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1.  Restrictive Cardiomyopathy Caused by Troponin Mutations: Application of Disease Animal Models in Translational Studies 
Cardiac troponin I (cTnI) plays a critical role in regulation of cardiac function. Studies have shown that the deficiency of cTnI or mutations in cTnI (particularly in the C-terminus of cTnI) results in diastolic dysfunction (impaired relaxation) due to an increased myofibril sensitivity to calcium. The first clinical study revealing the association between restrictive cardiomyopathy (RCM) with cardiac troponin mutations was reported in 2003. In order to illustrate the mechanisms underlying the cTnI mutation caused cardiomyopathy, we have generated a cTnI gene knockout mouse model and transgenic mouse lines with the reported point mutations in cTnI C-terminus. In this paper, we summarize our studies using these animal models from our laboratory and the other in vitro studies using reconstituted filament and cultured cells. The potential mechanisms underlying diastolic dysfunction and heart failure caused by these cTnI C-terminal mutations are discussed as well. Furthermore, calcium desensitizing in correction of impaired relaxation in myocardial cells due to cTnI mutations is discussed. Finally, we describe a model of translational study, i.e., from bedside to bench and from bench to bedside. These studies may enrich our understanding of the mechanism underlying inherited cardiomyopathies and provide the clues to search for target-oriented medication aiming at the treatment of diastolic dysfunction and heart failure.
PMCID: PMC5165243  PMID: 28066262
myofibrils; troponin; mutation; cardiomyopathy; diastolic dysfunction; animal models
2.  Cost-effectiveness analysis of rotavirus vaccination in China: Projected possibility of scale-up from the current domestic option 
BMC Infectious Diseases  2016;16:677.
Rotavirus infection causes considerable disease burden of acute gastroenteritis (AGE) hospitalization and death among children less than 5 years in China. Although two rotavirus vaccines (Rotarix and RotaTeq) have been licensed in more than 100 countries in the world, the Lanzhou Lamb rotavirus vaccine (LLR) is the only vaccine licensed in China. This study aims to forecast the potential impacts of the two international vaccines compared to domestic LLR.
An economic evaluation was performed using a Markov simulation model. We compared costs at the societal aspect and health impacts with and without a vaccination program by LLR, Rotarix or RotaTeq. Parameters including demographic, epidemiological data, costs and efficacy of vaccines were obtained from literature review. The model incorporated the impact of vaccination on reduction of incidence of rotavirus infection and severity of AGE indicated by hospitalization, inpatient visits and deaths. Outcomes are presented in terms of quality-adjusted life years (QALYs) gained and incremental cost-effectiveness ratio (ICER) compared to status quo.
In a hypothetical cohort of 100,000 infants, the two international vaccines showed very good cost-effectiveness, with ICER of Rotateq and Rotarix shifting from LLR of $1715.11/QALY and $2105.66/QALY, respectively. Rotateq and Rotarix had significantly decreased incidence compared to LLR, particularly among infants aged 6 months to 2 years.
RotaTeq is expected to introduce in the national routine immunization program to reduce disease burden of rotavirus infection with universal coverage.
PMCID: PMC5111341  PMID: 27846803
Rotavirus; Vaccination; China; Cost-effectiveness; Routine immunization
3.  SGFSC: speeding the gene functional similarity calculation based on hash tables 
BMC Bioinformatics  2016;17:445.
In recent years, many measures of gene functional similarity have been proposed and widely used in all kinds of essential research. These methods are mainly divided into two categories: pairwise approaches and group-wise approaches. However, a common problem with these methods is their time consumption, especially when measuring the gene functional similarities of a large number of gene pairs. The problem of computational efficiency for pairwise approaches is even more prominent because they are dependent on the combination of semantic similarity. Therefore, the efficient measurement of gene functional similarity remains a challenging problem.
To speed current gene functional similarity calculation methods, a novel two-step computing strategy is proposed: (1) establish a hash table for each method to store essential information obtained from the Gene Ontology (GO) graph and (2) measure gene functional similarity based on the corresponding hash table. There is no need to traverse the GO graph repeatedly for each method with the help of the hash table. The analysis of time complexity shows that the computational efficiency of these methods is significantly improved. We also implement a novel Speeding Gene Functional Similarity Calculation tool, namely SGFSC, which is bundled with seven typical measures using our proposed strategy. Further experiments show the great advantage of SGFSC in measuring gene functional similarity on the whole genomic scale.
