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1.  Breakdown of Richardson's Law in Electron Emission from Individual Self-Joule-Heated Carbon Nanotubes 
Scientific Reports  2014;4:5102.
Probing the validity of classical macroscopic physical laws at the nanoscale is important for nanoscience research. Herein, we report on experimental evidence that electron emission from individual hot carbon nanotubes (CNTs) heated by self-Joule-heating does not obey Richardson's law of thermionic emission. By using an in-situ multi-probe measurement technique, electron emission density (J) and temperature (T) of individual self-Joule-heated CNTs are simultaneously determined. Experimental ln(J/T2) − 1/T plots are found to exhibit an upward bending feature deviating from the straight lines in Richardson plots, and the measured electron emission density is more than one order of magnitude higher than that predicted by Richardson's law. The breakdown of Richardson's law implies a much better electron emission performance of individual CNTs as compared to their macroscopic allotropes and clusters, and the need of new theoretical descriptions of electron emission from individual low-dimensional nanostructures.
PMCID: PMC4037708  PMID: 24869719
2.  Genome Wide Association Study Identifies 20 Novel Promising Genes Associated with Milk Fatty Acid Traits in Chinese Holstein 
PLoS ONE  2014;9(5):e96186.
Detecting genes associated with milk fat composition could provide valuable insights into the complex genetic networks of genes underling variation in fatty acids synthesis and point towards opportunities for changing milk fat composition via selective breeding. In this study, we conducted a genome-wide association study (GWAS) for 22 milk fatty acids in 784 Chinese Holstein cows with the PLINK software. Genotypes were obtained with the Illumina BovineSNP50 Bead chip and a total of 40,604 informative, high-quality single nucleotide polymorphisms (SNPs) were used. Totally, 83 genome-wide significant SNPs and 314 suggestive significant SNPs associated with 18 milk fatty acid traits were detected. Chromosome regions that affect milk fatty acid traits were mainly observed on BTA1, 2, 5, 6, 7, 9, 13, 14, 18, 19, 20, 21, 23, 26 and 27. Of these, 146 SNPs were associated with more than one milk fatty acid trait; most of studied fatty acid traits were significant associated with multiple SNPs, especially C18:0 (105 SNPs), C18 index (93 SNPs), and C14 index (84 SNPs); Several SNPs are close to or within the DGAT1, SCD1 and FASN genes which are well-known to affect milk composition traits of dairy cattle. Combined with the previously reported QTL regions and the biological functions of the genes, 20 novel promising candidates for C10:0, C12:0, C14:0, C14:1, C14 index, C18:0, C18:1n9c, C18 index, SFA, UFA and SFA/UFA were found, which composed of HTR1B, CPM, PRKG1, MINPP1, LIPJ, LIPK, EHHADH, MOGAT1, ECHS1, STAT1, SORBS1, NFKB2, AGPAT3, CHUK, OSBPL8, PRLR, IGF1R, ACSL3, GHR and OXCT1. Our findings provide a groundwork for unraveling the key genes and causal mutations affecting milk fatty acid traits in dairy cattle.
PMCID: PMC4032272  PMID: 24858810
3.  Differential Modulations of KCNQ1 by Auxiliary Proteins KCNE1 and KCNE2 
Scientific Reports  2014;4:4973.
KCNQ1 channels play vital roles in cardiovascular, gastric and other systems. The conductance and dynamics of KCNQ1 could be modulated by different single transmembrane helical auxiliary proteins (such as KCNE1, KCNE2 and others). In this study, detail KCNQ1 function modulations by different regions of KCNE1 or KCNE2 were examined using combinational methods of electrophysiology, immunofluorescence, solution NMR and related backbone flexibility analysis. In the presence of KCNE2 N-terminus, decreased surface expression and consequent low activities of KCNQ1 were observed. The transmembrane domains (TMDs) of KCNE1 and KCNE2 were illustrated to associate with the KCNQ1 channel in different modes: Ile64 in KCNE2-TMD interacting with Phe340 and Phe275 in KCNQ1, while two pairs of interacting residues (Phe340-Thr58 and Ala244-Tyr65) in the KCNQ1/KCNE1 complex. The KCNE1 C-terminus could modulate gating property of KCNQ1, whereas KCNE2 C-terminus had only minimal influences on KCNQ1. All of the results demonstrated different KCNQ1 function modulations by different regions of the two auxiliary proteins.
