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1.  Vagal nerve stimulation improves mitochondrial dynamics via an M3 receptor/CaMKKβ/AMPK pathway in isoproterenol‐induced myocardial ischaemia 
Mitochondrial dynamics—fission and fusion—are associated with ischaemic heart disease (IHD). This study explored the protective effect of vagal nerve stimulation (VNS) against isoproterenol (ISO)‐induced myocardial ischaemia in a rat model and tested whether VNS plays a role in preventing disorders of mitochondrial dynamics and function. Isoproterenol not only caused cardiac injury but also increased the expression of mitochondrial fission proteins [dynamin‐related peptide1 (Drp1) and mitochondrial fission protein1 (Fis‐1)) and decreased the expression of fusion proteins (optic atrophy‐1 (OPA1) and mitofusins1/2 (Mfn1/2)], thereby disrupting mitochondrial dynamics and leading to increase in mitochondrial fragments. Interestingly, VNS restored mitochondrial dynamics through regulation of Drp1, Fis‐1, OPA1 and Mfn1/2; enhanced ATP content and mitochondrial membrane potential; reduced mitochondrial permeability transition pore (MPTP) opening; and improved mitochondrial ultrastructure and size. Furthermore, VNS reduced the size of the myocardial infarction and ameliorated cardiomyocyte apoptosis and cardiac dysfunction induced by ISO. Moreover, VNS activated AMP‐activated protein kinase (AMPK), which was accompanied by phosphorylation of Ca2+/calmodulin‐dependent protein kinase kinase β (CaMKKβ) during myocardial ischaemia. Treatment with subtype‐3 of muscarinic acetylcholine receptor (M3R) antagonist 4‐diphenylacetoxy‐N‐methylpiperidine methiodide or AMPK inhibitor Compound C abolished the protective effects of VNS on mitochondrial dynamics and function, suggesting that M3R/CaMKKβ/AMPK signalling are involved in mediating beneficial effects of VNS. This study demonstrates that VNS modulates mitochondrial dynamics and improves mitochondrial function, possibly through the M3R/CaMKKβ/AMPK pathway, to attenuate ISO‐induced cardiac damage in rats. Targeting mitochondrial dynamics may provide a novel therapeutic strategy in IHD.
PMCID: PMC5192749  PMID: 27491814
myocardial ischaemia; vagal nerve stimulation; mitochondrial dynamics; mitochondrial function; AMP‐activated protein kinase; subtype‐3 of muscarinic acetylcholine receptor; cardioprotection
2.  Association between higher expression of interleukin-8 (IL-8) and haplotype −353A/−251A/+678T of IL-8 gene with preeclampsia 
Medicine  2016;95(52):e5537.
Preeclampsia (PE) is a common pregnancy-specific disorder associated with significant maternal and fetal morbidity and mortality worldwide.
The present study was performed to investigate the role of a CXC chemokine interleukin-8 (IL-8), in the pathogenesis of PE. IL-8 expression levels were assessed in placental and serum samples from 160 pregnant women with PE (N = 68 severe, 92 mild) and 140 healthy donors.
Results from enzyme-linked immunosorbent assay showed that the concentration of serum IL-8 in PE patients (180.27 ± 5.81 ng/L) was significantly higher than that in healthy controls (41.57 ± 5.67 ng/L). Patients with severe PE had even higher serum IL-8 levels. Similar messenger RNA and protein expression patterns of IL-8 in placental tissues were confirmed by quantitative real-time polymerase chain reaction and immunohistochemical assay (N = 30 each in the mild PE, severe PE, and control groups). In addition, single nucleotide polymorphisms of IL-8 gene were detected with polymerase chain reaction-restricted fragment length polymorphism/SSP. The frequency of IL-8-251A allele was significantly higher than that in controls (58.4% vs 48.9%, P < 0.05). The occurrence frequency of haplotype −353A/−251A/+678T (AAT) in PE subjects was 27.2% as compared to 21.9% in the control participants (P < 0.05).
Our study reveals that IL-8 expression is positively associated with the severity of PE. Presence of haplotype AAT in pregnant women appears to be a risk factor for PE.
PMCID: PMC5207544  PMID: 28033248
IL-8; inflammation; preeclampsia; single nucleotide polymorphism
3.  Robust Lys63-Linked Ubiquitination of RIG-I Promotes Cytokine Eruption in Early Influenza B Virus Infection 
Journal of Virology  2016;90(14):6263-6275.
Influenza A and B virus infections both cause a host innate immunity response. Here, we report that the robust production of type I and III interferons (IFNs), IFN-stimulated genes, and proinflammatory factors can be induced by influenza B virus rather than influenza A virus infection in alveolar epithelial (A549) cells during early infection. This response is mainly dependent on the retinoic acid-inducible gene I (RIG-I)-mediated signaling pathway. Infection by influenza B virus promotes intense Lys63-linked ubiquitination of RIG-I, resulting in cytokine eruption. It is known that the influenza A virus NS1 protein (NS1-A) interacts with RIG-I and TRIM25 to suppress the activation of RIG-I-mediated signaling. However, the present results indicate that the influenza B virus NS1 protein (NS1-B) is unable to interact with RIG-I but engages in the formation of a RIG-I/TRIM25/NS1-B ternary complex. Furthermore, we demonstrate that the N-terminal RNA-binding domain (RBD) of NS1-B is responsible for interaction with TRIM25 and that this interaction blocks the inhibitory effect of the NS1-B C-terminal effector domain (TED) on RIG-I ubiquitination. Our findings reveal a novel mechanism for the host cytokine response to influenza B virus infection through regulatory interplay between host and viral proteins.
