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Find video protocols related to scientific articles indexed in Pubmed.
Inflammatory factor increases cyclooxygenase expression on the development of no-reflow.
Clin. Exp. Pharmacol. Physiol.
PUBLISHED: 11-18-2014
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No-reflow after reperfusion therapy for myocardial infarction is a strong predictor of clinical outcome. Increased level of inflammatory factors including C-reactive protein (CRP) levels in patients with acute myocardial infarction (AMI) undergoing primary percutaneous coronary intervention (PCI) may affect myocardial perfusion. However mechanisms that no-reflow increases in inflammation stress on the no-reflow phenomenon of AMI are not clear. The purpose of current study was to determine the effects and molecular mechanisms of CRP on the expression of cyclooxygenase (COX) on the development of no-reflow. We first demonstrated inflammatory factors CRP and interleukin-6 (IL-6) were significantly increased in no-reflow patients, suggesting that inflammatory factors play an important role on the development of no-reflow. The next we research the mechanisms by generating the animal model mimicking the no-reflow phenomenon. Compared with the normal reflow rats, COX1 and COX2 were both increased in no-reflow rats. And COX inhibitor indomethacin significantly reduced the no-reflow area. In addition, human coronary artery endothelial cells (HCAEC) were treated with CRP at clinically relevant concentrations for different durations. CRP significantly increased COX1 and COX2 protein levels in a time and concentration-dependent manner. The extracellular signal-regulated kinase (ERK) and Jun N-terminal kinase (JNK) of CRP-treated HCAEC cultures were also activated. Furthermore, ERk inhibitor and JNK inhibitor blocked CRP-induced COX1 and COX2 expression. Together, our data suggested that inflammatory factors CRP can promote the no-reflow development by increasing COX1 and COX2 expression which is partially regulated by ERK and JNK activity. This article is protected by copyright. All rights reserved.
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Whole genome sequencing to understand the genetic architecture of common gene expression and biomarker phenotypes.
Hum. Mol. Genet.
PUBLISHED: 11-06-2014
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Initial results from sequencing studies suggest that there are relatively few low frequency (<5%) variants associated with large effects on common phenotypes. We performed low pass whole genome sequencing in 680 individuals from the InCHIANTI study to test two primary hypotheses: i) that sequencing would detect single low frequency - large effect variants that explained similar amounts of phenotypic variance as single common variants, and ii) that some common variant associations could be explained by low frequency variants. We tested two sets of disease-related common phenotypes for which we had statistical power to detect large numbers of common variant - common phenotype associations - 11,132 cis-gene expression traits in 450 individuals and 93 circulating biomarkers in all 680 individuals. From a total of 11,657,229 high quality variants of which 6,129,221 and 5,528,008 were common and low frequency (<5%) respectively, low frequency - large effect associations comprised 7% of detectable cis-gene expression traits (89 of 1,314 cis-eQTLs at P<1x10(-06) (FDR ?5%)) and 1 of 8 biomarker associations at P<8x10(-10). Very few (30 of 1,232; 2%) common variant associations were fully explained by low frequency variants. Our data show that whole genome sequencing can identify low frequency variants undetected by genotyping based approaches when sample sizes are sufficiently large to detect substantial numbers of common variant associations, and that common variant associations are rarely explained by single low frequency variants of large effect.
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A Statistical Analysis of the Effects of Urease Pre-treatment on the Measurement of the Urinary Metabolome by Gas Chromatography-Mass Spectrometry.
Metabolomics
PUBLISHED: 09-26-2014
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Urease pre-treatment of urine has been utilized since the early 1960s to remove high levels of urea from samples prior to further processing and analysis by gas chromatography-mass spectrometry (GC-MS). Aside from the obvious depletion or elimination of urea, the effect, if any, of urease pre-treatment on the urinary metabolome has not been studied in detail. Here, we report the results of three separate but related experiments that were designed to assess possible indirect effects of urease pre-treatment on the urinary metabolome as measured by GC-MS. In total, 235 GC-MS analyses were performed and over 106 identified and 200 unidentified metabolites were quantified across the three experiments. The results showed that data from urease pre-treated samples 1) had the same or lower coefficients of variance among reproducibly detected metabolites, 2) more accurately reflected quantitative differences and the expected ratios among different urine volumes, and 3) increased the number of metabolite identifications. Overall, we observed no negative consequences of urease pre-treatment. In contrast, urease pretreatment enhanced the ability to distinguish between volume-based and biological sample types compared to no treatment. Taken together, these results show that urease pretreatment of urine offers multiple beneficial effects that outweigh any artifacts that may be introduced to the data in urinary metabolomics analyses.
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[Development and evaluation of a high-fat/high-fructose diet-induced nonalcoholic steatohepatitis mouse model].
Zhonghua Gan Zang Bing Za Zhi
PUBLISHED: 09-10-2014
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To develop and evaluate a mouse model of nonalcoholic steatohepatitis (NASH) induced by a high-fat and high-fructose (HFHFr) diet.
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Identification of metabolites of rupestonic acid in rat urine by liquid chromatography combined with electrospray ionization quadrupole time-of-flight tandem mass spectrometry.
Biomed. Chromatogr.
PUBLISHED: 09-03-2014
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Rupestonic acid, a potential anti-influenza agent, is an important and characteristic compound in Artemisia rupestris L., a well-known traditional Uighur medicine for the treatment of colds. In the present study, high-performance liquid chromatography combined with electrospray ionization quadrupole time-of-flight tandem mass spectrometry was used to detect and identify the metabolites in rat urine after oral administration of rupestonic acid. A total of 10 metabolites were identified or partially characterized. The structure elucidations of the metabolites were performed by comparing the changes in accurate molecular masses and fragment ions with those of the parent compound. The results showed that the main metabolites of rupestonic acid in rat urine were formed by oxidation, hydrogenation and glucuronidation. A metabolism pathway was proposed for the first time based on the characterized structures. This metabolism study can provide essential information for drug discovery, design and clinical application of rupestonic acid. Copyright © 2014 John Wiley & Sons, Ltd.
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A global view of transcriptome dynamics during Sporisorium scitamineum challenge in sugarcane by RNA-Seq.
