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1.  Expression of semaphorin 3A and neuropilin 1 with clinicopathological features and survival in human tongue cancer 
Objective: To investigate the association between semaphorin 3A (SEMA 3A) and its receptor neuropilin 1 (NRP1) and the clinicopathologic characteristics of patients with tongue cancer. Study Design: Forty-three tongue squamous cell carcinoma specimens were included. Immunohistochemical staining of SEMA3A and NRP1 was performed on 15 normal tongue epithelium specimens and the 43 tumour specimens. Immunoreactivity was evaluated based on the staining intensity and distribution score. Statistical analyses were performed using Chi-squared and Spearman tests and Kaplan-Meier analysis. Results: SEMA3A was significantly down-regulated in tongue cancer compared with normal tongue (P=0.025), while NRP1 was over-expressed in tumours (P<0.001). SEMA3A expression inversely correlated with nodal metastasis (P=0.017). NRP1 expression did not correlate with any clinicopathological characteristics. Higher SEMA3A expression strongly predicted longer survival (P=0.005). Scores for the NRP1/SEMA3A ratio of ≥1 predicted shorter survival (P=0.045). Conclusions: Aberrant expression of SEMA3A and its receptor NRP1 might be involved in the development of tongue cancer and might be useful prognostic markers in this tumour type.
Key words:Semaphorin 3A, neuropilin 1, tongue, squamous cell carcinoma.
doi:10.4317/medoral.18168
PMCID: PMC3505717  PMID: 22926477
2.  Deep RNA sequencing reveals a high frequency of alternative splicing events in the fungus Trichoderma longibrachiatum 
BMC Genomics  2015;16(1):54.
Background
Alternative splicing is crucial for proteome diversity and functional complexity in higher organisms. However, the alternative splicing landscape in fungi is still elusive.
Results
The transcriptome of the filamentous fungus Trichoderma longibrachiatum was deep sequenced using Illumina Solexa technology. A total of 14305 splice junctions were discovered. Analyses of alternative splicing events revealed that the number of all alternative splicing events (10034), intron retentions (IR, 9369), alternative 5’ splice sites (A5SS, 167), and alternative 3’ splice sites (A3SS, 302) is 7.3, 7.4, 5.1, and 5.9-fold higher, respectively, than those observed in the fungus Aspergillus oryzae using Illumina Solexa technology. This unexpectedly high ratio of alternative splicing suggests that alternative splicing is important to the transcriptome diversity of T. longibrachiatum. Alternatively spliced introns had longer lengths, higher GC contents, and lower splice site scores than constitutive introns. Further analysis demonstrated that the isoform relative frequencies were correlated with the splice site scores of the isoforms. Moreover, comparative transcriptomics determined that most enzymes related to glycolysis and the citrate cycle and glyoxylate cycle as well as a few carbohydrate-active enzymes are transcriptionally regulated.
Conclusions
This study, consisting of a comprehensive analysis of the alternative splicing landscape in the filamentous fungus T. longibrachiatum, revealed an unexpectedly high ratio of alternative splicing events and provided new insights into transcriptome diversity in fungi.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1251-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s12864-015-1251-8
PMCID: PMC4324775  PMID: 25652134
Alternative splicing; Fungi; RNA-Seq; Intron retention; Transcriptome; Trichoderma longibrachiatum
3.  Genome-wide analysis of the R2R3-MYB transcription factor genes in Chinese cabbage (Brassica rapa ssp. pekinensis) reveals their stress and hormone responsive patterns 
BMC Genomics  2015;16(1):17.
Background
The MYB superfamily is one of the most abundant transcription factor (TF) families in plants. MYB proteins include highly conserved N-terminal MYB repeats (1R, R2R3, 3R, and atypical) and various C-terminal sequences that confer extensive functions. However, the functions of most MYB genes are unknown, and have been little studied in Chinese cabbage.
Results
Here, we analyzed 256 (55.2% of total MYBs) R2R3-MYB genes from Chinese cabbage (Brassica rapa ssp. pekinensis) and anchored them onto the 10 chromosomes and three subgenomes. The R2R3-, 3R- and atypical MYB proteins in Chinese cabbage formed 45 subgroups based on domain similarity and phylogenetic topology. Organization and syntenic analysis revealed the genomic distribution and collinear relationships of the R2R3-BrMYBs. Synonymous nucleotide substitution (Ka/Ks) analysis showed that the Chinese cabbage MYB DNA-binding domain is under strong purifying selection. Moreover, RNA-seq data revealed tissue-specific and distinct R2R3-BrMYB expression profiles, and quantitative real-time PCR (qPCR) analysis in leaves showed stress responsive expression and crosstalk with ABA-auxin signaling cascades.
