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1.  Genome sequences of two closely related strains of Escherichia coli K-12 GM4792 
Escherichia coli lab strains K-12 GM4792 Lac+ and GM4792 Lac- carry opposite lactose markers, which are useful for distinguishing evolved lines as they produce different colored colonies. The two closely related strains are chosen as ancestors for our ongoing studies of experimental evolution. Here, we describe the genome sequences, annotation, and features of GM4792 Lac+ and GM4792 Lac-. GM4792 Lac+ has a 4,622,342-bp long chromosome with 4,061 protein-coding genes and 83 RNA genes. Similarly, the genome of GM4792 Lac- consists of a 4,621,656-bp chromosome containing 4,043 protein-coding genes and 74 RNA genes. Genome comparison analysis reveals that the differences between GM4792 Lac+ and GM4792 Lac- are minimal and limited to only the targeted lac region. Moreover, a previous study on competitive experimentation indicates the two strains are identical or nearly identical in survivability except for lactose utilization in a nitrogen-limited environment. Therefore, at both a genetic and a phenotypic level, GM4792 Lac+ and GM4792 Lac-, with opposite neutral markers, are ideal systems for future experimental evolution studies.
Electronic supplementary material
The online version of this article (doi:10.1186/s40793-015-0114-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4675052  PMID: 26664654
Escherichia coli K12; GM4792; Lactose; Gram-negative; Genome comparison; Experimental evolution; Variant analysis
2.  Correlation between bone mineral density and serum trace element contents of elderly males in Beijing urban area 
Trace element levels are associated with the incidence of osteoporotic fractures, but related mechanisms remain unknown. Trace elements may interfere with growth, development and maintenance of bones. Therefore, we investigated whether plasma trace element levels are associated with bone mineral density in elderly males in Beijing. After epidemiologically investigating 91 elderly males with age ranging from 50 years to 80 years, we obtained a total of 30 healthy (group 1), 31 osteopoenic (group 2) and 30 osteoporotic (group 3) subjects. Blood was collected, and serum concentrations of trace elements were detected. Elderly males in the three groups were carefully matched in terms of body mass index. Iron, manganese, zinc, copper, selenium, cadmium and lead were analysed by inductively coupled plasma-mass spectrometry. Bone mineral density (BMD) was measured by QDR-2000 dual-energy X-ray absorptiometry. Correlation between BMD and serum element contents was analysed using SPSS16.0. The plasma levels of manganese, zinc, copper, selenium and lead were similar in all of the groups (P>0.05). Cadmium was significantly and negatively correlated with BMD of the lumbar vertebrae (P<0.05). Moreover, cadmium and iron contents significantly differed in osteoporotic and healthy groups. These elements may directly and correlatively affect BMD in elderly males. Many trace elements may directly and correlatively influence BMD. Future studies should be conducted to evaluate serum and bone levels of these trace elements to determine the relationship of these trace elements with osteoporosis.
PMCID: PMC4694461  PMID: 26770561
Osteoporosis; bone mineral density; element
3.  Renoprotective effects of olmesartan medoxomil on diabetic nephropathy in streptozotocin-induced diabetes in rats 
Biomedical Reports  2013;2(1):24-28.
Olmesartan medoxomil (OM) is one of the newest members of the angiotensin receptor blocker (ARB) family. The renoprotective effects of the angiotensin II type 1 receptor antagonist OM was investigated in a streptozotocin (STZ)-induced diabetic rat model. In this study, we investigated whether OM was able to ameliorate diabetic nephropathy (DN). Thirty male Sprague Dawley rats were assigned to 3 groups: the non-diabetic (group A, n=10), the untreated STZ-induced DN control (group B, n=10) and the STZ-induced DN treated with OM (group C, n=10). Blood pressure (BP) and glucose, creatinine (Cr), blood urea nitrogen (BUN), superoxide dismutase (SOD), malondialdehyde (MDA) microalbumin and urinary protein concentrations were measured. In STZ diabetic rats, BP, glucose, Cr, BUN, MDA and urinary protein levels were significantly increased compared to the non-diabetic control group. OM significantly improved the biological indices in the DN rats. The renal pathological changes were also observed under a light microscope. Our results suggested that OM exerted renoprotective effects on rats with STZ-induced diabetes.
PMCID: PMC3917007  PMID: 24649063
renoprotective effects; olmesartan medoxomil; diabetic nephropathy
4.  Tolerance and efficacy of autologous or donor-derived T cells expressing CD19 chimeric antigen receptors in adult B-ALL with extramedullary leukemia 
Oncoimmunology  2015;4(11):e1027469.
