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1.  Myosin-II controls cellular branching morphogenesis and migration in 3D by minimizing cell surface curvature 
Nature cell biology  2015;17(2):137-147.
In many cases cell function is intimately linked to cell shape control. We utilized endothelial cell branching morphogenesis as a model to understand the role of myosin-II in shape control of invasive cells migrating in 3D collagen gels. We applied principles of differential geometry and mathematical morphology to 3D image sets to parameterize cell branch structure and local cell surface curvature. We find that Rho/ROCK-stimulated myosin-II contractility minimizes cell-scale branching by recognizing and minimizing local cell surface curvature. Utilizing micro-fabrication to constrain cell shape identifies a positive feedback mechanism in which low curvature stabilizes myosin-II cortical association, where it acts to maintain minimal curvature. The feedback between myosin-II regulation by and control of curvature drives cycles of localized cortical myosin-II assembly and disassembly. These cycles in turn mediate alternating phases of directionally biased branch initiation and retraction to guide 3D cell migration.
doi:10.1038/ncb3092
PMCID: PMC4312523  PMID: 25621949
2.  Inferring drug-disease associations based on known protein complexes 
BMC Medical Genomics  2015;8(Suppl 2):S2.
Inferring drug-disease associations is critical in unveiling disease mechanisms, as well as discovering novel functions of available drugs, or drug repositioning. Previous work is primarily based on drug-gene-disease relationship, which throws away many important information since genes execute their functions through interacting others. To overcome this issue, we propose a novel methodology that discover the drug-disease association based on protein complexes. Firstly, the integrated heterogeneous network consisting of drugs, protein complexes, and disease are constructed, where we assign weights to the drug-disease association by using probability. Then, from the tripartite network, we get the indirect weighted relationships between drugs and diseases. The larger the weight, the higher the reliability of the correlation. We apply our method to mental disorders and hypertension, and validate the result by using comparative toxicogenomics database. Our ranked results can be directly reinforced by existing biomedical literature, suggesting that our proposed method obtains higher specificity and sensitivity. The proposed method offers new insight into drug-disease discovery. Our method is publicly available at http://1.complexdrug.sinaapp.com/Drug_Complex_Disease/Data_Download.html.
doi:10.1186/1755-8794-8-S2-S2
PMCID: PMC4460611  PMID: 26044949
Drug-disease associations; protein complexes; drug repositioning; weighted network
3.  Granger causal time-dependent source connectivity in the somatosensory network 
Scientific Reports  2015;5:10399.
Exploration of transient Granger causal interactions in neural sources of electrophysiological activities provides deeper insights into brain information processing mechanisms. However, the underlying neural patterns are confounded by time-dependent dynamics, non-stationarity and observational noise contamination. Here we investigate transient Granger causal interactions using source time-series of somatosensory evoked magnetoencephalographic (MEG) elicited by air puff stimulation of right index finger and recorded using 306-channel MEG from 21 healthy subjects. A new time-varying connectivity approach, combining renormalised partial directed coherence with state space modelling, is employed to estimate fast changing information flow among the sources. Source analysis confirmed that somatosensory evoked MEG was mainly generated from the contralateral primary somatosensory cortex (SI) and bilateral secondary somatosensory cortices (SII). Transient Granger causality shows a serial processing of somatosensory information, 1) from contralateral SI to contralateral SII, 2) from contralateral SI to ipsilateral SII, 3) from contralateral SII to contralateral SI, and 4) from contralateral SII to ipsilateral SII. These results are consistent with established anatomical connectivity between somatosensory regions and previous source modeling results, thereby providing empirical validation of the time-varying connectivity analysis. We argue that the suggested approach provides novel information regarding transient cortical dynamic connectivity, which previous approaches could not assess.
doi:10.1038/srep10399
PMCID: PMC4441010  PMID: 25997414
4.  Identifying module biomarker in type 2 diabetes mellitus by discriminative area of functional activity 
BMC Bioinformatics  2015;16(1):92.
Background
Identifying diagnosis and prognosis biomarkers from expression profiling data is of great significance for achieving personalized medicine and designing therapeutic strategy in complex diseases. However, the reproducibility of identified biomarkers across tissues and experiments is still a challenge for this issue.
Results
We propose a strategy based on discriminative area of module activities to identify gene biomarkers which interconnect as a subnetwork or module by integrating gene expression data and protein-protein interactions. Then, we implement the procedure in T2DM as a case study and identify a module biomarker with 32 genes from mRNA expression data in skeletal muscle for T2DM. This module biomarker is enriched with known causal genes and related functions of T2DM. Further analysis shows that the module biomarker is of superior performance in classification, and has consistently high accuracies across tissues and experiments.
Conclusion
The proposed approach can efficiently identify robust and functionally meaningful module biomarkers in T2DM, and could be employed in biomarker discovery of other complex diseases characterized by expression profiles.
Electronic supplementary material
The online version of this article (doi:10.1186/s12859-015-0519-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s12859-015-0519-y
PMCID: PMC4374500  PMID: 25888350
Computational biology; Gene expression profiling; Network biomarker; Type 2 diabetes mellitus
5.  Identifying overlapping mutated driver pathways by constructing gene networks in cancer 
BMC Bioinformatics  2015;16(Suppl 5):S3.
