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1.  Conotruncal Heart Defects and Common Variants in Maternal and Fetal Genes in Folate, Homocysteine and Transsulfuration Pathways 
We investigated the association between conotruncal heart defects (CTDs) and maternal and fetal single nucleotide polymorphisms (SNPs) in 60 genes in the folate, homocysteine and pathways. We also investigated whether periconceptional maternal folic acid supplementation modified associations between CTDs and SNPs.
Participants were enrolled in the National Birth Defects Prevention Study between 1997 and 2007. DNA samples from 616 case-parental triads affected by CTDs and 1,645 control-parental triads were genotyped using an Illumina® Golden Gate custom SNP panel. A hybrid design analysis, optimizing data from case and control trios, was used to identify maternal and fetal SNPs associated with CTDs.
Among 921 SNPs, 17 maternal and 17 fetal SNPs had a Bayesian false-discovery probability (BFDP) of <0.8. Ten of the 17 maternal SNPs and 2 of the 17 fetal SNPs were found within the glutamate-cysteine ligase, catalytic subunit (GCLC) gene. Fetal SNPs with the lowest BFDP (rs2612101, rs2847607, rs2847326, rs2847324) were found within the thymidylate synthetase (TYMS) gene. Additional analyses indicated that the risk of CTDs associated with candidate SNPs was modified by periconceptional folic acid supplementation. Nineteen maternal and 9 fetal SNPs had BFDP <0.8 for gene-by-environment (GxE) interactions with maternal folic acid supplementation.
These results support previous studies suggesting that maternal and fetal SNPs within folate, homocysteine and transsulfuration pathways are associated with CTD risk. Maternal use of supplements containing folic acid may modify the impact of SNPs on the developing heart.
PMCID: PMC4118819  PMID: 24535845
conotruncal heart defects; single nucleotide polymorphisms; oxidative stress; genetics; folic acid; gene X environment interaction
2.  Tumor regression grades: Potential outcome predictor of locally advanced rectal adenocarcinoma after preoperative radiotherapy 
AIM: To analyze tumor regression grade (TRG) for prognosis of locally advanced rectal adenocarcinoma (LARA) treated with preoperative radiotherapy.
METHODS: One hundred and ninety patients with clinical stage II/III LARA were studied. All patients underwent radical surgery (between 2004 and 2010) after 30-Gy/10-fraction preoperative radiotherapy (pre-RT). All 190 patients received a short course of pre-RT and were reassessed for disease recurrence and survival; the slides of surgical specimens were reviewed and classified according to Mandard TRG. We compared patients with good response (Mandard TRG1 or TRG2) vs patients with bad/poor response (Mandard TRG3-5). Outcomes evaluated were 5-year overall survival (OS), 5-year disease-free survival (DFS), and local, distant and mixed recurrence. Fisher’s exact test or χ2 test, log-rank test and proportional hazards regression analysis were used to calculate the probability that Mandard TRG was associated with patient outcomes.
RESULTS: One hundred and sixty-six of 190 patients (87.4%) were identified as Mandard bad responders (TRG3-5). High Mandard grade was correlated with tumor height (41.7% < 6 cm vs 58.3% ≥ 6 cm, P = 0.050), ypT stage (75% ypT0-2 vs 25% ypT3-4, P = 0.000), and ypN stage (75% ypN0 vs 25% ypN1, P = 0.031). In univariate survival analysis, Mandard grade bad responders had significantly worse OS and DFS than good responders (TRG1/2) (OS, 83.1% vs 96.4%, P = 0.000; DFS, 72.3% vs 92.0%, P = 0.002). In multivariate survival analysis, Mandard bad responders had significantly worse DFS than Mandard good responders (DFS 3.8 years (95%CI: 1.2-12.2 years, P = 0.026).
CONCLUSION: Mandard grade good responders had a favorable prognosis. TRG may be a potential predictor for DFS in LARA after pre-RT.
PMCID: PMC4323462
Tumor regression grade; Preoperative radiotherapy; Rectal adenocarcinoma; Disease-free survival
3.  Multimodal Physical Activity Recognition by Fusing Temporal and Cepstral Information 
A physical activity (PA) recognition algorithm for a wearable wireless sensor network using both ambulatory electrocardiogram (ECG) and accelerometer signals is proposed. First, in the time domain, the cardiac activity mean and the motion artifact noise of the ECG signal are modeled by a Hermite polynomial expansion and principal component analysis, respectively. A set of time domain accelerometer features is also extracted. A support vector machine (SVM) is employed for supervised classification using these time domain features. Second, motivated by their potential for handling convolutional noise, cepstral features extracted from ECG and accelerometer signals based on a frame level analysis are modeled using Gaussian mixture models (GMMs). Third, to reduce the dimension of the tri-axial accelerometer cepstral features which are concatenated and fused at the feature level, heteroscedastic linear discriminant analysis is performed. Finally, to improve the overall recognition performance, fusion of the multi-modal (ECG and accelerometer) and multidomain (time domain SVM and cepstral domain GMM) subsystems at the score level is performed. The classification accuracy ranges from 79.3% to 97.3% for various testing scenarios and outperforms the state-of-the-art single accelerometer based PA recognition system by over 24% relative error reduction on our nine-category PA database.
