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1.  Linked PNPLA3 polymorphisms confer susceptibility to nonalcoholic steatohepatitis and decreased viral load in chronic hepatitis B 
AIM: To investigate the association of PNPLA3 polymorphisms with concurrent chronic hepatitis B (CHB) and nonalcoholic fatty liver disease (NAFLD).
METHODS: A cohort of Han patients with biopsy-proven CHB, with or without NAFLD (CHB group, n = 51; CHB + NAFLD group, n = 57), and normal controls (normal group, n = 47) were recruited from Northern (Tianjin), Central (Shanghai), and Southern (Zhangzhou) China. Their PNPLA3 polymorphisms were genotyped by gene sequencing. The association between PNPLA3 polymorphisms and susceptibility to NAFLD, and clinical characteristics of NAFLD were evaluated on the basis of physical indices, liver function tests, glycolipid metabolism, and histopathologic scoring. The association of PNPLA3 polymorphisms and hepatitis B virus (HBV) load was determined by the serum level of HBV DNA.
RESULTS: After adjusting for age, sex, and body mass index, we found that four linked single nucleotide polymorphisms (SNPs) of PNPLA3, including the rs738409 G allele (CHB + NAFLD group vs CHB group: odds ratio [OR] = 2.77, 95% confidence interval [CI]: 1.18-6.54; P = 0.02), rs3747206 T allele (CHB + NAFLD group vs CHB group: OR = 2.77, 95%CI: 1.18-6.54; P = 0.02), rs4823173 A allele (CHB + NAFLD group vs CHB group: OR = 2.73, 95%CI: 1.16-6.44; P = 0.02), and rs2072906 G allele (CHB + NAFLD group vs CHB group: OR = 3.05, 95%CI: 1.28-7.26; P = 0.01), conferred high risk to NAFLD in CHB patients. In patients with both CHB and NAFLD, these genotypes of PNPLA3 polymorphisms were associated with increased susceptibility to nonalcoholic steatohepatitis (NASH) (NAFLD activity score ≥ 3; P = 0.01-0.03) and liver fibrosis (> 1 Metavir grading; P = 0.01-0.04). As compared to those with C/C and C/G at rs738409, C/C and C/T at rs3747206, G/G and G/A at rs4823173, and A/A and A/G at rs2072906, patients in the CHB + NAFLD group with G/G at rs738409, T/T at rs3747206, A/A at rs4823173, and G/G at rs2072906 showed significantly lower serum levels of HBV DNA (P < 0.01-0.05).
CONCLUSION: Four linked SNPs of PNPLA3 (rs738409, rs3747206, rs4823173, and rs2072906) are correlated with susceptibility to NAFLD, NASH, liver fibrosis, and HBV dynamics in CHB patients.
PMCID: PMC4515841
Chronic hepatitis B; Hepatitis B virus; Nonalcoholic fatty liver disease; PNPLA3; Single-nucleotide polymorphism
2.  Implementation of Cell Samples as Controls in National Proficiency Testing for Clopidogrel Therapy-Related CYP2C19 Genotyping in China: A Novel Approach 
PLoS ONE  2015;10(7):e0134174.
Laboratories are increasingly requested to perform CYP2C19 genetic testing when managing clopidogrel therapy, especially in patients with acute coronary syndrome undergoing percutaneous coronary intervention. To ensure high quality molecular testing and ascertain that the referring clinician has the correct information for CYP2C19 genotype–directed antiplatelet therapy, a proficiency testing scheme was set up to evaluate the laboratory performance for the entire testing process. Proficiency panels of 10 cell samples encompassing the common CYP2C19 genetic polymorphisms were distributed to 62 participating laboratories for routine molecular testing and the responses were analyzed for accuracy of genotyping and the reporting of results. Data including the number of samples tested, the accreditation/certification status, and test methodology of each individual laboratory were also reviewed. Fifty-seven of the 62 participants correctly identified the CYP2C19 variants in all samples. There were six genotyping errors, with a corresponding analytical sensitivity of 98.5% (333/338 challenges; 95% confidence interval: 96.5–99.5%) and an analytic specificity of 99.6% (281/282; 95% confidence interval: 98.0–99.9%). Reports of the CYP2C19 genotyping results often lacked essential information. In conclusion, clinical laboratories demonstrated good analytical sensitivity and specificity; however, the pharmacogenetic testing community requires additional education regarding the correct reporting of CYP2C19 genetic test results.
PMCID: PMC4517881  PMID: 26218263
3.  Reliability and Validity of the Beijing Version of the Montreal Cognitive Assessment in the Evaluation of Cognitive Function of Adult Patients with OSAHS 
PLoS ONE  2015;10(7):e0132361.
The patients with obstructive sleep apnea hypopnea syndrome (OSAHS) tend to develop cognitive deficits, which usually go unrecognized, and can affect their daily life. The Beijing version of the Montreal cognitive assessment (MoCA-BJ), a Chinese version of MoCA, has been used for the assessment of cognitive functions of OSAHS patients in clinical practice. So far, its reliability and validity have not been tested. This study examined the reliability and validity of MoCA-BJ in a cohort of adult OSAHS patients.