IMPORTANCE Influenza B virus generally causes local mild epidemics but is occasionally lethal to individuals. Existing studies describe the broad characteristics of influenza B virus epidemiology and pathology. However, to develop better prevention and treatments for the disease, determining the concrete molecular mechanisms of pathogenesis becomes pivotal to understand how the host reacts to the challenge of influenza B virus. Thus, we aimed to characterize the host innate immune response to influenza B virus infection. Here, we show that vigorous Lys63-linked ubiquitination of RIG-I and cytokine eruption dependent on RIG-I-mediated signal transduction are induced by virus infection. Additionally, TRIM25 positively regulates RIG-I-mediated signaling by ablating the inhibitory function of NS1-B on RIG-I ubiquitination.
PMCID: PMC4936144  PMID: 27122586
4.  Mitochondrial Biomarkers Reflect Semen Quality: Results from the MARCHS Study in Chongqing, China 
PLoS ONE  2016;11(12):e0168823.
Unexplained infertility requires that more sensitive and mechanism-based biomarkers should be developed and used independently of or in addition to conventional semen parameters for an infertility diagnosis. In the present study, semen samples were collected from young men participating in the Male Reproductive Health in Chongqing College students (MARCHS) cohort study in the follow-up stage in 2014. Conventional semen parameters were measured in all 656 participants, whereas sperm mitochondrial membrane potential (MMP), mitochondrial DNA copy number (mtDNAcn), mtDNA integrity and apoptotic parameters were measured among 627, 386, 362, and 628 participants, respectively. We found that sperm MMP was significantly positively correlated with all of conventional semen parameters including semen volume (r = 0.090, p = 0.025), sperm concentration (r = 0.301, p<0.01), total sperm count (r = 0.324, p<0.01), and progressive motility (r = 0.399, p<0.01); sperm MMP was also negatively correlated with Annexin V+ sperm (r = -0.553, p<0.01); mtDNAcn was significantly negatively correlated with sperm concentration (r = -0.214, p<0.01), total sperm count (r = -0.232, p<0.01), and progressive motility (r = -0.164, p = 0.01); mtDNA integrity was also significantly positively correlated with sperm concentration (r = 0.195, p<0.01), total sperm count (r = 0.185, p<0.01), and progressive motility (r = 0.106, p = 0.043). After adjusting for potential confounders, these relationships remained significant. Furthermore, we explored the potential effects of lifestyles on such mitochondrial biomarkers and found that the current drinkers displayed a higher level of sperm MMP; additionally, mt DNAcn was increased with age. The results indicated that certain mitochondrial biomarkers could serve as predictors of semen quality in a general population, and the study provides a baseline for the effects of population characteristics and lifestyles on such mitochondrial markers.
PMCID: PMC5179063  PMID: 28006017
5.  Transcriptome analysis of genes involved in anthocyanins biosynthesis and transport in berries of black and white spine grapes (Vitis davidii) 
Hereditas  2016;153:17.
The color of berry skin is an important economic trait for grape and is essentially determined by the components and content of anthocyanins. The fruit color of Chinese wild grapes is generally black, and the profile of anthocyanins in Chinese wild grapes is significantly different from that of Vitis vinifera. However, V. davidii is the only species that possesses white berry varieties among Chinese wild grape species. Thus, we performed a transcriptomic analysis to compare the difference of transcriptional level in black and white V. davidii, in order to find some key genes that are related to anthocyanins accumulation in V. davidii.
The results of anthocyanins detection revealed that 3,5-O-diglucoside anthocyanins is the predominant anthocyanins in V. davidii. It showed obvious differences from V. vinifera in the profile of the composition of anthocyanins. The transcriptome sequencing by Illumina mRNA-Seq technology generated an average of 57 million 100-base pair clean reads from each sample. Differential gene expression analysis revealed thousands of differential expression genes (DEGs) in the pairwise comparison of different fruit developmental stages between and within black and white V. davidii. After the analysis of functional category enrichment and differential expression patterns of DEGs, 46 genes were selected as the candidate genes. Some genes have been reported as being related to anthocyanins accumulation, and some genes were newly found in our study as probably being related to anthocyanins accumulation. We inferred that 3AT (VIT_03s0017g00870) played an important role in anthocyanin acylation, GST4 (VIT_04s0079g00690) and AM2 (VIT_16s0050g00910) played important roles in anthocyanins transport in V. davidii. The expression of some selected DEGs was further confirmed by quantitative real-time PCR (qRT-PCR).
The present study investigated the transcriptomic profiles of berry skin from black and white spine grapes at three fruit developmental stages by Illumina mRNA-Seq technology. It revealed the variety specificity of anthocyanins accumulation in V. davidi at the transcriptional level. The data reported here will provide a valuable resource for understanding anthocyanins accumulation in grapes, especially in V. davidii.