PLoS ONE
PUBLISHED: 08-29-2014
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Sugarcane smut caused by Sporisorium scitamineum is a critical fungal disease in the sugarcane industry. However, molecular mechanistic studies of pathological response of sugarcane to S. scitamineum are scarce and preliminary. Here, transcriptome analysis of sugarcane disease induced by S. scitamineum at 24, 48 and 120 h was conducted, using an S. scitamineum-resistant and -susceptible genotype (Yacheng05-179 and "ROC"22). The reliability of Illumina data was confirmed by real-time quantitative PCR. In total, transcriptome sequencing of eight samples revealed gene annotations of 65,852 unigenes. Correlation analysis of differentially expressed genes indicated that after S. scitamineum infection, most differentially expressed genes and related metabolic pathways in both sugarcane genotypes were common, covering most biological activities. However, expression of resistance-associated genes in Yacheng05-179 (24-48 h) occurred earlier than those in "ROC"22 (48-120 h), and more transcript expressions were observed in the former, suggesting resistance specificity and early timing of these genes in non-affinity sugarcane and S. scitamineum interactions. Obtained unigenes were related to cellular components, molecular functions and biological processes. From these data, functional annotations associated with resistance were obtained, including signal transduction mechanisms, energy production and conversion, inorganic ion transport and metabolism, and defense mechanisms. Pathway enrichment analysis revealed that differentially expressed genes are involved in plant hormone signal transduction, flavonoid biosynthesis, plant-pathogen interaction, cell wall fortification pathway and other resistance-associated metabolic pathways. Disease inoculation experiments and the validation of in vitro antibacterial activity of the chitinase gene ScChi show that this sugarcane chitinase gene identified through RNA-Seq analysis is relevant to plant-pathogen interactions. In conclusion, expression data here represent the most comprehensive dataset available for sugarcane smut induced by S. scitamineum and will serve as a resource for finally unraveling the molecular mechanisms of sugarcane responses to S. scitamineum.
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Functionalized Nanoscale Micelles with Brain Targeting Ability and Intercellular Microenvironment Biosensitivity for Anti-Intracranial Infection Applications.
Adv Healthc Mater
PUBLISHED: 08-13-2014
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Due to complication factors such as blood-brain barrier (BBB), integrating high efficiency of brain target ability with specific cargo releasing into one nanocarrier seems more important. A brain targeting nanoscale system is developed using dehydroascorbic acid (DHA) as targeting moiety. DHA has high affinity with GLUT1 on BBB. More importantly, the GLUT1 transportation of DHA represents a "one-way" accumulative priority from blood into brain. The artificial micelles are fabricated by a disulfide linkage, forming a bio-responsive inner barrier, which can maintain micelles highly stable in circulation and shield the leakage of entrapped drug before reaching the targeting cells. The designed micelles can cross BBB and be further internalized by brain cells. Once within the cells, the drug release can be triggered by high intracellular level of glutathione (GSH). Itraconazole (ITZ) is selected as the model drug because of its poor brain permeability and low stability in blood. It demonstrates that the functionalized nanoscale micelles can achieve highly effective direct drug delivery to targeting site. Based on the markedly increased stability in blood circulation and improved brain delivery efficiency of ITZ, DHA-modified micelles show highly effective in anti-intracranial infection. Therefore, this smart nanodevice shows a promising application for the treatment of brain diseases.
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Structural analysis of N- and O-glycans using ZIC-HILIC/dialysis coupled to NMR detection.
Fungal Genet. Biol.
PUBLISHED: 08-10-2014
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Protein glycosylation, an important and complex post-translational modification (PTM), is involved in various biological processes, including the receptor-ligand and cell-cell interaction, and plays a crucial role in many biological functions. However, little is known about the glycan structures of important biological complex samples, and the conventional glycan enrichment strategy (i.e., size-exclusion column [SEC] separation) prior to nuclear magnetic resonance (NMR) detection is time-consuming and tedious. In this study, we developed a glycan enrichment strategy that couples Zwitterionic hydrophilic interaction liquid chromatography (ZIC-HILIC) with dialysis to enrich the glycans from the pronase E digests of RNase B, followed by NMR analysis of the glycoconjugate. Our results suggest that the ZIC-HILIC enrichment coupled with dialysis is a simple, fast, and efficient sample preparation approach. The approach was thus applied to analysis of a biological complex sample, the pronase E digest of the secreted proteins from the fungus Aspergillus niger. The NMR spectra revealed that the secreted proteins from A. niger contain both N-linked glycans with a high-mannose core similar to the structure of the glycan from RNase B, and O-linked glycans bearing mannose and glucose with 1?3 and 1?6 linkages. In all, our study provides compelling evidence that ZIC-HILIC separation coupled with dialysis is very effective and accessible in preparing glycans for the downstream NMR analysis, which could greatly facilitate the future NMR-based glycoproteomics research.
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FTO genetic variants, dietary intake and body mass index: insights from 177 330 individuals.
Qibin Qi, Tuomas O Kilpeläinen, Mary K Downer, Toshiko Tanaka, Caren E Smith, Ivonne Sluijs, Emily Sonestedt, Audrey Y Chu, Frida Renstrom, Xiaochen Lin, Lars H Angquist, Jinyan Huang, Zhonghua Liu, Yanping Li, Muhammad Asif Ali, Min Xu, Tarunveer Singh Ahluwalia, Jolanda M A Boer, Peng Chen, Makoto Daimon, Johan Eriksson, Markus Perola, Yechiel Friedlander, Yu-Tang Gao, Denise H M Heppe, John W Holloway, Denise K Houston, Stavroula Kanoni, Yu-Mi Kim, Maarit A Laaksonen, Tiina Jääskeläinen, Nanette R Lee, Terho Lehtimäki, Rozenn N Lemaitre, Wei Lu, Robert N Luben, Ani Manichaikul, Satu Mannisto, Pedro Marques-Vidal, Keri L Monda, Julius S Ngwa, Louis Pérusse, Frank J A van Rooij, Yong-Bing Xiang, Wanqing Wen, Mary K Wojczynski, Jingwen Zhu, Ingrid B Borecki, Claude Bouchard, Qiuyin Cai, Cyrus Cooper, George V Dedoussis, Panos Deloukas, Luigi Ferrucci, Nita G Forouhi, Torben Hansen, Lene Christiansen, Albert Hofman, Ingegerd Johansson, Torben Jørgensen, Shigeru Karasawa, Kay-Tee Khaw, Mi-Kyung Kim, Kati Kristiansson, Huaixing Li, Xu Lin, Yongmei Liu, Kurt K Lohman, Jirong Long, Vera Mikkilä, Dariush Mozaffarian, Kari North, Oluf Pedersen, Olli Raitakari, Harri Rissanen, Jaakko Tuomilehto, Yvonne T van der Schouw, André G Uitterlinden, M Carola Zillikens, Oscar H Franco, E Shyong Tai, Xiao Ou Shu, David S Siscovick, Ulla Toft, W M Monique Verschuren, Peter Vollenweider, Nicholas J Wareham, Jacqueline C M Witteman, Wei Zheng, Paul M Ridker, Jae H Kang, Liming Liang, Majken K Jensen, Gary C Curhan, Louis R Pasquale, David J Hunter, Karen L Mohlke, Matti Uusitupa, L Adrienne Cupples, Tuomo Rankinen, Marju Orho-Melander, Tao Wang, Daniel I Chasman, Paul W Franks, Thorkild I A Sørensen, Frank B Hu, Ruth J F Loos, Jennifer A Nettleton, Lu Qi.
