammatory cytokine expression and secretion, and p38 and NFκB activation.
doi:10.1371/journal.pone.0095935
PMCID: PMC3995878  PMID: 24755612
15.  A Critical Role for Protein Degradation in the Nucleus Accumbens Core in Cocaine Reward Memory 
Neuropsychopharmacology  2013;38(5):778-790.
The intense associative memories that develop between cocaine-paired contexts and rewarding stimuli contribute to cocaine seeking and relapse. Previous studies have shown impairment in cocaine reward memories by manipulating a labile state induced by memory retrieval, but the mechanisms that underlie the destabilization of cocaine reward memory are unknown. In this study, using a Pavlovian cocaine-induced conditioned place preference (CPP) procedure in rats, we tested the contribution of ubiquitin-proteasome system-dependent protein degradation in destabilization of cocaine reward memory. First, we found that polyubiquitinated protein expression levels and polyubiquitinated N-ethylmaleimide-sensitive fusion (NSF) markedly increased 15 min after retrieval while NSF protein levels decreased 1 h after retrieval in the synaptosomal membrane fraction in the nucleus accumbens (NAc) core. We then found that infusion of the proteasome inhibitor lactacystin into the NAc core prevented the impairment of memory reconsolidation induced by the protein synthesis inhibitor anisomycin and reversed the effects of anisomycin on NSF and glutamate receptor 2 (GluR2) protein levels in the synaptosomal membrane fraction in the NAc core. We also found that lactacystin infusion into the NAc core but not into the shell immediately after extinction training sessions inhibited CPP extinction and reversed the extinction training-induced decrease in NSF and GluR2 in the synaptosomal membrane fraction in the NAc core. Finally, infusions of lactacystin by itself into the NAc core immediately after each training session or before the CPP retrieval test had no effect on the consolidation and retrieval of cocaine reward memory. These findings suggest that ubiquitin-proteasome system-dependent protein degradation is critical for retrieval-induced memory destabilization.
doi:10.1038/npp.2012.243
PMCID: PMC3672001  PMID: 23303053
cocaine; addiction; memory; reconsolidation; extinction; protein degradation
16.  On the Status and Comparison of Glucose Intolerance in Female Breast Cancer Patients at Initial Diagnosis and during Chemotherapy through an Oral Glucose Tolerance Test 
PLoS ONE  2014;9(4):e93630.
Aims
This study is to estimate the status and comparison of glucose intolerance in female breast cancer patients at initial diagnosis and during chemotherapy through an oral glucose tolerance test (OGTT), as well as to learn the effect of chemotherapy on the glucose metabolism of breast cancer patients.
Methods
All the 79 breast cancer patients at initial diagnosis, with the mean age of 53.2 years, and 96 breast cancer patients before the 5th or 6th cycle of chemotherapy, with the mean age of 51.5 years, participated in the study from December 2012 to October 2013. After an overnight fast, participants underwent OGTT test, and fasting and 2-hour glucose levels were measured to identify undiagnosed diabetes and prediabetes (i.e., impaired fasting glucose or impaired glucose tolerance) in them. Previously diagnosed diabetes among the female breast cancer patients was determined on the self-report and the medical record.
Results
The overall incidences of total normal glucose tolerance, prediabetes, diabetes in female breast cancer patients at initial diagnosis and during chemotherapy were 24.1% and 38.5% (p<0.05), 50.6% and 28.1% (p<0.05), and 25.3% and 33.3% (p>0.05), respectively, and the differences of normal glucose tolerance and prediabetes instead of diabetes between the two groups were statistically significant. About 84% of the total diabetes and prediabetes in the female breast cancer patients at initial diagnosis and 79.7% of those during chemotherapy need to be diagnosed with OGTT.
Conclusions
Breast cancer patients have high incidences of diabetes and prediabetes. After chemotherapy even with steroids, some breast cancer patients with abnormal glucose metabolism may even become normal. Isolated hyperglycemia 2 hours after glucose loading is common, and OGTT should be made for breast cancer patients at initial diagnosis and during chemotherapy.
doi:10.1371/journal.pone.0093630
PMCID: PMC3972194  PMID: 24690937
17.  Heterogeneous Effect of Two Selectin Gene Polymorphisms on Coronary Artery Disease Risk: A Meta-Analysis 
PLoS ONE  2014;9(2):e88152.
Background
The selectins play important roles in the inflammatory process of coronary artery disease (CAD) and myocardial infarction (MI). Previous studies have shown ambiguous findings regarding a possible association between the selectin genes and CAD. The E-selectin Ser128Arg polymorphism and the P-selectin Thr715Pro polymorphism have been investigated widely but with inconsistent results. We performed a comprehensive meta-analysis to shed light on this issue.