Electronic supplementary material
The online version of this article (doi:10.1186/s41065-016-0021-1) contains supplementary material, which is available to authorized users.
PMCID: PMC5226110  PMID: 28096779
Vitis davidii; Berry skin; Anthocyanins; Transcriptome analysis; Candidate genes
6.  Novel strategies and underlying protective mechanisms of modulation of vagal activity in cardiovascular diseases 
British Journal of Pharmacology  2015;172(23):5489-5500.
Cardiovascular disease remains a major cause of disability and death worldwide. Autonomic imbalance, characterized by suppressed vagal (parasympathetic) activity and increased sympathetic activity, correlates with various pathological conditions, including heart failure, arrhythmia, ischaemia/reperfusion injury and hypertension. Conventionally, pharmacological interventions, such as β‐blocker treatment, have primarily targeted suppressing sympathetic over‐activation, while vagal modulation has always been neglected. Emerging evidence has documented the improvement of cardiac and vascular function mediated by the vagal nerve. Many investigators have tried to explore the effective ways to enhance vagal tone and normalize the autonomic nervous system. In this review, we attempt to give an overview of these therapeutic strategies, including direct vagal activation (electrical vagal stimulation, ACh administration and ACh receptor activation), pharmacological modulation (adenosine, cholinesterase inhibitors, statins) and exercise training. This overview provides valuable information for combination therapy, contributing to establishment of a comprehensive system on vagal modulation from the aspects of clinical application and lifestyle improvement. In addition, the mechanisms contributing to the benefits of enhancing vagal tone are diverse and have not yet been fully defined. We endeavour to outline the recent findings that advance our knowledge regarding the many favourable effects exerted by vagal activation: anti‐inflammatory pathways, modulation of NOS and NO signalling, regulation of redox state, improvement of mitochondrial biogenesis and function, and potential calcium regulation. This review may help to develop novel therapeutic strategies targeting enhancing vagal activity for the treatment of cardiovascular diseases.
Linked Articles
This article is part of a themed section on Chinese Innovation in Cardiovascular Drug Discovery. To view the other articles in this section visit
PMCID: PMC4667861  PMID: 25378088
7.  Resampling to Address the Winner’s Curse in Genetic Association Analysis of Time to Event 
Genetic epidemiology  2015;39(7):518-528.
The “winner’s curse” is a subtle and difficult problem in interpretation of genetic association, in which association estimates from large-scale gene detection studies are larger in magnitude than those from subsequent replication studies. This is practically important because use of a biased estimate from the original study will yield an under-estimate of sample size requirements for replication, leaving the investigators with an underpowered study. Motivated by investigation of the genetics of type 1 diabetes complications in a longitudinal cohort of participants in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Genetics Study, we apply a bootstrap resampling method in analysis of time to nephropathy under a Cox proportional hazards model, examining 1213 SNPs in 201 candidate genes custom-genotyped in 1361 white probands. Among 15 top-ranked SNPs, bias reduction in log hazard ratio estimates ranges from 43.1 to 80.5%. In simulation studies based on the observed DCCT/EDIC genotype data, genome-wide bootstrap estimates for false positive SNPs and for true positive SNPs with low to moderate power are closer to the true values than uncorrected naïve estimates, but tend to over-correct SNPs with high power. This bias-reduction technique is generally applicable for complex trait studies including quantitative, binary, and time-to-event traits.
PMCID: PMC4609263  PMID: 26411674
bootstrap; cohort studies; DCCT/EDIC Genetics Study; genotype; phenotype; selection bias; survival analysis
8.  The 3.8Å resolution cryo-EM structure of Zika Virus# 
Science (New York, N.Y.)  2016;352(6284):467-470.
The recent rapid spread of Zika virus and its unexpected linkage to birth defects and an autoimmune-neurological syndrome has generated worldwide concern. Zika virus is a flavivirus like dengue, yellow fever and West Nile viruses. We present the 3.8Å resolution structure of mature Zika virus determined by cryo-electron microscopy. The structure of Zika virus is similar to other known flavivirus structures except for the ~10 amino acids that surround the Asn154 glycosylation site found in each of the 180 envelope glycoproteins that make up the icosahedral shell. The carbohydrate moiety associated with this residue, recognizable in the cryo-EM electron density, may function as an attachment site of the virus to host cells. This region varies not only among Zika virus strains but also in other flaviviruses and suggests that changes in this region influence virus transmission and disease.
PMCID: PMC4845755  PMID: 27033547
9.  Differentially expressed circulating LncRNAs and mRNA identified by microarray analysis in obese patients 
Scientific Reports  2016;6:35421.
Circulating long non-coding RNAs (lncRNAs) serve as valuable biomarkers in a number of human diseases. However, lncRNA biomarkers have yet to be identified in obesity. We aim to characterize circulating lncRNA expression in obese and non-obese human subjects. First, we assessed the genome-wide circulating lncRNA expression profiles in blood from 3 obese and 3 non-obese human subjects. We found a significant decrease in circulating levels of three lncRNAs (lncRNA-p5549, lncRNA-p21015 and lncRNA-p19461) in obese human subjects only. Next, using RT-PCR we measured the expression levels of these three lncRNAs in 33 obese and 33 non-obese human subjects and found similar differences. Moreover, we found a negative correlation between circulating levels of these three lncRNAs and body mass index (BMI), waist circumference, waist to hip ratio and fasting insulin. There was also a significant negative correlation between expression of lncRNA-p19461 and homeostasis model assessment-estimated insulin resistance. Finally, we tested the circulating levels of these three lncRNAs in 8 obese human subjects after a 12-week diet-induced weight loss program. We found that only lncRNA-p19461 expression level significantly increased. In summary, circulating lncRNAs are deregulated in obesity. Weight loss–induced changes in this profile support this observation and suggest a potential mechanistic relevance.