PMCID: PMC4326092  PMID: 20699202
Accelerometer; cepstrum; electrocardiogram; multimodal signal processing; physical activity recognition
4.  Community structure of gut fungi during different developmental stages of the Chinese white pine beetle (Dendroctonus armandi) 
Scientific Reports  2015;5:8411.
The Chinese white pine beetle is arguably the most destructive forest insect in the Qinling Mountains in Northern China. Little is known about the structure of the fungal communities associated with Dendroctonus armandi, even though this wood-boring insect plays important roles in ecosystem and biological invasion processes that result in huge economic losses in pine forests. The aim of this study was to investigate the fungal community structure present in the galleries and guts of D. armandi at different developmental stages using PCR-denaturing gradient gel electrophoresis (DGGE). Analysis of PCR-amplified 18S rRNA gene fragments of fungi from the guts of D. armandi revealed fungal communities of low complexity that differed according to the developmental stage. Yeast of the genus Candida and the filamentous fungi Ophiostoma predominated in D. armandi and its galleries. In particular, Candida accounted for 56% of the fungal community in the pupal stage. Characterizing the evolution and content of the intestinal microbial community structure in D. armandi may facilitate the development of new pest control strategies.
PMCID: PMC4325321  PMID: 25672215
5.  Influences of Stigma and HIV Transmission Knowledge on Member Support for Faith-Placed HIV Initiatives in Chinese Immigrant Buddhist and Protestant Religious Institutions in New York City 
Ethnic religious institutions in the US are uniquely positioned to influence HIV programming within Asian immigrant communities at-large. This paper examined how knowledge of HIV transmission and stigma potentially influenced attendees’ support for their institutions’ involvement in HIV programs. Quantitative questionnaires were individually administered to 400 Chinese attendees of Protestant churches, and 402 attendees of Buddhist temples in New York City. Mediational analyses indicated that HIV-stigma significantly mediated the direct effects of HIV transmission knowledge on attendees’ support of their institution’s involvement in HIV education (bias corrected and accelerated [BCa] 95% confidence interval [CI], 0.004 to 0.051), HIV care (BCa 95% CI, 0.019 to 0.078), and stigma reduction initiatives (BCa 95% CI, 0.013 to 0.070), while controlling for religious affiliation, age, gender, and education. To mobilize Chinese churches and temples to engage in HIV programming, it remains important to support educational programs on HIV transmission that specifically helps to mitigate stigma towards persons living with HIV.
PMCID: PMC4319707  PMID: 24059881
HIV; Stigma; Immigrants; Asian; Christian; Buddhist
6.  Deferoxamine attenuates lipopolysaccharide-induced neuroinflammation and memory impairment in mice 
Neuroinflammation often results in enduring cognitive impairment and is a risk factor for postoperative cognitive dysfunction. There are currently no effective treatments for infection-induced cognitive impairment. Previous studies have shown that the iron chelator deferoxamine (DFO) can increase the resistance of neurons to injury and disease by stimulating adaptive cellular stress responses. However, the impact of DFO on the cognitive sequelae of neuroinflammation is unknown.
A mouse model of lipopolysaccharide (LPS)-induced cognitive impairment was established to evaluate the neuroprotective effects of DFO against LPS-induced memory deficits and neuroinflammation. Adult C57BL/6 mice were treated with 0.5 μg of DFO 3 days prior to intracerebroventricular microinjection of 2 μg of LPS. Cognitive function was assessed using a Morris water maze from post-injection days 1 to 3. Animal behavioral tests, as well as pathological and biochemical assays were performed to evaluate the LPS-induced hippocampal damage and the neuroprotective effect of DFO.
Treatment of mice with LPS resulted in deficits in cognitive performance in the Morris water maze without changing locomotor activity, which were ameliorated by pretreatment with DFO. DFO prevented LPS-induced microglial activation and elevations of IL-1β and TNF-α levels in the hippocampus. Moreover, DFO attenuated elevated expression of caspase-3, modulated GSK3β activity, and prevented LPS-induced increases of MDA and SOD levels in the hippocampus. DFO also significantly blocked LPS-induced iron accumulation and altered expression of proteins related to iron metabolism in the hippocampus.