Hum. Mol. Genet.
PUBLISHED: 08-07-2014
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FTO is the strongest known genetic susceptibility locus for obesity. Experimental studies in animals suggest the potential roles of FTO in regulating food intake. The interactive relation among FTO variants, dietary intake and body mass index (BMI) is complex and results from previous often small-scale studies in humans are highly inconsistent. We performed large-scale analyses based on data from 177 330 adults (154 439 Whites, 5776 African Americans and 17 115 Asians) from 40 studies to examine: (i) the association between the FTO-rs9939609 variant (or a proxy single-nucleotide polymorphism) and total energy and macronutrient intake and (ii) the interaction between the FTO variant and dietary intake on BMI. The minor allele (A-allele) of the FTO-rs9939609 variant was associated with higher BMI in Whites (effect per allele = 0.34 [0.31, 0.37] kg/m(2), P = 1.9 × 10(-105)), and all participants (0.30 [0.30, 0.35] kg/m(2), P = 3.6 × 10(-107)). The BMI-increasing allele of the FTO variant showed a significant association with higher dietary protein intake (effect per allele = 0.08 [0.06, 0.10] %, P = 2.4 × 10(-16)), and relative weak associations with lower total energy intake (-6.4 [-10.1, -2.6] kcal/day, P = 0.001) and lower dietary carbohydrate intake (-0.07 [-0.11, -0.02] %, P = 0.004). The associations with protein (P = 7.5 × 10(-9)) and total energy (P = 0.002) were attenuated but remained significant after adjustment for BMI. We did not find significant interactions between the FTO variant and dietary intake of total energy, protein, carbohydrate or fat on BMI. Our findings suggest a positive association between the BMI-increasing allele of FTO variant and higher dietary protein intake and offer insight into potential link between FTO, dietary protein intake and adiposity.
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Uncertainty analyses on the calculation of water environmental capacity by an innovative holistic method and its application to the Dongjiang River.
J Environ Sci (China)
PUBLISHED: 07-09-2014
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The estimation and allocation of water environmental capacity (WEC) are essential to water quality management and social-economic interests. However, there is inevitable uncertainty in the capacity estimation due to model conceptualization, data collection and parameter calibration. An innovative holistic approach was developed, which took both independence and relevance between parameters into account to analyze the uncertainties in WEC calculation and estimate the margin of safety. The Dongjiang River was taken as the case to demonstrate the method, focusing on the chemical oxygen demand and NH4(+)-N that were the two major water quality problems in the river. The results showed that the proposed holistic approach is very promising and applicable compared to traditional methods of uncertainty analysis.
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The choice of reference genes for assessing gene expression in sugarcane under salinity and drought stresses.
Sci Rep
PUBLISHED: 07-04-2014
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Sugarcane (Saccharum spp. hybrids) is a world-wide cash crop for sugar and biofuel in tropical and subtropical regions and suffers serious losses in cane yield and sugar content under salinity and drought stresses. Although real-time quantitative PCR has a numerous advantage in the expression quantification of stress-related genes for the elaboration of the corresponding molecular mechanism in sugarcane, the variation happened across the process of gene expression quantification should be normalized and monitored by introducing one or several reference genes. To validate suitable reference genes or gene sets for sugarcane gene expression normalization, 13 candidate reference genes have been tested across 12 NaCl- and PEG-treated sugarcane samples for four sugarcane genotypes using four commonly used systematic statistical algorithms termed geNorm, BestKeeper, NormFinder and the deltaCt method. The results demonstrated that glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and eukaryotic elongation factor 1-alpha (eEF-1a) were identified as suitable reference genes for gene expression normalization under salinity/drought-treatment in sugarcane. Moreover, the expression analyses of SuSK and 6PGDH further validated that a combination of clathrin adaptor complex (CAC) and cullin (CUL) as reference should be better for gene expression normalization. These results can facilitate the future research on gene expression in sugarcane under salinity and drought stresses.
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Selective fluorescence detection of monosaccharides using a material composite formed between graphene oxide and boronate-based receptors.
ACS Appl Mater Interfaces
PUBLISHED: 06-25-2014
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We have developed a novel class of simple materials for sensing monosaccharides by the functionalization of graphene oxide (GO) with boronate-based fluorescence probes (BA1 and BA2). The composite materials were characterized by atomic force microscopy, Raman spectroscopy, and UV-vis/fluorescence spectroscopy. The strong fluorescence of the BA probes is quenched in the presence of GO through fluorescence resonance energy transfer. The BA@GO composite sensors formed provide a useful platform for fluorogenic detection of monosaccharides based on the strong affinity between the boronic acid receptor and monosaccharides. The BA@GO composite sensor displayed a "turn-on" fluorescence response with a good linear relationship toward fructose over a range of other saccharides.
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Reduced risk of lung cancer with metformin therapy in diabetic patients: a systematic review and meta-analysis.
Am. J. Epidemiol.