PMCID: PMC4021338  PMID: 24827085
4.  Altered Methylation in Tandem Repeat Element and Elemental Component Levels in Inhalable Air Particles 
Exposure to particulate matter (PM) has been associated with lung cancer risk in epidemiology investigations. Elemental components of PM have been suggested to have critical roles in PM toxicity, but the molecular mechanisms underlying their association with cancer risks remain poorly understood. DNA methylation has emerged as a promising biomarker for environmental-related diseases, including lung cancer. In this study, we evaluated the effects of PM elemental components on methylation of three tandem repeats in a highly-exposed population in Beijing, China. The Beijing Truck Driver Air Pollution Study was conducted shortly before the 2008 Beijing Olympic Games (June 15-July 27, 2008) and included 60 truck drivers and 60 office workers. On two days separated by 1-2 weeks, we measured blood DNA methylation of SATα, NBL2, D4Z4, and personal exposure to eight elemental components in PM2.5, including aluminum (Al), silicon (Si), sulfur (S), potassium (K), calcium (Ca) titanium (Ti), iron (Fe), and zinc (Zn). We estimated the associations of individual elemental component with each tandem repeat methylation in generalized estimating equations (GEE) models adjusted for PM2.5 mass and other covariates. Out of the eight examined elements, NBL2 methylation was positively associated with concentrations of Si (0.121, 95%CI: 0.030; 0.212, FDR=0.047) and Ca (0.065, 95%CI: 0.014; 0.115, FDR=0.047) in truck drivers. In office workers, SATα methylation was positively associated with concentrations of S (0.115, 95%CI: 0.034; 0.196, FDR=0.042). PM-associated differences in blood tandem-repeat methylation may help detect biological effects of the exposure and identify individuals who may eventually experience higher lung cancer risk.
PMCID: PMC4001244  PMID: 24273195
Tandem repeats; DNA methylation; lung cancer
5.  The enforced expression of c-Myc in pig fibroblasts triggers mesenchymal-epithelial transition (MET) via F-actin reorganization and RhoA/Rock pathway inactivation 
Cell Cycle  2013;12(7):1119-1127.
In previous studies from other labs it has been well demonstrated that the ectopic expression of c-Myc in mammary epithelial cells can induce epithelial-mesenchymal transition (EMT), whereas in our pilot experiment, epithelial-like morphological changes were unexpectedly observed in c-Myc-expressing pig fibroblasts [i.e., porcine embryonic fibroblasts (PEFs) and porcine dermal fibroblasts (PDFs)] and pig mesenchymal stem cells, suggesting that the same c-Myc gene is entitled to trigger EMT in epithelial cells and mesenchymal-epithelial transition (MET) in fibroblasts. This prompted us to characterize the existence of a MET in c-Myc-expressing PEFs and PDFs at the molecular level. qRT-PCR, immunofluorescence and western blot analysis illustrated that epithelial-like morphological changes were accompanied by the increased expression of epithelial markers [such as cell adhesion proteins (E-cadherin, α-catenin and Bves), tight junction protein occludin and cytokeratins (Krt8 and Krt18)], the reduced expression of mesenchymal markers [vimentin, fibronectin 1 (FN1), snail1, collagen family of proteins (COL1A1, COL5A2) and matrix metalloproteinase (MMP) family (MMP12 and MMP14)] and the decreased cell motility and increased cell adhesion in c-Myc-expressing PEFs and PDFs. Furthermore, the ectopic expression of c-Myc in pig fibroblasts disrupted the stress fiber network, suppressed the formation of filopodia and lamellipodia, and resulted in RhoA/Rock pathway inactivation, which finally participates in epithelial-like morphological conversion. Taken together, these findings demonstrate, for the first time, that the enforced expression of c-Myc in fibroblasts can trigger MET, to which cytoskeleton depolymerization and RhoA/Rock pathway inactivation contribute.
PMCID: PMC3646867  PMID: 23466707
RhoA/Rock pathway; Tibetan miniature pigs; c-Myc; cytoskeleton reorganization; dermal fibroblasts; embryonic fibroblasts; mesenchymal stem cells; mesenchymal-epithelial transition (MET)
6.  The effects of ambient temperature on cerebrovascular mortality: an epidemiologic study in four climatic zones in China 
Environmental Health  2014;13:24.
Little evidence is available about the association between temperature and cerebrovascular mortality in China. This study aims to examine the effects of ambient temperature on cerebrovascular mortality in different climatic zones in China.
We obtained daily data on weather conditions, air pollution and cerebrovascular deaths from five cities (Beijing, Tianjin, Shanghai, Wuhan, and Guangzhou) in China during 2004-2008. We examined city-specific associations between ambient temperature and the cerebrovascular mortality, while adjusting for season, long-term trends, day of the week, relative humidity and air pollution. We examined cold effects using a 1°C decrease in temperature below a city-specific threshold, and hot effects using a 1°C increase in temperature above a city-specific threshold. We used a meta-analysis to summarize the cold and hot effects across the five cities.
Beijing and Tianjin (with low mean temperature) had lower thresholds than Shanghai, Wuhan and Guangzhou (with high mean temperature). In Beijing, Tianjin, Wuhan and Guangzhou cold effects were delayed, while in Shanghai there was no or short induction. Hot effects were acute in all five cities. The cold effects lasted longer than hot effects. The hot effects were followed by mortality displacement. The pooled relative risk associated with a 1°C decrease in temperature below thresholds (cold effect) was 1.037 (95% confidence interval (CI): 1.020, 1.053). The pooled relative risk associated with a 1°C increase in temperature above thresholds (hot effect) was 1.014 (95% CI: 0.979, 1.050).
