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1.  Modulation of the Human T Cell Response by a Novel Non-Mitogenic Anti-CD3 Antibody 
PLoS ONE  2014;9(4):e94324.
The agonistic anti-human CD3ε antibody (Ab), OKT3, has been used to control acute transplant rejection. The in vivo administration of OKT3 was previously shown to induce the partial depletion of T cells and unresponsiveness (anergy) in the remaining CD4+ T cells. However, this therapy is also associated with the systemic release of several cytokines, which leads to a series of adverse side effects. We established a novel anti-human CD3ε Ab, 20-2b2, which recognized a close, but different determinant on the CD3ε molecule from that recognized by OKT3. 20-2b2 was non-mitogenic for human CD4+ T cells, could inhibit the activation of T cells in vitro, and induced T cell anergy in in vivo experiments using humanized mice. Cytokine release in humanized mice induced by the administration of 20-2b2 was significantly less than that induced by OKT3. Our results indicated that the CD3ε molecule is still an attractive, effective, and useful target for the modulation of T cell responses. The establishment of other Abs that recognize CD3ε, even though the determinant recognized by those Abs may be close to or different from that recognized by OKT3, may represent a novel approach for the development of safer Ab therapies using anti-CD3 Abs, in addition to the modification of OKT3 in terms of the induction of cytokine production.
PMCID: PMC3978038  PMID: 24710513
2.  Association of Clinical Symptomatic Hypoglycemia With Cardiovascular Events and Total Mortality in Type 2 Diabetes 
Diabetes Care  2013;36(4):894-900.
Hypoglycemia is associated with serious health outcomes for patients treated for diabetes. However, the outcome of outpatients with type 2 diabetes who have experienced hypoglycemia episodes is largely unknown.
The study population, derived from the National Health Insurance Research Database released by the Taiwan National Health Research Institutes during 1998–2009, comprised 77,611 patients with newly diagnosed type 2 diabetes. We designed a prospective study consisting of randomly selected hypoglycemic type 2 diabetic patients and matched type 2 diabetic patients without hypoglycemia. We investigated the relationships of hypoglycemia with total mortality and cardiovascular events, including stroke, coronary heart disease, cardiovascular diseases, and all-cause hospitalization.
There were 1,844 hypoglycemic events (500 inpatients and 1,344 outpatients) among the 77,611 patients. Both mild (outpatient) and severe (inpatient) hypoglycemia cases had a higher percentage of comorbidities, including hypertension, renal diseases, cancer, stroke, and heart disease. In multivariate Cox regression models, including diabetes treatment adjustment, diabetic patients with hypoglycemia had a significantly higher risk of cardiovascular events during clinical treatment periods. After constructing a model adjusted with propensity scores, mild and severe hypoglycemia still demonstrated higher hazard ratios (HRs) for cardiovascular diseases (HR 2.09 [95% CI 1.63–2.67]), all-cause hospitalization (2.51 [2.00–3.16]), and total mortality (2.48 [1.41–4.38]).
Symptomatic hypoglycemia, whether clinically mild or severe, is associated with an increased risk of cardiovascular events, all-cause hospitalization, and all-cause mortality. More attention may be needed for diabetic patients with hypoglycemic episodes.
PMCID: PMC3609481  PMID: 23223349
3.  Crystal Structure of ORF210 from E. coli O157:H1 Phage CBA120 (TSP1), a Putative Tailspike Protein 
PLoS ONE  2014;9(3):e93156.
Bacteriophage tailspike proteins act as primary receptors, often possessing endoglycosidase activity toward bacterial lipopolysaccharides or other exopolysaccharides, which enable phage absorption and subsequent DNA injection into the host. Phage CBA120, a contractile long-tailed Viunalikevirus phage infects the virulent Escherichia coli O157:H7. This phage encodes four putative tailspike proteins exhibiting little amino acid sequence identity, whose biological roles and substrate specificities are unknown. Here we focus on the first tailspike, TSP1, encoded by the orf210 gene. We have discovered that TSP1 is resistant to protease degradation, exhibits high thermal stability, but does not cleave the O157 antigen. An immune-dot blot has shown that TSP1 binds strongly to non-O157:H7 E. coli cells and more weakly to K. pneumoniae cells, but exhibits little binding to E. coli O157:H7 strains. To facilitate structure-function studies, we have determined the crystal structure of TSP1 to a resolution limit of 1.8 Å. Similar to other tailspikes proteins, TSP1 assembles into elongated homotrimers. The receptor binding region of each subunit adopts a right-handed parallel β helix, reminiscent yet not identical to several known tailspike structures. The structure of the N-terminal domain that binds to the virion particle has not been seen previously. Potential endoglycosidase catalytic sites at the three subunit interfaces contain two adjacent glutamic acids, unlike any catalytic machinery observed in other tailspikes. To identify potential sugar binding sites, the crystal structures of TSP1 in complexes with glucose, α-maltose, or α-lactose were determined. These structures revealed that each sugar binds in a different location and none of the environments appears consistent with an endoglycosidase catalytic site. Such sites may serve to bind sugar units of a yet to be identified bacterial exopolysaccharide.
