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1.  Two Outbreak Sources of Influenza A (H7N9) Viruses Have Been Established in China 
Journal of Virology  2016;90(12):5561-5573.
ABSTRACT
Due to enzootic infections in poultry and persistent human infections in China, influenza A (H7N9) virus has remained a public health threat. The Yangtze River Delta region, which is located in eastern China, is well recognized as the original source for H7N9 outbreaks. Based on the evolutionary analysis of H7N9 viruses from all three outbreak waves since 2013, we identified the Pearl River Delta region as an additional H7N9 outbreak source. H7N9 viruses are repeatedly introduced from these two sources to the other areas, and the persistent circulation of H7N9 viruses occurs in poultry, causing continuous outbreak waves. Poultry movements may contribute to the geographic expansion of the virus. In addition, the AnH1 genotype, which was predominant during wave 1, was replaced by JS537, JS18828, and AnH1887 genotypes during waves 2 and 3. The establishment of a new source and the continuous evolution of the virus hamper the elimination of H7N9 viruses, thus posing a long-term threat of H7N9 infection in humans. Therefore, both surveillance of H7N9 viruses in humans and poultry and supervision of poultry movements should be strengthened.
IMPORTANCE Since its occurrence in humans in eastern China in spring 2013, the avian H7N9 viruses have been demonstrating the continuing pandemic threat posed by the current influenza ecosystem in China. As the viruses are silently circulated in poultry, with potentially severe outcomes in humans, H7N9 virus activity in humans in China is very important to understand. In this study, we identified a newly emerged H7N9 outbreak source in the Pearl River Delta region. Both sources in the Yangtze River Delta region and the Pearl River Delta region have been established and found to be responsible for the H7N9 outbreaks in mainland China.
doi:10.1128/JVI.03173-15
PMCID: PMC4886776  PMID: 27030268
2.  Efficacy and Safety of Lenalidomide for Treatment of Low-/Intermediate-1-Risk Myelodysplastic Syndromes with or without 5q Deletion: A Systematic Review and Meta-Analysis 
PLoS ONE  2016;11(11):e0165948.
Background
Lenalidomide could effectively induce red blood cell (RBC) transfusion independence (TI) in patients with lower-risk (Low/Intermediate-1) myelodysplastic syndrome (MDS) with or without 5q deletion. However whether lenalidomide ultimately improves the overall survival (OS) of lower-risk MDS patients and reduces the progression to AML remains controversial.
Method
A meta-analysis was conducted to examine the efficacy and safety of lenalidomide in the treatment of lower-risk MDS. Efficacy was assessed according to erythroid hematologic response (HI-E), cytogenetic response (CyR), OS and AML progression. Safety was evaluated based on the occurrence rates of grades 3–4 adverse events (AEs).
Results
Seventeen studies were included consisting of a total of 2160 patients. The analysis indicated that the overall rate of HI-E was 58% with 95% confidence interval (CI) of 43–74%. The pooled estimates for the rates of CyR, complete CyR, and partial CyR were 44% (95% CI 19–68%), 21% (95% CI 13–30%) and 23% (95% CI 15–32%), respectively. The patients with 5q deletion had significantly higher rate of HI-E and CyR than those without 5q deletion (P = 0.002 and 0.001, respectively). The incidences of grades 3–4 neutropenia, thrombocytopenia, leukopenia, anemia, deep vein thrombosis, diarrhea, fatigue and rash were 51% (95% CI 30–73%), 31% (95% CI 20–42%), 9% (95% CI 5–13%), 7% (95% CI 2–12%), 3% (95% CI 2–5%), 3% (95% CI 1–5%), 2% (95% CI 1–4%) and 2% (95% CI 1–3%), respectively. Lenalidomide significantly improved OS (HR: 0.62, 95% CI 0.47–0.83, P = 0.001) and lowered the risk of AML progression in del(5q) patients (RR: 0.61, 95% CI 0.41–0.91, P = 0.014).
Conclusions
In spite of the AEs, lenalidomide could be effectively and safely used for the treatment of lower-risk MDS patients with or without 5q deletion.
doi:10.1371/journal.pone.0165948
PMCID: PMC5100926  PMID: 27824902
3.  Water-soluble acacetin prodrug confers significant cardioprotection against ischemia/reperfusion injury 
Scientific Reports  2016;6:36435.
The morbidity and mortality of patients with ischemic cardiomyopathy resulted from ischemia/reperfusion injury are very high. The present study investigates whether our previously synthesized water-soluble phosphate prodrug of acacetin was cardioprotective against ischemia/reperfusion injury in an in vivo rat model. We found that intravenous administration of acacetin prodrug (10 mg/kg) decreased the ventricular arrhythmia score and duration, reduced ventricular fibrillation and infarct size, and improved the impaired heart function induced by myocardial ischemia/reperfusion injury in anesthetized rats. The cardioprotective effects were further confirmed with the parent compound acacetin in an ex vivo rat regional ischemia/reperfusion heart model. Molecular mechanism analysis revealed that acacetin prevented the ischemia/reperfusion-induced reduction of the anti-oxidative proteins SOD-2 and thioredoxin, suppressed the release of inflammation cytokines TLR4, IL-6 and TNFα, and decreased myocyte apoptosis induced by ischemia/reperfusion. Our results demonstrate the novel evidence that acacetin prodrug confer significant in vivo cardioprotective effect against ischemia/reperfusion injury by preventing the reduction of endogenous anti-oxidants and the release of inflammatory cytokines, thereby inhibiting cardiomyocytes apoptosis, which suggests that the water-soluble acacetin prodrug is likely useful in the future as a new drug candidate for treating patients with acute coronary syndrome.
