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Lung cancer stands as the primary cause of cancer-related death across the globe. The standard therapeutic approach for lung cancer involves concurrent chemoradiotherapy, with consideration of prophylactic cranial irradiation for younger or well-performing patients. In this study, we aimed to investigate prognostic factors and the impacts of different treatment methods on overall survival for stage IIIA small cell lung cancer in Taiwan. We obtained data from the Taiwan Cancer Registry, which included clinical and pathology data of 579 stage IIIA small cell lung cancer patients from January 2010 to December 2018, for this retrospective study. The enrolled patients had data on age, sex, Charlson Comorbidity Index score, histologic grading, clinical T, clinical N, clinical stage, treatment modality, and overall survival time. We compared overall survival among different subgroups to assess the impacts of these prognostic factors. The five-year survival rate for all patients was 20.57%, with a median survival time of 15.79 months. The data suggest that Charlson Comorbidity Index score, histologic grade, and clinical stage subgroups did not reach statistically significant differences. During the multivariate analysis, age over 70 years, sex, and treatment method were determined to be statistically significant independent prognostic factors. Patients who underwent surgical intervention exhibited significantly better outcomes compared to those who did not undergo operation.. In conclusion, stage IIIA small cell lung cancer is a highly heterogeneous disease. Operation should be considered as one of the alternative treatments in stage IIIA Small cell lung cancer patients.

Introduction The purpose of the current study is to compare definitive chemoradiotherapy and esophagectomy with adjuvant chemoradiotherapy in patients with cT1-3/N0-3 esophageal squamous cell carcinoma in survival. Methods Records from 2008 to 2014 of 4931 patients with clinical T1-3/N0-3 esophageal squamous cell carcinoma receiving definitive chemoradiotherapy or esophagectomy with adjuvant chemoradiotherapy were obtained from the Taiwan Cancer Registry. Univariable and multivariable analyses were performed and propensity score matching was used to minimize the bias. Overall survival was compared between definitive chemoradiotherapy and esophagectomy with adjuvant chemoradiotherapy, and also in the three different clinical stages. Results Definitive chemoradiotherapy was performed on 4381 patients, and 550 patients received esophagectomy adjuvant chemoradiotherapy. Each group produced 456 patients for comparison after propensity score matching. The 1-year, 2-year, and 3-year overall survival rates for matched patients in with definitive chemoradiotherapy group were 57.18%, 31.92%, and 23.8%. The 1-year, 2-year, and 3-year overall survival rates for matched patients treated in the esophagectomy with adjuvant chemoradiotherapy group were 72.35%, 45.74%, and 34.04%(pConclusions Esophagectomy with adjuvant chemoradiotherapy provided better survival than definitive chemoradiotherapy in clinical II/III esophageal squamous cell carcinoma. However, more data are needed to conduct a convincing conclusion in clinical stage I patients.

Based on expectation states theory, we examined the mechanism underlying the effect of employees' sense of power on supervisors' voice endorsement, and tested our hypothesized model on a sample of 307 employees from 60 work teams. We used a two-time lagged design and paired questionnaire survey. Our analysis indicated that employees' sense of power enhanced supervisors' voice endorsement, and supervisors' perceived voice constructiveness mediated this relationship. Multilevel analyses showed that power distance negatively moderated the influence of sense of power on perceived voice constructiveness and negatively moderated its indirect effect on voice endorsement.

This research sought to ascertain the relationship between hematocrit (HCT) and mortality in patients with sepsis.MethodsA retrospective analysis was conducted on the clinical data of septic patients who were hospitalized between 2008 and 2019 in an advanced academic medical center in Boston, Massachusetts, registered in the Medical Information Mart for Intensive Care IV (MIMIC-IV) database, We analyzed basic information including gender, age, race, and types of the first admission, laboratory indicators including HCT, platelets, white blood cells, albumin, bilirubin, hemoglobin, and serum creatinine, and 30-day mortality. A Cox proportional hazards regression model was utilized to analyze the relationship between HCT and 30-day mortality in patients with sepsis.ResultsThis research recruited 2057 patients who met the research requirements from 2008 to 2019. According to the HCT level, it was classified into the low HCT level, the regular HCT level, and the high HCT level. The 30-day mortality rate was 62.6%, 27.5%, and 9.9% for patients with the low HCT level, the regular HCT level, and the high HCT level, respectively (p < 0.05). The multivariate Cox proportional hazard regression model analysis displayed that compared with patients with the regular HCT level, the 30-day mortality of patients with the low HCT level increased by 58.9% (hazard ratio = 1.589, 95% confidence interval (CI) = 1.009-2.979, p < 0.05).ConclusionThe low HCT level is an independent risk factor for the increase of the 30-day mortality in patients with sepsis and can be used as a significant predictor of the clinical outcome of sepsis.

