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1.  Tools and strategies for physiological genomics: the Rat Genome Database 
Physiological genomics  2005;23(2):246-256.
The broad goal of physiological genomics research is to link genes to their functions using appropriate experimental and computational techniques. Modern genomics experiments enable the generation of vast quantities of data, and interpretation of this data requires the integration of information derived from many diverse sources. Computational biology and bioinformatics offer the ability to manage and channel this information torrent. The Rat Genome Database (RGD; http://rgd.mcw.edu) has developed computational tools and strategies specifically supporting the goal of linking genes to their functional roles in rat and, using comparative genomics, to human and mouse. We present an overview of the database with a focus on these unique computational tools and describe strategies for the use of these resources in the area of physiological genomics.
doi:10.1152/physiolgenomics.00040.2005
PMCID: PMC4505745  PMID: 16106031
ontologies; comparative genomics; model organism; bioinformatics; physiological genomics
2.  Hunting for dark matter with ultra-stable fibre as frequency delay system 
Scientific Reports  2015;5:11469.
Many cosmological observations point towards the existence of dark-matter(DM) particles and consider them as the main component of the matter content of the universe. The goal of revealing the nature of dark-matter has triggered the development of new, extremely sensitive detectors. It has been demonstrated that the frequencies and phases of optical clock have a transient shift during the DMs’ arrival due to the DM-SM(Standard Model) coupling. A simple, reliable and feasible experimental scheme is firstly proposed in this paper, based on “frequency-delay system” to search dark-matter by “self-frequency comparison” of an optical clock. During the arrival of a dark-matter, frequency discrepancy is expected between two signals with a short time difference(~ms) of the same optical clock to exhibit the interaction between atoms and dark-matter. Furthermore, this process can determine the exact position of dark-matter when it is crossing the optical clocks, therefore a network of detecting stations located in different places is recommended to reduce the misjudgment risk to an acceptable level.
doi:10.1038/srep11469
PMCID: PMC4498180  PMID: 26159113
3.  Phosphorylation of Beet black scorch virus coat protein by PKA is required for assembly and stability of virus particles 
Scientific Reports  2015;5:11585.
Plant virus coat proteins (CPs) play a fundamental role in protection of genomic RNAs, virion assembly, and viral movement. Although phosphorylation of several CPs during virus infection have been reported, little information is available about CP phosphorylation of the spherical RNA plant viruses. Here, we demonstrate that the CP of Beet black scorch virus (BBSV), a member of the genus Necrovirus, can be phosphorylated at threonine-41 (T41) by cAMP-dependent protein kinase (PKA)-like kinase in vivo and in vitro. Mutant viruses containing a T41A non-phosphorylatable alanine substitution, and a T41E glutamic acid substitution to mimic threonine phosphorylation were able to replicate but were unable to move systemically in Nicotiana benthamiana. Interestingly, the T41A and T41E mutants generated unstable 17 nm virus-like particles that failed to package viral genomic (g) RNA, compared with wild-type BBSV with 30 nm virions during viral infection in N. benthamiana. Further analyses showed that the T41 mutations had little effect on the gRNA-binding activity of the CP. Therefore, we propose a model whereby CP phosphorylation plays an essential role in long-distance movement of BBSV that involves formation of stable virions.
doi:10.1038/srep11585
PMCID: PMC4479801  PMID: 26108567
4.  The First Complete Chloroplast Genome Sequences in Actinidiaceae: Genome Structure and Comparative Analysis 
PLoS ONE  2015;10(6):e0129347.
Actinidia chinensis is an important economic plant belonging to the basal lineage of the asterids. Availability of a complete Actinidia chloroplast genome sequence is crucial to understanding phylogenetic relationships among major lineages of angiosperms and facilitates kiwifruit genetic improvement. We report here the complete nucleotide sequences of the chloroplast genomes for Actinidia chinensis and A. chinensis var deliciosa obtained through de novo assembly of Illumina paired-end reads produced by total DNA sequencing. The total genome size ranges from 155,446 to 157,557 bp, with an inverted repeat (IR) of 24,013 to 24,391 bp, a large single copy region (LSC) of 87,984 to 88,337 bp and a small single copy region (SSC) of 20,332 to 20,336 bp. The genome encodes 113 different genes, including 79 unique protein-coding genes, 30 tRNA genes and 4 ribosomal RNA genes, with 16 duplicated in the inverted repeats, and a tRNA gene (trnfM-CAU) duplicated once in the LSC region. Comparisons of IR boundaries among four asterid species showed that IR/LSC borders were extended into the 5’ portion of the psbA gene and IR contraction occurred in Actinidia. The clap gene has been lost from the chloroplast genome in Actinidia, and may have been transferred to the nucleus during chloroplast evolution. Twenty-seven polymorphic simple sequence repeat (SSR) loci were identified in the Actinidia chloroplast genome. Maximum parsimony analyses of a 72-gene, 16 taxa angiosperm dataset strongly support the placement of Actinidiaceae in Ericales within the basal asterids.
doi:10.1371/journal.pone.0129347
PMCID: PMC4457681  PMID: 26046631
5.  Phosphorylation of TGB1 by protein kinase CK2 promotes barley stripe mosaic virus movement in monocots and dicots 
Journal of Experimental Botany  2015;66(15):4733-4747.
