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1.  Halogenated Diarylacetylenes Repress c-Myc Expression in Cancer Cells 
Halogenated diarylacetylenes that possess fluorine or chlorine substituents in one aryl ring and N-methylamino or N,N-dimethylamino in the other aryl ring inhibit the proliferation of LS174T colon cancer cells through the repression of c-myc expression and induction of the cyclin-dependent kinase inhibitor-1 (i.e., p21(Wif1/Cip1)) and represent potentially useful antineoplastic agents.
doi:10.1016/j.bmcl.2014.04.113
PMCID: PMC4096707  PMID: 24930834
2.  Spatiotemporal Clustering Analysis and Risk Assessments of Human Cutaneous Anthrax in China, 2005–2012 
PLoS ONE  2015;10(7):e0133736.
Objective
To investigate the epidemic characteristics of human cutaneous anthrax (CA) in China, detect the spatiotemporal clusters at the county level for preemptive public health interventions, and evaluate the differences in the epidemiological characteristics within and outside clusters.
Methods
CA cases reported during 2005–2012 from the national surveillance system were evaluated at the county level using space-time scan statistic. Comparative analysis of the epidemic characteristics within and outside identified clusters was performed using using the χ2 test or Kruskal-Wallis test.
Results
The group of 30–39 years had the highest incidence of CA, and the fatality rate increased with age, with persons ≥70 years showing a fatality rate of 4.04%. Seasonality analysis showed that most of CA cases occurred between May/June and September/October of each year. The primary spatiotemporal cluster contained 19 counties from June 2006 to May 2010, and it was mainly located straddling the borders of Sichuan, Gansu, and Qinghai provinces. In these high-risk areas, CA cases were predominantly found among younger, local, males, shepherds, who were living on agriculture and stockbreeding and characterized with high morbidity, low mortality and a shorter period from illness onset to diagnosis.
Conclusion
CA was geographically and persistently clustered in the Southwestern China during 2005–2012, with notable differences in the epidemic characteristics within and outside spatiotemporal clusters; this demonstrates the necessity for CA interventions such as enhanced surveillance, health education, mandatory and standard decontamination or disinfection procedures to be geographically targeted to the areas identified in this study.
doi:10.1371/journal.pone.0133736
PMCID: PMC4514625  PMID: 26208355
3.  TMEM140 is associated with the prognosis of glioma by promoting cell viability and invasion 
Background
Gliomas are the most common types of primary brain tumors in the adult central nervous system. TMEM140 is identified as an amplified gene in the human gastric cancer genome. However, the function of TMEM140 in gliomas has not been thoroughly elucidated. The aim of the current study was to determine the clinical significance of TMEM140 expression in patients with gliomas and its effect on tumor cell malignant phenotypes.
Methods
Immunohistochemical analysis and real-time reverse transcription PCR were performed to detect the expression levels of TMEM140 in 70 glioma brain tissue samples. Next, the correlation between the TMEM140 expression levels and the clinical characteristics and outcomes of glioma patients was statistically analyzed. TMEM140 expression was inhibited in two glioma cell lines (i.e., U87 and U373) using a knockdown method with small interfering RNA. Cell Counting Kit-8 and Transwell assays were used to investigate TMEM140 function during cell proliferation, invasion, and migration, respectively. Using flow cytometry and Western blot analysis, we subsequently determined the cell cycle and apoptosis profile of the TMEM140-silenced cells.
Results
TMEM140 protein expression was significantly higher in gliomas than in normal brain tissues (p < 0.0001). TMEM140 overexpression was strongly correlated with tumor size, histologic grade, and overall survival time (P < 0.05). TMEM140 decreased cell viability in vitro and dramatically decreased tumor volume in vivo. This phenomenon might be caused by G1 phase cell cycle arrest and cell apoptosis. TMEM140 silencing could suppress the viability, migration, and invasion of glioma cells.
Conclusions
Our results suggest that TMEM140 expression is a prognostic factor that might play an important role in the viability, migration, and invasion of glioma cells. This study highlights the importance of TMEM140 as a novel prognostic marker and as an attractive therapeutic target for gliomas.
doi:10.1186/s13045-015-0187-4
PMCID: PMC4511541  PMID: 26198430
TMEM140; Glioma; Cell viability; Invasion; Prognosis
4.  CRISPR-Cas9-Mediated Genome Editing in Leishmania donovani 
mBio  2015;6(4):e00861-15.
ABSTRACT
The prokaryotic CRISPR (clustered regularly interspaced short palindromic repeat)-Cas9, an RNA-guided endonuclease, has been shown to mediate efficient genome editing in a wide variety of organisms. In the present study, the CRISPR-Cas9 system has been adapted to Leishmania donovani, a protozoan parasite that causes fatal human visceral leishmaniasis. We introduced the Cas9 nuclease into L. donovani and generated guide RNA (gRNA) expression vectors by using the L. donovani rRNA promoter and the hepatitis delta virus (HDV) ribozyme. It is demonstrated within that L. donovani mainly used homology-directed repair (HDR) and microhomology-mediated end joining (MMEJ) to repair the Cas9 nuclease-created double-strand DNA break (DSB). The nonhomologous end-joining (NHEJ) pathway appears to be absent in L. donovani. With this CRISPR-Cas9 system, it was possible to generate knockouts without selection by insertion of an oligonucleotide donor with stop codons and 25-nucleotide homology arms into the Cas9 cleavage site. Likewise, we disrupted and precisely tagged endogenous genes by inserting a bleomycin drug selection marker and GFP gene into the Cas9 cleavage site. With the use of Hammerhead and HDV ribozymes, a double-gRNA expression vector that further improved gene-targeting efficiency was developed, and it was used to make precise deletion of the 3-kb miltefosine transporter gene (LdMT). In addition, this study identified a novel single point mutation caused by CRISPR-Cas9 in LdMT (M381T) that led to miltefosine resistance, a concern for the only available oral antileishmanial drug. Together, these results demonstrate that the CRISPR-Cas9 system represents an effective genome engineering tool for L. donovani.
