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1.  GCDFP-15, AR, and Her-2 as biomarkers for primary ductal adenocarcinoma of the lacrimal gland: a Chinese case and literature review 
OncoTargets and therapy  2015;8:1017-1024.
Primary ductal adenocarcinoma (PDA) of the lacrimal gland is a rare malignant epithelial tumor, and its clinicopathological characteristics are still unclear. This study aimed to report a novel case of PDA of the lacrimal gland in the People’s Republic of China, as well as to determine its histopathological and immunohistochemical characteristics to support early diagnosis and direct further therapy.
Patient and methods
Clinical data (including ocular examination, computed tomography, magnetic resonance imaging, positron emission tomography, mammography, and serum tumor marker examination) and treatment of a 49-year-old woman with a left lacrimal gland mass, which was diagnosed as PDA of the lacrimal gland, were reported. Histopathological and immunohistochemical studies were performed. Eleven papers regarding this uncommon neoplasm were reviewed.
Histopathologically, most of the tumor cells featured abundant granular eosinophilic cytoplasm, while few of them had a frothy appearance. The mass showed breast ductal carcinoma-like structural features, which most commonly demonstrated central necrosis, while less of these features showed cord-like infiltration. Immunohistochemically, the tumor cells were positive for GCDFP-15, CK 18 (++), AR (90%), Her-2 (+++), P53 (100%), and Ki-67 (with a proliferation index approximately 60%), while they were negative for ER, PR, P63, calponin, and CD 117.
This was the first Chinese case of PDA of the lacrimal gland that had been reported. We suggested that GCDFP-15, AR, and Her-2 should be tested as biomarkers for ductal adenocarcinoma of lacrimal gland to confirm diagnosis, guide therapy, and further predict prognosis.
PMCID: PMC4435050  PMID: 25999735
GCDFP-15; androgen receptors; Her-2; ductal adenocarcinoma; lacrimal gland; orbital tumor
2.  Functional and structural diversity in GH62 α-L-arabinofuranosidases from the thermophilic fungus Scytalidium thermophilum 
Microbial Biotechnology  2014;8(3):419-433.
The genome of the thermophilic fungus Scytalidium thermophilum (strain CBS 625.91) harbours a wide range of genes involved in carbohydrate degradation, including three genes, abf62A, abf62B and abf62C, predicted to encode glycoside hydrolase family 62 (GH62) enzymes. Transcriptome analysis showed that only abf62A and abf62C are actively expressed during growth on diverse substrates including straws from barley, alfalfa, triticale and canola. The abf62A and abf62C genes were expressed in Escherichia coli and the resulting recombinant proteins were characterized. Calcium-free crystal structures of Abf62C in apo and xylotriose bound forms were determined to 1.23 and 1.48 Å resolution respectively. Site-directed mutagenesis confirmed Asp55, Asp171 and Glu230 as catalytic triad residues, and revealed the critical role of non-catalytic residues Asp194, Trp229 and Tyr338 in positioning the scissile α-L-arabinofuranoside bond at the catalytic site. Further, the +2R substrate-binding site residues Tyr168 and Asn339, as well as the +2NR residue Tyr226, are involved in accommodating long-chain xylan polymers. Overall, our structural and functional analysis highlights characteristic differences between Abf62A and Abf62C, which represent divergent subgroups in the GH62 family.
PMCID: PMC4408175  PMID: 25267315
3.  Femtosecond laser in refractive and cataract surgeries 
In the past few years, 9 unique laser platforms have been brought to the market. As femtosecond (FS) laser-assisted ophthalmic surgery potentially improves patient safety and visual outcomes, this new technology indeed provides ophthalmologists a reliable new option. But this new technology also poses a range of new clinical and financial challenges for surgeons. We provide an overview of the evolution of FS laser technology for use in refractive and cataract surgeries. This review describes the available laser platforms and mainly focuses on discussing the development of ophthalmic surgery technologies.
PMCID: PMC4413590  PMID: 25938066
femtosecond; refractive surgery; cataract surgery
4.  Elucidation of the Molecular Basis for Arabinoxylan-Debranching Activity of a Thermostable Family GH62 α-l-Arabinofuranosidase from Streptomyces thermoviolaceus 
Applied and Environmental Microbiology  2014;80(17):5317-5329.
