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author:("Wang, hailing")
1.  Lack of association between CD14-159 C/T polymorphism and acute pancreatitis: a meta-analysis 
The CD14-159 C/T polymorphism has been implicated in susceptibility to acute pancreatitis (AP), but the results were inconclusive. The present meta-analysis aimed to explore the correlation between CD14-159 C/T polymorphism and AP risk. All eligible case-control studies published up to November 10th, 2014 were identified by searching PubMed, Web of Science, CNKI, and WanFang databases. Two reviewers independently identified the literature according to inclusion and exclusion criteria. Meta-analysis was performed using RevMan 5.2 and Stata 12.0 software. A total of five studies comprising 1211 cases and 932 controls were included. Overall, no significant association between CD14-159 C/T polymorphism and AP risk was found under all four genetic models [CT + TT vs CC: OR = 1.09, 95% CI (0.91, 1.31); TT vs CT + CC: OR = 1.04, 95% CI (0.83, 1.29); CT vs CC: OR = 1.08, 95% CI (0.89, 1.32); TT vs CC: OR = 1.15, 95% CI (0.88, 1.49)]; In stratification analysis by disease severity, we also failed to detect any association between CD14-159C/T polymorphism and the risk of mild AP (MAP) or severe AP (SAP); In subgroup analysis by ethnicity, similar results were observed in Asian and European populations. This meta-analysis suggested that the CD14-159C/T polymorphism is not associated with the susceptibility of acute pancreatitis.
PMCID: PMC4443155  PMID: 26064321
CD14; acute pancreatitis; polymorphism; meta-analysis
2.  Endemic and Imported Measles Virus–Associated Outbreaks among Adults, Beijing, China, 2013 
Emerging Infectious Diseases  2015;21(3):477-479.
In 2013, a resurgence of measles occurred in Beijing, China. The outbreaks occurred among adults and were associated with endemic genotype H1 and imported genotype D8 viruses. Migrant workers were disproportionately represented in the outbreaks; thus, vaccinating such workers against measles may be an effective strategy toward the elimination of this disease.
PMCID: PMC4344261  PMID: 25695536
adults; measles; outbreak; genotype H1; genotype D8; Beijing; China; viruses; endemic measles; imported measles
3.  An open science resource for establishing reliability and reproducibility in functional connectomics 
Zuo, Xi-Nian | Anderson, Jeffrey S | Bellec, Pierre | Birn, Rasmus M | Biswal, Bharat B | Blautzik, Janusch | Breitner, John C.S | Buckner, Randy L | Calhoun, Vince D | Castellanos, F. Xavier | Chen, Antao | Chen, Bing | Chen, Jiangtao | Chen, Xu | Colcombe, Stanley J | Courtney, William | Craddock, R Cameron | Di Martino, Adriana | Dong, Hao-Ming | Fu, Xiaolan | Gong, Qiyong | Gorgolewski, Krzysztof J | Han, Ying | He, Ye | He, Yong | Ho, Erica | Holmes, Avram | Hou, Xiao-Hui | Huckins, Jeremy | Jiang, Tianzi | Jiang, Yi | Kelley, William | Kelly, Clare | King, Margaret | LaConte, Stephen M | Lainhart, Janet E | Lei, Xu | Li, Hui-Jie | Li, Kaiming | Li, Kuncheng | Lin, Qixiang | Liu, Dongqiang | Liu, Jia | Liu, Xun | Liu, Yijun | Lu, Guangming | Lu, Jie | Luna, Beatriz | Luo, Jing | Lurie, Daniel | Mao, Ying | Margulies, Daniel S | Mayer, Andrew R | Meindl, Thomas | Meyerand, Mary E | Nan, Weizhi | Nielsen, Jared A | O’Connor, David | Paulsen, David | Prabhakaran, Vivek | Qi, Zhigang | Qiu, Jiang | Shao, Chunhong | Shehzad, Zarrar | Tang, Weijun | Villringer, Arno | Wang, Huiling | Wang, Kai | Wei, Dongtao | Wei, Gao-Xia | Weng, Xu-Chu | Wu, Xuehai | Xu, Ting | Yang, Ning | Yang, Zhi | Zang, Yu-Feng | Zhang, Lei | Zhang, Qinglin | Zhang, Zhe | Zhang, Zhiqiang | Zhao, Ke | Zhen, Zonglei | Zhou, Yuan | Zhu, Xing-Ting | Milham, Michael P
Scientific Data  2014;1:140049.
