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1.  Comparison of the Pharmacological Profiles of Selective PDE4B and PDE4D Inhibitors in the Central Nervous System 
Scientific Reports  2017;7:40115.
Inhibition of cyclic AMP (cAMP)-specific phosphodiesterase 4 (PDE4) has been proposed as a potential treatment for a series of neuropsychological conditions such as depression, anxiety and memory loss. However, the specific involvement of each of the PDE4 subtypes (PDE4A, 4B and 4C) in different categories of behavior has yet to be elucidated. In the present study, we compared the possible pharmacological effects of PDE4B and PDE4D selective inhibitors, A-33 and D159687, in mediating neurological function in mice. Both compounds were equally potent in stimulating cAMP signaling in the mouse hippocampal cell line HT-22 leading to an increase in CREB phosphorylation. In contrast, A-33 and D159687 displayed distinct neuropharmacological effects in mouse behavioral tests. A-33 has an antidepressant-like profile as indicated by reduced immobility time in the forced swim and tail suspension tasks, as well as reduced latency to feed in the novelty suppressed feeding test. D159687, on the other hand, had a procognitive profile as it improved memory in the novel object recognition test but had no antidepressant or anxiolytic benefit. The present data suggests that inhibitors targeting specific subtypes of PDE4 may exhibit differential pharmacological effects and aid a more efficient pharmacotherapy towards neuropsychological conditions.
PMCID: PMC5215650  PMID: 28054669
2.  T Cell Repertoire Diversity Is Decreased in Type 1 Diabetes Patients 
Type 1 diabetes mellitus (T1D) is an immune-mediated disease. The autoreactive T cells in T1D patients attack and destroy their own pancreatic cells. In order to systematically investigate the potential autoreactive T cell receptors (TCRs), we used a high-throughput immune repertoire sequencing technique to profile the spectrum of TCRs in individual T1D patients and controls. We sequenced the T cell repertoire of nine T1D patients, four type 2 diabetes (T2D) patients, and six nondiabetic controls. The diversity of the T cell repertoire in T1D patients was significantly decreased in comparison with T2D patients (P = 7.0E−08 for CD4+ T cells, P = 1.4E−04 for CD8+ T cells) and nondiabetic controls (P = 2.7E−09 for CD4+ T cells, P = 7.6E−06 for CD8+ T cells). Moreover, T1D patients had significantly more highly-expanded T cell clones than T2D patients (P = 5.2E−06 for CD4+ T cells, P = 1.9E−07 for CD8+ T cells) and nondiabetic controls (P = 1.7E−07 for CD4+ T cells, P = 3.3E−03 for CD8+ T cells). Furthermore, we identified a group of highly-expanded T cell receptor clones that are shared by more than two T1D patients. Although further validation in larger cohorts is needed, our data suggest that T cell receptor diversity measurements may become a valuable tool in investigating diabetes, such as using the diversity as an index to distinguish different types of diabetes.
PMCID: PMC5200939  PMID: 28024918
Diversity; High-throughput sequencing; Immune repertoire; T cell receptor; Type 1 diabetes
3.  Angiopoietin receptor Tie2 is required for vein specification and maintenance via regulating COUP-TFII 
eLife  null;5:e21032.
Mechanisms underlying the vein development remain largely unknown. Tie2 signaling mediates endothelial cell (EC) survival and vascular maturation and its activating mutations are linked to venous malformations. Here we show that vein formation are disrupted in mouse skin and mesentery when Tie2 signals are diminished by targeted deletion of Tek either ubiquitously or specifically in embryonic ECs. Postnatal Tie2 attenuation resulted in the degeneration of newly formed veins followed by the formation of haemangioma-like vascular tufts in retina and venous tortuosity. Mechanistically, Tie2 insufficiency compromised venous EC identity, as indicated by a significant decrease of COUP-TFII protein level, a key regulator in venogenesis. Consistently, angiopoietin-1 stimulation increased COUP-TFII in cultured ECs, while Tie2 knockdown or blockade of Tie2 downstream PI3K/Akt pathway reduced COUP-TFII which could be reverted by the proteasome inhibition. Together, our results imply that Tie2 is essential for venous specification and maintenance via Akt mediated stabilization of COUP-TFII.
PMCID: PMC5218530  PMID: 28005008
Tie2; COUP-TFII; vein specification; Mouse
4.  Factors Determining the Efficiency of Porcine Somatic Cell Nuclear Transfer: Data Analysis with Over 200,000 Reconstructed Embryos 
Cellular Reprogramming  2015;17(6):463-471.