PMCID: PMC3966878  PMID: 24671238
4.  Cognitive function, body mass index and mortality in a rural elderly Chinese cohort 
Previous studies have shown that poor cognition and low body mass index were associated with increased mortality. But few studies have investigated the association between cognition and mortality across the entire cognitive spectrum while adjusting for BMI. The objective of this study is to examine the associations between cognitive function, BMI and 7-year mortality in a rural elderly Chinese cohort.
A prospective cohort of 2,000 Chinese age 65 and over from four rural counties in China were followed for 7-years. Cognitive function, BMI and other covariate information were obtained at baseline. Cox’s proportional hazard models were used to determine the effects of cognitive function and BMI on mortality risk.
Of participants enrolled, 473 (23.7%) died during follow-up. Both lower cognitive function (HR = 1.48, p = 0.0049) and lower BMI (HR = 1.6, p < 0.0001) were independently associated with increased mortality risk compared to individuals with average cognitive function and normal weight. Higher cognitive function was associated with lower mortality risk (HR = 0.69, p = 0.0312). We found no significant difference in mortality risk between overweight/obese participants and those with normal weight.
Cognitive function and BMI were independent predictors of mortality risk. Intervention strategies for increasing cognitive function and maintaining adequate BMI may be important in reducing morality risk in the elderly population.
PMCID: PMC3974191  PMID: 24666663
5.  Cationised gelatin and hyaluronic acid coating enhances polyethylene terephthalate artificial ligament graft osseointegration in porcine bone tunnels 
International Orthopaedics  2012;37(3):507-513.
The aim of this study was to investigate whether cationised gelatin and hyaluronic acid (CH) coating could induce polyethylene terephthalate (PET) artificial ligament graft osseointegration in the bone tunnel.
Surface modification of PET artificial ligament graft was performed by layer-by-layer (LBL) self-assembly CH coating. Six pigs underwent anterior cruciate ligament (ACL) reconstruction on the right knees, with three pigs receiving the CH-coated PET grafts and the other three pigs non-CH-coated PET grafts as controls. They were sacrificed at three months after surgery and the graft-bone complexes were acquired for computed tomography (CT) scan and histological examination.
CT scans showed a significant difference at the distal femoral site (p = 0.031) or at the distal tibial site (p = 0.0078), but no significant difference in the bone tunnel areas’ enlargement at other sites (p > 0.05) between the CH group and the control group. Histologically, application of CH coating induced new bone formation between graft and bone at three months compared with the controls at the distal site. The interface width of the CH group was significantly lower than that of the control group at the distal femoral site (p = 0.0327) and at the distal tibial site (p = 0.0047).
The study has shown that CH coating on the PET artificial ligament surface has a positive biological effect in the induction of artificial ligament osseointegration within the bone tunnel at the distal site of the bone tunnel.
PMCID: PMC3580098  PMID: 23132501
6.  Identification of Coxiella burnetii Type IV Secretion Substrates Required for Intracellular Replication and Coxiella-Containing Vacuole Formation 
Journal of Bacteriology  2013;195(17):3914-3924.