High-density genetic linkage maps are necessary for precisely mapping quantitative trait loci (QTLs) controlling grain shape and size in wheat. By applying the Infinium iSelect 9K SNP assay, we have constructed a high-density genetic linkage map with 269 F 8 recombinant inbred lines (RILs) developed between a Chinese cornerstone wheat breeding parental line Yanda1817 and a high-yielding line Beinong6. The map contains 2431 SNPs and 128 SSR & EST-SSR markers in a total coverage of 3213.2 cM with an average interval of 1.26 cM per marker. Eighty-eight QTLs for thousand-grain weight (TGW), grain length (GL), grain width (GW) and grain thickness (GT) were detected in nine ecological environments (Beijing, Shijiazhuang and Kaifeng) during five years between 2010-2014 by inclusive composite interval mapping (ICIM) (LOD ≥ 2.5). Among which, 17 QTLs for TGW were mapped on chromosomes 1A, 1B, 2A, 2B, 3A, 3B, 3D, 4A, 4D, 5A, 5B and 6B with phenotypic variations ranging from 2.62% to 12.08%. Four stable QTLs for TGW could be detected in five and seven environments, respectively. Thirty-two QTLs for GL were mapped on chromosomes 1B, 1D, 2A, 2B, 2D, 3B, 3D, 4A, 4B, 4D, 5A, 5B, 6B, 7A and 7B, with phenotypic variations ranging from 2.62% to 44.39%. QGl.cau-2A.2 can be detected in all the environments with the largest phenotypic variations, indicating that it is a major and stable QTL. For GW, 12 QTLs were identified with phenotypic variations range from 3.69% to 12.30%. We found 27 QTLs for GT with phenotypic variations ranged from 2.55% to 36.42%. In particular, QTL QGt.cau-5A.1 with phenotypic variations of 6.82-23.59% was detected in all the nine environments. Moreover, pleiotropic effects were detected for several QTL loci responsible for grain shape and size that could serve as target regions for fine mapping and marker assisted selection in wheat breeding programs.

Contrary to the common expectation that the reference evapotranspiration (ETo), which is an indicator of the atmospheric evaporation capability, increases in warming climate, the decline of the ETo has been reported worldwide, and this contradiction between the expected increasing ETo and the observed decreasing one is now termed the "evaporation paradox". Based on the updated meteorological data (1960-2019), we separately detected the spatiotemporal characteristics and the causes of the "evaporation paradox" in three subregions, namely Huaibei, Jianghuai, and Sunan, and throughout the entire province of Jiangsu in southeastern China. Different from the reported continuous unidirectional variations in the ETo, in the province of Jiangsu, it generally showed a decreasing trend before 1990 but followed an increasing trend from 1990 to 2019, which led to the different characteristics of the "evaporation paradox" in the periods from 1960 to 1989, from 1990 to 2019, and from 1960 to 2019. In the first 30 years, the reduction of the wind speed (WS) was the main reason for the decreased ETo, which consequently gave rise to the "evaporation paradox" in spring and winter in the Huaibei region and only in winter in the two other subregions and throughout the entire province. We noticed that the "evaporation paradox" in spring in the Sunan region was expressed by the decreased daily mean air temperature (Tmean) and the increased ETo which was chiefly induced by the decreased relative humidity (RH) and the increased vapor pressure deficit (VPD). After 1990, the decreased WS also dominated the decreased ETo and resulted in the "evaporation paradox" in winter in the Jianghuai region. Furthermore, the decreased sunshine hour (SH) was the main factor influencing the decreased ETo, thereby inducing the "evaporation paradox" in summer and autumn in the Jianghuai region and only in autumn in the Huaibei region and throughout the whole province from 1990 to 2019. In the whole study period from 1960 to 2019, the decreased SH was also found to be responsible for the decreased ETo and for the "evaporation paradox" in summer in all the subregions and throughout the whole province. However, regarding the "evaporation paradox" in autumn, in winter, and in the entire year in the Huaibei region and throughout the whole province, the observed decreased ETo was largely due to the reduced WS from 1960 to 2019. In summary, in addition to the air temperature, the ETo has shifted due to the other meteorological variables (especially the WS, the SH, and the VPD) and shaped the unique spatiotemporal characteristics of the "evaporation paradox" in the province of Jiangsu in southeastern China. Moreover, future studies and simulations addressing the regional climate change and hydrological cycles should take account of the changeable key meteorological variables in different subregions and seasons of the province of Jiangsu.

The sequencing of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in patients with EGFR mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC) remains a matter of controversy. This cohort study analyzed the overall survival (OS) and progression-free survival (PFS) of afatinib compared with erlotinib and gefitinib first-line. EGFRm+, advanced NSCLC patients treated with either afatinib, erlotinib or gefitinib were retrospectively analyzed. A total of 107 patients were included. There was no statistically significant difference in PFS among the 3 groups. In the ≥ 60 years age group, the afatinib group had longer survival compared to the gefitinib group (p = 0.01). Median OS were 19.1, 22.9, and 35.6 months for gefitinib, erlotinib, and afatinib groups, respectively, with statistical significance between the gefitinib and afatinib groups (p = 0.009). Patients on afatinib also had longer median OS than erlotinib and gefitinib pooled together (35.5 versus 21.4 months; hazard ratio = 0.54, p = 0.016), despite similar median PFS. In conclusion, afatinib is a better choice compared to gefitinib or erlotinib for EGFRm+ patients. The OS obtained with afatinib is just 3 months shorter than osimertinib in the FLAURA trial. Direct comparison studies with osimertinib are still needed to determine optimal sequencing.