IMPORTANCE
Leishmania donovani is the causative agent of fatal visceral leishmaniasis. To understand Leishmania infection and pathogenesis and identify new drug targets for control of leishmaniasis, more-efficient ways to manipulate this parasite genome are required. In this study, we have implemented CRISPR-Cas9 genome-editing technology in L. donovani. Both single- and dual-gRNA expression vectors were developed using a strong RNA polymerase I promoter and ribozymes. With this system, it was possible to generate loss-of-function insertion and deletion mutations and introduce drug selection markers and the GFP sequence precisely into the L. donovani genome. These methods greatly improved the ability to manipulate this parasite genome and will help pave the way for high-throughput functional analysis of Leishmania genes. This study further revealed that double-stranded DNA breaks created by CRISPR-Cas9 were repaired by the homology-directed repair (HDR) pathway and microhomology-mediated end joining (MMEJ) in Leishmania.
doi:10.1128/mBio.00861-15
PMCID: PMC4513079  PMID: 26199327
5.  Plasma levels of lysophosphatidic acid in ovarian cancer versus controls: a meta-analysis 
Background
In this study, using a meta-analysis approach, we examined the correlation between serum levels of lysophosphastidic acid (LPA) and ovarian cancer (OC).
Methods
Relevant published studies were identified from multiple scientific literature databases by using a pre-determined electronic and manual search strategy. The search results were screened through a multi-step process to select high-quality case–control studies suitable for the present meta-analysis. Mean values and standardized mean differences (SMD) were calculated for plasma LPA levels. Two investigators independently extracted the data from the studies and performed data analysis using STATA software version 12.0 (Stata Corp, College Station, TX, USA).
Results
Nineteen case–control studies met our selection criteria and contained a total of 980 OC patients, 872 benign controls and 668 healthy controls. Our meta-analysis results revealed that the plasma levels of LPA in OC patients were significantly higher than benign controls (SMD = 2.36, 95 % CI: 1.61–3.10, P <0.001) and healthy controls (SMD = 2.32, 95 % CI: 1.77–2.87, P <0.001). Subgroup analysis by ethnicity showed that the plasma LPA levels in OC patients were significantly higher than the benign controls only in Asian populations (SMD = 2.52, 95 % CI: 1.79–3.25, P <0.001). However, a comparison between healthy controls and OC patients revealed that, in both Asians and Caucasians, the OC patients displayed significantly higher plasma LPA levels compared to healthy controls (all P <0.05).
Conclusion
Our meta-analysis showed strong evidence that a significantly higher plasma LPA levels are present in OC patients, compared to benign controls and healthy controls, and plasma LPA levels may be used as a biomarker or target of OC.
doi:10.1186/s12944-015-0071-9
PMCID: PMC4501043  PMID: 26174150
Lysophosphatidic acid; Ovarian cancer; Bioactive phospholipid; Meta-analysis
6.  Corneal Stroma Regeneration with Acellular Corneal Stroma Sheets and Keratocytes in a Rabbit Model 
PLoS ONE  2015;10(7):e0132705.
Acellular corneal stroma matrix has been used for corneal stroma engineering. However, because of its compact tissue structure, regrowth of keratocytes into the scaffold is difficult. Previously, we developed a sandwich model for cartilage engineering using acellular cartilage sheets. In the present study, we tested this model for corneal stroma regeneration using acellular porcine corneal stroma (APCS) sheets and keratocytes. Porcine corneas were decellularized by NaCl treatment, and the APCS was cut into 20-μm-thick sheets. A rabbit corneal stroma defect model was created by lamellar keratoplasty and repaired by transplantation of five pieces of APCS sheets with keratocytes. Six months after transplantation, transparent corneas were present in the experimental group, which were confirmed by anterior segment optical coherence tomography examination and transmittance examination. The biomechanical properties in the experimental group were similar to those of normal cornea. Histological analyses showed an even distribution of keratocytes and well-oriented matrix in the stroma layer in the experimental group. Together, these results demonstrated that the sandwich model using acellular corneal stroma sheets and keratocytes could be potentially useful for corneal stroma regeneration.
doi:10.1371/journal.pone.0132705
PMCID: PMC4500565  PMID: 26167895
7.  Transcriptional Activation of Multiple Operons Involved in para-Nitrophenol Degradation by Pseudomonas sp. Strain WBC-3 
Pseudomonas sp. strain WBC-3 utilizes para-nitrophenol (PNP) as a sole carbon and energy source. The genes involved in PNP degradation are organized in the following three operons: pnpA, pnpB, and pnpCDEFG. How the expression of the genes is regulated is unknown. In this study, an LysR-type transcriptional regulator (LTTR) is identified to activate the expression of the genes in response to the specific inducer PNP. While the LTTR coding gene pnpR was found to be not physically linked to any of the three catabolic operons, it was shown to be essential for the growth of strain WBC-3 on PNP. Furthermore, PnpR positively regulated its own expression, which is different from the function of classical LTTRs. A regulatory binding site (RBS) with a 17-bp imperfect palindromic sequence (GTT-N11-AAC) was identified in all pnpA, pnpB, pnpC, and pnpR promoters. Through electrophoretic mobility shift assays and mutagenic analyses, this motif was proven to be necessary for PnpR binding. This consensus motif is centered at positions approximately −55 bp relative to the four transcriptional start sites (TSSs). RBS integrity was required for both high-affinity PnpR binding and transcriptional activation of pnpA, pnpB, and pnpR. However, this integrity was essential only for high-affinity PnpR binding to the promoter of pnpCDEFG and not for its activation. Intriguingly, unlike other LTTRs studied, no changes in lengths of the PnpR binding regions of the pnpA and pnpB promoters were observed after the addition of the inducer PNP in DNase I footprinting.
doi:10.1128/AEM.02720-14
PMCID: PMC4272733  PMID: 25326309
8.  Distribution of cervical intraepithelial neoplasia on the cervix in Chinese women: pooled analysis of 19 population based screening studies 
BMC Cancer  2015;15:485.