Methods
Data were extracted by searches of MEDLINE, Embase, CNKI, Wanfang, Google Scholar, PORTA, GeNii, CiNii, J-STAGE, Nurimedia and Koreanstudies Information Service System [Kiss] up to October 2013, in which 10 studies on the Ser128Arg polymorphism with 3369 cases and 2577 controls and 10 studies on the Thr715Pro polymorphism with 5886 cases and 18345 controls. A random-effects model was used to calculate the combined odds ratios. The between-study heterogeneity and publication bias were addressed.
Results
The 128Arg carriers had a significant increased risk of CAD (allele comparison: P = 0.02, OR = 1.33, 95%CI 1.04–1.69, Pheterogeneity = 0.01); The 715Pro conferred a non-significant risk reduction relative to the 715Thr (allele comparison: P = 0.40, OR = 0.94, 95%CI 0.82–1.08, Pheterogeneity = 0.03).Subgroup analyses demonstrated that the 128Arg carriers had a significant increased risk of CAD among Asians (allele comparison: P = 0.001, OR = 2.07, 95%CI 1.33–3.24, Pheterogeneity = 0.77) but not among Caucasians (allele comparison: P = 0.33, OR = 1.13, 95%CI 0.88–1.45, Pheterogeneity = 0.08). Carrier status for the 715Pro was significantly associated with reduced risk of MI (allele comparison: P = 0.04, OR =  0.81, 95%CI 0.67–0.99, Pheterogeneity = 0.14). The asymmetric funnel plot and the Egger's test (P = 0.041) suggested the presence of publication bias for the Ser128Arg polymorphism.
Conclusion
Our results suggested there is an increase in the risk of CAD conferred by the Ser128Arg polymorphism and the thr715Pro polymorphism may be a protective factor of MI.
doi:10.1371/journal.pone.0088152
PMCID: PMC3912165  PMID: 24498435
18.  Exploring Variability in CT Characterization of Tumors: A Preliminary Phantom Study1 
Translational Oncology  2014;7(1):88-93.
PURPOSE: To explore the effects of computed tomography (CT) slice thickness and reconstruction algorithm on quantification of image features to characterize tumors using a chest phantom. MATERIALS AND METHODS: Twenty-two phantom lesions of known sizes (10 and 20 mm), shapes (spherical, elliptical, lobulated, and spiculated), and densities [-630, -10, and +100 Hounsfield Unit (HU)] were inserted into an anthropomorphic thorax phantom and scanned three times with relocations. The raw data were reconstructed using six imaging settings, i.e., a combination of three slice thicknesses of 1.25, 2.5, and 5 mm and two reconstruction kernels of lung and standard. Lesions were segmented and 14 image features representing lesion size, shape, and texture were calculated. Differences in the measured image features due to slice thickness and reconstruction algorithm were compared using linear regression method by adjusting three confounding variables (size, density, and shape). RESULTS: All 14 features were significantly different between 1.25 and 5 mm slice images. The 1.25 and 2.5 mm slice thicknesses were better than 5 mm for volume, density mean, density SD gray-level co-occurrence matrix (GLCM) energy and homogeneity. As for the reconstruction algorithm, there was no significant difference in uni-dimension, volume, shape index 9, and compactness. Lung reconstruction was better for density mean, whereas standard reconstruction was better for density SD. CONCLUSIONS: CT slice thickness and reconstruction algorithm can significantly affect the quantification of image features. Thinner (1.25 and 2.5 mm) and thicker (5 mm) slice images should not be used interchangeably. Sharper and smoother reconstructions significantly affect the density-based features.
PMCID: PMC4000020  PMID: 24772211
19.  HIV-1 Genetic Characteristics and Transmitted Drug Resistance among Men Who Have Sex with Men in Kunming, China 
PLoS ONE  2014;9(1):e87033.
Background
Yunnan has been severely affected by HIV/AIDS in China. Recently, the reported prevalence of HIV-1 among men who have sex with men (MSM) in Yunnan was high in China. To monitor dynamic HIV-1 epidemic among Yunnan MSM, HIV-1 genetic characteristics and transmitted drug resistance (TDR) were investigated.
Methods
Blood samples from 131 newly HIV-1 diagnosed MSM were continuously collected at fixed sites from January 2010 to December 2012 in Kunming City, Yunnan Province. Partial gag, pol and env genes were sequenced. Phylogenetic, evolutionary and genotypic drug resistance analyses were performed.