The ND18 strain of Barley stripe mosaic virus (BSMV) infects several lines of Brachypodium distachyon, a recently developed model system for genomics research in cereals. Among the inbred lines tested, Bd3-1 is highly resistant at 20 to 25 °C, whereas Bd21 is susceptible and infection results in an intense mosaic phenotype accompanied by high levels of replicating virus. We generated an F(6:7) recombinant inbred line (RIL) population from a cross between Bd3-1 and Bd21 and used the RILs, and an F(2) population of a second Bd21 × Bd3-1 cross to evaluate the inheritance of resistance. The results indicate that resistance segregates as expected for a single dominant gene, which we have designated Barley stripe mosaic virus resistance 1 (Bsr1). We constructed a genetic linkage map of the RIL population using SNP markers to map this gene to within 705 Kb of the distal end of the top of chromosome 3. Additional CAPS and Indel markers were used to fine map Bsr1 to a 23 Kb interval containing five putative genes. Our study demonstrates the power of using RILs to rapidly map the genetic determinants of BSMV resistance in Brachypodium. Moreover, the RILs and their associated genetic map, when combined with the complete genomic sequence of Brachypodium, provide new resources for genetic analyses of many other traits.

Barley stripe mosaic virus (BSMV) is a single-stranded RNA virus with three genome components designated alpha, beta, and gamma. BSMV vectors have previously been shown to be efficient virus induced gene silencing (VIGS) vehicles in barley and wheat and have provided important information about host genes functioning during pathogenesis as well as various aspects of genes functioning in development. To permit more effective use of BSMV VIGS for functional genomics experiments, we have developed an Agrobacterium delivery system for BSMV and have coupled this with a ligation independent cloning (LIC) strategy to mediate efficient cloning of host genes. Infiltrated Nicotiana benthamiana leaves provided excellent sources of virus for secondary BSMV infections and VIGS in cereals. The Agro/LIC BSMV VIGS vectors were able to function in high efficiency down regulation of phytoene desaturase (PDS), magnesium chelatase subunit H (ChlH), and plastid transketolase (TK) gene silencing in N. benthamiana and in the monocots, wheat, barley, and the model grass, Brachypodium distachyon. Suppression of an Arabidopsis orthologue cloned from wheat (TaPMR5) also interfered with wheat powdery mildew (Blumeria graminis f. sp. tritici) infections in a manner similar to that of the A. thaliana PMR5 loss-of-function allele. These results imply that the PMR5 gene has maintained similar functions across monocot and dicot families. Our BSMV VIGS system provides substantial advantages in expense, cloning efficiency, ease of manipulation and ability to apply VIGS for high throughput genomics studies.

There is great debate surrounding the demographic impact of China's population control policies, especially the one-birth restrictions, which ended only recently. We apply an objective, data-driven method to construct the total fertility rates and population size of a 'synthetic China', which is assumed to be not subjected to the two major population control policies implemented in the 1970s. We find that while the earlier, less restrictive 'later-longer-fewer' policy introduced in 1973 played a critical role in driving down the fertility rate, the role of the 'one-child policy' introduced in 1979 and its descendants was much less significant. According to our model, had China continued with the less restrictive policies that were implemented in 1973 and followed a standard development trajectory, the path of fertility transition and total population growth would have been statistically very similar to the pattern observed over the past three decades.

[This corrects the article DOI: 10.1371/journal.pone.0160230.].

Previous studies have demonstrated the genetic correlations between type 2 diabetes, obesity and dyslipidemia, and indicated that many genes have pleiotropic effects on them. However, these pleiotropic genes have not been well-defined. It is essential to identify pleiotropic genes using systematic approaches because systematically analyzing correlated traits is an effective way to enhance their statistical power. To identify potential pleiotropic genes for these three disorders, we performed a systematic analysis by incorporating GWAS (genome-wide associated study) datasets of six correlated traits related to type 2 diabetes, obesity and dyslipidemia using Meta-CCA (meta-analysis using canonical correlation analysis). Meta-CCA is an emerging method to systematically identify potential pleiotropic genes using GWAS summary statistics of multiple correlated traits. 2,720 genes were identified as significant genes after multiple testing (Bonferroni corrected p value < 0.05). Further, to refine the identified genes, we tested their relationship to the six correlated traits using VEGAS-2 (versatile gene-based association study-2). Only the genes significantly associated (Bonferroni corrected p value < 0.05) with more than one trait were kept. Finally, 25 genes (including two confirmed pleiotropic genes and eleven novel pleiotropic genes) were identified as potential pleiotropic genes. They were enriched in 5 pathways including the statin pathway and the PPAR (peroxisome proliferator-activated receptor) Alpha pathway. In summary, our study identified potential pleiotropic genes and pathways of type 2 diabetes, obesity and dyslipidemia, which may shed light on the common biological etiology and pathogenesis of these three disorders and provide promising insights for new therapies.