Cold temperatures are significantly associated with cerebrovascular mortality in China, while hot effect is not significant. People in colder climate cities were sensitive to hot temperatures, while people in warmer climate cities were vulnerable to cold temperature.
PMCID: PMC4021080  PMID: 24690204
Cerebrovascular disease; Meta-analysis; Mortality; Temperature; Time series analysis
7.  MRFalign: Protein Homology Detection through Alignment of Markov Random Fields 
PLoS Computational Biology  2014;10(3):e1003500.
Sequence-based protein homology detection has been extensively studied and so far the most sensitive method is based upon comparison of protein sequence profiles, which are derived from multiple sequence alignment (MSA) of sequence homologs in a protein family. A sequence profile is usually represented as a position-specific scoring matrix (PSSM) or an HMM (Hidden Markov Model) and accordingly PSSM-PSSM or HMM-HMM comparison is used for homolog detection. This paper presents a new homology detection method MRFalign, consisting of three key components: 1) a Markov Random Fields (MRF) representation of a protein family; 2) a scoring function measuring similarity of two MRFs; and 3) an efficient ADMM (Alternating Direction Method of Multipliers) algorithm aligning two MRFs. Compared to HMM that can only model very short-range residue correlation, MRFs can model long-range residue interaction pattern and thus, encode information for the global 3D structure of a protein family. Consequently, MRF-MRF comparison for remote homology detection shall be much more sensitive than HMM-HMM or PSSM-PSSM comparison. Experiments confirm that MRFalign outperforms several popular HMM or PSSM-based methods in terms of both alignment accuracy and remote homology detection and that MRFalign works particularly well for mainly beta proteins. For example, tested on the benchmark SCOP40 (8353 proteins) for homology detection, PSSM-PSSM and HMM-HMM succeed on 48% and 52% of proteins, respectively, at superfamily level, and on 15% and 27% of proteins, respectively, at fold level. In contrast, MRFalign succeeds on 57.3% and 42.5% of proteins at superfamily and fold level, respectively. This study implies that long-range residue interaction patterns are very helpful for sequence-based homology detection. The software is available for download at A summary of this paper appears in the proceedings of the RECOMB 2014 conference, April 2–5.
Author Summary
Sequence-based protein homology detection has been extensively studied, but it remains very challenging for remote homologs with divergent sequences. So far the most sensitive methods employ HMM-HMM comparison, which models a protein family using HMM (Hidden Markov Model) and then detects homologs using HMM-HMM alignment. HMM cannot model long-range residue interaction patterns and thus, carries very little information regarding the global 3D structure of a protein family. As such, HMM comparison is not sensitive enough for distantly-related homologs. In this paper, we present an MRF-MRF comparison method for homology detection. In particular, we model a protein family using Markov Random Fields (MRF) and then detect homologs by MRF-MRF alignment. Compared to HMM, MRFs are able to model long-range residue interaction pattern and thus, contains information for the overall 3D structure of a protein family. Consequently, MRF-MRF comparison is much more sensitive than HMM-HMM comparison. To implement MRF-MRF comparison, we have developed a new scoring function to measure the similarity of two MRFs and also an efficient ADMM algorithm to optimize the scoring function. Experiments confirm that MRF-MRF comparison indeed outperforms HMM-HMM comparison in terms of both alignment accuracy and remote homology detection, especially for mainly beta proteins.
PMCID: PMC3967925  PMID: 24675572
8.  Utility of R2* Obtained from T2*-Weighted Imaging in Differentiating Hepatocellular Carcinomas from Cavernous Hemangiomas of the Liver 
PLoS ONE  2014;9(3):e91751.
To evaluate the feasibility of applying R2* values to differentiate hepatocellular carcinomas (HCC) from cavernous hemangiomas of the liver (CHL).
Materials and Methods
This retrospective study was approved by the participating Institutional Review Board and written informed consent for all subjects were obtained. Seventy-three patients with 79 pathologically identified HCCs and 65 patients with 91 clinically or pathologically identified CHLs were enrolled in this study. All subjects underwent a breath-hold multi-echo T2* weighted MR imaging on a 1.5T clinical MR scanner. R2* values from HCC and CHL groups were compared using the Mann-Whitney non-parametric U test. A cut-off value of R2* was evaluated with receiver operator characteristic (ROC) analysis.
The mean R2* value was 23.32±12.23 Hz (95% confidence interval [CI]: 20.58 Hz, 26.06 Hz) for the HCC group, and 3.66±2.37 Hz (95% CI: 3.17 Hz, 4.15 Hz) for the CHL group. The mean R2* value for HCC was significantly higher than that of CHL (p<0.001). A threshold of 9.48 Hz for the minimum R2* value in the diagnosis of HCC resulted in a sensitivity of 96.20% (76 out of 79 patients), and a specificity of 97.80% (89 out of 91 patients). The positive predictive value (PPV), negative predictive value (NPV) and diagnostic accuracy for HCC were 97.44% (76 out of 78 patients), 96.74% (89 out of 92 patients) and 97.06% (165 out of 170 patients), respectively. The AUC for differentiation between these two groups was 0.994 (95% CI: 0.980, 1.000).