Background
Controversy remains whether a pattern of cervical intraepithelial neoplasia exists on the cervix. Our study aims at determining if the prevalence of histologically proven lesions differs by cervical four-quadrant location or by 12 o'clock surface locations of diagnosis.
Methods
We conducted a retrospective, histopathological study of 19 different population based cervical cancer screening studies from 1999 to 2010 by Cancer Hospital of Chinese Academy of Medical Sciences. The Institutional Review Board for human research subjects at CHCAMS approved all of the studies. During the colposcopy procedure, participant received either 4-quadrant biopsy or directed biopsy with/without endocervical curettage. Data of all samples were stratified by the methods of sampling. Kruskal-Wallis test was used to determine overall distribution of normal/CIN1, CIN2 and CIN3+ on the cervix.
Results
In total, 53,088 cervical samples were included in distribution analysis. 66.9 % samples were obtained by random biopsy, 16.1 % were by directed biopsy, and 17.0 % were by endocervical curettage. 95.9%of the biopsied samples were diagnosed as normal/CIN1, 2.0 % were CIN2, and 2.1 % were CIN3 + . CIN2 and CIN3+ were most often found in quadrants 2 and 3 (χKW2 = 46.6540, p < 0.0001) and at the 4- and 7-o'clock positions by directed biopsy (ORCIN2 = 2.572, 1.689, ORCIN3+ = 3.481, 1.678, respectively), and at the 5-, 6-, 7-, 9- and 12-o’clock positions by random biopsy. CIN3+ was least often found at the 11-o’clock position by directed biopsy (OR = 0.608).
Conclusions
Our results suggest a predisposition of specific locations on the cervix to CIN occurrence. Quadrants 2 and 3, especially the 4- and 7-o’clock positions should be preferentially targeted during biopsy. The decision for random biopsy should be reconsidered in future studies.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1494-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s12885-015-1494-4
PMCID: PMC4485364  PMID: 26122004
Colposcopy; Cervical intraepithelial neoplasia; Lesion location; Biopsy; Cervical cancer
9.  Spatiotemporal Distribution, Sources, and Photobleaching Imprint of Dissolved Organic Matter in the Yangtze Estuary and Its Adjacent Sea Using Fluorescence and Parallel Factor Analysis 
PLoS ONE  2015;10(6):e0130852.
To investigate the seasonal and interannual dynamics of dissolved organic matter (DOM) in the Yangtze Estuary, surface and bottom water samples in the Yangtze Estuary and its adjacent sea were collected and characterized using fluorescence excitation-emission matrices (EEMs) and parallel factor analysis (PARAFAC) in both dry and wet seasons in 2012 and 2013. Two protein-like components and three humic-like components were identified. Three humic-like components decreased linearly with increasing salinity (r>0.90, p<0.001), suggesting their distribution could primarily be controlled by physical mixing. By contrast, two protein-like components fell below the theoretical mixing line, largely due to microbial degradation and removal during mixing. Higher concentrations of humic-like components found in 2012 could be attributed to higher freshwater discharge relative to 2013. There was a lack of systematic patterns for three humic-like components between seasons and years, probably due to variations of other factors such as sources and characteristics. Highest concentrations of fluorescent components, observed in estuarine turbidity maximum (ETM) region, could be attributed to sediment resuspension and subsequent release of DOM, supported by higher concentrations of fluorescent components in bottom water than in surface water at two stations where sediments probably resuspended. Meanwhile, photobleaching could be reflected from the changes in the ratios between fluorescence intensity (Fmax) of humic-like components and chromophoric DOM (CDOM) absorption coefficient (a355) along the salinity gradient. This study demonstrates the abundance and composition of DOM in estuaries are controlled not only by hydrological conditions, but also by its sources, characteristics and related estuarine biogeochemical processes.
doi:10.1371/journal.pone.0130852
PMCID: PMC4479555  PMID: 26107640
10.  Abundance and significance of neuroligin-1 and glutamate in Hirschsprung’s disease 
AIM: To investigate the abundance and potential diagnostic significance of neuroligin-1 and glutamate (Glu) in Hirschsprung’s disease (HSCR).
METHODS: Ninety children with HSCR and 50 children without HSCR matched for similar nutritional status, age and basal metabolic index were studied. The expression and localization of neuroligin-1 and Glu were assessed using double-labeling immunofluorescence staining of longitudinal muscles with adherent myenteric plexus from the surgically excised colon of children with HSCR. Western blot analysis, quantitative real-time PCR (qRT-PCR) and immunohistochemistry were performed to evaluate the abundance of neuroligin-1 and Glu in different HSCR-affected segments (ganglionic, transitional, and aganglionic segments). Enzyme-linked immunosorbent assay (ELISA) was used to detect and compare serum Glu levels in the long-segment HSCR, short-segment HSCR and non-HSCR samples.
RESULTS: Neuroligin-1 and Glu were co-expressed highest to lowest in the ganglionic, transitional and aganglionic segments based on Western blot (neuroligin-1: 0.177 ± 0.008 vs 0.101 ± 0.006, 0.177 ± 0.008 vs 0.035 ± 0.005, and 0.101 ± 0.006 vs 0.035 ± 0.005, P < 0.005; Glu: 0.198 ± 0.006 vs 0.115 ± 0.008, 0.198 ± 0.006 vs 0.040 ± 0.003, and 0.115 ± 0.008 vs 0.040 ± 0.003, P < 0.005) and qRT-PCR (neuroligin-1: 9.58 × 10-5 ± 9.94 × 10-6 vs 2.49 × 10-5 ± 1.38 × 10-6, 9.58 × 10-5 ± 9.94 × 10-6 vs 7.17 × 10-6 ± 1.12 × 10-6, and 2.49 × 10-5 ± 1.38 × 10-6 vs 7.17 × 10-6 ± 1.12 × 10-6, P < 0.005). Serum Glu level was the highest to lowest in the non-HSCR, short-type HSCR and long-type HSCR samples based on ELISA (in nmol/μL, 0.93 ± 0.31 vs 0.57 ± 0.25, 0.93 ± 0.31 vs 0.23 ± 0.16, and 0.57 ± 0.25 vs 0.23 ± 0.16, P < 0.005).
