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1.  Arabidopsis Raf-Like Mitogen-Activated Protein Kinase Kinase Kinase Gene Raf43 Is Required for Tolerance to Multiple Abiotic Stresses 
PLoS ONE  2015;10(7):e0133975.
Mitogen-activated protein kinase (MAPK) cascades are critical signaling modules that mediate the transduction of extracellular stimuli into intracellular response. A relatively large number of MAPKKKs have been identified in a variety of plant genomes but only a few of them have been studied for their biological function. In the present study, we identified an Arabidopsis Raf-like MAPKKK gene Raf43 and studied its function in biotic and abiotic stress response using a T-DNA insertion mutant raf43-1 and two Raf43-overexpressing lines Raf43-OE#1 and Raf43-OE#13. Expression of Raf43 was induced by multiple abiotic and biotic stresses including treatments with drought, mannitol and oxidative stress or defense signaling molecule salicylic acid and infection with necrotrophic fungal pathogen Botrytis cinerea. Seed germination and seedling root growth of raf43-1 were significantly inhibited on MS medium containing mannitol, NaCl, H2O2 or methyl viologen (MV) while seed germination and seedling root growth of the Raf43-OE#1 and Raf43-OE#13 lines was similar to wild type Col-0 under the above stress conditions. Soil-grown raf43-1 plants exhibited reduced tolerance to MV, drought and salt stress. Abscisic acid inhibited significantly seed germination and seedling root growth of the raf43-1 line but had no effect on the two Raf43-overexpressing lines. Expression of stress-responsive RD17 and DREB2A genes was significantly down-regulated in raf43-1 plants. However, the raf43-1 and Raf43-overexpressing plants showed similar disease phenotype to the wild type plants after infection with B. cinerea or Pseudomonas syringae pv. tomato DC3000. Our results demonstrate that Raf43, encoding for a Raf-like MAPKKK, is required for tolerance to multiple abiotic stresses in Arabidopsis.
PMCID: PMC4519275  PMID: 26222830
2.  Induction of dsRNA-activated protein kinase links mitochondrial unfolded protein response to the pathogenesis of intestinal inflammation 
Gut  2011;61(9):1269-1278.
Inflammatory bowel diseases (IBDs) feature multiple cellular stress responses, including endoplasmic reticulum (ER) unfolded protein responses (UPRs). UPRs represent autoregulatory pathways that adjust organelle capacity to cellular demand. A similar mechanism, mitochondrial UPR (mtUPR), has been described for mitochondria. ER UPR in intestinal epithelial cells (IECs) contributes to the development of intestinal inflammation, and since mitochondrial alterations and dysfunction are implicated in the pathogenesis of IBDs, the authors characterised mtUPR in the context of intestinal inflammation.
Truncated ornithine transcarbamylase was used to selectively induce mtUPR in a murine IEC line. Dextran sodium sulphate (DSS) was administered to PKR (double-stranded-RNA-activated protein kinase) knockout mice to induce IEC stress in vivo and to test for their susceptibility to DSS-induced colitis. Expression levels of the mitochondrial chaperone chaperonin 60 (CPN60) and PKR were quantified in IECs from patients with IBDs and from murine models of colitis using immunohistochemistry and Western blot analysis.
Selective mtUPR induction by truncated ornithine transcarbamylase transfection triggered the phosphorylation of eukaryotic translation initiation factor (eIF) 2α and cJun through the recruitment of PKR. Using pharmacological inhibitors and small inhibitory RNA, the authors identified mtUPR-induced eIF2α phosphorylation and transcription factor activation (cJun/AP1) as being dependent on the activities of the mitochondrial protease ClpP and the cytoplasmic kinase PKR. Pkr−/− mice failed to induce CPN60 in IECs upon DSS treatment at early time points and subsequently showed an almost complete resistance to DSS-induced colitis. Under inflammatory conditions, primary IECs from patients with IBDs and two murine models of colitis exhibited a strong induction of the mtUPR marker protein CPN60 associated with enhanced expression of PKR.
PKR integrates mtUPR into the disease-relevant ER UPR via eIF2α phosphorylation and AP1 activation. Induction of mtUPR and PKR was observed in IECs from murine models and patients with IBDs. The authors’ results indicate that PKR might link mitochondrial stress to intestinal inflammation.