Our results suggest that DFO may possess a neuroprotective effect against LPS-induced neuroinflammation and cognitive deficits via mechanisms involving maintenance of less brain iron, prevention of neuroinflammation, and alleviation of oxidative stress and apoptosis.
PMCID: PMC4323121  PMID: 25644393
Deferoxamine; Neuroinflammation; Iron; Memory impairment; Oxidative stress; Apoptosis
7.  The Endoparasitoid, Cotesia vestalis, Regulates Host Physiology by Reprogramming the Neuropeptide Transcriptional Network 
Scientific Reports  2015;5:8173.
Endoparasitoids develop inside another insect by regulating host immunity and development via maternal factors injected into hosts during oviposition. Prior results have provided insights into parasitism-induced immunosuppression, including the neuropeptide accumulation in parasitized insects. Nonetheless, our understanding of neuropeptide influence on host development and behavior is not yet complete. We posed the hypothesis that parasitization alters expression of genes encoding pro-neuropeptides and used larvae of Plutella xylostella and its endoparasitoid, Cotesia vestalis to test our hypothesis. We prepared transcriptomes from the larval P. xylostella brain-CC-CA complex and identified transcripts encoding 19 neuropeptides. All corresponding cDNAs were confirmed by RACE. Our results demonstrate that parasitism significantly down-regulated, or delayed, expression of genes encoding pro-neuropeptides within 48 h post-parasitization. Changing expression of these genes may account for the previously reported decreased feeding behavior, reduced growth rates and aborted development in the host larvae. In effect, parasitization may operate at the molecular level within the CNS to create global changes in larval host biology. The significance of our finding is that, in addition to the known effects on immunity, parasitoids influence host pro-neuropeptide gene transcription. This finding reveals a new mechanism operating in host-parasitoid relationships to the advantage of the parasitoid.
PMCID: PMC4313088  PMID: 25640113
8.  Investigations of motility and fertilization potential in thawed cryopreserved mouse sperm from cold-stored epididymides 
Cryobiology  2013;68(1):12-17.
Cold transport of epididymides from genetically modified mice is an efficient alternative to the shipment of live animals between research facilities. Mouse sperm from epididymides cold-stored for short periods can maintain viability. We previously reported that cold storage of mouse epididymides in Lifor® perfusion medium prolonged sperm motility and fertilization potential and that the sperm efficiently fertilized oocytes when reduced glutathione was added to the fertilization medium. Cryopreservation usually results in decreased sperm viability; an optimized protocol for cold storage of epididymides plus sperm cryopreservation has yet to be established. Here, we examined the motility and fertilization potential of cryopreserved, thawed (frozen-thawed) sperm from previously cold-stored mouse epididymides. We also examined the protective effect of sphingosine-1-phosphate (S1P) on sperm viability when S1P was added to the preservation medium during cold storage. We assessed viability of frozen-thawed sperm from mouse epididymides that had been cold-transported domestically or internationally and investigated whether embryos fertilized in vitro with these sperm developed normally when implanted in pseudo-pregnant mice. Our results indicate that frozen-thawed sperm from epididymides cold-stored for up to 48 hours maintained high fertilization potential. Fertilization potential was reduced after cold storage for 72 hours, but not if S1P was included in the cold storage medium. Live pups were born normally to recipients after in vitro fertilization using frozen-thawed sperm from cold-transported epididymides. In summary, we demonstrate an improved protocol for cold-storage of epididymides that can facilitate transport of genetically engineered-mice and preserve sperm viability after cryopreservation.
PMCID: PMC4140441  PMID: 24201107
in vitro fertilization; cold storage; cold transport; sperm; epididymides; motility; sphingosine-1-phosphate
9.  Human Endogenous Retrovirus Type K Antibodies and mRNA as Serum Biomarkers of Early-Stage Breast Cancer 
A simple and accurate test to detect early-stage breast cancer has not been developed. Previous studies indicate that the level of human endogenous retrovirus type K (group HERV-K(HML-2)) transcription may be increased in human breast tumors. We hypothesized that HERV-K(HML-2) reactivation can serve as a biomarker for early detection of breast cancer. Serum samples were collected from women without cancer (controls) and patients with ductal carcinoma in situ (DCIS) and invasive breast cancer. ELISA assays were employed to detect serum anti-HERV-K(HML-2) antibody titers. RNA was extracted from sera and analyzed by real-time RT-PCR to quantitate the level of HERV-K(HML-2) mRNA. We measured significantly higher serum mRNA and serum antibody titers against HERV-K(HML-2) proteins in women with DCIS and stage I disease than in women without cancer. At optimized cutoffs for the antibody titers, the assay produced an area under the ROC curve (AUC) of 0.89 (95% confidence interval 0.77 to 1.00) for DCIS and of 0.95 (95% confidence interval 0.89 to 1.00) for invasive breast cancer. These AUCs are comparable to those observed for mammograms. We also found that serum HERV-K(HML-2) mRNA tended to be higher in breast cancer patients with a primary tumor who later on developed the metastatic disease than in patients who did not develop cancer metastasis. Our results show that HERV-K(HML-2) antibodies and mRNA are already elevated in the blood at an early stage of breast cancer, and further increase in patients who are at risk of developing a metastatic disease.