Data analysis in somatic cell nuclear transfer (SCNT) research is usually limited to several hundreds or thousands of reconstructed embryos. Here, we report mass results obtained with an established and consistent porcine SCNT system (handmade cloning [HMC]). During the experimental period, 228,230 reconstructed embryos and 82,969 blastocysts were produced. After being transferred into 656 recipients, 1070 piglets were obtained. First, the effects of different types of donor cells, including fetal fibroblasts (FFs), adult fibroblasts (AFs), adult preadipocytes (APs), and adult blood mesenchymal (BM) cells, were investigated on the further in vitro and in vivo development. Compared to adult donor cells (AFs, APs, BM cells, respectively), FF cells resulted in a lower blastocyst/reconstructed embryo rate (30.38% vs. 37.94%, 34.65%, and 34.87%, respectively), but a higher overall efficiency on the number of piglets born alive per total blastocysts transferred (1.50% vs. 0.86%, 1.03%, and 0.91%, respectively) and a lower rate of developmental abnormalities (10.87% vs. 56.57%, 24.39%, and 51.85%, respectively). Second, recloning was performed with cloned adult fibroblasts (CAFs) and cloned fetal fibroblasts (CFFs). When CAFs were used as the nuclear donor, fewer developmental abnormalities and higher overall efficiency were observed compared to AFs (56.57% vs. 28.13% and 0.86% vs. 1.59%, respectively). However, CFFs had an opposite effect on these parameters when compared with CAFs (94.12% vs. 10.87% and 0.31% vs. 1.50%, respectively). Third, effects of genetic modification on the efficiency of SCNT were investigated with transgenic fetal fibroblasts (TFFs) and gene knockout fetal fibroblasts (KOFFs). Genetic modification of FFs increased developmental abnormalities (38.96% and 25.24% vs. 10.87% for KOFFs, TFFs, and FFs, respectively). KOFFs resulted in lower overall efficiency compared to TFFs and FFs (0.68% vs. 1.62% and 1.50%, respectively). In conclusion, this is the first report of large-scale analysis of porcine cell nuclear transfer that provides important data for potential industrialization of HMC technology.
PMCID: PMC4677548  PMID: 26655078
5.  Synergistic antidepressant-like effect of ferulic acid in combination with piperine: involvement of monoaminergic system 
Metabolic brain disease  2015;30(6):1505-1514.
The lifetime prevalence rate for major depressive disorder (MDD) is approximately 17 % for most developed countries around the world. Dietary polyphenols are currently used as an adjuvant therapy to accelerate the therapeutic efficacy on depression. Ferulic acid (FA) or 4-hydroxy-3-methoxy-cinnamic acid (Fig. 1a) is a main polyphenolic component of Chinese herb Radix Angelicae Sinensis, which is found to have antidepressant-like effects through regulating serotonergic and noradrenergic function. The present study examined the synergistic effect of low doses of FA combined with subthreshold dose of piperine, a bioavailability enhancer, on depression-like behaviors in mice, and investigated the possible mechanism. The administration of FA, even in the highest dose tested, reduced immobility time by 60 % in the tail suspension and forced swimming tests (TST and FST) in mice when compared to control. The maximal antidepressant-like effect of FA was obtained with 200 mg/kg. In addition, piperine only produced a weak antidepressant-like effect in the TST and FST. However, the evidence from the interaction analysis suggested a synergistic effect when low doses of FA were combined with a subthreshold dose of piperine. Further neurochemical evidence such as monoamine levels in the frontal cortex, hippocampus, and hypothalamus and measurements of monoamine oxidase activity also supported a synergistic effect of FA and piperine in the enhancement of monoaminergic function. This finding supports the concept that the combination strategy might be an alternative therapy in the treatment of psychiatric disorders with high efficacy and low side effects.
PMCID: PMC4795470  PMID: 26220010
Ferulic acid; Piperine; Depression; Monoamines; MAO
6.  E-Cigarette Awareness, Use, and Harm Perception among Adults: A Meta-Analysis of Observational Studies 
PLoS ONE  2016;11(11):e0165938.
The aim of this study is to systematically review the published literature on the awareness, previous and current use, and harm perceptions of electronic cigarettes (e-cigarettes) among adults.
A search of the most current literature using the PubMed and Scopus database to identify articles published since 2003 yielded a total of 28 relevant articles.
The pooled prevalence of awareness, previous use, current use of e-cigarettes and perceived healthier of e-cigarettes than regular cigarettes (healthier perception) among adults were 61.2% (95% confidence interval (CI): 51.5–70.8%), 16.8% (95% CI: 14.0–19.6%), 11.1% (95% CI: 9.2–13.1%), and 52.6% (95% CI: 42.5–62.6%), respectively, using a random effects model. The subgroup analysis showed that pooled estimates were highest in the group of current smokers of regular cigarettes, except that the highest pooled rate of current use was seen in the group of former smokers of regular cigarettes (the corresponding rates were 71.9% (95% CI: 57.5–86.3%), 27.2% (95% CI: 18.8–35.6%), 16.8% (95% CI: 7.2–26.3%), and 63.1% (95% CI: 52.1–74.1%)), and the lowest pooled rates were in the group of non-smokers, except for the rate of healthier perception in the users of e-cigarettes (and the corresponding rates were 46.8% (95% CI: 26.8–66.8%), 2.5% (95% CI: 1.1–5.6%), 1.2% (95% CI: 0.4–2.1%), and 37.9% (95% CI: -0.5–76.3%)). The cumulative meta-analysis found that awareness increased over time, while the prevalence of previous use, current use, and healthier perception first experienced an increase followed by a decrease and remained stable thereafter.
E-cigarette awareness has been increasing, and e-cigarette use and perceived health risks are nearly invariable between 2009 and 2014. Given the substantial heterogeneity in the prevalence rate estimates, there is a need for more accurate and comparable prevalence estimates for e-cigarettes across the world.