doi:10.1038/srep36435
PMCID: PMC5098248  PMID: 27819271
4.  Effects of Individual, Spousal, and Offspring Socioeconomic Status on Mortality Among Elderly People in China 
Journal of Epidemiology  2016;26(11):602-609.
Background
The relationship between socio-economic status and health among elderly people has been well studied, but less is known about how spousal or offspring’s education affects mortality, especially in non-Western countries. We investigated these associations using a large sample of Chinese elderly.
Methods
The data came from the Chinese Longitudinal Healthy Longevity Survey (CLHLS) from the years 2005 to 2011 (n = 15 355, aged 65–105 years at baseline; 5046 died in 2008, and 2224 died in 2011). Educational attainment, occupational status, and household income per capita were used as indicators of socio-economic status. Spousal and offspring’s education were added into the final models. The Cox proportional hazards model was used to study mortality risk by gender.
Results
Adjusted for age, highly educated males and females had, on average, 29% and 37% lower mortality risk, respectively, than those with a lower education. Particularly among men, this effect was observed among those whose children had intermediate education only. A higher household income was also associated with lower mortality risk among the elderly. Male elderly living with a well-educated spouse (HR 0.79; 95% CI, 0.64–0.99) had a lower mortality risk than those living with a low-educated spouse.
Conclusions
Both the socio-economic status of the individual and the educational level of a co-resident spouse or child are associated with mortality risk in elderly people. The socio-economic position of family members plays an important role in producing health inequality among elderly people.
doi:10.2188/jea.JE20150252
PMCID: PMC5083324  PMID: 27150012
socioeconomic status; mortality risk; spousal and offspring’s education; CLHLS; Chinese elderly
5.  Large-scale identification of adverse drug reaction-related proteins through a random walk model 
Scientific Reports  2016;6:36325.
Adverse drug reactions (ADRs) are responsible for drug failure in clinical trials and affect life quality of patients. The identification of ADRs during the early phases of drug development is an important task. Therefore, predicting potential protein targets eliciting ADRs is essential for understanding the pathogenesis of ADRs. In this study, we proposed a computational algorithm,Integrated Network for Protein-ADR relations (INPADR), to infer potential protein-ADR relations based on an integrated network. First, the integrated network was constructed by connecting the protein-protein interaction network and the ADR similarity network using known protein-ADR relations. Then, candidate protein-ADR relations were further prioritized by performing a random walk with restart on this integrated network. Leave-one-out cross validation was used to evaluate the ability of the INPADR. An AUC of 0.8486 was obtained, which was a significant improvement compared to previous methods. We also applied the INPADR to two ADRs to evaluate its accuracy. The results suggested that the INPADR is capable of finding novel protein-ADR relations. This study provides new insight to our understanding of ADRs. The predicted ADR-related proteins will provide a reference for preclinical safety pharmacology studies and facilitate the identification of ADRs during the early phases of drug development.
doi:10.1038/srep36325
PMCID: PMC5090865  PMID: 27805066
6.  Gastrointestinal localization of metronidazole by a lactobacilli-inspired tetramic acid motif improves treatment outcomes in the hamster model of Clostridium difficile infection 
Journal of Antimicrobial Chemotherapy  2015;70(11):3061-3069.
Objectives
Metronidazole, a mainstay treatment for Clostridium difficile infection (CDI), is often ineffective for severe CDI. Whilst this is thought to arise from suboptimal levels of metronidazole in the colon due to rapid absorption, empirical validation is lacking. In contrast, reutericyclin, an antibacterial tetramic acid from Lactobacillus reuteri, concentrates in the gastrointestinal tract. In this study, we modified metronidazole with reutericyclin's tetramic acid motif to obtain non-absorbed compounds, enabling assessment of the impact of pharmacokinetics on treatment outcomes.
Methods
A series of metronidazole-bearing tetramic acid substituents were synthesized and evaluated in terms of anti-C. difficile activities, gastric permeability, in vivo pharmacokinetics, efficacy in the hamster model of CDI and mode of action.
Results
Most compounds were absorbed less than metronidazole in cell-based Caco-2 permeability assays. In hamsters, lead compounds compartmentalized in the colon rather than the bloodstream with negligible levels detected in the blood, in direct contrast with metronidazole, which was rapidly absorbed into the blood and was undetectable in caecum. Accordingly, four leads were more efficacious (P < 0.05) than metronidazole in C. difficile-infected animals. Improved efficacy was not due to an alternative mode of action, as the leads retained the mode of action of metronidazole.