152 OSAHS patients, ranging from mild, moderate to severe, 49 primary snoring subjects and 40 normal controls were evaluated for cognitive functions by employing both MoCA-BJ and the Mini Mental State Examination (MMSE). Forty of them were re-tested by MoCA-BJ 14 days after the first test. Internal consistency, test-retest reliability, discriminate and concurrent validity of MoCA-BJ were analyzed.
Internal consistency reliability by Cronbach’s alpha was adequate (0.73). Intra-class correlation coefficient (ICC), an measure of test-retest reliability, was 0.87 (P<0.001). The total MoCA-BJ scores were significant higher in normal controls than in OSAHS groups (p<0.05). The performances of visuospatial ability in severe OSAHS group were significantly weaker than in normal controls and primary snoring group. The performances of executive ability in severe OSAHS patients were weaker than in normal controls. An optimal cut-off between normal controls and non-normal subjects was at 26 points (total MoCA score). Moreover, cut-off between non-severe and severe OSAHS was at 2 points on visuospatial subscale. Analysis of the correlation between MoCA total scores and MMSE total scores revealed a statistically significant, though relatively weak, correlation (r=0.41, P<0.05).
In conclusion, our study showed that the Beijing version of the MoCA was reliable and stable. The MoCA-BJ was capable of detecting cognitive dysfunction by visuospatial and total MoCA-BJ score.
PMCID: PMC4514887  PMID: 26208289
4.  External Quality Assessment of Molecular Detection of Ebola Virus in China 
PLoS ONE  2015;10(7):e0132659.
In 2014, Ebola hemorrhagic fever broke out in West Africa. As contact between China and West Africa is frequent, the possibility that Ebola virus would enter China was high. Thus, an external assessment of the quality of Ebola virus detection was organized by the National Center for Clinical Laboratories in China. Virus-like particles encapsulating known sequences of epidemic strains of Ebola virus from 2014 were prepared as positive quality controls. The sample panel, which was composed of seven positive and three negative samples, was dispatched to 19 laboratories participating in this assessment of Ebola virus detection. Accurate detection was reported at 14 of the 19 participating laboratories, with a sensitivity of 91.43% and a specificity of 100%. Four participants (21.05%) reported false-negative results and were classified as “acceptable.” One participant (5.26%) did not detect any positive samples and was thus classified as “improvable.” Based on the results returned, the ability to detect weakly positive Ebola specimens should be improved. Furthermore, commercial assays and the standard primers offered by the Chinese Centers for Disease Control and Prevention were found to be most accurate and dependable for Ebola detection. A two-target detection approach is recommended for Ebola screening; this approach could reduce the probability of false-negative results. Additionally, standardization of operations and punctual adjustment of instruments are necessary for the control and prevention of Ebola virus.
PMCID: PMC4503447  PMID: 26177537
5.  Live Cell Integrated Surface Plasmon Resonance Biosensing Approach to Mimic the Regulation of Angiogenic Switch upon Anti-Cancer Drug Exposure 
Analytical Chemistry  2014;86(15):7305-7310.
In this work, we report a novel surface plasmon resonance (SPR) based live-cell biosensing platform to measure and compare the binding affinity of vascular endothelial growth factor (VEGF) to vascular endothelial growth factor receptor (VEGFR) and VEGF to bevacizumab. Results have shown that bevacizumab binds VEGF with a higher association rate and affinity compared to VEGFR. Further, this platform has been employed to mimic the in vivo condition of the VEGF–VEGFR angiogenic switch. Competitive binding to VEGF between VEGFR and bevacizumab was monitored in real-time using this platform. Results demonstrated a significant blockage of VEGF–VEGFR binding by bevacizumab. From the results, it is evident that the proposed strategy is simple and highly sensitive for the direct and real-time measurements of bevacizumab drug efficacy to the VEGF–VEGFR angiogenic switch in living SKOV-3 cells.
PMCID: PMC4372114  PMID: 25005895
6.  Navigating Longitudinal Clinical Notes with an Automated Method for Detecting New Information 
Automated methods to detect new information in clinical notes may be valuable for navigating and using information in these documents for patient care. Statistical language models were evaluated as a means to quantify new information over longitudinal clinical notes for a given patient. The new information proportion (NIP) in target notes decreased logarithmically with increasing numbers of previous notes to create the language model. For a given patient, the amount of new information had cyclic patterns. Higher NIP scores correlated with notes having more new information often with clinically significant events, and lower NIP scores indicated notes with less new information. Our analysis also revealed “copying and pasting” to be widely used in generating clinical notes by copying information from the most recent historical clinical notes forward. These methods can potentially aid clinicians in finding notes with more clinically relevant new information and in reviewing notes more purposefully which may increase the efficiency of clinicians in delivering patient care.
PMCID: PMC4495914  PMID: 23920658
Electronic Health Records; Natural Language Processing; Text Mining; Information Storage and Retrieval
7.  A Novel Audiovisual Brain-Computer Interface and Its Application in Awareness Detection 
Scientific Reports  2015;5:9962.