CONCLUSION: Neuroligin-1 and Glu may represent new markers of ganglion cells, whose expression may correlate with the pathogenesis, diagnosis, differential diagnosis or classification of HSCR.
doi:10.3748/wjg.v21.i23.7172
PMCID: PMC4476878  PMID: 26109803
Neuroligin-1; Hirschsprung’s disease; Glutamate; Ganglion cells; Pathogenesis
11.  Comparison of non-schistosomal rectosigmoid cancer and schistosomal rectosigmoid cancer 
AIM: To compare the clinicopathological features of patients with non-schistosomal rectosigmoid cancer and schistosomal rectosigmoid cancer.
METHODS: All the patients with rectosigmoid carcinoma who underwent laparoscopic radical surgical resection in the Shanghai Minimally Invasive Surgical Center at Ruijin Hospital affiliated to Shanghai Jiao-Tong University between October 2009 and October 2013 were included in this study. Twenty-six cases of colonic schistosomiasis diagnosed through colonoscopy and pathological examinations were collected. Symptoms, endoscopic findings and clinicopathological characteristics were evaluated retrospectively.
RESULTS: There were no significant differences between patients with and without schistosomiasis in gender, age, CEA, CA19-9, preoperative biopsy findings or postoperative pathology. Patients with rectosigmoid schistosomiasis had a significantly higher CA-125 level and a larger proportion of these patients were at an early tumor stage (P = 0.003). Various morphological characteristics of schistosomiasis combined with rectosigmoid cancer could be found by colonoscopic examination: 46% were fungating mass polyps, 23% were congestive and ulcerative polyps, 23% were cauliflower-like masses, 8% were annular masses. Only 27% of the patients were diagnosed with rectal carcinoma preoperatively after the biopsy. Computed tomography (CT) scans showed thickened intestinal walls combined with linear and tram-track calcifications in 26 patients.
CONCLUSION: Rectosigmoid carcinoma combined with schistosomiasis is associated with higher CA-125 values and early tumor stages. CA-125 and CT scans have a reasonable sensitivity for the accurate diagnosis.
doi:10.3748/wjg.v21.i23.7225
PMCID: PMC4476884  PMID: 26109809
Schistosomiasis; Rectosigmoid cancer; Colonoscopy; Biomarker; Diagnosis
12.  2′,6′-Dihalostyrylanilines, Pyridines, and Pyrimidines for the Inhibition of the Catalytic Subunit of Methionine S-Adenosyltransferase-2 
Journal of Medicinal Chemistry  2014;57(14):6083-6091.
Inhibition of the catalytic subunit of the heterodimeric methionine S-adenosyl transferase-2 (MAT2A) with fluorinated N,N-dialkylaminostilbenes (FIDAS agents) offers a potential avenue for the treatment of liver and colorectal cancers where upregulation of this enzyme occurs. A study of structure–activity relationships led to the identification of the most active compounds as those with (1) either a 2,6-difluorostyryl or 2-chloro-6-fluorostyryl subunit, (2) either an N-methylamino or N,N-dimethylamino group attached in a para orientation relative to the 2,6-dihalostyryl subunit, and (3) either an N-methylaniline or a 2-(N,N-dimethylamino)pyridine ring. These modifications led to FIDAS agents that were active in the low nanomolar range, that formed water-soluble hydrochloride salts, and that possessed the desired property of not inhibiting the human hERG potassium ion channel at concentrations at which the FIDAS agents inhibit MAT2A. The active FIDAS agents may inhibit cancer cells through alterations of methylation reactions essential for cancer cell survival and growth.
doi:10.1021/jm5004864
PMCID: PMC4111374  PMID: 24950374
13.  Do nuclear-encoded core subunits of mitochondrial complex I confer genetic susceptibility to schizophrenia in Han Chinese populations? 
Scientific Reports  2015;5:11076.
Schizophrenia is one of the most prevalent psychiatric disorders with complex genetic etiology. Accumulating evidence suggests that energy metabolism and oxidative stress play important roles in the pathophysiology of schizophrenia. Dysfunction of mitochondrial respiratory chain and altered expression of complex I subunits were frequently reported in schizophrenia. To investigate whether nuclear-encoded core subunit genes of mitochondrial complex I are associated with schizophrenia, we performed a genetic association study in Han Chinese. In total, 46 tag single nucleotide polymorphisms (SNPs) from 7 nuclear-encoded core genes of mitochondrial complex I were genotyped in 918 schizophrenia patients and 1042 healthy controls. We also analyzed these SNPs in a large sample mainly composed of Europeans through using the available GWAS datasets from the Psychiatric Genomics Consortium (PGC). No significant associations were detected between these SNPs and schizophrenia in Han Chinese and the PGC data set. However, we observed nominal significant associations of 2 SNPs in the NDUFS1 gene and 4 SNPs in the NDUFS2 gene with early onset schizophrenia (EOS), but none of these associations survived the Bonferroni correction. Taken together, our results suggested that common SNPs in the nuclear-encoded core subunit genes of mitochondrial complex I may not confer genetic susceptibility to schizophrenia.
doi:10.1038/srep11076
PMCID: PMC4459149  PMID: 26053550
14.  Identification and characterization of long non-coding RNAs involved in osmotic and salt stress in Medicago truncatula using genome-wide high-throughput sequencing 
BMC Plant Biology  2015;15:131.