Conclusions
This study provides the clearest empirical evidence that the high absorption of metronidazole lowers treatment outcomes for CDI and suggests a role for the tetramic acid motif for colon-specific drug delivery. This approach also has the potential to lower systemic toxicity and drug interactions of nitroheterocyclic drugs for treating gastrointestine-specific diseases.
doi:10.1093/jac/dkv231
PMCID: PMC4677261  PMID: 26286574
7.  Reassortant Eurasian Avian-Like Influenza A(H1N1) Virus from a Severely Ill Child, Hunan Province, China, 2015 
Emerging Infectious Diseases  2016;22(11):1930-1936.
Infectivity and virulence of this virus in mice are higher than for previous human-origin Eurasian avian–like viruses.
In 2015, a novel influenza A(H1N1) virus was isolated from a boy in China who had severe pneumonia. The virus was a genetic reassortant of Eurasian avian-like influenza A(H1N1) (EA-H1N1) virus. The hemagglutinin, neuraminidase, and matrix genes of the reassortant virus were highly similar to genes in EA-H1N1 swine influenza viruses, the polybasic 1 and 2, polymerase acidic, and nucleoprotein genes originated from influenza A(H1N1)pdm09 virus, and the nonstructural protein gene derived from classical swine influenza A(H1N1) (CS H1N1) virus. In a mouse model, the reassortant virus, termed influenza A/Hunan/42443/2015(H1N1) virus, showed higher infectivity and virulence than another human EA-H1N1 isolate, influenza A/Jiangsu/1/2011(H1N1) virus. In the respiratory tract of mice, virus replication by influenza A/Hunan/42443/2015(H1N1) virus was substantially higher than that by influenza A/Jiangsu/1/2011(H1N1) virus. Human-to-human transmission of influenza A/Hunan/42443/2015(H1N1) virus has not been detected; however, given the circulation of novel EA-H1N1 viruses in pigs, enhanced surveillance should be instituted among swine and humans.
doi:10.3201/eid2211.160181
PMCID: PMC5088044  PMID: 27767007
viruses; influenza virus; influenza A(H1N1) virus; influenza; reassortant virus; genetic reassortant; Eurasian avian-like virus; EA-H1N1; clinical features; infectivity; virulence; China; novel virus; human origin; swine influenza virus; respiratory infections
8.  Innate immune memory and homeostasis may be conferred through crosstalk between the TLR3 and TLR7 pathways 
Science signaling  2016;9(436):ra70.
Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns (PAMPs) and stimulate the innate immune response through the production of cytokines. The innate immune response depends on the timing of encountering PAMPs, suggesting a short-term “memory.” In particular, activation of TLR3 appears to prime macrophages for the subsequent activation of TLR7, which leads to synergistically increased production of cytokines. By developing a calibrated mathematical model for the kinetics of TLR3 and TLR7 pathway crosstalk and providing experimental validation, we demonstrated the involvement of the Janus-activated kinase (JAK)–signal transducer and activator of transcription (STAT) pathway in controlling the synergistic production of cytokines. Signaling through this pathway played a dual role: It mediated the synergistic production of cytokines, thus boosting the immune response, and it also maintained homeostasis to avoid an excessive inflammatory response. Thus, we propose that the JAK-STAT pathway provides a cytokine rheostat mechanism, which enables macrophages to fine-tune their responses to multiple, temporally separated infection events involving the TLR3 and TLR7 pathways.
doi:10.1126/scisignal.aac9340
PMCID: PMC5087126  PMID: 27405980
9.  The Prevalence of and Risk Factors Associated with Musculoskeletal Disorders among Sonographers in Central China: A Cross-Sectional Study 
PLoS ONE  2016;11(10):e0163903.
Objective
Studies from industrialized countries show that musculoskeletal disorders (MSD) occur commonly in sonographers. However, little is known about sonographers in China, where the awareness of ergonomics and MSD, workload, and available equipment/facilities may differ. We aimed to investigate the prevalence of MSD and associated risk factors in sonographers in central China.
Methods
A cross-sectional survey was conducted with 381 sonographers from 14 randomly selected tertiary hospitals in Hubei province, central China. Musculoskeletal symptoms (using the Nordic Questionnaire) and risk factors (mostly derived from the Health Benefit Trust survey instrument and the Dutch Musculoskeletal Questionnaire) were recorded. Multivariate logistic regression was used to quantify associations between risk factors and MSD.
Results
The 12-month period prevalence of MSD was 98.3%, being highest in the neck (93.5%) and shoulder (92.2%), followed by the lower back (83.2%), wrist/hand, upper back, and elbow. Factors contributing to neck pain were psychological fatigue, shoulder abduction and trunk bend-and-twist posture. Height-adjustable tables and chairs were protective factors. Shoulder pain was associated with female sex, health status, mental stress, shoulder abduction, and trunk bend-and-twist posture. Height-adjustable chairs and the awareness of adjusting the workstation before scanning were protective factors. Elbow pain was associated with health status and height-adjustable tables. Wrist/hand pain was associated with female sex, bending the wrist, and working with obese patients. Upper back pain was associated with shoulder abduction, height-adjustable chairs, and device location. Lower back pain was associated with the number of scans performed per day, awkward postures, bending the trunk, twisting or bending the neck forward, and using a footrest.