Results
Multiple genotypes were identified among MSM in Kunming, including CRF01_AE (64.9%), CRF07_BC (25.2%), unique recombinant forms (URFs, 5.3%), subtype B (3.1%) and CRF08_BC (1.5%). CRF01_AE and CRF07_BC were the predominant strains. The mean of genetic distance within CRF01_AE were larger than that within CRF07_BC. The estimated introducing time of CRF01_AE in Yunnan MSM (1996.9) is earlier than that of CRF07_BC (2002.8). In this study, subtype B was first identified in Yunnan MSM. CRF08_BC seems to be the distinctive strain in Yunnan MSM, which was seldom found among MSM outside Yunnan. The proportion of URFs increased, which further contributed to genetic diversity among MSM. Strikingly, genetic relatedness was found among these strains with MSM isolates from multiple provinces, which suggested that a nationwide transmission network may exist. TDR-associated mutations were identified in 4.6% individuals. The multivariate analysis revealed that non-native MSM and divorced/widowed MSM were independently associated with a higher TDR rate.
Conclusion
This work revealed diverse HIV-1 genetics, national transmission networks and a baseline level of TDR in MSM. These findings enhance our understanding of the distribution and evolution of HIV-1 in MSM, and are valuable for developing HIV prevention strategies for MSM.
doi:10.1371/journal.pone.0087033
PMCID: PMC3906090  PMID: 24489829
20.  Diabetes and Risk of Parkinson's Disease: An Updated Meta-Analysis of Case-Control Studies 
PLoS ONE  2014;9(1):e85781.
Background
Whether diabetes increases the risk of Parkinson's disease (PD) is still inconclusive. The objective of this updated meta-analysis is to synthesize evidence from case-control studies that evaluated the association between diabetes and the risk of PD.
Methods
Seven databases were searched to identify case-control studies that evaluated the association between diabetes and PD. The methodological quality of included studies was assessed using Newcastle-Ottawa scale. All data were analyzed using Review Manager 5.1 software. Subgroup analyses were also adopted, according to stratification on gender, geographic location, source of the control group, smoking, anti-diabetes drug prescription and duration of DM.
Results
Fourteen studies fulfilled inclusion criteria for meta-analysis, yielding a total of 21395 PD patients and 84579 control subjects. Individuals with diabetes were found to have a negative association with future PD (OR 0.75; 95% CI 0.58–0.98) in spite of significant heterogeneity. In subgroup analyses, the negative correlation was still found in studies from North America, non-PD control groups from general population, never smoking individuals, and DM ascertainment based on questionnaire or self-report. Stratification of gender and DM duration showed no significant association. No association was also found in European and Asian individuals, hospital-based controls, ever smoking subjects, DM assessment by medical record or physician diagnosis, and insulin prescription for DM.
Conclusion
Evidence from case-control studies suggested that diabetic individuals may have a decreased incidence of PD despite significant heterogeneity. More researches are warranted to clarify an understanding of the association between diabetes and risk of PD.
doi:10.1371/journal.pone.0085781
PMCID: PMC3897520  PMID: 24465703
21.  Generation of a Novel Dendritic-cell Vaccine Using Melanoma and Squamous Cancer Stem Cells 
We identified cancer stem cell (CSC)-enriched populations from murine melanoma D5 syngeneic to C57BL/6 mice and the squamous cancer SCC7 syngeneic to C3H mice using ALDEFLUOR/ALDH as a marker, and tested their immunogenicity using the cell lysate as a source of antigens to pulse dendritic cells (DCs). DCs pulsed with ALDHhigh CSC lysates induced significantly higher protective antitumor immunity than DCs pulsed with the lysates of unsorted whole tumor cell lysates in both models and in a lung metastasis setting and a s.c. tumor growth setting, respectively. This phenomenon was due to CSC vaccine-induced humoral as well as cellular anti-CSC responses. In particular, splenocytes isolated from the host subjected to CSC-DC vaccine produced significantly higher amount of IFNγ and GM-CSF than splenocytes isolated from the host subjected to unsorted tumor cell lysate pulsed-DC vaccine. These results support the efforts to develop an autologous CSC-based therapeutic vaccine for clinical use in an adjuvant setting.
doi:10.3791/50561
PMCID: PMC4063547  PMID: 24430104
Cancer Biology; Issue 83; Cancer stem cell (CSC); Dendritic cells (DC); Vaccine; Cancer immunotherapy; antitumor immunity; aldehyde dehydrogenase
22.  Correction: Model-Based Assessment of Estuary Ecosystem Health Using the Latent Health Factor Index, with Application to the Richibucto Estuary 
PLoS ONE  2014;9(1):10.1371/annotation/e5fb3d6a-143d-42a9-ad2e-ebfabd496dbd.