Xylan-debranching enzymes facilitate the complete hydrolysis of xylan and can be used to alter xylan chemistry. Here, the family GH62 α-l-arabinofuranosidase from Streptomyces thermoviolaceus (SthAbf62A) was shown to have a half-life of 60 min at 60°C and the ability to cleave α-1,3 l-arabinofuranose (l-Araf) from singly substituted xylopyranosyl (Xylp) backbone residues in wheat arabinoxylan; low levels of activity on arabinan as well as 4-nitrophenyl α-l-arabinofuranoside were also detected. After selective removal of α-1,3 l-Araf substituents from disubstituted Xylp residues present in wheat arabinoxylan, SthAbf62A could also cleave the remaining α-1,2 l-Araf substituents, confirming the ability of SthAbf62A to remove α-l-Araf residues that are (1→2) and (1→3) linked to monosubstituted β-d-Xylp sugars. Three-dimensional structures of SthAbf62A and its complex with xylotetraose and l-arabinose confirmed a five-bladed β-propeller fold and revealed a molecular Velcro in blade V between the β1 and β21 strands, a disulfide bond between Cys27 and Cys297, and a calcium ion coordinated in the central channel of the fold. The enzyme-arabinose complex structure further revealed a narrow and seemingly rigid l-arabinose binding pocket situated at the center of one side of the β propeller, which stabilized the arabinofuranosyl substituent through several hydrogen-bonding and hydrophobic interactions. The predicted catalytic amino acids were oriented toward this binding pocket, and the catalytic essentiality of Asp53 and Glu213 was confirmed by site-specific mutagenesis. Complex structures with xylotetraose revealed a shallow cleft for xylan backbone binding that is open at both ends and comprises multiple binding subsites above and flanking the l-arabinose binding pocket.
PMCID: PMC4136092  PMID: 24951792
5.  Electroporation of Functional Bacterial Effectors into Mammalian Cells 
The study of protein interactions in the context of living cells can generate critical information about localization, dynamics, and interacting partners. This information is particularly valuable in the context of host-pathogen interactions. Many pathogen proteins function within host cells in a variety of way such as, enabling evasion of the host immune system and survival within the intracellular environment. To study these pathogen-protein host-cell interactions, several approaches are commonly used, including: in vivo infection with a strain expressing a tagged or mutant protein, or introduction of pathogen genes via transfection or transduction. Each of these approaches has advantages and disadvantages. We sought a means to directly introduce exogenous proteins into cells. Electroporation is commonly used to introduce nucleic acids into cells, but has been more rarely applied to proteins although the biophysical basis is exactly the same. A standard electroporator was used to introduce affinity-tagged bacterial effectors into mammalian cells. Human epithelial and mouse macrophage cells were cultured by traditional methods, detached, and placed in 0.4 cm gap electroporation cuvettes with an exogenous bacterial pathogen protein of interest (e.g. Salmonella Typhimurium GtgE). After electroporation (0.3 kV) and a short (4 hr) recovery period, intracellular protein was verified by fluorescently labeling the protein via its affinity tag and examining spatial and temporal distribution by confocal microscopy. The electroporated protein was also shown to be functional inside the cell and capable of correct subcellular trafficking and protein-protein interaction. While the exogenous proteins tended to accumulate on the surface of the cells, the electroporated samples had large increases in intracellular effector concentration relative to incubation alone. The protocol is simple and fast enough to be done in a parallel fashion, allowing for high-throughput characterization of pathogen proteins in host cells including subcellular targeting and function of virulence proteins.
PMCID: PMC4331347  PMID: 25650771
Immunology; Issue 95; electroporation; protein; transfection; expression; localization; confocal microscopy; Salmonella; effector
6.  OTO: Ontology Term Organizer 
BMC Bioinformatics  2015;16(1):47.
The need to create controlled vocabularies such as ontologies for knowledge organization and access has been widely recognized in various domains. Despite the indispensable need of thorough domain knowledge in ontology construction, most software tools for ontology construction are designed for knowledge engineers and not for domain experts to use. The differences in the opinions of different domain experts and in the terminology usages in source literature are rarely addressed by existing software.
OTO software was developed based on the Agile principles. Through iterations of software release and user feedback, new features are added and existing features modified to make the tool more intuitive and efficient to use for small and large data sets. The software is open source and built in Java.
Ontology Term Organizer (OTO; is a user-friendly, web-based, consensus-promoting, open source application for organizing domain terms by dragging and dropping terms to appropriate locations. The application is designed for users with specific domain knowledge such as biology but not in-depth ontology construction skills. Specifically OTO can be used to establish is_a, part_of, synonym, and order relationships among terms in any domain that reflects the terminology usage in source literature and based on multiple experts’ opinions. The organized terms may be fed into formal ontologies to boost their coverage. All datasets organized on OTO are publicly available.
OTO has been used to organize the terms extracted from thirty volumes of Flora of North America and Flora of China combined, in addition to some smaller datasets of different taxon groups. User feedback indicates that the tool is efficient and user friendly. Being open source software, the application can be modified to fit varied term organization needs for different domains.
PMCID: PMC4339750  PMID: 25887779
Biodiversity informatics; Controlled vocabularies; Web-based application; Consensus-promoting; Community software
7.  Molecular Findings Among Patients Referred for Clinical Whole-Exome Sequencing 
JAMA  2014;312(18):1870-1879.
Clinical whole-exome sequencing is increasingly used for diagnostic evaluation of patients with suspected genetic disorders.
To perform clinical whole-exome sequencing and report (1) the rate of molecular diagnosis among phenotypic groups, (2) the spectrum of genetic alterations contributing to disease, and (3) the prevalence of medically actionable incidental findings such as FBN1 mutations causing Marfan syndrome.