Efforts to identify meaningful functional imaging-based biomarkers are limited by the ability to reliably characterize inter-individual differences in human brain function. Although a growing number of connectomics-based measures are reported to have moderate to high test-retest reliability, the variability in data acquisition, experimental designs, and analytic methods precludes the ability to generalize results. The Consortium for Reliability and Reproducibility (CoRR) is working to address this challenge and establish test-retest reliability as a minimum standard for methods development in functional connectomics. Specifically, CoRR has aggregated 1,629 typical individuals’ resting state fMRI (rfMRI) data (5,093 rfMRI scans) from 18 international sites, and is openly sharing them via the International Data-sharing Neuroimaging Initiative (INDI). To allow researchers to generate various estimates of reliability and reproducibility, a variety of data acquisition procedures and experimental designs are included. Similarly, to enable users to assess the impact of commonly encountered artifacts (for example, motion) on characterizations of inter-individual variation, datasets of varying quality are included.
PMCID: PMC4421932  PMID: 25977800
4.  Evolutionary genetics of genotype H1 measles viruses in China from 1993 to 2012 
The Journal of General Virology  2014;95(Pt 9):1892-1899.
Virologic surveillance is a critical component of measles management. One of the criteria for verification of elimination of endemic measles is genetic analysis of wild-type viruses to demonstrate lack of an indigenous genotype. Measles is yet to be eliminated in China, and genotype H1 has been detected continuously since virologic surveillance was initiated in 1993. Virologic surveillance has been very active in China, providing a unique opportunity to conduct a detailed study of the evolution of a single, endemic genotype over a timespan of nearly two decades. Phylogenetic analysis performed on the 450 nt coding sequence for the C-terminal 150 amino acids of the nucleoprotein (N-450), fusion (F) gene and haemagglutinin (H) gene confirmed the continued circulation of genotype H1 viruses for 19 years. No evidence of selective pressure for the H protein was found. The substitution rates ranged from 0.75×10−3 substitutions site−1 year−1 for H to 1.65×10−3 substitutions site−1 year−1 for N-450. The time of most recent common ancestor (TMRCA) for genotype H1 was estimated as approximately 1985 (95 % highest probability density, 1979–1989). Finally, the overall diversity of measles sequences from China decreased from 2005 to 2012, coincident with a substantial decrease in measles cases. The results suggest that detailed evolutionary analyses should facilitate the documentation of eventual measles elimination in China. Moreover, the molecular approaches used in this study can be applied in other countries approaching measles elimination.
PMCID: PMC4135087  PMID: 24914068
5.  Clinicopathologic characteristics and prognostic value of various histological types in advanced gastric cancer 
The prognostic value of histological types in gastric cancer is not well defined. This study aims to clarify the clinicopathologic features of various WHO histological types and their prognostic significance in advanced gastric cancer (AGC). We retrospectively reviewed 741 patients with gastric cancer in our hospital from 1997 to 2007. The AGC (741 cases) were divided into five histological types: well-differentiated carcinoma (WD), moderately differentiated carcinoma (MD), poorly differentiated carcinoma (PD), mucinous carcinoma (MC), and signet ring cell carcinoma (SRC). The various AGC histological types presented significant differences in their clinical and tumor features. The five-year survival rates of patients with WD, MD, PD, MC, and SRC were 87.1%, 57.1%, 50.6%, 62.7%, and 43.4%, respectively (P=0.012). Multivariate analysis showed that cell differentiation, age, depth of invasion, and lymph node metastasis were independent prognostic factors in AGC, whereas MC and SRC were not. Cell differentiation is related to tumor aggression or patient stage. Advanced stage SRC carcinoma had more aggressive features and worse prognosis than the other types. MC carcinoma survival is correlated with the stage at diagnosis. The degree of cell differentiation is an important predictor of survival in AGC.
PMCID: PMC4203181  PMID: 25337210
Advanced gastric cancer; histologic type; prognosis; cell differentiation
6.  Vascular Endothelial Growth Factor expression in peripheral blood of patients with pregnancy induced hypertension syndrome and its clinical significance 
Objective: This study was conducted was to detect vascular endothelial growth factor (VEGF) levels in peripheral blood of patients with pregnancy-induced hypertension (PIH) syndrome and to investigate VEGF correlation with PIH occurrence.
Methods: Double-antibody enzyme-linked immunosorbent assay and fluorescent quantitative polymerase chain reaction were used to detect VEGF levels in the peripheral blood of non-pregnant women (normal group, 30 cases), normal pregnant women (pregnancy group, 30 cases) and PIH patients (PIH group, 30 cases).