The engineering of T lymphocytes to express chimeric antigen receptors (CARs) aims to establish T cell-mediated tumor immunity rapidly. In this study, we conducted a pilot clinical trial of autologous or donor- derived T cells genetically modified to express a CAR targeting the B-cell antigen CD19 harboring 4-1BB and the CD3ζ moiety. All enrolled patients had relapsed or chemotherapy-refractory B-cell lineage acute lymphocytic leukemia (B-ALL). Of the nine patients, six had definite extramedullary involvement, and the rate of overall survival at 18 weeks was 56%. One of the two patients who received conditioning chemotherapy achieved a three-month durable complete response with partial regression of extramedullary lesions. Four of seven patients who did not receive conditioning chemotherapy achieved dramatic regression or a mixed response in the haematopoietic system and extramedullary tissues for two to nine months. Grade 2–3 graft-versus-host disease (GVHD) was observed in two patients who received substantial donor-derived anti-CD19 CART (chimeric antigen receptor-modified T) cells 3–4 weeks after cell infusions. These results show for the first time that donor-derived anti-CD19 CART cells can cause GVHD and regression of extramedullary B-ALL. This study is registered at as NCT01864889.
PMCID: PMC4590028  PMID: 26451310
anti-CD19 chimeric antigen receptor (CAR) T cells; B-cell acute lymphoblastic leukemia (B-ALL); graft-versus-host disease (GVHD); refractory
5.  Inhibition of autophagy overcomes glucocorticoid resistance in lymphoid malignant cells 
Cancer Biology & Therapy  2015;16(3):466-476.
Glucocorticoid (GC) resistance remains a major obstacle to successful treatment of lymphoid malignancies. Till now, the precise mechanism of GC resistance remains unclear. In the present study, dexamethasone (Dex) inhibited cell proliferation, arrested cell cycle in G0/G1-phase, and induced apoptosis in Dex-sensitive acute lymphoblastic leukemia cells. However, Dex failed to cause cell death in Dex-resistant lymphoid malignant cells. Intriguingly, we found that autophagy was induced by Dex in resistant cells, as indicated by autophagosomes formation, LC3-I to LC3-II conversion, p62 degradation, and formation of acidic autophagic vacuoles. Moreover, the results showed that Dex reduced the activity of mTOR pathway, as determined by decreased phosphorylation levels of mTOR, Akt, P70S6K and 4E-BP1 in resistant cells. Inhibition of autophagy by either chloroquine (CQ) or 3-methyladenine (3-MA) overcame Dex-resistance in lymphoid malignant cells by increasing apoptotic cell death in vitro. Consistently, inhibition of autophagy by stably knockdown of Beclin1 sensitized Dex-resistant lymphoid malignant cells to induction of apoptosis in vivo. Thus, inhibition of autophagy has the potential to improve lymphoid malignancy treatment by overcoming GC resistance.
PMCID: PMC4622576  PMID: 25778879
autophagy; apoptosis; dexamethasone; glucocorticoid resistance; lymphoid malignancy
6.  Different definitions of CpG island methylator phenotype and outcomes of colorectal cancer: a systematic review 
Clinical Epigenetics  2016;8:25.
Contradictory results were reported for the prognostic role of CpG island methylator phenotype (CIMP) among colorectal cancer (CRC) patients. Differences in the definitions of CIMP were the most common explanation for these discrepancies. The aim of this systematic review was to give an overview of the published studies on CRC prognosis according to the different definitions of CIMP. A systematic literature search was performed in MEDLINE and ISI Web of Science for articles published until 3 April 2015. Data extraction included information about the study population, the definition of CIMP, and investigated outcomes. Thirty-six studies were included in this systematic review. Among them, 30 studies reported the association of CIMP and CRC prognosis and 11 studies reported the association of CIMP with survival after CRC therapy. Overall, 16 different definitions of CIMP were identified. The majority of studies reported a poorer prognosis for patients with CIMP-positive (CIMP+)/CIMP-high (CIMP-H) CRC than with CIMP-negative (CIMP−)/CIMP-low (CIMP-L) CRC. Inconsistent results or varying effect strengths could not be explained by different CIMP definitions used. No consistent variation in response to specific therapies according to CIMP status was found. Comparative analyses of different CIMP panels in the same large study populations are needed to further clarify the role of CIMP definitions and to find out how methylation information can best be used to predict CRC prognosis and response to specific CRC therapies.
Electronic supplementary material
The online version of this article (doi:10.1186/s13148-016-0191-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4776403  PMID: 26941852
Colorectal cancer; CpG island methylator phenotype; Prognosis; Chemotherapy
7.  Inhibition of p70S6K1 activation by Pdcd4 overcomes the resistance to an IGF-1R/IR inhibitor in colon carcinoma cells 
Molecular cancer therapeutics  2015;14(3):799-809.