Conclusions
This study suggests a high prevalence of MSD in sonographers in central China. Hence, it is necessary to improve the awareness of MSD by training, and the ergonomics of their current work environment by addressing physical workload, and psychological and equipment/facility-related factors.
doi:10.1371/journal.pone.0163903
PMCID: PMC5047644  PMID: 27695095
10.  MicroRNA‐214 Is Upregulated in Heart Failure Patients and Suppresses XBP1‐Mediated Endothelial Cells Angiogenesis 
Journal of Cellular Physiology  2015;230(8):1964-1973.
More and more miRNAs have been shown to regulate gene expression in the heart and dysregulation of their expression has been linked to cardiovascular diseases including the miR‐199a/214 cluster. However, the signature of circulating miR‐214 expression and its possible roles during the development of heart failure has been less well studied. In this study, we elucidated the biological and clinical significance of miR‐214 dysregulation in heart failure. Firstly, circulating miR‐214 was measured by quantitative PCR, and we found that miR‐214 was upregulated in the serum of chronic heart failure patients, as well as in hypertrophic and failing hearts of humans and mice. Adeno‐associated virus serotype 9 (AAV9)‐mediated miR‐214 silencing attenuates isoproterenol (ISO) infusion‐induced cardiac dysfunction and impairment of cardiac angiogenesis in mice. Mechanistically, miR‐214 overexpression reduces angiogenesis of HUVECs by targeting XBP1, an important transcription factor of unfolded protein response, and XBP1 silencing decreases HUVECs proliferation and angiogenesis similar to miR‐214 overexpression. Furthermore, ectopic expression of XBP1 enhances endothelial cells proliferation and tube formation, and reverses anti‐angiogenic effect of miR‐214 over expression. All these findings suggest that miR‐214 is an important regulator of angiogenesis in heart in vitro and in vivo, likely via regulating the expression of XBP1, and demonstrate that miR‐214 plays an essential role in the control/inhibition of cardiac angiogenesis. J. Cell. Physiol. 230: 1964–1973, 2015. © 2015 The Authors. Journal of Cellular Physiology published by Wiley Periodicals, Inc.
doi:10.1002/jcp.24942
PMCID: PMC4911176  PMID: 25656649
11.  Dysregulation of long non-coding RNA profiles in human colorectal cancer and its association with overall survival 
Oncology Letters  2016;12(5):4068-4074.
Long non-coding RNAs (lncRNAs) emerged as key regulators of diverse roles during colorectal cancer (CRC) carcinogenesis, but their specific function still remains to be explored. The present study aimed to re-annotate the Affymetrix Human Exon 1.0 ST Array for defining differential lncRNAs in CRC. Their prognostic relevance was also developed for screening key regulators in CRC. The CRC datasets E-GEOD-31737, E-MATB-829, Affymetrix colon cancer dataset and E-GEOD-24550 were re-purposed for searching differential lncRNAs and exploring their association with overall survival (OS). The identified lncRNAs were validated in CRC tissues or cell lines. As a result, 462, 286 and 166 differential lncRNAs were identified, respectively, in three predictive datasets. Among them, 48 lncRNAs were commonly observed to exhibit differential expression in the three datasets. Notably, the overexpression of family with sequence similarity 83 member H (FAM83H)-antisense (AS) 1 (P=0.038) and VPS9 domain containing 1 (VPS9D1)-AS1 (P=0.020) indicated shorter OS time than lower expression. The overexpression of FAM83H-AS1 (P=0.033) and VPS9D1-AS1 (P=0.011) was validated in cancerous tissues. Thus, FAM83H-AS1 and VPS9D1-AS1 may potentially enhance carcinogenesis or may be developed as prognostic biomarkers for CRC. In conclusion, a total of 48 CRC-related lncRNAs were identified, the majority of which were confirmed to exhibit dysregulation. FAM83H-AS1 and VPS9D1-AS1 could have a potential use as prognostic biomarkers for CRC patients.
doi:10.3892/ol.2016.5138
PMCID: PMC5104233  PMID: 27895773
colorectal cancer; long non-coding RNA; microarrays; prognosis
12.  Aggregate-based sub-CMC Solubilization of Hexadecane by Surfactants 
RSC advances  2015;5(95):78142-78149.
Solubilization of hexadecane by two surfactants, SDBS and Triton X-100, at concentrations near the critical micelle concentration (CMC) and the related aggregation behavior was investigated in this study. Solubilization was observed at surfactant concentrations lower than CMC, and the apparent solubility of hexadecane increased linearly with surfactant concentration for both surfactants. The capacity of SDBS to solubilize hexadecane is stronger at concentrations below CMC than above CMC. In contrast, Triton X-100 shows no difference. The results of dynamic light scattering (DLS) and cryogenic TEM analysis show aggregate formation at surfactant concentrations lower than CMC. DLS-based size of the aggregates (d) decreases with increasing surfactant concentration. Zeta potential of the SDBS aggregates decreases with increasing SDBS concentration, whereas it increases for Triton X-100. The surface excess (Γ) of SDBS calculated based on hexadecane solubility and aggregate size data increases rapidly with increasing bulk concentration, and then asymptotically approaches the maximum surface excess (Γmax). Conversely, there is only a minor increase in Γ for Triton X-100. Comparison of Γ and d indicates that excess of surfactant molecules at aggregate surface has great impact on surface curvature. The results of this study demonstrate formation of aggregates at surfactant concentrations below CMC for hexadecane solubilization, and indicate the potential of employing low-concentration strategy for surfactant application such as remediation of HOC contaminated sites.