The proposed strategy is successful in speeding current gene functional similarity calculation methods. SGFSC is an efficient tool that is freely available at The source code of SGFSC can be downloaded from
PMCID: PMC5096311  PMID: 27814675
Gene ontology; Hash table; Gene functional similarity
4.  Clinical Adverse Effects of Endothelin Receptor Antagonists: Insights From the Meta‐Analysis of 4894 Patients From 24 Randomized Double‐Blind Placebo‐Controlled Clinical Trials 
Evidence of the clinical safety of endothelin receptor antagonists (ERAs) is limited and derived mainly from individual trials; therefore, we conducted a meta‐analysis.
Methods and Results
After systematic searches of the Medline, Embase, and Cochrane Library databases and the website, randomized controlled trials with patients receiving ERAs (bosentan, macitentan, or ambrisentan) in at least 1 treatment group were included. All reported adverse events of ERAs were evaluated. Summary relative risks and 95% CIs were calculated using random‐ or fixed‐effects models according to between‐study heterogeneity. In total, 24 randomized trials including 4894 patients met the inclusion criteria. Meta‐analysis showed that the incidence of abnormal liver function (7.91% versus 2.84%; risk ratio [RR] 2.38, 95% CI 1.36–4.18), peripheral edema (14.36% versus 9.68%; RR 1.44, 95% CI 1.20–1.74), and anemia (6.23% versus 2.44%; RR 2.69, 95% CI 1.78–4.07) was significantly higher in the ERA group compared with placebo. In comparisons of individual ERAs with placebo, bosentan (RR 3.78, 95% CI 2.42–5.91) but not macitentan (RR 1.17, 95% CI 0.42–3.31) significantly increased the risk of abnormal liver function, whereas ambrisentan (RR 0.06, 95% CI 0.01–0.45) significantly decreased that risk. Bosentan (RR 1.47, 95% CI 1.06–2.03) and ambrisentan (RR 2.02, 95% CI 1.40–2.91) but not macitentan (RR 1.08, 95% CI 0.81–1.46) significantly increased the risk of peripheral edema. Bosentan (RR 3.09, 95% CI 1.52–6.30) and macitentan (RR 2.63, 95% CI 1.54–4.47) but not ambrisentan (RR 1.30, 95% CI 0.20–8.48) significantly increased the risk of anemia. ERAs were not found to increase other reported adverse events compared with placebo.
The present meta‐analysis showed that the main adverse effects of treatment with ERAs were hepatic transaminitis (bosentan), peripheral edema (bosentan and ambrisentan), and anemia (bosentan and macitentan).
PMCID: PMC5210319  PMID: 27912207
adverse drug event; endothelin; endothelin receptor antagonists; meta‐analysis; Pulmonary Hypertension
5.  A gene-based information gain method for detecting gene–gene interactions in case–control studies 
European Journal of Human Genetics  2015;23(11):1566-1572.
Currently, most methods for detecting gene–gene interactions (GGIs) in genome-wide association studies are divided into SNP-based methods and gene-based methods. Generally, the gene-based methods can be more powerful than SNP-based methods. Some gene-based entropy methods can only capture the linear relationship between genes. We therefore proposed a nonparametric gene-based information gain method (GBIGM) that can capture both linear relationship and nonlinear correlation between genes. Through simulation with different odds ratio, sample size and prevalence rate, GBIGM was shown to be valid and more powerful than classic KCCU method and SNP-based entropy method. In the analysis of data from 17 genes on rheumatoid arthritis, GBIGM was more effective than the other two methods as it obtains fewer significant results, which was important for biological verification. Therefore, GBIGM is a suitable and powerful tool for detecting GGIs in case–control studies.
PMCID: PMC4613483  PMID: 25758991
6.  The myosin X motor is optimized for movement on actin bundles 
Nature Communications  2016;7:12456.
Myosin X has features not found in other myosins. Its structure must underlie its unique ability to generate filopodia, which are essential for neuritogenesis, wound healing, cancer metastasis and some pathogenic infections. By determining high-resolution structures of key components of this motor, and characterizing the in vitro behaviour of the native dimer, we identify the features that explain the myosin X dimer behaviour. Single-molecule studies demonstrate that a native myosin X dimer moves on actin bundles with higher velocities and takes larger steps than on single actin filaments. The largest steps on actin bundles are larger than previously reported for artificially dimerized myosin X constructs or any other myosin. Our model and kinetic data explain why these large steps and high velocities can only occur on bundled filaments. Thus, myosin X functions as an antiparallel dimer in cells with a unique geometry optimized for movement on actin bundles.