Highlight
CK2 phosphorylation of the TGB1 protein has a critical role in promoting barley stripe mosaic virus movement in monocots and dicots by affecting the interactions between TGB1 and TGB3 proteins.
The barley stripe mosaic virus (BSMV) triple gene block 1 (TGB1) protein is required for virus cell-to-cell movement. However, little information is available about how these activities are regulated by post-translational modifications. In this study, we showed that the BSMV Xinjiang strain TGB1 (XJTGB1) is phosphorylated in vivo and in vitro by protein kinase CK2 from barley and Nicotiana benthamiana. Liquid chromatography tandem mass spectrometry analysis and in vitro phosphorylation assays demonstrated that Thr-401 is the major phosphorylation site of the XJTGB1 protein, and suggested that a Thr-395 kinase docking site supports Thr-401 phosphorylation. Substitution of Thr-395 with alanine (T395A) only moderately impaired virus cell-to-cell movement and systemic infection. In contrast, the Thr-401 alanine (T401A) virus mutant was unable to systemically infect N. benthamiana but had only minor effects in monocot hosts. Substitution of Thr-395 or Thr-401 with aspartic acid interfered with monocot and dicot cell-to-cell movement and the plants failed to develop systemic infections. However, virus derivatives with single glutamic acid substitutions at Thr-395 and Thr-401 developed nearly normal systemic infections in the monocot hosts but were unable to infect N. benthamiana systemically, and none of the double mutants was able to infect dicot and monocot hosts. The mutant XJTGB1T395A/T401A weakened in vitro interactions between XJTGB1 and XJTGB3 proteins but had little effect on XJTGB1 RNA-binding ability. Taken together, our results support a critical role of CK2 phosphorylation in the movement of BSMV in monocots and dicots, and provide new insights into the roles of phosphorylation in TGB protein functions.
doi:10.1093/jxb/erv237
PMCID: PMC4507770  PMID: 25998907
Barley stripe mosaic virus; triple gene block 1 (TGB1) protein; phosphorylation; protein kinase CK2; promotion; viral movement.
6.  Chronic hypoxia in pregnancy affected vascular tone of renal interlobar arteries in the offspring 
Scientific Reports  2015;5:9723.
Hypoxia during pregnancy could affect development of fetuses as well as cardiovascular systems in the offspring. This study was the first to demonstrate the influence and related mechanisms of prenatal hypoxia (PH) on renal interlobar arteries (RIA) in the 5-month-old male rat offspring. Following chronic hypoxia during pregnancy, phenylephrine induced significantly higher pressor responses and greater vasoconstrictions in the offspring. Nitric oxide mediated vessel relaxation was altered in the RIA. Phenylephrine-stimulated free intracellular calcium was significantly higher in the RIA of the PH group. The activity and expression of L-type calcium channel (Cav1.2), not T-type calcium channel (Cav3.2), was up-regulated. The whole-cell currents of calcium channels and the currents of Cav1.2 were increased compared with the control. In addition, the whole-cell K+ currents were decreased in the offspring exposed to prenatal hypoxia. Activity of large-conductance Ca2+-activated K+ channels and the expression of MaxiKα was decreased in the PH group. The results provide new information regarding the influence of prenatal hypoxia on the development of the renal vascular system, and possible underlying cellular and ion channel mechanisms involved.
doi:10.1038/srep09723
PMCID: PMC4434890  PMID: 25983078
7.  Induction of anterior gradient 2 (AGR2) plays a key role in insulin-like growth factor-1 (IGF-1)-induced breast cancer cell proliferation and migration 
Anterior gradient 2 (AGR2) is a promising anti-tumor target associated with estrogen receptor expression and metastatic progression of breast cancer. Insulin-like growth factor-1 (IGF-1) is another potent factor that stimulates breast cancer progression and mediates anti-estrogen drug resistance. However, the precise mechanism and connections between these two factors in breast cancer drug resistance have not been fully elucidated. Here, for the first time, we decipher that IGF-1 remarkably induces AGR2 in the MCF7 cell line, through an estrogen response element (ERE) between −802 and −808 bp and a leucine zipper transcription factor-binding site located between −972 and −982 bp on the AGR2 promoter. We also found that the ERK1/2 and AKT pathways mediate estrogen receptor-α at the upstream of ERE and that the JNK pathway activates the leucine zipper site through the c-Jun/c-Fos complex. Additionally, our data suggest that knockdown of AGR2 reduces IGF-1-induced cell proliferation, migration and cell cycle progression. Therefore, we report that AGR2 is a key modulator involved in IGF-1-induced breast cancer development. We propose that the identification of the mechanism linking the IGF-1/insulin signal and AGR2 promoter activation is important, because it provides insights into the development of anti-breast cancer drugs.