R2* is a significant MRI biomarker to differentiate HCC from CHL with satisfying sensitivity and specificity.
PMCID: PMC3954770  PMID: 24632579
9.  Bovine Induced Pluripotent Stem Cells Are More Resistant to Apoptosis than Testicular Cells in Response to Mono-(2-ethylhexyl) Phthalate 
Although the androgen receptor (AR) has been implicated in the promotion of apoptosis in testicular cells (TSCs), the molecular pathway underlying AR-mediated apoptosis and its sensitivity to environmental hormones in TSCs and induced pluripotent stem cells (iPSCs) remain unclear. We generated the iPSCs from bovine TSCs via the electroporation of OCT4. The established iPSCs were supplemented with leukemia inhibitory factor and bone morphogenetic protein 4 to maintain and stabilize the expression of stemness genes and their pluripotency. Apoptosis signaling was assessed after exposure to mono-(2-ethylhexyl) phthalate (MEHP), the active metabolite of di-(2-ethylhexyl) phthalate. Here, we report that iPSCs were more resistant to MEHP-induced apoptosis than were original TSCs. MEHP also repressed the expression of AR and inactivated WNT signaling, and then led to the commitment of cells to apoptosis via the cyclin dependent kinase inhibitor p21CIP1. The loss of the frizzed receptor 7 and the gain of p21CIP were responsible for the stimulatory effect of MEHP on AR-mediated apoptosis. Our results suggest that testicular iPSCs can be used to study the signaling pathways involved in the response to environmental disruptors, and to assess the toxicity of environmental endocrine disruptors in terms of the maintenance of stemness and pluripotency.
PMCID: PMC3975437  PMID: 24658443
bovine iPSCs; testicular cells; OCT4; electroporation; endocrine disruptor; frizzled receptor; WNT signal; androgen receptor
10.  Redox-regulation of mitochondrial ATP synthase 
Reversible cysteine oxidative post-translational modifications (Ox-PTMs) represent an important mechanism to regulate protein structure and function. In mitochondria, redox-reactions can modulate components of the electron transport chain (ETC), the F1FO-ATP synthase complex and other matrix proteins/enzymes. Emerging evidence has linked Ox-PTMs to mitochondrial dysfunction and heart failure, highlighting some potential therapeutic avenues. Ox-PTMs can modify a variety of amino acid residues, including cysteine, and have the potential to modulate the function of a large number of proteins. Among this group, there is a selected subset of amino acid residues that can function as redox-switches. These unique sites are proposed to monitor the cell's oxidative balance through their response to the various Ox-PTMs. In this review, the role of Ox-PTMs in the regulation of the F1FO-ATP synthase complex is discussed in the context of heart failure and its possible clinical treatment.
PMCID: PMC3936247  PMID: 23312134
11.  Outcome prediction values of soluble human epidermal growth factor receptor-2 extracellular domain in metastatic breast cancer 
Background: HER-2 overexpression is an independent predictor for poor prognosis of breast cancer patients. Recently, extracellular domain of HER-2 (ECD) was found detectable in the serum of breast cancer patients. In this prospective study, we wonder whether ECD levels predict the clinical outcome of metastatic breast cancer patients. Methods: ECD were measured in 190 women with metastatic breast cancer. Chi-square test was performed to determine the relationship between ECD status and clinical outcomes. Kaplan-Meier curves were applied for survival analysis. Results: Elevated ECD levels were significantly associated with short-term response to Herceptin treatment. The median PFS was significantly longer in ECD-Low patients. The patients who remained low ECD levels or achieved low ECD levels after treatments have significantly longer PFS than those whose levels remained high or converted from low to high. Conclusions: Overall, our results support the clinical utility of measuring serum HER2 ECD levels in patients with advanced breast cancer. Baseline and serial measurements of serum ECD levels are reliably predictive of clinical outcome of breast cancer patients.
PMCID: PMC3971315  PMID: 24696727
Epidermal growth factor receptor-2 (EGFR-2); extracellular domain; metastatic breast cancer
12.  Zhankuic Acid A Isolated from Taiwanofungus camphoratus Is a Novel Selective TLR4/MD-2 Antagonist with Anti-Inflammatory Properties 
TLR4, a membrane receptor that functions in complex with its accessory protein myeloid differentiation factor-2 (MD-2), is a therapeutic target for bacterial infections. Taiwanofungus camphoratus is highly valued as a medicinal mushroom for cancer, hypertension, and inflammation in traditional medicine. Zhankuic acid A (ZAA) is the major pharmacologically active compound of T. camphoratus. The mechanism of action of T. camphoratus or ZAA has not been fully elucidated. We analyzed the structure of human TLR4/MD-2 complex with ZAA by X-score and HotLig modeling approaches. Two Abs against MD-2 were used to verify the MD-2/ZAA interaction. The inflammation and survival of the mice pretreated with ZAA and injected with LPS were monitored. The modeling structure shows that ZAA binds the MD-2 hydrophobic pocket exclusively via specific molecular recognition; the contact interface is dominated by hydrophobic interactions. Binding of ZAA to MD-2 reduced Ab recognition to native MD-2, similar to the effect of LPS binding. Furthermore, ZAA significantly ameliorated LPS-induced endotoxemia and Salmonella-induced diarrhea in mice. Our results suggest that ZAA, which can compete with LPS for binding to MD-2 as a TLR4/MD-2 antagonist, may be a potential therapeutic agent for gram-negative bacterial infections.