Conclusions
In this study, we identified the largest MYB gene family in plants to date. Our results indicate that members of this superfamily may be involved in plant development, stress responses and leaf senescence, highlighting their functional diversity.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1216-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s12864-015-1216-y
PMCID: PMC4334723  PMID: 25613160
Genome-wide analysis; R2R3-MYB transcription factor; Stress responses; Hormone signals; Chinese cabbage
4.  Effects of Electroacupuncture Stimulation at “Zusanli” Acupoint on Hepatic NO Release and Blood Perfusion in Mice 
The study is to observe the influence of electroacupuncture (EA) stimulation at “Zusanli” (ST36) on the release of nitric oxide (NO) and blood perfusion (BP) in the liver and further explore whether the hepatic blood perfusion (HBP) changes were regulated by EA ST36 induced NO in nitric oxide synthase inhibited mice. The HBP change of the mice was detected by laser speckle perfusion imaging (LSPI) before and after being given interventions, and the NO in liver tissue was detected by nitric acid reductase in each group. The NO levels and HBP in the L-NAME group were significantly lower than those in the control group (P < 0.01). The NO level and HBP increase in EA group were significantly higher than those in control group (P < 0.05). The NO level in the L-NAME EA group was slightly higher than that in the L-NAME group. The HBP increase in the L-NAME EA group was not statistically significant. These results showed that EA could accelerate the synthesis of NO and thereby increase HBP via vasodilation in liver tissue.
doi:10.1155/2015/826805
PMCID: PMC4306412  PMID: 25649678
5.  Impact of Water Content and Temperature on the Degradation of Cry1Ac Protein in Leaves and Buds of Bt Cotton in the Soil 
PLoS ONE  2015;10(1):e115240.
Determining the influence of soil environmental factors on degradation of Cry1Ac protein from Bt cotton residues is vital for assessing the ecological risks of this commercialized transgenic crop. In this study, the degradation of Cry1Ac protein in leaves and in buds of Bt cotton in soil was evaluated under different soil water content and temperature settings in the laboratory. An exponential model and a shift-log model were used to fit the degradation dynamics of Cry1Ac protein and estimate the DT50 and DT90 values. The results showed that Cry1Ac protein in the leaves and buds underwent rapid degradation in the early stage (before day 48), followed by a slow decline in the later stage under different soil water content and temperature. Cry1Ac protein degraded the most rapidly in the early stage at 35°C with 70% soil water holding capacity. The DT50 values were 12.29 d and 10.17 d and the DT90 values were 41.06 d and 33.96 d in the leaves and buds, respectively. Our findings indicated that the soil temperature was a major factor influencing the degradation of Cry1Ac protein from Bt cotton residues. Additionally, the relative higher temperature (25°C and 35°C) was found to be more conducive to degradation of Cry1Ac protein in the soil and the greater water content (100%WHC) retarded the process. These findings suggested that under appropriate soil temperature and water content, Cry1Ac protein from Bt cotton residues will not persist and accumulate in soil.
doi:10.1371/journal.pone.0115240
PMCID: PMC4283960  PMID: 25559638
6.  A Pilot Study on Effects of Acupuncture and Moxibustion by Hyperspectral Imaging Technique 
This study was to observe the effects of acupuncture and moxibustion on spectrum features of acupoint using hyperspectral imaging (HSI) technique. HSI of the Neiguan (PC6) in the acupuncture groups, moxibustion groups, and control groups was scanned by the hyperspectral imager to analyze the spectrum features and the variations within the wavelength of 400–1000 nm and explore the relationship between the spectral characteristics and effects of acupuncture and moxibustion. The light absorption intensity was slightly reduced within the wave band of 540–590 nm after acupuncture. The absorption intensity of PC6 before moxibustion was significantly higher than that after moxibustion, and the maximum reduction was found at the wavelength of 580 nm with 20.5% reduction, P < 0.05. There was no significant change of the spectrum of palm and PC6 and the spectrum curves of the acupoint were basically identical in control group. The light absorption intensity of PC6 of human body was weakened after Acu-mox. Specific wavelengths were all exhibited at 580 nm and the effect of moxibustion was more significant. HSI technique can be used to measure the spectral characteristics of the acupoint areas. This first time research would be significant and beneficial for study on the effect of acupuncture and moxibustion.
doi:10.1155/2014/135212
PMCID: PMC4269316  PMID: 25544851
7.  Vitamin C treatment attenuates hemorrhagic shock related multi-organ injuries through the induction of heme oxygenase-1 
Background
Vitamin C (VitC) has recently been shown to exert beneficial effects, including protecting organ function and inhibiting inflammation, in various critical care conditions, but the specific mechanism remains unclear. Induction of heme oxygenase (HO)-1, a heat shock protein, has been shown to prevent organ injuries in hemorrhagic shock (HS) but the relationship between VitC and HO-1 are still ill-defined so far. Here we conducted a systemic in vivo study to investigate if VitC promoted HO-1 expression in multiple organs, and then tested if the HO-1 induction property of VitC was related to its organ protection and anti-inflammatory effect.