PMCID: PMC5115669  PMID: 27861501
7.  Identification of Differentially Expressed Genes in Pelvic Organ Prolapse by RNA-Seq 
Pelvic organ prolapse (POP) brings major health issues for women, affecting 40% of postmenopausal women, and directly affects bladder and bowel function, as well as quality of life. In light of the projected growth in demand for care for pelvic floor disorders, determining the etiology and progression of POP has important public health implications.
Uterosacral ligaments (USLs) samples of POP patients and normal controls were enrolled for RNA-Seq, and functional annotation analysis and Protein-Protein interaction (PPI) networks construction were performed for differentially expressed genes (DEGs).
A total of 81 DEGs were identified between POP and normal control, and distinctly classify all samples into normal and POP group by hierarchical clustering. Sixty-six DEGs demonstrated the same expression pattern among the POP samples with different stages. For those DEGs, canonical Wnt receptor signaling pathway was the most significantly enriched GO term (P value=3.33E-07), and neuroactive ligand-receptor interaction was the most significantly enriched pathway (P value=1.24E-03). In The PPI networks of 81 dysregulated genes, significant hub proteins contained TOP2A (Degree=54), KCNA5 (Degree=22) and PLA2G2A (Degree=19), suggesting their important role in the development of POP.
This RNA-seq analysis identified a POP signature of 81 genes, and some ECM-related genes, including COMP, NDP, and SNAI2 might participate in the pathology of POP and be applied as potential therapeutic targets.
PMCID: PMC5110227  PMID: 27818488
Gene Expression; High-Throughput Screening Assays; Pelvic Organ Prolapse
8.  Novel Polymorphic Multilocus Microsatellite Markers to Distinguish Candida tropicalis Isolates 
PLoS ONE  2016;11(11):e0166156.
Candida tropicalis is an important pathogen. Here we developed and evaluated a polymorphic multilocus microsatellite scheme employing novel genetic markers for genotyping of C. tropicalis. Using 10 isolates from 10 unique (separate) patients to screen over 4000 tandem repeats from the C. tropicalis genome (strain MYA-3404), six new candidate microsatellite loci (ctm1, ctm3, ctm8, ctm18, ctm24 and ctm26) were selected according to amplification success, observed polymorphisms and stability of flanking regions by preliminary testing. Two known microsatellite loci CT14 and URA3 were also studied. The 6-locus scheme was then tested against a set of 82 different isolates from 32 patients. Microsatellite genotypes of isolates from the same patient (two to five isolates per patient) were identical. The six loci produced eight to 17 allele types and identified 11 to 24 genotypes amongst 32 patients’ isolates, achieving a discriminatory power (DP) of 0.76 to 0.97 (versus 0.78 for both CT14 and URA3 loci, respectively). Testing of a combination of only three loci, ctm1, ctm3 and ctm24, also achieved maximum typing efficiency (DP = 0.99, 29 genotypes). The microsatellite typing scheme had good correlation compared with pulsed-field gel electrophoresis, although was slightly less discriminatory. The new six-locus microsatellite typing scheme is a potentially valuable tool for genotyping and investigating microevolution of C. tropicalis.
PMCID: PMC5098789  PMID: 27820850
9.  Knockdown of Decoy Receptor 3 Impairs Growth and Invasiveness of Hepatocellular Carcinoma Cell Line of HepG2 
Chinese Medical Journal  2016;129(21):2623-2629.
Decoy receptor 3 (DcR3) binds to Fas ligand (FasL) and inhibits FasL-induced apoptosis. The receptor is overexpressed in hepatocellular carcinoma (HCC), and it is associated with the growth and metastatic spread of tumors. DcR3 holds promises as a new target for the treatment of HCC, but little is known regarding the molecular mechanisms underlying the oncogenic properties of DcR3. The present work, therefore, examined the role of DcR3 in regulating the growth and invasive property of liver cancer cell HepG2.
HepG2 cells were stably transfected with lentivirus-based short hairpin RNA vector targeting DcR3. After the knockdown of DcR3 was confirmed, cell proliferation, clone formation, ability of migrating across transwell membrane, and wound healing were assessed in vitro. Matrix metalloproteinase-9 (MMP 9) and vascular epithelial growth factor (VEGF)-C and D expressions of the DcR3 knockdown were also studied. Comparisons between multiple groups were done using one-way analysis of variance (ANOVA), while pairwise comparisons were performed using Student's t test. P < 0.05 was regarded statistically significant.
DcR3 was overexpressed in HepG2 compared to other HCC cell lines and normal hepatocyte Lo-2. Stable knockdown of DcR3 slowed down the growth of HepG2 (P < 0.05) and reduced the number of clones formed by 50% compared to those without DcR3 knockdown (P < 0.05). The knockdown also reduced the migration of HepG2 across transwell matrix membrane by five folds compared to the control (P < 0.05) and suppressed the closure of scratch wound (P < 0.05). In addition, the messenger RNA levels of MMP 9, VEGF-C, and VEGF-D were significantly suppressed by DcR3 knockdown by 90% when compared with the mock control (P < 0.05).