doi:10.1007/s12032-015-0577-z
PMCID: PMC4451465  PMID: 25956506
Anterior gradient 2; Insulin-like growth factor-1; Breast cancer; Estrogen response element; Activator protein-1 site
8.  High expression of protein phosphatase 4 is associated with the aggressive malignant behavior of colorectal carcinoma 
Molecular Cancer  2015;14:95.
Background
Recent evidence suggests an important role of protein phosphatase 4 (PP4C) in the progression of several cancers, including breast cancer, lung cancer and pancreatic ductal adenocarcinoma. However, the contribution of PP4C to colorectal carcinoma (CRC) remains elusive.
Methods
The expression of PP4C in CRC tissues compared with matched non-tumor tissues and CRC cells was detected using quantitative RT-PCR, immunohistochemistry and western blotting assays. Through univariate and Kaplan-Meier analysis, we correlated the PP4C expression with clinicopathological features and patient survival. A series of experiments, including cell proliferation, lentiviral infection, cell invasion and MMP gelatinase activity assays, were performed to investigate the underlying mechanisms. Through further experiments, tumor growth and metastasis were evaluated in vivo using a xenogenous subcutaneously implant model and a tail vein metastasis model.
Results
In the present study, we found that PP4C expression is frequently increased in human CRC and that the upregulation of PP4C correlates with a more invasive tumor phenotype and poor prognosis. The ectopic expression of PP4C promoted CRC cell proliferation, migration and invasion in vitro and tumor growth and lung metastasis in vivo. Silencing the expression of PP4C resulted in the inhibition of cell proliferation and invasion. Further investigations showed that phosphorylated Akt (p-AKT) is required for the PP4C-mediated upregulation of MMP-2 and MMP-9, which promotes cell invasion.
Conclusions
Our data suggested a potential role of PP4C in tumor progression and provided novel insights into the mechanism of how this factor positively regulated cell proliferation and invasion in CRC cells.
doi:10.1186/s12943-015-0356-7
PMCID: PMC4416320  PMID: 25927939
Colorectal carcinoma; PP4C; Cell invasion; Prognosis; AKT
9.  High-salt diets during pregnancy affected fetal and offspring renal renin–angiotensin system 
The Journal of endocrinology  2013;218(1):61-73.
Intrauterine environments are related to fetal renal development and postnatal health. Influence of salty diets during pregnancy on renal functions and renin–angiotensin system (RAS) was determined in the ovine fetuses and offspring. Pregnant ewes were fed high-salt diet (HSD) or normal-salt diet (NSD) for 2 months during middle-to-late gestation. Fetal renal functions, plasma hormones, and mRNA and protein expressions of the key elements of renal RAS were measured in the fetuses and offspring. Fetal renal excretion of sodium was increased while urine volume decreased in the HSD group. Fetal blood urea nitrogen was increased, while kidney weight:body weight ratio decreased in the HSD group. The altered ratio was also observed in the offspring aged 15 and 90 days. Maternal and fetal plasma antidiuretic hormone was elevated without changes in plasma renin activity and Ang I levels, while plasma Ang II was decreased. The key elements of local renal RAS, including angiotensinogen, angiotensin converting enzyme (ACE), ACE2, AT1, and AT2 receptor expression in both mRNA and protein, except renin, were altered following maternal high salt intake. The results suggest that high intake of salt during pregnancy affected fetal renal development associated with an altered expression of the renal key elements of RAS, some alterations of fetal origins remained after birth as possible risks in developing renal or cardiovascular diseases.
doi:10.1530/JOE-13-0139
PMCID: PMC4406098  PMID: 23620529
Fetus; offspring; renal function; high salt; rennin–angiotensin system
10.  Photocatalytic Removal of Microcystin-LR by Advanced WO3-Based Nanoparticles under Simulated Solar Light 
The Scientific World Journal  2015;2015:720706.