Currently, detecting awareness in patients with disorders of consciousness (DOC) is a challenging task, which is commonly addressed through behavioral observation scales such as the JFK Coma Recovery Scale-Revised. Brain-computer interfaces (BCIs) provide an alternative approach to detect awareness in patients with DOC. However, these patients have a much lower capability of using BCIs compared to healthy individuals. This study proposed a novel BCI using temporally, spatially, and semantically congruent audiovisual stimuli involving numbers (i.e., visual and spoken numbers). Subjects were instructed to selectively attend to the target stimuli cued by instruction. Ten healthy subjects first participated in the experiment to evaluate the system. The results indicated that the audiovisual BCI system outperformed auditory-only and visual-only systems. Through event-related potential analysis, we observed audiovisual integration effects for target stimuli, which enhanced the discriminability between brain responses for target and nontarget stimuli and thus improved the performance of the audiovisual BCI. This system was then applied to detect the awareness of seven DOC patients, five of whom exhibited command following as well as number recognition. Thus, this audiovisual BCI system may be used as a supportive bedside tool for awareness detection in patients with DOC.
PMCID: PMC4485169  PMID: 26123281
8.  An integrated approach to reveal miRNAs’ impacts on the functional consequence of copy number alterations in cancer 
Scientific Reports  2015;5:11567.
Copy number alteration (CNA) is known to induce gene expression changes mainly through dosage effect, and therefore affect the initiation and progression of tumor. However, tumor samples exhibit heterogeneity in gene dosage sensitivity due to the complicated mechanisms of transcriptional regulation. Currently, no high-throughput method has been available for identifying the regulatory factors affecting the functional consequences of CNA, and determining their effects on cancer. In view of the important regulatory role of miRNA, we investigated the influence of miRNAs on the dosage sensitivities of genes within the CNA regions. By integrating copy number, mRNA expression, miRNA expression profiles of three kinds of cancer, we observed a tendency for high dosage-sensitivity genes to be more targeted by miRNAs in cancer, and identified the miRNAs regulating the dosage sensitivity of amplified/deleted target genes. The results show that miRNAs can modulate oncogenic biological functions by regulating the genes within the CNA regions, and thus play a role as a trigger or balancer in cancer, affecting cancer processes, even survival. This work provided a framework for analyzing the regulation of dosage effect, which will shed a light on understanding the oncogenic and tumor suppressive mechanisms of CNA. Besides, new cancer-related miRNAs were identified.
PMCID: PMC4477324  PMID: 26099552
9.  Photochemical generation and kinetic studies of a putative porphyrin-ruthenium(V)-oxo species 
Photo-disproportionation of a bis-porphyrin-diruthenium(IV) μ-oxo dimer gave a porphyrin-ruthenium(III) species and a putative poprhyrin-ruthenium(V)-oxo species that can be detected and studied in real time via laser flash photolysis methods. As determined by its spectral and kinetic behavior, the same oxo transient was also formed by photolysis of a porphyrin-ruthenium(III) N-oxide adduct. Second-order rate constants for reactions with several substrates at 22 °C were determined; representative values of rate constants were kox = 6.6 × 103 M−1 s−1 for diphenylmethanol, kox = 2.5 × 103 M−1 s−1 for styrene, and kox = 1.8 × 103 M−1 s−1 for cyclohexene. The putative porphyrin-ruthenium(V)-oxo transient reacted 5–6 orders of magnitude faster than the corresponding trans-dioxoruthenium(VI)-oxo porphyrins, and the rate constants obtained in this work were similar to those of corrole-iron(V)-oxo derivative. The high reactivity for the photochemically generated ruthenium-oxo species in comparison to other poprhyrin-metal-oxo intermediates suggests it is a true ruthenium(V)-oxo species.
PMCID: PMC4071932  PMID: 24770388
Ruthenium; porphyrin; oxidation; kinetics; and laser flash photolysis
10.  Transplantation of Induced Pluripotent Stem Cells Alleviates Cerebral Inflammation and Neural Damage in Hemorrhagic Stroke 
PLoS ONE  2015;10(6):e0129881.
Little is known about the effects of induced pluripotent stem cell (iPSC) treatment on acute cerebral inflammation and injuries after intracerebral hemorrhage (ICH), though they have shown promising therapeutic potentials in ischemic stoke.
An ICH model was established by stereotactic injection of collagenase VII into the left striatum of male Sprague-Dawley (SD) rats. Six hours later, ICH rats were randomly divided into two groups and received intracerebrally 10 μl of PBS with or without 1×106 of iPSCs. Subsequently, neural function of all ICH rats was assessed at days 1, 3, 7, 14, 28 and 42 after ICH. Inflammatory cells, cytokines and neural apoptosis in the rats’ perihematomal regions, and brain water content were determined on day 2 or 3 post ICH. iPSC differentiation was determined on day 28 post ICH. Nissl+ cells and glial fibrillary acidic protein (GFAP)+ cells in the perihematoma and the survival rates of rats in two groups were determined on post-ICH day 42.
Compared with control animals, iPSCs treatment not only improved neurological function and survival rate, but also resulted in fewer intracephalic infiltrations of neutrophils and microglia, along with decreased interleukin (IL)-1β, IL-6 and tumour necrosis factor-alpha (TNF-α), and increased IL-10 in the perihematomal tissues of ICH rats. Furthermore, brain oedema formation, apoptosis, injured neurons and glial scar formation were decreased in iPSCs-transplanted rats.
Our findings indicate that iPSCs transplantation attenuate cerebral inflammatory reactions and neural injuries after ICH, and suggests that multiple mechanisms including inflammation modulation, neuroprotection and functional recovery might be involved simultaneously in the therapeutic benefit of iPSC treatment against hemorrhagic stroke.