Observational study of 2000 consecutive patients with clinical whole-exome sequencing analyzed between June 2012 and August 2014. Whole-exome sequencing tests were performed at a clinical genetics laboratory in the United States. Results were reported by clinical molecular geneticists certified by the American Board of Medical Genetics and Genomics. Tests were ordered by the patient’s physician. The patients were primarily pediatric (1756 [88%]; mean age, 6 years; 888 females [44%], 1101 males [55%], and 11 fetuses [1% gender unknown]), demonstrating diverse clinical manifestations most often including nervous system dysfunction such as developmental delay.
Whole-exome sequencing diagnosis rate overall and by phenotypic category, mode of inheritance, spectrum of genetic events, and reporting of incidental findings.
A molecular diagnosis was reported for 504 patients (25.2%) with 58% of the diagnostic mutations not previously reported. Molecular diagnosis rates for each phenotypic category were 143/526 (27.2%; 95% CI, 23.5%–31.2%) for the neurological group, 282/1147 (24.6%; 95% CI, 22.1%–27.2%) for the neurological plus other organ systems group, 30/83 (36.1%; 95% CI, 26.1%–47.5%) for the specific neurological group, and 49/244 (20.1%; 95% CI, 15.6%–25.8%) for the nonneurological group. The Mendelian disease patterns of the 527 molecular diagnoses included 280 (53.1%) autosomal dominant, 181 (34.3%) autosomal recessive (including 5 with uniparental disomy), 65 (12.3%) X-linked, and 1 (0.2%) mitochondrial. Of 504 patients with a molecular diagnosis, 23 (4.6%) had blended phenotypes resulting from 2 single gene defects. About 30% of the positive cases harbored mutations in disease genes reported since 2011. There were 95 medically actionable incidental findings in genes unrelated to the phenotype but with immediate implications for management in 92 patients (4.6%), including 59 patients (3%) with mutations in genes recommended for reporting by the American College of Medical Genetics and Genomics.
Whole-exome sequencing provided a potential molecular diagnosis for 25% of a large cohort of patients referred for evaluation of suspected genetic conditions, including detection of rare genetic events and new mutations contributing to disease. The yield of whole-exome sequencing may offer advantages over traditional molecular diagnostic approaches in certain patients.
PMCID: PMC4326249  PMID: 25326635
8.  Finding Our Way through Phenotypes 
Deans, Andrew R. | Lewis, Suzanna E. | Huala, Eva | Anzaldo, Salvatore S. | Ashburner, Michael | Balhoff, James P. | Blackburn, David C. | Blake, Judith A. | Burleigh, J. Gordon | Chanet, Bruno | Cooper, Laurel D. | Courtot, Mélanie | Csösz, Sándor | Cui, Hong | Dahdul, Wasila | Das, Sandip | Dececchi, T. Alexander | Dettai, Agnes | Diogo, Rui | Druzinsky, Robert E. | Dumontier, Michel | Franz, Nico M. | Friedrich, Frank | Gkoutos, George V. | Haendel, Melissa | Harmon, Luke J. | Hayamizu, Terry F. | He, Yongqun | Hines, Heather M. | Ibrahim, Nizar | Jackson, Laura M. | Jaiswal, Pankaj | James-Zorn, Christina | Köhler, Sebastian | Lecointre, Guillaume | Lapp, Hilmar | Lawrence, Carolyn J. | Le Novère, Nicolas | Lundberg, John G. | Macklin, James | Mast, Austin R. | Midford, Peter E. | Mikó, István | Mungall, Christopher J. | Oellrich, Anika | Osumi-Sutherland, David | Parkinson, Helen | Ramírez, Martín J. | Richter, Stefan | Robinson, Peter N. | Ruttenberg, Alan | Schulz, Katja S. | Segerdell, Erik | Seltmann, Katja C. | Sharkey, Michael J. | Smith, Aaron D. | Smith, Barry | Specht, Chelsea D. | Squires, R. Burke | Thacker, Robert W. | Thessen, Anne | Fernandez-Triana, Jose | Vihinen, Mauno | Vize, Peter D. | Vogt, Lars | Wall, Christine E. | Walls, Ramona L. | Westerfeld, Monte | Wharton, Robert A. | Wirkner, Christian S. | Woolley, James B. | Yoder, Matthew J. | Zorn, Aaron M. | Mabee, Paula
PLoS Biology  2015;13(1):e1002033.
Imagine if we could compute across phenotype data as easily as genomic data; this article calls for efforts to realize this vision and discusses the potential benefits.
Despite a large and multifaceted effort to understand the vast landscape of phenotypic data, their current form inhibits productive data analysis. The lack of a community-wide, consensus-based, human- and machine-interpretable language for describing phenotypes and their genomic and environmental contexts is perhaps the most pressing scientific bottleneck to integration across many key fields in biology, including genomics, systems biology, development, medicine, evolution, ecology, and systematics. Here we survey the current phenomics landscape, including data resources and handling, and the progress that has been made to accurately capture relevant data descriptions for phenotypes. We present an example of the kind of integration across domains that computable phenotypes would enable, and we call upon the broader biology community, publishers, and relevant funding agencies to support efforts to surmount today's data barriers and facilitate analytical reproducibility.