A series of advanced WO3-based photocatalysts including CuO/WO3, Pd/WO3, and Pt/WO3 were synthesized for the photocatalytic removal of microcystin-LR (MC-LR) under simulated solar light. In the present study, Pt/WO3 exhibited the best performance for the photocatalytic degradation of MC-LR. The MC-LR degradation can be described by pseudo-first-order kinetic model. Chloride ion (Cl−) with proper concentration could enhance the MC-LR degradation. The presence of metal cations (Cu2+ and Fe3+) improved the photocatalytic degradation of MC-LR. This study suggests that Pt/WO3 photocatalytic oxidation under solar light is a promising option for the purification of water containing MC-LR.
doi:10.1155/2015/720706
PMCID: PMC4390111  PMID: 25884038
11.  Hepatic abscess with hepatobronchial fistula following percutaneous radiofrequency ablation for hepatocellular carcinoma: A case report 
Oncology Letters  2015;9(5):2289-2292.
Radiofrequency ablation (RFA) has a low rate of complication and is one of the most effective and minimally invasive techniques for the treatment of liver tumors. However, a number of complications may occur in rare cases, including bronchobiliary fistula, hollow viscera perforation, diaphragmatic perforation and hernia. The present study reports a case of hepatic abscess with hepatobronchial fistula following RFA of hepatocellular carcinoma; this led to severe lung infection, respiratory failure and mortality. The present case report aims to improve understanding of the cause and mechanism of the complications arising through RFA of the liver, and highlight important factors in the prevention and management process. This case indicates that the complications of RFA may be prevented or effectively managed through preoperative evaluation, intraoperative and postoperative monitoring.
doi:10.3892/ol.2015.3044
PMCID: PMC4467370  PMID: 26137058
hepatocellular carcinoma; radiofrequency ablation; bronchial fistula; infection
12.  Protective effects of vascular endothelial growth factor in cultured brain endothelial cells against hypoglycemia 
Metabolic Brain Disease  2015;30(4):999-1007.
Hypoglycemia is a common and serious problem among patients with type 1 diabetes receiving treatment with insulin. Clinical studies have demonstrated that hypoglycemic edema is involved in the initiation of hypoglycemic brain damage. However, the mechanisms of this edema are poorly understood. Vascular endothelial growth factor (VEGF), a potent regulator of blood vessel function, has been observed an important candidate hormone induced by hypoglycemia to protect neurons by restoring plasma glucose. Whether VEGF has a protective effect against hypoglycemia-induced damage in brain endothelial cells is still unknown. To investigate the effects of hypoglycemia on cerebral microvascular endothelial cells and assess the protective effect of exogenous VEGF on endothelial cells during hypoglycemia, confluent monolayers of the brain endothelial cell line bEnd.3 were treated with normal (5.5 mM glucose), hypoglycemic (0, 0.5, 1 mM glucose) medium or hypoglycemic medium in the presence of VEGF. The results clearly showed that hypoglycemia significantly downregulated the expression of claudin-5 in bEnd.3 cells, without affecting ZO-1 and occludin expression and distribution. Besides, transendothelial permeability significantly increased under hypoglycemic conditions compared to that under control conditions. Moreover, the hypoglycemic medium in presence of VEGF decreased endothelial permeability via the inhibition of claudin-5 degradation and improved hypoglycemia-induced cell toxicity. Furthermore, Glucose transporter-1 (Glut-1) and apoptosis regulator Bcl-2 expression were significantly upregulated. Taken together, hypoglycemia can significantly increase paraendocellular permeability by downregulating claudin-5 expression. We further showed that VEGF protected brain endothelial cells against hypoglycemia by enhancing glucose passage, reducing endothelial cell death, and ameliorating paraendocellular permeability.
doi:10.1007/s11011-015-9659-z
PMCID: PMC4491374  PMID: 25761767
Hypoglycemia; Tight junctions; VEGF; Glut-1; Bcl-2
13.  Cytoplasmic Expression of Pontin in Renal Cell Carcinoma Correlates with Tumor Invasion, Metastasis and Patients’ Survival 
PLoS ONE  2015;10(3):e0118659.
Renal cell carcinoma (RCC) is the most lethal of all genitourinary malignancies. Distant metastasis represents the major cause of death in patients with RCC. Recent studies have implicated the AAA+ ATPase pontin in many cellular activities that are highly relevant to carcinogenesis. In this study, we demonstrate for the first time that pontin was up-regulated in RCC, and plays a previously unknown pro-invasive role in the metastatic progression of RCC through epithelial-to-mesenchymal transition (EMT) pathway. 28 pairs of freshly frozen clear cell RCC samples and the matched normal renal tissues analyzed by quantitative RT-PCR and western blotting demonstrated that pontin was up-regulated in clear cell RCC tissues than in normal renal tissues. In addition, immunohistochemistry was used to evaluate subcellular pontin expression in 95 RCC patients, and found that overexpression of pontin in cytoplasm positively correlated with the metastatic features, predicting unfavorable outcomes of RCC patients. Furthermore, in vitro experiments show pontin was predominantly expressed in cytoplasm of RCC cell lines, and a significant suppression of cell migration and invasion in pontin siRNA treated RCC cell lines was observed. Mechanistic studies show that pontin depletion up-regulated the E-cadherin protein and down-regulated vimentin protein, and decreased nuclear β-catenin expression, suggesting the involvement of EMT in pontin induced metastatic progression. Together, our data suggest pontin as a potential prognostic biomarker in RCC, and provide new promising therapeutic targets for clinical intervention of kidney cancers.