Background
Long non-coding RNAs (lncRNAs) have been shown to play crucially regulatory roles in diverse biological processes involving complex mechanisms. However, information regarding the number, sequences, characteristics and potential functions of lncRNAs in plants is so far overly limited.
Results
Using high-throughput sequencing and bioinformatics analysis, we identified a total of 23,324 putative lncRNAs from control, osmotic stress- and salt stress-treated leaf and root samples of Medicago truncatula, a model legume species. Out of these lncRNAs, 7,863 and 5,561 lncRNAs were identified from osmotic stress-treated leaf and root samples, respectively. While, 7,361 and 7,874 lncRNAs were identified from salt stress-treated leaf and root samples, respectively. To reveal their potential functions, we analyzed Gene Ontology (GO) terms of genes that overlap with or are neighbors of the stress-responsive lncRNAs. Enrichments in GO terms in biological processes such as signal transduction, energy synthesis, molecule metabolism, detoxification, transcription and translation were found.
Conclusions
LncRNAs are likely involved in regulating plant’s responses and adaptation to osmotic and salt stresses in complex regulatory networks with protein-coding genes. These findings are of importance for our understanding of the potential roles of lncRNAs in responses of plants in general and M. truncatula in particular to abiotic stresses.
Electronic supplementary material
The online version of this article (doi:10.1186/s12870-015-0530-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12870-015-0530-5
PMCID: PMC4457090  PMID: 26048392
Long non-coding RNAs (lncRNAs); Osmotic stress; Salt stress; Medicago truncatula; Legume plants; High-throughput sequencing; Transcriptional regulation
15.  Incubation temperature affects the immune function of hatchling soft-shelled turtles, Pelodiscus sinensis 
Scientific Reports  2015;5:10594.
Identifying how developmental temperature affects the immune system is critical for understanding how ectothermic animals defend against pathogens and their fitness in the changing world. However, reptiles have received little attention regarding this issue. We incubated eggs at three ecologically relevant temperatures to determine how incubation temperature affects the immune function of hatchling soft-shelled turtles, Pelodiscus sinensis. When exposed to bacterial infections, hatchlings from 24 °C had lower cumulative mortalities (55%, therefore, higher immunocompetence) than those from 28 °C (85%) or 32 °C (100%). Consistent with higher immunocompetence, hatchlings from low incubation temperature had higher IgM, IgD, and CD3γ expressions than their counterparts from the other two higher incubation temperatures. Conversely, the activity of immunity-related enzymes did not match the among-temperature difference in immune function. Specifically, enzyme activity was higher at intermediate temperatures (alkaline phosphatase) or was not affected by incubation temperature (acid phosphatase, lysozyme). Our study is the first to provide unequivocal evidence (at the molecular and organismal level) about the significant effect of incubation temperature on offspring immunity in reptiles. Our results also indicate that the reduced immunity induced by high developmental temperatures might increase the vulnerability of reptiles to the outbreak of diseases under global warming scenarios.
doi:10.1038/srep10594
PMCID: PMC4450580  PMID: 26028216
16.  Tissue lipid metabolism and hepatic metabolomic profiling in response to supplementation of fermented cottonseedmeal in the diets of broiler chickens*  
This study investigated the effects of fermented cottonseed meal (FCSM) on lipid metabolites, lipid metabolism-related gene expression in liver tissues and abdominal adipose tissues, and hepatic metabolomic profiling in broiler chickens. One hundred and eighty 21-d-old broiler chickens were randomly divided into three diet groups with six replicates of 10 birds in each group. The three diets consisted of a control diet supplemented with unfermented cottonseed meal, an experimental diet of cottonseed meal fermented by Candida tropicalis, and a second experimental diet of cottonseed meal fermented by C. tropicalis plus Saccharomyces cerevisae. The results showed that FCSM intake significantly decreased the levels of abdominal fat and hepatic triglycerides (P<0.05 for both). Dietary FCSM supplementation down-regulated the mRNA expression of fatty acid synthase and acetyl CoA carboxylase in liver tissues and the lipoprotein lipase expression in abdominal fat tissues (P<0.05 for both). FCSM intake resulted in significant metabolic changes of multiple pathways in the liver involving the tricarboxylic acid cycle, synthesis of fatty acids, and the metabolism of glycerolipid and amino acids. These findings indicated that FCSM regulated lipid metabolism by increasing or decreasing the expression of the lipid-related gene and by altering multiple endogenous metabolites. Lipid metabolism regulation is a complex process, this discovery provided new essential information about the effects of FCSM diets in broiler chickens and demonstrated the great potential of nutrimetabolomics in researching complex nutrients added to animal diets.
doi:10.1631/jzus.B1400255
PMCID: PMC4471596  PMID: 26055906
Fermented cottonseed meal; Lipid metabolism; Broiler; Gene expression; Metabolomics
17.  Accurate Prediction of Immunogenic T-Cell Epitopes from Epitope Sequences Using the Genetic Algorithm-Based Ensemble Learning 
PLoS ONE  2015;10(5):e0128194.
Background
T-cell epitopes play the important role in T-cell immune response, and they are critical components in the epitope-based vaccine design. Immunogenicity is the ability to trigger an immune response. The accurate prediction of immunogenic T-cell epitopes is significant for designing useful vaccines and understanding the immune system.
Methods
In this paper, we attempt to differentiate immunogenic epitopes from non-immunogenic epitopes based on their primary structures. First of all, we explore a variety of sequence-derived features, and analyze their relationship with epitope immunogenicity. To effectively utilize various features, a genetic algorithm (GA)-based ensemble method is proposed to determine the optimal feature subset and develop the high-accuracy ensemble model. In the GA optimization, a chromosome is to represent a feature subset in the search space. For each feature subset, the selected features are utilized to construct the base predictors, and an ensemble model is developed by taking the average of outputs from base predictors. The objective of GA is to search for the optimal feature subset, which leads to the ensemble model with the best cross validation AUC (area under ROC curve) on the training set.
