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1.  Bone Morphogenetic Protein-9 Enhances Osteogenic Differentiation of Human Periodontal Ligament Stem Cells via the JNK Pathway 
PLoS ONE  2017;12(1):e0169123.
Bone morphogenetic protein-9 (BMP9) shows great osteoinductive potential in bone regeneration. Periodontal ligament stem cells (PDLSCs) with multi-differentiation capability and low immunogenicity are increasingly used as seed cells for periodontal regenerative therapies. In the present study, we investigated the potent osteogenic activity of BMP9 on human PDLSCs (hPDLSCs), in which the c-Jun N-terminal kinase (JNK) pathway is possibly involved. Our results showed that JNK inhibition by the specific inhibitor SP600125 or adenovirus expressing small interfering RNA (siRNA) targeting JNK (AdR-si-JNK) significantly decreased BMP9-induced gene and protein expression of early and late osteogenic markers, such as runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP), osteopontin (OPN), and osteocalcin (OCN), in hPDLSCs. We also confirmed the in-vivo positive effect of JNKs on ectopic bone formation induced by hPDLSCs injected into the musculature of athymic nude mice and BMP9 ex vivo gene delivery. For the cellular mechanism, we found that BMP9 activated the phosphorylation of JNKs and Smad2/3, and that JNKs may engage in cross-talk with the Smad2/3 pathway in BMP9-mediated osteogenesis.
doi:10.1371/journal.pone.0169123
PMCID: PMC5214565  PMID: 28052093
2.  Validation of Brunei’s Malay EQ-5D Questionnaire in Patients with Type 2 Diabetes 
PLoS ONE  2016;11(11):e0165555.
Background
The Malay spoken in Brunei a South East Asian country where Malay is the national language is distinctive and different from Malay spoken in Malaysia, Singapore and Indonesia. This study aimed to develop a Brunei Malay version of the 5-level EQ-5D questionnaire (EQ-5D-5L) and to assess its psychometric properties among patients with type 2 diabetes mellitus (T2DM).
Methods
The Brunei Malay EQ-5D-5L was developed by culturally adapting two existing Malay versions. A total of 154 Bruneians with T2DM completed the questionnaire in two different points of time with one week apart. Known-groups validity of the utility-based EQ-5D-5L index and visual analogue scale (EQ-VAS) was evaluated by comparing subgroups of patients known to differ in health status. Test-retest reliability was assessed using the intraclass correlation coefficient (ICC) or Cohen’s kappa.
Results
As hypothesized, patients known to have ‘better’ health had higher EQ-5D-5L index scores than those having ‘worse’ health in all 7 known-groups comparisons. The hypothesized difference in the EQ-VAS scores was observed in only 4 of the 7 known-groups comparisons. Kappa values ranged from 0.206 to 0.446 for the EQ-5D-5L items; the ICC value for the EQ-5D-5L index and EQ-VAS was 0.626 and 0.521, respectively.
Conclusions
The utility-based EQ-5D-5L index appears to be valid and reliable for measuring the health of Brunei patients with T2DM. The validity of the EQ-VAS in Brunei requires further investigation.
doi:10.1371/journal.pone.0165555
PMCID: PMC5105939  PMID: 27835652
3.  A Retrospective Study of Preferable Alternative Route to Right Internal Jugular Vein for Placing Tunneled Dialysis Catheters: Right External Jugular Vein versus Left Internal Jugular Vein 
PLoS ONE  2016;11(1):e0146411.
Background
Right internal jugular vein (IJV) is a preferred access route for tunneled (cuffed) dialysis catheters (TDCs), and both right external jugular vein (EJV) and left IJV are alternative routes for patients in case the right IJV isn’t available for TDC placement. This retrospective study aimed to determine if a disparity exists between the two alternative routes in hemodialysis patients in terms of outcomes of TDCs.
Methods
49 hemodialysis patients who required TDCs through right EJV (n = 21) or left IJV (n = 28) as long-term vascular access were included in this study. The primary end point was cumulative catheter patency. Secondary end points include primary catheter patency, proportion of patients that never required urokinase and incidence of catheter-related bloodstream infections (CRBSI).
Results
A total of 20,870 catheter-days were evaluated and the median was 384 (interquartile range, 262–605) catheter-days. Fewer catheters were removed in the right EJV group than in the left IJV group (P = 0.007). Mean cumulative catheter patency was higher in the right EJV group compared with the left IJV group (P = 0.031). There was no significant difference between the two groups in the incidence of CRBSI, primary catheter patency or proportion of patients that never required urokinase use. Total indwell time of antecedent catheters was identified as an independent risk factor for cumulative catheter patency by Cox regression hazards test with an HR of 2.212 (95% CI, 1.363–3.588; p = 0.001).
Conclusions
Right EJV might be superior to left IJV as an alternative insertion route for TDC placement in hemodialysis patients whose right IJVs are unavailable.
doi:10.1371/journal.pone.0146411
PMCID: PMC4709068  PMID: 26751380
4.  Reduced Gut Acidity Induces an Obese-Like Phenotype in Drosophila melanogaster and in Mice 
PLoS ONE  2015;10(10):e0139722.