Methods
Firstly, to determine the HO-1 induction property of VitC, the HO-1 level were measured in tissues including kidney, liver and lung of the normal and HS model of Sprague–Dawley (SD) rats after VitC treatment (100 mg/kg body weight). Secondly, to testify if VitC prevented HS related organ injuries via inducing HO-1, the HS model of rats were separately pre- and post-treated with VitC, and some of them also received Zinc protoporphyrin (Znpp), a specific HO-1 inhibitor. The HO-1 activity in tissues was tested; the organ injuries (as judged by histological changes in tissues and the biochemical indicators level in serum) and inflammatory response in tissues (as judged by the level of pro-inflammatory cytokines Tumor necrosis factor-α and Interleukin-6 ) were analyzed.
Results
The HO-1 mRNA and protein level in kidney, liver, and lung were highly induced by VitC treatement under normal and HS conditions. The HO-1 activity in tissues was enhanced by both VitC pre- and post-treatment, which was shown to improve the organ injuries and inhibit the inflammatory response in the HS model of rats. Of note, the beneficial effects of VitC were abolished after HO-1 activity was blocked by Znpp.
Conclusions
VitC led to a profound induction of HO-1 in multiple organs including the kidney, liver and lung, and this property might be responsible for the organ protection and inflammation inhibitory effects of both pre- and post-treatment with VitC in HS.
doi:10.1186/1472-6882-14-442
PMCID: PMC4246491  PMID: 25387896
8.  Relationship between single nucleotide polymorphisms in the 3’-untranslated region of the vascular endothelial growth factor gene and susceptibility to diabetic peripheral neuropathy in China 
Archives of Medical Science : AMS  2013;10(5):1028-1034.
Introduction
This study is to elucidate the relationship between a 936C/T mutation at the 3’-untranslated region of the human vascular endothelial growth factor (VEGF) gene and diabetic peripheral neuropathy (DPN).
Material and methods
All subjects recruited in this study were divided into DM (diabetes without neuropathy, retinopathy or nephropathy), DPN (diabetes with peripheral neuropathy only) and healthy control groups. The gene polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism, as well as other clinical methods including serum VEGF by ELISA.
Results
The C allele frequency and CC genotype frequency in the DPN group were higher than those in the NC group and DM group. The T allele frequency and CT+TT genotype (carrying the T allele) frequency in the DPN group were lower than those in the NC group (χ2 = 19.051 and 18.533, both p < 0.001) and DM group (χ2 = 11.117 and 11.156, both p = 0.001). However, there was no statistically significant difference in the three genotype (CC/CT+TT) frequencies and allele (C/T) frequencies between the DM group and the NC group. The multivariate logistic regression analysis showed that the levels of glycated hemoglobin (HbA1c), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and plasma VEGF positively correlated with DPN, while the 936C/T gene polymorphism of VEGF negatively correlated with DPN.
Conclusions
Allele 936C of VEGF may serve as a genetic marker susceptible to DPN, while allele 936T may be a protective genetic marker of DPN.
doi:10.5114/aoms.2013.39381
PMCID: PMC4223128  PMID: 25395956
vascular endothelial growth factor; polymorphisms; type 2 diabetes mellitus; diabetic peripheral neuropathy
9.  Association between non-alcoholic fatty liver disease and arterial stiffness in the non-obese, non-hypertensive, and non-diabetic young and middle-aged Chinese population 
Background and objective: Non-alcoholic fatty liver disease (NAFLD) is associated with arterial stiffness in the general population. Age, obesity, hypertension, and diabetics are risk factors for arterial stiffness. In this study, we aimed to investigate the association between NAFLD and arterial stiffness as measured by brachial-ankle pulse wave velocity (baPWV) in the non-obese, non-hypertensive, and non-diabetic young and middle-aged Chinese population. Methods: A cross-sectional study with 1296 non-obese, non-hypertensive, and non-diabetic young and middle-aged (20–65 years) subjects undergoing routine medical check-ups in the International Health Care Center of the Second Affiliated Hospital of School of Medicine of Zhejiang University was carried out. Fatty liver was diagnosed by ultrasonography, and baPWV was measured using an automatic waveform analyzer. The subjects were classified into two groups according to the presence of NAFLD, and divided into a further two groups according to their baPWV. Results: The overall incidence of NAFLD was 19.0%, and NAFLD patients had a significantly higher level of baPWV than the controls ((1321±158) cm/s vs. (1244±154) cm/s; P<0.001). The incidence of NAFLD was clearly higher in the increased baPWV group than in the normal baPWV group (29.3% vs. 16.9%; P<0.001), and the incidence increased in line with the increase of baPWV quartiles in the normal range as well as with the severity of arterial stiffness (both P for trend <0.001). Multiple linear logistic regression analysis showed that the presence of NAFLD was positively and independently associated with baPWV. Conclusions: Our results suggest that the presence of NAFLD is associated with arterial stiffness as measured by baPWV in the non-obese, non-hypertensive, and non-diabetic young and middle-aged Chinese population.
doi:10.1631/jzus.B1400028
PMCID: PMC4201316  PMID: 25294377
Non-alcoholic fatty liver disease; Arterial stiffness; Brachial-ankle pulse wave velocity; Risk factor
10.  Sample size requirements for training high-dimensional risk predictors 
Biostatistics (Oxford, England)  2013;14(4):639-652.