Coxiella burnetii, the etiological agent of acute and chronic Q fever in humans, is a naturally intracellular pathogen that directs the formation of an acidic Coxiella-containing vacuole (CCV) derived from the host lysosomal network. Central to its pathogenesis is a specialized type IVB secretion system (T4SS) that delivers effectors essential for intracellular replication and CCV formation. Using a bioinformatics-guided approach, 234 T4SS candidate substrates were identified. Expression of each candidate as a TEM-1 β-lactamase fusion protein led to the identification of 53 substrates that were translocated in a Dot/Icm-dependent manner. Ectopic expression in HeLa cells revealed that these substrates trafficked to distinct subcellular sites, including the endoplasmic reticulum, mitochondrion, and nucleus. Expression in Saccharomyces cerevisiae identified several substrates that were capable of interfering with yeast growth, suggesting that these substrates target crucial host processes. To determine if any of these T4SS substrates are necessary for intracellular replication, we isolated 20 clonal T4SS substrate mutants using the Himar1 transposon and transposase. Among these, 10 mutants exhibited defects in intracellular growth and CCV formation in HeLa and J774A.1 cells but displayed normal growth in bacteriological medium. Collectively, these results indicate that C. burnetii encodes a large repertoire of T4SS substrates that play integral roles in host cell subversion and CCV formation and suggest less redundancy in effector function than has been found in the comparative Legionella Dot/Icm model.
PMCID: PMC3754607  PMID: 23813730
7.  Epoxyeicosatrienoic acid-stimulated proliferation in cancer cells involves EGF-R phosphorylation mediated by activation of metalloproteinases and release of HB-EGF 
Acta pharmacologica Sinica  2010;31(2):211-218.
Arachidonic acid is metabolized to biologically active epoxyeicosatrienoic acids (EETs) by cytochrome P450 (CYP) epoxygenases. Previous studies showed that CYP epoxygenases promote neoplastic growth and induce potent mitogenic effects in human carcinoma cells; however, the exact molecular mechanisms involved in EET-induced tumor cell proliferation remain unclear. Exogenous 14,15-EET was added or a mutant CYP epoxygenase (CYP102 F87V, an active 14,15-epoxygenase) was transfected into three human derived cancer cell lines; Tca-8113, A549, HepG2 and MDA-MB-231. The effects of elevated EETs on tyrosine phosphorylation of the EGF receptor and ERK1/2 activation were then assessed. In this study, we found that addition of 14,15-EET and CYP102 F87V transfection markedly increased tyrosine phosphorylation of EGF-R and ERK1/2, an effect that was blocked by a selective EGF-R tyrosine kinase inhibitor (tyrphostin AG1478), a broad-spectrum metalloproteinase inhibitor (1,10-phenanthroline) and an inhibitor of HB-EGF release (CRM197) in Tca-8113 cells. In addition, AG1478, 1,10-phenanthroline and CRM197 also inhibited the tyrosine phosphorylation of EGF-R and ERK1/2 induced by 14,15-EET in A549, HepG2 and MDA-MB-231 cancer cell lines. These data suggest that EET-induced transactivation of EGF-R depends on activation of metalloproteinases and subsequent release of HB-EGF in cancer cells.
PMCID: PMC3938287  PMID: 20139904
arachidonic acid; cytochrome P450 epoxygenase; epoxyeicosatrienoic acids; tumor cell proliferation; EGF-R; ERK1/2; AG1478; phenanthroline; CRM197
8.  Meta-Analysis of Peripheral Blood Apolipoprotein E Levels in Alzheimer’s Disease 
PLoS ONE  2014;9(2):e89041.
Peripheral blood Apolipoprotein E (ApoE) levels have been proposed as biomarkers of Alzheimer’s disease (AD), but previous studies on levels of ApoE in blood remain inconsistent. This meta-analysis was designed to re-examine the potential role of peripheral ApoE in AD diagnosis and its potential value as a candidate biomarker.
We conducted a systematic literature search of MEDLINE, EMBASE, the Cochrane library, and BIOSIS previews for case-control studies measuring ApoE levels in serum or plasma from AD subjects and healthy controls. The pooled weighted mean difference (WMD) and 95% confidence interval (CI) were used to estimate the association between ApoE levels and AD risk.
Eight studies with a total of 2250 controls and 1498 AD cases were identified and analyzed. The pooled WMD from a random-effect model of AD participants compared with the healthy controls was −5.59 mg/l (95% CI: [−8.12, −3.06]). The overall pattern in WMD was not varied by characteristics of study, including age, country, assay method, publication year, and sample type.
Our meta-analysis supports a lowered level of blood ApoE in AD patients, and indicates its potential value as an important risk factor for AD. Further investigation employing standardized assay for ApoE measurement are still warranted to uncover the precise role of ApoE in the pathophysiology of AD.