Myosin X is a molecular motor unique in its ability to generate filopodia, but the mechanism explaining this behaviour is not known. Here, through a combination of structure, single-molecule assays and modelling the authors show that myosin X is optimized for transport along actin bundles.
PMCID: PMC5025751  PMID: 27580874
7.  Changes of grey matter volume in first-episode drug-naive adult major depressive disorder patients with different age-onset 
NeuroImage : Clinical  2016;12:492-498.
Little is known about the pathological mechanism of early adult onset depression (EOD) and later adult onset depression (LOD). We seek to determine whether grey matter volume (GMV) change in EOD and LOD are different, which could also delineate EOD and LOD.
In present study, 147 first-episode, drug-naive patients with major depressive disorder (MDD), age between 18 and 45, were divided into two groups on the basis of age of MDD onset: the early adult onset group (age 18–29) and the later adult onset group (age 30–44), and a total of 130 gender-, and age-, matched healthy controls (HC) were also divided into two groups which fit for each patient group. Magnetic resonance imaging was conducted on all subjects. The voxel-based morphometry (VBM) approach was employed to analyze the images.
Widespread abnormalities of GMV throughout parietal, temporal, limbic regions, occipital cortex and cerebellum were observed in MDD patients. Compare to young HC, reduced GMV in right fusiform gyrus, right middle temporal gyrus, vermis III and increased GMV in right middle occipital gyrus were seen in the EOD group. In contrast, relative to old HC, decreased GMV in the right hippocampus and increased GMV in the left middle temporal gyrus were observed in the LOD group. Compared to the LOD group, the EOD group had smaller GMV in right posterior cingulate cortex. There was no significant correlation between GMV of the right posterior cingulate cortex and the score of the depression rating scale in patients group.
The GMV of the brain areas that were related to mood regulation was decreased in the first-episode, drug-naive adult patients with MDD. Adult patients with EOD and LOD exhibited different GMV changes relative to each age-matched comparison group, suggesting depressed adult patients with different age-onset might have different pathological mechanism.
•Grey matter volume widely decreased in the drug-naive adult patients with MDD.•Depressed patients with different age-onset have different grey matter change.•30 years old is an appropriate cutoff age for different age-onset depression.
PMCID: PMC5026687  PMID: 27668175
Major depressive disorder; Different age at onset; Magnetic resonance imaging; Grey matter volume
8.  Genome Wide Association Study Identifies L3MBTL4 as a Novel Susceptibility Gene for Hypertension 
Scientific Reports  2016;6:30811.
Hypertension is a major global health burden and a leading risk factor for cardiovascular diseases. Although its heritability has been documented previously, contributing loci identified to date account for only a small fraction of blood pressure (BP) variation, which strongly suggests the existence of undiscovered variants. To identify novel variants, we conducted a three staged genetic study in 21,990 hypertensive cases and normotensive controls. Four single nucleotide polymorphisms (SNPs) at three new genes (L3MBTL4 rs403814, Pmeta = 6.128 × 10−9; LOC729251, and TCEANC) and seven SNPs at five previously reported genes were identified as being significantly associated with hypertension. Through functional analysis, we found that L3MBTL4 is predominantly expressed in vascular smooth muscle cells and up-regulated in spontaneously hypertensive rats. Rats with ubiquitous over-expression of L3MBTL4 exhibited significantly elevated BP, increased thickness of the vascular media layer and cardiac hypertrophy. Mechanistically, L3MBTL4 over-expression could lead to down-regulation of latent transforming growth factor-β binding protein 1 (LTBP1), and phosphorylation activation of the mitogen-activated protein kinases (MAPK) signaling pathway, which is known to trigger the pathological progression of vascular remodeling and BP elevation. These findings pinpointed L3MBTL4 as a critical contributor to the development and progression of hypertension and uncovers a novel target for therapeutic intervention.