PMCID: PMC4514769  PMID: 21997551
3.  Genome Sequence of Brevibacillus formosus F12T for a Genome-Sequencing Project for Genomic Taxonomy and Phylogenomics of Bacillus-Like Bacteria 
Genome Announcements  2015;3(4):e00753-15.
Brevibacillus formosus F12T is a Gram-positive, spore-forming, and strictly aerobic bacterium. Here, we report the draft 6.215-Mb genome sequence of B. formosus F12T, which will provide useful information for genomic taxonomy and phylogenomics of Bacillus-like bacteria, as well as for the functional gene mining and application of B. formosus.
PMCID: PMC4513144  PMID: 26205874
4.  Identification of ULK1 as a novel biomarker involved in miR-4487 and miR-595 regulation in neuroblastoma SH-SY5Y cell autophagy 
Scientific Reports  2015;5:11035.
Autophagy, referring to an evolutionarily conserved, multi-step lysosomal degradation process, has been well-known to be initiated by Unc-51 like kinase 1 (ULK1) with some links to Parkinson’s disease (PD). MicroRNAs (miRNAs), small and non-coding endogenous RNAs 22 ~ 24 nucleotides (nt) in length, have been demonstrated to play an essential role for modulating autophagy. Recently, the relationships between miRNAs and autophagy have been widely reported in PD; however, how microRNAs regulate autophagy still remains in its infancy. Thus, in this study, we computationally constructed the ULK1-regulated autophagic kinase subnetwork in PD and further identified ULK1 able to negatively regulate p70S6K in starvation-induced autophagy of neuroblastoma SH-SY5Y cells. Combination of in silico prediction and microarray analyses, we identified that miR-4487 and miR-595 could target ULK1 and experimentally verified they could negatively or positively regulate ULK1-mediated autophagy. In conclusion, these results may uncover the novel ULK1-p70S6K autophagic pathway, as well as miR-4487 and miR-595 as new ULK1 target miRNAs. Thus, these findings would provide a clue to explore ULK1 and its target miRNAs as potential biomarkers in the future PD therapy.
PMCID: PMC4505320  PMID: 26183158
5.  The Role of Temporal Envelope and Fine Structure in Mandarin Lexical Tone Perception in Auditory Neuropathy Spectrum Disorder 
PLoS ONE  2015;10(6):e0129710.
Temporal information in a signal can be partitioned into temporal envelope (E) and fine structure (FS). Fine structure is important for lexical tone perception for normal-hearing (NH) listeners, and listeners with sensorineural hearing loss (SNHL) have an impaired ability to use FS in lexical tone perception due to the reduced frequency resolution. The present study was aimed to assess which of the acoustic aspects (E or FS) played a more important role in lexical tone perception in subjects with auditory neuropathy spectrum disorder (ANSD) and to determine whether it was the deficit in temporal resolution or frequency resolution that might lead to more detrimental effects on FS processing in pitch perception. Fifty-eight native Mandarin Chinese-speaking subjects (27 with ANSD, 16 with SNHL, and 15 with NH) were assessed for (1) their ability to recognize lexical tones using acoustic E or FS cues with the “auditory chimera” technique, (2) temporal resolution as measured with temporal gap detection (TGD) threshold, and (3) frequency resolution as measured with the Q10dB values of the psychophysical tuning curves. Overall, 26.5%, 60.2%, and 92.1% of lexical tone responses were consistent with FS cues for tone perception for listeners with ANSD, SNHL, and NH, respectively. The mean TGD threshold was significantly higher for listeners with ANSD (11.9 ms) than for SNHL (4.0 ms; p < 0.001) and NH (3.9 ms; p < 0.001) listeners, with no significant difference between SNHL and NH listeners. In contrast, the mean Q10dB for listeners with SNHL (1.8±0.4) was significantly lower than that for ANSD (3.5±1.0; p < 0.001) and NH (3.4±0.9; p < 0.001) listeners, with no significant difference between ANSD and NH listeners. These results suggest that reduced temporal resolution, as opposed to reduced frequency selectivity, in ANSD subjects leads to greater degradation of FS processing for pitch perception.
PMCID: PMC4459992  PMID: 26052707
6.  A novel method to identify pathways associated with renal cell carcinoma based on a gene co-expression network 
Oncology Reports  2015;34(2):567-576.