Results
Two datasets named ‘IMMA2’ and ‘PAAQD’ are adopted as the benchmark datasets. Compared with the state-of-the-art methods POPI, POPISK, PAAQD and our previous method, the GA-based ensemble method produces much better performances, achieving the AUC score of 0.846 on IMMA2 dataset and the AUC score of 0.829 on PAAQD dataset. The statistical analysis demonstrates the performance improvements of GA-based ensemble method are statistically significant.
Conclusions
The proposed method is a promising tool for predicting the immunogenic epitopes. The source codes and datasets are available in S1 File.
doi:10.1371/journal.pone.0128194
PMCID: PMC4447411  PMID: 26020952
18.  Surgical Versus Non-Surgical Treatment for Vertebral Compression Fracture with Osteopenia: A Systematic Review and Meta-Analysis 
PLoS ONE  2015;10(5):e0127145.
Background
Surgical and non-surgical interventions are the two categories for treatment of vertebral compression fractures (VCFs). However, there is clinical uncertainty over optimal management. This study aimed to examine the safety and effectiveness of surgical management for treatment of VCFs with osteopenia compared with non-surgical treatment.
Methods
We conducted a systematic search through electronic databases from inception to June 2014, with no limits on study data or language. Randomized controlled trials (RCTs) evaluating surgical versus non-surgical interventions for treatment of patients with VCFs due to osteopenia were considered. Primary outcomes were pain and adverse effects. A random-effects model was used to calculate the pooled mean difference (MD) or risk ratios with 95% confidence interval (CI).
Results
Sixteen reports (11 studies) met the inclusion criteria, and provided data for the meta-analysis with a total of 1,401 participants. Compared with conservative treatment, surgical treatment was more effective in reducing pain (short-term: MD -2.05, 95% CI -3.55 to -0.56, P=0.007; mid-term: MD -1.70, 95% CI -2.78 to -0.62, P=0.002; long-term: MD -1.24, 95% CI -2.20 to -0.29, P=0.01) and disability on the Roland–Morris Disability score (short-term: MD -4.97, 95% CI -8.71 to -1.23, P=0.009), as well as improving quality of life on the Short-Form 36 Physical Component Summary score (short-term: MD 5.53, 95% CI 1.45 to 9.61, P=0.008) and the Quality of Life Questionnaire of the European Foundation for Osteoporosis score (short-term: MD -5.01, 95% CI -8.11 to -1.91, P=0.002). Indirect comparisons between vertebroplasty and kyphoplasty found no evidence that the treatment effect differed across the two interventions for any outcomes assessed. Compared with the sham procedure, surgical treatment showed no evidence of improvement in pain relief and physical function. Based on these two comparisons, no significant difference between groups was noted in the pooled results for adverse events.
Conclusion
Compared to conservative treatment, surgical treatment was more effective in decreasing pain in the short,mid and long terms. However, no significant mid- and long-term differences in physical function and quality of life was observed. Little good evidence is available for surgical treatment compared with that for sham procedure. PV and BK are currently used to treat VCFs with osteopenia, with little difference in treatment effects. Evidence of better quality and from a larger sample size is required before a recommendation can be made.
Systematic Review Registration
http://www.crd.york.ac.uk/PROSPERO PROSPERO registration number: CRD42013005142.
doi:10.1371/journal.pone.0127145
PMCID: PMC4447413  PMID: 26020950
19.  Clinicopathological characteristics and treatment outcomes of Chinese patients with genitourinary embryonal rhabdomyosarcoma 
Background
Genitourinary embryonal rhabdomyosarcoma is rarely reported in China. This retrospective analysis aimed to characterize the clinicopathologic features and treatment outcomes of genitourinary embryonal rhabdomyosarcoma in a sample of Chinese patients.
Methods
Basic demographic and clinical data of 29 patients, who were diagnosed with genitourinary embryonal rhabdomyosarcoma between January 2000 and December 2011, were retrieved and analyzed.
Results
In these patients, 25 were males and 4 were females with a median age of 12 years. Paratesticule was the most common lesion site, followed by the prostate, bladder, and vagina. The median tumor size was 5.80 cm. Six patients had clinically positive regional nodes. At the initial diagnosis, patients had a metastatic disease. According to the TNM staging classification for the IRS-IV, phase I lesions were detected in ten cases, phase II lesions in six cases, phase III lesions in four cases, and phase IV lesions in nine cases. The median survival of all patients was 63 (range from 6 to 118) months. The 1-, 3-, and 5-year survival rates for these patients were 93%, 83%, and 52%, respectively. Multivariate analyses demonstrated that staging and anemia were significant predictors of prognosis.
Conclusions
Our findings suggest that metastasis predicts a poor prognosis. Chemotherapy played an important role in comprehensive treatment. Palliative and neo-adjuvant chemotherapy could increase median survival time.
doi:10.1186/s12957-015-0574-x
PMCID: PMC4475326  PMID: 26018798
Genitourinary embryonal rhabdomyosarcoma; Chinese patients; Treatment; Chemotherapy
20.  IgG4-related kidney disease from the renal pelvis that mimicked urothelial carcinoma: a case report 
BMC Urology  2015;15:44.
Background
IgG4-related kidney disease is a comprehensive term for renal lesions associated with IgG4-related disease, which mainly manifests as plasma cell-rich tubulointerstitial nephritis with increased IgG4+ plasma cells and fibrosis. IgG4-related kidney disease in the renal pelvis is rare.