Results: VEGF level in the pregnancy group was significantly higher than in the normal group, and the difference between these two groups was significant (P < 0.001). In the pregnancy group, VEGF reached the maximum level at the metaphase stage of pregnancy and started to decrease at advanced pregnancy. VEGF level in the PIH group was significantly lower than in the pregnancy group at advanced pregnancy (P < 0.01), and VEGF level significantly and gradually decreased with PIH aggravation (P < 0.05).
Conclusions: The significant decrease of VEGF level after pregnancy was possibly an important factor of PIH pathogenesis.
PMCID: PMC4048521  PMID: 24948994
Cardiovascular; Hypertension; Pregnancy complications; Vascular endothelial growth factor
7.  Pediatric Colonoscopy in South China: A 12-Year Experience in a Tertiary Center 
PLoS ONE  2014;9(4):e95933.
To investigate: 1) the demographics and clinical characteristics, 2) the findings, and 3) the safety and effectiveness in a cohort of Chinese pediatric patients undergoing colonoscopy.
The study participants were consecutive patients aged ≤14 years old that underwent their first colonoscopy in the endoscopy center at the First Affiliated Hospital, Sun Yat-sen University between Jan. 1, 2001 and Dec. 31, 2012. Demographic, clinical, endoscopic, and pathological findings were collected.
The cohort consisted of 322 patients, including 218 boys (67.7%) and 104 girls (32.3%). The median age was 8.0 years old and ranged from 9 months to 14 years old. Hematochezia (48.8%) and abdominal pain/discomfort (41.3%) were the most common presentations preceding pediatric colonoscopy. The caecal intubation success rate was 96.3%. No serious complications occurred during the procedures. A total of 227 patients (70.5%) received a positive diagnosis under endoscopy, including 138 patients with polyps and 53 patients with inflammatory bowel disease (IBD). Among the patients with polyps, 71.0% were juvenile polyps. Comparisons between years 2001–2006 and 2007–2012 showed that the IBD detection rate increased significantly (4.6% vs. 22.4%, P<0.001), while the opposite occurred for the polyp detection rate (73.1% vs. 27.6%, P<0.001).
Colonoscopy in pediatric patients is a safe and effective procedure. Polyps are the primary finding during colonoscopy. In South China there has been an increase in pediatric patients diagnosed with IBD over the past decade. However, a large epidemiological study is needed to confirm our findings.
PMCID: PMC3997494  PMID: 24759776
8.  Vitamin E Facilitates the Inactivation of the Kinase Akt by the Phosphatase PHLPP1 
Science signaling  2013;6(267):ra19.
Vitamin E is a fat-soluble vitamin that includes isomers of tocopherols and tocotrienols which are known for their antioxidant properties. Tocopherols are the predominant form encountered in the diet and through supplementation, and have garnered interest for their potential cancer therapeutic and chemopreventive effects, which include the dephosphorylation of Akt, a serine/threonine kinase that plays a pivotal role in important cellular processes, such as cell growth, survival, metabolism and motility. Full catalytic activation of Akt requires phosphorylation at both Thr308 and Ser473. Dephosphorylation of Ser473 drastically reduces Akt catalytic activity and the number of downstream substrates it can regulate. The mechanism by which α- and γ-tocopherol facilitate the selective dephosphorylation of the kinase Akt at Ser473 was investigated. We showed that this site-specific Akt dephosphorylation was mediated through the pleckstrin homology (PH) domain-dependent recruitment to the plasma membrane of Akt and PHLPP1 (PH domain leucine-rich repeat protein phosphatase, isoform 1), a phosphatase that dephosphorylates Akt at Ser473. The ability of α- and γ-tocopherol to induce PHLPP-mediated Akt inhibition established PHLPP as a “druggable” target. We structurally optimized these tocopherols to obtain derivatives with greater in vitro potency and in vivo tumor-suppressive activity in two prostate xenograft tumor models. Binding affinities for the PH domains of Akt and PHLPP1 were greater than for other PH domain-containing proteins, which may underlie the preferential membrane recruitment of these proteins. Molecular modeling revealed the structural determinants of the interaction with the PH domain of Akt that may inform strategies for continued structural optimization. These findings describe a mechanism by which tocopherols facilitate the dephosphorylation of Akt at Ser473, thereby providing insights into the mode of antitumor action of tocopherols and a rationale for the translational development of tocopherols into novel PH domain-targeted Akt inhibitors.
PMCID: PMC3910367  PMID: 23512990
9.  Lesions of Cholinergic Pedunculopontine Tegmental Nucleus Neurons Fail to Affect Cocaine or Heroin Self-Administration or Conditioned Place Preference in Rats 
PLoS ONE  2014;9(1):e84412.