In order to identify genes involved in stress and metabolic regulation, we carried out a Drosophila P-element-mediated mutagenesis screen for starvation resistance. We isolated a mutant, m2, that showed a 23% increase in survival time under starvation conditions. The P-element insertion was mapped to the region upstream of the vha16-1 gene, which encodes the c subunit of the vacuolar-type H+-ATPase. We found that vha16-1 is highly expressed in the fly midgut, and that m2 mutant flies are hypomorphic for vha16-1 and also exhibit reduced midgut acidity. This deficit is likely to induce altered metabolism and contribute to accelerated aging, since vha16-1 mutant flies are short-lived and display increases in body weight and lipid accumulation. Similar phenotypes were also induced by pharmacological treatment, through feeding normal flies and mice with a carbonic anhydrase inhibitor (acetazolamide) or proton pump inhibitor (PPI, lansoprazole) to suppress gut acid production. Our study may thus provide a useful model for investigating chronic acid suppression in patients.
doi:10.1371/journal.pone.0139722
PMCID: PMC4593636  PMID: 26436771
5.  Marital Status, Lifestyle and Dementia: A Nationwide Survey in Taiwan 
PLoS ONE  2015;10(9):e0139154.
Background
Evidence of an association between lifestyle and marital status and risk of dementia is limited in Asia.
Methods
In this nationwide population-based cross-sectional survey, participants were selected by computerized random sampling from all 19 counties in Taiwan. A total of 10432 residents were assessed by a door-to-door in-person survey, among whom 7035 were normal and 929 were diagnosed with dementia using the criteria recommended by National Institute on Aging-Alzheimer’s Association. Premorbid lifestyle habits and demographic data including marital status were compared between normal subjects and participants with dementia.
Results
After adjustment for age, gender, education, body mass index, smoking, drinking, marital status, sleep habits, exercise, social engagement and co-morbidities including hypertension, diabetes and cerebrovascular diseases, an increased risk for dementia was found in people with widow or widower status (OR 1.42, 95% CI 1.15–1.77) and people who used to take a nap in the afternoon (OR 1.33, 95% CI 1.02–1.72). Decreased risk was found in people with the habit of regular exercise (OR 0.12, 95% CI 0.09–0.16), adequate night sleep (OR 0.55, 95% CI 0.39–0.76) and regular social engagement (OR 0.53, 95% CI 0.36–0.77).
Conclusions
Our results provide preliminary evidence of possible risk-reduction effects for dementia, including regular exercise even in modest amounts, social engagement and adequate night sleep, whereas people with the widow/widower status or who used to take an afternoon nap might have increased risk of dementia.
doi:10.1371/journal.pone.0139154
PMCID: PMC4587383  PMID: 26413719
6.  Urban-Rural Differences in Cardiovascular Disease Risk Factors: A Cross-Sectional Study of Schoolchildren in Wuhan, China 
PLoS ONE  2015;10(9):e0137615.
Background
China’s rapid population growth and urban migration has developed healthcare inequity across the urban-rural divide. Past studies comparing cardiovascular disease (CVD) risk factor prevalence amongst urban-rural Chinese children are sparse and conflicting. We examined the association between urban-rural residence and risk of offspring CVD in Chinese children.
Methods
A cross-sectional study was conducted in Wuhan, China, during May and June 2010. CVD risk factors include; waist circumference (WC), systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting blood glucose (FBG), triglycerides (TG), high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, body mass index (BMI), cardiorespiratory fitness (CRF), metabolic syndrome (MetS), and metabolic risk score (MRS). Analysis of covariance and multivariable logistic regression were used to estimate associations between urban-rural residence and offspring CVD risks.
Findings
A total of 579 Chinese children (338 boys and 241 girls) aged 9.6 (0.7) years participated in this study. Rural boys had significantly lower CRF and higher FBG, TG, and MRS, while urban boys had significantly higher LDL and DBP. Rural girls had significantly higher BMI, FBG, and TG, as well as lower CRF. Rural children were at increased risks for decreased CRF, elevated MRS, and TG, (OR:2.04, 95%CI:1.29–3.25), (OR:2.33, 95%CI:1.50–3.62), and (OR:2.40, 95%CI:1.62–3.57), respectively. Rural girls and mothers were at increased risks for overweight(OR:7.19, 95%CI:1.64–31.6)/obesity (OR:1.683, 95%CI:1.01–2.82). However, rural boys and fathers were less likely to have overweight(OR:0.62, 95%CI:0.34–1.12)/obesity (OR:0.68, 95%CI:0.48–0.97).
Conclusions
Rural residence was significantly associated with increased CVD risks amongst Chinese children. It is important to provide interventions aiming at China’s urban-rural healthcare inequity and community-based approaches that reduce familial CVD risk.
doi:10.1371/journal.pone.0137615
PMCID: PMC4564102  PMID: 26352586
7.  Development of a Efficient and Sensitive Dispersive Liquid–Liquid Microextraction Technique for Extraction and Preconcentration of 10 β2-Agonists in Animal Urine 
PLoS ONE  2015;10(9):e0137194.