PMCID: PMC4285398  PMID: 25562316
9.  CD147 promotes Src-dependent activation of Rac1 signaling through STAT3/DOCK8 during the motility of hepatocellular carcinoma cells 
Oncotarget  2014;6(1):243-257.
Metastasis is considered a dynamic process in tumor development that is related to abnormal migration and invasion. Tumor cells can move as individual cells in two interconvertible modes: mesenchymal-type and amoeboid. Previously, we reported that the interaction between CD147 and Annexin II can inhibit the amoeboid movement in hepatocellular carcinoma (HCC) cells. However, the mechanism of CD147 involved in mesenchymal movement is still unclear. Notably, our results show overexpression of CD147 led to mesenchymal-type movement in HCC cells. Evidence indicated that the mesenchymal-type cell movement induced by CD147 was Src dependent, as observed by confocal microscopy and Rac1 activity assay. The phosphorylation of Src (pY416-Src) can be up-regulated by CD147, and this regulation is mediated by focal adhesion kinase (FAK). Next, we identified DOCK8 as a GEF for Rac1, a key molecule driving mesenchymal-type movement. We also found that Src promotes STAT3 phosphorylation and STAT3 facilitates DOCK8 transcription, thus enhancing DOCK8 expression and Rac1 activation. This study provides a novel mechanism of CD147 regulating mesenchymal-type movement in HCC cells.
PMCID: PMC4381592  PMID: 25428919
CD147; Src; Rac1; DOCK8; STAT3
10.  Radon Concentrations in Drinking Water in Beijing City, China and Contribution to Radiation Dose 
222Rn concentrations in drinking water samples from Beijing City, China, were determined based on a simple method for the continuous monitoring of radon using a radon-in-air monitor coupled to an air-water exchanger. A total of 89 water samples were sampled and analyzed for their 222Rn content. The observed radon levels ranged from detection limit up to 49 Bq/L. The calculated arithmetic and geometric means of radon concentrations in all measured samples were equal to 5.87 and 4.63 Bq/L, respectively. The average annual effective dose from ingestion of radon in drinking water was 2.78 μSv, and that of inhalation of water-borne radon was 28.5 μSv. It is concluded that it is not the ingestion of waterborne radon, but inhalation of the radon escaping from water that is a substantial part of the radiological hazard. Radon in water is a big concern for public health, especially for consumers who directly use well water with very high radon concentration.
PMCID: PMC4245603  PMID: 25350007
radon; drinking water; well water; public water; radiation dose
11.  Etanercept in the treatment of ankylosing spondylitis: A systematic review and meta-analysis 
Etanercept (ETN) has been widely applied in the treatment of ankylosing spondylitis (AS). As the use of ETN has increased, associated adverse effects have been reported frequently. Previous meta-analyses have focused on comparing the differences in clinical outcomes between ETN and placebo (PBO). The present meta-analysis evaluated randomised controlled trials (RCTs) to compare the effects of ETN and a PBO or sulfasalazine (SSZ) in patients with AS. The study population characteristics and the main results, including the Assessment in AS 20% response (ASAS 20), the Bath AS Disease Activity Index (BASDAI) and the Bath AS Functional Index (BASFI), were extracted. The pooled odds ratios (ORs) or weighted mean differences (MDs) were calculated using a fixed or random effects model. Fifteen randomised controlled trials (RCTs) involving 2,194 subjects were included. Compared with a PBO, ETN significantly improved the ASAS 20 [P<0.00001; OR, 8.25; 95% confidence interval (CI), 5.92–11.50], BASDAI (P<0.00001; MD, −18.81; 95% CI, −24.47 to −13.15) and BASFI (P<0.00001; standard MD, −0.68; 95% CI, −0.85 to −0.50). In comparison with SSZ, ETN significantly decreased the BASDAI (P<0.00001; MD, −2.40; 95% CI, −2.89 to −1.90) and C-reactive protein (CRP) levels (P<0.0001; MD, −8.01; 95% CI, −11.73 to −4.29). The most common adverse effect of ETN was an injection site reaction. This meta-analysis shows that ETN monotherapy is effective in improving physical function and reducing disease activity in patients with AS. Compared with SSZ, ETN markedly decreased the BASDAI and CRP levels. However, the efficacy of ETN in treating AS requires further evaluation by more RCTs in a larger population of patients prior to recommending ETN as a substitute for synthetic disease-modifying antirheumatic drug (DMARD) monotherapy, or combinations of synthetic DMARDs.