Background
Large-scale cancer genomic projects are providing lots of data on genomic, epigenomic and gene expression aberrations in many cancer types. One key challenge is to detect functional driver pathways and to filter out nonfunctional passenger genes in cancer genomics. Vandin et al. introduced the Maximum Weight Sub-matrix Problem to find driver pathways and showed that it is an NP-hard problem.
Methods
To find a better solution and solve the problem more efficiently, we present a network-based method (NBM) to detect overlapping driver pathways automatically. This algorithm can directly find driver pathways or gene sets de novo from somatic mutation data utilizing two combinatorial properties, high coverage and high exclusivity, without any prior information. We firstly construct gene networks based on the approximate exclusivity between each pair of genes using somatic mutation data from many cancer patients. Secondly, we present a new greedy strategy to add or remove genes for obtaining overlapping gene sets with driver mutations according to the properties of high exclusivity and high coverage.
Results
To assess the efficiency of the proposed NBM, we apply the method on simulated data and compare results obtained from the NBM, RME, Dendrix and Multi-Dendrix. NBM obtains optimal results in less than nine seconds on a conventional computer and the time complexity is much less than the three other methods. To further verify the performance of NBM, we apply the method to analyze somatic mutation data from five real biological data sets such as the mutation profiles of 90 glioblastoma tumor samples and 163 lung carcinoma samples. NBM detects groups of genes which overlap with known pathways, including P53, RB and RTK/RAS/PI(3)K signaling pathways. New gene sets with p-value less than 1e-3 are found from the somatic mutation data.
Conclusions
NBM can detect more biologically relevant gene sets. Results show that NBM outperforms other algorithms for detecting driver pathways or gene sets. Further research will be conducted with the use of novel machine learning techniques.
doi:10.1186/1471-2105-16-S5-S3
PMCID: PMC4402595  PMID: 25859819
Driver pathways; Network-based method; Somatic mutations; High coverage; High exclusivity
6.  Early enteral and parenteral nutritional support after hepatectomy in patients with hepatic carcinoma: a systematic review and meta-analysis 
OncoTargets and therapy  2015;8:623-631.
Background
This study sought to conduct a systematic review providing a comparative analysis of enteral nutrition (EN) and parenteral nutrition (PN) after hepatectomy.
Methods
PubMed, Embase, and the China National Knowledge Infrastructure databases were searched for publications describing randomized controlled trials that compared early EN and PN after hepatectomy. The time period for this search was from January 1990 to December 2013. In accordance with the inclusion criteria of this study, two researchers independently screened the retrieved literature, extracted data, and assessed methodological quality. A meta-analysis of the included publications was then performed using RevMan 5.2 software.
Results
The meta-analysis results indicated statistically significant differences between the group that received EN and the group that received PN during the early stages after hepatectomy with respect to average total bilirubin and alanine aminotransferase levels after nutrition, pre-albumin levels, incidence of diarrhea and abdominal bloating, time to flatus, and average cost of nutrition. To varying degrees, better results were observed in the EN group than in the PN group for these metrics.
Conclusion
During the early stages after hepatectomy, EN has obvious advantages relative to PN; thus, EN merits more widespread promotion and application in this clinical context.
doi:10.2147/OTT.S73275
PMCID: PMC4360806  PMID: 25792846
hepatectomy; enteral nutrition; parenteral nutrition; systematic review; meta-analysis
7.  Anti-inflammatory effect of 1,25-dihydroxyvitamin D3 is associated with crosstalk between signal transducer and activator of transcription 5 and the vitamin D receptor in human monocytes 
1,25-Dihydroxyvitamin D3 (1,25-(OH)2D3) has an anti-inflammatory effect on human monocytes incubated with sera from patients with type 2 diabetes/diabetic nephropathy; however, the detailed mechanism behind the effect remains to be explored. The current study further validated the effects of 1,25-(OH)2D3 and lipopolysaccharide (LPS) + human recombinant interleukin (IL)-15 on the expression of the vitamin D receptor (VDR) and phosphorylated signal transducer and activator of transcription 5 (p-STAT5) in human monocytes and explored the possible interaction between VDR and p-STAT5. Synchronized THP-1 cells were divided into pre-intervened groups, namely the control, LPS + IL-15 and 1,25-(OH)2D3, groups, according to their differing treatments. The expression of STAT5 and p-STAT5 was evaluated by western blot analysis; the concentration of IL-6 in the supernatant was determined using an enzyme-linked immunosorbent assay; the expression of cytoskeletal proteins was observed using immunofluorescence and laser confocal microscopy; and the possible intranuclear interaction between VDR and p-STAT5 was investigated using immunofluorescence, immuno-coprecipitation and western blot analysis. LPS + IL-15 upregulated p-STAT5 expression and the IL-6 level (P<0.05), with cytoskeletal rearrangement. These effects were partially prevented through pretreatment with 1,25-(OH)2D3. The LPS + IL-15 group and the 1,25-(OH)2D3 group exhibited an interaction between p-STAT5 and VDR in the nucleus, with the latter group showing a significant increase compared with the former (P<0.05). The immuno-coprecipitation results provided evidence of the interaction between VDR and p-STAT5, which suggests the existence of STAT5-VDR crosstalk in THP-1 monocytes. Cytoskeletal rearrangement, VDR and p-STAT5 potentially have interactions in THP-1 monocytes. The anti-inflammatory effect of 1,25-(OH)2D3 may be associated with crosstalk between STAT5 and VDR, which further induces cytoskeletal rearrangement.