Dispersive liquid–liquid microextraction (DLLME) coupled with ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS) was developed for the extraction and determination of 10 β2-agonists in animal urine. Some experimental parameters, such as the type and volume of the extraction solvent, the concentration of the dispersant, the salt concentration, the pH value of the sample solution, the extraction time and the speed of centrifugation, were investigated and optimized. Under the optimized conditions, a good enrichment factors (4.8 to 32.3) were obtained for the extraction. The enrichment factor show that the concentration rate of DLLME is significantly higher than other pretreatment methods, and the detection sensitivity has been greatly improved. The calibration curves were linear, the correlation coefficient ranged from 0.9928 to 0.9999 for the concentration range of 0.05 to 50 ngmL-1 and 0.1 to 50 ngmL-1, and the relative standard deviations (RSDs, n = 15, intra and inter-day precision) at a concentration of 5 ngmL-1 were in the range of 1.8 to 14.6%. The limits of detection (LODs) for the 10 β2-agonists, based on a signal-to-noise ratio (S/N) of 3, were in the range of 0.01 to 0.03 ngmL-1. The proposed method was used to identify β2-agonists in three types of animal urine (swine, cattle, sheep), and the relative recoveries from each matrix were in the range of 89.2 to 106.8%, 90.0 to 109.8% and 89.2 to 107.2%, respectively.
doi:10.1371/journal.pone.0137194
PMCID: PMC4562641  PMID: 26348922
8.  Genome-Wide Loss of Heterozygosity and DNA Copy Number Aberration in HPV-Negative Oral Squamous Cell Carcinoma and Their Associations with Disease-Specific Survival 
PLoS ONE  2015;10(8):e0135074.
Oral squamous cell cancer of the oral cavity and oropharynx (OSCC) is associated with high case-fatality. For reasons that are largely unknown, patients with the same clinical and pathologic staging have heterogeneous response to treatment and different probability of recurrence and survival, with patients with Human Papillomavirus (HPV)-positive oropharyngeal tumors having the most favorable survival. To gain insight into the complexity of OSCC and to identify potential chromosomal changes that may be associated with OSCC mortality, we used Affymtrix 6.0 SNP arrays to examine paired DNA from peripheral blood and tumor cell populations isolated by laser capture microdissection to assess genome-wide loss of heterozygosity (LOH) and DNA copy number aberration (CNA) and their associations with risk factors, tumor characteristics, and oral cancer-specific mortality among 75 patients with HPV-negative OSCC. We found a highly heterogeneous and complex genomic landscape of HPV-negative tumors, and identified regions in 4q, 8p, 9p and 11q that seem to play an important role in oral cancer biology and survival from this disease. If confirmed, these findings could assist in designing personalized treatment or in the creation of models to predict survival in patients with HPV-negative OSCC.
doi:10.1371/journal.pone.0135074
PMCID: PMC4527746  PMID: 26247464
9.  2-Deoxy-d-Glucose Can Complement Doxorubicin and Sorafenib to Suppress the Growth of Papillary Thyroid Carcinoma Cells 
PLoS ONE  2015;10(7):e0130959.
Tumor cells display a shift in energy metabolism from oxidative phosphorylation to aerobic glycolysis. A subset of papillary thyroid carcinoma (PTC) is refractory to surgery and radioactive iodine ablation. Doxorubicin and sorafenib are the drugs of choice for treating advanced thyroid cancer but both induce adverse effects. In this study, we assessed the anti-cancer activity of 2-deoxy-d-glucose (2-DG) alone and in combination with doxorubicin or sorafenib in PTC cell lines with (BCPAP) and without (CG3) the BRAFV600E mutation. BCPAP cells were more glycolytic than CG3 cells, as evidenced by their higher extracellular l-lactate production, lower intracellular ATP level, lower oxygen consumption rate (OCR), and lower ratio of OCR/extracellular acidification rate. However, dose-dependent reduction in cell viability, intracellular ATP depletion, and extracellular l-lactate production were observed after 2-DG treatment. Regression analysis showed that cell growth in both cell lines was dependent on ATP generation. 2-DG increased the chemosensitivity of BCPAP and CG3 cell lines to doxorubicin and sorafenib. These results demonstrate that the therapeutic effects of low combined doses of 2-DG and doxorubicin or sorafenib are similar to those of high doses of doxorubicin or sorafenib alone in PTC cell lines regardless of the BRAFV600E mutation.
doi:10.1371/journal.pone.0130959
PMCID: PMC4489888  PMID: 26134286
10.  The Effects of Anti-Dementia and Nootropic Treatments on the Mortality of Patients with Dementia: A Population-Based Cohort Study in Taiwan 
PLoS ONE  2015;10(6):e0130993.
Background
Few studies have examined the contribution of treatment on the mortality of dementia based on a population-based study.
Objective
To investigate the effects of anti-dementia and nootropic treatments on the mortality of dementia using a population-based cohort study.
Methods
12,193 incident dementia patients were found from 2000 to 2010. Their data were compared with 12,193 age- and sex-matched non-dementia controls that were randomly selected from the same database. Dementia was classified into vascular (VaD) and degenerative dementia. Mortality incidence and hazard ratios (HRs) were calculated.
Results
The median survival time was 3.39 years (95% confidence interval [CI]: 2.88–3.79) for VaD without medication, 6.62 years (95% CI: 6.24–7.21) for VaD with nootropics, 3.01 years (95% CI: 2.85–3.21) for degenerative dementia without medication, 8.11 years (95% CI: 6.30–8.55) for degenerative dementia with anti-dementia medication, 6.00 years (95% CI: 5.73–6.17) for degenerative dementia with nootropics, and 9.03 years (95% CI: 8.02–9.87) for degenerative dementia with both anti-dementia and nootropic medications. Compared to the non-dementia group, the HRs among individuals with degenerative dementia were 2.69 (95% CI: 2.55–2.83) without medication, 1.46 (95% CI: 1.39–1.54) with nootropics, 1.05 (95% CI: 0.82–1.34) with anti-dementia medication, and 0.92 (95% CI: 0.80–1.05) with both nootropic and anti-dementia medications. VaD with nootropics had a lower mortality (HR: 1.25, 95% CI: 1.15–1.37) than VaD without medication (HR: 2.46, 95% CI: 2.22–2.72).