Cholinergic input to the ventral tegmental area (VTA) is known to contribute to reward. Although it is known that the pedunculopontine tegmental nucleus (PPTg) provides an important source of excitatory input to the dopamine system, the specific role of PPTg cholinergic input to the VTA in cocaine reward has not been previously determined. We used a diphtheria toxin conjugated to urotensin-II (Dtx::UII), the endogenous ligand for urotensin-II receptors expressed by PPTg cholinergic but not glutamatergic or GABAergic cells, to lesion cholinergic PPTg neurons. Dtx::UII toxin infusion resulted in the loss of 95.78 (±0.65)% of PPTg cholinergic cells but did not significantly alter either cocaine or heroin self-administration or the development of cocaine or heroin conditioned place preferences. Thus, cholinergic cells originating in PPTg do not appear to be critical for the rewarding effects of cocaine or of heroin.
PMCID: PMC3897371  PMID: 24465410
10.  Genetic Characterization of the Hemagglutinin Genes of Wild-Type Measles Virus Circulating in China, 1993–2009 
PLoS ONE  2013;8(9):e73374.
China experienced several large measles outbreaks in the past two decades, and a series of enhanced control measures were implemented to achieve the goal of measles elimination. Molecular epidemiologic surveillance of wild-type measles viruses (MeV) provides valuable information about the viral transmission patterns. Since 1993, virologic surveillnace has confirmed that a single endemic genotype H1 viruses have been predominantly circulating in China. A component of molecular surveillance is to monitor the genetic characteristics of the hemagglutinin (H) gene of MeV, the major target for virus neutralizing antibodies.
Principal Findings
Analysis of the sequences of the complete H gene from 56 representative wild-type MeV strains circulating in China during 1993–2009 showed that the H gene sequences were clustered into 2 groups, cluster 1 and cluster 2. Cluster1 strains were the most frequently detected cluster and had a widespread distribution in China after 2000. The predicted amino acid sequences of the H protein were relatively conserved at most of the functionally significant amino acid positions. However, most of the genotype H1 cluster1 viruses had an amino acid substitution (Ser240Asn), which removed a predicted N-linked glycosylation site. In addition, the substitution of Pro397Leu in the hemagglutinin noose epitope (HNE) was identified in 23 of 56 strains. The evolutionary rate of the H gene of the genotype H1 viruses was estimated to be approximately 0.76×10−3 substitutions per site per year, and the ratio of dN to dS (dN/dS) was <1 indicating the absence of selective pressure.
Although H genes of the genotype H1 strains were conserved and not subjected to selective pressure, several amino acid substitutions were observed in functionally important positions. Therefore the antigenic and genetic properties of H genes of wild-type MeVs should be monitored as part of routine molecular surveillance for measles in China.
PMCID: PMC3779233  PMID: 24073194
11.  PDLIM5 gene polymorphisms and short term antidepressant response in Chinese major depressive disorders 
Several investigations have suggested that PDLIM5 plays a key role in the pathophysiology of major depressive disorder (MDD), and that PDLIM5 might be a therapeutic target for the action of antidepressant. In this study, we sought to investigate whether variations of PDLIM5 gene sequence could predict response to antidepressants in MDD patients. We selected 3 SNPs (rs10008257, rs2433320, 2452600) of PDLIM5 gene, and performed an association analysis of PDLIM5 and the efficacy of fluoxetine treatment in 185 Han Chinese MDD patients. The results show that the rs2433320 of PDLIM5 gene are associated with fluoxetine therapeutic response in MDD patients (X2 = 8.2960, df = 2, P = 0.0145) after correction with the Bonferroni multiple test, the HAMD score of the GG genotype group was significantly lower than that of the AA and AG genotype group at 1, 2, 4 and 6 weeks. The results support the idea that the PDLIM5 gene is likely to be involved in the antidepressant response in MDD.
PMCID: PMC3762623  PMID: 24040476
PDLIM5; antidepressant; pharmacogenetics; major depressive disorder
12.  Negative life events and corticotropin-releasing-hormone receptor1 gene in recurrent major depressive disorder 
Scientific Reports  2013;3:1548.
Major depressive disorder (MDD) is a long-term, recurrent condition that often takes a chronic course. It seems imperative that research should be focused on gaining a better understanding of what predicts recurrent MDD. As a major mediator of the stress response, corticotropin-releasing-hormone receptor 1 (CRHR1) has been demonstrated to be an important contributor to the pathogenesis of MDD. In this study, we show a significant increase in the G-allele (rs242939) of the CRHR1 gene in the recurrent MDD group compared with the control group, and an overrepresentation of G-G-T hyplotype of the CRHR1 gene in recurrent MDD. We also demonstrate the interaction of the CRHR1 gene and negative life events in recurrent MDD. These results suggest that the CRHR1 gene could modify the susceptibility to developing recurrent MDD following negative life events in adulthood.