There are co-morbidity between osteoporosis (OP) and rheumatoid arthritis (RA). Some genetic risk factors have been identified for these two phenotypes respectively in previous research; however, they accounted for only a small portion of the underlying total genetic variances. Here, we sought to identify additional common genetic loci associated with OP and/or RA. The conditional false discovery rate (cFDR) approach allows detection of additional genetic factors (those respective ones as well as common pleiotropic ones) for the two associated phenotypes. We collected and analyzed summary statistics provided by large, multi-center GWAS studies of FNK (femoral neck) BMD (a major risk factor for osteoporosis) (n = 53,236) and RA (n = 80,799). The conditional quantile-quantile (Q-Q) plots can assess the enrichment of SNPs related to FNK BMD and RA, respectively. Furthermore, we identified shared loci between FNK BMD and RA using conjunction cFDR (ccFDR). We found strong enrichment of p-values in FNK BMD when conditional Q-Q was done on RA and vice versa. We identified 30 novel OP-RA associated pleiotropic loci that have not been reported in previous OP or RA GWAS, 18 of which located in the MHC (major histocompatibility complex) region previously reported to play an important role in immune system and bone health. We identified some specific novel polygenic factors for OP and RA respectively, and identified 30 novel OP-RA associated pleiotropic loci. These discovery findings may offer novel pathobiological insights, and suggest new targets and pathways for drug development in OP and RA patients.

The increasing dengue burden and epidemic severity worldwide have highlighted the need to improve surveillance. In non-endemic areas such as Taiwan, where outbreaks start mostly with imported cases from Southeast Asia, a closer examination of surveillance dynamics to detect cases early is necessary. To evaluate problems with dengue surveillance and investigate the involvement of different factors at various epidemic stages, we investigated 632 laboratory-confirmed indigenous dengue cases in Kaohsiung City, Taiwan during 2009-2010. The estimated sensitivity of clinical surveillance was 82.4% (521/632). Initially, the modified serological surveillance (targeting only the contacts of laboratory-confirmed dengue cases) identified clinically unrecognized afebrile cases in younger patients who visited private clinics and accounted for 30.4% (35/115) of the early-stage cases. Multivariate regression indicated that hospital/medical center visits [Adjusted Odds Ratio (aOR): 11.6, 95% confidence interval (CI): 6.3-21.4], middle epidemic stage [aOR: 2.4 (1.2-4.7)], fever [aOR: 2.3 (2.3-12.9)], and musculo-articular pain [aOR: 1.9 (1.05-3.3)] were significantly associated with clinical reporting. However, cases with pruritus/rash [aOR: 0.47 (0.26-0.83)] and diarrhea [aOR: 0.47 (0.26-0.85)] were underreported. In conclusion, multiple factors contributed to dengue surveillance problems. To prevent a large-scale epidemic and minimize severe dengue cases, there is a need for integrated surveillance incorporating entomological, clinical, serological, and virological surveillance systems to detect early cases, followed by immediate prevention and control measures and continuous evaluation to ensure effectiveness. This effort will be particularly important for an arbovirus, such as Zika virus, with a high asymptomatic infection ratio. For dengue- non-endemic countries, we recommend serological surveillance be implemented in areas with high Aedes mosquito indices or many breeding sites. Syndromic surveillance, spatial analysis and monitoring changes in epidemiological characteristics using a geographical information system, as well as epidemic prediction models involving epidemiological, meteorological and environmental variables will be helpful for early risk communication to increase awareness.

Polymer gel dosimeters have been proven useful for dose evaluation in radiotherapy treatments. Previous studies have demonstrated that using a polymer gel dosimeter requires a 24 h reaction time to stabilize and further evaluate the measured dose distribution in two-dimensional dosimetry. In this study, the short-term stability within 24 h and feasibility of N-isopropylacrylamide (NIPAM) polymer gel dosimeters for use in three-dimensional dosimetry were evaluated using magnetic resonance imaging (MRI). NIPAM gels were used to measure the dose volume in a clinical case of intensity-modulated radiation therapy (IMRT). For dose readouts, MR images of irradiated NIPAM gel phantoms were acquired at 2, 5, 12, and 24 h after dose delivery. The mean standard errors of dose conversion from using dose calibration curves (DRC) were calculated. The measured dose volumes at the four time points were compared with those calculated using a treatment planning system (TPS). The mean standard errors of the dose conversion from using the DRCs were lower than 1 Gy. Mean pass rates of 2, 5, 12, and 24 h axial dose maps calculated using gamma evaluation with 3% dose difference and 3 mm distance-to-agreement criteria were 83.5% ± 0.9%, 85.9% ± 0.6%, 98.7% ± 0.3%, and 98.5% ± 0.9%, respectively. Compared with the dose volume histogram of the TPS, the absolute mean relative volume differences of the 2, 5, 12, and 24 h measured dose volumes were lower than 1% for the irradiated region with an absorbed dose higher than 2.8 Gy. It was concluded that a 12 h reaction time was sufficient to acquire accurate dose volume using the NIPAM gels with MR readouts.