PMCID: PMC3928366  PMID: 24558469
9.  Intracranial Rosai-Dorfman Disease 
Case Reports in Radiology  2014;2014:724379.
Rosai-Dorfman disease (RDD) is a rare, benign pseudolymphomatous condition, predominantly involving lymph nodes. Rosai-Dorfman disease (RDD) (sinus histiocytes with massive lymphadenopathy) rarely affects the intracranial region without involvement of other sites. It is a rare and idiopathic histoproliferation disorder characterized by painless lymphadenopathy. We report a case of 43-year-old male who presented with unconsciousness; MRI was done and right temporofrontal mass was found. Excision was done, and on histopathology it confirmed RDD.
PMCID: PMC3965928
10.  Ribose-phosphate pyrophosphokinase 1 (PRPS1) associated with deltamethrin resistance in Culex pipiens pallens 
Parasitology research  2012;112(2):847-854.
Ribose-phosphate pyrophosphokinase 1 (PRPS1) was identified and isolated as a differentially expressed gene between deltamethrin-susceptible (DS) and deltamethrin-resistant (DR) Culex pipiens pallens and Aedes albopictus C6/36 cell line through microarray and 2D-Gel. An open reading frame of PRPS1 cloned from C. pipiens pallens has 1,011 bp and encodes for a 336 amino acids protein which shares high homology with Culex quinquefasciatus. Real-time polymerase chain reaction was used to determine the transcript expression level of PRPS1 in DS and DR strains. The expression levels of PRPS1 were higher in DR laboratory strains and natural population JXZ-DR, JXZ-LDR. PRPS1 was also detected and expressed at all developmental stages of C. pipiens pallens and increased expression level in DR3 strain than DS strain in the third and fourth instar larvae, female and male stages. In addition, to further investigate the role of PRPS1 in deltamethrin resistance, PRPS1 was transiently expressed in A. albopictus C6/36 cells and detected by western blotting. Cells transfected with PRPS1 had an increased resistance to deltamethrin compared with control cells. These results suggested that the increased expression level of PRPS1 may play roles in the regulation of deltamethrin resistance.
PMCID: PMC3720864  PMID: 23250545
11.  Genome sequence of Anopheles sinensis provides insight into genetics basis of mosquito competence for malaria parasites 
BMC Genomics  2014;15:42.
Anopheles sinensis is an important mosquito vector of Plasmodium vivax, which is the most frequent and widely distributed cause of recurring malaria throughout Asia, and particularly in China, Korea, and Japan.
We performed 454 next-generation sequencing and obtained a draft sequence of A. sinensis assembled into scaffolds spanning 220.8 million base pairs. Analysis of this genome sequence, we observed expansion and contraction of several immune-related gene families in anopheline relative to culicine mosquito species. These differences suggest that species-specific immune responses to Plasmodium invasion underpin the biological differences in susceptibility to Plasmodium infection that characterize these two mosquito subfamilies.
The A. sinensis genome produced in this study, provides an important resource for analyzing the genetic basis of susceptibility and resistance of mosquitoes to Plasmodium parasites research which will ultimately facilitate the design of urgently needed interventions against this debilitating mosquito-borne disease.
PMCID: PMC3901762  PMID: 24438588
Genome; Anopheles sinensis; Malaria
12.  Efficacy of mosapride plus proton pump inhibitors for treatment of gastroesophageal reflux disease: A systematic review 
AIM: To assess the potential benefits of mosapride plus proton pump inhibitors (PPIs) in the treatment of gastroesophageal reflux disease.
METHODS: A literature search was performed through MEDLINE, EMBASE, and the ISI Web of Knowledge. The clinical trials that compared the benefit of mosapride plus PPI treatment with that of PPI monotherapy were analyzed. The rate of responders was evaluated by the pooled relative risk (PRR) and improvement in symptom scores was assessed by single effect size of a standardized mean, while Hedges’g was used as the effect size. Pooled effect sizes with 95%CIs were calculated using a fixed-effects model. Between-study heterogeneity was assessed using Q test and I2 analyses. In addition, studies that assessed the additional efficacy of mosapride in PPI-resistant patients were also reviewed.