PMCID: PMC4969609  PMID: 27480026
9.  Increasing HIV Incidence among Men Who Have Sex with Men in Jiangsu Province, China: Results from Five Consecutive Surveys, 2011–2015 
Epidemics of HIV among men who have sex with men (MSM) are major public health concerns in most parts of China. This study examined the trends in HIV incidence and associated factors among MSM in Jiangsu Province. Five consecutive cross-sectional surveys were conducted among MSM from 2011 to 2015 in eight cities throughout Jiangsu Province. Participants were recruited from MSM venues or via the internet. Demographic and behavioral data were collected through HIV bio-behavioral surveys. Blood specimens were collected to test for HIV and syphilis. HIV incidence was estimated by the IgG-capture BED-EIA (BED) method and a chi-square trend test was used to compare differences over the years. Multivariate logistic regression analysis was used to identify factors associated with recent infection. A total of 2433, 2678, 2591, 2610 and 2541 participants were enrolled in 2011, 2012, 2013, 2014 and 2015, respectively. HIV incidence increased from 5.10% in 2011 to 6.62% in 2015 (p = 0.025). MSM who had an education level of junior high school or less (aOR = 1.472, p = 0.018), engaged in condomless anal sex in the past 6 months (aOR = 2.389, p < 0.001), did not have an HIV test in the past 12 months (aOR = 3.215, p < 0.001), and were currently infected with syphilis (aOR = 2.025, p = 0.001) were likely to be recently infected with HIV. HIV incidence is increasing among MSM in Jiangsu Province, China. Condom usage and HIV testing promotion should be prioritized when attempting to reduce HIV transmission among MSM in China.
PMCID: PMC4997481  PMID: 27509513
HIV incidence; IgG-capture BED-EIA; men who have sex with men; China
10.  eSNPO: An eQTL-based SNP Ontology and SNP functional enrichment analysis platform 
Scientific Reports  2016;6:30595.
Genome-wide association studies (GWASs) have mined many common genetic variants associated with human complex traits like diseases. After that, the functional annotation and enrichment analysis of significant SNPs are important tasks. Classic methods are always based on physical positions of SNPs and genes. Expression quantitative trait loci (eQTLs) are genomic loci that contribute to variation in gene expression levels and have been proven efficient to connect SNPs and genes. In this work, we integrated the eQTL data and Gene Ontology (GO), constructed associations between SNPs and GO terms, then performed functional enrichment analysis. Finally, we constructed an eQTL-based SNP Ontology and SNP functional enrichment analysis platform. Taking Parkinson Disease (PD) as an example, the proposed platform and method are efficient. We believe eSNPO will be a useful resource for SNP functional annotation and enrichment analysis after we have got significant disease related SNPs.
PMCID: PMC4965794  PMID: 27470167
11.  Engineering Factor Xa Inhibitor with Multiple Platelet-Binding Sites Facilitates its Platelet Targeting 
Scientific Reports  2016;6:29895.
Targeted delivery of antithrombotic drugs centralizes the effects in the thrombosis site and reduces the hemorrhage side effects in uninjured vessels. We have recently reported that the platelet-targeting factor Xa (FXa) inhibitors, constructed by engineering one Arg-Gly-Asp (RGD) motif into Ancylostoma caninum anticoagulant peptide 5 (AcAP5), can reduce the risk of systemic bleeding than non-targeted AcAP5 in mouse arterial injury model. Increasing the number of platelet-binding sites of FXa inhibitors may facilitate their adhesion to activated platelets, and further lower the bleeding risks. For this purpose, we introduced three RGD motifs into AcAP5 to generate a variant NR4 containing three platelet-binding sites. NR4 reserved its inherent anti-FXa activity. Protein-protein docking showed that all three RGD motifs were capable of binding to platelet receptor αIIbβ3. Molecular dynamics simulation demonstrated that NR4 has more opportunities to interact with αIIbβ3 than single-RGD-containing NR3. Flow cytometry analysis and rat arterial thrombosis model further confirmed that NR4 possesses enhanced platelet targeting activity. Moreover, NR4-treated mice showed a trend toward less tail bleeding time than NR3-treated mice in carotid artery endothelium injury model. Therefore, our data suggest that engineering multiple binding sites in one recombinant protein is a useful tool to improve its platelet-targeting efficiency.
PMCID: PMC4949463  PMID: 27432161
12.  Constructing Bi24O31Cl10/BiOCl heterojunction via a simple thermal annealing route for achieving enhanced photocatalytic activity and selectivity 
Scientific Reports  2016;6:28689.
This work reports on the construction of a Bi24O31Cl10/BiOCl heterojunction via a simple thermal annealing method. The X-ray diffraction (XRD) results indicated that the phase transformation from BiOCl to Bi24O31Cl10 could be realized during the thermal annealing process. The high-resolution transmission electron microscopy (HRTEM) images, X-ray photoelectron spectroscopy (XPS) binding energy shifts, Raman spectra and Fouier transform infrared spectroscopy (FT-IR) spectra confirmed the formation of the Bi24O31Cl10/BiOCl heterojunction. The obtained Bi24O31Cl10/BiOCl photocatalyst showed excellent conversion efficiency and selectivity toward photocatalytic conversion of benzyl alcohol to benzaldehyde under visible light irradiation. The radical scavengers and electron spin resonance (ESR) results suggested that the photogenerated holes were the dominant reactive species responsible for the photocatalytic oxidation of benzyl alcohol and superoxide radicals were not involved in the photocatalytic process. The in-situ generation of Bi24O31Cl10/BiOCl heterojunction may own superior interfacial contact than the two-step synthesized heterojunctions, which promotes the transfer of photogenerated charge carriers and is favorable for excellent photocatalytic activities.