doi:10.3892/etm.2015.2321
PMCID: PMC4471802  PMID: 26136886
1,25-dihydroxyvitamin D3; monocyte; lipopolysaccharide; interleukin-15; vitamin D receptor; signal transducer and transcription activator
8.  HPOSim: An R Package for Phenotypic Similarity Measure and Enrichment Analysis Based on the Human Phenotype Ontology 
PLoS ONE  2015;10(2):e0115692.
Background
Phenotypic features associated with genes and diseases play an important role in disease-related studies and most of the available methods focus solely on the Online Mendelian Inheritance in Man (OMIM) database without considering the controlled vocabulary. The Human Phenotype Ontology (HPO) provides a standardized and controlled vocabulary covering phenotypic abnormalities in human diseases, and becomes a comprehensive resource for computational analysis of human disease phenotypes. Most of the existing HPO-based software tools cannot be used offline and provide only few similarity measures. Therefore, there is a critical need for developing a comprehensive and offline software for phenotypic features similarity based on HPO.
Results
HPOSim is an R package for analyzing phenotypic similarity for genes and diseases based on HPO data. Seven commonly used semantic similarity measures are implemented in HPOSim. Enrichment analysis of gene sets and disease sets are also implemented, including hypergeometric enrichment analysis and network ontology analysis (NOA).
Conclusions
HPOSim can be used to predict disease genes and explore disease-related function of gene modules. HPOSim is open source and freely available at SourceForge (https://sourceforge.net/p/hposim/).
doi:10.1371/journal.pone.0115692
PMCID: PMC4321842  PMID: 25664462
9.  Sustained activation of c-Jun N-terminal and extracellular signal-regulated kinases in port-wine stain blood vessels 
Background
Port-wine stain (PWS) is a congenital, progressive vascular malformation but the pathogenesis remains incompletely understood.
Objective
We sought to investigate the activation status of various kinases, including extracellular signal-regulated kinase, c-Jun N-terminal kinase, AKT, phosphatidylinositol 3-kinase, P70 ribosomal S6 kinase, and phosphoinositide phospholipase C γ subunit, in PWS biopsy tissues.
Methods
Immunohistochemistry was performed on 19 skin biopsy samples from 11 patients with PWS.
Results
c-Jun N-terminal kinase, extracellular signal-regulated kinase, and P70 ribosomal S6 kinase in pediatric and adult PWS blood vessels were consecutively activated. Activation of AKT and phosphatidylinositol 3-kinase was found in many adult hypertrophic PWS blood vessels but not in infants. Phosphoinositide phospholipase C γ subunit showed strong activation in nodular PWS blood vessels.
Limitation
Infantile PWS sample size was small.
Conclusion
Our data suggest a subsequent activation profile of various kinases during different stages of PWS: (1) c-Jun N-terminal and extracellular signal-regulated kinases are firstly and consecutively activated in all PWS tissues, which may contribute to both the pathogenesis and progressive development of PWS; (2) AKT and phosphatidylinositol 3-kinase are subsequently activated, and are involved in the hypertrophic development of PWS blood vessels; and (3) phosphoinositide phospholipase C γ subunit is activated in the most advanced stage of PWS and may participate in nodular formation.
doi:10.1016/j.jaad.2014.07.025
PMCID: PMC4250318  PMID: 25135651
AKT; c-Jun N-terminal kinase; extracellular signal-regulated kinase; mitogen-activated protein kinase; port-wine stain; vascular malformation
10.  A single-nucleotide polymorphism of miR-146a and psoriasis: an association and functional study 
Epidermal growth factor receptor (EGFR), which is overexpressed in psoriatic lesions, has been proven to contribute to the hyperproliferation of keratinocytes in psoriasis. Single nucleotide polymorphisms (SNPs) involved in miRNAs that can regulate the expression of EGFR could potentially influence the development of psoriasis. The present study investigated the association between a functional SNP of rs2910164 in miR-146a and the risk of psoriasis in the Chinese Han population. A total of 521 Han Chinese patients with psoriasis and 582 healthy controls were recruited in this study. The miR-146a rs2910164 SNP was genotyped by polymerase chain reaction-restriction fragment length polymorphism. Overall, a significantly increased risk of psoriasis was associated with the rs2910164 miR-146a CG and GG genotypes (adjusted OR, 1.38; 95% CI, 1.06–1.80). Furthermore, the rs2910164G allele in miR-146a attenuated its inhibitory regulation on the expression of EGFR as well as the proliferation of human keratinocytes, and lowered the level of miR-146a in the psoriatic lesions. These findings indicate that the rs2910164G allele in miR-146a weakens its suppression on the proliferation of keratinocytes probably through the decreased inhibition of the target gene, EGFR, which may account for the increased risk of psoriasis in this study population.