Loss of DcR3 impaired the growth and invasive property of HCC cell line of HepG2. Targeting DcR3 may be a potential therapeutic approach for the treatment of HCC.
PMCID: PMC5125343  PMID: 27779171
Decoy Receptor 3; Hepatocellular Carcinoma; Matrix Metalloproteinase 9; Neoplasm Metastasis; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor D
10.  A Comprehensive Evaluation of the Bruker Biotyper MS and Vitek MS Matrix-Assisted Laser Desorption Ionization–Time of Flight Mass Spectrometry Systems for Identification of Yeasts, Part of the National China Hospital Invasive Fungal Surveillance Net (CHIF-NET) Study, 2012 to 2013 
Journal of Clinical Microbiology  2016;54(5):1376-1380.
Among the 2,683 yeast isolates representing 41 different species (25 Candida and Candida-related species and 16 non-Candida yeast species) collected in the National China Hospital Invasive Fungal Surveillance Net (CHIF-NET) program (2012 to 2013), the Bruker Biotyper MS matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) system exhibited significantly higher accuracy rates than the Vitek MS system for identification of all yeast isolates (98.8% versus 95.4%, P <0.001 by Pearson's chi-square test) and for all Candida and Candida-related species isolates (99.4% versus 95.5%, P < 0.001).
PMCID: PMC4844720  PMID: 26912761
11.  Low-Concentration Ciprofloxacin Selects Plasmid-Mediated Quinolone Resistance Encoding Genes and Affects Bacterial Taxa in Soil Containing Manure 
The spread of antimicrobial resistance in environment is promoted at least in part by the inappropriate use of antibiotics in animals and humans. The present study was designed to investigate the impact of different concentrations of ciprofloxacin in soil containing manure on the development of plasmid-mediated quinolone resistance (PMQR) – encoding genes and the abundance of soil bacterial communities. For these studies, high-throughput next-generation sequencing of 16S rRNA, real-time polymerase chain reaction and standard microbiologic culture methods were utilized. We demonstrated that the dissipate rate of relative abundances of some of PMQR-encoding genes, such as qnrS, oqxA and aac(6′)-Ib-cr, were significantly lower with ciprofloxacin 0.04 and 0.4 mg/kg exposure as compared to no-ciprofloxacin control and ciprofloxacin 4 mg/kg exposure during 2 month. Also, the number of ciprofloxacin resistant bacteria was significantly greater in ciprofloxacin 0.04 and 0.4 mg/kg exposure as compared with no-ciprofloxacin control and the ciprofloxacin 4 mg/kg exposure. In addition, lower ciprofloxacin concentration provided a selective advantage for the populations of Xanthomonadales and Bacillales in orders while Agrobacterium, Bacillus, Enterococcus, and Burkholderia in genera. These findings suggest that lower concentration of ciprofloxacin resulted in a slower rate of PMQR-encoding genes dissipation and selected development of ciprofloxacin-resistant bacteria in soil amended with manure.
PMCID: PMC5088497  PMID: 27847506
ciprofloxacin; manure; soil; PMQR-encoding genes; bacterial taxa
12.  Antifouling phenyl ethers and other compounds from the invertebrates and their symbiotic fungi collected from the South China Sea 
AMB Express  2016;6:102.
Marine organism-derived secondary metabolites are promising potential sources for discovering environmentally safe antifouling agents. In present study, 55 marine secondary metabolites and their synthesized derivatives were tested and evaluated for their antifouling activities and security. These compounds include 44 natural products isolated from marine invertebrates and their symbiotic microorganisms collected from the South China Sea and 11 structural modified products derived from the isolated compounds. The natural secondary metabolites, covering phenyl ether derivatives, terpenoids, 9, 11-secosteroids, anthraquinones, alkaloids, nucleoside derivatives and peptides, were isolated from two corals, one sponge and five symbiotic fungi. All of the isolated and synthesized compounds were tested for their antifouling activities against the cyprids of barnacle Balanus (Amphibalanus) amphitrite Darwin. Noticeably, five phenyl ether derivatives (9, 11, 13–15) exhibited potent anti-larval settlement activity with the EC50 values lower than 3.05 μM and the LC50/EC50 ratios higher than 15. The study of structure–activity relationship (SAR) revealed that the introduction of acetoxy groups and bromine atoms to phenyl ether derivatives could significantly improve their antifouling activities. This is the first report on the SAR of phenyl ether derivatives on antifouling activity against barnacle B. amphitrite. The polybrominated diphenyl ether derivative, 2, 4, 6, 2′, 4′, 6′-hexabromo-diorcinol (13), which displayed excellent antifouling activity, was considered as a promising candidate of environmentally friendly antifouling agents.
Electronic supplementary material
The online version of this article (doi:10.1186/s13568-016-0272-2) contains supplementary material, which is available to authorized users.
PMCID: PMC5081312  PMID: 27785778
Antifouling; Anti-larval settlement; Balanus amphitrite; Marine natural product; Phenyl ether derivative
13.  Use of next generation sequence to investigate potential novel macrolide resistance mechanisms in a population of Moraxella catarrhalis isolates 
Scientific Reports  2016;6:35711.