Agents targeting insulin-like growth factor 1 receptor (IGF-1R) are being actively examined in clinical trials. Although there has been some initial success of single agent targeting IGF-1R, attempts in later studies failed due to resistance. This study aimed to understand the effects of programmed cell death 4 (Pdcd4) on the chemosensitivity of the IGF-1R inhibitor, OSI-906, in colorectal cancer (CRC) cells and the mechanism underlying this impact. Using OSI-906 resistant and sensitive CRC cells, we found that the Pdcd4 level directly correlates with cell chemosensitivity to OSI-906. In addition, tumors derived from Pdcd4 knockdown cells resist the growth inhibitory effect of OSI-906 in a CRC xenograft mouse model. Moreover, Pdcd4 enhances the antiproliferative effect of OSI-906 in resistant cells through suppression of p70S6K1 activation. Knockdown of p70S6K1, but not p70S6K2, significantly increases the chemosensitivity of OSI-906 in cultured CRC cells. Furthermore, the combination of OSI-906 and PF4708671, a p70S6K1 inhibitor, efficiently suppresses the growth of OSI-906 resistant colon tumor cells in vitro and in vivo. Taken together, activation of p70S6K1 that is inhibited by Pdcd4 is essential for resistance to IGF-1R inhibitor in colon tumor cells, and the combinational treatment of OSI-906 and PF-4708671 results in enhanced antiproliferation effects in CRC cells in vitro and in vivo, providing a novel venue to overcome the resistance to IGF-1R inhibitor in treating colorectal cancer.
PMCID: PMC4456303  PMID: 25573956
Pdcd4; OSI-906; S6K; PF-4708671; IGF-1R/IR
9.  Genetic variants of CDH13 determine the susceptibility to chronic obstructive pulmonary disease in a Chinese population 
Acta Pharmacologica Sinica  2016;37(3):390-397.
Adiponectin has been implicated in the development of chronic obstructive pulmonary disease (COPD). The CDH13 gene encodes T-cadherin that is an adiponectin receptor, and genetic variants of CDH13 determine blood adiponectin levels. The aim of this study was to investigate the effects of CDH13 variants on COPD susceptibility in a Chinese population.
Ten single-nucleotide polymorphisms (SNP) in CDH13 were screened using the SNaPshot method in 279 COPD patients and 367 control subjects. Association of genotypes or haplotypes constructed from these loci with COPD was analyzed in different genetic models.
Among the 10 SNPs tested, rs4783244 and rs12922394 exhibited significant differences in allele or genotype frequencies between COPD patients and control subjects, whereas 8 other SNPs did not. The minor allele T was associated with decreased risk of COPD in the recessive model at rs4783244 (OR=0.42, P=0.023) and in the dominant model at rs12922394 (OR=0.70, P=0.022). The genotype TT at either rs4783244 or rs12922394 was associated with a significantly low level of plasma adiponectin when compared to genotypes GG and CC (P<0.05). Haplotypes GC in block 1 (rs4783244-rs12922394) as well as GTAC and ATGT in block 3 (rs4783266-rs11640522-rs11646849-rs11860282) significantly increased the risk of COPD, whereas haplotypes TT in block 1, TG in block 2 (rs11646011- rs11640875) and ATGC in block 3 were protective against COPD.
CDH13 genetic variants determine Chinese individuals' susceptibility to COPD and thus are efficient genetic biomarkers for early detection of COPD.
PMCID: PMC4775852  PMID: 26806298
CDH13; adiponectin; chronic obstructive pulmonary disease; biomarker; genetic polymorphism; haplotype; Chinese individuals
10.  NaCl stress-induced transcriptomics analysis of Salix linearistipularis (syn. Salix mongolica) 
Salix linearistipularis (syn. S. mongolica) is a woody halophyte, which is distributed naturally in saline-alkali soil of Songnen plain, Heilongjiang, China. It plays an important role in maintaining ecological balance and in improving saline soil. Furthermore, S. linearistipularis is also a genetic resource; however, there is no available information of genomic background for salt tolerance mechanism. We conducted the transcriptome analysis of S. linearistipularis to understand the mechanisms of salt tolerance by using RNA-seq technology.
The transcription profiles of both the salt stress (SLH-treated) and the control (SLH-control) sample for S. linearistipularis were obtained by using RNA-seq in this study. By comparative analysis, only 3034 of 53,362 all-unigenes between two samples were expressed differently at more than 1.5-fold (\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\left| {fold - change} \right| \ge 1.5$$\end{document}fold-change≥1.5, FDR ≤ 0.05), including 1397 up-regulated genes and 1637 down-regulated genes. In total, 2199 genes were classified into 50 Gene Ontology (GO) terms and 1103 genes were involved in 116 biological pathways. To find salt stress related genes, all-unigenes of S. linearistipularis were classified into three categories according to their degree of the differentially expressed genes (DEGs) at 0–1.5-fold (non differently expressed genes, N-DEGs), at 1.5–4.0-fold and more than 4.0-fold. The pathways of three categorized genes were compared with the DEGs of Arabidopsis thaliana, showing that 22, 10 and 1 pathway of S. linearistipularis were overlapped with A. thaliana. Degree of the overlapping was categorized as 0–1.5-fold, 1.5–4.0-fold and more than 4.0-folds.