PMCID: PMC4191919  PMID: 23873154
HERV-K; endogenous retroviruses; early detection; biomarkers; breast cancer; metastasis
10.  Identification of constituent herbs in ginseng decoctions by DNA markers 
Chinese Medicine  2015;10(1):1.
DNA in herbal decoctions is usually fragmented by extensive boiling and is usually regarded as unsuitable for molecular authentication. This study aims to evaluate the feasibility for molecular authentication methods by multiplex polymerase chain reaction (PCR) and DNA sequencing for decoctions.
The DNA extraction procedure, sample pulverization and boiling time were examined in (1) single herb decoction with Panax ginseng (“ginseng”) or P. quinquefolius (“American ginseng”), (2) decoctions of two classical ginseng prescriptions of five herbal materials (Aconitum carmichaeli, Atractylodes macrocephala, P. ginseng, Glycyrrhiza uralensis and Zingiber officinale) and (3) a commercial ready-to-serve ginseng soup. Primers were designed from 26S-18S, ITS2 and trnH-psbA region, with DNA sequences obtained from GenBank. Multiplex PCR was also employed in ginseng or American ginseng decoctions to differentiate between these two herbs.
All six herbal species tested in this study could be identified in decoctions. We had four main observations: (1) sample pulverization before boiling improved PCR detection; (2) prolonged boiling increased the DNA concentration but decreased the intactness of DNA fragments; (3) ginseng could be differentiated from American ginseng by multiplex PCR; (4) identification of individual herbs in multi-herb decoctions with prolonged boiling time of 180 min could be achieved.
DNA could be amplified from extensively boiled ginseng decoctions, multi-herb decoctions and commercial soup although DNA degradation was critical to successful PCR.
Electronic supplementary material
The online version of this article (doi:10.1186/s13020-015-0029-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4318153  PMID: 25657815
Ginseng; Decoction; Molecular authentication; DNA marker; Multiplex PCR; DNA sequencing
11.  Nanocomplexation of thrombin with cationic amylose derivative for improved stability and hemostatic efficacy 
As a topical hemostatic agent, thrombin has wide application for many surgical treatments. However, native thrombin always suffers from its physical and chemical instabilities. In this work, a nanocomplexation strategy was developed for modifying the stability and hemostatic efficacy of thrombin, in which a water-soluble cationic amylose derivative containing poly(l-lysine) dendrons was prepared by a click reaction and then used to complex thrombin in an aqueous system. For resultant thrombin nanocomplexes, their morphology and particle size distribution were investigated. Their stabilities were studied in terms of activity retention percentages under different storage time, pH values, and illumination time. In addition, their ability to achieve in vitro fibrinogen and blood coagulation were evaluated. Via a rat hepatic hemorrhage model and a rat iliac artery hemorrhage model, these thrombin nanocomplexes were confirmed to have good tissue biocompatibility and in vivo hemostatic effectiveness.
PMCID: PMC4321601
thrombin; nanoparticles; amylose derivative; complexation; stability; hemostatic activity
12.  Improvement of the Survival of Human Autologous Fat Transplantation by Adipose-Derived Stem-Cells-Assisted Lipotransfer Combined with bFGF 
The Scientific World Journal  2015;2015:968057.
Adipose-derived stem cells (ASCs) transplanted along with autologous adipose tissue may improve fat graft survival; however, the efficacy of ASCs has been diluted by low vascularization. This study was designed to test the hypothesis that basic fibroblast growth factor (bFGF) may improve the effects of ASCs because it owns the property to boost angiogenesis. In the present study, human fat tissues were mixed with ASCs, ASCs plus 100 U bFGF, or medium as the control and then injected subcutaneously into immunologically compromised nude mice for 12 weeks. Our findings demonstrated that mixture with the ASCs significantly increased the weight and volume of the fat grafts compared to control grafts, and histological analysis revealed that both ASCs and ASCs plus bFGF grafts consisted predominantly of adipose tissue and had significantly less fibrosis but greater microvascular density compared with control and also grafts mixed with ASCs had a high expression of angiogenic factors. More importantly, the bFGF treated fat grafts shown elevate in survival, vascularization, and angiogenic factors expression when compared with the grafts that received ASCs alone. These results indicated that bFGF together with ASCs can enhance the efficacy of autologous fat transplantation and increase blood vessel generation involved in the benefits from bFGF.