PUBLISHED: 06-10-2014
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Emerging evidence from epidemiologic studies and basic science suggests an inverse association between metformin use and cancer risk in diabetic patients. However, the association with lung cancer is not consistent. We summarized the evidence currently available (2009-2013) and explored sources of heterogeneity. Metformin therapy was associated with significantly lower risks of cancers of the lung (4 studies; pooled relative risk = 0.71, 95% confidence interval (CI): 0.55, 0.95; P = 0.02) and respiratory system (6 studies; pooled relative risk = 0.85, 95% CI: 0.75, 0.96; P = 0.01). There was evidence of moderate heterogeneity (I(2) > 50%). The major sources of heterogeneity were smoking adjustment status and cancer site. The relative risk from studies that adjusted for smoking was 1.16-fold (95% CI: 1.00, 1.35) closer to the null than that from studies not adjusting for smoking. The relative risk of respiratory cancer was 1.23-fold (95% CI: 1.02, 1.49) closer to the null than that for lung cancer. In conclusion, metformin use appears to be associated with lower risks of lung and respiratory cancer in diabetic patients. However, caution regarding overestimation is needed, since adjustment for smoking attenuates the association.
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LOW-RANK APPROXIMATION BASED NON-NEGATIVE MULTI-WAY ARRAY DECOMPOSITION ON EVENT-RELATED POTENTIALS.
Int J Neural Syst
PUBLISHED: 05-14-2014
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Non-negative tensor factorization (NTF) has been successfully applied to analyze event-related potentials (ERPs), and shown superiority in terms of capturing multi-domain features. However, the time-frequency representation of ERPs by higher-order tensors are usually large-scale, which prevents the popularity of most tensor factorization algorithms. To overcome this issue, we introduce a non-negative canonical polyadic decomposition (NCPD) based on low-rank approximation (LRA) and hierarchical alternating least square (HALS) techniques. We applied NCPD (LRAHALS and benchmark HALS) and CPD to extract multi-domain features of a visual ERP. The features and components extracted by LRAHALS NCPD and HALS NCPD were very similar, but LRAHALS NCPD was 70 times faster than HALS NCPD. Moreover, the desired multi-domain feature of the ERP by NCPD showed a significant group difference (control versus depressed participants) and a difference in emotion processing (fearful versus happy faces). This was more satisfactory than that by CPD, which revealed only a group difference.
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Genome sequencing of Sporisorium scitamineum provides insights into the pathogenic mechanisms of sugarcane smut.
BMC Genomics
PUBLISHED: 05-10-2014
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Sugarcane smut can cause losses in cane yield and sugar content that range from 30 % to total crop failure. Losses tend to increase with the passage of years. Sporisorium scitamineum is the fungus that causes sugarcane smut. This fungus has the potential to infect all sugarcane species unless a species is resistant to biotrophic fungal pathogens. However, it remains unclear how the fungus breaks through the cell walls of sugarcane and causes the formation of black or gray whip-like structures on the sugarcane plants.
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Recombinant covalently closed circular hepatitis B virus DNA induces prolonged viral persistence in immunocompetent mice.
J. Virol.
PUBLISHED: 05-07-2014
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It remains crucial to develop a laboratory model for studying hepatitis B virus (HBV) chronic infection. We hereby produced a recombinant covalently closed circular DNA (rcccDNA) in view of the key role of cccDNA in HBV persistence. A loxP-chimeric intron was engineered into a monomeric HBV genome in a precursor plasmid (prcccDNA), which was excised using Cre/loxP-mediated DNA recombination into a 3.3-kb rcccDNA in the nuclei of hepatocytes. The chimeric intron was spliced from RNA transcripts without interrupting the HBV life cycle. In cultured hepatoma cells, cotransfection of prcccDNA and pCMV-Cre (encoding Cre recombinase) resulted in accumulation of nuclear rcccDNA that was heat stable and epigenetically organized as a minichromosome. A mouse model of HBV infection was developed by hydrodynamic injection of prcccDNA. In the presence of Cre recombinase, rcccDNA was induced in the mouse liver with effective viral replication and expression, triggering a compromised T-cell response against HBV. Significant T-cell hyporesponsiveness occurred in mice receiving 4 ?g prcccDNA, resulting in prolonged HBV antigenemia for up to 9 weeks. Persistent liver injury was observed as elevated alanine transaminase activity in serum and sustained inflammatory infiltration in the liver. Although a T-cell dysfunction was induced similarly, mice injected with a plasmid containing a linear HBV replicon showed rapid viral clearance within 2 weeks. Collectively, our study provides an innovative approach for producing a cccDNA surrogate that established HBV persistence in immunocompetent mice. It also represents a useful model system in vitro and in vivo for evaluating antiviral treatments against HBV cccDNA. Importance: (i) Unlike plasmids that contain a linear HBV replicon, rcccDNA established HBV persistence with sustained liver injury in immunocompetent mice. This method could be a prototype for developing a mouse model of chronic HBV infection. (ii) An exogenous intron was engineered into the HBV genome for functionally seamless DNA recombination. This original approach could be also extended to other viral studies. (iii) rcccDNA was substantially induced in the nuclei of hepatocytes and could be easily distinguished by its exogenous intron using PCR. This convenient model system affords the opportunity to test antivirals directly targeting HBV cccDNA.
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Effect of externally applied jidesheng anti-venom on skin and soft-tissue necrosis after Chinese cobra bite: a retrospective study.
J Tradit Chin Med
PUBLISHED: 05-03-2014
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To evaluate the effects of Jidesheng anti-venom used externally for skin and soft-tissue necrosis from Chinese cobra bite.
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RNA-seq analyses of multiple meristems of soybean: novel and alternative transcripts, evolutionary and functional implications.
BMC Plant Biol.
PUBLISHED: 04-05-2014
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Soybean is one of the most important crops, providing large amounts of dietary proteins and edible oil, and is also an excellent model for studying evolution of duplicated genes. However, relative to the model plants Arabidopsis and rice, the present knowledge about soybean transcriptome is quite limited.
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Th2-type inflammation under conditions of pre-existing chronic disease is associated with liver damage in patients with avian influenza H7N9 virus.
Microbes Infect.