PMCID: PMC4919631  PMID: 27340032
13.  Efficacy and safety of icotinib in patients with brain metastases from lung adenocarcinoma 
OncoTargets and therapy  2016;9:2911-2917.
The objective of this study was to evaluate the efficacy and safety of icotinib in patients with brain metastases (BMs) from lung adenocarcinoma.
Patients and methods
Clinical data of 28 cases with BMs from lung adenocarcinoma were retrospectively analyzed. All the patients took 125 mg icotinib orally three times a day. Progression of disease, intolerable adverse reactions, and number of deaths were recorded.
For all the patients, the remission rate of icotinib was 67.8% and the disease control rate was 96.4%. The median overall survival time of patients was 21.2 months, and the median progression-free survival time of patients was 10.9 months. Only mild adverse events of grade 1/2 were observed during the treatment.
Icotinib was an effective and safe strategy to treat patients with BMs from lung adenocarcinoma.
PMCID: PMC4876100  PMID: 27274284
icotinib; lung adenocarcinoma; brain metastases
14.  Differential expression profiles and pathways of genes in sugarcane leaf at elongation stage in response to drought stress 
Scientific Reports  2016;6:25698.
Water stress causes considerable yield losses in sugarcane. To investigate differentially expressed genes under water stress, a pot experiment was performed with the sugarcane variety GT21 at three water-deficit levels (mild, moderate, and severe) during the elongation stage and gene expression was analyzed using microarray technology. Physiological parameters of sugarcane showed significant alterations in response to drought stress. Based on the expression profile of 15,593 sugarcane genes, 1,501 (9.6%) genes were differentially expressed under different water-level treatments; 821 genes were upregulated and 680 genes were downregulated. A gene similarity analysis showed that approximately 62.6% of the differentially expressed genes shared homology with functional proteins. In a Gene Ontology (GO) analysis, 901 differentially expressed genes were assigned to 36 GO categories. Moreover, 325 differentially expressed genes were classified into 101 pathway categories involved in various processes, such as the biosynthesis of secondary metabolites, ribosomes, carbon metabolism, etc. In addition, some unannotated genes were detected; these may provide a basis for studies of water-deficit tolerance. The reliability of the observed expression patterns was confirmed by RT-PCR. The results of this study may help identify useful genes for improving drought tolerance in sugarcane.
PMCID: PMC4864372  PMID: 27170459
15.  The Status of the Quality Control in Acupuncture-Neuroimaging Studies 
Using neuroimaging techniques to explore the central mechanism of acupuncture gains increasing attention, but the quality control of acupuncture-neuroimaging study remains to be improved. We searched the PubMed Database during 1995 to 2014. The original English articles with neuroimaging scan performed on human beings were included. The data involved quality control including the author, sample size, characteristics of the participant, neuroimaging technology, and acupuncture intervention were extracted and analyzed. The rigorous inclusion and exclusion criteria are important guaranty for the participants' homogeneity. The standard operation process of acupuncture and the stricter requirement for acupuncturist play significant role in quality control. More attention should be paid to the quality control in future studies to improve the reproducibility and reliability of the acupuncture-neuroimaging studies.
PMCID: PMC4875991  PMID: 27242911
16.  The Effects of Bevacizumab in Augmenting Trabeculectomy for Glaucoma 
Medicine  2016;95(15):e3223.
The aim of the study was to assess the effects of bevacizumab in augmenting trabeculectomy for glaucoma.
We searched the databases of Cochrane Library, PubMed, Embase, CNKI, and VIP. All the databases were retrieved from the time databases established to September, 2015. The keywords we used were as follows: “bevacizumab,” “anti-VEGF,” “avastin,” “trabeculectomy,” “glaucoma,” and so on. We used a method of the freedom word search and the MeSH search combined, which was recommended by Cochrane Systematic Review Manual 5.1.2. Randomized controlled trails (RCTs) of frequently used bevacizumab in trabeculectomy for glaucoma were included. Study selection, data extraction, quality assessment, and data analysis were performed according to the Cochrane standards.