Although previous studies have confirmed that 23S rRNA gene mutation could be responsible for most of macrolide resistance in M. catarrhalis, a recent study suggested otherwise. Next generation sequence based comparative genomics has revolutionized the mining of potential novel drug resistant mechanisms. In this study, two pairs of resistant and susceptible M. catarrhalis isolates with different multilocus sequence types, were investigated for potential differential genes or informative single nucleotide polymorphisms (SNPs). The identified genes and SNPs were evaluated in 188 clinical isolates. From initially 12 selected differential genes and 12 informative SNPs, 10 differential genes (mboIA, mcbC, mcbI, mboIB, MCR_1794, MCR_1795, lgt2B/C, dpnI, mcbB, and mcbA) and 6 SNPs (C619T of rumA, T140C of rplF, G643A of MCR_0020, T270G of MCR_1465, C1348A of copB, and G238A of rrmA) were identified as possibly linked to macrolide resistance in M. catarrhalis. Most of the identified differential genes and SNPs are related to methylation of ribosomal RNA (rRNA) or DNA, especially MCR_0020 and rrmA. Further studies are needed to determine the function and/or evolution process, of the identified genes or SNPs, to establish whether some novel or combined mechanisms are truly involved in M. catarrhalis macrolide resistance mechanism.
PMCID: PMC5075928  PMID: 27774989
14.  Splenic dendritic cells survey red blood cells for missing self-CD47 to trigger adaptive immune responses 
Immunity  2015;43(4):764-775.
Sheep red blood cells (SRBCs) have long been used as a model antigen for eliciting systemic immune responses yet the basis for their adjuvant activity has been unknown. Here we show that SRBCs failed to engage the inhibitory mouse SIRPα receptor on splenic CD4+ dendritic cells (DCs), and this led to DC activation. Removal of the SIRPα ligand, CD47, from self-RBCs was sufficient to convert them into an adjuvant for adaptive immune responses. DC capture of Cd47−/− RBCs and DC activation occurred within minutes in a src-family kinase and CD18 integrin-dependent manner. These findings provide an explanation for the adjuvant mechanism of SRBCs and reveal that splenic DCs survey blood cells for missing self-CD47, a process that may contribute to detecting and mounting immune responses against pathogen-infected RBCs.
Graphical abstract
PMCID: PMC4618158  PMID: 26453377
15.  Molecular Epidemiology and Antimicrobial Susceptibility of Clostridium difficile Isolates from a University Teaching Hospital in China 
While the developed world has seen a significant increase in the number of scientific articles on Clostridium difficile infection (CDI), the developing world still lags behind on this subject due to limited laboratory capacity, low awareness, and limited surveillance of this problem. As such, CDI is considered a neglected but potentially huge problem in developing countries. The major aim of this study was to systemically evaluate the utility of several molecular typing tools for CDI, including their relevance in epidemiological studies in developing countries such as China. A total of 116 non-repetitive toxigenic C. difficile isolates from Chinese patients, were studied. The isolates comprised 83 (71.6%) A+B+CDT- isolates, 27 (23.3%) A-B+CDT- isolates, and 6 (5.1%) A+B+CDT+ isolates. Typing methods evaluated included multilocus variable-number tandem-repeat analysis, PCR ribotyping, multilocus sequence typing, and sequencing of slpA and tcdC genes, which identified 113, 30, 22, 18, and 8 genotypes each and exhibited discriminatory powers of 0.999, 0.916, 0.907, 0.883, and 0.765, respectively. Compared to A+B+ strains, A-B+ strains exhibited higher prevalence of drug resistance to clindamycin, erythromycin, levofloxacin, rifampicin, rifaximin, and tetracycline. Furthermore, drug resistance rates of strains with different PCR ribotypes differed, supporting the importance of molecular typing in management and control of CDI. Based on our earlier suggestion to improve the diagnostic laboratory capacity of CDI in developing countries, setting up efficient surveillance programs complemented by relevant molecular typing methods is warranted.
PMCID: PMC5065952  PMID: 27799923
Clostridium difficile; molecular typing; antimicrobial resistance; surveillance; China
16.  Purification and characterization of a novel phloretin-2′-O-glycosyltransferase favoring phloridzin biosynthesis 
Scientific Reports  2016;6:35274.
Phloretin-2′-O-glycosyltransferase (P2′GT) catalyzes the last glycosylation step in the biosynthesis of phloridzin that contributes to the flavor, color and health benefits of apples and processed apple products. In this work, a novel P2′GT of Malus x domestica (MdP2′GT) with a specific activity of 46.82 μkat/Kg protein toward phloretin and uridine diphosphate glucose (UDPG) at an optimal temperature of 30 °C and pH 8.0 was purified from the engineered Pichia pastoris broth to homogeneity by anion exchange chromatography, His-Trap affinity chromatography and gel filtration. The purified MdP2′GT was low N-glycosylated and secreted as a stable dimer with a molecular mass of 70.7 kDa in its native form. Importantly, MdP2′GT also exhibited activity towards quercetin and adenosine diphosphate glucose (ADPG), kaempferol and UDPG, quercetin and UDP-galactose, isoliquiritigenin and UDPG, and luteolin and UDPG, producing only one isoquercitrin, astragalin, hyperoside, isoliquiritin, or cynaroside, respectively. This broad spectrum of activities make MdP2′GT a promising biocatalyst for the industrial preparation of the corresponding polyphenol glycosides, preferably for their subsequent isolation and purification. Besides, MdP2′GT displayed the lowest Km and the highest kcat/Km for phloretin and UDPG compared to all previously reported P2′GTs, making MdP2′GT favor phloridzin synthesis the most.