Rheumatoid arthritis (RA) is a chronic autoimmune rheumatic disease that can cause painful swelling in the joint lining, morning stiffness, and joint deformation/destruction. These symptoms decrease both quality of life and life expectancy. However, if RA can be diagnosed in the early stages, it can be controlled with pharmacotherapy. Although many studies have examined the possibility of early assessment and diagnosis, few have considered the relationship between significant risk factors and the early assessment of RA. In this paper, we present a novel framework for early RA assessment that utilizes data preprocessing, risk pattern mining, validation, and analysis. Under our proposed framework, two risk patterns can be discovered. Type I refers to well-known risk patterns that have been identified by existing studies, whereas Type II denotes unknown relationship risk patterns that have rarely or never been reported in the literature. These Type II patterns are very valuable in supporting novel hypotheses in clinical trials of RA, and constitute the main contribution of this work. To ensure the robustness of our experimental evaluation, we use a nationwide clinical database containing information on 1,314 RA-diagnosed patients over a 12-year follow-up period (1997-2008) and 965,279 non-RA patients. Our proposed framework is employed on this large-scale population-based dataset, and is shown to effectively discover rich RA risk patterns. These patterns may assist physicians in patient assessment, and enhance opportunities for early detection of RA. The proposed framework is broadly applicable to the mining of risk patterns for major disease assessments. This enables the identification of early risk patterns that are significantly associated with a target disease.

Mammalian target of rapamycin (mTOR) is a serine/threonine kinase and mTOR signaling is important in regulating cell growth and proliferation. Recent studies using oocyte- and granulosa cell-specific deletion of mTOR inhibitor genes TSC1 or TSC2 demonstrated the important role of mTOR signaling in the promotion of ovarian follicle development. We now report that treatment of ovaries from juvenile mice with an mTOR activator MHY1485 stimulated mTOR, S6K1 and rpS6 phosphorylation. Culturing ovaries for 4 days with MHY1485 increased ovarian explant weights and follicle development. In vivo studies further demonstrated that pre-incubation of these ovaries with MHY1485 for 2 days, followed by allo-grafting into kidney capsules of adult ovariectomized hosts for 5 days, led to marked increases in graft weights and promotion of follicle development. Mature oocytes derived from MHY1485-activated ovarian grafts could be successfully fertilized, leading the delivery of healthy pups. We further treated ovaries with the mTOR activator together with AKT activators (PTEN inhibitor and phosphoinositol-3-kinase stimulator) before grafting and found additive enhancement of follicle growth. Our studies demonstrate the ability of an mTOR activator in promoting follicle growth, leading to a potential strategy to stimulate preantral follicle growth in infertile patients.

Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive loss of dopaminergic neurons in the basal ganglia. Single photon emission computed tomography (SPECT) scans using [99mTc]TRODAT-1 can image dopamine transporters and provide valuable diagnostic information of PD. In this study, we optimized the scanning parameters for [99mTc]TRODAT-1/SPECT using the Taguchi analysis to improve image quality. SPECT scans were performed on forty-five healthy volunteers according to an L9 orthogonal array. Three parameters were considered, including the injection activity, uptake duration, and acquisition time per projection. The signal-to-noise ratio (SNR) was calculated from the striatum/occipital activity ratio as an image quality index. Ten healthy subjects and fifteen PD patients were used to verify the optimal parameters. The estimated optimal parameters were 962 MBq for [99mTc]TRODAT-1 injection, 260 min for uptake duration, and 60 s/projection for data acquisition. The uptake duration and time per projection were the two dominant factors which had an F-value of 18.638 (38%) and 25.933 (53%), respectively. Strong cross interactions existed between the injection activity/uptake duration and injection activity/time per projection. Therefore, under the consideration of as low as reasonably achievable (ALARA) for radiation protection, we can decrease the injection activity to 740 MBq. The image quality remains almost the same for clinical applications.

School children may transmit pathogens with cluster cases occurring on campuses and in families. In response to the 2009 influenza A (H1N1) pandemic, Taipei City Government officials developed a School-based Infectious Disease Syndromic Surveillance System (SID-SSS). Teachers and nurses from preschools to universities in all 12 districts within Taipei are required to daily report cases of symptomatic children or sick leave requests through the SID-SSS. The pre-diagnosis at schools is submitted firstly as common pediatric disease syndrome-groups and re-submitted after confirmation by physicians. We retrieved these data from January 2010 to August 2011 for spatio-temporal analysis and evaluated the temporal trends with cases obtained from both the Emergency Department-based Syndromic Surveillance System (ED-SSS) and the Longitudinal Health Insurance Database 2005 (LHID2005). Through the SID-SSS, enterovirus-like illness (EVI) and influenza-like illness (ILI) were the two most reported syndrome groups (77.6% and 15.8% among a total of 19,334 cases, respectively). The pre-diagnosis judgments made by school teachers and nurses showed high consistency with physicians' clinical diagnoses for EVI (97.8%) and ILI (98.9%). Most importantly, the SID-SSS had better timeliness with earlier peaks of EVI and ILI than those in the ED-SSS. Furthermore, both of the syndrome groups in these two surveillance systems had the best correlation reaching 0.98 and 0.95, respectively (p