Eight randomized controlled trails involving 212 eyes in the experimental (bevacizumab or bevacizumab + mitomycin C) groups and 214 eyes in the control (mitomycin C or placebo) groups were selected. Compared with placebo, bevacizumab significantly increased the complete success rate [OR = 2.79, 95%CI, (1.47, 5.29), P = 0.002], what else, bevacizumab also significantly decreased the intraocular pressure (IOP) [MD = 3.07, 95% CI, (0.87, 5.27), P = 0.006] at the 6-month after trabeculectomy and the number of antiglaucoma medications [MD = 1.23, 95% CI, (0.66, 1.80), P < 0.0001]. Additionally, it also increased the risk of bleb leak [OR = 5.24, 95% CI, (1.30, 21.10), P = 0.02]. When compared with mitomycin C (MMC), bevacizumab significantly increased the rate of encysted blebs [OR = 4.62, 95% CI, (1.02, 20.91), P = 0.05]. However, there was no significantly difference between the bevacizumab + MMC groups and MMC groups whatever the items were.
Bevacizumab was an effective way in trabeculectomy concerning the complete success rate, IOP, and anti-glaucoma medications reduction when compared with placebo; however, it increased the risk of bleb leakage. And it significantly increased the rate of encysted blebs compared with MMC.
PMCID: PMC4839804  PMID: 27082560
17.  The Genome Sequence of Alcaligenes faecalis NBIB-017 Contains Genes with Potentially High Activities against Erwinia carotovora 
Genome Announcements  2016;4(2):e00222-16.
Alcaligenes faecalis NBIB-017, a Gram-negative bacterium, was isolated from soil in China. Here, we provide the complete genome sequence of this bacterium, which possesses a high number of genes encoding antibacterial factors, including proteins and small molecular peptides.
PMCID: PMC4824260  PMID: 27056227
18.  Enabling Delay of Gratification Behavior in Those Not So Predisposed: The Moderating Role of Social Support 
The presence of delay of gratification (DG) in childhood is correlated with success later in a person's life. Is there any way of helping adults with a low level of DG to obtain similar success? The present research examines how social support helps those low in DG nonetheless to act similarly to those high in DG. This research includes both correlational studies and experiments that manipulate social support as well as both field studies and a laboratory study. The results show that with high social support, employees (Study 1) and university students (Study 2) low in DG report vocational and academic DG behavioral intentions, respectively, similar to those high in DG. Study 3 found that participants low in DG who were primed with high social support expressed job-choice DG similar to those high in the DG. Study 4 controlled for mood and self-image and found that participants low in DG who were primed with high social support expressed more money-choice DG than those high in the DG. Study 5 showed that social support moderated the relationship between DG and actual DG behaviors. These findings provide evidence for a moderating role of social support in the expression of DG behavior.
PMCID: PMC4796028  PMID: 27047408
delay of gratification; social support; expression of DG Behavior; moderator
19.  Involvement of HCN Channel in Muscarinic Inhibitory Action on Tonic Firing of Dorsolateral Striatal Cholinergic Interneurons 
The striatum is the most prominent nucleus in the basal ganglia and plays an important role in motor movement regulation. The cholinergic interneurons (ChIs) in striatum are involved in the motion regulation by releasing acetylcholine (ACh) and modulating the output of striatal projection neurons. Here, we report that muscarinic ACh receptor (M receptor) agonists, ACh and Oxotremorine (OXO-M), decreased the firing frequency of ChIs by blocking the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Scopolamine (SCO), a nonselective antagonist of M receptors, abolished the inhibition. OXO-M exerted its function by activating the Gi/o cAMP signaling cascade. The single-cell reverse transcription polymerase chain reaction (scRT-PCR) revealed that all the five subtypes of M receptors and four subtypes of HCN channels were expressed on ChIs. Among them, M2 receptors and HCN2 channels were the most dominant ones and expressed in every single studied cholinergic interneuron (ChI).Our results suggest that ACh regulates not only the output of striatal projection neurons, but also the firing activity of ChIs themselves by activating presynaptic M receptors in the dorsal striatum. The activation of M2 receptors and blockage of HCN2 channels may play an important role in ACh inhibition on the excitability of ChIs. This finding adds a new G-protein coupled receptor mediated regulation on ChIs and provides a cellular mechanism for control of cholinergic activity and ACh release in the dorsal striatum.
PMCID: PMC4801847  PMID: 27047336
cholinergic interneurons; muscarinic receptor; HCN channel; scRT-PCR; muscarinic inhibitory
20.  Polygenic Analysis of Late-Onset Alzheimer’s Disease from Mainland China 
PLoS ONE  2015;10(12):e0144898.