Conclusion
Pharmacological treatments have beneficial effects for patients with dementia in prolonging their survival.
doi:10.1371/journal.pone.0130993
PMCID: PMC4476616  PMID: 26098910
11.  Association of Adiponectin Gene Polymorphism with Nonalcoholic Fatty Liver Disease in Taiwanese Patients with Type 2 Diabetes 
PLoS ONE  2015;10(6):e0127521.
Objective
Patients with type 2 diabetes and nonalcoholic fatty liver disease (NAFLD) have a higher prevalence of cardiovascular diseases. In this study we investigated the frequency of single nucleotide polymorphisms (SNPs) of several candidate genes associated with NAFLD in Taiwanese patients with type 2 diabetes mellitus (DM) and NAFLD and in those with DM but without fatty liver disease.
Methods
We enrolled 350 patients with type 2 DM and NAFLD and 209 patients with DM but without NAFLD. Body mass index (BMI), % body fat (% BF), glycated hemoglobin (HbA1c), high molecular weight (HMW) isoform of adiponectin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride (TG) levels were measured. Thirteen SNPs in 5 genes (adiponectin, leptin, peroxisome proliferator-activated receptor alpha, adiponutrin/patatin-like phospholipase domain-containing protein 3 and peroxisome proliferator-activated receptor γ co-activator 1α ) were measured.
Results
Only adiponectin rs266729 polymorphism was associated with susceptibility to NAFLD (p = 0.001). Subgroup analysis revealed that the proportion of subjects with homozygous genotype GG was higher in patients with NAFLD (31%) than in controls (11%) and that the proportions of heterozygous CG and homozygous CC were higher in controls (37% and 52%, respectively) than in patients with NAFLD (33% and 36%, respectively). Patients with NAFLD carrying the GG genotype of rs266729 showed significantly lower serum HMW adiponectin levels than patients carrying the GC or CC genotype (3.75±0.37 vs. 3.99±0.66 vs. 4.79±0.58 μg/ml, p< 0.001). Body fat and serum HMW adiponectin levels were the strongest predictors of developing NAFLD (p < 0.001 and 0.004, respectively).
Conclusions
In patients with type 2 diabetes gene polymorphism of adiponectin rs266729 is associated with risk of NAFLD. G allele of rs266729 is associated with hypoadiponectinemia. Low serum adiponectin level may precipitate liver steatosis in patients with type 2 diabetes.
doi:10.1371/journal.pone.0127521
PMCID: PMC4456357  PMID: 26042596
12.  Care Needs and Clinical Outcomes of Older People with Dementia: A Population-Based Propensity Score-Matched Cohort Study 
PLoS ONE  2015;10(5):e0124973.
Objective
To explore the healthcare resource utilization, psychotropic drug use and mortality of older people with dementia.
Design
A nationwide propensity score-matched cohort study.
Setting
National Health Insurance Research database.
Participants
A total of 32,649 elderly people with dementia and their propensity-score matched controls (n=32,649).
Measurements
Outpatient visits, inpatient care, psychotropic drug use, in-hospital mortality and all-cause mortality at 90 and 365 days.
Results
Compared to the non-dementia group, a higher proportion of patients with dementia used inpatient services (1 year after index date: 20.91% vs. 9.55%), and the dementia group had more outpatient visits (median [standard deviation]: 7.00 [8.87] vs. 3.00 [8.30]). Furthermore, dementia cases with acute admission had the highest psychotropic drug utilization both at baseline and at the post-index dates (difference-in-differences: all <0.001). Dementia was associated with an increased risk of all-cause mortality (90 days, Odds ratio (OR)=1.85 [95%CI 1.67-2.05], p<0.001; 365 days, OR=1.59 [1.50-1.69], p<0.001) and in-hospital mortality (90 days, OR=1.97 [1.71-2.27], p<0.001; 365 days, OR=1.82 [1.61-2.05], p<0.001) compared to matched controls.
Conclusions
When older people with dementia are admitted for acute illnesses, they may increase their use of psychotropic agents and their risk of death, particularly in-hospital mortality.
doi:10.1371/journal.pone.0124973
PMCID: PMC4425532  PMID: 25955163
13.  Post-Injury Treatment with 7,8-Dihydroxyflavone, a TrkB Receptor Agonist, Protects against Experimental Traumatic Brain Injury via PI3K/Akt Signaling 
PLoS ONE  2014;9(11):e113397.
Tropomyosin-related kinase B (TrkB) signaling is critical for promoting neuronal survival following brain damage. The present study investigated the effects and underlying mechanisms of TrkB activation by the TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) on traumatic brain injury (TBI). Mice subjected to controlled cortical impact received intraperitoneal 7,8-DHF or vehicle injection 10 min post-injury and subsequently daily for 3 days. Behavioral studies, histology analysis and brain water content assessment were performed. Levels of TrkB signaling-related molecules and apoptosis-related proteins were analyzed. The protective effect of 7,8-DHF was also investigated in primary neurons subjected to stretch injury. Treatment with 20 mg/kg 7,8-DHF attenuated functional deficits and brain damage up to post-injury day 28. 7,8-DHF also reduced brain edema, neuronal death, and apoptosis at day 4. These changes were accompanied by a significant decrease in cleaved caspase-3 and increase in Bcl-2/Bax ratio. 7,8-DHF enhanced phosphorylation of TrkB, Akt (Ser473/Thr308), and Bad at day 4, but had no effect on Erk 1/2 phosphorylation. Moreover, 7,8-DHF increased brain-derived neurotrophic factor levels and promoted cAMP response element-binding protein (CREB) activation. This beneficial effect was attenuated by inhibition of TrkB or PI3K/Akt. 7,8-DHF also promoted survival and reduced apoptosis in cortical neurons subjected to stretch injury. Remarkably, delayed administration of 7,8-DHF at 3 h post-injury reduced brain tissue damage. Our study demonstrates that activation of TrkB signaling by 7,8-DHF protects against TBI via the PI3K/Akt but not Erk pathway, and this protective effect may be amplified via the PI3K/Akt-CREB cascades.