PMCID: PMC3607833  PMID: 23529111
13.  Human Parainfluenza Virus-Associated Respiratory Tract Infection among Children and Genetic Analysis of HPIV-3 Strains in Beijing, China 
PLoS ONE  2012;7(8):e43893.
The relevance of human parainfluenza viruses (HPIVs) to the epidemiology of acute respiratory infections (ARI) in China is unclear. From May 2008 to September 2010, 443 nasopharyngeal aspirates (NPAs) from hospitalized pediatric patients (age from 1 to 93 months) in Beijing were collected and screened for HPIVs and other common respiratory viruses by real-time RT-PCR. Sixty-two of 443 samples were positive for HPIVs with 4 positive for HPIV-2 and 58 positive for HPIV-3, indicating that HPIV-3 was the predominant virus present during the study period. A phylogenetic tree based on all the available HN (hemagglutinin-neuraminidase) sequences of HPIV-3 indicated that three distinct clusters (A,B, and C) were circulating with some temporal and regional clustering. Cluster C was further divided into sub-clusters, C1, C2, C3 and C4. HPIV-3 from Beijing isolates belonged to sub-cluster C3, and were grouped with the isolates from two Provinces of China and the neighboring country of Japan. Genetic analysis based on entire HN gene revealed that the HPIV-3 isolates from Beijing were highly similar with 97.2%–100% identity at the nucleotide level and these could be divided into two closely related lineages, C3a and C3b. These findings suggested that there was co-circulation of multiple lineages of HPIV-3 in the Beijing region during the study period. This is the first study to describe the epidemiology and molecular characterization of HPIVs in China.
PMCID: PMC3429441  PMID: 22937119
14.  Single Endemic Genotype of Measles Virus Continuously Circulating in China for at Least 16 Years 
PLoS ONE  2012;7(4):e34401.
The incidence of measles in China from 1991 to 2008 was reviewed, and the nucleotide sequences from 1507 measles viruses (MeV) isolated during 1993 to 2008 were phylogenetically analyzed. The results showed that measles epidemics peaked approximately every 3 to 5 years with the range of measles cases detected between 56,850 and 140,048 per year. The Chinese MeV strains represented three genotypes; 1501 H1, 1 H2 and 5 A. Genotype H1 was the predominant genotype throughout China continuously circulating for at least 16 years. Genotype H1 sequences could be divided into two distinct clusters, H1a and H1b. A 4.2% average nucleotide divergence was found between the H1a and H1b clusters, and the nucleotide sequence and predicted amino acid homologies of H1a viruses were 92.3%–100% and 84.7%–100%, H1b were 97.1%–100% and 95.3%–100%, respectively. Viruses from both clusters were distributed throughout China with no apparent geographic restriction and multiple co-circulating lineages were present in many provinces. Cluster H1a and H1b viruses were co-circulating during 1993 to 2005, while no H1b viruses were detected after 2005 and the transmission of that cluster has presumably been interrupted. Analysis of the nucleotide and predicted amino acid changes in the N proteins of H1a and H1b viruses showed no evidence of selective pressure. This study investigated the genotype and cluster distribution of MeV in China over a 16-year period to establish a genetic baseline before MeV elimination in Western Pacific Region (WPR). Continuous and extensive MeV surveillance and the ability to quickly identify imported cases of measles will become more critical as measles elimination goals are achieved in China in the near future. This is the first report that a single endemic genotype of measles virus has been found to be continuously circulating in one country for at least 16 years.
PMCID: PMC3332093  PMID: 22532829
15.  High-Affinity Peptide Against MT1-MMP for In Vivo Tumor Imaging 
Membrane type-1 matrix metalloproteinase (MT1-MMP) is a key member of the matrix metalloproteinase (MMP) family. It participates in pericellular proteolysis of extracellular matrix (ECM) macromolecules and is essential for many biological and pathological processes, such as tumor development, angiogenesis and metastasis. A ligand that specifically binds to MT1-MMP may facilitate the labeling of this molecule, allow imaging at the cellular and organism levels, and provide a means for targeted drug delivery specific to MT1-MMP. A non-substrate MT1-MMP binding peptide was identified by screening a Ph. D.™ - 12 phage display peptide library and conjugated with near-infrared fluorescent (NIRF) dye Cy5.5 for tumor imaging. Peptide HWKHLHNTKTFL (denoted as MT1-AF7p) showed high MT1-MMP binding affinity. Computer modeling verified that MT1-AF7p binds to the MT-loop region of MT1-MMP and interacts with MT1-MMP through hydrogen bonding and hydrophobic interactions. MDA-MB-435 xenografts with high MT1-MMP expression had significantly higher tumor accumulation and better tumor contrast than the low MT1-MMP expressing A549 xenografts after intravenous injection of Cy5.5-MT1-AF7p. A novel non-substrate affinity peptide MT1-AF7p was found for MT1-MMP high affinity and specificity. Using NIRF imaging, we have demonstrated specific targeting of MT1-AF7p to MT1-MMP-expressing tumors. Thus, MT1-AF7p is an important tool for noninvasive monitoring of MT1-MMP expression in tumors, and it shows great potential as an imaging agent for MT1-MMP – positive tumors.