RESULTS: This systematic review included information on a total of 587 patients based on 7 trials. Four trials compared the efficacy of combination therapy of mosapride plus a PPI with that of PPI monotherapy. The statistical analysis for the effect of additional mosapride showed equivocal results (PRR = 1.132; 95%CI: 0.934-1.372; P = 0.205; Hedges’g = 0.24; 95%CI: 0.03-0.46; P = 0.023). No heterogeneity and publication bias were found among the studies. Three open-labeled trials assessed the additional efficacy of mosapride in PPI-resistant patients. However, since these trials did not set the control group, the results may be considerably biased.
CONCLUSION: Mosapride combined therapy is not more effective than PPI alone as first-line therapy. Whether it is effective in PPI-resistant patients needs to be determined.
PMCID: PMC3870566  PMID: 24379638
Mosapride; Proton pump inhibitor; Gastroesophageal reflux disease; Systematic review; Combined therapy
13.  The CCR4-NOT Complex Mediates Deadenylation and Degradation of Stem Cell mRNAs and Promotes Planarian Stem Cell Differentiation 
PLoS Genetics  2013;9(12):e1004003.
Post-transcriptional regulatory mechanisms are of fundamental importance to form robust genetic networks, but their roles in stem cell pluripotency remain poorly understood. Here, we use freshwater planarians as a model system to investigate this and uncover a role for CCR4-NOT mediated deadenylation of mRNAs in stem cell differentiation. Planarian adult stem cells, the so-called neoblasts, drive the almost unlimited regenerative capabilities of planarians and allow their ongoing homeostatic tissue turnover. While many genes have been demonstrated to be required for these processes, currently almost no mechanistic insight is available into their regulation. We show that knockdown of planarian Not1, the CCR4-NOT deadenylating complex scaffolding subunit, abrogates regeneration and normal homeostasis. This abrogation is primarily due to severe impairment of their differentiation potential. We describe a stem cell specific increase in the mRNA levels of key neoblast genes after Smed-not1 knock down, consistent with a role of the CCR4-NOT complex in degradation of neoblast mRNAs upon the onset of differentiation. We also observe a stem cell specific increase in the frequency of longer poly(A) tails in these same mRNAs, showing that stem cells after Smed-not1 knock down fail to differentiate as they accumulate populations of transcripts with longer poly(A) tails. As other transcripts are unaffected our data hint at a targeted regulation of these key stem cell mRNAs by post-transcriptional regulators such as RNA-binding proteins or microRNAs. Together, our results show that the CCR4-NOT complex is crucial for stem cell differentiation and controls stem cell-specific degradation of mRNAs, thus providing clear mechanistic insight into this aspect of neoblast biology.
Author Summary
Although transcriptional regulation in stem cells is a very active subject, much less is known about how post-transcriptional mechanisms of gene expression affect stem cells. Here, we use freshwater planarians in order to address this question. Planarians have a striking regenerative capacity driven by a population of pluripotent stem cells, the neoblasts. Control of both proliferation and differentiation is thought to rely heavily on post-transcriptional mechanisms, but their precise role is unknown. Poly(A) tail length regulation is an important mechanism of post-transcriptional control of gene expression as changes can be very rapid, and longer poly(A) tails are linked to increased mRNA stability and translational activity. We investigated the role of the CCR4-NOT complex, the major deadenylating complex in eukaryotes, by knocking down its main scaffolding subunit called Not1. Neoblasts in knock down animals are unable to differentiate and accumulate mRNAs with longer poly(A) tails. Our results show that the CCR4-NOT complex is needed for the targeted degradation of specific mRNAs expressed in stem cells, and the failure of this process likely prevents neoblasts from differentiating. These results reveal a new functional aspect of the CCR4-NOT complex and offer a mechanistic insight into the regulation of planarian stem cells.
PMCID: PMC3868585  PMID: 24367277
14.  OBATOCLAX and ABT-737 Induce ER Stress Responses in Human Melanoma Cells that Limit Induction of Apoptosis 
PLoS ONE  2013;8(12):e84073.
Anti-apoptotic Bcl-2 family proteins, in particular, Mcl-1, are known to play a critical role in resistance of human melanoma cells to induction of apoptosis by endoplasmic reticulum stress and other agents. The present study examined whether the BH3 mimetics, Obatoclax and ABT-737, which inhibit multiple anti-apoptotic Bcl-2 family proteins, would overcome resistance to apoptosis. We report that both agents induced a strong unfolded protein response (UPR) and that RNAi knockdown of UPR signalling proteins ATF6, IRE1α and XBP-1 inhibited Mcl-1 upregulation and increased sensitivity to the agents. These results demonstrate that inhibition of anti-apoptotic Bcl-2 proteins by Obatoclax and ABT-737 appears to elicit a protective feedback response in melanoma cells, by upregulation of Mcl-1 via induction of the UPR. We also report that Obatoclax, but not ABT-737, strongly induces autophagy, which appears to play a role in determining melanoma sensitivity to the agents.