Our study revealed that the N-DEGs of 22 pathways in S. linearistipularis were overlapped with the DEGs of A. thaliana. This result suggests that those overlapped genes that contrasted with the up- or down-regulated genes in A. thaliana were possibility evolved into housekeeping genes in S. linearistipularis under salt stress.
Electronic supplementary material
The online version of this article (doi:10.1186/s40709-016-0038-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4772304  PMID: 26933650
Salix linearistipularis; RNA-Seq; Biological pathway; Salt stress; Differently expressed genes (DEGs); Non differently expressed genes (N-DEGs)
11.  Differential Proteomic Analysis of Human Saliva using Tandem Mass Tags Quantification for Gastric Cancer Detection 
Scientific Reports  2016;6:22165.
Novel biomarkers and non-invasive diagnostic methods are urgently needed for the screening of gastric cancer to reduce its high mortality. We employed quantitative proteomics approach to develop discriminatory biomarker signatures from human saliva for the detection of gastric cancer. Salivary proteins were analyzed and compared between gastric cancer patients and matched control subjects by using tandem mass tags (TMT) technology. More than 500 proteins were identified with quantification, and 48 of them showed significant difference expression (p < 0.05) between normal controls and gastric cancer patients, including 7 up-regulated proteins and 41 down-regulated proteins. Five proteins were selected for initial verification by ELISA and three were successfully verified, namely cystatin B (CSTB), triosephosphate isomerase (TPI1), and deleted in malignant brain tumors 1 protein (DMBT1). All three proteins could differentiate gastric cancer patients from normal control subjects, dramatically (p < 0.05). The combination of these three biomarkers could reach 85% sensitivity and 80% specificity for the detection of gastric cancer with accuracy of 0.93. This study provides the proof of concept of salivary biomarkers for the non-invasive detection of gastric cancer. It is highly encouraging to turn these biomarkers into an applicable clinical test after large scale validation.
PMCID: PMC4766442  PMID: 26911362
12.  Dating the period when intensive anthropogenic activity began to influence the Sanjiang Plain, Northeast China 
Scientific Reports  2016;6:22153.
Dating the start of intensive anthropogenic influence on ecosystems is important for identifying the conditions necessary for ecosystem recovery. However, few studies have focused on determining when anthropogenic influences on wetland began through sedimentary archives. To fill this critical gap in our knowledge, combustion sources and emission intensities, reconstructed via black carbon (BC) and polycyclic aromatic hydrocarbons (PAHs) were analyzed in two wetlands in the Sanjiang Plain in Northeast China. 14C provided age control for the sedimentary records. By combining previous sedimentary and archaeological studies, we attempt to date the beginning of intensive anthropogenic influences on the Sanjiang Plain. Our results showed that BC deposition fluxes increased from 0.02 to 0.7 g C/m2.yr during the last 10,000 years. An upward trend was apparent during the last 500 years. Before 1200 cal yr BP, human activities were minor, such that the wetland ecosystem in the Sanjiang Plain before this period may represent the reference conditions that for the recovery of these wetlands. As the human population increased after 1200 cal yr BP, combustion sources changed and residential areas became a major source of BC and PAHs. In this way, the wetland ecosystem gradually became more heavily influenced by human activities.
PMCID: PMC4764887  PMID: 26907560
13.  TPhP exposure disturbs carbohydrate metabolism, lipid metabolism, and the DNA damage repair system in zebrafish liver 
Scientific Reports  2016;6:21827.
Triphenyl phosphate is a high production volume organophosphate flame retardant that has been detected in multiple environmental media at increasing concentrations. The environmental and health risks of triphenyl phosphate have drawn attention because of the multiplex toxicity of this chemical compound. However, few studies have paid close attention to the impacts of triphenyl phosphate on liver metabolism. We investigated hepatic histopathological, metabolomic and transcriptomic responses of zebrafish after exposure to 0.050 mg/L and 0.300 mg/L triphenyl phosphate for 7 days. Metabolomic analysis revealed significant changes in the contents of glucose, UDP-glucose, lactate, succinate, fumarate, choline, acetylcarnitine, and several fatty acids. Transcriptomic analysis revealed that related pathways, such as the glycosphingolipid biosynthesis, PPAR signaling pathway and fatty acid elongation, were significantly affected. These results suggest that triphenyl phosphate exposure markedly disturbs hepatic carbohydrate and lipid metabolism in zebrafish. Moreover, DNA replication, the cell cycle, and non-homologous end-joining and base excision repair were strongly affected, thus indicating that triphenyl phosphate hinders the DNA damage repair system in zebrafish liver cells. The present study provides a systematic analysis of the triphenyl phosphate-induced toxic effects in zebrafish liver and demonstrates that low concentrations of triphenyl phosphate affect normal metabolism and cell cycle.