PMCID: PMC3085951  PMID: 21295090
matrix metalloproteinase; MT1-MMP (MMP-14); phage display peptide library; near-infrared fluorescence optical imaging
16.  Interaction between CRHR1 and BDNF Genes Increases the Risk of Recurrent Major Depressive Disorder in Chinese Population 
PLoS ONE  2011;6(12):e28733.
An important etiological hypothesis about depression is stress has neurotoxic effects that damage the hippocampal cells. Corticotropin-releasing hormone (CRH) regulates brain-derived neurotrophic factor (BDNF) expression through influencing cAMP and Ca2+ signaling pathways during the course. The aim of this study is to examine the single and combined effects of CRH receptor 1 (CRHR1) and BDNF genes in recurrent major depressive disorder (MDD).
Methodology/Principal Finding
The sample consists of 181 patients with recurrent MDD and 186 healthy controls. Whether genetic variations interaction between CRHR1 and BDNF genes might be associated with increased susceptibility to recurrent MDD was studied by using a gene-based association analysis of single-nucleotide polymorphisms (SNPs). CRHR1 gene (rs1876828, rs242939 and rs242941) and BDNF gene (rs6265) were identified in the samples of patients diagnosed with recurrent MDD and matched controls. Allelic association between CRHR1 rs242939 and recurrent MDD was found in our sample (allelic: p = 0.018, genotypic: p = 0.022) with an Odds Ratio 0.454 (95% CI 0.266–0.775). A global test of these four haplotypes showed a significant difference between recurrent MDD group and control group (chi-2 = 13.117, df = 3, P = 0.016. Furthermore, BDNF and CRHR1 interactions were found in the significant 2-locus, gene–gene interaction models (p = 0.05) using a generalized multifactor dimensionality reduction (GMDR) method.
Our results suggest that an interaction between CRHR1 and BDNF genes constitutes susceptibility to recurrent MDD.
PMCID: PMC3237493  PMID: 22194899
17.  Emergence and Transmission Pathways of Rapidly Evolving Evolutionary Branch C4a Strains of Human Enterovirus 71 in the Central Plain of China 
PLoS ONE  2011;6(11):e27895.
Large-scale outbreaks of hand, foot, and mouth disease (HFMD) occurred repeatedly in the Central Plain of China (Shandong, Anhui, and Henan provinces) from 2007 until now. These epidemics have increased in size and severity each year and are a major public health concern in mainland China.
Principal Findings
Phylogenetic analysis was performed and a Bayesian Markov chain Monte Carlo tree was constructed based on the complete VP1 sequences of HEV71 isolates. These analyses showed that the HFMD epidemic in the Central Plain of China was caused by at least 5 chains of HEV71 transmission and that the virus continued to circulate and evolve over the winter seasons between outbreaks. Between 1998 and 2010, there were 2 stages of HEV71 circulation in mainland China, with a shift from evolutionary branch C4b to C4a in 2003–2004. The evolution rate of C4a HEV71 was 4.99×10-3 substitutions per site per year, faster than the mean of all HEV71 genotypes. The most recent common ancestor estimates for the Chinese clusters dated to October 1994 and November 1993 for the C4a and C4b evolutionary branches, respectively. Compared with all C4a HEV71 strains, a nucleotide substitution in all C4b HEV71 genome (A to C reversion at nt2503 in the VP1 coding region, which caused amino acid substitution of VP1–10: Gln to His) had reverted.
The data suggest that C4a HEV71 strains introduced into the Central Plain of China are responsible for the recent outbreaks. The relationships among HEV71 isolates determined from the combined sequence and epidemiological data reveal the underlying seasonal dynamics of HEV71 circulation. At least 5 HEV71 lineages circulated in the Central Plain of China from 2007 to 2009, and the Shandong and Anhui lineages were found to have passed through a genetic bottleneck during the low-transmission winter season.