PMCID: PMC4324956
14.  Lifestyle factors associated with childhood obesity: a cross-sectional study in Shanghai, China 
BMC Research Notes  2015;8:6.
Limited research has been conducted to investigate factors associated with overweight and obesity of children in China, where obesity has been increasing. This study investigated associations of lifestyle factors with overweight or obesity among Chinese primary school-aged children.
A cross-sectional survey was conducted with 2400 children aged 6–12 from 11 primary schools. Children completed a self-administered questionnaire assisted by their parents at home. The survey included questions on self-reported height and weight, screen time, physical activity, modes of travel to/from school, and dietary habits. Multilevel models were conducted to examine factors associated with overweight or obesity.
15.6% of children were overweight and 11.2% were obese; nearly 80% of children spent ≤2 hrs./day either on physical activities or screen time. Compared with those spent >3 hrs./day on screen time, children who spent ≤2 hrs./day or between 2-3 hrs./day were significantly less likely to be obese after adjusting for other variables (AOR = 0.34, 95% CI: 0.20-0.60, P < 0.01; or AOR = 0.41, 95% CI: 0.20-0.84, P = 0.02 respectively). Children spent ≤2 hrs./day on screen time were less likely to become overweight or obesity, compared with >3 hrs./day (AOR = 0.62, 95% CI: 0.38-0.99, P < 0.05).
Screen time is independently associated with childhood obesity, and needs be focused for obesity prevention in school-aged children in China.
PMCID: PMC4305265  PMID: 25595610
Obesity; Screen time; Physical activity; Sugar-sweetened beverage
15.  Genome Sequence of a Novel Recombinant Coxsackievirus A6 Strain from Shanghai, China, 2013 
Genome Announcements  2015;3(1):e01347-14.
A novel recombinant coxsackievirus A6 (CVA6) strain was isolated during a coxsackievirus A6 outbreak in Shanghai, China, in 2013. Genomic sequence and similarity plot analysis showed that the novel CVA6 strain shared higher similarity with a recent CVA4 strain rather than the recent CVA6 strain in the 2C and 3′ untranslated regions (UTRs).
PMCID: PMC4290982  PMID: 25573929
16.  Long-term impacts of adolescent risperidone treatment on behavioral responsiveness to olanzapine and clozapine in adulthood 
This preclinical study investigated how a short-term risperidone treatment in adolescence impacts antipsychotic response to olanzapine and clozapine in adulthood. Antipsychotic effect was indexed by a drug’s suppressive effect on avoidance responding in a rat conditioned avoidance response (CAR) model. Male adolescent Sprague-Dawley rats were first treated with risperidone (1.0 mg/kg, sc) or sterile water and tested in the CAR model for 5 consecutive days from postnatal days P 40 to 44. After they became adults (~P 80–84), they were switched to olanzapine (0.5 mg/kg, sc), clozapine (5.0 mg/kg, sc) or vehicle treatment and tested for avoidance for additional 5 days. During the adolescent period, repeated risperidone treatment produced a persistent inhibition of avoidance response. Throughout the 5 days of adulthood drug testing, rats previously treated with risperidone in adolescence made significantly fewer avoidance responses than the vehicle ones when they all were switched to olanzapine, indicating a risperidone-induced enhancement of behavioral sensitivity to olanzapine. In contrast, when switched to clozapine, rats previously treated with risperidone made significantly more avoidance responses than the vehicle rats, indicating a risperidone-induced decrease of behavioral sensitivity to clozapine. Performance in the prepulse inhibition of acoustic startle response in adulthood was not altered by adolescent risperidone treatment. Collectively, adolescent risperidone exposure induced a long-term change in behavioral sensitivity to other atypical antipsychotic drugs, with the specific direction of change (i.e. increase or decrease) dependent on the drug. These long-lasting changes are likely mediated by drug-induced neuroplastic changes and may also have significant clinical implications for antipsychotic treatment of chronic patients with an early onset of psychotic symptoms.
PMCID: PMC3859461  PMID: 24140929
Risperidone; Olanzapine; Clozapine; Conditioned avoidance response; Adolescence; Sensitization
17.  Intraoperative Optical Imaging and Tissue Interrogation During Urologic Surgery 
Current opinion in urology  2014;24(1):66-74.
Purpose of review
To review optical imaging technologies in urologic surgery aimed to facilitate intraoperative imaging and tissue interrogation.