The aim of the present study was to develop a novel method for identifying pathways associated with renal cell carcinoma (RCC) based on a gene co-expression network. A framework was established where a co-expression network was derived from the database as well as various co-expression approaches. First, the backbone of the network based on differentially expressed (DE) genes between RCC patients and normal controls was constructed by the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. The differentially co-expressed links were detected by Pearson’s correlation, the empirical Bayesian (EB) approach and Weighted Gene Co-expression Network Analysis (WGCNA). The co-expressed gene pairs were merged by a rank-based algorithm. We obtained 842; 371; 2,883 and 1,595 co-expressed gene pairs from the co-expression networks of the STRING database, Pearson’s correlation EB method and WGCNA, respectively. Two hundred and eighty-one differentially co-expressed (DC) gene pairs were obtained from the merged network using this novel method. Pathway enrichment analysis based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database and the network enrichment analysis (NEA) method were performed to verify feasibility of the merged method. Results of the KEGG and NEA pathway analyses showed that the network was associated with RCC. The suggested method was computationally efficient to identify pathways associated with RCC and has been identified as a useful complement to traditional co-expression analysis.
PMCID: PMC4487672  PMID: 26058425
renal cell carcinoma; pathway; co-expression network; merge; rank
7.  Robotic thoracic surgery of the posterior superior mediastinal mass 
PMCID: PMC4481364  PMID: 26207255
8.  Robotic thoracic surgery of the left pleural cupula mediastinal mass 
PMCID: PMC4486908  PMID: 26207234
9.  Robotic thoracic surgery of the right posterior inferior mediastinal mass 
PMCID: PMC4486924  PMID: 26207233
10.  An embryo of protocells: The capsule of graphene with selective ion channels 
Scientific Reports  2015;5:10258.
The synthesis of artificial cell is a route for searching the origin of protocell. Here, we create a novel cell model of graphene capsules with selective ion channels, indicating that graphene might be an embryo of protocell membrane. Firstly, we found that the highly oxidized graphene and phospholipid-graphene oxide composite would curl into capsules under a strongly acidic saturated solution of heavy metallic salt solution at low temperature. Secondly, L-amino acids exhibited higher reactivity than D-amino acids on graphene oxides to form peptides, and the formed peptides in the influence of graphene would be transformed into a secondary structure, promoting the formation of left-handed proteins. Lastly, monolayer nanoporous graphene, prepared by unfocused 84Kr25+, has a high selectivity for permeation of the monovalent metal ions ( Rb+ > K+ > Cs+ > Na+ > Li+, based on permeation concentration), but does not allow Cl- go through. It is similar to K+ channels, which would cause an influx of K+ into capsule of graphene with the increase of pH in the primitive ocean, creating a suitable inner condition for the origin of life. Therefore, we built a model cell of graphene, which would provide a route for reproducing the origin of life.
PMCID: PMC4437305  PMID: 25989440
11.  Steroid Anti-Inflammatory Effects Did Not Improve Organ Quality in Brain-Dead Rats 
BioMed Research International  2015;2015:207534.
Effect of glucocorticoid administration on improving the outcomes of kidney and liver allografts has not been clearly elucidated. This study investigated the effect of prednisolone administration after onset of brain death (BD) on kidney and liver in a controlled rat model of BD. BD was induced in rats by inflating an epidurally placed balloon catheter. Animals were treated with saline or prednisolone (5, 12.5, or 22.5 mg/kg) one hour after the onset of BD. After 4 hours of BD, experiments were terminated and serum and tissues were collected. Tissue gene and protein expression were measured for markers of inflammation, apoptosis, and cellular stress response markers. Prednisolone caused a reduction of plasma levels of IL-6, while the tissue expression of IL-6, IL-1β, and MCP-1 in both kidney and liver were also reduced. Creatinine plasma levels, complement (C3) expression, HSP-70, HO-1, Bcl2/BAX ratio, and PMN influx did not significantly change in kidney nor liver. Plasma AST and LDH levels were increased in the prednisolone treated group. Our results demonstrate prednisolone can has an anti-inflammatory effect mediated through reducing serum circulating cytokines. However, this anti-inflammatory effect does not translate into improved kidney function and indeed was associated with increased liver injury markers.