doi:10.1111/jcmm.12359
PMCID: PMC4224556  PMID: 25209759
psoriasis; microRNA; SNP; miR-146a; EGFR
11.  Epidemiology of dyslipidemia in Chinese adults: meta-analysis of prevalence, awareness, treatment, and control 
Background
Numerous epidemiology studies on dyslipidemia have been conducted in China. However, a nationally representative estimate for dyslipidemia prevalence is lacking. The aim of this study is to appraise the nationwide prevalence, awareness, treatment, and control rates of dyslipidemia in adults in China.
Methods
We performed a systematic review of the related observational studies published since 2003 by searching English and Chinese literature databases. Meta-analyses were conducted in eligible studies using a random effect model to summarize the dyslipidemia prevalence, awareness, treatment, and control rates. Heterogeneity and publication bias were analyzed. Sensitivity analyses were performed to explain heterogeneity and examine the impact of study quality on the results of meta-analyses.
Results
Thirty-eight papers were included for meta-analyses, with a total sample size of 387,825. The prevalence, awareness, treatment, and control rates of dyslipidemia were 41.9% (95% CI: 37.7% – 46.2%), 24.4% (95% CI: 14.4% – 38.4%), 8.8% (95% CI: 7.7% – 10.0%), and 4.3% (95% CI: 4.1% – 4.5%), respectively. The prevalence of hypercholesterolemia, hypertriglyceridemia, mixed hyperlipidemia, low levels of high-density lipoprotein cholesterol, and high levels of low-density lipoprotein cholesterol were 10.1% (95% CI: 5.8% – 16.9%), 17.7% (95% CI: 14.0% – 22.1%), 5.1% (95% CI: 3.1% – 8.2%), 11.0% (95% CI: 8.0% – 15.0%), and 8.8% (95% CI: 4.1% – 17.8%), respectively. Sensitivity analyses revealed that males had a higher prevalence of dyslipidemia (43.2%) than females (35.6%). Study samples of age 30 and above in the eastern region tended to have higher prevalence of dyslipidemia. The quality of the studies has a slight impact on the pooled estimates.
Conclusions
The overall pooled prevalence of dyslipidemia in Chinese adults was estimated to be 41.9%, with males having a higher rate than females.
Electronic supplementary material
The online version of this article (doi:10.1186/s12963-014-0028-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12963-014-0028-7
PMCID: PMC4219092  PMID: 25371655
Dyslipidemia; Prevalence; Awareness rate; Treatment rate; Control rate; Meta-analysis
12.  Glucose sensing by carotid body glomus cells: potential implications in disease 
The carotid body (CB) is a key chemoreceptor organ in which glomus cells sense changes in blood O2, CO2, and pH levels. CB glomus cells have also been found to detect hypoglycemia in both non-primate mammals and humans. O2 and low-glucose responses share a common final pathway involving membrane depolarization, extracellular calcium influx, increase in cytosolic calcium concentration, and neurotransmitter secretion, which stimulates afferent sensory fibers to evoke sympathoadrenal activation. On the other hand, hypoxia and low glucose induce separate signal transduction pathways. Unlike O2 sensing, the response of the CB to low glucose is not altered by rotenone, with the low glucose-activated background cationic current unaffected by hypoxia. Responses of the CB to hypoglycemia and hypoxia can be potentiated by each other. The counter-regulatory response to hypoglycemia by the CB is essential for the brain, an organ that is particularly sensitive to low glucose. CB glucose sensing could be altered in diabetic patients, particularly those under insulin treatment, as well as in other medical conditions such as sleep apnea or obstructive pulmonary diseases, where chronic hypoxemia presents with plastic modifications in CB structure and function. The current review will focus on the following main aspects: (1) the CB as a low glucose sensor in both in vitro and in vivo models; (2) molecular and ionic mechanisms of low glucose sensing by glomus cells, (3) the interplay between low glucose and O2 sensing in CB, and (4) the role of CB low glucose sensing in the pathophysiology of cardiorespiratory and metabolic diseases, and how this may serve as a potential therapeutic target.
doi:10.3389/fphys.2014.00398
PMCID: PMC4197775  PMID: 25360117
carotid body; glucose sensing; O2 sensing; hypoglycemia; intermittent hypoxia; sleep apnea; chronic hypoxia; diabetes
13.  Novel Role of Kallistatin in Vascular Repair by Promoting Mobility, Viability, and Function of Endothelial Progenitor Cells 
Background
Kallistatin exerts pleiotropic activities in inhibiting inflammation, apoptosis, and oxidative stress in endothelial cells. Because endothelial progenitor cells (EPCs) play a significant role in vascular repair, we investigated whether kallistatin contributes to vascular regeneration by enhancing EPC migration and function.