PMCID: PMC4472717  PMID: 26086994
11.  Expression of circulating miR-486 and miR-150 in patients with acute myocardial infarction 
With its high morbidity and mortality, acute myocardial infarction (AMI) places a major burden on society and on individual patients. Correct, early correct diagnosis is crucial to the management of AMI.
In this study, the expression of circulating miR-486 and miR-150 was investigated in AMI patients and the two miRNAs were evaluated as potential biomarkers for AMI. Plasma samples from 110 patients with AMI (65 patients with ST-segment elevation myocardial infarction (STEMI) and 45 patients with non-ST-segment elevation myocardial infarction (NSTEMI)) and 110 healthy adults were collected. Circulating levels of miR-486 and miR-150 were detected using quantitative real-time PCR in plasma samples.
Results showed that the levels of miR-486 and miR-150 were significantly higher in AMI patients than in healthy controls. Receiver operating characteristic (ROC) curve analyses indicated that the two plasma miRNAs were of significant diagnostic value for AMI, especially NSTEMI. The combined ROC analysis revealed an AUC value of 0.771 in discriminating AMI patients from healthy controls and an AUC value of 0.845 in discriminating NSTEMI patients from healthy controls.
Results indicated that the levels of circulating miR-486 and miR-150 are associated with AMI. They may be novel and powerful biomarkers for AMI, especially for NSTEMI.
PMCID: PMC4466864  PMID: 26077801
Acute myocardial infarction; MicroRNAs; Biomarker
12.  Quetiapine mitigates the ethanol-induced oxidative stress in brain tissue, but not in the liver, of the rat 
Quetiapine, an atypical antipsychotic, has been employed to treat alcoholic patients with comorbid psychopathology. It was shown to scavenge hydroxyl radicals and to protect cultured cells from noxious effects of oxidative stress, a pathophysiological mechanism involved in the toxicity of alcohol. This study compared the redox status of the liver and the brain regions of prefrontal cortex, hippocampus, and cerebellum of rats treated with or without ethanol and quetiapine. Ethanol administration for 1 week induced oxidative stress in the liver and decreased the activity of glutathione peroxidase and total antioxidant capacity (TAC) there. Coadministration of quetiapine did not protect glutathione peroxidase and TAC in the liver against the noxious effect of ethanol, thus was unable to mitigate the ethanol-induced oxidative stress there. The ethanol-induced alteration in the redox status in the prefrontal cortex is mild, whereas the hippocampus and cerebellum are more susceptible to ethanol intoxication. For all the examined brain regions, coadministration of quetiapine exerted effective protection on the antioxidants catalase and total superoxide dismutase and on the TAC, thus completely blocking the ethanol-induced oxidative stress in these brain regions. These protective effects may explain the clinical observations that quetiapine reduced psychiatric symptoms intensity and maintained a good level of tolerability in chronic alcoholism with comorbid psychopathology.
PMCID: PMC4474454  PMID: 26109862
ethanol; quetiapine; oxidative stress; antioxidant
13.  Results of the National External Quality Assessment for Toxoplasmosis Serological Testing in China 
PLoS ONE  2015;10(6):e0130003.
Toxoplasmosis is typically diagnosed by serologic testing. External quality assessment (EQA) of clinical laboratories could ensure the accuracy and reliability of serological tests. We assessed the quality of toxoplasma serological assays in Chinese clinical laboratories by an EQA performed between 2004 and 2013 by the National Center for Clinical Laboratories.
Methodology and Findings
EQA panels were prepared and shipped at room temperature to participating laboratories that employed toxoplasma IgG and IgM serological detection. By 2013, 5,384 EQA test reports for toxoplasma-specific IgM and 2,666 reports for toxoplasma-specific IgG were collected. Enzyme-linked immunosorbent (ELISA) and chemical immunofluorescent assays were the most commonly used detection methods. The overall coincidence rates of negative samples were better than those of positive samples. The overall EQA score for toxoplasma-specific IgM detection ranged between 84.3% and 99.6%. The ratio of laboratories that achieved correct IgG detection ranged from 61.1% to 99.3%. However, the inter- and intra-assay variabilities were found to be considerable. The most common problem was failure to detect low titers of antibody.
The EQA scheme showed an improvement in toxoplasma serological testing in China. However, further optimization of assay sensitivity to detect challenging samples remains a future challenge.
PMCID: PMC4466578  PMID: 26066047
14.  Cardiospecific CD36 suppression by lentivirus-mediated RNA interference prevents cardiac hypertrophy and systolic dysfunction in high-fat-diet induced obese mice 
Fatty acid (FA) catabolism abnormality has been proved to play an important role in obesity-related cardiomyopathy. We hypothesized that cardiospecific suppression of CD36, the predominant membrane FA transporter, would protect against obesity-related cardiomyopathy.
Four-wk-old male C57BL/6 J mice were fed with either high-fat-diet (HFD) or control-normal-diet for 2 wk. Then they were subjected to intramyocardial injection with recombinant lentiviral vectors containing short hairpin RNAs to selectively downregulate the expression of either cardiac CD36 or irrelevant gene by RNA interference. After a 10-wk continuation of the diet, biochemical, functional, morphological, histological, metabolic and molecular profiles were assessed.