A common objective of biomarker studies is to develop a predictor of patient survival outcome. Determining the number of samples required to train a predictor from survival data is important for designing such studies. Existing sample size methods for training studies use parametric models for the high-dimensional data and cannot handle a right-censored dependent variable. We present a new training sample size method that is non-parametric with respect to the high-dimensional vectors, and is developed for a right-censored response. The method can be applied to any prediction algorithm that satisfies a set of conditions. The sample size is chosen so that the expected performance of the predictor is within a user-defined tolerance of optimal. The central method is based on a pilot dataset. To quantify uncertainty, a method to construct a confidence interval for the tolerance is developed. Adequacy of the size of the pilot dataset is discussed. An alternative model-based version of our method for estimating the tolerance when no adequate pilot dataset is available is presented. The model-based method requires a covariance matrix be specified, but we show that the identity covariance matrix provides adequate sample size when the user specifies three key quantities. Application of the sample size method to two microarray datasets is discussed.
doi:10.1093/biostatistics/kxt022
PMCID: PMC3770001  PMID: 23873895
Conditional score; Cox regression; High-dimensional data; Risk prediction; Sample size; Training set
11.  Prognostic role of microRNA-145 in various human malignant neoplasms: a meta-analysis of 18 related studies 
Background
Recent studies show that microRNA-145 (miR-145) might be an attractive tumor biomarker of considerable prognostic value. To clarify the preliminary predictive value of miR-145 for prognosis in various malignant neoplasms, we conducted a meta-analysis of 18 relevant studies.
Methods
Eligible studies were identified by searching the online databases PubMed, EMBASE, and Web of Science up to March 2014. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) for patient survival and disease progress were calculated to investigate the association with miR-145 expression.
Results
In total, 18 eligible studies were included in this meta-analysis. Our results showed that upregulated miR-145 significantly predicted a favorable overall survival (OS) (HR = 0.47, 95% CI 0.31 to 0.72), but failed to show a significant relation with disease prognosis. In stratified analyses, high miR-145 expression predicted favorable OS in both Whites and Asians but the intensity of the association in Whites (HR = 0.67, 95% CI 0.47 to 0.95) was not as strong as in Asians (HR = 0.35, 95% CI 0.19 to 0.64). High miR-145 expression also predicted better progression-free survival (PFS) in Asians (HR = 0.43, 95% CI 0.21 to 0.89), but not in Whites. In addition, a significantly favorable OS associated with upregulated miR-145 expression was observed in both squamous cell (SCC) (HR = 0.34, 95% CI 0.13 to 0.93) and glioblastoma (HR = 0.72, 95% CI 0.52 to 0.99).
Conclusions
Our findings indicate that high miR-145 expression is better at predicting patient survival rather than disease progression for malignant tumors, especially for SCC and glioblastoma in Asians. Considering the insufficient evidence, further investigations and more studies are needed.
doi:10.1186/1477-7819-12-254
PMCID: PMC4249768  PMID: 25106061
Malignant neoplasm; miR-145; Prognosis; Overall survival; Progression-free survival
12.  Prophylactic Cranial Irradiation May Impose a Detrimental Effect on Overall Survival of Patients with Nonsmall Cell Lung Cancer: A Systematic Review and Meta-Analysis 
PLoS ONE  2014;9(7):e103431.
Purpose
To determine the role of brain metastases (BM) and overall survival (OS) in patients with non-small cell lung cancer (NSCLC) by performing a meta-analysis of the RCTs (randomized controlled clinical trials) and non-RCTs (non-randomized controlled clinical trials) published in the literature.
Methods
A meta-analysis was performed using trials identified through PubMed, EMBASE and Cochrane databases. Two investigators independently assessed the quality of the trials and extracted data. The outcomes included BM, OS, median survival (MS), response rate (RR), Hazard ratios (HRs) and odds ratios (ORs), and their 95% confidence intervals (CIs) were pooled using ReMan software.
Results
Twelve trials (6 RCTs and 6 non-RCTs) involving 1,718 NSCLC patients met the inclusion criteria. They were grouped on the basis of study design for separate Meta-analyses. The results showed that prophylactic cranial irradiation (PCI) reduced the risk of BM as compared with non-PCI in NSCLC patients (OR = 0.30, 95% [CI]: 0.21–0.43, p<0.00001). However, HRs for OS favored non-PCI (HR = 1.19, 95% [CI]: 1.06–1.33, p = 0.004), without evidence of heterogeneity between the studies.
