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1.  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
2.  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
3.  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
4.  Epidemiology of dyslipidemia in Chinese adults: meta-analysis of prevalence, awareness, treatment, and control 
Population Health Metrics  2014;12(1):28.
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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  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
14.  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
15.  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
16.  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
17.  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
18.  ppiPre: predicting protein-protein interactions by combining heterogeneous features 
BMC Systems Biology  2013;7(Suppl 2):S8.
Background
Protein-protein interactions (PPIs) are crucial in cellular processes. Since the current biological experimental techniques are time-consuming and expensive, and the results suffer from the problems of incompleteness and noise, developing computational methods and software tools to predict PPIs is necessary. Although several approaches have been proposed, the species supported are often limited and additional data like homologous interactions in other species, protein sequence and protein expression are often required. And predictive abilities of different features for different kinds of PPI data have not been studied.
Results
In this paper, we propose ppiPre, an open-source framework for PPI analysis and prediction using a combination of heterogeneous features including three GO-based semantic similarities, one KEGG-based co-pathway similarity and three topology-based similarities. It supports up to twenty species. Only the original PPI data and gold-standard PPI data are required from users. The experiments on binary and co-complex gold-standard yeast PPI data sets show that there exist big differences among the predictive abilities of different features on different kinds of PPI data sets. And the prediction performance on the two data sets shows that ppiPre is capable of handling PPI data in different kinds and sizes. ppiPre is implemented in the R language and is freely available on the CRAN (http://cran.r-project.org/web/packages/ppiPre/).
Conclusions
We applied our framework to both binary and co-complex gold-standard PPI data sets. The detailed analysis on three GO aspects suggests that different GO aspects should be used on different kinds of data sets, and that combining all the three aspects of GO often gets the best result. The analysis also shows that using only features based solely on the topology of the PPI network can get a very good result when predicting the co-complex PPI data. ppiPre provides useful functions for analysing PPI data and can be used to predict PPIs for multiple species.
doi:10.1186/1752-0509-7-S2-S8
PMCID: PMC3851814  PMID: 24565177
19.  The structure of XIAP BIR2: understanding the selectivity of the BIR domains 
The high-resolution crystal structures of apo and peptide-bound XIAP BIR2 are presented and compared with BIR3 structures to understand their selectivity. This crystal system can be used to determine the structures of BIR2–inhibitor complexes.
XIAP, a member of the inhibitor of apoptosis family of proteins, is a critical regulator of apoptosis. Inhibition of the BIR domain–caspase interaction is a promising approach towards treating cancer. Previous work has been directed towards inhibiting the BIR3–caspase-9 interaction, which blocks the intrinsic apoptotic pathway; selectively inhibiting the BIR2–caspase-3 interaction would also block the extrinsic pathway. The BIR2 domain of XIAP has successfully been crystallized; peptides and small-molecule inhibitors can be soaked into these crystals, which diffract to high resolution. Here, the BIR2 apo crystal structure and the structures of five BIR2–tetrapeptide complexes are described. The structural flexibility observed on comparing these structures, along with a comparison with XIAP BIR3, affords an understanding of the structural elements that drive selectivity between BIR2 and BIR3 and which can be used to design BIR2-selective inhibitors.
doi:10.1107/S0907444913016284
PMCID: PMC3760131  PMID: 23999295
apoptosis; XIAP; BIR domains; caspases; extrinsic pathway; inhibitor of apoptosis; peptide complex; SMAC; AVPI
20.  Detection of Deregulated Modules Using Deregulatory Linked Path 
PLoS ONE  2013;8(7):e70412.