doi:10.1371/journal.pone.0118659
PMCID: PMC4353622  PMID: 25751257
14.  Association of Gamma-Aminobutyric Acid A Receptor α2 Gene (GABRA2) with Alcohol Use Disorder 
Neuropsychopharmacology  2013;39(4):907-918.
Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in mammalian brain. GABA receptor are involved in a number of complex disorders, including substance abuse. No variants of the commonly studied GABA receptor genes that have been associated with substance dependence have been determined to be functional or pathogenic. To reconcile the conflicting associations with substance dependence traits, we performed a meta-analysis of variants in the GABAA receptor genes (GABRB2, GABRA6, GABRA1, and GABRG2 on chromosome 5q and GABRA2 on chromosome 4p12) using genotype data from 4739 cases of alcohol, opioid, or methamphetamine dependence and 4924 controls. Then, we combined the data from candidate gene association studies in the literature with two alcohol dependence (AD) samples, including 1691 cases and 1712 controls from the Study of Addiction: Genetics and Environment (SAGE), and 2644 cases and 494 controls from our own study. Using a Bonferroni-corrected threshold of 0.007, we found strong associations between GABRA2 and AD (P=9 × 10−6 and odds ratio (OR) 95% confidence interval (CI)=1.27 (1.15, 1.4) for rs567926, P=4 × 10−5 and OR=1.21 (1.1, 1.32) for rs279858), and between GABRG2 and both dependence on alcohol and dependence on heroin (P=0.0005 and OR=1.22 (1.09, 1.37) for rs211014). Significant association was also observed between GABRA6 rs3219151 and AD. The GABRA2 rs279858 association was observed in the SAGE data sets with a combined P of 9 × 10−6 (OR=1.17 (1.09, 1.26)). When all of these data sets, including our samples, were meta-analyzed, associations of both GABRA2 single-nucleotide polymorphisms remained (for rs567926, P=7 × 10−5 (OR=1.18 (1.09, 1.29)) in all the studies, and P=8 × 10−6 (OR=1.25 (1.13, 1.38)) in subjects of European ancestry and for rs279858, P=5 × 10−6 (OR=1.18 (1.1, 1.26)) in subjects of European ancestry. Findings from this extensive meta-analysis of five GABAA receptor genes and substance abuse support their involvement (with the best evidence for GABRA2) in the pathogenesis of AD. Further replications with larger samples are warranted.
doi:10.1038/npp.2013.291
PMCID: PMC3924525  PMID: 24136292
addiction and substance abuse; alcohol and alcoholism; association; biological psychiatry; GABA; gamma-aminobutyric acid receptor; meta-analysis; addiction; gamma-aminobutyric acid receptor; association; meta-analysis; susceptibility gene
15.  Association of the HTR2A Gene with Alcohol and Heroin Abuse 
Human genetics  2013;133(3):357-365.
Positive genetic associations of rs6313 (102T/C at exon 1) and rs6311 (-1438A/G) on the 5-hydroxytryptamine (serotonin) 2A receptor gene (HTR2A or 5-HT2A) were reported for alcohol and drug abuse, however, other association studies failed to produce consistent results supporting the susceptibility of the two single nucleotide polymorphisms (SNPs). To clarify the associations of the HTR2A gene with substance use disorders, we performed a meta-analysis based on the genotypes from the available candidate gene association studies of the two SNPs with alcohol and drug abuse from multiple populations. Evidence of association was found for HTR2A rs6313 in all the combined studies (e.g., allelic P = 0.0048 and OR = 0.86, 95% CI 0.77 – 0.95) and also in the combined studies of alcohol dependence (abuse) (e.g., allelic P = 0.0001 and OR = 0.71, 95% CI 0.59 – 0.85). The same association trend was also observed in the SAGE (Study of Addiction: Genetics and Environment) datasets. The meta-analysis supports a contribution of the HTR2A gene to the susceptibility to substance use disorders, particularly alcohol dependence.