PMCID: PMC4761896  PMID: 26898711
14.  Jujuboside B Reduces Vascular Tension by Increasing Ca2+ Influx and Activating Endothelial Nitric Oxide Synthase 
PLoS ONE  2016;11(2):e0149386.
Jujuboside B has been reported to have protective effect on many cardiovascular diseases. However, the effects of Jujuboside B on vascular tension and endothelial function are unknown. The present study investigated the effects of Jujuboside B on reducing vascular tension, protecting endothelial function and the potential mechanisms. The tension of isolated rat thoracic aorta ring was measured by Wire myograph system. The concentration of nitric oxide (NO) and the activity of endothelial nitric oxide synthase (eNOS) in human aortic endothelial cells (HAECs) were determined by Griess reagent method and enzyme-linked immune sorbent assay. The protein levels of eNOS and p-eNOS at Serine-1177 were determined by western blot analysis. Intracellular Ca2+ concentration in HAECs was measured by laser confocal imaging microscopy. Results showed that Jujuboside B reduced the tension of rat thoracic aorta rings with intact endothelium in a dose-dependent manner. L-NAME, KN93, EGTA, SKF96365, iberiotoxin and glibenclamide significantly attenuated Jujuboside B-induced vasodilation in endothelium-intact tissues. In contrast, indometacin and 4-DAMP had no such effects. Jujuboside B also promoted NO generation and increased eNOS activity, which were attenuated by L-NAME, EGTA and SKF96365. Moreover, Jujuboside B increased intracellular Ca2+ concentration dose-dependently, which was inhibited by EGTA and SKF96365. Besides, Jujuboside B induced a rapid Ca2+ influx instantaneously after depleting intracellular Ca2+ store, which was significantly inhibited by SKF96365. In conclusion, this study preliminarily confirmed that Jujuboside B reduced vascular tension endothelium-dependently. The underlying mechanisms involved that Jujuboside B increased extracellular Ca2+ influx through endothelial transient receptor potential cation (TRPC) channels, phosphorylated eNOS and promoted NO generation in vascular endothelial cells. In addition, Jujuboside B-induced vasodilation involved endothelium-dependent hyperpolarizaiton through endothelial potassium channels. Jujuboside B is a natural compound with new pharmacological effects on improving endothelial dysfunction and treating vascular diseases.
PMCID: PMC4762982  PMID: 26901291
16.  Characterization of SSR genomic abundance and identification of SSR markers for population genetics in Chinese jujube (Ziziphus jujuba Mill.) 
PeerJ  2016;4:e1735.
Chinese jujube (Ziziphus jujuba Mill. [Rhamnaceae]), native to China, is a major dried fruit crop in Asia. Although many simple sequence repeat (SSR) markers are available for phylogenetic analysis of jujube cultivars, few of these are validated on the level of jujube populations. In this study, we first examined the abundance of jujube SSRs with repeated unit lengths of 1–6 base pairs, and compared their distribution with those in Arabidopsis thaliana. We identified 280,596 SSRs in the assembled genome of jujube. The density of SSRs in jujube was 872.60 loci/Mb, which was much higher than in A. thaliana (221.78 loci/Mb). (A+ T)-rich repeats were dominant in the jujube genome. We then randomly selected 100 SSRs in the jujube genome with long repeats and used them to successfully design 70 primer pairs. After screening using a series of criteria, a set of 20 fluorescently labeled primer pairs was further selected and screened for polymorphisms among three jujube populations. The average number of alleles per locus was 12.8. Among the three populations, mean observed and expected heterozygosities ranged from 0.858 to 0.967 and 0.578 to 0.844, respectively. After testing in three populations, all SSRs loci were in Hardy-Weinberg equilibrium (HWE) in at least one population. Finally, removing high null allele frequency loci and linked loci, a set of 17 unlinked loci was in HWE. These markers will facilitate the study of jujube genetic structure and help elucidate the evolutionary history of this important fruit crop.