PMCID: PMC5059724  PMID: 27731384
17.  Urinary Sodium and Potassium Excretion and Carotid Atherosclerosis in Chinese Men and Women 
Nutrients  2016;8(10):612.
Limited studies have examined the association between sodium (Na) and potassium (K) levels and the risk of atherosclerosis. This study examined whether higher Na and Na/K levels and low K levels were independent risk factors for atherosclerosis. This community-based cross-sectional study included 3290 subjects (1067 men and 2223 women) 40 to 75 years of age in Guangzhou, China, between 2011 and 2013. Urinary excretion of Na and K were measured from the first morning void, and creatinine-adjusted values were used. The intima-media thickness (IMT) of the carotid common artery and the carotid bifurcation was measured with high-resolution B-mode ultrasonography. Dietary K and Na intake and other covariates were obtained by face-to-face interviews. A significant positive association was seen between urinary Na excretion and carotid atherosclerosis after adjustment for age, sex, and other lifestyle covariates. The odds ratios (OR) and 95% confidence interval (CI) of the highest (vs. lowest) quartile of urinary Na were 1.32 (1.04–1.66) for carotid plaques, 1.48 (1.18–1.87) for increased common carotid artery IMT, and 1.55 (1.23–1.96) for increased carotid bifurcation IMT (all p-trend < 0.01). A similar positive association was observed between urinary Na/K levels and carotid plaque and increased IMT, and between dietary Na intake and increased bifurcation IMT. Regarding potassium data, we only found a significantly lower presence of carotid plaque (OR 0.72, 95% CI 0.57–0.91) for quartile 2 (vs. 1) of urinary K. Our findings suggest that higher levels of urinary excretion Na and Na/K are significantly associated with greater presence of carotid atherosclerosis in Chinese adults.
PMCID: PMC5084000  PMID: 27706075
sodium; potassium; carotid atherosclerosis; Chinese adults
18.  Loss of ZBTB20 impairs circadian output and leads to unimodal behavioral rhythms 
eLife  null;5:e17171.
Many animals display morning and evening bimodal activities in the day/night cycle. However, little is known regarding the potential components involved in the regulation of bimodal behavioral rhythms in mammals. Here, we identified that the zinc finger protein gene Zbtb20 plays a crucial role in the regulation of bimodal activities in mice. Depletion of Zbtb20 in nerve system resulted in the loss of early evening activity, but the increase of morning activity. We found that Zbtb20-deficient mice exhibited a pronounced decrease in the expression of Prokr2 and resembled phenotypes of Prok2 and Prokr2-knockout mice. Injection of adeno-associated virus-double-floxed Prokr2 in suprachiasmatic nucleus could partly restore evening activity in Nestin-Cre; Zbtb20fl/fl (NS-ZB20KO) mice. Furthermore, loss of Zbtb20 in Foxg1 loci, but intact in the suprachiasmatic nucleus, was not responsible for the unimodal activity of NS-ZB20KO mice. Our study provides evidence that ZBTB20-mediated PROKR2 signaling is critical for the evening behavioral rhythms.
PMCID: PMC5033604  PMID: 27657167
circadian output gene; locomotor; ZBTB20; PROKR2; behavior rhythms; neurodegenerative disorders; Mouse
19.  Clinical and Laboratory Characteristics of Patients with Nontuberculous Mycobacterium Bloodstream Infection in a Tertiary Referral Hospital in Beijing, China 
Chinese Medical Journal  2016;129(18):2220-2225.
Nontuberculous Mycobacterium (NTM) bloodstream infection (BSI) is relatively rare. We aimed in this study to evaluate the clinical characteristics, laboratory evaluation, and outcomes of patients with NTM BSI.
We retrospectively reviewed the clinical records of inpatients with NTM BSI at our institution between January 2008 and January 2015 and recorded clinical parameters including age, gender, underlying disease, clinical manifestation, organs involved with NTM disease, species of NTM, laboratory data, treatment and outcome of these patients. We also reviewed the reported cases and case series of NTM BSI by searching PubMed, EMBASE, and Wanfang databases. Data of normal distribution were expressed by mean ± standard deviation (SD). Data of nonnormal distribution were expressed by median and interquartile range (IQR).
Among the ten patients with NTM BSI, the median age was 51 years (IQR 29–57 years) and three patients were males. Eight patients were immunocompromised, with underlying diseases including human immunodeficiency virus (HIV) infection (one patient), rheumatic diseases (two patients), breast cancer (one patient), myelodysplastic syndrome (two patients), and aplastic anemia (two patients). Other organ(s) involved were lung (two patients), endocardium (two patients), brain, spinal cord, and soft tissue (one each patient). The median lymphocyte was 0.66 × 109/L (IQR 0.24–1.93 × 109/L). The median cluster of differentiation 4 (CD4) cell count was 179/mm3 (IQR 82–619/mm3). Five patients died (three with hematological diseases, one with breast cancer, and one with rheumatic disease), three recovered, and two were lost to follow-up.