doi:10.1371/journal.pone.0113397
PMCID: PMC4240709  PMID: 25415296
14.  Determinants of Fatigue after First-Ever Ischemic Stroke during Acute Phase 
PLoS ONE  2014;9(10):e110037.
Background and Purpose
Fatigue after stroke is common and has a negative impact on rehabilitation and survival. However, its pathogenesis and contributing factors remain unclear. The purpose of this study was to identify factors influencing the occurrence of fatigue after first-ever ischemic stroke in acute phase.
Methods
We examined 265 consecutive patients with first-ever ischemic stroke during acute phase (within 2 weeks) in two tertiary stroke care hospitals in Henan, China. We documented patients’ demographic and clinical characteristics through face-to-face interviews using structured questionnaires and reviews of medical records. Post-stroke fatigue was defined as a score of ≥4 using the Fatigue Severity Scale. Multivariate logistic regression was used to examine post-stroke fatigue in relation to socio-demographic, lifestyle, clinical characteristics and family function.
Results
About 40% first-ever ischemic stroke patients experienced post-stroke fatigue in acute phase. Post-stroke fatigue was associated with lack of exercise before stroke (adjusted odds ratio 4.01, 95% CI 1.95–8.24), family dysfunction (2.63, 1.20–5.80), depression (2.39, 1.02–5.58), the presence of pre-stroke fatigue (4.89, 2.13–11.21), use of sedative medications (4.14, 1.58–10.88), coronary heart disease (3.38, 1.46–7.79) and more severe Modified Rankin Scale (2.55, 1.65–3.95).
Conclusions
The causes of post-stroke fatigue are multifaceted. More physical exercise, improving family function, reducing depression and appropriate use of sedative medications may be helpful in preventing post-stroke fatigue.
doi:10.1371/journal.pone.0110037
PMCID: PMC4193856  PMID: 25302807
15.  Identification of Important Nodes in Directed Biological Networks: A Network Motif Approach 
PLoS ONE  2014;9(8):e106132.
Identification of important nodes in complex networks has attracted an increasing attention over the last decade. Various measures have been proposed to characterize the importance of nodes in complex networks, such as the degree, betweenness and PageRank. Different measures consider different aspects of complex networks. Although there are numerous results reported on undirected complex networks, few results have been reported on directed biological networks. Based on network motifs and principal component analysis (PCA), this paper aims at introducing a new measure to characterize node importance in directed biological networks. Investigations on five real-world biological networks indicate that the proposed method can robustly identify actually important nodes in different networks, such as finding command interneurons, global regulators and non-hub but evolutionary conserved actually important nodes in biological networks. Receiver Operating Characteristic (ROC) curves for the five networks indicate remarkable prediction accuracy of the proposed measure. The proposed index provides an alternative complex network metric. Potential implications of the related investigations include identifying network control and regulation targets, biological networks modeling and analysis, as well as networked medicine.
doi:10.1371/journal.pone.0106132
PMCID: PMC4149525  PMID: 25170616
16.  Opposite Effects of Neuropeptide FF on Central Antinociception Induced by Endomorphin-1 and Endomorphin-2 in Mice 
PLoS ONE  2014;9(8):e103773.
Neuropeptide FF (NPFF) is known to be an endogenous opioid-modulating peptide. Nevertheless, very few researches focused on the interaction between NPFF and endogenous opioid peptides. In the present study, we have investigated the effects of NPFF system on the supraspinal antinociceptive effects induced by the endogenous µ-opioid receptor agonists, endomorphin-1 (EM-1) and endomorphin-2 (EM-2). In the mouse tail-flick assay, intracerebroventricular injection of EM-1 induced antinociception via µ-opioid receptor while the antinociception of intracerebroventricular injected EM-2 was mediated by both µ- and κ-opioid receptors. In addition, central administration of NPFF significantly reduced EM-1-induced central antinociception, but enhanced EM-2-induced central antinociception. The results using the selective NPFF1 and NPFF2 receptor agonists indicated that the EM-1-modulating action of NPFF was mainly mediated by NPFF2 receptor, while NPFF potentiated EM-2-induecd antinociception via both NPFF1 and NPFF2 receptors. To further investigate the roles of µ- and κ-opioid systems in the opposite effects of NPFF on central antinociception of endomprphins, the µ- and κ-opioid receptors selective agonists DAMGO and U69593, respectively, were used. Our results showed that NPFF could reduce the central antinociception of DAMGO via NPFF2 receptor and enhance the central antinociception of U69593 via both NPFF1 and NPFF2 receptors. Taken together, our data demonstrate that NPFF exerts opposite effects on central antinociception of endomorphins and provide the first evidence that NPFF potentiate antinociception of EM-2, which might result from the interaction between NPFF and κ-opioid systems.
doi:10.1371/journal.pone.0103773
PMCID: PMC4121275  PMID: 25090615
17.  Comparative Mitogenomics of Plant Bugs (Hemiptera: Miridae): Identifying the AGG Codon Reassignments between Serine and Lysine 
PLoS ONE  2014;9(7):e101375.