doi:10.1039/C5RA12388G
PMCID: PMC4765384  PMID: 26925230
surfactant; SDBS; Triton X-100; critical micelle concentration; solubilization; aggregation
13.  Safety and Efficacy of Transplantation with Allogeneic Skin Tumors to Treat Chemically-Induced Skin Tumors in Mice 
Background
Transplantation with allogeneic cells has become a promising modality for cancer therapy, which can induce graft-versus-tumor (GVT) effect. This study was aimed at assessing the safety, efficacy, and tissue type GVT (tGVT) response of transplantation with allogeneic skin tumors to treat chemically-induced skin tumors in mice.
Material/Methods
FVB/N and ICR mice were exposed topically to chemicals to induce skin tumors. Healthy ICR mice were transplanted with allogeneic skin tumors from FVB/N mice to test the safety. The tumor-bearing ICR mice were transplanted with, or without, allogeneic skin tumors to test the efficacy. The body weights (BW), body condition scores (BCS), tumor volumes in situ, metastasis tumors, overall survival, and serum cytokines were measured longitudinally.
Results
Transplantation with no more than 0.03 g allogeneic skin tumors from FVB/N mice to healthy ICR mice was safe. After transplantation with allogeneic skin tumors to treat tumor-bearing mice, it inhibited the growth of tumors slightly at early stage, accompanied by fewer metastatic tumors at 24 days after transplantation (21.05% vs. 47.37%), while there were no statistically significant differences in the values of BW, BCS, tumor volumes in situ, metastasis tumors, and overall survival between the transplanted and non-transplanted groups. The levels of serum interleukin (IL)-2 were significantly reduced in the controls (P<0.05), but not in the recipients, which may be associated with the tGVT response.
Conclusions
Our results suggest that transplantation with allogeneic skin tumors is a safe treatment in mice, which can induce short-term tGVT response mediated by IL-2.
doi:10.12659/MSM.900148
PMCID: PMC5019137  PMID: 27587310
Allografts; Immunotherapy; Skin Neoplasms; Transplantation
14.  The Role of Annealing Process in Ag-Based BaSnO3 Multilayer Thin Films 
The BaSnO3/Ag/BaSnO3 multilayer structure was designed and fabricated on a quartz glass by magnetron sputtering, followed by an annealing process at a temperature from 150 to 750 °C in air. In this paper, we investigated the influence of the annealing temperature on the structural, optical, and electrical properties of the multilayers and proposed the mechanisms of conduction and transmittance. The maximum value of the figure of merit of 31.8 × 10−3 Ω−1 was achieved for the BaSnO3/Ag/BaSnO3 multilayer thin films annealed at 150 °C, while the average optical transmittance in the visible ranges was >84 %, the resistivity was 5.71 × 10−5 Ω cm, and the sheet resistance was 5.57 Ω/sq. When annealed at below 600 °C, the values of resistivity and transmittance of the multilayers were within an acceptable range (resistivity <5.0 × 10−4 Ω cm, transmittance >80 %). The observed property of the multilayer film is suitable for the application of transparent conductive electrodes.
doi:10.1186/s11671-016-1579-2
PMCID: PMC4992480  PMID: 27544775
TCFs; BaSnO3; Magnetron sputtering; Multilayer; Thin films
15.  Glucagon-like peptide-1 attenuates advanced oxidation protein product-mediated damage in islet microvascular endothelial cells partly through the RAGE pathway 
Advanced oxidation protein products (AOPPs) are knownt to play a role in the pathogenesis of diseases and related complications. However, whether AOPPs affect the survival of islet microvascular endothelial cells (IMECs) has not been reported to date, at least to the best of our knowledge. In this study, we aimed to investigate the mechanisms underlying AOPP-mediated damage in IMECs and the protective role of glucagon-like peptide-1 (GLP-1), which has been suggested to exert beneficial effects on the cardiovascular system. IMECs were treated with AOPPs (0–200 µg/ml) for 0–72 h in the presence or absence of GLP-1 (100 nmol/l). Apoptosis, cell viability and reactive oxygen species (ROS) production were examined, the expression levels of p53, Bax, receptor for advanced glycation end-products (RAGE) and NAD(P)H oxidase subunit were determined, and the activity of NAD(P)H oxidase, caspase-9 and caspase-3 was also determined. The results revealed that AOPPs increased the expression of RAGE, p47phox and p22phox; induced NAD(P)H oxidase-dependent ROS generation, increased p53 and Bax expression, enhanced the activity of caspase-9 and caspase-3, and induced cell apoptosis. Treatment with GLP-1 decreased the expression of RAGE, inhibited NAD(P)H oxidase activity, decreased cell apoptosis and increased cell viability. On the whole, our findings indicate that AOPPs induce the apoptosis of IMECs via the RAGE-NAD(P) H oxidase-dependent pathway and that treatment with GLP-1 effectively reverses these detrimental effects by decreasing AOPP-induced RAGE expression and restoring the redox balance. Our data may indicate that GLP-1 may prove to be beneficial in attenuating the progression of diabetes mellitus.