PMCID: PMC4768703  PMID: 26925343
Genome; Jujube; Population genetics; Microsatellite; SSR abundance; SSR primers
17.  Nonlinear estimation of BOLD signals with the aid of cerebral blood volume imaging 
The hemodynamic balloon model describes the change in coupling from underlying neural activity to observed blood oxygen level dependent (BOLD) response. It plays an increasing important role in brain research using magnetic resonance imaging (MRI) techniques. However, changes in the BOLD signal are sensitive to the resting blood volume fraction (i.e., \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$V_0$$\end{document}V0) associated with the regional vasculature. In previous studies the value was arbitrarily set to a physiologically plausible value to circumvent the ill-posedness of the inverse problem. These approaches fail to explore actual \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$V_0$$\end{document}V0 value and could yield inaccurate model estimation.
The present study represents the first empiric attempt to derive the actual \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$V_0$$\end{document}V0 from data obtained using cerebral blood volume imaging, with the aim of augmenting the existing estimation schemes. Bimanual finger tapping experiments were performed to determine how \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$V_0$$\end{document}V0 influences the model estimation of BOLD signals within a single-region and multiple-regions (i.e., dynamic causal modeling). In order to show the significance of applying the true \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$V_0$$\end{document}V0, we have presented the different results obtained when using the real \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$V_0$$\end{document}V0 and assumed \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$V_0$$\end{document}V0 in terms of single-region model estimation and dynamic causal modeling.
The results show that \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$V_0$$\end{document}V0 significantly influences the estimation results within a single-region and multiple-regions. Using the actual \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$V_0$$\end{document}V0 might yield more realistic and physiologically meaningful model estimation results.
Incorporating regional venous information in the analysis of the hemodynamic model can provide more reliable and accurate parameter estimations and model predictions, and improve the inference about brain connectivity based on fMRI data.
PMCID: PMC4761419  PMID: 26897355
Blood volume fraction; Cerebral blood volume imaging; Dynamic causal modeling
18.  Partial protection against 2009 pandemic influenza A (H1N1) of seasonal influenza vaccination and related regional factors: Updated systematic review and meta-analyses 
Human Vaccines & Immunotherapeutics  2015;11(6):1337-1344.
This updated systematic review and meta-analyses aims to systematically evaluate the cross-protection of seasonal influenza vaccines against the 2009 pandemic A (H1N1) influenza infection, and investigate the potential effect of the influenza strains circulating previous to the pandemic on the association between vaccine receipt and pandemic infection. In addition, subgroup analysis was performed based on the study locations and previous circulating influenza viruses. Relevant articles in English and Chinese from 2009 to October 2013 were systematically searched, and 21 eligible studies were included. For case-control studies, an insignificant 20% reduced risk for pandemic influenza infection based on combined national data (OR = 0.80; 95%CI: 0.60, 1.05) was calculated for people receiving seasonal influenza vaccination. However, for RCTs, an insignificant increase in the risk of seasonal influenza vaccines was observed (RR = 1.27; 95% CI: 0.46, 3.53). For the subgroup analysis, a significant 35% cross-protection was observed in the subgroup where influenza A outbreaks were detected before the 2009 pandemic. Moreover, the results indicated that seasonal influenza vaccination may reduce the risk of influenza-like illnesses (ILIs) (RR = 0.91; 95% CI: 0.84, 0.99). Our findings partially support the hypothesis that seasonal vaccines may offer moderate cross-protection for adults against laboratory-confirmed pandemic influenza A (H1N1) infection and ILIs. Further immunological studies are needed to understand the mechanism underlying these findings.
PMCID: PMC4514212  PMID: 25692308
influenza A; meta-analysis; seasonal influenza vaccine; systematic review; vaccine effectiveness
19.  Hepatocyte TRAF3 promotes liver steatosis and systemic insulin resistance through targeting TAK1-dependent signalling 
Nature Communications  2016;7:10592.
Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, insulin resistance and a systemic pro-inflammatory response. Here we show that tumour necrosis factor receptor-associated factor 3 (TRAF3) is upregulated in mouse and human livers with hepatic steatosis. After 24 weeks on a high-fat diet (HFD), obesity, insulin resistance, hepatic steatosis and inflammatory responses are significantly ameliorated in liver-specific TRAF3-knockout mice, but exacerbated in transgenic mice overexpressing TRAF3 in hepatocytes. The detrimental effects of TRAF3 on hepatic steatosis and related pathologies are confirmed in ob/ob mice. We further show that in response to HFD, hepatocyte TRAF3 binds to TGF-β-activated kinase 1 (TAK1) to induce TAK1 ubiquitination and subsequent autophosphorylation, thereby enhancing the activation of downstream IKKβ–NF-κB and MKK–JNK–IRS1307 signalling cascades, while disrupting AKT–GSK3β/FOXO1 signalling. The TRAF3–TAK1 interaction and TAK1 ubiquitination are indispensable for TRAF3-regulated hepatic steatosis. In conclusion, hepatocyte TRAF3 promotes HFD-induced or genetic hepatic steatosis in a TAK1-dependent manner.