Understanding the emergence of cooperation in spatial public goods game remains a grand challenge across disciplines. In most previous studies, it is assumed that the investments of all the cooperators are identical, and often equal to 1. However, it is worth mentioning that players are diverse and heterogeneous when choosing actions in the rapidly developing modern society and researchers have shown more interest to the heterogeneity of players recently. For modeling the heterogeneous players without loss of generality, it is assumed in this work that the investment of a cooperator is a random variable with uniform distribution, the mean value of which is equal to 1. The results of extensive numerical simulations convincingly indicate that heterogeneous investments can promote cooperation. Specifically, a large value of the variance of the random variable can decrease the two critical values for the result of behavioral evolution effectively. Moreover, the larger the variance is, the better the promotion effect will be. In addition, this article has discussed the impact of heterogeneous investments when the coevolution of both strategy and investment is taken into account. Comparing the promotion effect of coevolution of strategy and investment with that of strategy imitation only, we can conclude that the coevolution of strategy and investment decreases the asymptotic fraction of cooperators by weakening the heterogeneity of investments, which further demonstrates that heterogeneous investments can promote cooperation in spatial public goods game.

OBJECTIVE: Our purpose was to validate an early enhancement time point for accurately measuring the myocardial contrast partition coefficient (lambda) using dynamic-equilibrium magnetic resonance imaging. MATERIALS AND METHODS: The pre- and post-contrast longitudinal relaxation rates (reciprocal of T1) of the interventricular septum (R1(m)) and blood pool (R1(b)) were obtained from fifteen healthy volunteers and three diabetic patients with hypertension using two optimized T1 mapping sequences (modified Look-Locker inversion recovery) on a 3-Tesla magnetic resonance scanner. Reference lambda values were calculated as the slope of the regression line of R1(m) versus R1(b) at dynamic equilibrium (multi-point regression method). The simplified pre-/post-enhancement two-acquisition method (two-point method) was used to calculate lambda by relating the change in R1(m) and R1(b) using different protocols according to the acquisition stage of the post-enhancement data point. The agreement with the referential method was tested by calculating Pearson's correlation coefficient and the intra-class correlation coefficient. RESULTS: The lambda values measured by the two-point method increased (from 0.479 ± 0.041 to 0.534 ± 0.043) over time from 6 to 45 minutes after contrast and exhibited good correlation with the reference at each time point (r ≥ 0.875, p

The limitations in general methods to evaluate clustering will remain difficult to overcome if verifying the clustering validity continues to be based on clustering results and evaluation index values. This study focuses on a clustering process to analyze crisp clustering validity. First, we define the properties that must be satisfied by valid clustering processes and model clustering processes based on program graphs and transition systems. We then recast the analysis of clustering validity as the problem of verifying whether the model of clustering processes satisfies the specified properties with model checking. That is, we try to build a bridge between clustering and model checking. Experiments on several datasets indicate the effectiveness and suitability of our algorithms. Compared with traditional evaluation indices, our formal method can not only indicate whether the clustering results are valid but, in the case the results are invalid, can also detect the objects that have led to the invalidity.

Gallic acid (GA), a naturally abundant plant phenolic compound in vegetables and fruits, has been shown to have potent anti-oxidative and anti-obesity activity. However, the effects of GA on nonalcoholic fatty liver disease (NAFLD) are poorly understood. In this study, we investigated the beneficial effects of GA administration on nutritional hepatosteatosis model by a more "holistic view" approach, namely 1H NMR-based metabolomics, in order to prove efficacy and to obtain information that might lead to a better understanding of the mode of action of GA. Male C57BL/6 mice were placed for 16 weeks on either a normal chow diet, a high fat diet (HFD, 60%), or a high fat diet supplemented with GA (50 and 100 mg/kg/day, orally). Liver histopathology and serum biochemical examinations indicated that the daily administration of GA protects against hepatic steatosis, obesity, hypercholesterolemia, and insulin resistance among the HFD-induced NAFLD mice. In addition, partial least squares discriminant analysis scores plots demonstrated that the cluster of HFD fed mice is clearly separated from the normal group mice plots, indicating that the metabolic characteristics of these two groups are distinctively different. Specifically, the GA-treated mice are located closer to the normal group of mice, indicating that the HFD-induced disturbances to the metabolic profile were partially reversed by GA treatment. Our results show that the hepatoprotective effect of GA occurs in part through a reversing of the HFD caused disturbances to a range of metabolic pathways, including lipid metabolism, glucose metabolism (glycolysis and gluconeogenesis), amino acids metabolism, choline metabolism and gut-microbiota-associated metabolism. Taken together, this study suggested that a 1H NMR-based metabolomics approach is a useful platform for natural product functional evaluation. The selected metabolites are potentially useful as preventive action biomarkers and could also be used to help our further understanding of the effect of GA in hepatosteatosis mice.