PMCID: PMC3868604  PMID: 24367627
15.  Indole-3-Carbinol Inhibits Nasopharyngeal Carcinoma Growth through Cell Cycle Arrest In Vivo and In Vitro 
PLoS ONE  2013;8(12):e82288.
Nasopharyngeal carcinoma is a common malignant tumor in the head and neck. Because of frequent recurrence and distant metastasis which are the main causes of death, better treatment is needed. Indole-3-carbinol (I3C), a natural phytochemical found in the vegetables of the cruciferous family, shows anticancer effect through various signal pathways. I3C induces G1 arrest in NPC cell line with downregulation of cell cycle-related proteins, such as CDK4, CDK6, cyclin D1 and pRb. In vivo, nude mice receiving I3C protectively or therapeutically exhibited smaller tumors than control group after they were inoculated with nasopharyngeal carcinoma cells. The expression of CDK4, CDK6, cyclin D1 and pRb in preventive treatment group and drug treatment group both decreased compared with the control group. We conclude that I3C can inhibit the growth of NPC in vitro and in vivo by suppressing the expression of CDK and cyclin families. The drug was safe and had no toxic effects on normal tissues and organs.
PMCID: PMC3864926  PMID: 24358165
16.  Correction: High Weight Loss during Radiation Treatment Changes the Prognosis in Under-/Normal Weight Nasopharyngeal Carcinoma Patients for the Worse: A Retrospective Analysis of 2433 Cases 
PLoS ONE  2013;8(12):10.1371/annotation/3dc37158-1f60-436e-9bd5-2a822aa2c9cb.
PMCID: PMC3865324
17.  The prevalence and determinants of impaired fasting glucose in the population of Taiwan 
BMC Public Health  2013;13:1123.
A current prevalence and relevant risk factors for impaired fasting glucose (IFG) have been reported by various ethnic groups and countries. By contrast, nationwide data for the incidence of IFG in Taiwan have not been presented in the past 15 years. The aim for this manuscript was to estimate the prevalence of IFG and associated risk factors in the population of Taiwan.
For this cross-sectional research, we used a nationally representative sample (N = 2604) obtained from the 2005–2008 Nutrition and Health Survey in Taiwan (NAHSIT), and adopted a stratified multistage sampling design. The tools employed for data collection included questionnaire interviews, anthropometry measurements, and laboratory analysis.
The prevalence of IFG among adults in Taiwan is 35.8% (a fasting glucose level between 100 and 125 mg/dl is considered abnormal). An estimated number of people with IFG is 6.5 million. A higher prevalence of IFG is observed in men younger than 65 years compared to women. However, this trend is reversed for the elderly population. The factors significantly associated with IFG include the following: sex, age, overweight (27 > BMI ≥ 24), obesity (BMI ≥ 27), waist circumference (men ≥ 90 cm, women ≥ 80 cm), hypertension, and hyperlipidemia.
IFG among adults in Taiwan is a health concern that requires attention. We recommend targeting the younger population, especially overweight and obese men between the ages of 19 and 40 years, to provide applicable healthy lifestyle counseling and services. Furthermore, appropriate screening of elderly people is required to detect undiagnosed IFG cases and provide early intervention and treatment.
PMCID: PMC3866508  PMID: 24304589
Impaired fasting glucose (IFG); Prevalence; Adult; Epidemiology; Taiwan
18.  (E)-2-Methyl-3-phenyl­selanyl-4-(phenyl­sulfin­yl)oct-3-en-2-ol 
In the title compound, C21H26O2SSe, the S atom adopts a pyramidal geometry (bond-angle sum = 304°) and the n-butyl chain shows an extended conformation. An intra­molecular C—H⋯O hydrogen bond closes an S(8) ring. In the crystal, inversion dimers are formed with molecules linked by pairs of O—H⋯O=S hydrogen bonds, generating R 2 2(14) loops. Weak C—H⋯O inter­actions also occur.