PUBLISHED: 03-29-2014
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Most patients infected with avian H7N9 influenza virus develop severe disease, including respiratory failure, acute respiratory distress syndrome (ARDS), and multi-organ failure. The pathogenesis of H7N9 infection is not fully understood. This study revealed that H7N9-infected patients who had fatal outcomes or critical illness all had pre-existing chronic diseases. The patients did not have obvious systemic inflammation compared to the healthy controls. However, their fatal outcomes and critically severe illness were significantly associated with high serum levels of tumor necrosis factor (TNF)-?. Interestingly, the degree of liver damage in these patients significantly correlated with their serum levels of Th2 cytokines, interleukin (IL)-4, and IL-9. Taken together, our results suggest that Th2-type inflammation in H7N9-infected patients with pre-existing chronic diseases likely contributes to the pathogenesis of H7N9 infection and is linked to poor clinical outcomes.
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Infusion of allogeneic umbilical cord blood hematopoietic stem cells in patients with chemotherapy-related myelosuppression.
Exp Ther Med
PUBLISHED: 03-24-2014
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Chemotherapy-induced myelosuppression is one of the main problems in the treatment of cancer. In the present study, the effects of allogeneic umbilical cord blood hematopoietic stem cell (UCB-HSC) infusion were investigated on the treatment of chemotherapy-related myelosuppression. In total, 65 patients (male, 42; female, 23) diagnosed with chemotherapy-related myelosuppression were included in the study. The majority of the patients were classified with stage II myelosupression at enrolment, and an average concentration of 7.07×10(9)/l UCB-HSCs were transfused through the peripheral vein. The minimum values of the white blood cell (WBC) count, hemoglobin (Hb) level, platelet (PLT) count and Karnofsky performance status (KPS) scores were recorded prior to and between days 7 and 14 following UCB-HSC infusion. When assessing the overall data, the results revealed that the mean WBC and PLT counts increased significantly following UCB-HSC infusion. However, the subgroup analyses based on gender and KPS score revealed that UCB-HSC infusion was more successful in male patients and those with a higher KPS score. Spearman's correlation analysis revealed a linear correlation between the number of transfused UCB-HSCs and the changes in the WBC and PLT counts following treatment. In conclusion, the results indicated that peripheral vein infusion of non-human leukocyte antigen matched UCB-HSCs can markedly improve chemotherapy-related myelosuppression in a safe and effective manner.
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The effect of age on the median effective dose (ED50) of intrathecally administered plain bupivacaine for motor block.
Anesth. Analg.
PUBLISHED: 03-22-2014
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In this study, we sought to determine the median effective dose (ED50) for motor block of intrathecally administered plain bupivacaine in adults (20-80 years) and to assess the effect of age on ED50 required for motor block.
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Multiple nonglycemic genomic loci are newly associated with blood level of glycated hemoglobin in East Asians.
Diabetes
PUBLISHED: 03-19-2014
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Glycated hemoglobin A1c (HbA1c) is used as a measure of glycemic control and also as a diagnostic criterion for diabetes. To discover novel loci harboring common variants associated with HbA1c in East Asians, we conducted a meta-analysis of 13 genome-wide association studies (GWAS; N = 21,026). We replicated our findings in three additional studies comprising 11,576 individuals of East Asian ancestry. Ten variants showed associations that reached genome-wide significance in the discovery data set, of which nine (four novel variants at TMEM79 [P value = 1.3 × 10(-23)], HBS1L/MYB [8.5 × 10(-15)], MYO9B [9.0 × 10(-12)], and CYBA [1.1 × 10(-8)] as well as five variants at loci that had been previously identified [CDKAL1, G6PC2/ABCB11, GCK, ANK1, and FN3KI]) showed consistent evidence of association in replication data sets. These variants explained 1.76% of the variance in HbA1c. Several of these variants (TMEM79, HBS1L/MYB, CYBA, MYO9B, ANK1, and FN3K) showed no association with either blood glucose or type 2 diabetes. Among individuals with nondiabetic levels of fasting glucose (<7.0 mmol/L) but elevated HbA1c (?6.5%), 36.1% had HbA1c <6.5% after adjustment for these six variants. Our East Asian GWAS meta-analysis has identified novel variants associated with HbA1c as well as demonstrated that the effects of known variants are largely transferable across ethnic groups. Variants affecting erythrocyte parameters rather than glucose metabolism may be relevant to the use of HbA1c for diagnosing diabetes in these populations.
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Elevated plasma retinol-binding protein 4 is associated with increased risk of type 2 diabetes in middle-aged and elderly Chinese adults.
J. Nutr.
PUBLISHED: 03-19-2014
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The association between circulating retinol-binding protein 4 (RBP4) and risk of type 2 diabetes has been inconsistent in cross-sectional studies, but prospective evidence is limited. We aimed to investigate whether plasma RBP4 is associated with future development of type 2 diabetes and whether the association could be explained by iron or other risk factors. A total of 2091 Chinese adults aged 50-70 y were followed up for 6 y. Baseline dietary intakes and fasting plasma RBP4, ferritin, adiponectin, C-reactive protein (CRP), ?-glutamyltransferase, creatinine, and erythrocyte fatty acids were determined. Self-reported doctor-diagnosed diabetes, or usage of antidiabetic agents, or fasting plasma glucose concentration at the follow-up visit ?7.0 mmol/L was defined as an incident diabetes case. Plasma RBP4 concentration was significantly associated with dietary heme iron intake, plasma ferritin concentration, and other established risk factors. After multivariate adjustment for demographic and lifestyle variables, relative risk (RR) for type 2 diabetes when the extreme quartiles of RBP4 were compared was 1.75 (95% CI: 1.30, 2.37; P-trend < 0.001). This association remained significant when the extreme quartiles were compared (RR = 1.48; 95% CI: 1.06, 2.05; P-trend = 0.036) after further controlling for ferritin and dietary factors, as well as other risk factors, including body mass index, adiponectin, CRP, lipids, liver and kidney function, insulin resistance, and hypertension. A threshold effect of RBP4 concentrations on incident diabetes was suggested by restricted quadratic spline analysis (P = 0.026 for nonlinearity). Our study indicates that plasma RBP4 is independently associated with the 6-y risk of developing type 2 diabetes.
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Comparison of carotenoid accumulation and biosynthetic gene expression between Valencia and Rohde Red Valencia sweet oranges.