Insect mitochondrial genomes are very important to understand the molecular evolution as well as for phylogenetic and phylogeographic studies of the insects. The Miridae are the largest family of Heteroptera encompassing more than 11,000 described species and of great economic importance. For better understanding the diversity and the evolution of plant bugs, we sequence five new mitochondrial genomes and present the first comparative analysis of nine mitochondrial genomes of mirids available to date. Our result showed that gene content, gene arrangement, base composition and sequences of mitochondrial transcription termination factor were conserved in plant bugs. Intra-genus species shared more conserved genomic characteristics, such as nucleotide and amino acid composition of protein-coding genes, secondary structure and anticodon mutations of tRNAs, and non-coding sequences. Control region possessed several distinct characteristics, including: variable size, abundant tandem repetitions, and intra-genus conservation; and was useful in evolutionary and population genetic studies. The AGG codon reassignments were investigated between serine and lysine in the genera Adelphocoris and other cimicomorphans. Our analysis revealed correlated evolution between reassignments of the AGG codon and specific point mutations at the antidocons of tRNALys and tRNASer(AGN). Phylogenetic analysis indicated that mitochondrial genome sequences were useful in resolving family level relationship of Cimicomorpha. Comparative evolutionary analysis of plant bug mitochondrial genomes allowed the identification of previously neglected coding genes or non-coding regions as potential molecular markers. The finding of the AGG codon reassignments between serine and lysine indicated the parallel evolution of the genetic code in Hemiptera mitochondrial genomes.
doi:10.1371/journal.pone.0101375
PMCID: PMC4079613  PMID: 24988409
18.  A Nationwide Survey of Mild Cognitive Impairment and Dementia, Including Very Mild Dementia, in Taiwan 
PLoS ONE  2014;9(6):e100303.
An increasing population of dementia patients produces substantial societal impacts. We assessed the prevalence of mild cognitive impairment (MCI) and all-cause dementia, including very mild dementia (VMD), in Taiwan. In a nationwide population-based cross-sectional survey, participants were selected by computerized random sampling from all 19 Taiwan counties and were enrolled between December 2011 and March 2013. Cases were identified through in-person interviews based on the National Institute on Aging-Alzheimer’s Association clinical criteria. Demographic data and histories involving mental status and function in daily living were collected. The principal objective assessments were the Taiwanese Mental Status Examination and Clinical Dementia Rating. In all, 10,432 people aged 65 years or older (mean age 76.2±6.7, 52.3% women) were interviewed. The age-adjusted prevalence of all-cause dementia was 8.04% (95% CI 7.47–8.61), including a 3.25% (95% CI 2.89–3.61) prevalence of VMD; that of MCI was 18.76% (95% CI 17.91–19.61). Women had a higher prevalence than men of both all-cause dementia (9.71% vs. 6.36%) and MCI (21.63% vs. 15.57%). MCI affects a considerable portion of the population aged 65 and above in Taiwan. The inclusion of VMD yields dementia prevalence rates higher than those previously reported from Taiwan. Old age, female gender, and a low educational level are significant associated factors.
doi:10.1371/journal.pone.0100303
PMCID: PMC4062510  PMID: 24940604
19.  Laminoplasty and Laminectomy Hybrid Decompression for the Treatment of Cervical Spondylotic Myelopathy with Hypertrophic Ligamentum Flavum: A Retrospective Study 
PLoS ONE  2014;9(4):e95482.
Objective
To report the outcomes of a posterior hybrid decompression protocol for the treatment of cervical spondylotic myelopathy (CSM) associated with hypertrophic ligamentum flavum (HLF).
Background
Laminoplasty is widely used in patients with CSM; however, for CSM patients with HLF, traditional laminoplasty does not include resection of a pathological ligamentum flavum.
Methods
This study retrospectively reviewed 116 CSM patients with HLF who underwent hybrid decompression with a minimum of 12 months of follow-up. The procedure consisted of reconstruction of the C4 and C6 laminae using CENTERPIECE plates with spinous process autografts, and resection of the C3, C5, and C7 laminae. Surgical outcomes were assessed using Japanese Orthopedic Association (JOA) score, recovery rate, cervical lordotic angle, cervical range of motion, spinal canal sagittal diameter, bone healing rates on both the hinge and open sides, dural sac expansion at the level of maximum compression, drift-back distance of the spinal cord, and postoperative neck pain assessed by visual analog scale.
Results
No hardware failure or restenosis was noted. Postoperative JOA score improved significantly, with a mean recovery rate of 65.3±15.5%. Mean cervical lordotic angle had decreased 4.9 degrees by 1 year after surgery (P<0.05). Preservation of cervical range of motion was satisfactory postoperatively. Bone healing rates 6 months after surgery were 100% on the hinge side and 92.2% on the open side. Satisfactory decompression was demonstrated by a significantly increased sagittal canal diameter and cross-sectional area of the dural sac together with a significant drift-back distance of the spinal cord. The dural sac was also adequately expanded at the time of the final follow-up visit.
Conclusion
Hybrid laminectomy and autograft laminoplasty decompression using Centerpiece plates may facilitate bone healing and produce a comparatively satisfactory prognosis for CSM patients with HLF.
doi:10.1371/journal.pone.0095482
PMCID: PMC3989326  PMID: 24740151
20.  Genetic Polymorphism of Apolipoprotein A5 Gene and Susceptibility to Type 2 Diabetes Mellitus: A Meta-Analysis of 15,137 Subjects 
PLoS ONE  2014;9(2):e89167.