PMCID: PMC5073332  PMID: 27767123
10.  BcsZ inhibits biofilm phenotypes and promotes virulence by blocking cellulose production in Salmonella enterica serovar Typhimurium 
Cellulose, a 1,4 beta-glucan polysaccharide, is produced by a variety of organisms including bacteria. Although the production of cellulose has a high biological, ecological and economical impact, regulatory mechanisms of cellulose biosynthesis are mostly unknown. Family eight cellulases are regularly associated with cellulose biosynthesis operons in bacteria; however, their function is poorly characterized. In this study, we analysed the role of the cellulase BcsZ encoded by the bcsABZC cellulose biosynthesis operon of Salmonella enterica serovar Typhimurium (S. Typhimurium) in biofilm related behavior. We also investigated the involvement of BcsZ in pathogenesis of S. Typhimurium including a murine typhoid fever infection model.
In S. Typhimurium, cellulase BcsZ with a putative periplasmic location negatively regulates cellulose biosynthesis. Moreover, as assessed with a non-polar mutant, BcsZ affects cellulose-associated phenotypes such as the rdar biofilm morphotype, cell clumping, biofilm formation, pellicle formation and flagella-dependent motility. Strikingly, although upregulation of cellulose biosynthesis was not observed on agar plate medium at 37 °C, BcsZ is required for efficient pathogen-host interaction. Key virulence phenotypes of S. Typhimurium such as invasion of epithelial cells and proliferation in macrophages were positively regulated by BcsZ. Further on, a bcsZ mutant was outcompeted by the wild type in organ colonization in the murine typhoid fever infection model. Selected phenotypes were relieved upon deletion of the cellulose synthase BcsA and/or the central biofilm activator CsgD.
Although the protein scaffold has an additional physiological role, our findings indicate that the catalytic activity of BcsZ effectively downregulates CsgD activated cellulose biosynthesis. Repression of cellulose production by BcsZ subsequently enables Salmonella to efficiently colonize the host.
Electronic supplementary material
The online version of this article (doi:10.1186/s12934-016-0576-6) contains supplementary material, which is available to authorized users.
PMCID: PMC5070118  PMID: 27756305
Cellulose; Cellulase; BcsZ; Biofilm; CsgD; Salmonella
11.  P53 inhibitor pifithrin-α prevents the renal tubular epithelial cells against injury 
The injury and repair of renal tubular epithelial cells play an important role in the pathological process of acute kidney injury (AKI). This study aimed to clarify the role of cell cycle change in renal tubular epithelial cell injury and repair in vivo and in vitro. Sprague-Dawley rats received bilateral renal pedicle clamping for 45 min (ischemia) followed by reperfusion. Pifithrin-α, a p53 inhibitor, was administered at 24 h before renal ischemia and 3 and 14 days after reperfusion. Results showed the tubular epithelial cells in M phase increased significantly at 2 h to 72 h after ischemia/reperfusion (I/R), while pifithrin-α decreased them. Renal I/R caused renal tubular epithelial damage in rats, which was improved by pifithrin-α. The α-SMA mRNA expression was up-regulated significantly after I/R, while it was down-regulated by pifithrin-α.NRK-52E cells were cultured in vitro, cell damage was induced by addition of TNF-α, and then cells were treated with pifithrin-α. Cells treated with TNF-α alone in G2/M phase increased significantly, but they were reduced in the presence of pifithrin-α. In NRK-52E cells treated with pifithrin-α for 6 h, NGAL mRNA expression was significantly lower than in cells without pifithrin-α treatment. After NRK-52E cells were treated with pifithrin-α for 24 h, α-SMA and FN mRNA expression was significantly lower than in cells without the treatment. In summary, pifithrin-α can facilitate the progression of renal tubular epithelial cells through G2/M phase, protecting them against injury.
PMCID: PMC5095300  PMID: 27829991
Acute kidney injury (AKI); renal tubular epithelial cell; cell cycle; G2/M phase; pifithrin-α
12.  Mst1 inhibits CMECs autophagy and participates in the development of diabetic coronary microvascular dysfunction 
Scientific Reports  2016;6:34199.