Plant Sci.
PUBLISHED: 03-17-2014
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Carotenoid accumulation and biosynthetic gene expression levels during fruit maturation were compared between ordinary Valencia (VAL) and its more deeply colored mutant Rohde Red Valencia orange (RRV). The two cultivars exhibited different carotenoid profiles and regulatory mechanisms in flavedo and juice sacs, respectively. In flavedo, there was uncoordinated carotenoid accumulation and gene expression in RRV during green stages, which might be related to the expression of certain gene(s) in the MEP (methylerythritol phosphate) pathway. The carotenoid biosynthesis pathway shifting from ?,?-xanthophylls to ?,?-xanthophylls synthesis occurred in RRV earlier than VAL during orange stages. In juice sacs, the low carotenoid content in both cultivars coincided with low expression of LCYE-Contig03 and LCYE-Contig24 during green stages, suggesting LCYE might be a limiting step for carotenoid accumulation. VAL mainly accumulated violaxanthin, but RRV accumulated ?-cryptoxanthin and violaxanthin during orange stages, which corresponded to differences in juice color. Several upstream genes (PDS-Contig17, LCYB-Contig19, and ZDS members) and a downstream gene (ZEP) were expressed at higher levels in RRV than VAL, which might be responsible for greater accumulation of ?-cryptoxanthin and violaxanthin in RRV, respectively.
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Cocirculation of three hemagglutinin and two neuraminidase subtypes of avian influenza viruses in Huzhou, China, April 2013: implication for the origin of the novel H7N9 virus.
J. Virol.
PUBLISHED: 03-12-2014
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We detected three avian influenza hemagglutinin (HA) subtypes (H7, H9, and H5) and two neuraminidase (NA) subtypes (N9 and N2), as well as H7N9-related H9N9 reassortant intermediates, cocirculating among poultry in Huzhou, China, during April 2013. The results of our study reveal not only that Huzhou is one of the geographic origins of the novel H7N9 virus but also that cocirculation poses a potential threat to humans in the future.
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FTO genotype, dietary protein, and change in appetite: the Preventing Overweight Using Novel Dietary Strategies trial.
Am. J. Clin. Nutr.
PUBLISHED: 03-12-2014
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A common obesity-risk variant rs9939609 in the fat mass- and obesity-associated (FTO) gene was recently shown to affect appetite, and the gene is sensitive to the regulation of amino acids.
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A novel asymmetrical arc-shaped electrode ion trap for improving the performance of a miniature mass spectrometer.
Rapid Commun. Mass Spectrom.
PUBLISHED: 03-02-2014
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The pivotal challenge associated with miniature mass analyzers is their proper design and construction without sacrificing performance. In order to analyze and improve the performance of a miniature linear ion trap with odd and even multipole fields, we designed a novel asymmetrical arc-shaped electrode ion trap (AAEIT), and tested the properties of AAEITs with different dimensions.
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A combination vaccine comprising of inactivated enterovirus 71 and coxsackievirus A16 elicits balanced protective immunity against both viruses.
Vaccine
PUBLISHED: 02-25-2014
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Enterovirus 71 (EV71) and coxsackievirus A16 (CA16) are the two major causative agents of hand, foot and mouth disease (HFMD), which is an infectious disease frequently occurring in children. A bivalent vaccine against both EV71 and CA16 is highly desirable. In the present study, we compare monovalent inactivated EV71, monovalent inactivated CA16, and a combination vaccine candidate comprising of both inactivated EV71 and CA16, for their immunogenicity and in vivo protective efficacy. The two monovalent vaccines were found to elicit serum antibodies that potently neutralized the homologous virus but had no or weak neutralization activity against the heterologous one; in contrast, the bivalent vaccine immunized sera efficiently neutralized both EV71 and CA16. More importantly, passive immunization with the bivalent vaccine protected mice against either EV71 or CA16 lethal infections, whereas the monovalent vaccines only prevented the homologous but not the heterologous challenges. Together, our results demonstrate that the experimental bivalent vaccine comprising of inactivated EV71 and CA16 induces a balanced protective immunity against both EV71 and CA16, and thus provide proof-of-concept for further development of multivalent vaccines for broad protection against HFMD.
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SSC(high)CD11b(high)Ly-6C(high)Ly-6G(low) myeloid cells curtail CD4 T cell response by inducible nitric oxide synthase in murine hepatitis.
Int. J. Biochem. Cell Biol.
PUBLISHED: 02-01-2014
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Myeloid-derived suppressor cells (MDSCs) play an important role in maintaining immune tolerance in response to tumors and inflammatory diseases. Several liver MDSCs have been described in hepatitis in humans and mouse models. Although all the murine MDSCs are CD11b(+)Gr-1(+), their true phenotype and mechanism of suppression remain elusive. This study revealed that SSC(high)CD11b(high)Ly-6C(high)Ly-6G(low) monocytic cells but not the other liver-infiltrating, CD11b(+)Gr-1(+) subsets could suppress CD4 T cell responses. Their suppressive activity was remarkably effective even at a ratio of 1:50 when co-cultured with CD4 T cells. Mechanistically, the suppression was dependent on nitric oxide production by inducible nitric oxide synthase (iNOS). Furthermore, the suppressive function by these liver MDSCs was found to require direct contact with activated CD4 T cells. Adoptive transfer experiments demonstrate that these liver MDSCs can dramatically ameliorate concanavalin A (Con A)-induced fulminant hepatitis in mice. Finally, MDSC-mediated suppression in vivo was dependent on iNOS expression. Altogether, SSC(high)CD11b(high)Ly-6C(high)Ly-6G(low) cells represent authentic MDSCs in the inflammatory liver and may function to minimize collateral damage caused by an overzealous CD4 T cell response following hepatitis infection.
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Metal pollution (Cd, Pb, Zn, and As) in agricultural soils and soybean, Glycine max, in southern China.