PMCID: PMC4186333  PMID: 25289064
etanercept; ankylosing spondylitis; systematic review; meta-analysis
12.  Nose to tail, roots to shoots: spatial descriptors for phenotypic diversity in the Biological Spatial Ontology 
Spatial terminology is used in anatomy to indicate precise, relative positions of structures in an organism. While these terms are often standardized within specific fields of biology, they can differ dramatically across taxa. Such differences in usage can impair our ability to unambiguously refer to anatomical position when comparing anatomy or phenotypes across species. We developed the Biological Spatial Ontology (BSPO) to standardize the description of spatial and topological relationships across taxa to enable the discovery of comparable phenotypes.
BSPO currently contains 146 classes and 58 relations representing anatomical axes, gradients, regions, planes, sides, and surfaces. These concepts can be used at multiple biological scales and in a diversity of taxa, including plants, animals and fungi. The BSPO is used to provide a source of anatomical location descriptors for logically defining anatomical entity classes in anatomy ontologies. Spatial reasoning is further enhanced in anatomy ontologies by integrating spatial relations such as dorsal_to into class descriptions (e.g., ‘dorsolateral placode’ dorsal_to some ‘epibranchial placode’).
The BSPO is currently used by projects that require standardized anatomical descriptors for phenotype annotation and ontology integration across a diversity of taxa. Anatomical location classes are also useful for describing phenotypic differences, such as morphological variation in position of structures resulting from evolution within and across species.
PMCID: PMC4137724  PMID: 25140222
Anatomy; Spatial relationships; Position; Axes; Reasoning; BSPO; Ontology; Phenotype
13.  Synergistic antitumor activity of reversine combined with aspirin in cervical carcinoma in vitro and in vivo 
Cytotechnology  2013;65(4):643-653.
A recent report showed that reversine treatment could induce murine myoblasts dedifferentiation into multipotent progenitor cells and inhibit proliferation of some tumors, and other reports showed that apoptosis of lung adenocarcinoma cells could be induced by aspirin. The aim of the present study was to evaluate the synergistic antitumor effects of reversine and aspirin on cervical cancer. The inhibition rate of reversine and aspirin on cervical cancer cell lines’ (HeLa and U14) was determined by MTT method, cell cycle of HeLa and U14 cells was analyzed by FACS, mitochondrial membrane potential of HeLa and U14 was detected using a JC-1 kit. HeLa and U14 colony formation was analyzed by soft agar colony formation assay. The expression of caspase-3, Bcl-2/Bax, cyclin D1 and p21 was detected by qRT-PCR and Western Blotting. Moreover, tumor weight and tumor volume was assessed using a murine model of cervical cancer with U14 cells subcutaneously (s.c.) administered into the neck, separately or combined with drug administration via the intraperitoneal (i.p.) route. The inhibition rate of cells in the combination group (10 μmol/L reversine, 10 mmol/L aspirin) increased significantly in comparison to that when the drugs were used alone (P < 0.05); moreover, this combination could synergistically inhibit the proliferation of five cervical cancer cell lines (HeLa, U14, Siha, Caski and C33A). In the therapeutic mouse model, tumor weight and tumor volume of cervical cancer bearing mice was more reduced when compared with the control agents (P < 0.05) in tumor-bearing mice. The combination of reversine and aspirin exerts synergistic growth inhibition and apoptosis induction on cervical cancers cells.
PMCID: PMC3720971  PMID: 23475158
Reversine; Aspirin; Cervical carcinoma; Apoptosis
14.  Proteomic analysis of immature rat pups brain in response to hypoxia and ischemia challenge 
Hypoxia and ischemia significantly affects perinatal brain development, even worse in preterm infants. However, the details of the mechanism leading to permanent brain damage after hypoxia-ischemia attack have not been fully elucidated. Proteomics could provide insight into the potential mechanism and help to promote the clinical treatment. In this study, quantitative analysis was performed 24 hours after hypoxia-ischemia using liquid-chromatography mass spectrometry coupled to label-free analysis. Compared to control, 193 proteins were present only in hypoxic-ischemic group. In addition, 34 proteins were more than 2 folds up-regulated and 14 proteins were more than 2 folds down-regulated in hypoxia-ischemia group. Gene Ontology database showed that the majority of differentially expressed proteins comprised mitochondrial proteins et al. Molecular function analysis revealed that the majority of proteins were involved in ion binding et al. Biological process analysis showed that the majority of proteins were involved in response to organic substance et al. STRING 9.0 software analysis were used to explore the complex interactions existed among the proteins. Western blot were used to verify the fold changes of some proteins-microtubule-associated protein 2 and microtubule-associated protein tau. This novel study performed a full-scale screening of the proteomics research in hypoxic-ischemic brain damage of immature rat.
PMCID: PMC4152027  PMID: 25197337
Hypoxia; ischemia; preterm; proteomics
15.  Structural and Functional Characterization of DUF1471 Domains of Salmonella Proteins SrfN, YdgH/SssB, and YahO 
PLoS ONE  2014;9(7):e101787.