Recently, a number of single nucleotide polymorphisms (SNPs) were identified to be associated with late-onset Alzheimer disease (LOAD) through genome-wide association study data. Identification of SNP-SNP interaction played an important role in better understanding genetic basis of LOAD. In this study, fifty-eight SNPs were screened in a cohort of 229 LOAD cases and 318 controls from mainland China, and their interaction was evaluated by a series of analysis methods. Seven risk SNPs and six protective SNPs were identified to be associated with LOAD. Risk SNPs included rs9331888 (CLU), rs6691117 (CR1), rs4938933 (MS4A), rs9349407 (CD2AP), rs1160985 (TOMM40), rs4945261 (GAB2) and rs5984894 (PCDH11X); Protective SNPs consisted of rs744373 (BIN1), rs1562990 (MS4A), rs597668 (EXOC3L2), rs9271192 (HLA-DRB5/DRB1), rs157581 and rs11556505 (TOMM40). Among positive SNPs presented above, we found the interaction between rs4938933 (risk) and rs1562990 (protective) in MS4A weakened their each effect for LOAD; for three significant SNPs in TOMM40, their cumulative interaction induced the two protective SNPs effects lost and made the risk SNP effect aggravate for LOAD. Finally, we found rs6656401-rs3865444 (CR1-CD33) pairs were significantly associated with decreasing LOAD risk, while rs28834970-rs6656401 (PTK2B-CR1), and rs28834970-rs6656401 (PTK2B-CD33) were associated with increasing LOAD risk. In a word, our study indicates that SNP-SNP interaction existed in the same gene or cross different genes, which could weaken or aggravate their initial single effects for LOAD.
PMCID: PMC4683047  PMID: 26680604
21.  Potential drawbacks in cell-assisted lipotransfer: A systematic review of existing reports (Review) 
Molecular Medicine Reports  2015;13(2):1063-1069.
Cell-assisted lipotransfer (CAL) has been widely used in various clinical applications, including breast augmentation following mammectomy, soft-tissue reconstruction and wound healing. However, the clinical application of CAL has been restricted due to the transplanted fat tissues being readily liquefied and absorbed. The present review examines 57 previously published studies involving CAL, including fat grafting or fat transfer with human adipose-stem cells in all known databases. Of these 57 articles, seven reported the clinical application of CAL. In the 57 studies, the majority of the fat tissues were obtained from the abdomen via liposuction of the seven clinical studies, four were performed in patients requiring breast augmentation, one in a patient requiring facial augmentation, one in a patient requiring soft tissue augmentation/reconstruction and one in a patient requiring fat in their upper arms. Despite the potential risks, there has been an increased demand for CAL in in cosmetic or aesthetic applications. Thus, criteria and guidelines are necessary for the clinical application of CAL technology.
PMCID: PMC4732852  PMID: 26677061
cell-assisted lipotransfer; adipose-derived stem cells; plastic surgery
22.  The challenges and promises of allogeneic mesenchymal stem cells for use as a cell-based therapy 
Mesenchymal stem cells (MSCs) are ideal for cell-based therapy in various inflammatory diseases because of their immunosuppressive and tissue repair properties. Moreover, their immunosuppressive properties and low immunogenicity contribute to a reduced or weakened immune response elicited by the implantation of allogeneic MSCs compared with other cell types. Therefore, implantation of allogeneic MSCs may be a promising cell-based therapy. In this review, we first summarize the unique advantages of allogeneic MSCs for therapeutic applications. Second, we critically analyze the factors influencing their therapeutic effects, including administration routes, detection time-points, disease models, differentiation of MSCs in vivo, and timing and dosage of MSC administration. Finally, current approaches to allogeneic MSC application are discussed. In conclusion, allogeneic MSCs are a promising option because of their low immunogenicity and immunosuppressive and tissue repair capabilities. Further investigations are needed to enhance the consistency and efficacy of MSCs when used as a cell-based therapy in inflammatory diseases as well as for tissue repair.
PMCID: PMC4665863  PMID: 26620426
23.  Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities 
PLoS ONE  2015;10(11):e0141782.
Epilepsy and intellectual/developmental disabilities (ID/DD) have a high rate of co-occurrence. Here, we investigated gene mutations in Chinese children with unexplained epilepsy and ID/DD.
We used targeted next-generation sequencing to detect mutations within 300 genes related to epilepsy and ID/DD in 253 Chinese children with unexplained epilepsy and ID/DD. A series of filtering criteria was used to find the possible pathogenic variations. Validation and parental origin analyses were performed by Sanger sequencing. We reviewed the phenotypes of patients with each mutated gene.