The identification of deregulated modules (such as induced by oncogenes) is a crucial step for exploring the pathogenic process of complex diseases. Most of the existing methods focus on deregulation of genes rather than the links of the path among them. In this study, we emphasize on the detection of deregulated links, and develop a novel and effective regulatory path-based approach in finding deregulated modules. Observing that a regulatory pathway between two genes might involve in multiple rather than a single path, we identify condition-specific core regulatory path (CCRP) to detect the significant deregulation of regulatory links. Using time-series gene expression, we define the regulatory strength within each gene pair based on statistical dependence analysis. The CCRPs in regulatory networks can then be identified using the shortest path algorithm. Finally, we derive the deregulated modules by integrating the differential edges (as deregulated links) of the CCRPs between the case and the control group. To demonstrate the effectiveness of our approach, we apply the method to expression data associated with different states of Human Epidermal Growth Factor Receptor 2 (HER2). The experimental results show that the genes as well as the links in the deregulated modules are significantly enriched in multiple KEGG pathways and GO biological processes, most of which can be validated to suffer from impact of this oncogene based on previous studies. Additionally, we find the regulatory mechanism associated with the crucial gene SNAI1 significantly deregulated resulting from the activation of HER2. Hence, our method provides not only a strategy for detecting the deregulated links in regulatory networks, but also a way to identify concerning deregulated modules, thus contributing to the target selection of edgetic drugs.
doi:10.1371/journal.pone.0070412
PMCID: PMC3722188  PMID: 23894653
21.  Effect of Iron Deficiency on c-kit+ Cardiac Stem Cells In Vitro 
PLoS ONE  2013;8(6):e65721.
Aim
Iron deficiency is a common comorbidity in chronic heart failure (CHF) which may exacerbate CHF. The c-kit+ cardiac stem cells (CSCs) play a vital role in cardiac function repair. However, much is unknown regarding the role of iron deficiency in regulating c-kit+ CSCs function. In this study, we investigated whether iron deficiency regulates c-kit+ CSCs proliferation, migration, apoptosis, and differentiation in vitro.
Method
All c-kit+ CSCs were isolated from adult C57BL/6 mice. The c-kit+ CSCs were cultured with deferoxamine (DFO, an iron chelator), mimosine (MIM, another iron chelator), or a complex of DFO and iron (Fe(III)), respectively. Cell migration was assayed using a 48-well chamber system. Proliferation, cell cycle, and apoptosis of c-kit+ CSCs were analyzed with BrdU labeling, population doubling time assay, CCK-8 assay, and flow cytometry. Caspase-3 protein level and activity were examined with Western blotting and spectrophotometric detection. The changes in the expression of cardiac-specific proteins (GATA-4,TNI, and β-MHC) and cell cycle-related proteins (cyclin D1, RB, and pRB) were detected with Western blotting.
Result
DFO and MIM suppressed c-kit+ CSCs proliferation and differentiation. They also modulated cell cycle and cardiac-specific protein expression. Iron chelators down-regulated the expression and phosphorylation of cell cycle-related proteins. Iron reversed those suppressive effects of DFO. DFO and MIM didn’t affect c-kit+ CSCs migration and apoptosis.
Conclusion
Iron deficiency suppressed proliferation and differentiation of c-kit+ CSCs. This may partly explain how iron deficiency affects CHF prognosis.
doi:10.1371/journal.pone.0065721
PMCID: PMC3677875  PMID: 23762416
22.  Sulindac inhibits tumor cell invasion by suppressing NF-κB mediated transcription of microRNAs 
Oncogene  2012;31(48):4979-4986.
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been widely reported to display strong efficacy for cancer chemoprevention, although their mechanism of action is poorly understood. The most well documented effects of NSAIDs include inhibition of tumor cell proliferation and induction of apoptosis, but their effect on tumor cell invasion has not been well studied. Here we show that the NSAID, sulindac sulfide (SS) can potently inhibit the invasion of human MDA-MB-231 breast and HCT116 colon tumor cells in vitro at concentrations less than those required to inhibit tumor cell growth. To study the molecular basis for this activity, we investigated the involvement of microRNA (miRNA). A total of 132 miRNAs were found to be altered in response to SS treatment including miR-10b, miR-17, miR-21, and miR-9, which have been previously implicated in tumor invasion and metastasis. We confirmed that these miRNA can stimulate tumor cell invasion and show that SS can attenuate their invasive effects by down-regulating their expression. Employing luciferase and chromatin immunoprecipitation assays, NF-κB was found to bind the promoters of all four miRNAs to suppress their expression at the transcriptional level. We show that SS can inhibit the translocation of NF-κB to the nucleus by decreasing the phosphorylation of IKKβ and IκB. Analysis of the promoter sequences of the miRNAs suppressed by SS revealed that 81 of 115 sequences contained NF-κB binding sites. These results show that SS can inhibit tumor cell invasion by suppressing NF-κB mediated transcription of miRNAs.
doi:10.1038/onc.2011.655
PMCID: PMC3372649  PMID: 22286762
sulindac; invasion; microRNA; NF-κB
23.  DEVD-Based Hydrogelator Minimizes Cellular Apoptosis Induction 
Scientific Reports  2013;3:1848.