Bacterial species in the Enterobacteriaceae typically contain multiple paralogues of a small domain of unknown function (DUF1471) from a family of conserved proteins also known as YhcN or BhsA/McbA. Proteins containing DUF1471 may have a single or three copies of this domain. Representatives of this family have been demonstrated to play roles in several cellular processes including stress response, biofilm formation, and pathogenesis. We have conducted NMR and X-ray crystallographic studies of four DUF1471 domains from Salmonella representing three different paralogous DUF1471 subfamilies: SrfN, YahO, and SssB/YdgH (two of its three DUF1471 domains: the N-terminal domain I (residues 21–91), and the C-terminal domain III (residues 244–314)). Notably, SrfN has been shown to have a role in intracellular infection by Salmonella Typhimurium. These domains share less than 35% pairwise sequence identity. Structures of all four domains show a mixed α+β fold that is most similar to that of bacterial lipoprotein RcsF. However, all four DUF1471 sequences lack the redox sensitive cysteine residues essential for RcsF activity in a phospho-relay pathway, suggesting that DUF1471 domains perform a different function(s). SrfN forms a dimer in contrast to YahO and SssB domains I and III, which are monomers in solution. A putative binding site for oxyanions such as phosphate and sulfate was identified in SrfN, and an interaction between the SrfN dimer and sulfated polysaccharides was demonstrated, suggesting a direct role for this DUF1471 domain at the host-pathogen interface.
PMCID: PMC4092069  PMID: 25010333
16.  Acupuncture-moxibustion in treating irritable bowel syndrome: How does it work? 
Irritable bowel syndrome (IBS) is a functional intestinal disease characterized by abdominal pain or discomfort and altered bowel habits. It has drawn great attention because of its high prevalence, reoccurring symptoms, and severe influence on patients’ lives. Many clinical studies have demonstrated the efficacy of acupuncture-moxibustion in treating IBS. Increasing attention has been paid to research regarding the action mechanisms of acupuncture-moxibustion for IBS, and the adoption of modern techniques has achieved some progress. This article reviews the latest advances among action mechanism studies from the perspectives of gastrointestinal motility, visceral hypersensitivity, the brain-gut axis, the neuroendocrine system, and the immune system. It is shown that acupuncture-moxibustion can effectively regulate the above items, and thus, this treatment should have a high efficacy in the treatment of IBS. This article also identifies existing problems in current mechanism research and raises several ideas for future studies. Further revelations regarding these action mechanisms will promote the application of acupuncture-moxibustion in treating IBS.
PMCID: PMC4033444  PMID: 24876727
Irritable bowel syndrome; Acupuncture-moxibustion; Mechanism study; Gastrointestinal motility; Visceral hypersensitivity; Brain-gut axis
17.  Association of Saccade Duration and Saccade Acceleration/Deceleration Asymmetry during Visually Guided Saccade in Schizophrenia Patients 
PLoS ONE  2014;9(5):e97308.
To examine the difference between schizophrenia patients and normal controls on velocity and acceleration of saccade, by using the basic visually guided saccade (VGS) paradigm.
Eighteen schizophrenia outpatients and fourteen normal controls participated in the VGS task. Multiple indicators, including amplitude, duration, velocity, latency, accuracy rate, acceleration, and deceleration were analyzed. Asymmetric acceleration index (AAI) was introduced to describe the difference between peak acceleration and peak deceleration. The correlation coefficient (RAD) of AAI and duration was computed to examine the difference between schizophrenia patients and normal controls.
No significant difference between patients and normal controls was found on amplitude, duration, latency, and accuracy rate. However, RAD values of schizophrenia patients were significantly lower than the control group.
Compared to normal controls, association of saccade duration and saccade acceleration/deceleration asymmetry during visually guided saccade was lower in schizophrenia patients.
PMCID: PMC4023985  PMID: 24837253
18.  The effect of transcutaneous electrical acupoint stimulation on pregnancy rates in women undergoing in vitro fertilization: a study protocol for a randomized controlled trial 
Trials  2014;15:162.
The latest meta-analysis demonstrated that acupuncture improves pregnancy rates among women undergoing in vitro fertilization-embryo transfer (IVF-ET), and surface acupoint stimulation, such as transcutaneous electrical acupoint stimulation (TEAS), may have the same or better potential.
To explore the effect of TEAS on the clinical pregnancy rate (CPR) and live birth rate (LBR) compared with real acupuncture and controls in women undergoing IVF, a multicenter, randomized controlled trial will be conducted. The inclusion criteria are the following: infertile women <40 years of age undergoing a fresh IVF or intracytoplasmic sperm injection cycle, and the study will be restricted to women with the potential for a lower success rate as defined by two or more previous unsuccessful ETs (fresh or frozen). Those who have severe illnesses possibly precluding IVF or pregnancy, have FSH levels greater than 20 IU/L, received donor eggs, had been previously randomized for this study or had undergone acupuncture (in any modality) as infertility treatment will be excluded. The subjects will be randomly assigned to the TEAS group (IVF + TEAS), the electro-acupuncture (EA) group (IVF + EA), or the control group (only IVF). A total sample size of 2,220 women is required to detect differences in CPR among the three groups. TEAS or EA treatments will start once every two or three days from day 3 of menstruation in the ovarian stimulation cycle until the day of ET. The parameters of TEAS or EA will be the following: a frequency of 2/100 Hz, a moderate electrical current of 3 to 5 mA for TEAS and 0.8 to 1.0 mA for EA. The primary outcome is CPR. Secondary outcomes are LBR, the number of oocytes aspirated and the total gonadotropin dose used in the stimulation cycle.