doi:10.3892/ijmm.2016.2711
PMCID: PMC5029952  PMID: 27574116
advanced oxidation protein products; glucagon like peptide-1; islet microvascular endothelial cells; receptor for advanced glycation end-products; NAD(P)H oxidase; apoptosis
16.  Zeeman splitting and dynamical mass generation in Dirac semimetal ZrTe5 
Nature Communications  2016;7:12516.
Dirac semimetals have attracted extensive attentions in recent years. It has been theoretically suggested that many-body interactions may drive exotic phase transitions, spontaneously generating a Dirac mass for the nominally massless Dirac electrons. So far, signature of interaction-driven transition has been lacking. In this work, we report high-magnetic-field transport measurements of the Dirac semimetal candidate ZrTe5. Owing to the large g factor in ZrTe5, the Zeeman splitting can be observed at magnetic field as low as 3 T. Most prominently, high pulsed magnetic field up to 60 T drives the system into the ultra-quantum limit, where we observe abrupt changes in the magnetoresistance, indicating field-induced phase transitions. This is interpreted as an interaction-induced spontaneous mass generation of the Dirac fermions, which bears resemblance to the dynamical mass generation of nucleons in high-energy physics. Our work establishes Dirac semimetals as ideal platforms for investigating emerging correlation effects in topological matters.
It has been predicted that the presence of strong electronic correlations may generate new phases in materials with topologically non-trivial band structure. Here, the authors demonstrate the generation of Dirac mass in the correlated Dirac semimetal candidate ZrTe5 under high magnetic fields.
doi:10.1038/ncomms12516
PMCID: PMC4990656  PMID: 27515493
17.  Discovery of potential prognostic long non-coding RNA biomarkers for predicting the risk of tumor recurrence of breast cancer patients 
Scientific Reports  2016;6:31038.
Deregulation of long non-coding RNAs (lncRNAs) expression has been proven to be involved in the development and progression of cancer. However, expression pattern and prognostic value of lncRNAs in breast cancer recurrence remain unclear. Here, we analyzed lncRNA expression profiles of breast cancer patients who did or did not develop recurrence by repurposing existing microarray datasets from the Gene Expression Omnibus database, and identified 12 differentially expressed lncRNAs that were closely associated with tumor recurrence of breast cancer patients. We constructed a lncRNA-focus molecular signature by the risk scoring method based on the expression levels of 12 relapse-related lncRNAs from the discovery cohort, which classified patients into high-risk and low-risk groups with significantly different recurrence-free survival (HR = 2.72, 95% confidence interval 2.07–3.57; p = 4.8e-13). The 12-lncRNA signature also represented similar prognostic value in two out of three independent validation cohorts. Furthermore, the prognostic power of the 12-lncRNA signature was independent of known clinical prognostic factors in at least two cohorts. Functional analysis suggested that the predicted relapse-related lncRNAs may be involved in known breast cancer-related biological processes and pathways. Our results highlighted the potential of lncRNAs as novel candidate biomarkers to identify breast cancer patients at high risk of tumor recurrence.
doi:10.1038/srep31038
PMCID: PMC4977495  PMID: 27503456
18.  Duplicated copy of CHRNA7 increases risk and worsens prognosis of COPD and lung cancer 
European Journal of Human Genetics  2014;23(8):1019-1024.
Recent genome-wide association studies implicated that the nicotinic acetylcholine receptors (nAChRs) are common susceptible genes of two contextual diseases: chronic obstructive pulmonary disease (COPD) and lung cancer. We aimed to test whether the copy number variations (CNVs) in nAChRs have hereditary contributions to development of the two diseases. In two, two-stage, case–control studies of southern and eastern Chinese, a common CNV-3956 that duplicates the cholinergic receptor, nicotinic, α7 (CHRNA7) gene was genotyped in a total of 7880 subjects and its biological phenotype was assessed. The ≥4-copy of CNV-3956 increased COPD risk (≥4-copy vs 2/3-copy: OR=1.44, 95% CI=1.23–1.68) and caused poor lung function, and it similarly augmented risk (OR=1.49, 95% CI=1.29–1.73) and worsened prognosis (hazard ratio (HR)=1.25, 95% CI=1.07–1.45) of lung cancer. The ≥4-copy was estimated to account for 1.56% of COPD heritability and 1.87% of lung cancer heritability, respectively. Phenotypic analysis further showed that the ≥4-copy of CNV-3956 improved CHRNA7 expression in vivo and increased the carriers' smoking amount. The CNV-3956 of CHRNA7 contributed to increased risks and poor prognoses of both COPD and lung cancer, and this may be a genetic biomarker of the two diseases.
doi:10.1038/ejhg.2014.229
PMCID: PMC4795111  PMID: 25407004
19.  Deregulation of XBP1 expression contributes to myocardial vascular endothelial growth factor‐A expression and angiogenesis during cardiac hypertrophy in vivo  
Aging Cell  2016;15(4):625-633.