HFD administration elicited obesity, cardiac hypertrophy and systolic dysfunction accompanied with elevated serum levels of blood urea nitrogen (BUN), creatinine, fasting serum glucose (FSG), total cholesterol (TC) and triglyceride. Additionally, HFD consumption promoted lipid accumulation and reactive oxygen species (ROS) generation in the cardiomyocytes. Cardiospecific CD36 inhibition protected against HFD induced cardiac remodeling by decreasing heart/body weight ratio, increasing left ventricular (LV) ejection fraction and fractional shortening as well as normalizing LV diameter, without influencing body weight gain. Inhibition of cardiac CD36 also mitigated obesity induced alteration in BUN, creatinine and triglyceride, but had no effect on FSG or TC. Moreover, cardiospecific CD36 deficiency corrected myocardial lipid overaccumulation and intracellular ROS overproduction that were induced by HFD feeding.
Cardiospecific CD36 inhibition protects against the aggravation of cardiac functional and morphological changes associated with HFD induced obesity. CD36 represents a potential therapeutic target for obesity cardiomyopathy.
PMCID: PMC4464858  PMID: 26036798
Obesity; Cardiomyopathy; CD36; RNA interference; Lipotoxicity
15.  Fiber based optical tweezers for simultaneous in situ force exertion and measurements in a 3D polyacrylamide gel compartment 
Biomedical Optics Express  2015;6(7):2325-2336.
Optical tweezers play an important role in biological applications. However, it is difficult for traditional optical tweezers based on objective lenses to work in a three-dimensional (3D) solid far away from the substrate. In this work, we develop a fiber based optical trapping system, namely inclined dual fiber optical tweezers, that can simultaneously apply and measure forces both in water and in a 3D polyacrylamide gel matrix. In addition, we demonstrate in situ, non-invasive characterization of local mechanical properties of polyacrylamide gel by measurements on an embedded bead. The fiber optical tweezers measurements agree well with those of atomic force microscopy (AFM). The inclined dual fiber optical tweezers provide a promising and versatile tool for cell mechanics study in 3D environments.
PMCID: PMC4505692  PMID: 26203364
(350.4855) Optical tweezers or optical manipulation; (060.2310) Fiber optics
In this study we report on potential drug-drug interactions between drugs occurring in patient clinical data. Results are based on relationships in SemMedDB, a database of structured knowledge extracted from all MEDLINE citations (titles and abstracts) using SemRep. The core of our methodology is to construct two potential drug-drug interaction schemas, based on relationships extracted from SemMedDB. In the first schema, Drug1 and Drug2 interact through Drug1’s effect on some gene, which in turn affects Drug2. In the second, Drug1 affects Gene1, while Drug2 affects Gene2. Gene1 and Gene2, together, then have an effect on some biological function. After checking each drug pair from the medication lists of each of 22 patients, we found 19 known and 62 unknown drug-drug interactions using both schemas. For example, our results suggest that the interaction of Lisinopril, an ACE inhibitor commonly prescribed for hypertension, and the antidepressant sertraline can potentially increase the likelihood and possibly the severity of psoriasis. We also assessed the relationships extracted by SemRep from a linguistic perspective and found that the precision of SemRep was 0.58 for 300 randomly selected sentences from MEDLINE. Our study demonstrates that the use of structured knowledge in the form of relationships from the biomedical literature can support the discovery of potential drug-drug interactions occurring in patient clinical data. Moreover, SemMedDB provides a good knowledge resource for expanding the range of drugs, genes, and biological functions considered as elements in various drug-drug interaction pathways.
PMCID: PMC4058371  PMID: 24448204
Drug-drug interactions; MEDLINE; SemRep; SemMedDB; Natural language processing; Clinical data; Semantic predication
17.  Detection of miR-33 Expression and the Verification of Its Target Genes in the Fatty Liver of Geese 
Background: miRNAs are single-stranded, small RNA molecules with a length of 18–25 nucleotides. They bind to the 3′ untranslated regions of mRNA transcripts to reduce the translation of these transcripts or to cause their degradation. The roles of these molecules differ in biological processes, such as cell differentiation, proliferation, apoptosis and tumor genesis. miRNA-33 is encoded by the gene introns of proteins that bind sterol-regulatory elements. This molecule cooperates with these proteins to control cholesterol homeostasis, fatty acid levels and the genes that are related to the expression of fat metabolism. The examination of miR-33 expression and its target genes can promote the in-depth study of the miRNA regulation mechanism in the formation process of goose fatty liver and can lay a foundation for research into human fatty liver. Methodology/principal findings: (1) Through real-time fluorescent quantitative polymerase chain reaction (TaqMan MicroRNA Assay), we detected the expression of miR-33 during the feeding of Landes geese. The expression level of miR-33 increases significantly in the liver after 19 days in comparison with the control group; (2) By using the bioinformatics software programs TargetScan, miRDB and miRCosm to predict the target genes of miR-33 according to laboratory prophase transcriptome results and references, we screen nine target genes: adenosine triphosphate binding cassette transporters A1, adenosine triphosphate binding cassette transporters G1, Neimann Pick C, carnitine O-octanoyltransferase (CROT), cyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase, beta subunit (HADHB), AMP-activated protein kinase, alpha subunit 1 (AMPKα1), insulin receptor substrate 2, glutamic pyruvate transaminase and adipose differentiation-related protein. The dual luciferase reporter gene system in the CHO cell line verifies that CROT, HADHB and NPC1 are the target genes of miR-33 in geese. The inhibition rate of CROT is highest and reaches 70%; (3) The seed sequence (5′ 2–8 bases) is the acting site of miR-33. The two predicted target sites of CROT are the target sites of miR-33. Moreover, the predicted target site of HADHB and NPC1 is the target site of miR-33. Conclusions/significance: (1) After 19 days of overfeeding, the expression level of miR-33 increases significantly in the livers of geese; (2) CROT, HADHB and NPC1 are the target genes of miR-33 in geese. These genes determine the combined target site.