This study will provide significant evidence for using a new method (TEAS) in IVF.
Trial registration
ClinicalTrials.govID: NCT01608048 (05/24/2012).
PMCID: PMC4020380  PMID: 24886647
acupuncture; transcutaneous electrical acupoint stimulation; TEAS
19.  Alkyl Caffeates Improve the Antioxidant Activity, Antitumor Property and Oxidation Stability of Edible Oil 
PLoS ONE  2014;9(4):e95909.
Caffeic acid (CA) is distributed widely in nature and possesses strong antioxidant activity. However, CA has lower solubility in non-polar media, which limits its application in fat-soluble food. To increase the lipophilicity of natural antioxidant CA, a series of alkyl caffeates were synthesized and their antioxidant and antitumor activities were investigated. The antioxidant parameters, including the induction period, acid value and unsaturated fatty acid content, of the alkyl caffeates in edible oil were firstly investigated. The results indicated that alkyl caffeates had a lower DPPH IC50 (14–23 µM) compared to CA, dibutyl hydroxy toluene (BHT) and Vitamin C (24–51 µM), and significantly inhibited four human cancer cells (SW620, SW480, SGC7901 and HepG2) with inhibition ratio of 71.4–78.0% by a MTT assay. With regard to the induction period and acid value assays, methyl and butyl caffeates had higher abilities than BHT to restrain the oxidation process and improve the stability of edible oil. The addition of ethyl caffeate to oil allowed maintenance of a higher unsaturated fatty acid methyl ester content (68.53%) at high temperatures. Overall, the alkyl caffeats with short chain length (n<5) assessed better oxidative stability than those with long chain length. To date, this is the first report to the correlations among the antioxidant activity, anticancer activity and oxidative stability of alkyl caffeates.
PMCID: PMC3997486  PMID: 24760050
20.  Design of stapled α-helical peptides to specifically activate Wnt/β-catenin signaling 
Cell Research  2013;23(4):581-584.
PMCID: PMC3616433  PMID: 23439249
21.  Electroconvulsive Therapy on Severe Obsessive-Compulsive Disorder Comorbid Depressive Symptoms 
Psychiatry Investigation  2014;11(2):210-213.
Electroconvulsive therapy (ECT) is not currently used as a first-line treatment for obsessive-compulsive disorder (OCD). However, several related case reports have demonstrated that ECT seems to be effective for severe OCD, especially when first-line therapies have failed. In this study, we describe the courses, detailed parameters, effects, and follow-up information relating to three patients with severe OCD who were treated by modified bifrontal ECT after their first-line anti-OCD treatments pharmacotherapy, behavioral therapy, and cognitive behavioral therapy failed. The number of ECT procedures administered in each case is as follows: Case 1, eight; Case 2, three; and Case 3, four. In all three cases, the patients' depressive symptoms improved considerably after the ECT procedures. In addition, the condition of all three patients' OCD significantly improved and remained stable at regular follow-ups. ECT may play an effective role in treating severe OCD.
PMCID: PMC4023099  PMID: 24843380
Obsessive-compulsive disorder; Electroconvulsive therapy; Depression
22.  Negative regulation of miRNA-9 on oligodendrocyte lineage gene 1 during hypoxic-ischemic brain damage 
Neural Regeneration Research  2014;9(5):513-518.
Oligodendrocyte lineage gene 1 plays a key role in hypoxic-ischemic brain damage and myelin repair. miRNA-9 is involved in the occurrence of many related neurological disorders. Bioinformatics analysis demonstrated that miRNA-9 complementarily, but incompletely, bound oligodendrocyte lineage gene 1, but whether miRNA-9 regulates oligodendrocyte lineage gene 1 remains poorly understood. Whole brain slices of 3-day-old Sprague-Dawley rats were cultured and divided into four groups: control group; oxygen-glucose deprivation group (treatment with 8% O2 + 92% N2 and sugar-free medium for 60 minutes); transfection control group (after oxygen and glucose deprivation for 60 minutes, transfected with control plasmid) and miRNA-9 transfection group (after oxygen and glucose deprivation for 60 minutes, transfected with miRNA-9 plasmid). From the third day of transfection, and with increasing culture days, oligodendrocyte lineage gene 1 expression increased in each group, peaked at 14 days, and then decreased at 21 days. Real-time quantitative PCR results, however, demonstrated that oligodendrocyte lineage gene 1 expression was lower in the miRNA-9 transfection group than that in the transfection control group at 1, 3, 7, 14, 21 and 28 days after transfection. Results suggested that miRNA-9 possibly negatively regulated oligodendrocyte lineage gene 1 in brain tissues during hypoxic-ischemic brain damage.