doi:10.1007/s00439-013-1388-y
PMCID: PMC4085799  PMID: 24178752
Meta-analysis; Addiction; Linkage Disequilibrium; Heterogeneity; Synaptic Terminal
16.  A new mouse model for wound healing in hemophilia A 
Purpose: To establish a new mouse model for wound healing studies on hemophilia A. Methods: Total 54 male mice with different genotypes including wild-type nude mice, heterozygous mice (FVIII-/-/Nu) and FVIII deficient mice (FVIII-/-) were generated and verified by PCR. Mice were subjected to wound healing research by making a 5 mm-thickness wound on mice skin and applying recombinant human epidermal growth factor (EGF, 10 μg/g) ointment, FVIII ointment (30 IU) or the ointment base to heal the wounds. Furthermore, keratinocytes were isolated from these newborn mice and subjected to migration assay by stimulation of EGF (ng/ml), insulin (10 μM) or vehicle. Results: A new hemophilic mouse model (FVIII-/-/Nu) was constructed successfully after genotyping verified by PCR. Compared to FVIII-/- mice, FVIII-/-/Nu and Nu mice showed greater degree of wound contraction and loss of the crust. Topical treatment with EGF exhibited faster wound healing than FVIII and ointment base. Insulin treatment showed more increased migration distance than treated with EGF or vehicle. FVIII-/-/Nu mice showed greater migration than FVIII-/- and Nu mice. Conclusions: A new mouse model (FVIII-/-/Nu) for wound healing in hemophilia A was constructed, and topical treatment of insulin may be a better therapy than EGF for healing wounds in hemophilia A.
PMCID: PMC4440121  PMID: 26045812
Wound healing; keratinocytes; recombinant human epidermal growth factor; insulin
17.  The Microgeographical Patterns of Morphological and Molecular Variation of a Mixed Ploidy Population in the Species Complex Actinidia chinensis 
PLoS ONE  2015;10(2):e0117596.
Polyploidy and hybridization are thought to have significant impacts on both the evolution and diversification of the genus Actinidia, but the structure and patterns of morphology and molecular diversity relating to ploidy variation of wild Actinidia plants remain much less understood. Here, we examine the distribution of morphological variation and ploidy levels along geographic and environmental variables of a large mixed-ploidy population of the A. chinensis species complex. We then characterize the extent of both genetic and epigenetic diversity and differentiation exhibited between individuals of different ploidy levels. Our results showed that while there are three ploidy levels in this population, hexaploids were constituted the majority (70.3%). Individuals with different ploidy levels were microgeographically structured in relation to elevation and extent of niche disturbance. The morphological characters examined revealed clear difference between diploids and hexaploids, however tetraploids exhibited intermediate forms. Both genetic and epigenetic diversity were high but the differentiation among cytotypes was weak, suggesting extensive gene flow and/or shared ancestral variation occurred in this population even across ploidy levels. Epigenetic variation was clearly correlated with changes in altitudes, a trend of continuous genetic variation and gradual increase of epigenomic heterogeneities of individuals was also observed. Our results show that complex interactions between the locally microgeographical environment, ploidy and gene flow impact A. chinensis genetic and epigenetic variation. We posit that an increase in ploidy does not broaden the species habitat range, but rather permits A. chinensis adaptation to specific niches.
doi:10.1371/journal.pone.0117596
PMCID: PMC4319829  PMID: 25658107
18.  Digitization and Visualization of Greenhouse Tomato Plants in Indoor Environments 
Sensors (Basel, Switzerland)  2015;15(2):4019-4051.
This paper is concerned with the digitization and visualization of potted greenhouse tomato plants in indoor environments. For the digitization, an inexpensive and efficient commercial stereo sensor—a Microsoft Kinect—is used to separate visual information about tomato plants from background. Based on the Kinect, a 4-step approach that can automatically detect and segment stems of tomato plants is proposed, including acquisition and preprocessing of image data, detection of stem segments, removing false detections and automatic segmentation of stem segments. Correctly segmented texture samples including stems and leaves are then stored in a texture database for further usage. Two types of tomato plants—the cherry tomato variety and the ordinary variety are studied in this paper. The stem detection accuracy (under a simulated greenhouse environment) for the cherry tomato variety is 98.4% at a true positive rate of 78.0%, whereas the detection accuracy for the ordinary variety is 94.5% at a true positive of 72.5%. In visualization, we combine L-system theory and digitized tomato organ texture data to build realistic 3D virtual tomato plant models that are capable of exhibiting various structures and poses in real time. In particular, we also simulate the growth process on virtual tomato plants by exerting controls on two L-systems via parameters concerning the age and the form of lateral branches. This research may provide useful visual cues for improving intelligent greenhouse control systems and meanwhile may facilitate research on artificial organisms.
doi:10.3390/s150204019
PMCID: PMC4367398  PMID: 25675284
plant digitization; plant visualization; stem detection; L-system; tomato plant; greenhouse climate control
19.  Maternal High-Salt Intake During Pregnancy Reprogrammed Renin–Angiotensin System-Mediated Cardiomyocyte Apoptosis in the Adult Offspring Heart 
Reproductive Sciences  2014;21(1):52-62.