We identified 32 novel and 16 reported mutations within 24 genes in 46 patients. The detection rate was 18% (46/253) in the whole group and 26% (17/65) in the early-onset (before three months after birth) epilepsy group. To our knowledge, we are the first to report KCNAB1 is a disease-causing gene of epilepsy by identifying a novel de novo mutation (c.1062dupCA p.Leu355HisfsTer5) within this gene in one patient with early infantile epileptic encephalopathy (EIEE). Patients with an SCN1A mutation accounted for the largest proportion, 17% (8/46). A total of 38% (9/24) of the mutated genes re-occurred at least 2 times and 63% (15/24) occurred only one time. Ion channel genes are the most common (8/24) and genes related to synapse are the next most common to occur (5/24).
We have established genetic diagnosis for 46 patients of our cohort. Early-onset epilepsy had the highest detection rate. KCNAB1 mutation was first identified in EIEE patient. We expanded the phenotype and mutation spectrum of the genes we identified. The mutated genes in this cohort are mostly isolated. This suggests that epilepsy and ID/DD phenotypes occur as a consequence of brain dysfunction caused by a highly diverse population of mutated genes. Ion channel genes and genes related to synapse were more common mutated in this patient cohort.
PMCID: PMC4636363  PMID: 26544041
24.  Antibacterial Activity of Shikimic Acid from Pine Needles of Cedrus deodara against Staphylococcus aureus through Damage to Cell Membrane 
Shikimic acid (SA) has been reported to possess antibacterial activity against Staphylococcus aureus, whereas the mode of action of SA is still elusive. In this study, the antibacterial activity and mechanism of SA toward S. aureus by cell membrane damage was investigated. After SA treatment, massive K+ and nucleotide leakage from S. aureus, and a significant change in the membrane potential was observed, suggesting SA may act on the membrane by destroying the cell membrane permeability. Through transmission electron microscopic observations we further confirmed that SA can disrupt the cell membrane and membrane integrity. Meanwhile, SA was found to be capable of reducing the membrane fluidity of the S. aureus cell. Moreover, the fluorescence experiments indicated that SA could quench fluorescence of Phe residues of the membrane proteins, thus demonstrating that SA can bind to S. aureus membrane proteins. Therefore, these results showed the antibacterial activity of SA against S. aureus could be caused by the interactions of SA with S. aureus membrane proteins and lipids, resulting in causing cell membrane dysfunction and bacterial damage or even death. This study reveals the potential use of SA as an antibacterial agent.
PMCID: PMC4661873  PMID: 26580596
shikimic acid; antibacterial activity; Staphylococcus aureus; membrane damage; membrane proteins; membrane lipids
25.  Causes of Death among AIDS Patients after Introduction of Free Combination Antiretroviral Therapy (cART) in Three Chinese Provinces, 2010–2011 
PLoS ONE  2015;10(10):e0139998.
Although AIDS-related deaths have had significant economic and social impact following an increased disease burden internationally, few studies have evaluated the cause of AIDS-related deaths among patients with AIDS on combination anti-retroviral therapy (cART) in China. This study examines the causes of death among AIDS-patients in China and uses a methodology to increase data accuracy compared to the previous studies on AIDS-related mortality in China, that have taken the reported cause of death in the National HIV Registry at face-value.
Death certificates/medical records were examined and a cross-sectional survey was conducted in three provinces to verify the causes of death among AIDS patients who died between January 1, 2010 and June 30, 2011. Chi-square analysis was conducted to examine the categorical variables by causes of death and by ART status. Univariate and multivariate logistic regression were used to evaluate factors associated with AIDS-related death versus non-AIDS related death.
This study used a sample of 1,109 subjects. The average age at death was 44.5 years. AIDS-related deaths were significantly higher than non-AIDS and injury-related deaths. In the sample, 41.9% (465/1109) were deceased within a year of HIV diagnosis and 52.7% (584/1109) of the deceased AIDS patients were not on cART. For AIDS-related deaths (n = 798), statistically significant factors included CD4 count <200 cells/mm3 at the time of cART initiation (AOR 1.94, 95%CI 1.24–3.05), ART naïve (AOR 1.69, 95%CI 1.09–2.61; p = 0.019) and age <39 years (AOR 2.96, 95%CI 1.77–4.96).
For the AIDS patients that were deceased, only those who initiated cART while at a CD4 count ≥200 cells/mm3 were less likely to die from AIDS-related causes compared to those who didn’t initiate ART at all.
PMCID: PMC4624241  PMID: 26506621

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