PMCID: PMC4153509  PMID: 25206848
nerve regeneration; brain injury; miRNA-9; oligodendrocyte lineage gene 1; hypoxic-ischemic; brain damage; premature birth; brain slice culture; NSFC grant; neural regeneration
23.  POU5F1 Enhances the Invasiveness of Cancer Stem-Like Cells in Lung Adenocarcinoma by Upregulation of MMP-2 Expression 
PLoS ONE  2013;8(12):e83373.
Lung cancer is the leading cause of cancer-related human deaths. Exploration of the mechanisms underlying the metastasis of cancer stem-like cells (CSLCs) will open new avenues in lung cancer diagnosis and therapy. Here, we demonstrated that CSLCs-derived from lung adenocarcinoma (LAC) cells displayed highly invasive and migratory capabilities via expressing high levels of POU5F1 and MMP-2. We found that POU5F1 directly regulated MMP-2 transcription via interaction with the promoter of MMP-2. POU5F1 knockdown in LACSLCs reduced MMP-2 protein abundance, leading to inhibition of the cell invasion, migration and tumorigenesis potentials of LAC cells. Clinically, aberrantly high expressions of POU5F1 and MMP-2 were inversely correlated with the survival of LAC patients, and the double-positive POU5F1 and MMP-2 showed the worst prediction for the patient’s poor survival. These results indicate that POU5F1 can bind to the MMP-2 promoter for the degradation of surrounding extracellular matrix, and therefore promote invasive and migratory capabilities of LACSLCs. Moreover, our data implicate that the pathological detection of the double-positive expressions for POU5F1 and MMP-2 will be useful as diagnostic and prognostic biomarkers in LAC to advance anti-metastasis therapy.
PMCID: PMC3875455  PMID: 24386189
24.  Creating Rat Model for Hypoxic Brain Damage in Neonates by Oxygen Deprivation 
PLoS ONE  2013;8(12):e83589.
Current study explores the feasibility of using a non-surgical method of oxygen deprivation to create Hypoxic brain damage in neonatal rats for medical studies. 7-day-old Sprague Dowley (SD) rats were kept in a container with low oxygen level (8%) for 1.5h. A second group had bilateral cephalic artery ligation before the 1.5h-low oxygen treatment, a method similar to the popular Rice method, to expose the brain to both hypoxic and ischemic situations. Short term neural functions and brain water weights were evaluated 1 day after the hypoxic treatment. Brain pathology and histology were also examined at 1 day and 3 days after the hypoxic treatment. Both groups showed impaired neural functions and increased brain water weight compared to the controls. Histology studies also revealed injuries in the subcortex, hippocampus and lateral ventricle in the brains from both groups. There is no significant difference in the degree of brain damages observed in the two groups. Our work demonstrated that oxygen deprivation alone is sufficient to cause brain damages similar to those seen in Hypoxic-ischemic brain disease (HIBD). Because this method avoids the invasive surgical procedure and therefore reduces the stress and mortality of laboratory animals during the experiment, we recommend it to be the favorable method for creating rat models for HIBD studies.
PMCID: PMC3866139  PMID: 24358300
25.  Biochemical and Structural Studies of Conserved Maf Proteins Revealed Nucleotide Pyrophosphatases with a Preference for Modified Nucleotides 
Chemistry & Biology  2013;20(11):1386-1398.
Maf (for multicopy associated filamentation) proteins represent a large family of conserved proteins implicated in cell division arrest but whose biochemical activity remains unknown. Here, we show that the prokaryotic and eukaryotic Maf proteins exhibit nucleotide pyrophosphatase activity against 5-methyl-UTP, pseudo-UTP, 5-methyl-CTP, and 7-methyl-GTP, which represent the most abundant modified bases in all organisms, as well as against canonical nucleotides dTTP, UTP, and CTP. Overexpression of the Maf protein YhdE in E. coli cells increased intracellular levels of dTMP and UMP, confirming that dTTP and UTP are the in vivo substrates of this protein. Crystal structures and site-directed mutagenesis of Maf proteins revealed the determinants of their activity and substrate specificity. Thus, pyrophosphatase activity of Maf proteins toward canonical and modified nucleotides might provide the molecular mechanism for a dual role of these proteins in cell division arrest and house cleaning.
Graphical Abstract
•Maf proteins represent a family of nucleoside triphosphate pyrophosphatases•Maf proteins hydrolyze the canonical nucleotides dTTP, UTP, and CTP•Maf proteins are also active against m5UTP, m5CTP, pseudo-UTP, and m7GTP•Maf structures reveal the molecular mechanisms of their substrate selectivity
Tchigvintsev et al. show that Maf proteins are a family of nucleotide pyrophosphatases active against both canonical and modified nucleotides. This suggests that Mafs might have a dual role in cell division and in the prevention of the incorporation of modified nucleotides into cellular nucleic acids.
PMCID: PMC3899018  PMID: 24210219

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