Herein, we report the rational design of a DEVD-based heptapeptide hydrogelator 1 which is susceptible to caspase-3 (CASP3), and its isomeric control hydrogelator 2 with a DEDV-based heptapeptide sequence. Self-assembly of 1 in water results in flexuous, long nanofibers to form supramolecular hydrogel I with higher mechanical strength than that of hydrogel II which is composed of rigid, short nanofibers of 2. In vitro enzymatic analysis indicated that 1 is susceptive to CASP3 while 2 is not. 3-(4,5-dimethylthiazol-2-yl) 2,5 diphenyl tetrazolium bromide (MTT) and Western blot analyses indicated that DEDV-based hydrogelator 2 induces cell death via apoptotic pathway while the DEVD-based hydrogelator 1 minimizes cellular apoptosis induction.
doi:10.1038/srep01848
PMCID: PMC3654485  PMID: 23673405
24.  Bone Morphogenetic Protein-2-Induced Signaling and Osteogenesis Is Regulated by Cell Shape, RhoA/ROCK, and Cytoskeletal Tension 
Stem Cells and Development  2011;21(7):1176-1186.
Abstract
Osteogenic differentiation of human mesenchymal stem cells (hMSCs) is classically thought to be mediated by different cytokines such as the bone morphogenetic proteins (BMPs). Here, we report that cell adhesion to extracellular matrix (ECM), and its effects on cell shape and cytoskeletal mechanics, regulates BMP-induced signaling and osteogenic differentiation of hMSCs. Using micropatterned substrates to progressively restrict cell spreading and flattening against ECM, we demonstrated that BMP-induced osteogenesis is progressively antagonized with decreased cell spreading. BMP triggered rapid and sustained RhoA/Rho-associated protein kinase (ROCK) activity and contractile tension only in spread cells, and this signaling was required for BMP-induced osteogenesis. Exploring the molecular basis for this effect, we found that restricting cell spreading, reducing ROCK signaling, or inhibiting cytoskeletal tension prevented BMP-induced SMA/mothers against decapentaplegic (SMAD)1 c-terminal phosphorylation, SMAD1 dimerization with SMAD4, and SMAD1 translocation into the nucleus. Together, these findings demonstrate the direct involvement of cell spreading and RhoA/ROCK-mediated cytoskeletal tension generation in BMP-induced signaling and early stages of in vitro osteogenesis, and highlight the essential interplay between biochemical and mechanical cues in stem cell differentiation.
doi:10.1089/scd.2011.0293
PMCID: PMC3328763  PMID: 21967638
25.  Controlled intracellular self-assembly of gadolinium nanoparticles as smart molecular MR contrast agents 
Scientific Reports  2013;3:1024.
Herein we developed a new “smart” Gd-based MR contrast agent (i.e., 1) which is susceptive to furin, a protease overexpressed in tumor. Under the action of furin, 1 condenses to form dimers (1-Ds) and the latter self-assemble into gadolinium nanparticles (Gd-NPs). Relaxivity of 1-D is more than 2 folds of those of 1 and magnevist at 1.5 T, and 1.4 folds of that of 1 at 3 T. Intracellular condensation of 1 in furin-overexpressed MDA-MB-468 cells was proven with direct two-photon laser microscopy (TPLM) fluorescence imaging of the cells incubated with the europium analog of 1 (i.e., 2). Intracellular Gd-NPs of 1 were uncovered and characterized for the first time. MRI of MDA-MB-468 tumors showed that 1 has enhanced MR contrast within the tumors than that of its scrambled control 1-Scr.
doi:10.1038/srep01024
PMCID: PMC3535584  PMID: 23289066

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