Methods and Results
We examined the effect of endogenous kallistatin on circulating EPCs in a rat model of vascular injury and the mechanisms of kallistatin on EPC mobility and function in vitro. In deoxycorticosterone acetate–salt hypertensive rats, we found that kallistatin depletion augmented glomerular endothelial cell loss and diminished circulating EPC number, whereas kallistatin gene delivery increased EPC levels. In cultured EPCs, kallistatin significantly reduced tumor necrosis factor‐α–induced apoptosis and caspase‐3 activity, but kallistatin's effects were blocked by phosphoinositide 3‐kinase inhibitor (LY294002) and nitric oxide (NO) synthase inhibitor (l‐NAME). Kallistatin stimulated the proliferation, migration, adhesion and tube formation of EPCs; however, kallistatin's actions were abolished by LY294002, l‐NAME, endothelial NO synthase–small interfering RNA, constitutively active glycogen synthase kinase‐3β, or vascular endothelial growth factor antibody. Kallistatin also increased Akt, glycogen synthase kinase‐3β, and endothelial NO synthase phosphorylation; endothelial NO synthase, vascular endothelial growth factor, and matrix metalloproteinase‐2 synthesis and activity; and NO and vascular endothelial growth factor levels. Kallistatin's actions on phosphoinositide 3‐kinase–Akt signaling were blocked by LY294002, l‐NAME, and anti–vascular endothelial growth factor antibody.
Conclusions
Endogenous kallistatin plays a novel role in protection against vascular injury in hypertensive rats by promoting the mobility, viability, and vasculogenic capacity of EPCs via enhancing NO and vascular endothelial growth factor levels through activation of phosphoinositide 3‐kinase–Akt signaling. Kallistatin therapy may be a promising approach in the treatment of vascular diseases.
doi:10.1161/JAHA.114.001194
PMCID: PMC4323828  PMID: 25237049
angiogenesis; apoptosis; endothelial progenitor cells; kallistatin; nitric oxide
14.  ROCK Is Involved in Vasculogenic Mimicry Formation in Hepatocellular Carcinoma Cell Line 
PLoS ONE  2014;9(9):e107661.
Ras homolog family member A (RhoA) and Rho-associated coiled coil-containing protein kinases 1 and 2 (ROCK1 and 2) are key regulators of focal adhesion, actomyosin contraction and cell motility. RhoA/ROCK signaling has emerged as an attractive target for the development of new cancer therapeutics. Whether RhoA/ROCK is involved in regulating the formation of tumor cell vasculogenic mimicry (VM) is largely unknown. To confirm this hypothesis, we performed in vitro experiments using hepatocellular carcinoma (HCC) cell lines. Firstly, we demonstrated that HCC cells with higher active RhoA/ROCK expression were prone to form VM channels, as compared with RhoA/ROCK low-expressing cells. Furthermore, Y27632 (a specific inhibitor of ROCK) rather than exoenzyme C3 (a specific inhibitor of RhoA) effectively inhibited the formation of tubular network structures in a dose-dependent manner. To elucidate the possible mechanism of ROCK on VM formation, real-time qPCR, western blot and immunofluorescence were used to detect changes of the key VM-related factors, including VE-cadherin, erythropoietin-producing hepatocellular carcinoma-A2 (EphA2), phosphoinositide 3-kinase (PI3K), matrix metalloproteinase (MMP)14, MMP2, MMP9 and laminin 5γ2-chain (LAMC2), and epithelial-mesenchymal-transition (EMT) markers: E-cadherin and Vimentin. The results showed that all the expression profiles were attenuated by blockage of ROCK. In addition, in vitro cell migration and invasion assays showed that Y27632 inhibited the migration and invasion capacity of HCC cell lines in a dose-dependent manner markedly. These data indicate that ROCK is an important mediator in the formation of tumor cell VM, and suggest that ROCK inhibition may prove useful in the treatment of VM in HCC.
doi:10.1371/journal.pone.0107661
PMCID: PMC4169566  PMID: 25238232
15.  Heparanase promotes human gastric cancer cells migration and invasion by increasing Src and p38 phosphorylation expression 
Gastric cancer is one of the most common cancers and it remains difficult to cure, primarily because most cancer stem like cells possess higher capability of invasion and metastasis. Heparanase acts as a master regulator of the aggressive tumor phenotype in part by enhancing expression of proteins and activating signaling molecules. There were less associated with heparanase of molecular biology mechanism in human gastric cancer. We first evaluated the endogenous expression of heparanase in human gastric cancer cell lines and found Heparanase expression higher in SGC-7901 than MGC-803. Using the technology of RNAi in SGC-7901 cells down regulated heparanase gene, and reduced SGC-7901 cells migration and invasion. On the other hand, recombinant heparanase protein added in MGC-803 cells enhanced MGC-803 cell migration and invasion. The elevated cell migration and invasion were impaired by treatment of Src inhibitor pp2 or p38 inhibitor SB 203580. We further found that Stable knockdown of heparanase in SGC-7901 cells decreased phosphorylation of Src and p38. The phosphorylation of p38 was inhibited in response to pp2 treatment while the addition of SB 203580 to SGC-7901 cells did not change phosphorylation of Src. These data suggest that heparanase facilitates invasion and migration of human gastric cancer cells probably through elevating phosphorylation of Src and p38.