Cardiovascular complications account for a substantial proportion of morbidity and mortality in diabetic patients. Abnormalities of cardiac microvascular endothelial cells (CMECs) lead to impaired cardiac microvascular vessel integrity and subsequent cardiac dysfunction, underlining the importance of coronary microvascular dysfunction. In this study, experimental diabetes models were constructed using Mst1 transgenic, Mst1 knockout and sirt1 knockout mice. Diabetic Mst1 transgenic mice exhibited impaired cardiac microvessel integrity and decreased cardiac function. Mst1 overexpression deceased CMECs autophagy as evidenced by decreased LC3 expression and enhanced protein aggregation when subjected to high glucose culture. Mst1 knockout improved cardiac microvessel integrity and enhanced cardiac functions in diabetic mice. Mst1 knockdown up-regulated autophagy as indicated by more typical autophagosomes and increased LC3 expression in CMECs subjected to high glucose cultures. Mst1 knockdown also promoted autophagic flux in the presence of bafilomycin A1. Mst1 overexpression increased CMECs apoptosis, whereas Mst1 knockout decreased CMECs apoptosis. Sirt1 knockout abolished the effects of Mst1 overexpression in cardiac microvascular injury and cardiac dysfunction. In conclusion, Mst1 knockout preserved cardiac microvessel integrity and improved cardiac functions in diabetic mice. Mst1 decreased sirt1 activity, inhibited autophagy and enhanced apoptosis in CMECs, thus participating in the pathogenesis of diabetic coronary microvascular dysfunction.
PMCID: PMC5040958  PMID: 27680548
13.  Long noncoding RNA MALAT1 promotes uveal melanoma cell growth and invasion by silencing of miR-140 
Increasing evidences have demonstrated that long noncoding RNAs (LncRNAs) play a significant role in the development of tumor. However, the role of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in uveal melanoma remains unknown. In this study, we demonstrated that the expression of MALAT1 was upregulated in the uveal melanoma tissues compared to normal tissues. Among them, MALAT1 was upregulated in 72% (18/25) uveal melanoma tissues compared to their paired normal tissues. Knockdown of MALAT1 suppressed uveal melanoma cell proliferation, colony information, invasion and migration. Moreover, we showed that knockdown of MALAT1 promoted miR-140 expression and suppressed Slug and ADAM10 expression in the MUM-2C cell. In addition, we demonstrated that miR-140 was downregulated in the uveal melanoma tissues compared to normal tissues and cell lines. The expression level of MALAT1 was inversely correlated with the expression level of miR-140 in uveal melanoma tissues. These results suggested that MALAT1 served as an oncogenic LncRNA in the development of uveal melanoma.
PMCID: PMC5040691  PMID: 27725873
Long noncoding RNA; LncRNAs; MALAT1; uveal melanoma; mir-140
14.  Resampling to Address the Winner's Curse in Genetic Association Analysis of Time to Event 
Genetic Epidemiology  2015;39(7):518-528.
The “winner's curse” is a subtle and difficult problem in interpretation of genetic association, in which association estimates from large‐scale gene detection studies are larger in magnitude than those from subsequent replication studies. This is practically important because use of a biased estimate from the original study will yield an underestimate of sample size requirements for replication, leaving the investigators with an underpowered study. Motivated by investigation of the genetics of type 1 diabetes complications in a longitudinal cohort of participants in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Genetics Study, we apply a bootstrap resampling method in analysis of time to nephropathy under a Cox proportional hazards model, examining 1,213 single‐nucleotide polymorphisms (SNPs) in 201 candidate genes custom genotyped in 1,361 white probands. Among 15 top‐ranked SNPs, bias reduction in log hazard ratio estimates ranges from 43.1% to 80.5%. In simulation studies based on the observed DCCT/EDIC genotype data, genome‐wide bootstrap estimates for false‐positive SNPs and for true‐positive SNPs with low‐to‐moderate power are closer to the true values than uncorrected naïve estimates, but tend to overcorrect SNPs with high power. This bias‐reduction technique is generally applicable for complex trait studies including quantitative, binary, and time‐to‐event traits.
PMCID: PMC4609263  PMID: 26411674
bootstrap; cohort studies; DCCT/EDIC Genetics Study; genotype; phenotype; selection bias; survival analysis
15.  Diagnostic performance of confocal laser endomicroscopy for optical diagnosis of gastric intestinal metaplasia: a meta-analysis 
BMC Gastroenterology  2016;16(1):109.
Gastric intestinal metaplasia (IM) is generally considered as a precancerous condition, a related risk factor for intestinal-type gastric cancer. However, an accurate endoscopic diagnosis of IM is a clinical challenge. Confocal Laser Endomicroscopy (CLE) is a newly technique that can provide real-time magnified images and visualize tissues at cellular or subcellular levels. The aim of this study is to clarify the diagnostic value of CLE in detection of IM in patients at high risk of gastric cancer.
Systematic literature searches up to April 2015 in PubMed, Embase, Web of Science, Cochrane Library databases were conducted by two reviewers independently. The Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool was applied to assess study quality and to reduce potential bias. A meta-analysis using Meta-Disc (version 1.4) and STATA software (version 13) was performed.
A total of four studies enrolled 218 patients and 579 lesions were included in this meta-analysis. On per-lesion basis, the pooled sensitivity and specificity of CLE were 0.97(95 % confidence interval (CI) = 0.94–0.98) and 0.94 (95 % CI = 0.91–0.97) respectively. The pooled positive likelihood ratio (PLR) and negative likelihood ratio (NLR) were 15.20 (95 % CI = 9.46–24.41) and 0.04 (95 % CI = 0.02–0.07) respectively. The pooled diagnostic odds ratio (DOR) was 479.59 (95 % CI = 205.64–1118.51) and summary receiver operating curve (SROC) area under the curve was 0.9884. There was no statistical significance of publication bias.