PMCID: PMC3220707  PMID: 22125635
18.  Atrogin-1 Affects Muscle Protein Synthesis and Degradation When Energy Metabolism Is Impaired by the Antidiabetes Drug Berberine 
Diabetes  2010;59(8):1879-1889.
Defects in insulin/IGF-1 signaling stimulate muscle protein loss by suppressing protein synthesis and increasing protein degradation. Since an herbal compound, berberine, lowers blood levels of glucose and lipids, we proposed that it would improve insulin/IGF-1 signaling, blocking muscle protein losses.
We evaluated whether berberine ameliorates muscle atrophy in db/db mice, a model of type 2 diabetes, by measuring protein synthesis and degradation in muscles of normal and db/db mice treated with or without berberine. We also examined mechanisms for berberine-induced changes in muscle protein metabolism.
Berberine administration decreased protein synthesis and increased degradation in muscles of normal and db/db mice. The protein catabolic mechanism depended on berberine-stimulated expression of the E3 ubiquitin ligase, atrogin-1. Atrogin-1 not only increased proteolysis but also reduced protein synthesis by mechanisms that were independent of decreased phosphorylation of Akt or forkhead transcription factors. Impaired protein synthesis was dependent on a reduction in eIF3-f, an essential regulator of protein synthesis. Berberine impaired energy metabolism, activating AMP-activated protein kinase and providing an alternative mechanism for the stimulation of atrogin-1 expression. When we increased mitochondrial biogenesis by expressing peroxisome proliferator–activated receptor γ coactivator-1α, berberine-induced changes in muscle protein metabolism were prevented.
Berberine impairs muscle metabolism by two novel mechanisms. It impairs mitochonidrial function stimulating the expression of atrogin-1 without affecting phosphorylation of forkhead transcription factors. The increase in atrogin-1 not only stimulated protein degradation but also suppressed protein synthesis, causing muscle atrophy.
PMCID: PMC2911075  PMID: 20522589
19.  PTEN Inhibition Improves Muscle Regeneration in Mice Fed a High-Fat Diet 
Diabetes  2010;59(6):1312-1320.
Mechanisms impairing wound healing in diabetes are poorly understood. To identify mechanisms, we induced insulin resistance by chronically feeding mice a high-fat diet (HFD). We also examined the regulation of phosphatidylinositol 3,4,5-trisphosphate (PIP3) during muscle regeneration because augmented IGF-1 signaling can improve muscle regeneration.
Muscle regeneration was induced by cardiotoxin injury, and we evaluated satellite cell activation and muscle maturation in HFD-fed mice. We also measured PIP3 and the enzymes regulating its level, IRS-1–associated phosphatidylinositol 3-kinase (PI3K) and PTEN. Using primary cultures of muscle, we examined how fatty acids affect PTEN expression and how PTEN knockout influences muscle growth. Mice with muscle-specific PTEN knockout were used to examine how the HFD changes muscle regeneration.
The HFD raised circulating fatty acids and impaired the growth of regenerating myofibers while delaying myofiber maturation and increasing collagen deposition. These changes were independent of impaired proliferation of muscle progenitor or satellite cells but were principally related to increased expression of PTEN, which reduced PIP3 in muscle. In cultured muscle cells, palmitate directly stimulated PTEN expression and reduced cell growth. Knocking out PTEN restored cell growth. In mice, muscle-specific PTEN knockout improved the defects in muscle repair induced by HFD.
Insulin resistance impairs muscle regeneration by preventing myofiber maturation. The mechanism involves fatty acid–stimulated PTEN expression, which lowers muscle PIP3. If similar pathways occur in diabetic patients, therapeutic strategies directed at improving the repair of damaged muscle could include suppression of PTEN activity.
PMCID: PMC2874691  PMID: 20200318
20.  New Measles Virus Genotype Associated with Outbreak, China 
Emerging Infectious Diseases  2010;16(6):943-947.
Better understanding of transmission patterns will enhance control and elimination programs.
To determine the origin of the virus associated with a measles outbreak in Menglian County, Yunnan Province, People’s Republic of China, in 2009, we conducted genetic analyses. Phylogenetic analyses based on nucleoprotein (N) and hemagglutinin (H) gene sequences showed that these Menglian viruses were not closely related to sequences of any World Health Organization (WHO) reference strains representing the 23 currently recognized genotypes. The minimum nucleotide divergence between the Menglian viruses and the most closely related reference strain, genotype D7, was 3.3% for the N gene and 3.0% for the H gene. A search of the databases of GenBank, WHO, and the Health Protection Agency Measles Nucleotide Surveillance showed that the Menglian viruses, together with the 2 older non-Menglian viruses, could be members of a new proposed measles genotype, d11. The new genotype designation will allow for better description of measles transmission patterns, especially in the Southeast Asian and Western Pacific regions.