PMCID: PMC4452233  PMID: 26090389
12.  Cordyceps sinensis attenuates renal fibrosis and suppresses BAG3 induction in obstructed rat kidney 
BAG3 regulates a number of cellular processes, including cell proliferation, apoptosis, adhesion and migration, and epithelial-mesenchymal transition (EMT). However, the role of BAG3 in renal tubular EMT and renal interstitial fibrosis remains elusive. This study aimed to examine the dynamic expression of BAG3 during renal fibrosis, and to investigate the efficacy of Cordyceps sinensis (C. sinensis) on renal fibrosis. A rat model of unilateral ureteral obstruction (UUO) was established, and the expression of BAG3 and α-SMA, and the efficacy of C. sinensis on renal fibrosis induced by UUO were examined. The results showed that UUO led to collagen accumulation, which was significantly suppressed by C. sinensis. UUO increased the expression of BAG3 and α-SMA, a mesenchymal marker, while UUO induced BAG3 and α-SMA expression was significantly inhibited by C. sinensis. In addition, immunohistochemical staining demonstrated that BAG3 immunoreactivity was restricted to tubular epithelium. In conclusion, BAG3 is a potential target for the prevention and/or treatment of renal fibrosis, and C. Sinensis is a promising agent for renal fibrosis.
PMCID: PMC4494144  PMID: 26175854
BAG3; Cordyceps sinensis; unilateral ureteral obstruction; renal fibrosis
13.  Quantitative assessment of amyotrophic lateral sclerosis with diffusion tensor imaging in 3.0T magnetic resonance 
Diffusion tensor imaging (DTI) was used to measure the fractional anisotropy (FA) and apparent diffusion coefficient (ADC) value in amyotrophic lateral sclerosis (ALS) patients to determine their diagnostic value. 69 ALS patients and 23 healthy controls were scanned with DTI sequence in 3.0T MR, and FA and ADC values in 18 regions were evaluated. Compared with the controls, the ADC values of patients in bilateral centrum semiovale, deep frontal and parietal white matter were significantly increased (P < 0.05), while the FA values in cerebral peduncle, posterior limb of internal capsule (PLIC), corona radiata, centrumsemiovale, bilateral deep frontal white matter, the genu and the splenium of the corpus callosum were significantly decreased (P < 0.05). When the FA cut-off value was set to ≤ 0.6860 for the cerebral peduncle, sensitivity (SE) and specificity (SP) of ALS were 95.7% and 83.9% respectively. When the cut-off value was set to ≤ 0.7085 for PLIC, SE and SP were 95.7% and 85.7% respectively. When the cut-off value was set to ≤ 0.6950 for corona radiata, SE and SP were 100.0% and 95.7%, respectively. DTI can be used to quantitatively evaluate injury in ALS patients.
PMCID: PMC4509358  PMID: 26221413
Amyotrophic lateral sclerosis; diffusion tensor imaging; fractional anisotropy; quantitative measurment
14.  Impact of Conditional miRNA126 Overexpression on Apoptosis-Resistant Endothelial Cell Production 
PLoS ONE  2015;10(5):e0126661.
The activation of endothelial cells is essential to repair damage caused by atherosclerosis via endothelial cell proliferation and migration. Overexpression of VEGF (vascular endothelial growth factor) and the downstream gene, B-cell lymphoma-2 (BCL-2) could result in apoptosis-resistant endothelial cells, which are responsible for aggravated hyperplasia and instable plaques generation. Previous studies have shown that miRNA126 could regulate the expression of VEGF. Here, we verified the existence of a miRNA126 binding site in VEGF’s 3’UTR. Additionally, VEGF regulated BCL-2 expression via AP1 (Activator Protein 1) binding site in BCL-2’s promoter. Next, we established an apoptosis-resistant endothelial cell line and constructed a lentiviral vector to express miRNA126 under the control of the BCL-2 promoter to investigate whether conditional expression of miRNA126 could modulate VEGF and BCL-2 expression in apoptosis-resistant endothelial cells. This lentiviral system specifically expressed miRNA126 in cells with high BCL-2 levels, downregulated VEGF expression, inhibited MAPK pathway activation and downregulated BCL-2 expression via suppression of AP1, and as a whole, reduced apoptosis-resistant endothelial cells, while the effects of miRNA126 on normal endothelial cells were relatively small. Our results demonstrate that conditional miRNA126 overexpression under the control of the downstream BCL-2 promoter provides a flexible regulatory strategy for reducing the apoptosis-resistant endothelial cells without having a significant impact on normal endothelial cells.