PMCID: PMC4203173  PMID: 25337202
Gastric cancer; heparanase; src kinase; p38 kinase; migration; invasion
16.  Controllability and observability analysis for vertex domination centrality in directed networks 
Scientific Reports  2014;4:5399.
Topological centrality is a significant measure for characterising the relative importance of a node in a complex network. For directed networks that model dynamic processes, however, it is of more practical importance to quantify a vertex's ability to dominate (control or observe) the state of other vertices. In this paper, based on the determination of controllable and observable subspaces under the global minimum-cost condition, we introduce a novel direction-specific index, domination centrality, to assess the intervention capabilities of vertices in a directed network. Statistical studies demonstrate that the domination centrality is, to a great extent, encoded by the underlying network's degree distribution and that most network positions through which one can intervene in a system are vertices with high domination centrality rather than network hubs. To analyse the interaction and functional dependence between vertices when they are used to dominate a network, we define the domination similarity and detect significant functional modules in glossary and metabolic networks through clustering analysis. The experimental results provide strong evidence that our indices are effective and practical in accurately depicting the structure of directed networks.
doi:10.1038/srep05399
PMCID: PMC4066263  PMID: 24954137
17.  Facilitating Neuronal Connectivity Analysis of Evoked Responses by Exposing Local Activity with Principal Component Analysis Preprocessing: Simulation of Evoked MEG 
Brain topography  2012;26(2):201-211.
When connectivity analysis is carried out for event related EEG and MEG, the presence of strong spatial correlations from spontaneous activity in background may mask the local neuronal evoked activity and lead to spurious connections. In this paper, we hypothesized PCA decomposition could be used to diminish the background activity and further improve the performance of connectivity analysis in event related experiments. The idea was tested using simulation, where we found that for the 306-channel Elekta Neuromag system, the first 4 PCs represent the dominant background activity, and the source connectivity pattern after preprocessing is consistent with the true connectivity pattern designed in the simulation. Improving signal to noise of the evoked responses by discarding the first few PCs demonstrates increased coherences at major physiological frequency bands when removing the first few PCs. Furthermore, the evoked information was maintained after PCA preprocessing. In conclusion, it is demonstrated that the first few PCs represent background activity, and PCA decomposition can be employed to remove it to expose the evoked activity for the channels under investigation. Therefore, PCA can be applied as a preprocessing approach to improve neuronal connectivity analysis for event related data.
doi:10.1007/s10548-012-0250-1
PMCID: PMC3993084  PMID: 22918837
Principle Component Analysis; Event Related Response; Neuronal Connectivity; MEG
18.  Activation of beta 1 but not beta 3 integrin increases cell traction forces 
FEBS letters  2013;587(6):763-769.
Cell-generated traction forces induce integrin activation, leading to focal adhesion growth and cell spreading. It remains unknown, however, whether integrin activation feeds back to impact the generation of cytoskeletal tension. Here, we used elastomeric micropost arrays to measure cellular traction forces in wildtype and integrin-null cells. We report that activation of β1 but not β3 integrin, by either increasing density of immobilized fibronectin or treating with manganese, elicited fibroblast spreading and cytoskeletal tension. Furthermore, this force generation required Rho kinase and myosin activity. These findings suggest that integrin activation and cell traction forces comprise a bi-directional signaling unit of cell adhesion.
doi:10.1016/j.febslet.2013.01.068
PMCID: PMC3966909  PMID: 23395612
integrin; adhesion; cytoskeletal tension; cell traction force; micropost array; cell spreading
19.  Detecting Overlapping Protein Complexes by Rough-Fuzzy Clustering in Protein-Protein Interaction Networks 
PLoS ONE  2014;9(3):e91856.
In this paper, we present a novel rough-fuzzy clustering (RFC) method to detect overlapping protein complexes in protein-protein interaction (PPI) networks. RFC focuses on fuzzy relation model rather than graph model by integrating fuzzy sets and rough sets, employs the upper and lower approximations of rough sets to deal with overlapping complexes, and calculates the number of complexes automatically. Fuzzy relation between proteins is established and then transformed into fuzzy equivalence relation. Non-overlapping complexes correspond to equivalence classes satisfying certain equivalence relation. To obtain overlapping complexes, we calculate the similarity between one protein and each complex, and then determine whether the protein belongs to one or multiple complexes by computing the ratio of each similarity to maximum similarity. To validate RFC quantitatively, we test it in Gavin, Collins, Krogan and BioGRID datasets. Experiment results show that there is a good correspondence to reference complexes in MIPS and SGD databases. Then we compare RFC with several previous methods, including ClusterONE, CMC, MCL, GCE, OSLOM and CFinder. Results show the precision, sensitivity and separation are 32.4%, 42.9% and 81.9% higher than mean of the five methods in four weighted networks, and are 0.5%, 11.2% and 66.1% higher than mean of the six methods in five unweighted networks. Our method RFC works well for protein complexes detection and provides a new insight of network division, and it can also be applied to identify overlapping community structure in social networks and LFR benchmark networks.
doi:10.1371/journal.pone.0091856
PMCID: PMC3958373  PMID: 24642838
20.  Metal Impurities Cause False Positives in High-Throughput Screening Campaigns 
ACS Medicinal Chemistry Letters  2012;4(2):197-200.