doi:10.1371/annotation/e5fb3d6a-143d-42a9-ad2e-ebfabd496dbd
PMCID: PMC3880366
23.  Rare ADH Variant Constellations are Specific for Alcohol Dependence 
Aims: Some of the well-known functional alcohol dehydrogenase (ADH) gene variants (e.g. ADH1B*2, ADH1B*3 and ADH1C*2) that significantly affect the risk of alcohol dependence are rare variants in most populations. In the present study, we comprehensively examined the associations between rare ADH variants [minor allele frequency (MAF) <0.05] and alcohol dependence, with several other neuropsychiatric and neurological disorders as reference. Methods: A total of 49,358 subjects in 22 independent cohorts with 11 different neuropsychiatric and neurological disorders were analyzed, including 3 cohorts with alcohol dependence. The entire ADH gene cluster (ADH7–ADH1C–ADH1B–ADH1A–ADH6–ADH4–ADH5 at Chr4) was imputed in all samples using the same reference panels that included whole-genome sequencing data. We stringently cleaned the phenotype and genotype data to obtain a total of 870 single nucleotide polymorphisms with 0< MAF <0.05 for association analysis. Results: We found that a rare variant constellation across the entire ADH gene cluster was significantly associated with alcohol dependence in European-Americans (Fp1: simulated global P = 0.045), European-Australians (Fp5: global P = 0.027; collapsing: P = 0.038) and African-Americans (Fp5: global P = 0.050; collapsing: P = 0.038), but not with any other neuropsychiatric disease. Association signals in this region came principally from ADH6, ADH7, ADH1B and ADH1C. In particular, a rare ADH6 variant constellation showed a replicable association with alcohol dependence across these three independent cohorts. No individual rare variants were statistically significantly associated with any disease examined after group- and region-wide correction for multiple comparisons. Conclusion: We conclude that rare ADH variants are specific for alcohol dependence. The ADH gene cluster may harbor a causal variant(s) for alcohol dependence.
doi:10.1093/alcalc/ags104
PMCID: PMC3523382  PMID: 23019235
24.  Characterization of a Novel Transgenic Mouse Tumor Model for Targeting HER2+ Cancer Stem Cells 
HER2 is an oncogenic tumor-associated antigen overexpressed in 20-25% of breast cancers, which is associated with increased invasion, metastasis of the disease and resistance to therapy. Recent studies have further shown that HER2 can increase the population of breast cancer stem cells (BCSCs). However, there is currently no in vivo model for the study of HER2+ BCSCs. In this study, we characterized a mouse breast cancer model for HER2+ BCSCs. This was accomplished by inoculating mouse mammary tumor EO771 cells engineered with human wild-type HER2 (EO771E2) into C57BL/6 HER2 transgenic mice to test and confirm the stable human HER2 expression in the model. More importantly, we detected a subpopulation of EO771E2 cells with a high activity of aldehyde dehydrogenases (ALDHhigh). We demonstrated that the isolated ALDHhigh EO771E2 cells possessed key properties of BCSCs including enhanced tumorigenicity, generation of heterogeneous tumors and the capacity to self-renewal in vitro. In conclusion, the tumors formed in C57BL/6 HER2 transgenic mice with EO771E2 cell injection revealed stable and functional human HER2 expression. These tumors contain a subset of ALDHhigh cells which are small in number, but are enriched in cancer stem cells. This model is deemed to be useful for experiments aimed to develop novel treatments to target HER2+ BCSCs.
doi:10.7150/ijbs.6309
PMCID: PMC3879588  PMID: 24391448
HER2; breast cancer; cancer stem cells; mouse model; antitumor immunity.
25.  Regulation of the DNA damage response on male meiotic sex chromosomes 
Nature communications  2013;4:2105.
During meiotic prophase in males, the sex chromosomes partially synapse to form the XY body. This is a unique structure that recruits proteins involved in the DNA damage response, which is believed to be important for silencing of the sex chromosomes. It remains elusive how the DNA damage response in the XY body is regulated. H2AX-MDC1-RNF8 signaling, which is well characterized in somatic cells, is dispensable for the recruitment of proteins to the unsynapsed axes in the XY body. However, the DNA damage response that spreads over the sex chromosomes is largely similar to that in somatic cells. Here we show that accumulation of some components of the DNA damage response pathway on the XY body occurs upstream of H2AX-MDC1-RNF8 signalling, and downstream from this cascade of events for others. This analysis shows that there are important differences between the regulation of the DNA damage response at the XY body and at DNA damage sites in somatic cells.
doi:10.1038/ncomms3105
PMCID: PMC3759350  PMID: 23812044

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