PMCID: PMC4427270  PMID: 25961846
15.  Atorvastatin Improves Inflammatory Response in Atherosclerosis by Upregulating the Expression of GARP 
Mediators of Inflammation  2015;2015:841472.
Regulatory T cells play an important role in the progression of atherosclerosis. GARP is a newly biological membrane molecule existed on activated Tregs, which is related to the release of TGF-β. The antiatherosclerosis effects of statins partly depend on their multiple immune modulatory potencies. In this paper, we present that atorvastatin could upregulate the expression of GARP and TGF-β in CD4+ T cells and increase the numbers of CD4+LAP+ and CD4+Foxp3+ regulatory T cells in ApoE−/− mice. Also, we indicate that atorvastatin promotes the aggregation of GARP+ and Foxp3+ cells and secretory of the TGF-β1 in atherosclerotic plaques. Furthermore, we prove that atorvastatin could delay the procession of atherosclerosis and improve the stability of atherosclerotic plaques. Interestingly, we report that inhibition of GARP distinctly inhibits the anti-inflammatory effects of atorvastatin. We conclude that atorvastatin improves the inflammatory response in atherosclerosis partly by upregulating the expression of GARP on regulatory T cells.
PMCID: PMC4442006  PMID: 26063978
16.  High frequency of loss of PTEN expression in human solid salivary adenoid cystic carcinoma and its implication for targeted therapy 
Oncotarget  2015;6(13):11477-11491.
Salivary gland tumor (SGT) is one of the least studied cancers due to its rarity and heterogeneous histological types. Here, we reported that loss of PTEN expression was most frequently found in the poorly differentiated, high grade solid adenoid cystic carcinomas. Loss of PTEN expression correlated with activation of mTOR by increased phosphorylated S6 ribosome protein. We further functionally studied the role of PTEN in a pair of human SACC cell lines, SACC-83 and SACC-LM. Reduced PTEN level was correlated with the metastasis potential. When we knocked down PTEN in the SACC-83 cell line, we observed increased proliferation and enhanced migration/invasion in vitro, and increased tumor size in vivo. We further tested the therapeutical effect by applying a PI3K/mTOR inhibitor NVP-BEZ235 to both SACC cell lines. Decreased cell proliferation, increased apoptosis, as well as reduced cell migration/invasion were observed in both cell lines upon the NVP-BEZ235 treatment. Moreover, the NVP-BEZ235 treatment in a SGT xenograft mouse model significantly reduced primary tumor size and lung metastasis. Taken together, our results demonstrated that PTEN is a potent tumor suppressor in human SGTs, and targeting PI3K/mTOR pathway may be effective in the targeted therapy for human SGT patients with loss of PTEN expression.
PMCID: PMC4484470  PMID: 25909167
salivary gland tumors; adenoid cystic carcinoma; PTEN; targeted therapy
17.  Bacterial Pathogens and Community Composition in Advanced Sewage Treatment Systems Revealed by Metagenomics Analysis Based on High-Throughput Sequencing 
PLoS ONE  2015;10(5):e0125549.
This study used 454 pyrosequencing, Illumina high-throughput sequencing and metagenomic analysis to investigate bacterial pathogens and their potential virulence in a sewage treatment plant (STP) applying both conventional and advanced treatment processes. Pyrosequencing and Illumina sequencing consistently demonstrated that Arcobacter genus occupied over 43.42% of total abundance of potential pathogens in the STP. At species level, potential pathogens Arcobacter butzleri, Aeromonas hydrophila and Klebsiella pneumonia dominated in raw sewage, which was also confirmed by quantitative real time PCR. Illumina sequencing also revealed prevalence of various types of pathogenicity islands and virulence proteins in the STP. Most of the potential pathogens and virulence factors were eliminated in the STP, and the removal efficiency mainly depended on oxidation ditch. Compared with sand filtration, magnetic resin seemed to have higher removals in most of the potential pathogens and virulence factors. However, presence of the residual A. butzleri in the final effluent still deserves more concerns. The findings indicate that sewage acts as an important source of environmental pathogens, but STPs can effectively control their spread in the environment. Joint use of the high-throughput sequencing technologies is considered a reliable method for deep and comprehensive overview of environmental bacterial virulence.