PMCID: PMC3948111  PMID: 24532584
13.  6-Alkynyl fucose is a bioorthogonal analog for O-fucosylation of epidermal growth factor-like repeats and thrombospondin Type-1 repeats by protein O-fucosyltransferases 1 and 2 
Glycobiology  2012;23(2):188-198.
Protein O-fucosyltransferase 1 (Pofut1) and protein O-fucosyltransferase 2 (Pofut2) add O-linked fucose at distinct consensus sequences in properly folded epidermal growth factor (EGF)-like repeats and thrombospondin type-1 (TSR) repeats, respectively. Glycan chain elongation past O-fucose can occur to yield a tetrasaccharide on EGF repeats and a disaccharide on TSRs. Elimination of Pofut1 in mice causes embryonic lethality with Notch-like phenotypes demonstrating that O-fucosylation of Notch is essential for its function. Similarly, elimination of Pofut2 results in an early embryonic lethal phenotype in mice, although the molecular mechanism for the lethality is unknown. The recent development of sugar analogs has revolutionized the study of glycans by providing a convenient method for labeling and tracking glycosylation. In order to study O-fucosylation, we took advantage of the recently developed reporter, 6-alkynyl fucose. Using the Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC), or “click” reaction, azido-biotin allows tagging and detection of 6AF-modified proteins. Here we examine whether proteins containing EGF repeats or TSRs with O-fucose consensus sequences are specifically modified with 6AF in cell culture. Using mass spectrometry (MS), we demonstrate that 6AF is efficiently incorporated onto the appropriate consensus sequences on EGF repeats and TSRs. Furthermore, the elongation of the O-fucose monosaccharide on EGF repeats and TSRs is not hampered when 6AF is used. These results show that 6AF is efficiently utilized in a truly bioorthogonal manner by Pofut1, Pofut2 and the enzymes that elongate O-fucose, providing evidence that 6AF is a significant new tool in the study of protein O-fucosylation.
PMCID: PMC3531295  PMID: 23045360
6-Alkynyl fucose; click chemistry; epidermal growth factor-like-repeat; O-fucose; thrombospondin type-1 repeat
14.  Pretreatment of Mice with Oligonucleotide prop5 Protects Them from Influenza Virus Infections 
Viruses  2014;6(2):573-581.
Influenza A virus is a successful parasite and requires host factors to complete its life cycle. Prop5 is an antisense oligonucleotide, targeting programmed cell death protein 5 (PDCD5). In this study, we tested the antiviral activity of prop5 against mouse-adapted A/FM/1/47 strain of influenza A virus in a mouse model. Prop5 intranasally administered the mice at dosages of 10 and 20 mg/kg/d at 24 h and 30 min before infection, provided 80% and 100% survival rates and prolonged mean survival days in comparison with influenza virus-infected mice (both p < 0.01). Moreover, viral titres in mice pretreated with prop5, at dose of 10 and 20 mg/kg/d, had declined significantly on day two, four, and six post-infection compared with the yields in infected mice (p < 0.05 or p < 0.01); lung index in mice pretreated with prop5 (20 mg/kg/d) had been inhibited on day six post-infection (p < 0.05). Western blotting and immunohistochemistry showed that prop5 could down-regulate the PDCD5 protein expression levels in lung tissues of infected mice. These data indicate that antisense oligonucleotide prop5 is a promising drug for prophylaxis and control influenza virus infections and provides an insight into the host-pathogen interaction.
PMCID: PMC3939472  PMID: 24509810
influenza A virus; host factor; antisense oligonucleotide; prop5
15.  New insights into the regulation of Axin function in canonical Wnt signaling pathway 
Protein & Cell  2014;5(3):186-193.
The Wnt signaling pathway plays crucial roles during embryonic development, whose aberration is implicated in a variety of human cancers. Axin, a key component of canonical Wnt pathway, plays dual roles in modulating Wnt signaling: on one hand, Axin scaffolds the “β-catenin destruction complex” to promote β-catenin degradation and therefore inhibits the Wnt signal transduction; on the other hand, Axin interacts with LRP5/6 and facilitates the recruitment of GSK3 to the plasma membrane to promote LRP5/6 phosphorylation and Wnt signaling. The differential assemblies of Axin with these two distinct complexes have to be tightly controlled for appropriate transduction of the “on” or “off” Wnt signal. So far, there are multiple mechanisms revealed in the regulation of Axin activity, such as post-transcriptional modulation, homo/hetero-polymerization and auto-inhibition. These mechanisms may work cooperatively to modulate the function of Axin, thereby playing an important role in controlling the canonical Wnt signaling. In this review, we will focus on the recent progresses regarding the regulation of Axin function in canonical Wnt signaling.