Bull Environ Contam Toxicol
PUBLISHED: 01-28-2014
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Crops produced on metal-polluted agricultural soils may lead to chronic toxicity to humans via the food chain. To assess metal pollution in agricultural soils and soybean in southern China, 30 soybean grain samples and 17 soybean-field soil samples were collected from 17 sites in southern China, and metal concentrations of samples were analyzed by graphite furnace atomic absorption spectrophotometer. The integrated pollution index was used to evaluate if the samples were contaminated by Cd, Pb, Zn and As. Results showed that Cd concentration of 12 samples, Pb concentration of 2 samples, Zn concentration of 2 samples, and As concentrations of 2 samples were above the maximum permissible levels in soils. The integrated pollution index indicated that 11 of 17 soil samples were polluted by metals. Metal concentrations in soybean grain samples ranged from 0.11 to 0.91 mg kg(-1) for Cd; 0.34 to 2.83 mg kg(-1) for Pb; 42 to 88 mg kg(-1) for Zn; and 0.26 to 5.07 mg kg(-1) for As, which means all 30 soybean grain samples were polluted by Pb, Pb/Cd, Cd/Pb/As or Pb/As. Taken together, our study provides evidence that metal pollution is an important concern in agricultural soils and soybeans in southern China.
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Discovery of biclonal origin and a novel oncogene SLC12A5 in colon cancer by single-cell sequencing.
Cell Res.
PUBLISHED: 01-22-2014
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Single-cell sequencing is a powerful tool for delineating clonal relationship and identifying key driver genes for personalized cancer management. Here we performed single-cell sequencing analysis of a case of colon cancer. Population genetics analyses identified two independent clones in tumor cell population. The major tumor clone harbored APC and TP53 mutations as early oncogenic events, whereas the minor clone contained preponderant CDC27 and PABPC1 mutations. The absence of APC and TP53 mutations in the minor clone supports that these two clones were derived from two cellular origins. Examination of somatic mutation allele frequency spectra of additional 21 whole-tissue exome-sequenced cases revealed the heterogeneity of clonal origins in colon cancer. Next, we identified a mutated gene SLC12A5 that showed a high frequency of mutation at the single-cell level but exhibited low prevalence at the population level. Functional characterization of mutant SLC12A5 revealed its potential oncogenic effect in colon cancer. Our study provides the first exome-wide evidence at single-cell level supporting that colon cancer could be of a biclonal origin, and suggests that low-prevalence mutations in a cohort may also play important protumorigenic roles at the individual level.
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Multiscale reconstruction algorithm for compressed sensing.
ISA Trans
PUBLISHED: 01-21-2014
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Compressed sensing (CS) method has attracted increasing attention owing to providing a novel insight for signal and image processing technology. Acquiring high-quality reconstruction results plays a crucial role in successful applications of CS method. This paper presents a multiscale reconstruction model that simultaneously considers the inaccuracy properties on the measurement data and the measurement matrix. Based on the wavelet analysis method, the original inverse problem is decomposed into a sequence of inverse problems, which are solved successively from the largest scale to the original scale. An objective functional, that integrate the beneficial advantages of the least trimmed sum of absolute deviations (LTA) estimation and the combinational M-estimation, is proposed. An iteration scheme that incorporates the advantages of the homotopy method and the evolutionary programming (EP) algorithm is designed for solving the proposed objective functional. Numerical simulations are implemented to validate the feasibility of the proposed reconstruction method.
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Establishment and application of a loop-mediated isothermal amplification (LAMP) system for detection of cry1Ac transgenic sugarcane.
Sci Rep
PUBLISHED: 01-20-2014
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To meet the demand for detection of foreign genes in genetically modified (GM) sugarcane necessary for regulation of gene technology, an efficient method with high specificity and rapidity was developed for the cry1Ac gene, based on loop-mediated isothermal amplification (LAMP). A set of four primers was designed using the sequence of cry1Ac along with optimized reaction conditions: 5.25?mM of Mg(2+), 4:1 ratio of inner primer to outer primer, 2.0?U of Bst DNA polymerase in a reaction volume of 25.0??L. Three post-LAMP detection methods (precipitation, calcein (0.60?mM) with Mn(2+) (0.05?mM) complex and SYBR Green I visualization), were shown to be effective. The sensitivity of the LAMP method was tenfold higher than that of conventional PCR when using templates of the recombinant cry1Ac plasmid or genomic DNA from cry1Ac transgenic sugarcane plants. More importantly, this system allowed detection of the foreign gene on-site when screening GM sugarcane without complex and expensive instruments, using the naked eye. This method can not only provide technological support for detection of cry1Ac, but can also further facilitate the use of this detection technique for other transgenes in GM sugarcane.
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?B-Crystallin R120G variant causes cardiac arrhythmias and alterations in the expression of Ca(2+) -handling proteins and endoplasmic reticulum stress in mice.
Clin. Exp. Pharmacol. Physiol.
PUBLISHED: 01-19-2014
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Mutations of ?B-crystallin (Cry?B), a small heat shock protein abundantly expressed in cardiac and skeletal muscles, are known to cause desmin-related myopathies. The Cry?B R120G allele has been linked to a familial desminopathy and, in transgenic mice, causes a sudden death at about 28 weeks of age. To investigate the mechanisms of the sudden cardiac arrest of Cry?B R120G transgenic mice, we prepared protein samples from left ventricular tissues of two different age groups (10 and 28 weeks) and examined Ca(2+) -handling proteins. Expression of sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) 2, phospholamban, ryanodine receptor 2 and calsequestrin 2 was significantly decreased in 28- versus 10-week-old Cry?B R120G transgenic mice. In addition, low heart rate variability, including heart rate, total power and low frequency, was observed and continuous electrocardiogram monitoring revealed cardiac arrhythmias, such as ventricular tachycardia, atrioventricular block and atrial flutter, in 28-week-old Cry?B R120G transgenic mice. In contrast, expression of endoplasmic reticulum (ER) degradation enhancing ?-mannosidase-like protein, inositol requirement 1 and X-box binding protein 1 were increased significantly in 28- versus 10-week-old Cry?BR120G transgenic mice, suggesting that the Cry?BR120G transgenic mice exhibit increased ER stress compared with wild-type mice. Together, the data suggest that the Cry?B R120G dominant variant induces ER stress and impairs Ca(2+) regulation, leading to ageing-related cardiac dysfunction, arrhythmias and decreased autonomic tone with shortened lifespan.
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Polyelectrolyte multilayers on PTMSP as asymmetric membranes for gas separations: Langmuir-Blodgett versus self-assembly methods of anchoring.