PMCID: PMC4418606  PMID: 25938416
19.  Ethnobotanical study on medicinal plants used by Maonan people in China 
This paper is based on an ethnobotanical investigation that focused on the traditional medicinal plants used by local Maonan people to treat human diseases in Maonan concentration regions. The Maonan people have relied on traditional medicine since ancient times, especially medicinal plants. The aim of this study is to document medicinal plants used by the Maonans and to report the status of medicinal plants and associated traditional knowledge.
Ethnobotanical data were collected from June 2012 to September 2014 in Huanjiang Maonan Autonomous County, northern Guangxi, southwest China. In total, 118 knowledgeable informants were interviewed. Following statistically sampling method, eighteen villages from 5 townships were selected to conduct field investigations. Information was collected through the approache of participatory observation, semi-structured interviews, ranking exercises, key informant interviews, focus group discussions, and participatory rural appraisals.
A total of 368 medicinal plant species were investigated and documented together with their medicinal uses by the Maonans, most of which were obtained from the wild ecosystems. The plants were used to treat 95 human diseases. Grinding was a widely used method to prepare traditional herbal medicines. There were significant relationships between gender and age, and between gender and informants’ knowledge of medicinal plant use. Deforestation for agricultural purposes was identified as the most destructive factor of medicinal plants, followed by drought and over-harvest.
The species diversity of medicinal plants used by the Maonans in the study area was very rich. Medicinal plants played a significant role in healing various human disorders in the Maonan communities. However, the conflicts between traditional inheriting system and recent socio-economic changes (and other factors) resulted in the reduction or loss of both medicinal plants and associated indigenous knowledge. Thus, conservation efforts and policies, and innovation of inheriting system are necessary for protecting the medicinal plants and associated indigenous knowledge. Awareness is also needed to be raised among local Maonans focusing on sustainable utilization and management of both medicinal plants and traditional knowledge.
PMCID: PMC4449599  PMID: 25925830
Medicinal plants; Traditional knowledge; The Maonans; Ethnomedicine; Huanjiang county
20.  Comparison of osteotomy versus non-osteotomy approach for congenital scoliosis: a retrospective study of three surgical techniques 
Anz Journal of Surgery  2014;85(4):249-254.
Currently, there are many reports about congenital scoliosis (CS) treatment, but there are still controversies existing with respect to selecting its surgical methods.
Retrospective analyses were conducted on 31 CS patients. The surgical treatments included the following: posterior instrumentation (10 patients; group 1), pedicle subtraction osteotomy (11 patients; group 2) and vertebral column resection (10 patients; group 3).
All patients had remarkable improvements in morphology, image findings, visual analogue scale and American Spinal Injury Association classification. Groups 2 and 3 had greater preoperative sagittal Cobb's angle (25.0, 62.2 and 9.2°, respectively), greater intra-operative blood loss (604.5, 620.0 and 460.0 mL, respectively) and fewer fused segments (5.8, 6.3 and 9.2, respectively) than group 1. As compared with group 1, groups 2 and 3 had greater correction rate of coronal Cobb's angle (79.6 ± 12.8, 78.2 ± 10.1% versus 56.1 ± 11.1%), and coronal trunk inclination (77.6 ± 14.2, 85.2 ± 11.0% versus 45.0 ± 42.5%). The sagittal Cobb's angle correction rates of three groups were 67.7 ± 42.9, 79.3 ± 27.6, 84.3 ± 12.1%, respectively, which showed no significant difference (P = 0.461). With an average follow-up of 3.5, 3.2 and 4.0 years, the correction loss rate of coronal Cobb's angle in group 1 was higher than those of groups 2 and 3.
For CS patients, osteotomy procedure had less fused segments, along with a greater correction rate and lower correction loss, which were more advantageous for those with severe deformity in sagittal plane or nerve decompression requirements.
PMCID: PMC4409081  PMID: 25316619
congenital kyphosis; congenital scoliosis; orthopedagogics; osteotomy; spinal deformity; spinal fusion
21.  A Neutral Thermostable β-1,4-Glucanase from Humicola insolens Y1 with Potential for Applications in Various Industries 
PLoS ONE  2015;10(4):e0124925.