PMCID: PMC3967064  PMID: 24474204
Wnt signaling; Axin; post-transcriptional modification; polymerization; auto-inhibition
16.  New insights into the regulation of Axin function in canonical Wnt signaling pathway 
Protein & Cell  2014;5(3):186-193.
The Wnt signaling pathway plays crucial roles during embryonic development, whose aberration is implicated in a variety of human cancers. Axin, a key component of canonical Wnt pathway, plays dual roles in modulating Wnt signaling: on one hand, Axin scaffolds the “β-catenin destruction complex” to promote β-catenin degradation and therefore inhibits the Wnt signal transduction; on the other hand, Axin interacts with LRP5/6 and facilitates the recruitment of GSK3 to the plasma membrane to promote LRP5/6 phosphorylation and Wnt signaling. The differential assemblies of Axin with these two distinct complexes have to be tightly controlled for appropriate transduction of the “on” or “off” Wnt signal. So far, there are multiple mechanisms revealed in the regulation of Axin activity, such as post-transcriptional modulation, homo/hetero-polymerization and auto-inhibition. These mechanisms may work cooperatively to modulate the function of Axin, thereby playing an important role in controlling the canonical Wnt signaling. In this review, we will focus on the recent progresses regarding the regulation of Axin function in canonical Wnt signaling.
PMCID: PMC3967064  PMID: 24474204
Wnt signaling; Axin; post-transcriptional modification; polymerization; auto-inhibition
17.  Slit/Robo Signaling Mediates Spatial Positioning of Spiral Ganglion Neurons during Development of Cochlear Innervation 
The Journal of Neuroscience  2013;33(30):12242-12254.
During the development of periphery auditory circuits, spiral ganglion neurons (SGNs) extend their neurites to innervate cochlear hair cells (HCs) with their soma aggregated into a cluster spatially segregated from the cochlear sensory epithelium. The molecular mechanisms underlying this spatial patterning remain unclear. In this study, in situ hybridization in the mouse cochlea suggests that Slit2 and its receptor, Robo1/2, exhibit apparently complementary expression patterns in the spiral ganglion and its nearby region, the spiral limbus. In Slit2 and Robo1/2 mutants, the spatial restriction of SGNs was disrupted. Mispositioned SGNs were found to scatter in the space between the cochlear epithelium and the main body of spiral ganglion, and the neurites of mispositioned SGNs were misrouted and failed to innervate HCs. Furthermore, in Robo1/2 mutants, SGNs were displaced toward the cochlear epithelium as an entirety. Examination of different embryonic stages in the mutants revealed that the mispositioning of SGNs was due to a progressive displacement to ectopic locations after their initial normal settlement at an earlier stage. Our results suggest that Slit/Robo signaling imposes a restriction force on SGNs to ensure their precise positioning for correct SGN-HC innervations.
PMCID: PMC3721837  PMID: 23884932
18.  Local Plasticity of Dendritic Excitability Can Be Autonomous of Synaptic Plasticity and Regulated by Activity-Based Phosphorylation of Kv4.2 
PLoS ONE  2014;9(1):e84086.
While plasticity is typically associated with persistent modifications of synaptic strengths, recent studies indicated that modulations of dendritic excitability may form the other part of the engram and dynamically affect computational processing and output of neuronal circuits. However it remains unknown whether modulation of dendritic excitability is controlled by synaptic changes or whether it can be distinct from them. Here we report the first observation of the induction of a persistent plastic decrease in dendritic excitability decoupled from synaptic stimulation, which is localized and purely activity-based. In rats this local plasticity decrease is conferred by CamKII mediated phosphorylation of A-type potassium channels upon interaction of a back propagating action potential (bAP) with dendritic depolarization.
PMCID: PMC3880279  PMID: 24404150
19.  Finite element analysis of rapid canine retraction through reducing resistance and distraction 
The aims of this study were to compare different surgical approaches to rapid canine retraction by designing and selecting the most effective method of reducing resistance by a three-dimensional finite element analysis.
Material and Methods
Three-dimensional finite element models of different approaches to rapid canine retraction by reducing resistance and distraction were established, including maxillary teeth, periodontal ligament, and alveolar. The models were designed to dissect the periodontal ligament, root, and alveolar separately. A 1.5 N force vector was loaded bilaterally to the center of the crown between first molar and canine, to retract the canine distally. The value of total deformation was used to assess the initial displacement of the canine and molar at the beginning of force loading. Stress intensity and force distribution were analyzed and evaluated by Ansys 13.0 through comparison of equivalent (von Mises) stress and maximum shear stress.