We reported all cases in our hospital diagnosed with bloodstream NTM infection that was rarely reported. In this group of patients, patients usually had a high fever and could have multiple organ involvements. All patients with poor prognosis had underlying diseases.
PMCID: PMC5022344  PMID: 27625095
Bloodstream Infection; Hematogenous Disseminated; Nontuberculous Mycobacterium
20.  Self-reported knowledge on diabetes and its related factors among Chinese college students: a cross-sectional study 
BMJ Open  2016;6(9):e011963.
An increasing trend in the prevalence of type 2 diabetes has been observed among youths; however, little is known about how informed young people are of its existence and dangers. This study is to assess the level of knowledge on type 2 diabetes among Chinese college students and to explore related factors influencing the knowledge.
A cross-sectional survey was conducted among college students in Guangzhou, China, from September to November 2013.
A total of 658 students were randomly recruited using a multistage sampling method and were invited to participate in the confidential interviews.
Primary and secondary outcome measures
Self-reported knowledge on diabetes and its main sources were measured by a self-designed questionnaire.
A total of 521 students participated in this study. The mean total score of knowledge was 13.3±3.44 of 22. Less than 50% of participants could correctly answer the questions about the onset of type 2 diabetes, the adverse effects of sedentary lifestyles, the complications, the therapeutic methods and the monitoring index of diabetes. The factors associated with higher levels of knowledge about type 2 diabetes in stepwise regression models were: being in a high grade, having a better academic performance, having a medical specialty and having relatives or friends with diabetes. Newspapers and books (61.4%), television and the Internet (46.3%) were the major sources of knowledge about type 2 diabetes, and more than half of the participants (55.9%) considered that medical staff was the most reliable source.
The college students had limited knowledge about type 2 diabetes. Public education, especially among individuals with non-medical specialties, a low-level grade, poor academic performance or no relatives and friends with diabetes, would be extremely beneficial.
PMCID: PMC5020855  PMID: 27609848
21.  Association Between Rectus Abdominis Denervation and Ventilation Dysfunction in Patients with Amyotrophic Lateral Sclerosis 
Chinese Medical Journal  2016;129(17):2063-2066.
Spontaneous potentials in electromyography (EMG) of paraspinal muscles are associated with diaphragm denervation and, therefore, poor respiratory function in amyotrophic lateral sclerosis (ALS) is understandable. EMG changes in the rectus abdominis (RA) display an effect similar to those in paraspinal muscles with respect to the function of lower motor neurons in the thoracic spinal cord. The RA denervation was examined to determine its association with ventilation dysfunction in ALS.
We collected the clinical data of 128 patients with sporadic ALS in Department of Neurology of Peking University Third Hospital from 2009 to 2013. EMG, Revised ALS Functional Rating Scale (ALSFRS-R) and forced vital capacity (FVC) were performed in all patients and the differences in the EMG changes in RA between those with and without FVC ≥ 80% were analysed.
The mean FVC value was 83.4% ± 17.1% (range: 45%–131%) of the predicted value. A total of 79 patients displayed FVC ≥80%, and 49 patients displayed FVC <80%. Compared with the patients displaying a normal FVC (60/79, 75.9%), spontaneous activity in RA was significantly different among those patients displaying an FVC <80% (47/49, 95.9%). In addition, spontaneous potentials in RA were more frequently detected in patients exhibiting dyspnea (32/33, 97.0%) than in patients without dyspnea (75/95, 78.9%).
Spontaneous potentials in RA are associated with ventilation dysfunction and dyspnea in ALS patients.
PMCID: PMC5009589  PMID: 27569232
Denervation; Dyspnea; Forced Vital Capacity; Rectus Abdominis; Ventilation Dysfunction
22.  Using Matrix-Assisted Laser Desorption Ionization-Time of Flight (MALDI-TOF) Complemented with Selected 16S rRNA and gyrB Genes Sequencing to Practically Identify Clinical Important Viridans Group Streptococci (VGS) 
There are challenges in viridans group streptococci (VGS) identification especially for the mitis group. Few studies have investigated the performance of MALDI-TOF MS system in VGS identification. Using 16S rRNA gene and gyrB gene sequencing as a gold standard, the performance of two MALDI-TOF MS instruments in the identification of 181 VGS clinical isolates was studied. The Bruker Biotyper and Vitek MS IVD systems correctly identified 88.4% and 98.9% of the 181 isolates, respectively. The Vitek MS RUO system was the least reliable, only correctly identifying 38.7% of the isolates to species level with several misidentifications and invalid results. The Bruker Biotyper system was very unreliable in the identification of species within the mitis group. Among 22 non-pneumococci isolates (S. mitis/S. oralis/S. pseudopneumoniae), Biotyper misidentified 21 of them as S. pneumoniae leading to a low sensitivity and low positive predictive value in these species. In contrast, the Vitek MS IVD demonstrated a better resolution for pneumococci and non-pneumococci despite the inability to distinguish between S. mitis/S. oralis. For more accurate species-level identification, further improvements in the VGS spectra databases are needed. Based on MALDI-TOF analysis and selected 16S rRNA gene plus gyrB genes sequencing, we designed a practical VGS identification algorithm.