PMCID: PMC4490470  PMID: 26057744
miR-33; goose fatty liver; target gene; fat metabolism
18.  Transcriptional Factors Mediating Retinoic Acid Signals in the Control of Energy Metabolism 
Retinoic acid (RA), an active metabolite of vitamin A (VA), is important for many physiological processes including energy metabolism. This is mainly achieved through RA-regulated gene expression in metabolically active cells. RA regulates gene expression mainly through the activation of two subfamilies in the nuclear receptor superfamily, retinoic acid receptors (RARs) and retinoid X receptors (RXRs). RAR/RXR heterodimers or RXR/RXR homodimers bind to RA response element in the promoters of RA target genes and regulate their expressions upon ligand binding. The development of metabolic diseases such as obesity and type 2 diabetes is often associated with profound changes in the expressions of genes involved in glucose and lipid metabolism in metabolically active cells. RA regulates some of these gene expressions. Recently, in vivo and in vitro studies have demonstrated that status and metabolism of VA regulate macronutrient metabolism. Some studies have shown that, in addition to RARs and RXRs, hepatocyte nuclear factor 4α, chicken ovalbumin upstream promoter-transcription factor II, and peroxisome proliferator activated receptor β/δ may function as transcriptional factors mediating RA response. Herein, we summarize current progresses regarding the VA metabolism and the role of nuclear receptors in mediating RA signals, with an emphasis on their implication in energy metabolism.
PMCID: PMC4490549  PMID: 26110391
vitamin A; retinoic acid; retinoic acid receptor; retinoid X receptor; hepatic nuclear factor 4α; chicken ovalbumin upstream-transcription factor II; peroxisome proliferator activated receptor β/δ; metabolism
19.  Comparison of the clinical characteristics and survival between Uyghur patients with hepatitis virus-related and non-B, non-C hepatocellular carcinoma in Xinjiang, China 
To compare the clinical characteristics and prognosis between hepatitis virus-related hepatocellular carcinoma (viral HCC) and non-B, non-C HCC (NBC-HCC) among Uyghur patients in Xinjiang province, China.
Between 01/01/2000 and 31/12/2012, 319 Uyghur HCC patients were treated at the Cancer Centre of The First Affiliated Hospital of Xinjiang Medical University. The data for the patients were obtained from a retrospective review of the patients’ medical records. A total of 18 patients were excluded from the study because of incomplete information. The patients were classified into two groups: viral HCC and NBC-HCC. The clinical characteristics and prognostic factors were statistically analysed.
For all 301 patients, gender (P=0.000), area of residence (P=0.002), diabetes mellitus (P=0.009), BMI (P=0.000), cirrhosis (P=0.000), tumour stage (P=0.004), Child-Pugh class (P=0.000), the TBIL level (P=0.000), and the alpha-fetoprotein (AFP) level (P=0.000) were significantly different between the NBC-HCC and viral HCC groups. The NBC-HCC patients tended to be diagnosed at advanced stages; however, the NBC-HCC patients exhibited lower Child-Pugh scores than the viral HCC patients. In all patients examined, the 0.5-, 1-, 3- and 5-year overall survival (OS) rates were 35.6%, 20.3%, 12.6% and 4.5%, respectively. No significant difference in OS was observed between the two groups (P=0.124). Cox multivariate analysis revealed that age (RR =1.539, P=0.001), TNM stage (RR =12.708, P=0.000), portal vein tumour thrombus (PVTT) (RR =2.003, P=0.000), Child-Pugh class (RR =1.715, P=0.000), and TACE + radiotherapy/RFA (RR =0.567, P=0.000) were significant independent prognostic factors for HCC patients.
The clinical characteristics differ between Uyghur patients with NBC-HCC and viral HCC. HCC in the Xinjiang region displays specific regional characteristics. Age, TNM stage, PVTT, Child-Pugh class and TACE + radiotherapy/RFA are significant risk factors that influence patient survival.
PMCID: PMC4490201  PMID: 26157324
Hepatocellular carcinoma (HCC); Uyghur people; non-B, non-C HCC (NBC-HCC); hepatitis virus-related HCC (viral HCC); clinical characteristics
20.  Saturated Fatty Acid Inhibits Viral Replication in Chronic Hepatitis B Virus Infection With Nonalcoholic Fatty Liver Disease by Toll-Like Receptor 4-Mediated Innate Immune Response 
Hepatitis Monthly  2015;15(5):e27909.
Chronic Hepatitis B (CHB) infection is common in patients with Non-Alcoholic Fatty Liver Disease (NAFLD). The replication level of Hepatitis B Virus (HBV) was inversely correlated with hepatic steatosis. Toll-Like Receptor (TLR) 4-mediated innate immunity plays a pivotal role in the occurrence of NAFLD and controls HBV replication.