TRAF family proteins regulate immune signalling cascades. Here, the authors show that TRAF3 is upregulated in the liver in non-alcoholic fatty liver disease, promoting insulin resistance, inflammation and hepatic steatosis via its interaction with the kinase TAK1.
PMCID: PMC4757796  PMID: 26882989
20.  RPE and Choroid Mechanisms Underlying Ocular Growth and Myopia 
Myopia is the most common type of refractive errors and one of the world’s leading causes of blindness. Visual manipulations in animal models have provided convincing evidence for the role of environmental factors in myopia development. These models along with in vitro studies have provided important insights into underlying mechanisms. The key locations of the retinal pigment epithelium (RPE) and choroid make them plausible conduits for relaying growth regulatory signals originating in the retina to the sclera, which ultimately determines eye size and shape. Identifying the key signal molecules and their targets may lead to the development of new myopia control treatments. This section summarizes findings implicating the RPE and choroid in myopia development. For RPE and/or choroid, changes in morphology, activity of ion channels/transporters, as well as in gene and protein expression, have been linked to altered eye growth. Both tissues thus represent potential targets for novel therapies for myopia.
PMCID: PMC4755498  PMID: 26310157
21.  Corrigendum: Polyamine regulates tolerance to water stress in leaves of white clover associated with antioxidant defense and dehydrin genes via involvement in calcium messenger system and hydrogen peroxide signaling 
PMCID: PMC4753327  PMID: 26913009
antioxidant; dehydrin; gene expression; oxidative damage; polyamine; regulation; white clover (Trifolium repens)
22.  Efficacy of oseltamivir-peramivir combination therapy compared to oseltamivir monotherapy for Influenza A (H7N9) infection: a retrospective study 
Since the novel H7N9 avian influenza outbreak occurred in China in 2013, neuraminidase inhibitors (NAIs) such as oseltamivir and peramivir have been used as first-line drugs to treat the influenza virus infection. This study aimed to compare the efficacy of oseltamivir-peramivir combination therapy versus oseltamivir monotherapy.
A retrospective study of 82 H7N9 confirmed patients was conducted by reviewing medical charts at the First Affiliated Hospital of ZheJiang University in China from April 1, 2013 to Feb 28, 2014. The patients’ clinical information was collected systematically, and we compared the virology and clinical data between oseltamivir monotherapy group (43 patients) and oseltamivir-peramivir combination group (39 patients).
The median duration from NAIs administration to H7N9 virus-negative in oseltamivir monotherapy group and oseltamivir-peramivir combination group was 6.50 and 7.00 days (p >0.05), respectively. The median decline of Day 2 to Day 0 (initiation of NAIs therapy) viral load was 0.00 and 0.69 log10 copies/μl (p >0.05) respectively in the monotherapy vs. combination therapy groups. The incidence of new Acute Respiratory Distress Syndrome during NAI administration was 63.89 and 77.78 % (p >0.05); while the mortality rates were 25.58 and 43.59 % (p >0.05) in the oseltamivir group vs. oseltamivir-peramivir group.
Our results suggest that in adults with H7N9 virus infection, the use of oseltamivir-peramivir combination therapy was not superior to oseltamivir monotherapy.
PMCID: PMC4748590  PMID: 26864456
Influenza A; H7N9 virus; Oseltamivir; Peramivir
23.  Successful Chemo-Radiotherapy for Primary Anaplastic Large Cell Lymphoma of the Lung: A Case Report and Literature Review 
Patient: Male, 39
Final Diagnosis: Primary anaplastic large cell lymphoma of the lung
Symptoms: Hemoptysis • palpitation • shortness of breath
Medication: Cyclophosphamide • Doxorubicin • Vincristine • Prednisone
Clinical Procedure: Chemoradiotherapy
Specialty: Oncology
Rare disease
Primary anaplastic large cell lymphoma (ALCL) of the lung is an extremely rare disease. This disease is a great challenge for pneumologists due to its nonspecific clinical presentations and radiological findings. Appropriate invasive biopsy and immunohistochemistry are important for diagnosis. There is currently no standard treatment.
Case Report:
We report a very rare case of primary pulmonary ALCL in a 39-year-old man. The clinical features, imaging, pathological findings, treatment outcomes, and prognosis, are described. Successful treatment outcomes were achieved after 6 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy followed by involved field radiotherapy of 54Gy/27f. The patient was disease-free after follow-up for 65 months.