CLE is a promising endoscopic tool in the detection of IM with the relatively high diagnostic value in patients at high risk of gastric cancer.
PMCID: PMC5011919  PMID: 27596838
Confocal laser endomicroscopy; Intestinal metaplasia; Diagnostic performance
16.  Systematic medical assessment, referral and treatment for diabetes care in China using lay family health promoters: protocol for the SMARTDiabetes cluster randomised controlled trial 
Type 2 diabetes (T2DM) affects 113.9 million people in China, the largest number of any country in the world (JAMA 310:948–59, 2013). T2DM prevalence has risen dramatically from around 1 % in the 1980s to now over 10 % and is expected to continue rising. Despite the growing disease burden, few people with T2DM are achieving adequate management targets to prevent complications. Health system infrastructure in China is struggling to meet these gaps in care, and innovative, cost-effective and affordable solutions are needed. One promising strategy that may be particularly relevant to the Chinese context is improving support for lay family members to care for their relatives with T2DM.
We hypothesise that an interactive mobile health management system can support lay family health promoters (FHP) and healthcare staff to improve clinical outcomes for family members with T2DM through medical assessment, regular monitoring, lifestyle advice and the prescribing of guidelines recommended medications. This intervention will be implemented as a cluster randomised controlled trial involving 80 communities (40 communities in Beijing and 40 rural villages in Hebei province) and 2000 people with T2DM. Outcome analyses will be conducted blinded to intervention allocation.
The primary outcome is the proportion of patients achieving ≥2 “ABC” goals (HbA1c <7.0 %, blood pressure (BP) <140/80 mmHg and LDL cholesterol <100 mg/dl or 2.6 mmol/L) at the end of follow-up (Diabetes Care 36(Supplement 1):S11-S66, 2013). Secondary outcomes include the proportion of patients achieving individual ABC targets; mean changes in HbA1c, BP, LDL, renal function (serum creatinine and urinary albumin), body mass index, quality of life (QOL, EQ-5D), and healthcare utilisation from baseline; and cost-effectiveness/utility of intervention. Trial outcomes will be accompanied by detailed process and economic evaluations.
The Chinese government has prioritised prevention and treatment of diabetes as 1 of 11 National Basic Public Health Services. Despite great promise for mHealth interventions to improve access to effective health care, there remains uncertainty about how this can be successfully achieved. The findings are likely to inform policy on a scalable strategy to overcome sub-optimal access to effective health care in China.
Trial registration NCT02726100
PMCID: PMC4989287  PMID: 27535128
Type 2 diabetes; Capacity strengthening; mHealth; China; Implementation
17.  Dynamic DNA methylation landscape defines brown and white cell specificity during adipogenesis 
Molecular Metabolism  2016;5(10):1033-1041.
DNA methylation may be a stable epigenetic contributor to defining fat cell lineage.
We performed reduced representation bisulfite sequencing (RRBS) and RNA-seq to depict a genome-wide integrative view of the DNA methylome and transcriptome during brown and white adipogenesis.
Our analysis demonstrated that DNA methylation is a stable epigenetic signature for brown and white cell lineage before, during, and after differentiation. We identified 31 genes whose promoters were significantly differentially methylated between white and brown adipogenesis at all three time points of differentiation. Among them, five genes belong to the Hox family; their expression levels were anti-correlated with promoter methylation, suggesting a regulatory role of DNA methylation in transcription. Blocking DNA methylation with 5-Aza-cytidine increased the expression of these genes, with the most prominent effect on Hoxc10, a repressor of BAT marker expression.
Our data suggest that DNA methylation may play an important role in lineage-specific development in adipocytes.
•DNA methylation is a stable epigenetic signature for brown and white adipocyte lineage.•We identified 31 genes whose promoters were significantly differentially methylated between white and brown adipogenesis.•Blocking DNA methylation with 5-Aza-cytidine increase the expression of a group of HoxC genes.
PMCID: PMC5034609  PMID: 27689016
Brown adipogenesis; White adipogenesis; DNA methylation; Hoxc10; Next generation sequencing
18.  The Migrant Paradox in Children and the Role of Schools in Reducing Health Disparities: A Cross-Sectional Study of Migrant and Native Children in Beijing, China 
PLoS ONE  2016;11(7):e0160025.
Migrants usually exhibit similar or better health outcomes than native-born populations despite facing socioeconomic disadvantages and barriers to healthcare use; this is known as the “migrant paradox.” The migrant paradox among children is highly complex. This study explores whether the migrant paradox exists in the health of internal migrant children in China and the role of schools in reducing children’s health disparities, using a multi-stage stratified cluster sampling method. Participants were 1,641 student and parent pairs from Grades 4, 5, and 6 of eight primary schools in Beijing. The following school types were included: state schools with migrant children comprising over 70% of total children (SMS), private schools with migrant children comprising over 70% (PMS), and state schools with permanent resident children comprising over 70% (SRS). Children were divided into Groups A, B, C or D by the type of school they attended (A and B were drawn from SRSs, C was from SMSs, and D was from PMSs) and whether they were in the migrant population (B, C, and D were, but A was not). Related information was collected through medical examination and questionnaires completed by parents and children. Prevalence of caries, overweight and obesity, poor vision, and self-reported incidence of colds and diarrhea in the previous month were explored as health outcomes. The results partially demonstrated the existence of the migrant paradox and verified the role of schools in lowering health disparities among children; there are theoretical and practical implications for improving the health of migrant children.