We cloned a new glycoside hydrolase family 6 gene, Hicel6C, from the thermophilic fungus Humicola insolens Y1 and expressed it in Pichia pastoris. Using barley β-glucan as a substrate, recombinant HiCel6C protein exhibited neutral pH (6.5) and high temperature (70°C) optima. Distinct from most reported acidic fungal endo-β-1,4-glucanases, HiCel6C was alkali-tolerant, retaining greater than 98.0, 61.2, and 27.6% of peak activity at pH 8.0, 9.0, and 10.0, respectively, and exhibited good stability over a wide pH range (pH 5.0−11.0) and at temperatures up to 60°C. The Km and Vmax values of HiCel6C for barley β-glucan were 1.29 mg/mL and 752 μmol/min·mg, respectively. HiCel6C was strictly specific for the β-1,4-glucoside linkage exhibiting activity toward barley β-glucan, lichenan, and carboxy methylcellulose sodium salt (CMC-Na), but not toward laminarin (1,3-β-glucan). HiCel6C cleaved the internal glycosidic linkages of cellooligosaccharides randomly and thus represents an endo-cleaving enzyme. The predominant product of polysaccharide hydrolysis by HiCel6C was cellobiose, suggesting that it functions by an endo-processive mechanism. The favorable properties of HiCel6C make it a good candidate for basic research and for applications in the textile and brewing industries.
PMCID: PMC4409357  PMID: 25909505
22.  Innate PI3K p110δ regulates Th1/Th17 development and microbiota-dependent colitis 
The p110δ subunit of class IA phosphoinositide 3-kinase modulates signaling in innate immune cells. We previously demonstrated that mice harboring a kinase-dead p110δ subunit (p110δKD) develop spontaneous colitis. Macrophages contributed to the Th1/Th17 cytokine bias in p110δKD mice through increased IL-12 and IL-23 expression. Here, we show that the enteric microbiota is required for colitis development in germ free p110δKD mice. Colonic tissue and macrophages from p110δKD mice produce significantly less IL-10 compared to wild type (WT) mice. p110δKD APC co-cultured with naïve CD4+ antigen-specific T cells also produce significantly less IL-10, and induce more IFN-γ- and IL-17A-producing CD4+ T cells compared to WT APC. Illustrating the importance of APC – T cell interactions in colitis pathogenesis in vivo, Rag1-/-/p110δKD mice develop mild colonic inflammation and produced more colonic IL-12p40 compared to Rag1-/- mice. However, CD4+CD45RBhigh/low T cell Rag1-/-/p110δKD recipient mice develop severe colitis with increased percentages of IFN-γ- and IL-17A-producing lamina propria CD3+CD4+ T cells compared to Rag1-/- recipient mice. Intestinal tissue samples from patients with Crohn’s disease reveal significantly lower expression of PIK3CD compared to intestinal samples from non-IBD control subjects (p<0.05). PIK3CD expression inversely correlated with the ratio of IL12B:IL10 expression. In conclusion, the PI3K subunit p110δ controls homeostatic APC – T cell interactions by altering the balance between IL-10 and IL-12/23. Defects in p110δ expression and/or function may underlie the pathogenesis of human IBD and lead to new therapeutic strategies.
PMCID: PMC3992276  PMID: 24634494
Monocytes/Macrophages; Mucosa; Cytokines; Inflammation; Th1/Th2 Cells
23.  Prospective validation of an ultrasound-based thyroid imaging reporting and data system (TI-RADS) on 3980 thyroid nodules 
Objective: Ultrasound (US) features of solidity, hypoechogenicity or marked hypoechogenicity, microlobulated or irregular margins, microcalcifications, and taller-than-wide shape are suspicious characteristics for thyroid nodules. An US based Thyroid Imaging Reporting and Data System (TI-RADS) is classified based on the number of aforesaid features. TI-RADS category 3 included nodules without any suspicious features, and categories 4a, 4b, 4c, and 5 included nodules with one, two, three or four, or five suspicious US features. The purpose of the study was to prospectively validate the effectiveness of the TI-RADS. Methods: From October 2011 to June 2013, we prospectively categorized 3980 thyroid nodules (3752 benign and 228 malignant lesions) in 2921 patients using TI-RADS classification. TI-RADS categories 2 and 3 were considered as benign whereas TI-RADS categories 4 and 5 as malignant. The sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV) and accuracy were calculated. Results: Of the 3980 nodules, 2953 nodules were TI-RADS category 2 (0% malignancy), 466 nodules TI-RADS category 3 (1.3% malignancy), 186 nodules TI-RADS category 4a (4.8% malignancy), 165 nodules TI-RADS category 4b (30.3% malignancy), 188 nodules TI-RADS category 4c (75.5% malignancy), and 22 nodules TI-RADS category 5 (95.5% malignancy). The sensitivity, specificity, PPV, NPV and accuracy were 97%, 90%, 40%, 99%, and 91%, respectively. Conclusions: TI-RADS classification had great diagnostic value in diagnosing thyroid nodules. The actual probability of malignancy was in accord with the theory risk of malignancy.