Our study found that chemotherapy (such as CHOP) is recognized as the first-line regimen for primary ALCL of the lung. For patients with dyspnea caused by a mass blocking the main bronchus, chemoradiotherapy may be a reasonable therapeutic option. The prognosis is better for patients with positive ALK staining. CD56(+), age older than 60 years, Ann Arbor stage III or IV, survivin expression, PS>2, and high serum LDH level and IPI scores are the poor prognostic factors of ALCL.
PMCID: PMC4751921  PMID: 26852792
Chemoradiotherapy; Lung Diseases; Lymphoma, Large-Cell, Anaplastic
24.  Cancer-associated fibroblasts promote the progression of endometrial cancer via the SDF-1/CXCR4 axis 
Cancer-associated fibroblasts (CAFs) are believed to play an essential role in cancer initiation and development. However, little research has been undertaken to evaluate the role of CAFs in endometrial cancer (EC) progression. We aim to detect the functional contributions of CAFs to promote progression of EC.
Stromal fibroblasts were isolated from endometrioid adenocarcinomas and normal endometrial tissues. The conditioned media of cultured CAFs and normal fibroblasts (NFs) were collected to detect the level of stromal cell-derived factor-1alpha (SDF-1α), macrophage chemoattractant protein-1 (MCP-1), migration inhibitory factor (MIF), colony stimulating factor-1 (CSF-1), and interleukin-1 (IL-1) by ELISA. The CAFs or NFs were cocultured with EC cell lines to determine the proliferation, migration, and invasion by MTT assays and transwell chambers. Xenograft models were used to observe tumor growth. Matrix metalloproteinases (MMP)-2 and MMP-9 activity was evaluated by zymography. AMD3100 (a chemokine receptor 4 (CXCR4) antagonist) was used to block the SDF-1/CXCR4 axis. Neutralizing antibodies were used to detect PI3K/Akt and MAPK/Erk pathways by western blotting. SDF-1α and CXCR4 expressions were analyzed in xenotransplanted tumors and 348 cases by immunohistochemistry.
CAFs promoted proliferation, migration, and invasion as well as in vivo tumorigenesis of admixed EC cells significantly more than NFs by secreting SDF-1α. These effects were significantly inhibited by AMD3100. CAFs promoted EC progression via the SDF-1α/CXCR4 axis to activate the PI3K/Akt and MAPK/Erk signalings in a paracrine-dependent manner or increase MMP-2 and MMP-9 secretion in an autocrine-dependent manner. SDF-1α and CXCR4 expression upregulation accompanied clinical EC development and progression. High SDF-1α expression levels were associated with deep myometrial invasion, lymph node metastasis, and poor prognosis in EC.
Our data indicated that CAFs derived from EC tissues promoted EC progression via the SDF-1/CXCR4 axis in a paracrine- or autocrine-dependent manner. SDF-1α is a novel independent poor prognostic factor for EC patients’ survival. Targeting the SDF-1/CXCR4 axis might provide a novel therapeutic strategy for EC treatment.
PMCID: PMC4744391  PMID: 26851944
Tumor microenvironment; Cancer-associated fibroblasts; Endometrial cancer; Stromal cell-derived factor-1α; CXCR4; Prognosis
25.  Precocious leaf senescence by functional loss of PROTEIN S-ACYL TRANSFERASE14 involves the NPR1-dependent salicylic acid signaling 
Scientific Reports  2016;6:20309.
We report here that Arabidopsis PROTEIN S-ACYL TRANSFERASE14 (PAT14), through its palmitate transferase activity, acts at the vacuolar trafficking route to repress salicylic acid (SA) signaling, thus mediating age-dependent but not carbon starvation-induced leaf senescence. Functional loss of PAT14 resulted in precocious leaf senescence and its transcriptomic analysis revealed that senescence was dependent on salicylic acid. Overexpressing PAT14 suppressed the expression of SA responsive genes. Introducing the SA deficient mutants, npr1-5 and NahG, but not other hormonal mutants, completely suppressed the precocious leaf senescence of PAT14 loss-of-function, further supporting the epistatic relation between PAT14 and the SA pathway. By confocal fluorescence microscopy, we showed that PAT14 is localized at the Golgi, the trans-Golg network/early endosome, and prevacuolar compartments, indicating its roles through vacuolar trafficking. By reporter analysis and real time PCRs, we showed that the expression PAT14, unlike most of the senescence associated genes, is not developmentally regulated, suggesting post-transcriptional regulatory mechanisms on its functionality. We further showed that the maize and wheat homologs of PAT14 fully rescued the precocious leaf senescence of pat14-2, demonstrating that the role of PAT14 in suppressing SA signaling during age-dependent leaf senescence is evolutionarily conserved between dicots and monocots.
PMCID: PMC4740857  PMID: 26842807

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