Angiogenesis in glioma is associated with the poor prognosis of the disease and closely correlates with the highly invasive phenotype of glioma cells, which represents the most challenging impediment against the currently glioma treatments. Bmi-1, an onco-protein, has been implicated in the progression of various human cancers, including gliomas, whereas its role in glioma angiogenesis remains unclear. Our current study examined the effects of Bmi-1 on glioma angiogenesis in vitro as well as in vivo. We found that overexpression of Bmi-1 enhanced, whereas knockdown of Bmi-1 diminished, the capability of glioma cells to induce tubule formation and migration of endothelial cells and neovascularization in chicken chorioallantoic membrane. In vivo, Bmi-1 overexpression and knockdown, respectively, promoted and inhibited angiogenesis in orthotopically transplanted human gliomas. Furthermore, NF-κB activity and VEGF-C expression was induced by Bmi-1 overexpression, whereas Bmi-1 knockdown attenuated NF-κB signaling and decreased VEGF-C expression. Additionally suppression of NF-κB activity using a specific chemical inhibitor abrogated the NF-κB activation and the pro-angiogenic activities of glioma cells. Together, our data suggest that Bmi-1 plays an important role in glioma angiogenesis and therefore could represent a potential target for anti-angiogenic therapy against the disease.

Hippo pathway controls the organ size by modulating cell proliferation and apoptosis. However, the upstream regulation of hippo signaling by actin cytoskeleton is not clear. To elucidate the role of actin as an upstream regulator of Hippo signaling, the levels of F (filamentous)-actin in cells were elevated using jasplakinolide, an actin-stabilizing drug. Induction of F-actin formation in HeLa cells resulted in decreased phosphorylation of YAP, a key effector molecule for Hippo signaling. The activated YAP is localized to the cell nucleus and YAP increase was associated with increased expression of downstream CCN growth factors CCN1/CYR61 and CCN2/CTGF. The effect of the actin-stabilizing drug was blocked when YAP levels were suppressed in YAP "knock-down" cells. In summary, using an actin-stabilizing drug we show that actin cytoskeleton is one of the upstream regulators of Hippo signaling capable of activating YAP and increasing its downstream CCN growth factors.

[This corrects the article on p. e73763 in vol. 8.].

The dissimilatory metal reducing bacterium Shewanella oneidensis MR-1, known for its capacity of reducing iron and manganese oxides, has great environmental impacts. The iron oxides reducing process is affected by the coexistence of alternative electron acceptors in the environment, while investigation into it is limited so far. In this work, the impact of dimethyl sulphoxide (DMSO), a ubiquitous chemical in marine environment, on the reduction of hydrous ferric oxide (HFO) by S. oneidensis MR-1 was investigated. Results show that DMSO promoted HFO reduction by both wild type and ΔdmsE, but had no effect on the HFO reduction by ΔdmsB, indicating that such a promotion was dependent on the DMSO respiration. With the DMSO dosing, the levels of extracellular flavins and omcA expression were significantly increased in WT and further increased in ΔdmsE. Bioelectrochemical analysis show that DMSO also promoted the extracellular electron transfer of WT and ΔdmsE. These results demonstrate that DMSO could stimulate the HFO reduction through metabolic and genetic regulation in S. oneidensis MR-1, rather than compete for electrons with HFO. This may provide a potential respiratory pathway to enhance the microbial electron flows for environmental and engineering applications.

Gammadelta (γδ) T lymphocytes respond quickly upon antigen encounter to produce a cytokine response. In this study, we sought to understand how functions of γδ T cells are differentially regulated compared to αβ T cells. We found that cholesterol, an integral component of the plasma membrane and a regulator of TCR signaling, is increased in γδ T cells compared to αβ T cells, and modulates their function. Higher levels of activation markers, and increased lipid raft content in γδ cells suggest that γδ T cells are more activated. Cholesterol depletion effectively decreased lipid raft formation and activation of γδ T cells, indicating that increased cholesterol content contributes to the hyper-activated phenotype of γδ T cells, possibly through enhanced clustering of TCR signals in lipid rafts. TCR stimulation assays and western blotting revealed that instead of a lower TCR threshold, enhanced TCR signaling through ERK1/2 activation is likely the cause for high cholesterol-induced rapid activation and proliferation in γδ T cells. Our data indicate that cholesterol metabolism is differentially regulated in γδ T cells. The high intracellular cholesterol content leads to enhanced TCR signaling and increases activation and proliferation of γδ T cells.

Postoperative cognitive dysfunction (POCD) is a clinical phenomenon characterized by cognitive deficits in patients after anesthesia and surgery, especially in geriatric surgical patients. Although it has been documented that isoflurane exposure impaired cognitive function in several aged animal models, there are few clinical interventions and treatments available to prevent this disorder. Minocycline has been well established to exert neuroprotective effects in various experimental animal models and neurodegenerative diseases. Therefore, we hypothesized that pretreatment with minocycline attenuates isoflurane-induced cognitive decline in aged rats. In the present study, twenty-month-old rats were administered minocycline or an equal volume of saline by intraperitoneal injection 12 h before exposure to isoflurane. Then the rats were exposed to 1.3% isoflurane for 4 h. Two weeks later, spatial learning and memory of the rats were examined using the Morris Water Maze. We found that pretreatment with minocycline mitigated isoflurane-induced cognitive deficits and suppressed the isoflurane-induced excessive release of IL-1β and caspase-3 in the hippocampal CA1 region at 4 h after isoflurane exposure, as well as the number of TUNEL-positive nuclei. In addition, minocycline treatment also prevented the changes of synaptic ultrastructure in the hippocampal CA1 region induced by isoflurane. In conclusion, pretreatment with minocycline attenuated isoflurane-induced cognitive impairment in aged rats.