PMCID: PMC3914049  PMID: 24527011
19.  Planarian MBD2/3 is required for adult stem cell pluripotency independently of DNA methylation☆ 
Developmental Biology  2013;384(1):141-153.
Planarian adult stem cells (pASCs) or neoblasts represent an ideal system to study the evolution of stem cells and pluripotency as they underpin an unrivaled capacity for regeneration. We wish to understand the control of differentiation and pluripotency in pASCs and to understand how conserved, convergent or divergent these mechanisms are across the Bilateria. Here we show the planarian methyl-CpG Binding Domain 2/3 (mbd2/3) gene is required for pASC differentiation during regeneration and tissue homeostasis. The genome does not have detectable levels of 5-methylcytosine (5mC) and we find no role for a potential DNA methylase. We conclude that MBD proteins may have had an ancient role in broadly controlling animal stem cell pluripotency, but that DNA methylation is not involved in planarian stem cell differentiation.
•A single ancestral MBD2/3 protein is present in the planarian Schmidtea mediterranea.•The genome of S. mediterranea does not have pervasive cytosine methylation.•MBD2/3 is required for pluripotent stem cell differentiation down multiple but not all cell lineages.•MBD2/3 may have had an ancestral role in regulating stem cell pluripotency.
PMCID: PMC3824064  PMID: 24063805
Methyl binding domain; Pluripotency; Differentiation; Regeneration
20.  Two Novel Hepatocellular Carcinoma Cycle Inhibitory Cyclodepsipeptides from a Hydrothermal Vent Crab-Associated Fungus Aspergillus clavatus C2WU 
Marine Drugs  2013;11(12):4761-4772.
Two novel cyclodepsipeptides containing an unusual anthranilic acid dimer and a d-phenyllactic acid residues, clavatustides A (1) and B (2), were identified from cultured mycelia and broth of Aspergillus clavatus C2WU isolated from Xenograpsus testudinatus, which lives at extreme, toxic habitat around the sulphur-rich hydrothermal vents in Taiwan Kueishantao. This is the first example of cyclopeptides containing an anthranilic acid dimer in natural products, and the first report of microbial secondary metabolites from the hydrothermal vent crab. Clavatustides A (1) and B (2) suppressed the proliferation of hepatocellular carcinoma (HCC) cell lines (HepG2, SMMC-7721 and Bel-7402) in a dose-dependent manner, and induced an accumulation of HepG2 cells in G1 phase and reduction of cells in S phase.
PMCID: PMC3877885  PMID: 24317468
cyclodepsipeptide; Aspergillus clavatus; hydrothermal vent; carcinoma cycle inhibitory
21.  Silent geographical spread of the H7N9 virus by online knowledge analysis of the live bird trade with a distributed focused crawler 
Unlike those infected by H5N1, birds infected by the newly discovered H7N9 virus have no observable clinical symptoms. Public health workers in China do not know where the public health threat lies. In this study, we used a distributed focused crawler to analyze online knowledge of the live bird trade in first-wave provinces, namely, Jiangsu, Zhejiang, Anhui, and Shanghai, to track the new H7N9 virus and predict its spread. Of the 18 provinces proposed to be at high risk of infection, 10 reported human infections and one had poultry specimens that tested positive. Five provinces (Xinjiang, Yunnan, Guizhou, Shaanxi, and Tibet) as well as Hong Kong, Macao, and Taiwan were proposed to have no risk of H7N9 virus infection from the live bird trade. These data can help health authorities and the public to respond rapidly to reduce damage related to the spread of the virus.
PMCID: PMC3880875
H7N9; online knowledge; outbreak
22.  Circulating miR-30a, miR-126 and let-7b as biomarker for ischemic stroke in humans 
BMC Neurology  2013;13:178.
Recently, plasma miRNAs have been reported as biomarkers for various diseases. However, the knowledge on the association of plasma miRNAs with ischemic stroke is still lacking. In this study, we investigated whether plasma concentrations of miR-30a, miR-126 and let-7b may be biomarkers for ischemic stroke in humans.
One hundred ninety seven patients with ischemic stroke were recruited and their blood samples were collected at 24 h, 1 week, 4 weeks, 24 weeks and 48 weeks after symptoms onset, and fifty healthy volunteers were selected as control. Levels of miRNA were quantified by quantitative real-time PCR. Relative expression level of miRNA was calculated using 2-ΔΔct method. The ability to distinguish the ischemic stroke group from control group was characterized by receiver operating characteristic (ROC) curve, and the area under ROC curve (AUC) was calculated.