Summary
Endoplasmic reticulum (ER) stress has been reported to be involved in many cardiovascular diseases such as atherosclerosis, diabetes, myocardial ischemia, and hypertension that ultimately result in heart failure. XBP1 is a key ER stress signal transducer and an important pro‐survival factor of the unfolded protein response (UPR) in mammalian cells. The aim of this study was to establish a role for XBP1 in the deregulation of pro‐angiogenic factor VEGF expression and potential regulatory mechanisms in hypertrophic and failing heart. Western blots showed that myocardial XBP1s protein was significantly increased in both isoproterenol (ISO)‐induced and pressure‐overload‐induced hypertrophic and failing heart compared to normal control. Furthermore, XBP1 silencing exacerbates ISO‐induced cardiac dysfunction along with a reduction of myocardial capillary density and cardiac expression of pro‐angiogenic factor VEGF‐A in vivo. Consistently, experiments in cultured cardiomyocytes H9c2 (2‐1) cells showed that UPR‐induced VEGF‐A upregulation was determined by XBP1 expression level. Importantly, VEGF‐A expression was increased in failing human heart tissue and blood samples and was correlated with the levels of XBP1. These results suggest that XBP1 regulates VEGF‐mediated cardiac angiogenesis, which contributes to the progression of adaptive hypertrophy, and might provide novel targets for prevention and treatment of heart failure.
doi:10.1111/acel.12460
PMCID: PMC4933664  PMID: 27133203
angiogenesis; cardiac hypertrophy; unfolded protein response; vascular endothelial growth factor‐A; XBP1
20.  Sustained live poultry market surveillance contributes to early warnings for human infection with avian influenza viruses 
Sporadic human infections with the highly pathogenic avian influenza (HPAI) A (H5N6) virus have been reported in different provinces in China since April 2014. From June 2015 to January 2016, routine live poultry market (LPM) surveillance was conducted in Shenzhen, Guangdong Province. H5N6 viruses were not detected until November 2015. The H5N6 virus-positive rate increased markedly beginning in December 2015, and viruses were detected in LPMs in all districts of the city. Coincidently, two human cases with histories of poultry exposure developed symptoms and were diagnosed as H5N6-positive in Shenzhen during late December 2015 and early January 2016. Similar viruses were identified in environmental samples collected in the LPMs and the patients. In contrast to previously reported H5N6 viruses, viruses with six internal genes derived from the H9N2 or H7N9 viruses were detected in the present study. The increased H5N6 virus-positive rate in the LPMs and the subsequent human infections demonstrated that sustained LPM surveillance for avian influenza viruses provides an early warning for human infections. Interventions, such as LPM closures, should be immediately implemented to reduce the risk of human infection with the H5N6 virus when the virus is widely detected during LPM surveillance.
doi:10.1038/emi.2016.75
PMCID: PMC5034097  PMID: 27485495
early warning; HPAI H5N6 virus; human infection; live poultry market; reassortant; surveillance
21.  MMP1 gene expression enhances myoblast migration and engraftment following implanting into mdx/SCID mice 
Cell Adhesion & Migration  2015;9(4):283-292.
Myoblast transplantation (MT) is a method to introduce healthy genes into abnormal skeletal muscle. It has been considered as a therapeutic modality in the last few decades for diseases such as Duchenne Muscular Dystrophy (DMD). However, challenges including cell death and poor graft engraftment have limited its application. The current experiment utilizes MMP1 gene transfer to improve the efficacy of myoblast transplantation into the diseased dystrophic skeletal muscle of mdx mice. Our results indicated that MMP1 expression can promote myogenic differentiation and fusion capacities, increase migration of MMP1 expressing myoblasts in vitro, as well as improve engraftment of dystrophin positive myofibers in vivo. Taken together, our observation suggests that the addition of MMP1 can overcome limitations in MT and improve its clinical efficacy.
doi:10.4161/19336918.2014.983799
PMCID: PMC4594355  PMID: 26223276
differentiation; duchenne muscular dystrophy (DMD); matrix metalloproteinase (MMP); mdx mice; migration; myoblast transplantation; skeletal muscle
22.  Percutaneous Reduction and Fixation with Kirschner Wires versus Open Reduction Internal Fixation for the Management of Calcaneal Fractures: A Meta-Analysis 
Scientific Reports  2016;6:30480.