Studies using animal models demonstrated the importance of autocrine/paracrine factors secreted by preimplantation embryos and reproductive tracts for embryonic development and implantation. Although in vitro fertilization-embryo transfer (IVF-ET) is an established procedure, there is no evidence that present culture conditions are optimal for human early embryonic development. In this study, key polypeptide ligands known to be important for early embryonic development in animal models were tested for their ability to improve human early embryo development and blastocyst outgrowth in vitro. We confirmed the expression of key ligand/receptor pairs in cleavage embryos derived from discarded human tri-pronuclear zygotes and in human endometrium. Combined treatment with key embryonic growth factors (brain-derived neurotrophic factor, colony-stimulating factor, epidermal growth factor, granulocyte macrophage colony-stimulating factor, insulin-like growth factor-1, glial cell-line derived neurotrophic factor, and artemin) in serum-free media promoted >2.5-fold the development of tri-pronuclear zygotes to blastocysts. For normally fertilized embryos, day 3 surplus embryos cultured individually with the key growth factors showed >3-fold increases in the development of 6-8 cell stage embryos to blastocysts and >7-fold increase in the proportion of high quality blastocysts based on Gardner's criteria. Growth factor treatment also led to a 2-fold promotion of blastocyst outgrowth in vitro when day 7 surplus hatching blastocysts were used. When failed-to-be-fertilized oocytes were used to perform somatic cell nuclear transfer (SCNT) using fibroblasts as donor karyoplasts, inclusion of growth factors increased the progression of reconstructed SCNT embryos to >4-cell stage embryos. Growth factor supplementation of serum-free cultures could promote optimal early embryonic development and implantation in IVF-ET and SCNT procedures. This approach is valuable for infertility treatment and future derivation of patient-specific embryonic stem cells.

Self-renewal is a feature common to both adult and embryonic stem (ES) cells, as well as tumor stem cells (TSCs). The cyclin-dependent kinase inhibitor, p18(INK4c), is a known tumor suppressor that can inhibit self-renewal of tumor cells or adult stem cells. Here, we demonstrate an opposite effect of p18 on ES cells in comparison with teratoma cells. Our results unexpectedly showed that overexpression of p18 accelerated the growth of mouse ES cells and embryonic bodies (EB); on the contrary, inhibited the growth of late stage teratoma. Up-regulation of ES cell markers (i.e., Oct4, Nanog, Sox2, and Rex1) were detected in both ES and EB cells, while concomitant down-regulation of various differentiation markers was observed in EB cells. These results demonstrate that p18 has an opposite effect on ES cells as compared with tumor cells and adult stem cells. Mechanistically, expression of CDK4 was significantly increased with overexpression of p18 in ES cells, likely leading to a release of CDK2 from the inhibition by p21 and p27. As a result, self-renewal of ES cells was enhanced. Our current study suggests that targeting p18 in different cell types may yield different outcomes, thereby having implications for therapeutic manipulations of cell cycle machinery in stem cells.

The response of thin polymer gel cassettes (called NIPAM gels) to ionizing radiation was investigated in this study. The NIPAM gels were prepared from gelatin, N-isopropyl acrylamide, tetrakis (hydroxymethyl) phosphoniumchloride, and N,N'-methylene-bis-acrylamide. Gel cassettes were irradiated in a phantom using a linear accelerator, and the polymerization morphology of irradiated NIPAM gel was characterized using scanning electron microscopy. The dose-response sensitivity of the NIPAM gels was evaluated using the differences in optical densities. The optical densities were obtained using a computer-controlled CCD camera that was connected to a planar illumination source for acquisition of optical transmission images. The central axis depth dose profiles of the phantom were extracted, and a comparison with ionization chamber measurements demonstrated similarities in profiles. The sensitivity, linearity of the response, accuracy, and reproducibility of the polymer gel cassettes were acceptable. However, the profiles of the half-blocked field irradiation showed no significant dispersion in the visible region. This study also extensively investigated the spatial stability of the NIPAM gel. The results showed that the gel cassette response remains stable for up to three months after irradiation.

Interleukin 22 (IL-22) is a T-cell secreted cytokine that modulates inflammatory response in nonhematopoietic tissues such as epithelium and liver. The function of IL-22 in adipose tissue is currently unknown. We generated a transgenic mouse model with overexpression of IL-22 specifically in adipose tissue. The IL-22 transgenic mice had no apparent changes in obesity and insulin resistance after feeding with high fat diet (HFD). Unexpectedly, all the IL-22 transgenic mice fed with HFD for four months developed spontaneous tumors in epididymal adipose tissue. Histological analysis indicated that the tumors were well-differentiated liposarcomas with infiltration of inflammatory cells. IL-22 overexpression promotes production of inflammatory cytokines such as IL-1β and IL-10 and stimulates ERK phosphorylation in adipose tissue. Furthermore, IL-22 treatment in differentiated 3T3-L1 adipocytes could induce IL-1β and IL-10 expression, together with stimulation of ERK phosphorylation. Taken together, our study not only established a novel mouse model with spontaneous liposarcoma, but also revealed that IL-22 overexpression may collaborate with diet-induced obesity to impact on tumor development in mouse.