Background
Several studies have investigated whether the polymorphism in the apolipoprotein A5 (APOA5) is associated with type 2 diabetes mellitus (T2DM) risk. However, those studies have produced inconsistent results. The purpose of this study was to investigate whether the APOA5 -1131T/C polymorphism (rs662799) confers significant susceptibility to T2DM using a meta-analysis.
Methods
PubMed, Embase, Web of Science, Cochrane database, CBMdisc, CNKI and Google Scholar were searched to get the genetic association studies. All statistical analyses were done with Stata 11.0.
Results
A total of 19 studies included 4,767 T2DM cases and 10,370 controls (four studies involving 555 T2DM cases and 2958 controls were performed among Europeans and 15 studies involving 4212 T2DM cases and 7412 controls were performed among Asians) were combined showing significant association between the APOA5 -1131T/C polymorphism and T2DM risk (for C allele vs. T allele: OR = 1.28, 95% CI = 1.17–1.40, p<0.00001; for C/C vs. T/T: OR = 1.57, 95% CI = 1.35–1.83, p<0.00001; for C/C vs. T/C+T/T: OR = 1.36, 95% CI = 1.18–1.57, p<0.0001; for C/C+T/C vs. T/T: OR = 1.32, 95% CI = 1.16–1.51, p<0.0001). In the subgroup analysis by ethnicity, significant association was also found among Asians (for C allele vs. T allele: OR = 1.31, 95% CI = 1.22–1.40, p<0.00001; for C/C vs. T/T: OR = 1.61, 95% CI = 1.38–1.88, p<0.00001; for C/C vs. T/C+T/T: OR = 1.39, 95% CI = 1.20–1.61, p<0.0001; for C/C+T/C vs. T/T: OR = 1.42, 95% CI = 1.25–1.62, p<0.00001). However, no significant association was found between the APOA5 -1131T/C polymorphism and T2DM risk among Europeans.
Conclusions
The present meta-analysis suggests that the APOA5 -1131T/C polymorphism is associated with an increased T2DM risk in Asian population.
doi:10.1371/journal.pone.0089167
PMCID: PMC3929635  PMID: 24586566
21.  Characterization of Four Novel Caspases from Litopenaeus vannamei (Lvcaspase2-5) and Their Role in WSSV Infection through dsRNA-Mediated Gene Silencing 
PLoS ONE  2013;8(12):e80418.
Apoptosis plays an important role in white spot syndrome virus (WSSV) pathogenesis, and caspases are central players in apoptosis. Here, we cloned four novel caspases (Lvcaspase2-5) from the Pacific white shrimp Litopenaeus vannamei, and investigated their potential roles in WSSV replication using dsRNA-mediated gene silencing. Lvcaspase2-5 have the typical domain structure of caspase family proteins, with the conserved consensus motifs p20 and p10. Lvcaspase2 and Lvcaspase5 were highly expressed in muscle, while Lvcaspase3 was highly expressed in hemocytes and Lvcaspase4 was mainly expressed in intestine. Lvcaspase2-5 could also be upregulated by WSSV infection, and they showed different patterns in various tissues. When overexpressed in Drosophila S2 cells, Lvcaspase2-5 showed different cellular localizations. Using dsRNA-medicated gene silencing, the expression of Lvcaspase2, Lvcaspase3, and Lvcaspase5 were effectively knocked down. In Lvcaspase2-, Lvcaspase3- or Lvcaspase5-silenced L. vannamei, expression of WSSV VP28 gene was significantly enhanced, suggesting protective roles for Lvcaspase2, Lvcaspase3 and Lvcaspase5 in the host defense against WSSV infection.
doi:10.1371/journal.pone.0080418
PMCID: PMC3871164  PMID: 24376496
22.  Urinary Function following Laparoscopic Lymphadenectomy for Male Rectal Cancer 
PLoS ONE  2013;8(11):e78701.
Objectives
Urinary function can be protected following open lateral node dissection (LND) with pelvic autonomic nerve preservation (PANP) for advanced rectal cancer. However data regarding urinary function after laparoscopic LND with PANP have not been reported. The goal of this study was to determine the effects of laparoscopic LND with PANP on urinary function in male patients with rectal cancer.
Methods
Urine flowmetry was performed using an Urodyn flowmeter. Patients were also asked to complete the standardized International Prostate Symptom Score (IPSS) questionnaire before surgery and 6 months after. In total, this study consisted of 60 males with advanced rectal cancer.
Results
No significant differences were seen in maximal urinary flow rate, voided volume or residual volume before and after surgery. The total IPSS score increased significantly after surgery and at least 41 patients (68.3%) reported there was no change in one of the seven IPSS questions.
Conclusions
Laparoscopic LND with PANP was relatively safe in preserving urinary function.
doi:10.1371/journal.pone.0078701
PMCID: PMC3827062  PMID: 24265709
23.  Transgenerational Variations in DNA Methylation Induced by Drought Stress in Two Rice Varieties with Distinguished Difference to Drought Resistance 
PLoS ONE  2013;8(11):e80253.