Conclusion
Our results suggest that although PCI decreased the risk of BM, it may impose a detrimental effect on OS of NSCLC patients.
doi:10.1371/journal.pone.0103431
PMCID: PMC4114791  PMID: 25072281
13.  Investigation of Hepatic Blood Perfusion by Laser Speckle Imaging and Changes of Hepatic Vasoactive Substances in Mice after Electroacupuncture 
The study was conducted to observe the effect of electroacupuncture (EA) on hepatic blood perfusion (HBP) and vascular regulation. We investigated 60 male anesthetized mice under the following 3 conditions: without EA stimulation (control group); EA stimulation at Zusanli (ST36 group); EA stimulation at nonacupoint (NA group) during 30 min. The HBP was measured using the laser speckle perfusion imaging (LSPI). The level of nitric oxide (NO), endothelin-1 (ET-1), and noradrenaline (NE) in liver tissue was detected by biochemical methods. Results were as follows. At each time point, HBP increase in ST36 group was higher than that in the NA group in anesthetized mice. HBP gradually decreased during 30 min in control group. The level of NO in ST36 group was higher than that in NA group. The level of both ET-1 and NE was the highest in control group, followed by NA group and ST36 group. It is concluded that EA at ST36 could increase HBP possibly by increasing the blood flow velocity (BFV), changing vascular activity, increasing the level of NO, and inhibiting the level of ET-1 in liver tissue.
doi:10.1155/2014/715316
PMCID: PMC4129169  PMID: 25140188
14.  Descriptions of three new species of the Termitophilous tribe Termitopaediini in China (Coleoptera, Staphylinidae, Aleocharinae) 
ZooKeys  2014;91-100.
Three new species belonging to two genera of the aleocharine tribe Termitopaediini Seevers, viz., Dioxeuta rara Song & Li, sp. n., D. yunnanensis Song & Li, sp. n., and Termitopulex sinensis Song & Li, sp. n. from Baihualing Natural Reserve (Southwest China: Yunnan) are described and illustrated. This is the first record of Termitopulex Fauvel, 1899 from China.
doi:10.3897/zookeys.424.7670
PMCID: PMC4106102  PMID: 25061397
Termitopaediini; Dioxeuta; Termitopulex; termitophily; taxonomy; new species; China; Oriental region
15.  Pharmacological Preconditioning with Vitamin C Attenuates Intestinal Injury via the Induction of Heme Oxygenase-1 after Hemorrhagic Shock in Rats 
PLoS ONE  2014;9(6):e99134.
Pre-induction of heme oxygenase (HO)-1, which is regarded as an effective method of “organ preconditioning”, exerts beneficial effects during hemorrhagic shock (HS). However, the available HO-1 inducers exhibit disadvantages such as toxicity or complex technical requirements. Therefore, a safe and convenient HO-1 inducer would be promising and could be exploited in the treatment of foreseeable hemorrhaging, such as prior to major surgery. Here we investigated the effect of vitamin C (VitC), a common antioxidant, on intestinal HO-1 expression and examined whether VitC pretreatment prevented HS related intestinal tissue injuries after HO-1 induction. First, we conducted an in vitro study and found that HO-1 expression in rat intestinal epithelial cells (IEC-6) was induced by non-toxic VitC in a time and concentration dependent manner, and the mechanism was related to the activation of extracellular signal-regulated kinase 1/2 (ERK1/2). Next, we conducted an in vivo study and found that VitC induced intestinal HO-1 protein expression (mainly observed in the intestinal epithelial cells) and HO-1 activity in normal SD rats, and that these HO-1 levels were further enhanced by VitC in a rat model of HS. The HS related intestinal injuries, including histological damage, pro-inflammatory cytokine levels (tumor necrosis factor and interleukin-6), neutrophil infiltration and apoptosis decreased after VitC pretreatment, and this alleviating of organ injuries was abrogated after the inhibition of HO-1 activity by zinc protoporphyrin-IX. It was of note that VitC did little histological damage to the intestine of the sham rats. These data suggested that VitC might be applied as a safe inducer of intestinal HO-1 and that VitC pretreatment attenuated HS related intestinal injuries via the induction of HO-1.
doi:10.1371/journal.pone.0099134
PMCID: PMC4057195  PMID: 24927128
16.  Time-varying Coefficient Proportional Hazards Model with Missing Covariates 
Statistics in medicine  2012;32(12):2013-2030.
SUMMARY
Missing covariates often arise in biomedical studies with survival outcomes. Existing approaches for missing covariates generally assume proportional hazards. The proportionality assumption may not hold in practice, as illustrated by data from a mouse leukemia study with covariate effects changing over time. To tackle this restriction, we study the missing data problem under the varying-coefficient proportional hazards model. Based on the local partial likelihood approach, we develop inverse selection probability weighted estimators. We consider reweighting and augmentation techniques for possible improvement of efficiency and robustness. The proposed estimators are assessed via simulation studies and illustrated by application to the mouse leukemia data.