PMCID: PMC4484032  PMID: 26131184
Thyroid imaging reporting and data system (TI-RADS); thyroid nodule; ultrasound; diagnosis
24.  Acoustic radiation force impulse elastography for differentiation of malignant and benign breast lesions: a meta-analysis 
This meta-analysis was aimed to assess the diagnostic performance of acoustic radiation force impulse (ARFI) elastography for the differentiation of malignant and benign breast lesions. The databases of PubMed, Web of ScienceTM, WanFang, Vip, SinoMed and China National Knowledge Infrastructure were searched for all studies that evaluated the diagnostic performance of ARFI including virtual touch tissue quantification (VTQ) and virtual touch tissue imaging (VTI). All the studies were published prior to Mar. 21, 2014. The studies published in English or Chinese were collected. A total of 11 studies, including 1,408 breast lesions from 1,245 women, were analyzed. The values of summary sensitivity and summary specificity were 0.843 (95% confidence interval [CI]: 0.811-0.872) and 0.932 (95% CI: 0.913-0.948) for VTQ of ARFI, and 0.864 (95% CI: 0.799-0.914) and 0.882 (95% CI: 0.832-0.922) for VTI of ARFI, respectively. Subgroup analysis excluding mucinous carcinoma and carcinoma in situ showed higher summary sensitivity (0.877 95% CI: 0.835-0.911), higher summary specificity (0.943 95% CI: 0.921-0.960) and lower heterogeneity (I2=23.5%). The cut-off values for shear wave velocity of VTQ ranged widely from 2.89 to 6.71 m/s, while the VTI ranged narrowly from 1.37 to 1.66. In general, ARFI elastography seems to be a good method for differentiation between benign and malignant breast lesions. However, its usefulness for identifying breast mucinous carcinoma and breast carcinoma in situ is limited. VTI seems to be more reliable and repeatable than VTQ.
PMCID: PMC4484950  PMID: 26131049
Breast lesion; acoustic radiation force impulse; ultrasound; elastography; meta-analysis
25.  Systems biology network-based discovery of a small molecule activator BL-AD008 targeting AMPK/ZIPK and inducing apoptosis in cervical cancer 
Oncotarget  2015;6(10):8071-8088.
The aim of this study was to discover a small molecule activator BL-AD008 targeting AMPK/ZIPK and inducing apoptosis in cervical cancer. In this study, we systematically constructed the global protein-protein interaction (PPI) network and predicted apoptosis-related protein connections by the Naïve Bayesian model. Then, we identified some classical apoptotic PPIs and other previously unrecognized PPIs between apoptotic kinases, such as AMPK and ZIPK. Subsequently, we screened a series of candidate compounds targeting AMPK/ZIPK, synthesized some compounds and eventually discovered a novel dual-target activator (BL-AD008). Moreover, we found BL-AD008 bear remarkable anti-proliferative activities toward cervical cancer cells and could induce apoptosis by death-receptor and mitochondrial pathways. Additionally, we found that BL-AD008-induced apoptosis was affected by the combination of AMPK and ZIPK. Then, we found that BL-AD008 bear its anti-tumor activities and induced apoptosis by targeting AMPK/ZIPK in vivo. In conclusion, these results demonstrate the ability of systems biology network to identify some key apoptotic kinase targets AMPK and ZIPK; thus providing a dual-target small molecule activator (BL-AD008) as a potential new apoptosis-modulating drug in future cervical cancer therapy.
PMCID: PMC4480736  PMID: 25797270
Systems biology network; Apoptosis; AMPK; ZIPK; Dual-target activator (BL-AD008)

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