Case presentation
We describe a 53-year-old Asian woman who was referred to our hospital with a space-occupying renal lesion discovered by medical examination. A physical examination and laboratory evaluation revealed no significant abnormalities. Computed tomography scans showed a soft-tissue mass with an irregular border and mild homogeneous enhancement in the right renal pelvis and calyces. A positron emission tomography/computed tomography scan revealed soft-tissue density shadows with increased radionuclide uptake. To investigate a suspected pelvic carcinoma, a right ureteronephrectomy was performed. A pathologic examination of the renal sections showed a dense lymphoplasmacytic infiltrate rich in IgG4+ plasma cells, with fibrosis beneath the urothelial epithelium of the renal pelvis. Postoperatively, the serum IgG4 level was significantly elevated. The patient was diagnosed with IgG4-related kidney disease.
Conclusion
We present a case of IgG4-related kidney disease mimicking urothelial carcinoma in the renal pelvis. When a buried and solitary hypovascular tumor is detected in the kidney, we must consider IgG4-related kidney disease as a differential diagnosis. Accordingly, elevated serum IgG4, radiologic findings, and pathologic examination may improve the diagnosis.
doi:10.1186/s12894-015-0041-6
PMCID: PMC4446108  PMID: 26013281
IgG4-related disease; IgG4-related kidney disease; Renal pelvis; Urothelial carcinoma
21.  Intrathecal Delivery of IL-6 Reactivates the Intrinsic Growth Capacity of Pyramidal Cells in the Sensorimotor Cortex after Spinal Cord Injury 
PLoS ONE  2015;10(5):e0127772.
We have previously demonstrated the growth-promoting effect of intrathecal delivery of recombinant rat IL-6 immediately after corticospinal tract (CST) injury. Our present study aims to further clarify whether intrathecal delivery of IL-6 after CST injury could reactivate the intrinsic growth capacity of pyramidal cells in the sensorimotor cortex which project long axons to the spinal cord. We examined, by ELISA, levels of cyclic adenosine monophosphate (cAMP), adenylyl cyclase (AC, which synthesizes cAMP), phosphodiesterases (PDE, which degrades cAMP), and, by RT-PCR, the expression of regeneration-associated genes in the rat sensorimotor cortex after intrathecal delivery of IL-6 for 7 days, started immediately after CST injury. Furthermore, we injected retrograde neuronal tracer Fluorogold (FG) to the spinal cord to label pyramidal cells in the sensorimotor cortex, layers V and VI, combined with βIII-tubulin immunostaining, then we analyzed by immunohistochemisty and western blot the expression of the co-receptor gp-130 of IL-6 family, and pSTAT3 and mTOR, downstream IL-6/JAK/STAT3 and PI3K/AKT/mTOR signaling pathways respectively. We showed that intrathecal delivery of IL-6 elevated cAMP level and upregulated the expression of regeneration-associated genes including GAP-43, SPRR1A, CAP-23 and JUN-B, and the expression of pSTAT3 and mTOR in pyramidal cells of the sensorimotor cortex. In contrast, AG490, an inhibitor of JAK, partially blocked these effects of IL-6. All these results indicate that intrathecal delivery of IL-6 immediately after spinal cord injury can reactivate the intrinsic growth capacity of pyramidal cells in the sensorimotor cortex and these effects of IL-6 were partially JAK/STAT3-dependent.
doi:10.1371/journal.pone.0127772
PMCID: PMC4437647  PMID: 25992975
22.  Histone deacetylation of memory T lymphocytes by You-Gui-Wan alleviates allergen-induced eosinophilic airway inflammation in asthma 
Chinese Medicine  2015;10:9.
Background
You-Gui pills (You-Gui-Wan; YGW) can promote T lymphocyte proliferation and differentiation, and restore Th1/Th2 balance in the treatment of asthma, but their mechanism of action is not fully known. This study aims to explore whether YGW can induce histone deacetylation or acetylation in memory T lymphocytes (Tm) for improvement of airway inflammation in asthma.
Methods
CD4+CD45RBlow cells, as Tm, were obtained by magnetic-activated cell sorting and flow cytometry from the spleens of BALB/c mice with ovalbumin (OVA)-induced asthma. Tm were cocultured with hydrocortisone (CORT; 1000 nM), serum containing low (0.225 g/kg), moderate (0.9 g/kg), or high (3.6 g/kg) doses of YGW, or medium only, and then adoptively transferred into naïve mice (n = 5 per group). Recipient mice were challenged with aerosolized OVA. The levels of IL-4, IL-5, IL-13, and IFN-γ in culture supernatants and bronchoalveolar lavage fluid (BALF) from the OVA-challenged mice were measured by ELISA. Histone deacetylase (HDAC) and histone acetyltransferase (HAT) activities and protein expressions of T-bet, GATA-3, and HDAC1–11 in lung tissue were measured by western blotting analyses. The alveolar eosinophilic inflammation index (AEII) was evaluated in the lungs of adoptive transfer recipient mice.
Results
YGW reduced inflammation and eosinophil infiltration into the lung tissues as evidenced by histology, with similar effects to those of CORT. High-, moderate-, and low-YGW increased HDAC (P < 0.0001, P = 0.0009 and P = 0.0253 respectively) and decreased HAT (P = 0.0001, P = 0.0000 and P = 0.0039, respectively) activities in dose-dependent manners in the lung tissues of adoptive transfer recipient mice. Increased histone deacetylation of Tm by YGW reduced the AEII by reducing GATA-3 (P = 0.014),IL-4 (P = 0.0004), IL-5 (P = 0.0067), and IL-13 (P = 0.0002), and inducing IFN-γ release (P = 0.0375). Moreover, YGW reduced inflammatory cytokines such as IL-4, IL-5, and IL-13 by upregulating the activities of HDAC7 (P = 0.003)/10 (P = 0.003), HDAC11 (P < 0.0001), and HDAC9–11 (P < 0.0001, P < 0.0001 and P < 0.0001, respectively), respectively, and increased IFN-γ release by increasing HDAC9 (P < 0.0001).
Conclusions
Histone deacetylation of Tm was observed during alleviation of allergen-induced eosinophilic airway inflammation in asthma by YGW.
doi:10.1186/s13020-015-0038-9
PMCID: PMC4465301  PMID: 26075017
23.  Titanium Elastic Nail (TEN) versus Reconstruction Plate Repair of Midshaft Clavicular Fractures: A Finite Element Study 
PLoS ONE  2015;10(5):e0126131.