Aims:
Excess salt intake during pregnancy may alter fetal organ structures and functions leading to increased risks in the development of cardiovascular diseases in later life. The present study determined whether and how the prenatal high-salt (HS) diets affect renin–angiotensin system (RAS) that may mediate cardiac cell death.
Methods and Results:
Angiotensin II receptors, AT1 and AT2, protein expression was increased in the myocardium of the offspring exposed to prenatal HS; apoptotic cells appeared in the myocardium of the adult offspring. Mitochondrion was isolated in cell experiments, and the data showed cardiomyocyte apoptosis requiring cytochrome C release. Pretreating H9C2 cells with AT2 agonist CGP42112A induced cell apoptosis in DNA fragments and activated caspase 3. CGP42112A increased mitochondrion cytochrome C release and apoptosis in the cells.
Conclusion:
Both in vitro and in vivo study demonstrated that cardiomyocyte apoptosis was related to AT2 activation. Prenatal HS diets may reprogram RAS that mediates apoptosis in the offspring myocardium, and AT2 may contribute to cardiomyocyte apoptosis via the cytochrome C release pathway.
doi:10.1177/1933719113488447
PMCID: PMC3857761  PMID: 23690339
angiotensin receptors; high salt; apoptosis; offspring heart
20.  FOXM1 Promotes Lung Adenocarcinoma Invasion and Metastasis by Upregulating SNAIL 
The forkhead box M1 (FOXM1) transcription factor is one of the key genes inducing tumor invasion and metastasis by an unknown mechanism. In this study, we set out to investigate the effects of FOXM1 overexpression on metastatic human lung adenocarcinoma and the underlying mechanism. FOXM1 expression was analyzed in 78 frozen lung adenocarcinoma tissue samples using an Affymetrix microarray and a 155-paraffin-embedded lung adenocarcinoma tissue microarray with immunohistochemical detection. FOXM1 was found to be overexpressed in lung adenocarcinoma, particularly in metastatic patients, compared to non-metastatic patients. Knockdown of FOXM1 by a specific siRNA significantly suppressed EMT progression, migration and invasion of lung adenocarcinoma cells in vitro, and tumor growth and metastasis in vivo, whereas restored expression of FOXM1 had the opposite effect. FOXM1 binds directly to the SNAIL promoter through two specific binding sites and constitutively transactivates it. Collectively, our findings indicate that FOXM1 may play an important role in advancing lung adenocarcinoma progression. Aberrant FOXM1 expression directly and constitutively activates SNAIL, thereby promoting lung adenocarcinoma metastasis. Inhibition of FOXM1-SNAIL signaling may present an ideal target for future treatment.
doi:10.7150/ijbs.10634
PMCID: PMC4279094  PMID: 25561901
Lung adenocarcinoma; Invasion; Metastasis; FOXM1; SNAIL
21.  Increased number of negative lymph nodes is associated with improved cancer specific survival in pathological IIIB and IIIC rectal cancer treated with preoperative radiotherapy 
Oncotarget  2014;5(23):12459-12471.
Preoperative radiation significantly decreases the number of retrieved lymph nodes (LNs) in rectal cancer, but little is known with respect to the prognostic significance of negative LN (NLN) counts under these circumstances. In this study, Surveillance, Epidemiology, and End Results Program (SEER)-registered ypIII stage rectal cancer patients, and patients from Fudan University Shanghai Cancer Center (FDSCC) were combined and analyzed. The results showed that the survival rate of patients with n (cutoff) or more NLNs increased gradually when n ranged from two to nine. After n reached 10 or greater, survival rates were approximately equivalent. Furthermore, the optimal cutoff value of 10 was validated as an independent prognostic factor in stage ypIIIB and ypIIIC patients by both univariate and multivariate analysis (P < 0.001); the number of NLNs could also stratify the prognosis of ypN(+) patients in more detail. Patients in the FDSCC set validated these findings and confirmed that NLN count was not decreased in the good tumor regression group relative to the poor tumor regression group. These results suggest that NLN count is an independent prognostic factor for ypIIIB and ypIIIC rectal cancer patients, and, together with the number of positive LNs, this will provide better prognostic information than the number of positive LNs alone.
PMCID: PMC4323013  PMID: 25514596
Rectal cancer; negative lymph nodes; prognosis; SEER
22.  Expression of Aquaporin 4 and Breakdown of the Blood-Brain Barrier after Hypoglycemia-Induced Brain Edema in Rats 
PLoS ONE  2014;9(9):e107022.