Recent findings
Emerging new optical imaging technologies can be integrated in the operating room environment during minimally invasive and open surgery. These technologies include macroscopic fluorescence imaging that provides contrast enhancement between normal and diseased tissue and microscopic imaging that provides tissue characterization.
Optical imaging technologies that have reached the clinical arena in urologic surgery are reviewed, including photodynamic diagnosis, near infrared fluorescence imaging, optical coherence tomography, and confocal laser endomicroscopy.
PMCID: PMC4057050  PMID: 24240512
image-guided surgery; optical imaging; fluorescence imaging; in vivo microscopy; minimally invasive surgery
18.  Protein-Protein Interaction and Pathway Analyses of Top Schizophrenia Genes Reveal Schizophrenia Susceptibility Genes Converge on Common Molecular Networks and Enrichment of Nucleosome (Chromatin) Assembly Genes in Schizophrenia Susceptibility Loci 
Schizophrenia Bulletin  2013;40(1):39-49.
Recent genome-wide association studies have identified many promising schizophrenia candidate genes and demonstrated that common polygenic variation contributes to schizophrenia risk. However, whether these genes represent perturbations to a common but limited set of underlying molecular processes (pathways) that modulate risk to schizophrenia remains elusive, and it is not known whether these genes converge on common biological pathways (networks) or represent different pathways. In addition, the theoretical and genetic mechanisms underlying the strong genetic heterogeneity of schizophrenia remain largely unknown. Using 4 well-defined data sets that contain top schizophrenia susceptibility genes and applying protein-protein interaction (PPI) network analysis, we investigated the interactions among proteins encoded by top schizophrenia susceptibility genes. We found proteins encoded by top schizophrenia susceptibility genes formed a highly significant interconnected network, and, compared with random networks, these PPI networks are statistically highly significant for both direct connectivity and indirect connectivity. We further validated these results using empirical functional data (transcriptome data from a clinical sample). These highly significant findings indicate that top schizophrenia susceptibility genes encode proteins that significantly directly interacted and formed a densely interconnected network, suggesting perturbations of common underlying molecular processes or pathways that modulate risk to schizophrenia. Our findings that schizophrenia susceptibility genes encode a highly interconnected protein network may also provide a novel explanation for the observed genetic heterogeneity of schizophrenia, ie, mutation in any member of this molecular network will lead to same functional consequences that eventually contribute to risk of schizophrenia.
PMCID: PMC3885298  PMID: 23671194
genome-wide association study; schizophrenia susceptibility genes; protein-protein interaction; common molecular networks; genetic heterogeneity; enrichment
19.  Proteogenomic analysis reveals unanticipated adaptations of colorectal tumor cells to deficiencies in DNA mismatch repair 
Cancer research  2013;74(1):387-397.
A growing body of genomic data on human cancers poses the critical question of how genomic variations translate to cancer phenotypes. We employed standardized shotgun proteomics and targeted protein quantitation platforms to analyze a panel of 10 colon cancer cell lines differing by mutations in DNA mismatch repair (MMR) genes. In addition, we performed transcriptome sequencing (RNA-seq) to enable detection of protein sequence variants from the proteomic data. Biological replicate cultures yielded highly consistent proteomic inventories with a cumulative total of 6,513 protein groups with a protein FDR of 3.17% across all cell lines. Networks of co-expressed proteins with differential expression based on MMR status revealed impact on protein folding, turnover and transport, on cellular metabolism and on DNA and RNA synthesis and repair. Analysis of variant amino acid sequences suggested higher stability of proteins affected by naturally occurring germline polymorphisms than of proteins affected by somatic protein sequence changes. The data provide evidence for multi-system adaptation to MMR deficiency with a stress response that targets misfolded proteins for degradation through the ubiquitin-dependent proteasome pathway. Enrichment analysis suggested epithelial-to-mesenchymal transition (EMT) in RKO cells, as evidenced by increased mobility and invasion properties compared to SW480. The observed proteomic profiles demonstrate previously unknown consequences of altered DNA repair and provide an expanded basis for mechanistic interpretation of MMR phenotypes.
PMCID: PMC3896054  PMID: 24247723
20.  Interleukin-17A promotes functional activation of systemic sclerosis patient-derived dermal vascular smooth muscle cells by extracellular-regulated protein kinases signalling pathway 
Arthritis Research & Therapy  2014;16(6):4223.
Dermal vascular smooth muscle cells (DVSMCs) are important for vascular wall fibrosis in microangiopathy of systemic sclerosis (SSc). T helper 17 cell-associated cytokines, particularly interleukin-17A (IL-17A), have been demonstrated to play a role in the pathogenesis of SSc. However, the effect of IL-17A on the DVSMCs in microangiopathy of SSc has not been established. In the present study, we investigated the effect of IL-17A on the SSc patient-derived DVSMCs.