doi:10.1002/sim.5652
PMCID: PMC3574968  PMID: 23044762
augmentation; inverse probability weighting; local partial likelihood; reweighting
17.  Survival Analysis with Time-Varying Covariates Measured at Random Times by Design 
Summary
Ecological momentary assessment (EMA) is a method for collecting real-time data in subjects’ environments. It often uses electronic devices to obtain information on psychological state through administration of questionnaires at times selected from a probability-based sampling design. This information can be used to model the impact of momentary variation in psychological state on the lifetimes to events such as smoking lapse. Motivated by this, a probability-sampling framework is proposed for estimating the impact of time-varying covariates on the lifetimes to events. Presented as an alternative to joint modeling of the covariate process as well as event lifetimes, this framework calls for sampling covariates at the event lifetimes and at times selected according to a probability-based sampling design. A design-unbiased estimator for the cumulative hazard is substituted into the log likelihood, and the resulting objective function is maximized to obtain the proposed estimator. This estimator has two quantifiable sources of variation, that due to the survival model and that due to sampling the covariates. Data from a nicotine patch trial are used to illustrate the proposed approach.
doi:10.1111/j.1467-9876.2012.01064.x
PMCID: PMC3667965  PMID: 23729866
Ecological momentary assessment; Estimating equations; Parametric hazard; Smoking
18.  Expected estimating equations via EM for proportional hazards regression with covariate misclassification 
Biostatistics (Oxford, England)  2012;14(2):351-365.
In epidemiological and medical studies, covariate misclassification may occur when the observed categorical variables are not perfect measurements for an unobserved categorical latent predictor. It is well known that covariate measurement error in Cox regression may lead to biased estimation. Misclassification in covariates will cause bias, and adjustment for misclassification will be challenging when the gold standard variables are not available. In general, statistical modeling for misclassification is very different from that of the measurement error. In this paper, we investigate an approximate induced hazard estimator and propose an expected estimating equation estimator via an expectation–maximization algorithm to accommodate covariate misclassification when multiple surrogate variables are available. Finite sample performance is examined via simulation studies. The proposed method and other methods are applied to a human immunodeficiency virus clinical trial in which a few behavior variables from questionnaires are used as surrogates for a latent behavior variable.
doi:10.1093/biostatistics/kxs046
PMCID: PMC3590925  PMID: 23178735
EM algorithm; Estimating equation; Measurement error; Misclassification; Surrogate covariate
19.  Postweaning Exposure to Dietary Zearalenone, a Mycotoxin, Promotes Premature Onset of Puberty and Disrupts Early Pregnancy Events in Female Mice 
Toxicological Sciences  2013;132(2):431-442.
Zearalenone (ZEA) is a mycotoxin commonly found in contaminated livestock feed and human food with levels in the range of ppb and low ppm. It was hypothesized that ZEA, an endocrine disruptor, could affect puberty and early pregnancy. To test this hypothesis, newly weaned (3 weeks old) C57BL/6J female mice were exposed to 0, 0.002, 4, 10, and 40 ppm ZEA and 0.05 ppm diethylstilbestrol (positive control) in phytoestrogen-free AIN-93G diet. Females exposed to 10 and 40 ppm ZEA diets showed earlier onset of vaginal opening. Those treated with 40 ppm ZEA diet also had earlier first copulation plug and irregular estrous cyclicity. At 8 weeks old, all females were mated with untreated stud males on AIN-93G diet during mating. Treatment resumed upon identification of a vaginal plug on gestation day 0.5 (D0.5). Embryo implantation was assessed on D4.5. Exposure to 40 ppm ZEA diet resulted in reduced percentage of plugged mice with implantation sites, distended uterine appearance, and retained expression of progesterone receptor in D4.5 uterine epithelium. To determine the exposure timing and mechanisms of disrupted embryo implantation, four groups of females were fed with 0 or 40 ppm ZEA diets during premating (weaning to mating) and postmating (D0.5–D4.5), respectively. Premating exposure to 40 ppm ZEA diet reduced fertilization rate, whereas postmating exposure to 40 ppm ZEA diet delayed embryo transport and preimplantation embryo development, which subsequently affected embryo implantation. These data demonstrate that postweaning exposure to dietary ZEA can promote premature onset of puberty and disrupt early pregnancy events.
doi:10.1093/toxsci/kfs343
PMCID: PMC3595522  PMID: 23291560
zearalenone; vaginal opening; fertilization; embryo transport; embryo development; embryo implantation.
20.  Expansion of circulating TFH cells and their associated molecules: involvement in the immune landscape in patients with chronic HBV infection 
Virology Journal  2014;11:54.
Background
Blood CXCR5+CD4+ T cells are defined as circulating T follicular helper (TFH) cells, which is required for effective humoral immunity. This study aimed to investigate the role of circulating TFH cells in patients with chronic hepatitis B virus (CHB) infection.
Methods
The frequency and phenotype of circulating TFH cells were monitored by flow cytometry in CHB patients and in healthy controls (HC). The expression of BCL-6, IL-21, IL-4, CXCR5, and IL-6R mRNA was analyzed using real-time PCR. Serum HBsAg, HBeAg, HBeAb, HBV DNA loads, ALT and AST were determined. The potential association of the frequency of TFH cells and their surface markers with clinical parameters was assessed.