PMCID: PMC4961441  PMID: 27459507
19.  The Circular RNA Cdr1as Act as an Oncogene in Hepatocellular Carcinoma through Targeting miR-7 Expression 
PLoS ONE  2016;11(7):e0158347.
CircRNAs are a class of endogenous RNA that regulates gene expression at the post-transcriptional or transcriptionallevel through interacting with other molecules or microRNAs. Increasing studies have demonstrated that circRNAs play a crucial role in biology processes. CircRNAs are proved as potentialbiomarkers in many diseases including cancers. However, the role of Cdr1as in Hepatocellular carcinoma (HCC) remains to be elucidated. We demonstrated that Cdr1as expression was upregulated in HCC tissues compared with the adjacent non-tumor tissues. In addtion, miR-7 expression was downregulated in HCC tissues compared with the adjacent non-tumor tissues. Moreover, the expression level of miR-7 was inversely correlated with that in HCC tissues. Knockdown of Cdr1as suppressed the HCC cell proliferation and invasion. Overexpression of miR-7 inhibited the HCC cell proliferation and invasion. Overexpression of miR-7 could suppress the direct target gene CCNE1 and PIK3CD expression. Knockdown of Cdr1as suppressed the expression of miR-7 and also inhibited the CCNE1 and PIK3CD expression. Furthermore, knockdown of Cdr1as suppressed the HCC cell proliferation and invasion through targeting miR-7. These data suggested that Cdr1as acted as an oncogene partly through targeting miR-7 in HCC.
PMCID: PMC4938625  PMID: 27391479
20.  Cyclophilin A protects mice against infection by influenza A virus 
Scientific Reports  2016;6:28978.
Our previous studies indicate that Cyclophilin A (CypA) impairs the replication of influenza A virus in vitro. To further evaluate the antiviral functions of CypA and explore its mechanism, transgenic mice with overexpression of CypA by two specific promoters with SPC (CypA-SPC) or CMV (CypA-CMV) were developed. After challenge with the A/WSN/33(H1N1) influenza virus, CypA-SPC and CypA-CMV transgenic mice displayed nearly 2.5- and 3.8-fold stronger disease resistance to virus infection, respectively, compared to wild-type animals. Virus replication, pathological lesions and inflammatory cytokines were substantially reduced in both lines of transgenic mice. In addition, after infection there was an upregulation of genes associated with cell migration, immune function, and organ development; and a downregulation of genes associated with the positive regulation of immune cells and apoptosis in the peritoneal macrophages of CypA-overexpressing transgenic mice (CypA+). These results indicate that CypA is a key modulator of influenza virus resistance in mice, and that CypA+ mice constitutes an important model to study the roles of CypA in the regulation of immune responses and infections.
PMCID: PMC4926061  PMID: 27354005
21.  Deep brain stimulation of pallidal versus subthalamic for patients with Parkinson’s disease: a meta-analysis of controlled clinical trials 
Parkinson’s disease (PD) is a common neurodegenerative disorder that affects many people every year. Deep brain stimulation (DBS) is an effective nonpharmacological method to treat PD motor symptoms. This meta-analysis was conducted to evaluate the efficacy of subthalamic nucleus (STN)-DBS versus globus pallidus internus (GPi)-DBS in treating advanced PD.
Controlled clinical trials that compared STN-DBS to GPi-DBS for short-term treatment of PD in adults were researched up to November 2015. The primary outcomes were the Unified Parkinson’s Disease Rating Scale Section (UPDRS) III score and the levodopa-equivalent dosage (LED) after DBS. The secondary outcomes were the UPDRS II score and the Beck Depression Inventory (BDI) score.
Totally, 13 studies containing 1,148 PD patients were included in this meta-analysis to compare STN-DBS versus GPi-DBS. During the off-medication state, the pooled weighted mean difference (WMD) of UPDRS III and II scores were −2.18 (95% CI =−5.11 to 0.74) and −1.96 (95% CI =−3.84 to −0.08), respectively. During the on-medication state, the pooled WMD of UPDRS III and II scores were 0.15 (95% CI =−1.14 to 1.44) and 1.01 (95% CI =0.12 to 1.89), respectively. After DBS, the pooled WMD of LED and BDI were −254.48 (95% CI =−341.66) and 2.29 (95% CI =0.83 to 3.75), respectively.
These results indicate that during the off-medication state, the STN-DBS might be superior to GPi-DBS in improving the motor function and activities of daily living for PD patients; but during the on-medication state, the opposite result is observed. Meanwhile, the STN-DBS is superior at reducing the LED, whereas the GPi-DBS shows a significantly greater reduction in BDI score after DBS.
PMCID: PMC4922776  PMID: 27382286
Parkinson disease; deep brain stimulation; subthalamic nucleus; globus pallidus internus
22.  A family with Robertsonian translocation: a potential mechanism of speciation in humans 
Robertsonian translocations occur in approximately one in every 1000 newborns. Although most Robertsonian translocation carriers are healthy and have a normal lifespan, they are at increased risk of spontaneous abortions and risk of producing unbalanced gametes and, therefore unbalanced offspring. Here we reported a previously undescribed Robertsonian translocation.