Background
Hypoglycemia-induced brain edema is a severe clinical event that often results in death. The mechanisms by which hypoglycemia induces brain edema are unclear.
Methods
In a hypoglycemic injury model established in adult rats, brain edema was verified by measuring brain water content and visualizing water accumulation using hematoxylin and eosin staining. Temporal expression of aquaporin 4 (AQP4) and the integrity of the blood-brain barrier (BBB) were evaluated. We assessed the distribution and expression of AQP4 following glucose deprivation in astrocyte cultures.
Results
Brain edema was induced immediately after severe hypoglycemia but continued to progress even after recovery from hypoglycemia. Upregulation of AQP4 expression and moderate breakdown of the BBB were observed 24 h after recovery. In vitro, significant redistribution of AQP4 to the plasma membrane was induced following 6 h glucose deprivation.
Conclusion
Hypoglycemia-induced brain edema is caused by cytotoxic and vasogenic factors. Changes in AQP4 location and expression may play a protective role in edema resolution.
doi:10.1371/journal.pone.0107022
PMCID: PMC4180270  PMID: 25264602
24.  Relating gene expression evolution with CpG content changes 
BMC Genomics  2014;15(1):693.
Background
Previous studies have shown that CpG dinucleotides are enriched in a subset of promoters and the CpG content of promoters is positively correlated with gene expression levels. But the relationship between divergence of CpG content and gene expression evolution has not been investigated. Here we calculate the normalized CpG (nCpG) content in DNA regions around transcription start site (TSS) and transcription terminal site (TTS) of genes in nine organisms, and relate them with expression levels measured by RNA-seq.
Results
The nCpG content of TSS shows a bimodal distribution in all organisms except platypus, whereas the nCpG content of TTS only has a single peak. When the nCpG contents are compared between different organisms, we observe a different evolution pattern between TSS and TTS: compared with TTS, TSS exhibits a faster divergence rate between closely related species but are more conserved between distant species. More importantly, we demonstrate the link between gene expression evolution and nCpG content changes: up-/down- regulation of genes in an organism is accompanied by the nCpG content increase/decrease in their TSS and TTS proximal regions.
Conclusions
Our results suggest that gene expression changes between different organisms are correlated with the alterations in normalized CpG contents of promoters. Our analyses provide evidences for the impact of nCpG content on gene expression evolution.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-693) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2164-15-693
PMCID: PMC4148958  PMID: 25142157
25.  Multi-Cultural Association of the Serotonin Transporter Gene (SLC6A4) with Substance Use Disorder 
Neuropsychopharmacology  2013;38(9):1737-1747.
A number of studies have reported associations between the serotonin transporter gene (SLC6A4) and alcohol, heroin, cocaine, or methamphetamine abuse. Other studies have yielded contrary results. There are a number of reasons for non-replication, including inadequate statistical power, population stratification, and poor phenotype definition. This study was to test the association using a meta-analytic approach across a variety of racial and ethnic populations. Using the genotype data of 55 studies (7999 cases, 8264 controls, and 676 families or parent-offspring trios) published in the past 15 years, we have conducted comprehensive meta-analyses to examine the associations of the 5-HTTLPR and STin2 polymorphisms with substance use disorder. The meta-analyses support the associations of 5-HTTLPR with alcohol, heroin, cocaine, and methamphetamine dependence and abuse (eg, the smallest P-values were 0.0058 with odds ratio (OR)=0.54 (0.35, 0.84); 0.0024 with OR=0.77 (0.66, 0.91); 0.018 with OR=1.38 (1.06, 1.81); and 0.028 with OR=0.46 (0.23, 0.92) for alcohol, heroin, cocaine, and methamphetamine dependence/abuse, respectively). When all the phenotypes are combined, the P-value was 0.0006 with OR=0.86 (0.78, 0.94) in the combined European, Asian, and Mexican populations and P-value was 0.0028 with OR=1.41 (1.13, 1.78) in the African populations. Evidence of significant associations was also identified in other subgroup analyses regarding differently combined substance and populations. The effect sizes of 5-HTTLPR were comparable among the European, Asian, and Mexican populations, however, the risk allele was more frequent in Asians than in Europeans and Mexicans. The opposite directions of risk allele in African population might be driven by the opposite directions of risk allele in cocaine dependence. This meta-analysis supports that the association of the SLC6A4 gene with substance use disorder varies depending on substances with different risk allele frequencies in the multi-cultural populations. Further studies using larger sample size are warranted.
doi:10.1038/npp.2013.73
PMCID: PMC3717550  PMID: 23518607
addiction & substance abuse; alcohol & alcoholism; behavioral science; genetic association; meta-analysis; serotonin; meta-analysis; association; serotonin transporter; addiction; common genetic risk

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