This study aimed to investigate whether the TLR4-mediated innate immunity stimulates the pathogenesis of CHB in patients with NAFLD and to determine whether TLR4 plays a role in inhibiting HBV replication.
Materials and Methods:
The HBV transgenic mice were randomized into the HBV and HBV/NAFLD groups. HepG2.2.15 cells were treated with different concentrations (0 – 200 μM) of Stearic Acid (SA) to induce steatosis. The total RNA of the liver tissue was extracted for Real-Time Polymerase Chain Reaction (RT-PCR) detection, and immunohistochemistry or western blot was conducted for further validation. The Enzyme-Linked Immunosorbent Assay (ELISA) analysis was applied to evaluate the production of Interleukin 6 (IL-6), Tumor necrosis factor α (TNF-α) and Interferon β (IFN-β). Moreover, viral dynamics were analyzed using HBV DNA and HBV-related antigens (HBsAg and HBeAg).
Non-alcoholic fatty liver disease was induced in HBV-transgenic mice fed with High Fat Diet (HFD) for 8 - 24 weeks. Oil red-O staining positive droplets and the content of Triglyceride (TG) were increased in HepG2.2.15 cells treated with SA. TLR4, Myeloid differentiation factor 88 (MyD88), IL-6 and TNF-α expression levels were significantly higher in the HBV/NAFLD group and the steatotic HepG2.2.15 cells than those in their respective controls. Compared to the HBV group, significant reductions in serum levels of HBsAg, HBeAg, and HBV DNA titers occurred in the HBV/NAFLD group at 24 weeks, but the IFN-β level was remarkably increased. Similar data were also obtained from the steatoric HepG2.2.15 cells.
Saturated Fatty Acids (SFAs) served as a potential ligand for TLR4 and activated TLR4 signaling pathway, which might be involved in the pathogenesis. Thus, SFAs can accelerate the mechanism of inhibiting HBV replication in CHB with NAFLD.
PMCID: PMC4451278  PMID: 26045709
Diet, High-Fat; Stearic Acid; Toll-like receptor 4; Hepatitis B Virus; Nonalcoholic Fatty Liver Disease
21.  High resolution microtubule structures reveal the structural transitions in αβ–tubulin upon GTP hydrolysis 
Cell  2014;157(5):1117-1129.
Dynamic instability, the stochastic switching between growth and shrinkage, is essential for microtubule function. This behavior is driven by GTP hydrolysis in the microtubule lattice, and is inhibited by anticancer agents like Taxol. We provide new insight into the mechanism of dynamic instability, based on high-resolution cryo-EM structures (4.7–5.6 Å) of dynamic microtubules and microtubules stabilized by GMPCPP or Taxol. We infer that hydrolysis leads to a compaction around the E-site nucleotide at longitudinal interfaces, as well as movement of the α–tubulin intermediate domain and H7 helix. Displacement of the C-terminal helices in both α– and β–tubulin subunits suggests an effect on interactions with binding partners that contact this region. Taxol inhibits most of these conformational changes, allosterically inducing a GMPCPP-like state. Lateral interactions are similar in all conditions we examined, suggesting that microtubule lattice stability is primarily modulated at longitudinal interfaces.
PMCID: PMC4054694  PMID: 24855948
22.  Effects of Emergency Cervical Cerclage on Pregnancy Outcome: A Retrospective Study of 158 Cases 
The aim of this study was to evaluate the effectiveness and safety of emergency cervical cerclage in women with advanced cervical dilatation and bulging of fetal membranes. The study included 158 women who underwent emergency cervical cerclage because of cervix dilatation and protruding membranes in mid-trimester at Sun Yat-sen Memorial Hospital of Sun Yat-sen University. Pregnancy outcomes and pregnancy outcome related to clinical features were analyzed retrospectively. Analysis revealed that the placement of emergency cerclage led to the delivery of live infants with a success rate of 82.28%. The mean interval between cerclage and delivery was 52.16.±26.62 days, with a mean gestation at delivery of 30.3±4.7 weeks and a mean birth weight of 1934.69±570.37 g. No severe maternal complications such as maternal death, hematosepsis, and hysterorrhexis occurred after the operation. Two women (1.25%) had laceration of the cervix, 1 woman (0.61%) suffered pulmonary edema, and 2 women (1.25%) developed deep vein thrombosis (DVT). There were significant correlations between the pregnancy outcome and risk factors, including any presenting symptoms, cervical dilatation, postoperative white blood cell count, and C-reactive protein (CRP) value. No significant difference was found in women with good vs. poor outcome in terms of maternal age and obstetric histories. Emergency cervical cerclage is effective in prolonging pregnancy and improving neonatal outcome in women with cervical incompetence. It should be considered a viable option for women with a dilated cervix in mid-trimester.
PMCID: PMC4444177  PMID: 25975832
C-Reactive Protein; Obstetric Labor, Premature; Uterine Cervical Incompetence
23.  Association of elevated apoA-I glycation and reduced HDL-associated paraoxonase1, 3 activity, and their interaction with angiographic severity of coronary artery disease in patients with type 2 diabetes mellitus 
To investigate whether apolipoprotein A (apoA)-I glycation and paraoxonase (PON) activities are associated with the severity of coronary artery disease (CAD) in patients with type 2 diabetes mellitus (T2DM).