Case Presentation
We identified three Robertsonian translocation carriers in this family. Two were heterozygous translocation carriers of 45,XX or XY,der(14;15)(q10;q10) and their son was a homozygous translocation carrier of a 44,XY,der(14;15)(q10;q10), der(14;15)(q10;q10) karyotype. Chromosomal analysis of sperm showed 99.7 % of sperm from the homozygous translocation carrier were normal/balanced while only 79.9 % of sperm from the heterozygous translocation carrier were normal/balanced. There was a significantly higher frequency of aneuploidy for sex chromosome in the heterozygous translocation carrier.
The reproductive fitness of Robertsonian translocation carriers is reduced. Robertsonian translocation homozygosity can be a potential speciation in humans with 44 chromosomes.
PMCID: PMC4912789  PMID: 27330563
Chromosome karyotype; FISH; aCGH; Robertsonian translocation homozygosity; Evolution
23.  Oestrogen and parathyroid hormone alleviate lumbar intervertebral disc degeneration in ovariectomized rats and enhance Wnt/β-catenin pathway activity 
Scientific Reports  2016;6:27521.
To investigate the mitigation effect and mechanism of oestrogen and PTH on disc degeneration in rats after ovariectomy, as well as on Wnt/β-catenin pathway activity, thirty 3-month-old rats were ovariectomized and divided into three groups. Ten additional rats were used as controls. Eight weeks later, the rats were administered oestrogen or PTH for 12 weeks, and then discs were collected for tests. Results showed that nucleus pulposus cells in the Sham group were mostly notochord cells, while in the OVX group, cells gradually developed into chondrocyte-like cells. Oestrogen or PTH could partly recover the notochord cell number. After ovariectomy, the endplate roughened and endplate porosity decreased. After oestrogen or PTH treatment, the smoothness and porosity of endplate recovered. Compared with the Sham group, Aggrecan, Col2a and Wnt/β-catenin pathway expression in OVX group decreased, and either oestrogen or PTH treatment improved their expression. The biomechanical properties of intervertebral disc significantly changed after ovariectomy, and oestrogen or PTH treatment partly recovered them. Disc degeneration occurred with low oestrogen, and the underlying mechanisms involve nutrition supply disorders, cell type changes and decreased Wnt/β-catenin pathway activity. Oestrogen and PTH can retard disc degeneration in OVX rats and enhance Wnt/β-catenin pathway activity in nucleus pulposus.
PMCID: PMC4899752  PMID: 27279629
24.  AT101 exerts a synergetic efficacy in gastric cancer patients with 5-FU based treatment through promoting apoptosis and autophagy 
Oncotarget  2016;7(23):34430-34441.
Gastric cancer remains a disease with a high mortality rate despite of multiple therapeutic strategies. So far, it is very important to develop new treatment approaches to improve current therapeutic efficacy in gastric cancer. Apurinic/apyrimidinic endonuclease (APE1) involves in DNA base excision repair (BER) during DNA damage pathway. APE1 was found to be associated with poor overall survival with gastric cancer patients. In the in vitro experiment, we tested APE1 inhibitor-AT101 could potently inhibit gastric cancer cell growth and further induce cancer cell apoptosis and autophagy through p53-dependent pathway. Downregulation of APE1 by AT101 has ability to suppress gastric cancer cell migration and renewal through inhibition of CD133, Nanog and LC3expression. Based on findings that Her-2 positive expression cases has poor prognosis from our dataset and TCGA database, we investigated the role of AT101 in synergetic efficacy with 5-FU treatment in Her-2 overexpression gastric cancer in vivo, indicating that AT101 is able to enhance 5-FU in the shrinkage of xenograft mice tumor and induction of cell apoptosis. In summary, the data obtained from our study showed APE1 is guided as a potential therapeutic target for gastric cancer. AT101 could be regarded as a potent inhibitor to promote chemotherapeutic sensitivity in patients with gastric cancer.
PMCID: PMC5085166  PMID: 27144437
gastric cancer; AT101; APE1; 5-FU; Her-2 positive
25.  Comparative testis proteome dataset between cattleyak and yak 
Data in Brief  2016;8:420-425.
Cattleyak are hybrid between cattle and yak, which exhibit equivalent adaptability on the Qinghai-Tibetan Plateau as yak and much higher capability in economic traits. However, the F1 males of cattleyak are infertile due to spermatogenic arrest and this greatly restricts the effective utilization of this hybrid. In this data article, differentially expressed proteins (DEPs) were identified from testis proteome of cattleyak and yak using high-performance liquid chromatography–electrospray tandem mass spectrometry (LC–ESI-MS/MS). All the DEPs were subjected to functional classification by Gene Ontology (GO) analysis and gene-pathway annotation by Kyoto Encyclopedia of Genes and Genomes (KEGG). The comparative testis proteome dataset here can shed new light on the molecular characteristics of male infertility of cattleyak on proteome level, “Comparative iTRAQ proteomics revealed proteins associated with spermatogenic arrest of cattleyak” [1].
PMCID: PMC4910294  PMID: 27366779

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