Results
The frequency of CXCR5+CD4+ T cells was increased in CHB patients and positively correlated with ALT and AST but not with HBV DNA loads. Moreover, an expansion of ICOS-, PD-1-, CD40L-, and IL-21R-expressing TFH cells occurred in CHB patients, but failed to correlate with ALT, AST and HBV DNA loads. Interestingly, the frequency of CXCR5+CD4+ T cells and ICOS+CXCR5+CD4+ T cells was significantly higher in HBeAg positive CHB patients than in HC. Additionally, the percentages of CXCR5+CD4+ T cells were positively correlated with AST, and ICOS-expressing CXCR5+CD4+ T cells were negatively correlated with HBV DNA loads. No significant differences in the frequency of CXCR5+CD4+ T cells were observed between inactive carrier (IC) patients and healthy controls. However, ICOS-, PD-1-, CD40L-expressing TFH cells were increased in IC patients and positively correlated with AST. Furthermore, the expression of BCL-6, IL-21, IL-4, CXCR5, and IL-6R mRNA in TFH cells was higher in CHB patients than in HC.
Conclusions
These data demonstrate that circulating TFH cells may participate in HBV-related immune responses. In addition to the frequency of TFH cells, the phenotype of these cells plays an important role in CHB patients.
doi:10.1186/1743-422X-11-54
PMCID: PMC3994480  PMID: 24655429
T follicular helper cells; Hepatitis B virus; Interleukin 21; Inducible costimulator
21.  Renal tuberculosis and iliopsoas abscess: Two case reports 
The urinary system is the second most commonly affected site of extrapulmonary tuberculosis (TB). Due to the diverse and atypical clinical manifestations of urinary TB, the disease is easy to misdiagnose. In the present study, two cases of renal TB are reported, which had completely different clinical manifestations. The first case is a female who presented with loin pain and fever. Purified protein derivative (PPD) and TB antibody tests were negative and computed tomography (CT) scans showed a low density focus in the right kidney with an iliopsoas abscess. The typical CT findings indicated renal tuberculosis. Anti-TB drugs were effective proved the diagnosis. The second case is a male who presented with intermittent gross hematuria. Acid-fast bacilli in urine and TB antibody tests were positive. CT scans revealed a low density focus in the unilateral kidney with a slight expansion of the pelvis, calices and ureter. The patients were treated with the anti-TB drugs and the clinical manifestations disappeared. The diagnosis of urinary TB is challenging in certain cases; when there is no response to the usual antibiotics in patients with fever or gross hematuria, TB should be suspected. CT is the mainstay for investigating possible urinary TB.
doi:10.3892/etm.2014.1623
PMCID: PMC4043625  PMID: 24926373
renal tuberculosis; iliopsoas abscess
22.  Comparative Genomics Provide Insights into Evolution of Trichoderma Nutrition Style 
Genome Biology and Evolution  2014;6(2):379-390.
Saprotrophy on plant biomass is a recently developed nutrition strategy for Trichoderma. However, the physiology and evolution of this new nutrition strategy is still elusive. We report the deep sequencing and analysis of the genome of Trichoderma longibrachiatum, an efficient cellulase producer. The 31.7-Mb genome, smallest among the sequenced Trichoderma species, encodes fewer nutrition-related genes than saprotrophic T. reesei (Tr), including glycoside hydrolases and nonribosomal peptide synthetase–polyketide synthase. Homology and phylogenetic analyses suggest that a large number of nutrition-related genes, including GH18 chitinases, β-1,3/1,6-glucanases, cellulolytic enzymes, and hemicellulolytic enzymes, were lost in the common ancestor of T. longibrachiatum (Tl) and Tr. dN/dS (ω) calculation indicates that all the nutrition-related genes analyzed are under purifying selection. Cellulolytic enzymes, the key enzymes for saprotrophy on plant biomass, are under stronger purifying selection pressure in Tl and Tr than in mycoparasitic species, suggesting that development of the nutrition strategy of saprotrophy on plant biomass has increased the selection pressure. In addition, aspartic proteases, serine proteases, and metalloproteases are subject to stronger purifying selection pressure in Tl and Tr, suggesting that these enzymes may also play important roles in the nutrition. This study provides insights into the physiology and evolution of the nutrition strategy of Trichoderma.
doi:10.1093/gbe/evu018
PMCID: PMC3942035  PMID: 24482532
Trichoderma longibrachiatum; cellulolytic enzymes; carbohydrate-active enzymes; proteases; purifying selection; dN/dS
23.  Assessment of the AquaCrop Model for Use in Simulation of Irrigated Winter Wheat Canopy Cover, Biomass, and Grain Yield in the North China Plain 
PLoS ONE  2014;9(1):e86938.