PMCID: PMC5000867  PMID: 27617008
Streptococcus; viridans group streptococci (VGS); matrix-assisted laser desorption ionization-time of flight (MALDI-TOF); 16S rRNA gene; gyrB gene
23.  IL-21/IL-21R signaling suppresses intestinal inflammation induced by DSS through regulation of Th responses in lamina propria in mice 
Scientific Reports  2016;6:31881.
Serum level of IL-21 is increased in patients with inflammatory bowel diseases (IBD), suggesting that IL-21/IL-21 receptor (IL-21R) signaling may be involved in the pathogenesis of IBD. However, the role of IL-21/IL-21 receptor signaling plays in the pathogenesis of IBD is not very clear. In this study, using IL-21R.KO mice, we tested the role of IL-21/IL-21R signaling in the regulation of T helper cell responses during intestinal inflammation. Here we found that IL-21R.KO mice were more susceptible to DSS-induced colitis as compared with C57BL/6 mice. The spontaneous inflammatory cytokines released by macrophages in LP of colon were significantly increased, and Th2, Th17 and Treg responses were down-regulated markedly. However, Th1 responses were significantly up-regulated in IL-21R.KO mice. Meanwhile, the population of CD8+CD44+IFN-γ+ T cells was markedly elevated in LP of inflammatory intestine of IL-21RKO mice. In vivo, after disease onset, DSS-induced intestinal inflammation was ameliorated in C57BL/6 mice treated with rIL-21. Our results demonstrate that IL-21/IL-21R signaling contributes to protection against DSS-induced acute colitis through suppression of Th1 and activation of Th2, Th17 and Treg responses in mice. Therefore, therapeutic manipulation of IL-21/IL-21R activity may allow improved immunotherapy for IBD and other inflammatory diseases associated with Th cell responses.
PMCID: PMC4992961  PMID: 27545302
24.  Epidermal growth factor receptor kinase substrate 8 promotes the metastasis of cervical cancer via the epithelial-mesenchymal transition 
Molecular Medicine Reports  2016;14(4):3220-3228.
Epidermal growth factor receptor pathway substrate 8 (Eps8) has been identified as a novel substrate for epidermal growth factor receptor (EGFR) kinase and is involved in EGFR-mediated signaling pathways correlated with tumorigenesis, proliferation and metastasis in various cancer types. However, the precise role of Eps8 in cervical cancer metastasis remains to be elucidated. Immunohistochemistry revealed that Eps8 was significantly increased in cervical cancer specimens compared with squamous intraepithelial lesion and normal cervical tissues. Additionally, it was revealed that Eps8 expression not only correlated with cervical cancer progression, but also exhibited a close correlation with the epithelial-mesenchymal transition (EMT) markers, E-cadherin and vimentin. Furthermore, the present study focused predominantly on the EMT-associated role of Eps8 in the EMT, migration and invasion of cervical cancer cells. Eps8-short hairpin (sh) RNA was transfected into HeLa and SiHa cells to deplete its expression, and reverse transcription-quantitative polymerase chain reaction and western blot analyses were performed to confirm Eps8-knockdown and to investigate the influence of Eps8 on EMT markers. The present findings have revealed that Eps8 silencing led to the upregulation of the epithelial marker E-cadherin, while expression of the mesenchymal marker vimentin and the transcription factor snail was decreased at both mRNA and protein expression levels. Transwell cell migration and Matrigel invasion assays showed that downregulation of Eps8 significantly inhibited cell migration and invasion of HeLa and SiHa cells. Taken together, these results suggested that Eps8 promotes cervical cancer metastasis by orchestrating the EMT.
PMCID: PMC5042790  PMID: 27573546
Eps8; cervical cancer; cervical squamous intraepithelial lesion; epithelial-mesenchymal transition; metastasis
25.  Novel recombinant protein FlaA N/C increases tumor radiosensitivity via NF-κB signaling in murine breast cancer cells 
Oncology Letters  2016;12(4):2632-2640.
The recombinant protein flagellin A (FlaA) N/C, derived from the flagellin protein of Legionella pneumophila, has been shown to increase the expression of cytoprotective cytokines, activate the nuclear factor-κB (NF-κB) signaling pathway, and increase the survival of mice following total body irradiation. Determi ning whether FlaA N/C has a sensitizing effect on tumor radiation or a direct tumoricidal effect is critical for its application as an effective radiation protection agent. The present study investigated the molecular mechanism underlying the tumor radiosensitivity of FlaA N/C. FlaA N/C was found to increase tumor apoptosis and autophagy, regulate the cell cycle and increase radiosensitivity in 4T1 tumor cells. Furthermore, FlaA N/C was found to promote radiosensitivity by activating NF-κB signaling. Finally, the present study analyzed FlaA N/C-enhanced radiosensitivity in animal models, and FlaA N/C was found to significantly prolong the survival period of mice after total body radiation. This indicates that FlaA N/C might be a novel radiation sensitizer in tumor radiation therapy.
PMCID: PMC5038907  PMID: 27703525
breast cancer; flagellin; nuclear factor-κB signaling; radiosensitivity; tumor

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