The aim of our meta-analysis was to compare outcomes for two surgical treatments of calcaneal fractures, percutaneous reduction and fixation with Kirschner wires (PRFK) and open reduction internal fixation (ORIF), with the intent of evaluating the quality of evidence to inform practice. Search of MEDLINE, Cochrane and CNKI databases to identify randomized controlled trials (RCTs) comparing PRKF and ORIF on the following outcomes: post-operative function, complications and quality of the reduction. Odd ratios (OR) and weighted mean differences were pooled using either a fixed-effects or random-effects model, depending on the heterogeneity of the trials included in the analysis. Eighteen RCTs provided the data from 1407 patients. PRFK was associated with a lower risk of surgical wound complications, and ORIF with better post-operative function, angle of Gissane, calcaneal height, and calcaneal width. There were no statistically significant differences between the techniques with regards to post-operative Böhler’s angle. PRFK does not provide a substantive advantage over ORIF for the treatment of calcaneal fractures in adults. PRFK may, however, yield comparable functional outcomes to ORIF for closed Sanders type II calcaneal fractures but with less complication related to surgical wound healing.
doi:10.1038/srep30480
PMCID: PMC4960605  PMID: 27457262
23.  PATTERN: Pain Assessment for paTients who can’t TEll using Restricted Boltzmann machiNe 
Background
Accurately assessing pain for those who cannot make self-report of pain, such as minimally responsive or severely brain-injured patients, is challenging. In this paper, we attempted to address this challenge by answering the following questions: (1) if the pain has dependency structures in electronic signals and if so, (2) how to apply this pattern in predicting the state of pain. To this end, we have been investigating and comparing the performance of several machine learning techniques.
Methods
We first adopted different strategies, in which the collected original n-dimensional numerical data were converted into binary data. Pain states are represented in binary format and bound with above binary features to construct (n + 1) -dimensional data. We then modeled the joint distribution over all variables in this data using the Restricted Boltzmann Machine (RBM).
Results
Seventy-eight pain data items were collected. Four individuals with the number of recorded labels larger than 1000 were used in the experiment. Number of avaliable data items for the four patients varied from 22 to 28. Discriminant RBM achieved better accuracy in all four experiments.
Conclusion
The experimental results show that RBM models the distribution of our binary pain data well. We showed that discriminant RBM can be used in a classification task, and the initial result is advantageous over other classifiers such as support vector machine (SVM) using PCA representation and the LDA discriminant method.
doi:10.1186/s12911-016-0317-0
PMCID: PMC4959350  PMID: 27454233
24.  The Maternal Effect Genes UTX and JMJD3 Play Contrasting Roles in Mus musculus Preimplantation Embryo Development 
Scientific Reports  2016;6:26711.
During the process of embryonic development in mammals, epigenetic modifications must be erased and reconstructed. In particular, the trimethylation of histone 3 lysine 27 (H3K27me3) is associated with gene-specific transcriptional repression and contributes to the maintenance of the pluripotent embryos. In this study, we determined that the global levels of the H3K27me3 marker were elevated in MII oocyte chromatin and decrease to minimal levels at the 8-cell and morula stages. When the blastocyst hatched, H3K27me3 was re-established in the inner cell mass. We also determined that H3K27me3-specific demethylases, UTX and JMJD3, were observed at high transcript and protein levels in mouse preimplantation embryos. In the activated oocytes, when the H3K27me3 disappeared at the 8-cell stage, the UTX (but not JMJD3) protein levels were undetectable. Using RNA interference, we suppressed UTX and JMJD3 gene expression in the embryos and determined that the functions of UTX and JMJD3 were complementary. When JMJD3 levels were decreased by RNA interference, the embryo development rate and quality were improved, but the knockdown of UTX produced the opposite results. Understanding the epigenetic mechanisms controlling preimplantation development is critical to comprehending the basis of embryonic development and to devise methods and approaches to treat infertility.
doi:10.1038/srep26711
PMCID: PMC4935995  PMID: 27384759
25.  Association between NADPH oxidase (NOX) and lung cancer: a systematic review and meta-analysis 
Journal of Thoracic Disease  2016;8(7):1704-1711.
Background
Lung cancer is a leading cause of death worldwide. Considerable studies have reported that NADPH oxidase (NOX) expression or activity may play an important role in the tumorigenesis of lung cancer. However, the results are inconsistent. Thus, a systematic review and meta-analysis were conducted in this study.
Methods
A systematic search of electronic databases was performed. Statistical analysis was performed using the Comprehensive Meta-Analysis software (Version 3). The pooled Hedges’s g with 95% confidence intervals (95% CIs) or rate ratio with 95% CIs was adopted to assess the effect size. Fixed or random effect model was separately used based on the heterogeneity between the studies.
Results
A total of ten eligible studies were included in the current systematic review and overall meta-analysis showed that NOX/DUOX activity and mRNA were significantly in favor of lung cancer (Hedges’s g =1.216, P=0.034). Suppression of NOX function by pharmacologic inhibitor or expression by siRNA resulted in significant inhibition of lung cancer cell invasion and migration in in vitro experiments (Hedges’s g =2.422, P<0.001) and lung cancer formation in vivo studies (rate ratio =0.366, P=0.002).
Conclusions
Findings of this systematic review indicate that NOX activity and expression is associated with tumorigenesis of lung cancer and inhibition of NOX function or mRNA expression significantly blocks lung cancer formation and invasion. Suppressing NOX up-regulation or interfering NOX function in tumor microenvironment may be one important approach to prevent oxidative-stress-related carcinogenesis in the lung.
doi:10.21037/jtd.2016.06.31
PMCID: PMC4958839  PMID: 27499960
NADPH oxidase (NOX); lung cancer; systematic review; meta-analysis

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