Improving winter wheat water use efficiency in the North China Plain (NCP), China is essential in light of current irrigation water shortages. In this study, the AquaCrop model was used to calibrate, and validate winter wheat crop performance under various planting dates and irrigation application rates. All experiments were conducted at the Xiaotangshan experimental site in Beijing, China, during seasons of 2008/2009, 2009/2010, 2010/2011 and 2011/2012. This model was first calibrated using data from 2008/2009 and 2009/2010, and subsequently validated using data from 2010/2011 and 2011/2012. The results showed that the simulated canopy cover (CC), biomass yield (BY) and grain yield (GY) were consistent with the measured CC, BY and GY, with corresponding coefficients of determination (R2) of 0.93, 0.91 and 0.93, respectively. In addition, relationships between BY, GY and transpiration (T), (R2 = 0.57 and 0.71, respectively) was observed. These results suggest that frequent irrigation with a small amount of water significantly improved BY and GY. Collectively, these results indicate that the AquaCrop model can be used in the evaluation of various winter wheat irrigation strategies. The AquaCrop model predicted winter wheat CC, BY and GY with acceptable accuracy. Therefore, we concluded that AquaCrop is a useful decision-making tool for use in efforts to optimize wheat winter planting dates, and irrigation strategies.
doi:10.1371/journal.pone.0086938
PMCID: PMC3904961  PMID: 24489808
24.  Development of a genetic system for the deep-sea psychrophilic bacterium Pseudoalteromonas sp. SM9913 
Background
Pseudoalteromonas species are a group of marine gammaproteobacteria frequently found in deep-sea sediments, which may play important roles in deep-sea sediment ecosystem. Although genome sequence analysis of Pseudoalteromonas has revealed some specific features associated with adaptation to the extreme deep-sea environment, it is still difficult to study how Pseudoalteromonas adapt to the deep-sea environment due to the lack of a genetic manipulation system. The aim of this study is to develop a genetic system in the deep-sea sedimentary bacterium Pseudoalteromonas sp. SM9913, making it possible to perform gene mutation by homologous recombination.
Results
The sensitivity of Pseudoalteromonas sp. SM9913 to antibiotic was investigated and the erythromycin resistance gene was chosen as the selective marker. A shuttle vector pOriT-4Em was constructed and transferred into Pseudoalteromonas sp. SM9913 through intergeneric conjugation with an efficiency of 1.8 × 10-3, which is high enough to perform the gene knockout assay. A suicide vector pMT was constructed using pOriT-4Em as the bone vector and sacB gene as the counterselective marker. The epsT gene encoding the UDP-glucose lipid carrier transferase was selected as the target gene for inactivation by in-frame deletion. The epsT was in-frame deleted using a two-step integration–segregation strategy after transferring the suicide vector pMT into Pseudoalteromonas sp. SM9913. The ΔepsT mutant showed approximately 73% decrease in the yield of exopolysaccharides, indicating that epsT is an important gene involved in the EPS production of SM9913.
Conclusions
A conjugal transfer system was constructed in Pseudoalteromonas sp. SM9913 with a wide temperature range for selection and a high transfer efficiency, which will lay the foundation of genetic manipulation in this strain. The epsT gene of SM9913 was successfully deleted with no selective marker left in the chromosome of the host, which thus make it possible to knock out other genes in the same host. The construction of a gene knockout system for Pseudoalteromonas sp. SM9913 will contribute to the understanding of the molecular mechanism of how Pseudoalteromonas adapt to the deep-sea environment.
doi:10.1186/1475-2859-13-13
PMCID: PMC3930924  PMID: 24450434
25.  Minimally invasive plate osteosynthesis for distal radius fractures 
Indian Journal of Orthopaedics  2014;48(1):20-24.
Background:
Fractures of distal radius are common injury in all age groups. Cast treatment with or without close reduction is a viable option. However, the results are often unsatisfactory with restricted function. The open reduction and internal fixation often results in extensive soft tissue dissection and associated high rates of infect and delayed/nonunion. The distractor/external fixator have reported good functional and anatomical results but the incidence of pin traction infection nerve injury and cosmedic deformity are high. We introduced a modified operative technique for minimally invasive plate osteosynthesis (MIPO) for distal radial fracture and evaluated the functional outcomes and complications.
Materials and Methods:
22 distal radial fractures (10 left, 12 right) were treated using the MIPO technique and two small incisions with a palmar locking plate from August 2009 to August 2010. The wrist function was assessed according to Dienst wrist rating system, and postoperative complications were recorded.
Results:
According to Dienst wrist rating system, 13 patients showed excellent results, 6 cases showed good results and 3 patients had moderate results. No patient had poor results. Thus, the excellent and good rate was 86.4%. One patient had anesthesia in the thenar eminence and this symptom disappeared after 3 months. One patient had delayed healing in the proximal wrist crease. Two patients had mild pain on the ulnar side of the wrist and two patients had limited wrist joint function.
Conclusion:
The MIPO technique by using two small palmar incisions is safe and effective for treatment of distal radial fractures.
doi:10.4103/0019-5413.125483
PMCID: PMC3931148  PMID: 24600058
Distal radius fracture; minimally invasive plate fixation; palmar locking plate

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