Relative intensity of apoA-I glycation and activities of high-density lipoprotein (HDL)-associated PON1 and PON3 were determined in 205 consecutive T2DM patients with stable angina with (n = 144) or without (n = 61) significant CAD (luminal diameter stenosis ≥ 70 %). The severity of CAD was expressed by number of diseased coronary arteries, extent index, and cumulative coronary stenosis score (CCSS).
The relative intensity of apoA-I glycation was higher but the activities of HDL-associated PON1 and PON3 were lower in diabetic patients with significant CAD than in those without. The relative intensity of apoA-I glycation increased but the activities of HDL-associated PON1 and PON3 decreased stepwise from 1 - to 3 - vessel disease patients (P for trend < 0.001). After adjusting for possible confounding variables, the relative intensity of apoA-I glycation correlated positively, while the activities of HDL-associated PON1 and PON3 negatively, with extent index and CCSS, respectively. At high level of apoA-I glycation (8.70 ~ 12.50 %), low tertile of HDL-associated PON1 (7.03 ~ 38.97U/mL) and PON3 activities (7.11 ~ 22.30U/mL) was associated with a 1.97− and 2.49− fold increase of extent index and 1.73− and 2.68− fold increase of CCSS compared with high tertile of HDL-associated PON1 (57.85 ~ 154.82U/mL) and PON3 activities (39.63 ~ 124.10U/mL), respectively (all P < 0.01).
Elevated apoA-I glycation and decreased activities of HDL-associated PON1 and PON3, and their interaction are associated with the presence and severity of CAD in patients with T2DM.
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-015-0221-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4432963  PMID: 25964115
Diabetes mellitus; ApoA-I glycation; Paraoxonase; Coronary artery disease
24.  Microbial Community in High Arsenic Shallow Groundwater Aquifers in Hetao Basin of Inner Mongolia, China 
PLoS ONE  2015;10(5):e0125844.
A survey was carried out on the microbial community of 20 groundwater samples (4 low and 16 high arsenic groundwater) and 19 sediments from three boreholes (two high arsenic and one low arsenic boreholes) in a high arsenic groundwater system located in Hetao Basin, Inner Mongolia, using the 454 pyrosequencing approach. A total of 233,704 sequence reads were obtained and classified into 12–267 operational taxonomic units (OTUs). Groundwater and sediment samples were divided into low and high arsenic groups based on measured geochemical parameters and microbial communities, by hierarchical clustering and principal coordinates analysis. Richness and diversity of the microbial communities in high arsenic sediments are higher than those in high arsenic groundwater. Microbial community structure was significantly different either between low and high arsenic samples or between groundwater and sediments. Acinetobacter, Pseudomonas, Psychrobacter and Alishewanella were the top four genera in high arsenic groundwater, while Thiobacillus, Pseudomonas, Hydrogenophaga, Enterobacteriaceae, Sulfuricurvum and Arthrobacter dominated high arsenic sediments. Archaeal sequences in high arsenic groundwater were mostly related to methanogens. Biota-environment matching and co-inertia analyses showed that arsenic, total organic carbon, SO42-, SO42-/total sulfur ratio, and Fe2+ were important environmental factors shaping the observed microbial communities. The results of this study expand our current understanding of microbial ecology in high arsenic groundwater aquifers and emphasize the potential importance of microbes in arsenic transformation in the Hetao Basin, Inner Mongolia.
PMCID: PMC4429976  PMID: 25970606
25.  Clinicopathological analysis of 12 patients with autoimmune pancreatitis 
Autoimmune pancreatitis (AIP) is a rare type of chronic pancreatitis that is often misdiagnosed as pancreatic cancer (PaC). This study was undertaken to investigate the clinicopathological characteristics of AIP, in order to improve the diagnosis and treatment of the disease. Among the 271 patients with PaC who underwent pancreatoduodenectomy between January 2003 and December 2012 at the Sun Yat-Sen Memorial Hospital, chronic pancreatitis was identified and tissue samples obtained from 16 patients. The clinicopathological and imaging characteristics of 16 of the patients with chronic pancreatitis were analyzed retrospectively. The expression of immunoglobulin G4 (IgG4) in the pancreas tissue was detected by immunohistochemistry. Immunohistochemistry showed that IgG4 was highly expressed in 12 out of the 16 patients, and those 12 patients were diagnosed with AIP. Among those 12 patients, 6 presented with emaciation and 7 with jaundice and abdominal pain, respectively. Among the 16 included patients, 12 had an elevated level of serum γ-glutamyltransferase and 9 had an elevated level of serum carbohydrate antigen 19-9. The imaging features were as follows: Pancreatic enlargement in 11 patients (particularly pancreatic head enlargement), pancreatic miniature in 1, ‘sausage-like’ pancreatic changes in 4 and ‘halo’ sign pancreatic changes in 5. Massive plasma cell infiltration (11/12) and parenchymal fibrosis (8/12) were observed in the pancreatic tissues through pathology. These results suggest that combining imaging with IgG4 expression for the purpose of diagnosis can enhance the preoperative diagnostic value and reduce the rate of AIP misdiagnosis.
PMCID: PMC4487082  PMID: 26170922
autoimmune pancreatitis; immunoglobulin G4; diagnosis; differentiation

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