Adverse environmental conditions have large impacts on plant growth and crop production. One of the crucial mechanisms that plants use in variable and stressful natural environments is gene expression modulation through epigenetic modification. In this study, two rice varieties with different drought resistance levels were cultivated under drought stress from tilling stage to seed filling stage for six successive generations. The variations in DNA methylation of the original generation (G0) and the sixth generation (G6) of these two varieties in normal condition (CK) and under drought stress (DT) at seedling stage were assessed by using Methylation Sensitive Amplification Polymorphism (MSAP) method. The results revealed that drought stress had a cumulative effect on the DNA methylation pattern of both varieties, but these two varieties had different responses to drought stress in DNA methylation. The DNA methylation levels of II-32B (sensitive) and Huhan-3 (resistant) were around 39% and 32%, respectively. Genome-wide DNA methylation variations among generations or treatments accounted for around 13.1% of total MSAP loci in II-32B, but was only approximately 1.3% in Huhan-3. In II-32B, 27.6% of total differentially methylated loci (DML) were directly induced by drought stress and 3.2% of total DML stably transmitted their changed DNA methylation status to the next generation. In Huhan-3, the numbers were 48.8% and 29.8%, respectively. Therefore, entrainment had greater effect on Huhan-3 than on II-32B. Sequence analysis revealed that the DML were widely distributed on all 12 rice chromosomes and that it mainly occurred on the gene’s promoter and exon region. Some genes with DML respond to environmental stresses. The inheritance of epigenetic variations induced by drought stress may provide a new way to develop drought resistant rice varieties.
doi:10.1371/journal.pone.0080253
PMCID: PMC3823650  PMID: 24244664
24.  Analysis of Expression, Cellular Localization, and Function of Three Inhibitors of Apoptosis (IAPs) from Litopenaeus vannamei during WSSV Infection and in Regulation of Antimicrobial Peptide Genes (AMPs) 
PLoS ONE  2013;8(8):e72592.
Inhibitors of apoptosis (IAPs) play important roles in apoptosis and NF-κB activation. In this study, we cloned and characterized three IAPs (LvIAP1-3) from the Pacific white shrimp, Litopenaeusvannamei. LvIAP1-3 proteins shared signature domains and exhibited significant similarities with other IAP family proteins. The tissue distributions of LvIAP1-3 were studied. The expression of LvIAP1-3 was induced in the muscle after white spot syndrome virus (WSSV) infection. LvIAP1 expression in the gill, hemocytes, hepatopancreas, and intestine was responsive to WSSV and Vibrioalginolyticus infections. LvIAP2 expression in the gill, hemocytes, and hepatopancreas was also responsive to WSSV infection. The expression of LvIAP3 in the gill, hemocytes, and intestine was reduced after V. alginolyticus infection. When overexpressed in Drosophila S2 cells, GFP labeled-LvIAP2 was distributed in the cytoplasm and appeared as speck-like aggregates in the nucleus. Both LvIAP1 and LvIAP3 were widely distributed throughout the cytoplasm and nucleus. The expression of LvIAP1, LvIAP2, and LvIAP3 was significantly knocked down by dsRNA-mediated gene silencing. In the gill of LvIAP1- or LvIAP3-silenced shrimp, the expression of WSSV VP28 was significantly higher than that of the dsGFP control group, suggesting that LvIAP1 and LvIAP3 may play protective roles in host defense against WSSV infection. Intriguingly, the LvIAP2-silenced shrimp all died within 48 hours after dsLvIAP2 injection. In the hemocytes of LvIAP2-silenced shrimps, the expression of antimicrobial peptide genes (AMPs), including Penaeidins, lysozyme, crustins, Vibriopenaeicidae-induced cysteine and proline-rich peptides (VICPs), was significantly downregulated, while the expression of anti-lipopolysaccharide factors (ALFs) was upregulated. Moreover, LvIAP2 activated the promoters of the NF-κB pathway-controlled AMPs, such as shrimp Penaeidins and Drosophila drosomycin and attacin A, in Drosophila S2 cells. Taken together, these results reveal that LvIAP1 and LvIAP3 might participate in the host defense against WSSV infection, and LvIAP2 might be involved in the regulation of shrimp AMPs.
doi:10.1371/journal.pone.0072592
PMCID: PMC3743791  PMID: 23967321
25.  Deficiency of Adiponectin Protects against Ovariectomy-Induced Osteoporosis in Mice 
PLoS ONE  2013;8(7):e68497.
Adipokine adiponectin (APN) has been recently reported to play a role in regulating bone mineral density (BMD). To explore the mechanism by which APN affects BMD, we investigated BMD and biomechanical strength properties of the femur and vertebra in sham-operated (Sham) and ovariectomized (OVX) APN knockout (KO) mice as compared to their operated wild-type (WT) littermates. The results show that APN deficiency has no effect on BMD but induces increased ALP activity and osteoclast cell number. While OVX indeed leads to significant bone loss in both femora and vertebras of WT mice with comparable osteogenic activity and a significant increase in osteoclast cell number when compared to that of sham control. However, no differences in BMD, ALP activity and osteoclast cell number were found between Sham and OVX mice deficient for APN. Further studies using bone marrow derived mesenchymal stem cells (MSCs) demonstrate an enhanced osteogenic differentiation and extracellular matrix calcification in APN KO mice. The possible mechanism for APN deletion induced acceleration of osteogenesis could involve increased proliferation of MSCs and higher expression of Runx2 and Osterix genes. These findings indicate that APN deficiency can protect against OVX-induced osteoporosis in mice, suggesting a potential role of APN in regulating the balance of bone formation and bone resorption, especially in the development of post-menopausal osteoporosis.
doi:10.1371/journal.pone.0068497
PMCID: PMC3699501  PMID: 23844209

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