Circulating miR-30a and miR-126 levels were markedly down-regulated in all patients with ischemic stroke until 24 weeks. However, circulating let-7b was lower in patients with large-vessel atherosclerosis than healthy volunteers, whereas circulating let-7b had higher level in patients with other kinds of ischemic stroke until 24 weeks. Among all patients, circulating miRNAs levels returned to normal 48 weeks after symptom onset. Receiver operating characteristic (ROC) curve analysis showed that the areas under the curve (AUC) of plasma miR-30a were 0.91, 0.91, 0.92 and 0.93, the miR-126 were 0.92, 0.94, 0.93 and 0.92, and let-7b were 0.93, 0.92, 0.92 and 0.91 at 24 h, 1 w, 4 w and 24 w, respectively.
These data suggest that miR-30a, miR-126 and let-7b might be useful biomarkers for ischemic stroke in humans.
PMCID: PMC3840584  PMID: 24237608
Circulating miRNA; Biomarker; Stroke
23.  DriverDB: an exome sequencing database for cancer driver gene identification 
Nucleic Acids Research  2013;42(D1):D1048-D1054.
Exome sequencing (exome-seq) has aided in the discovery of a huge amount of mutations in cancers, yet challenges remain in converting oncogenomics data into information that is interpretable and accessible for clinical care. We constructed DriverDB (, a database which incorporates 6079 cases of exome-seq data, annotation databases (such as dbSNP, 1000 Genome and Cosmic) and published bioinformatics algorithms dedicated to driver gene/mutation identification. We provide two points of view, ‘Cancer’ and ‘Gene’, to help researchers to visualize the relationships between cancers and driver genes/mutations. The ‘Cancer’ section summarizes the calculated results of driver genes by eight computational methods for a specific cancer type/dataset and provides three levels of biological interpretation for realization of the relationships between driver genes. The ‘Gene’ section is designed to visualize the mutation information of a driver gene in five different aspects. Moreover, a ‘Meta-Analysis’ function is provided so researchers may identify driver genes in customer-defined samples. The novel driver genes/mutations identified hold potential for both basic research and biotech applications.
PMCID: PMC3965046  PMID: 24214964
24.  Polymorphism of Antigen MPT64 in Mycobacterium tuberculosis Strains 
Journal of Clinical Microbiology  2013;51(5):1558-1562.
We selected 180 clinical isolates of the Mycobacterium tuberculosis complex (MTBC) from patients in China and performed comparative sequence analysis of the mpt64 gene after amplification. From the results, we found that polymorphisms of the mpt64 gene in the MTBC may be the reason for changes in the antigen produced, which may in turn cause alterations of related functions, thereby allowing immune evasion.
PMCID: PMC3647925  PMID: 23390287
25.  Nanosilica coating for bonding improvements to zirconia 
Resin bonding to zirconia cannot be established from standard methods that are currently utilized in conventional silica-based dental ceramics. The solution–gelatin (sol–gel) process is a well developed silica-coating technique used to modify the surface of nonsilica-based ceramics. Here, we use this technique to improve resin bonding to zirconia, which we compared to zirconia surfaces treated with alumina sandblasting and tribochemical silica coating. We used the shear bond strength test to examine the effect of the various coatings on the short-term resin bonding of zirconia. Furthermore, we employed field emission scanning electron microscopy, energy-dispersive X-ray spectroscopy, atomic force microscopy, and Fourier transform infrared spectroscopy to characterize the zirconia surfaces. Water–mist spraying was used to evaluate the durability of the coatings. To evaluate the biological safety of the experimental sol–gel silica coating, we conducted an in vitro Salmonella typhimurium reverse mutation assay (Ames mutagenicity test), cytotoxicity tests, and in vivo oral mucous membrane irritation tests. When compared to the conventional tribochemical silica coating, the experimental sol–gel silica coating provided the same shear bond strength, higher silicon contents, and better durability. Moreover, we observed no apparent mutagenicity, cytotoxicity, or irritation in this study. Therefore, the sol–gel technique represents a promising method for producing silica coatings on zirconia.
PMCID: PMC3810896  PMID: 24179333
zirconia; bond; silica coating; tribochemical silica coating; biocompatibility

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