Organic impurities in compound libraries are known to often cause false-positive signals in screening campaigns for new leads, but organic impurities do not fully account for all false-positive results. We discovered inorganic impurities in our screening library that can also cause positive signals for a variety of targets and/or readout systems, including biochemical and biosensor assays. We investigated in depth the example of zinc for a specific project and in retrospect in various HTS screens at Roche and propose a straightforward counter screen using the chelator TPEN to rule out inhibition caused by zinc.
doi:10.1021/ml3003296
PMCID: PMC4027514  PMID: 24900642
HTS; false positive; assay interference; Pad4; Jak3; Ras; zinc; promiscuous inhibitor; lead identification
21.  A Network Based Method for Analysis of lncRNA-Disease Associations and Prediction of lncRNAs Implicated in Diseases 
PLoS ONE  2014;9(1):e87797.
Increasing evidence has indicated that long non-coding RNAs (lncRNAs) are implicated in and associated with many complex human diseases. Despite of the accumulation of lncRNA-disease associations, only a few studies had studied the roles of these associations in pathogenesis. In this paper, we investigated lncRNA-disease associations from a network view to understand the contribution of these lncRNAs to complex diseases. Specifically, we studied both the properties of the diseases in which the lncRNAs were implicated, and that of the lncRNAs associated with complex diseases. Regarding the fact that protein coding genes and lncRNAs are involved in human diseases, we constructed a coding-non-coding gene-disease bipartite network based on known associations between diseases and disease-causing genes. We then applied a propagation algorithm to uncover the hidden lncRNA-disease associations in this network. The algorithm was evaluated by leave-one-out cross validation on 103 diseases in which at least two genes were known to be involved, and achieved an AUC of 0.7881. Our algorithm successfully predicted 768 potential lncRNA-disease associations between 66 lncRNAs and 193 diseases. Furthermore, our results for Alzheimer's disease, pancreatic cancer, and gastric cancer were verified by other independent studies.
doi:10.1371/journal.pone.0087797
PMCID: PMC3909255  PMID: 24498199
22.  Autophagy Is Involved in the Cardioprotection Effect of Remote Limb Ischemic Postconditioning on Myocardial Ischemia/Reperfusion Injury in Normal Mice, but Not Diabetic Mice 
PLoS ONE  2014;9(1):e86838.
Background
Recent animal study and clinical trial data suggested that remote limb ischemic postconditioning (RIPostC) can invoke potent cardioprotection. However, during ischemia reperfusion injury (IR), the effect and mechanism of RIPostC on myocardium in subjects with or without diabetes mellitus (DM) are poorly understood. Autophagy plays a crucial role in alleviating myocardial IR injury. The aim of this study was to determine the effect of RIPostC on mice myocardial IR injury model with or without DM, and investigate the role of autophagy in this process.
Methodology and Results
Streptozocin (STZ) induced DM mice model and myocardial IR model were established. Using a noninvasive technique, RIPostC was induced in normal mice (ND) and DM mice by three cycles of ischemia (5 min) and reperfusion (5 min) in the left hindlimb. In ND group, RIPostC significantly reduced infarct size (32.6±3.0% in ND-RIPostC vs. 50.6±2.4% in ND-IR, p<0.05) and improved cardiac ejection fraction (49.70±3.46% in ND-RIPostC vs. 31.30±3.95% in ND-IR, p<0.05). However, in DM group, no RIPostC mediated cardioprotetion effect was observed. To analyze the role of autophagy, western blot and immunohistochemistry was performed. Our data showed that a decreased sequestosome 1 (SQSTM1/p62) level, an increased Beclin-1 level, and higher ratio of LC3-II/LC3-I were observed in ND RIPostC group, but not DM RIPostC group.
Conclusions
The current study suggested that RIPostC exerts cardioprotection effect on IR in normal mice, but not DM mice, and this difference is via, at least in part, the up-regulation of autophagy.
doi:10.1371/journal.pone.0086838
PMCID: PMC3900658  PMID: 24466263
23.  Neglected increases in rural road traffic mortality in China: findings based on health data from 2005 to 2010 
BMC Public Health  2013;13:1111.
Background
Recent changes in rural road traffic mortality have not been examined in China although rural residents were reported as having greater risk of road traffic injury than urban residents. We aimed to examine changes in urban and rural road traffic mortality rates between 2005 and 2010 in China.
Methods
Mortality rates came from the publicly available health data of the Ministry of Health-Vital Registration System that is based on a national representative sample (about 10% of total population), including 41 surveillance points in urban areas (15 large cities and 21 middle/small cities) and 85 surveillance points in rural areas. The causes of deaths were coded using the Tenth International Classification of Diseases (ICD-10). Linear regression was used to test the statistical significance of changes in mortality rates. We calculated the percent change in rates to quantify the change between 2005 and 2010, which was calculated as regression coefficient * 100 * 5 divided by the rate in 2005.