DVSMCs from patients with SSc and healthy subjects were incubated using IL-17A or serum derived from patients with SSc. Subsequently, the proliferation, collagen synthesis and secretion, and migration of DVSMCs were analysed using a cell counting kit-8 (CCK-8), dual-luciferase reporter assay, real-time reverse transcription-polymerase chain reaction (RT-PCR), Western blot, enzyme-linked immunosorbent assay (ELISA) and transwell assay. The protein phosphorylation of signalling pathways in the process of IL-17A-mediated DVSMC activation was investigated and validated by specific signalling pathway inhibitor.
IL-17A and serum from patients with SSc could promote the proliferation, collagen synthesis and secretion, and migration of DVSMCs. IL-17A neutralising antibody could inhibit the IL-17A-induced activation of DVSMCs. Additionally, IL-17A induced the activation of extracellular-regulated protein kinases 1/2 (ERK1/2) in DVSMCs, and ERK1/2 inhibitor could block the IL-17A-elicited activation of DVSMCs.
Our results suggested that IL-17A derived from patients with SSc might induce the proliferation, collagen synthesis and secretion, and migration of DVSMCs via ERK1/2 signalling pathway, raising the likelihood that IL-17A and ERK1/2 might be promising therapeutic targets for the treatment of SSc-related vasculopathy.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-014-0512-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4316765  PMID: 25551434
21.  Large-scale genome-wide association study of Asian population reveals genetic factors in FRMD4A and other loci influencing smoking initiation and nicotine dependence 
Human genetics  2011;131(6):1009-1021.
Diseases related to smoking are the second leading cause of death in the world. Cigarette smoking is a risk factor for several diseases such as cancer and cardiovascular and respiratory disorders. Despite increasing evidence of genetic determination, the susceptibility genes and loci underlying various aspects of smoking behavior are largely unknown. Moreover, almost all reported genome-wide association studies (GWASs) have been performed on samples of European origin, limiting the applicability of the results to other ethnic populations. In this first GWAS on smoking behavior in an Asian population, after analyzing 8,842 DNA samples from the Korea Association Resource project with 352,228 single nucleotide polymorphisms (SNPs) genotyped for each sample, we identified 8 SNPs significantly associated with smoking initiation (SI) and 4 with nicotine dependence (ND). Because of the current unavailability of an independent Asian smoking sample, we replicated the discoveries in independent samples of European-American and African-American origin. Of the 12 SNPs examined in the replicated samples, we identified two SNPs, in the regulator of G-protein signaling 17 gene (rs7747583, p valuemeta = 6.40 × 10−6; rs2349433, p valuemeta = 5.57 × 10−6), associated with SI. Also, we found two SNPs significantly associated with ND; one in the FERM domain containing 4A (rs4424567, p valuemeta = 2.30 × 10−6) and the other at 7q31.1 (rs848353, p valuemeta = 9.16 × 10−8). These SNPs represent novel targets for examination of smoking behavior and warrant further investigation using independent samples.
PMCID: PMC4275569  PMID: 22006218
23.  Ideotype Population Exploration: Growth, Photosynthesis, and Yield Components at Different Planting Densities in Winter Oilseed Rape (Brassica napus L.) 
PLoS ONE  2014;9(12):e114232.
Rapeseed is one of the most important edible oil crops in the world and the seed yield has lagged behind the increasing demand driven by population growth. Winter oilseed rape (Brassica napus L.) is widely cultivated with relatively low yield in China, so it is necessary to find the strategies to improve the expression of yield potential. Planting density has great effects on seed yield of crops. Hence, field experiments were conducted in Wuhan in the Yangtze River basin with one conventional variety (Zhongshuang 11, ZS11) and one hybrid variety (Huayouza 9, HYZ9) at five planting densities (27.0×104, 37.5×104, 48.0×104, 58.5×104, 69.0×104 plants ha–1) during 2010–2012 to investigate the yield components. The physiological traits for high-yield and normal-yield populations were measured during 2011–2013. Our results indicated that planting densities of 58.5×104 plants ha–1 in ZS11 and 48.0×104 plants ha–1 in HYZ9 have significantly higher yield compared with the density of 27.0×104 plants ha–1for both varieties. The ideal silique numbers for ZS11 and HYZ9 were ∼0.9×104 (n m–2) and ∼1×104 (n m-2), respectively, and ideal primary branches for ZS11 and HYZ9 were ∼250 (n m–2) and ∼300 (n m–2), respectively. The highest leaf area index (LAI) and silique wall area index (SAI) was ∼5.0 and 7.0, respectively. Moreover, higher leaf net photosynthetic rate (Pn) and water use efficiency (WUE) were observed in the high-yield populations. A significantly higher level of silique wall photosynthesis and rapid dry matter accumulation were supposed to result in the maximum seed yield. Our results suggest that increasing the planting density within certain range is a feasible approach for higher seed yield in winter rapeseed in China.