Background
The biomechanical characteristics of midshaft clavicular fractures treated with titanium elastic nail (TEN) is unclear. This study aimed to present a biomechanical finite element analysis of biomechanical characteristics involved in TEN fixation and reconstruction plate fixation for midshaft clavicular fractures.
Methods
Finite element models of the intact clavicle and of midshaft clavicular fractures fixed with TEN and with a reconstruction plate were built. The distal clavicle displacement, peak stress, and stress distribution on the 3 finite element models were calculated under the axial compression and cantilever bending.
Results
In both loading configurations, TEN generated the highest displacement of the distal clavicle, followed by the intact clavicle and the reconstruction plate. TEN showed higher peak bone and implant stresses, and is more likely to fail in both loading configurations compared with the reconstruction plate. TEN led to a stress distribution similar to that of the intact clavicle in both loading configurations, whereas the stress distribution with the reconstruction plate was nonphysiological in cantilever bending.
Conclusions
TEN is generally preferable for treating simple displaced fractures of the midshaft clavicle, because it showed a stress distribution similar to the intact clavicle. However, TEN provides less stability, and excessive exercise of and weight bearing on the ipsilateral shoulder should be avoided in the early postoperative period. Fixation with a reconstruction plate was more stable but showed obvious stress shielding. Therefore, for patients with a demand for early return to activity, reconstruction plate fixation may be preferred.
doi:10.1371/journal.pone.0126131
PMCID: PMC4428894  PMID: 25965409
24.  ψ-Bufarenogin, a novel anti-tumor compound, suppresses liver cancer growth by inhibiting receptor tyrosine kinase-mediated signaling 
Oncotarget  2015;6(13):11627-11639.
Resistance of hepatocellular carcinoma (HCC) to existing chemotherapeutic agents largely contributes to the poor prognosis of patients, and discovery of novel anti-HCC drug is in an urgent need. Herein we report ψ-Bufarenogin, a novel active compound that we isolated from the extract of toad skin, exhibited potent therapeutic effect in xenografted human hepatoma without notable side effects. In vitro, ψ-Bufarenogin suppressed HCC cells proliferation through impeding cell cycle progression, and it facilitated cell apoptosis by downregulating Mcl-1 expression. Moreover, ψ-Bufarenogin decreased the number of hepatoma stem cells through Sox2 depression and exhibited synergistic effect with conventional chemotherapeutics. Mechanistic study revealed that ψ-Bufarenogin impaired the activation of MEK/ERK pathway, which is essential in the proliferation of hepatoma cells. ψ-Bufarenogin notably suppressed PI3-K/Akt cascade, which was required in ψ-Bufarenogin-mediated reduction of Mcl-1 and Sox2. ψ-Bufarenogin inhibited the auto-phosphorylation and activation of epithelial growth factor receptor (EGFR) and hepatocyte growth factor receptor (c-Met), thereafter suppressed their primary downstream cascades Raf/MEK/ERK and PI3-K/Akt signaling. Taken together, ψ-Bufarenogin suppressed HCC growth via inhibiting, at least partially, receptor tyrosine kinases-regulated signaling, suggesting that ψ-Bufarenogin could be a novel lead compound for anti-HCC drug.
PMCID: PMC4484481  PMID: 25890498
ψ-Bufarenogin; hepatocellular carcinoma; epithelial growth factor receptor; hepatocyte growth factor receptor
25.  Sequential Combination Therapy with Pegylated Interferon Leads to Loss of Hepatitis B Surface Antigen and Hepatitis B e Antigen (HBeAg) Seroconversion in HBeAg-Positive Chronic Hepatitis B Patients Receiving Long-Term Entecavir Treatment 
Nucleos(t)ide analogues rarely result in a durable off-treatment response in chronic hepatitis B infection, whereas pegylated interferon (Peg-IFN) induces a long-lasting response only in a subset of patients. We assessed the effect of sequential combination therapy with Peg-IFN-α2a and entecavir in hepatitis B e antigen (HBeAg)-positive patients with prior long-term entecavir therapy and investigated the predictors of response to treatment. HBeAg-positive individuals who did not achieve HBeAg seroconversion during previous long-term entecavir therapy, receiving Peg-IFN-α2a added to ongoing entecavir therapy (sequential combination [S-C] therapy; n = 81) for 48 weeks or remaining on entecavir monotherapy (n = 116), were retrospectively included. A matched pair was created at a 1:1 ratio from each treatment group. The primary endpoint was HBeAg seroconversion at week 48. Subgroup analysis of response prediction was conducted for 81 patients with S-C therapy. More patients in the S-C therapy group achieved HBeAg seroconversion than those in the entecavir group (44% versus 6%; P < 0.0001). An HBeAg level of <200 signal-to-cutoff ratio (S/CO) at baseline was a strong predictor for higher HBeAg seroconversion than that achieved when HBeAg was ≥200 S/CO (64.2% versus 17.9%; P < 0.0001). Hepatitis B surface antigen (HBsAg) levels at baseline and the decrease in HBsAg levels predicted HBsAg loss in the S-C therapy group. The combination of baseline HBeAg of <200 S/CO and HBsAg of <1,000 IU/ml and an HBsAg decline at week 12 of ≥0.5 log10 IU/ml provided the highest rate of HBeAg seroconversion (92.31%) and HBsAg loss (83.3%) at week 48. Patients receiving sequential combination therapy have a higher rate of HBeAg seroconversion and are more likely to experience HBsAg clearance than do those continuing entecavir monotherapy. Sequential combination therapy can be guided by baseline HBsAg/HBeAg levels and on-treatment HBsAg dynamics.
doi:10.1128/AAC.00249-15
PMCID: PMC4468690  PMID: 25941216

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