PMCID: PMC3086224  PMID: 20507744
Measles virus; new genotype; phylogenetic analysis; viruses; research
21.  Chronic Mild Stress Induces Fluoxetine-Reversible Decreases in Hippocampal and Cerebrospinal Fluid Levels of the Neurotrophic Factor S100B and Its Specific Receptor 
Chronic mild stress (CMS) affects the hippocampal structure and function in the rat. S100B, a calcium-binding protein secreted by astrocytes, has been shown to be increased in serum of patients with depression and associated with good therapeutic response and clinical outcome. This work aimed to study the impact of CMS and fluoxetine on depressive-like behaviors in rats, as well as the concomitant expression of the astroglial protein S100B and of its receptor RAGE (receptor for advanced glycation end products) in the hippocampus and Cerebrospinal fluid of the same group of animals. S100B and sRAGE (circulating soluble form of RAGE) were measured in CSF by ELISA, and S100B and RAGE were measured in hippocampal slices by Western blot. Our study has demonstrated that stress and depression decrease S100B and RAGE/SRAGE expression and antidepressant treatment reverses or blocks these effects. This result suggested that S100B/RAGE interactions may be involved in the development and maintenance of depression and may play an important role in the mechanism of antidepressants’ therapeutic action.
PMCID: PMC3100818  PMID: 21614209
chronic mild stress; S100B; RAGE
22.  Endogenous glucocorticoids and impaired insulin signaling are both required to stimulate muscle wasting under pathophysiological conditions in mice 
The Journal of Clinical Investigation  2009;119(10):3059-3069.
Muscle wasting is associated with a number of pathophysiologic conditions, including metabolic acidosis, diabetes, sepsis, and high angiotensin II levels. Under these conditions, activation of muscle protein degradation requires endogenous glucocorticoids. As the mechanism(s) underlying this dependence on glucocorticoids have not been identified, we analyzed the effects of glucocorticoids on muscle wasting in a mouse model of acute diabetes. Adrenalectomized, acutely diabetic mice given a physiologic dose of glucocorticoids exhibited decreased IRS-1–associated PI3K activity in muscle and progressive muscle atrophy. These responses were related to increased association of PI3K with the glucocorticoid receptor (GR). In mice with muscle-specific GR deletion (referred to as MGRKO mice), acute diabetes minimally suppressed IRS-1–associated PI3K activity in muscle and did not cause muscle atrophy. However, when a physiologic dose of glucocorticoids was given to mice with muscle-specific IR deletion, muscle protein degradation was accelerated. Fluorescence resonance energy transfer and an in vitro competition assay revealed that activated GRs competed for PI3K, reducing its association with IRS-1. Reexpression of WT GRs or those with a mutation in the nuclear localization signal in the muscle of MGRKO mice indicated that competition for PI3K was a prominent mechanism underlying reduced IRS-1–associated PI3K activity. This nongenomic influence of the GR contributes to activation of muscle protein degradation. We therefore conclude that stimulation of muscle proteolysis requires 2 events, increased glucocorticoid levels and impaired insulin signaling.
PMCID: PMC2752071  PMID: 19759515
23.  A major single nucleotide polymorphism of the PDLIM5 gene associated with recurrent major depressive disorder 
The PDLIM5 gene is known to interact specifically with the N-type calcium channel α-1B subunit and protein kinase Cε and is critical for rapid, efficient potentiation of the calcium channel activation by protein kinase C in neurons. Increasing amounts of data suggested that PDLIM5 might be involved in the pathophysiology of major depressive disorder (MDD). The aim of this study was to examine whether genetic variations in the human PDLIM5 gene might contribute to the liability to develop MDD.
We undertook a gene-based association analysis of single nucleotide polymorphisms (SNPs). Three SNPs (rs10008257, rs2433320 and rs2452600) were identified in the PDLIM5 gene and genotyped in patients diagnosed with recurrent MDD and in matched control subjects.
We observed significant allele (p = 0.007) and genotype (p = 0.007) association with rs2433320, and the G allele of rs2433320 was significantly overrepresented in control subjects in comparison with MDD patients.
These results support the hypothesis of a protective effect for the G allele of rs2433320 in the PDLIM5 gene in recurrent MDD.
PMCID: PMC2186365  PMID: 18197271
PDLIM5; depressive disorder, major; polymorphism, single nucleotide

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