The maximum value of total deformation with the three kinds of models occurred in the distal part of the canine crown and gradually reduced from the crown to the apex of the canine; compared with the canines in model 3 and model 1, the canine in model 2 had the maximum value of displacement, up to 1.9812 mm. The lowest equivalent (von Mises) stress and the lowest maximum shear stress were concentrated mainly on the distal side of the canine root in model 2. The distribution of equivalent (von Mises) stress and maximum shear stress on the PDL of the canine in the three models was highly concentrated on the distal edge of the canine cervix.
Removal of the bone in the pathway of canine retraction results in low stress intensity for canine movement. Periodontal distraction aided by surgical undermining of the interseptal bone would reduce resistance and effectively accelerate the speed of canine retraction.
PMCID: PMC3908765  PMID: 24626249
Distraction osteogenesis; Oral surgical procedures; Orthodontics; Finite element analysis
20.  Biosensing Using Microring Resonator Interferograms 
Sensors (Basel, Switzerland)  2014;14(1):1184-1194.
Optical low-coherence interferometry (OLCI) takes advantage of the variation in refractive index in silicon-wire microring resonator (MRR) effective lengths to perform glucose biosensing using MRR interferograms. The MRR quality factor (Q), proportional to the effective length, could be improved using the silicon-wire propagation loss and coupling ratio from the MRR coupler. Our study showed that multimode interference (MMI) performed well in broad band response, but the splitting ratio drifted to 75/25 due to the stress issue. The glucose sensing sensitivity demonstrated 0.00279 meter per refractive-index-unit (RIU) with a Q factor of ∼30,000 under transverse electric polarization. The 1,310 nm DFB laser was built in the OLCI system as the optical ruler achieving 655 nm characterization accuracy. The lowest sensing limitation was therefore 2 × 10−4 RIU. Moreover, the MRR effective length from the glucose sensitivity could be utilized to experimentally demonstrate the silicon wire effective refractive index with a width of 0.45 μm and height of 0.26 μm.
PMCID: PMC3926609  PMID: 24434876
interferometry; biophotonics; microring resonator; silicon wire; multimode interference; birefringence
21.  Evodiamine Induces Transient Receptor Potential Vanilloid-1-Mediated Protective Autophagy in U87-MG Astrocytes 
Cerebral ischemia is a leading cause of mortality and morbidity worldwide, which results in cognitive and motor dysfunction, neurodegenerative diseases, and death. Evodiamine (Evo) is extracted from Evodia rutaecarpa Bentham, a plant widely used in Chinese herbal medicine, which possesses variable biological abilities, such as anticancer, anti-inflammation, antiobesity, anti-Alzheimer's disease, antimetastatic, antianoxic, and antinociceptive functions. But the effect of Evo on ischemic stroke is unclear. Increasing data suggest that activation of autophagy, an adaptive response to environmental stresses, could protect neurons from ischemia-induced cell death. In this study, we found that Evo induced autophagy in U87-MG astrocytes. A scavenger of extracellular calcium and an antagonist of transient receptor potential vanilloid-1 (TRPV-1) decreased the percentage of autophagy accompanied by an increase in apoptosis, suggesting that Evo may induce calcium-mediated protective autophagy resulting from an influx of extracellular calcium. The same phenomena were also confirmed by a small interfering RNA technique to knock down the expression of TRPV1. Finally, Evo-induced c-Jun N-terminal kinases (JNK) activation was reduced by a TRPV1 antagonist, indicating that Evo-induced autophagy may occur through a calcium/c-Jun N-terminal kinase (JNK) pathway. Collectively, Evo induced an influx of extracellular calcium, which led to JNK-mediated protective autophagy, and this provides a new option for ischemic stroke treatment.
PMCID: PMC3884692  PMID: 24454492
22.  Genome wide association studies for body conformation traits in the Chinese Holstein cattle population 
BMC Genomics  2013;14:897.
Genome-wide association study (GWAS) is a powerful tool for revealing the genetic basis of quantitative traits. However, studies using GWAS for conformation traits of cattle is comparatively less. This study aims to use GWAS to find the candidates genes for body conformation traits.
The Illumina BovineSNP50 BeadChip was used to identify single nucleotide polymorphisms (SNPs) that are associated with body conformation traits. A least absolute shrinkage and selection operator (LASSO) was applied to detect multiple SNPs simultaneously for 29 body conformation traits with 1,314 Chinese Holstein cattle and 52,166 SNPs. Totally, 59 genome-wide significant SNPs associated with 26 conformation traits were detected by genome-wide association analysis; five SNPs were within previously reported QTL regions (Animal Quantitative Trait Loci (QTL) database) and 11 were very close to the reported SNPs. Twenty-two SNPs were located within annotated gene regions, while the remainder were 0.6–826 kb away from known genes. Some of the genes had clear biological functions related to conformation traits. By combining information about the previously reported QTL regions and the biological functions of the genes, we identified DARC, GAS1, MTPN, HTR2A, ZNF521, PDIA6, and TMEM130 as the most promising candidate genes for capacity and body depth, chest width, foot angle, angularity, rear leg side view, teat length, and animal size traits, respectively. We also found four SNPs that affected four pairs of traits, and the genetic correlation between each pair of traits ranged from 0.35 to 0.86, suggesting that these SNPs may have a pleiotropic effect on each pair of traits.