PMCID: PMC4269386  PMID: 25517990
24.  Kimura’s disease of the lacrimal gland mimicking IgG4-related orbital disease 
BMC Ophthalmology  2014;14(1):158.
Kimura’s disease (KD) is a rare and benign chronic inflammatory soft tissue disorder of unknown origin, which predominantly inflicts young male adults in Asia. IgG4-related disease is a new disease concept, established this century and characterized by fibrosis and sclerosis of the involved organs, with infiltration of IgG4-positive plasma cells. These two kinds of diseases share similar characteristics, which may complicate their diagnosis.
Case presentation
A 47-year-old Chinese man presented to our Department of Ophthalmology with a 26-month history of painless swelling and redness left upper eyelid. Surgical excisions of the left lacrimal gland were performed. A histopathology examination showed follicular hyperplasia with reactive germinal centres and eosinophilic infiltration involving the interfollicular areas as well as proliferation of post capillary venules, all signs of Kimura disease. Immunohistochemical analysis of the cells demonstrated positive staining for CK, Vimentin, CD3, CD4, CD20, CD21, CD117, CD5, CD8, CD23, IgG and IgG4 (30 per high-power field) and negative staining for CD10 and CD34. Some ophthalmologists in our department questioned whether the histological and immunohistochemical findings were also compatible with features of IgG4-related diseases. There was no sign of recurrence during the twelve months of regular follow-up.
Kimura’s disease may present with high serum IgG4 levels, which may be an epiphenomenon related to chronic antigen exposure. As clinical doctors, especially ophthalmologists, we should recognize the possibility of the occurrence of increased serum levels of IgG4 in Kimura’s disease to ensure correct diagnosis.
PMCID: PMC4274717  PMID: 25511019
Kimura’s disease; IgG4-related disease; Lacrimal gland
25.  Intrathecal injection of fluorocitric acid inhibits the activation of glial cells causing reduced mirror pain in rats 
BMC Anesthesiology  2014;14(1):119.
Growing evidence has shown that unilateral nerve injury results in pain hypersensitivity in the ipsilateral and contralateral sides respective to the injury site. This phenomenon is known as mirror image pain (MIP). Glial cells have been indicated in the mechanism of MIP; however, it is not clear how glial cells are involved in MIP.
To observe phenomenon MIP and the following mechanism, 20 adult male Sprague–Dawley rats (weighing 180–220 g) were separated into two groups: Sham Group (n = 10) and left L5 spinal nerve ligated and sectioned (SNL) group (n = 10). Thermal hyperalgesia and mechanical hypersensitivity were measured for both groups to determine if the SNL model had Mirror image of Pain (MIP). Nav1.7 protein expression in DRG was analyzed using immunohistochemistry and western-blotting. And then to observe the effect of fluorocitrate on MIP, 15 rats were separated into three Groups: Sham Group (n = 5); SNL + FC group: intrathecal injection of Fluorocitric acid(FC) 1 nmol/10 μL (n = 5); SNL + NS group: intrathecal injection of 0.9% Normal Saline (n = 5). Behavior testing, immunocytochemistry, and western-blotting using dorsal root ganglion (DRG) from both sides were then conducted.
The results showed pain hypersensitivity in both hind-paws of the SNL animals, Mechanical tests showed the paw withdrawal threshold dropped from 13.30 ± 1.204 g to 2.57 ± 1.963 g at 14 d as will as the ipsilateral paw thermal withdrawal threshold dropped from 16.5 ± 2.236 s to 4.38 ± 2.544 s at 14d. Mechanical tests showed the contralateral paw withdrawal threshold dropped from 14.01 ± 1.412 to 4.2 ± 1.789 g at 7d will the thermal withdrawal threshold dropped from 16.8 ± 2.176 s to 7.6 ± 1.517 s at 7d. Nav1.7 expression increased and glial cells actived in bilateral side DRG after SNL compared with sham group. After intrathecal injection of fluorocitrate, the glial cell in bilatral DRG were inhibited and the pain behavior were reversed in both hindpaws too.
Fluorocitrate can inhibit the activation of glial cells in spinal cord and DRG, and reduce MIP.
PMCID: PMC4297429  PMID: 25598703
Mirror-image pain; Satellite glial cells; DL-fluorocitric acid; Nav1.7 protein

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