Results
In rural areas, road traffic mortality increased by 70%, changing from 13.3 per 100,000 population in 2005 to 22.7 per 100,000 population in 2010. In contrast, the road traffic mortality merely increased by 4% in the study time period, rising from 13.1 to 13.9 per 100,000 population in urban areas. Both the increases in road traffic mortality from motor vehicle crashes and from non-motor vehicle crashes were larger in rural areas than in urban areas (106% vs. 4%; 29% vs. 3%).
Conclusion
The tremendous increase in road traffic mortality in rural areas calls for urgent actions to reduce road traffic injuries to motor vehicle occupants, motorcyclists, bicyclists and pedestrians in in rural areas.
doi:10.1186/1471-2458-13-1111
PMCID: PMC4219524  PMID: 24289458
Road traffic mortality; Urban areas; Rural areas; Motor vehicle crash; China
24.  Adhesion Regulates MAP Kinase-Ternary Complex Factor Exchange to Control a Proliferative Transcriptional Switch 
Current biology : CB  2012;22(21):2017-2026.
Background
The ternary complex factors (TCFs; Elk1, Net, and Sap-1) are growth factor-responsive transcription co-factors of serum response factor (SRF) and are activated by map kinase (MAPK) phosphorylation to regulate immediate early gene transcription. Although cell adhesion also can regulate immediate early genes and proliferation, the mechanism for this effect has remained unexplored.
Results
Restricting adhesion and spreading of G0-synchronized cells on substrates with decreasing size of micropatterned islands of fibronectin suppressed serum-induced immediate early gene expression and S-phase entry. Knockdown of Sap-1 decreased expression of the immediate early genes egr1 and fos and subsequent proliferation normally present with high adhesion, whereas knockdown of Net rescued egr1 and fos expression and proliferation normally suppressed by low adhesion. ChIP studies showed increased occupancy of egr1 and fos promoters by Sap-1 with high adhesion, while low adhesion increased Net occupancy. This switch in TCF promoter binding was regulated by an adhesion-mediated switch in MAPK activity. Increasing adhesion enhanced serum-induced JNK activity while suppressing p38 activity, leading to increased Sap-1 phosphorylation and Net dephosphorylation, and switching Net with Sap-1 at egr1 and fos promoters to support proliferation. Microarray studies confirmed this switch in TCF regulation of proliferative genes and uncovered novel gene targets and functions co-regulated by Sap-1 and Net.
Conclusions
These data demonstrate a key role for the TCFs in adhesion-induced transcription and proliferation, and reveals a novel MAPK/TCF transcriptional switch that controls this process.
doi:10.1016/j.cub.2012.08.050
PMCID: PMC3586562  PMID: 23063436
adhesion; transcription; ternary complex factor; map kinase; proliferation; Sap-1/Elk4; Net/Elk3
25.  Novel Mutations of ABCB6 Associated with Autosomal Dominant Dyschromatosis Universalis Hereditaria 
PLoS ONE  2013;8(11):e79808.
Objective
Dyschromatosis universalis hereditaria (DUH) is a rare heterogeneous pigmentary genodermatosis, which was first described in 1933. The genetic cause has recently been discovered by the discovery of mutations in ABCB6. Here we investigated a Chinese family with typical features of autosomal dominant DUH and 3 unrelated patients with sporadic DUH.
Methods
Skin tissues were obtained from the proband, of this family and the 3 sporadic patients. Histopathological examination and immunohistochemical analysis of ABCB6 were performed. Peripheral blood DNA samples were obtained from 21 affected, 14 unaffected, 11 spouses in the family and the 3 sporadic patients. A genome-wide linkage scan for the family was carried out to localize the causative gene. Exome sequencing was performed from 3 affected and 1 unaffected in the family. Sanger sequencing of ABCB6 was further used to identify the causative gene for all samples obtained from available family members, the 3 sporadic patients and a panel of 455 ethnically-matched normal Chinese individuals.
Results
Histopathological analysis showed melanocytes in normal control’s skin tissue and the hyperpigmented area contained more melanized, mature melanosomes than those within the hypopigmented areas. Empty immature melanosomes were found in the hypopigmented melanocytes. Parametric multipoint linkage analysis produced a HLOD score of 4.68, with markers on chromosome 2q35-q37.2. A missense mutation (c.1663 C>A, p.Gln555Lys) in ABCB6 was identified in this family by exome and Sanger sequencing. The mutation perfectly cosegregated with the skin phenotype. An additional mutation (g.776 delC, c.459 delC) in ABCB6 was found in an unrelated sporadic patient. No mutation in ABCB6 was discovered in the other two sporadic patients. Neither of the two mutations was present in the 455 controls. Melanocytes showed positive immunoreactivity to ABCB6.
Conclusion
Our data add new variants to the repertoire of ABCB6 mutations with DUH.
doi:10.1371/journal.pone.0079808
PMCID: PMC3818219  PMID: 24224009

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