A total of 59 significant SNPs associated with 26 conformation traits were identified in the Chinese Holstein population. Six promising candidate genes were suggested, and four SNPs showed genetic correlation for four pairs of traits.
PMCID: PMC3879203  PMID: 24341352
Dairy cattle; GWAS; Body conformation traits; SNP; Holstein; QTL
23.  Ceramide Mediates Ox-LDL-Induced Human Vascular Smooth Muscle Cell Calcification via p38 Mitogen-Activated Protein Kinase Signaling 
PLoS ONE  2013;8(12):e82379.
Vascular calcification is associated with significant cardiovascular morbidity and mortality, and has been demonstrated as an actively regulated process resembling bone formation. Oxidized low density lipoprotein (Ox-LDL) has been identified as a regulatory factor involved in calcification of vascular smooth muscle cells (VSMCs). Additionally, over-expression of recombinant human neutral sphingomyelinase (N-SMase) has been shown to stimulate VSMC apoptosis, which plays an important role in the progression of vascular calcification. The aim of this study is to investigate whether ceramide regulates Ox-LDL-induced calcification of VSMCs via activation of p38 mitogen-activated protein kinase (MAPK) pathway. Ox-LDL increased the activity of N-SMase and the level of ceramide in cultured VSMCs. Calcification and the osteogenic transcription factor, Msx2 mRNA expression were reduced by N-SMase inhibitor, GW4869 in the presence of Ox-LDL. Usage of GW4869 inhibited Ox-LDL-induced apoptosis in VSMCs, an effect which was reversed by C2-ceramide. Additionally, C2-ceramide treatment accelerated VSMC calcification, with a concomitant increase in ALP activity. Furthermore, C2-ceramide treatment enhanced Ox-LDL-induced VSMC calcification. Addition of caspase inhibitor, ZVAD-fmk attenuated Ox-LDL-induced calcification. Both Ox-LDL and C2-ceramide treatment increased the phosphorylation of p38 MAPK. Inhibition of p38 MAPK by SB203580 attenuated Ox-LDL-induced calcification of VSMCs. These data suggest that Ox-LDL activates N-SMase-ceramide signaling pathway, and stimulates phosphorylation of p38 MAPK, leading to apoptosis in VSMCs, which initiates VSMC calcification.
PMCID: PMC3865066  PMID: 24358176
24.  Antcin C from Antrodia cinnamomea Protects Liver Cells Against Free Radical-Induced Oxidative Stress and Apoptosis In Vitro and In Vivo through Nrf2-Dependent Mechanism 
In this study, we investigated the cytoprotective effects of antcin C, a steroid-like compound isolated from Antrodia cinnamaomea against AAPH-induced oxidative stress and apoptosis in human hepatic HepG2 cells. Pretreatment with antcin C significantly protects hepatic cells from AAPH-induced cell death through the inhibition of ROS generation. Furthermore, AAPH-induced lipid peroxidation, ALT/AST secretion and GSH depletion was significantly inhibited by antcin C. The antioxidant potential of antcin C was correlated with induction of antioxidant genes including, HO-1, NQO-1, γ-GCLC, and SOD via transcriptional activation of Nrf2. The Nrf2 activation by antcin C is mediated by JNK1/2 and PI3K activation, whereas pharmacologic inhibition of JNK1/2 and PI3K abolished antcin C-induced Nrf2 activity. In addition, AAPH-induced apoptosis was significantly inhibited by antcin C through the down-regulation of pro-apoptotic factors including, Bax, cytochrome c, capase 9, -4, -12, -3, and PARP. In vivo studies also show that antcin C significantly protected mice liver from AAPH-induced hepatic injury as evidenced by reduction in hepatic enzymes in circulation. Further, immunocytochemistry analyses showed that antcin C significantly increased HO-1 and Nrf2 expression in mice liver tissues. These results strongly suggest that antcin C could protect liver cells from oxidative stress and cell death via Nrf2/ARE activation.
PMCID: PMC3874316  PMID: 24391672
25.  Lynx: a database and knowledge extraction engine for integrative medicine 
Nucleic Acids Research  2013;42(D1):D1007-D1012.
We have developed Lynx (—a web-based database and a knowledge extraction engine, supporting annotation and analysis of experimental data and generation of weighted hypotheses on molecular mechanisms contributing to human phenotypes and disorders of interest. Its underlying knowledge base (LynxKB) integrates various classes of information from >35 public databases and private collections, as well as manually curated data from our group and collaborators. Lynx provides advanced search capabilities and a variety of algorithms for enrichment analysis and network-based gene prioritization to assist the user in extracting meaningful knowledge from LynxKB and experimental data, whereas its service-oriented architecture provides public access to LynxKB and its analytical tools via user-friendly web services and interfaces.
PMCID: PMC3965040  PMID: 24270788

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