Langmuir
PUBLISHED: 01-10-2014
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Polyelectrolyte multilayers derived from poly(diallyldimethylamonium chloride) and poly(sodium 4-styrenesulfonate) have been deposited onto poly[1-(trimethylsilyl)-1-propyne] (PTMSP) with anchoring layers formed by Langmuir-Blodgett and self-assembly methods. Using gas permeation selectivity as a basis for judging the efficacy of each anchoring method, we have found that similar CO2/N2 selectivities (ranging from 110 to 140) could be achieved by both methods and that their permeances were also similar. Although LB anchors require fewer layers of polyelectrolyte to reach this level of selectivity, the greater ease associated with self-assembly and its applicability to curved, high-surface-area supports (e.g., PTMSP-coated hollow fibers) encourage its use with PTMSP in creating new membrane materials for the practical separation of gases.
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Hyper-IL-15 suppresses metastatic and autochthonous liver cancer by promoting tumour-specific CD8(+) T cell responses.
J. Hepatol.
PUBLISHED: 01-09-2014
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Liver cancer has a very dismal prognosis due to lack of effective therapy. Here, we studied the therapeutic effects of hyper-interleukin15 (hyper-IL-15), which is composed of IL-15 and the sushi domain of the IL-15 receptor ? chain, on metastatic and autochthonous liver cancers.
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Characterization of intact N- and O-linked glycopeptides using higher energy collisional dissociation.
Anal. Biochem.
PUBLISHED: 01-06-2014
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Simultaneous elucidation of the glycan structure and the glycosylation site are needed to reveal the biological function of protein glycosylation. In this study, we employed a recent type of fragmentation termed higher energy collisional dissociation (HCD) to examine fragmentation patterns of intact glycopeptides generated from a mixture of standard glycosylated proteins. The normalized collisional energy (NCE) value for HCD was varied from 30 to 60% to evaluate the optimal conditions for the fragmentation of peptide backbones and glycoconjugates. Our results indicated that HCD with lower NCE values preferentially fragmented the sugar chains attached to the peptides to generate a ladder of neutral loss of monosaccharides, thereby enabling the putative glycan structure characterization. In addition, detection of the oxonium ions enabled unambiguous differentiation of glycopeptides from non-glycopeptides. In contrast, HCD with higher NCE values preferentially fragmented the peptide backbone and, thus, provided information needed for confident peptide identification. We evaluated the HCD approach with alternating NCE parameters for confident characterization of intact N- and O-linked glycopeptides in a single liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. In addition, we applied a novel data analysis pipeline, so-called GlycoFinder, to form a basis for automated data analysis. Overall, 38 unique intact glycopeptides corresponding to eight glycosylation sites (six N-linked and two O-linked sites) were confidently identified from a standard protein mixture. This approach provided concurrent characterization of both the peptide and the glycan, thereby enabling comprehensive structural characterization of glycoproteins in a single LC-MS/MS analysis.
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Transcriptome profiling to discover putative genes associated with paraquat resistance in goosegrass (Eleusine indica L.).
PLoS ONE
PUBLISHED: 01-01-2014
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Goosegrass (Eleusine indica L.), a serious annual weed in the world, has evolved resistance to several herbicides including paraquat, a non-selective herbicide. The mechanism of paraquat resistance in weeds is only partially understood. To further study the molecular mechanism underlying paraquat resistance in goosegrass, we performed transcriptome analysis of susceptible and resistant biotypes of goosegrass with or without paraquat treatment.
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Comprehensive selection of reference genes for gene expression normalization in sugarcane by real time quantitative rt-PCR.
PLoS ONE
PUBLISHED: 01-01-2014
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The increasingly used real time quantitative reverse transcription-PCR (qRT-PCR) method for gene expression analysis requires one or several reference gene(s) acting as normalization factor(s). In order to facilitate gene expression studies in sugarcane (Saccharum officinarum), a non-model plant with limited genome information, the stability of 13 candidate reference genes was evaluated. The geNorm, NormFinder and deltaCt methods were used for selecting stably expressed internal controls across different tissues and under various experimental treatments. These results revealed that, among these 13 candidate reference genes, GAPDH, eEF-1a and eIF-4? were the most stable and suitable for use as normalization factors across all various experimental samples. In addition, APRT could be a candidate for examining the relationship between gene copy number and transcript levels in sugarcane tissue samples. According to the results evaluated by geNorm, combining CUL and eEF-1? in hormone treatment experiments; CAC and CUL in abiotic stress tests; GAPDH, eEF-1a and CUL in all treatment samples plus CAC, CUL, APRT and TIPS-41 in cultivar tissues as groups for normalization would lead to more accurate and reliable expression quantification in sugarcane. This is the first systematic validation of reference genes for quantification of transcript expression profiles in sugarcane. This study should provide useful information for selecting reference genes for more accurate quantification of gene expression in sugarcane and other plant species.
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High and low doses of ionizing radiation induce different secretome profiles in a human skin model.
PLoS ONE
PUBLISHED: 01-01-2014
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It is postulated that secreted soluble factors are important contributors of bystander effect and adaptive responses observed in low dose ionizing radiation. Using multidimensional liquid chromatography-mass spectrometry based proteomics, we quantified the changes of skin tissue secretome--the proteins secreted from a full thickness, reconstituted 3-dimensional skin tissue model 48 hr after exposure to 3, 10 and 200 cGy of X-rays. Overall, 135 proteins showed statistical significant difference between the sham (0 cGy) and any of the irradiated groups (3, 10 or 200 cGy) on the basis of Dunnett adjusted t-test; among these, 97 proteins showed a trend of downregulation and 9 proteins showed a trend of upregulation with increasing radiation dose. In addition, there were 21 and 8 proteins observed to have irregular trends with the 10 cGy irradiated group either having the highest or the lowest level among all three radiated doses. Moreover, two proteins, carboxypeptidase E and ubiquitin carboxyl-terminal hydrolase isozyme L1 were sensitive to ionizing radiation, but relatively independent of radiation dose. Conversely, proteasome activator complex subunit 2 protein appeared to be sensitive to the dose of radiation, as rapid upregulation of this protein was observed when radiation doses were increased from 3, to 10 or 200 cGy. These results suggest that different mechanisms of action exist at the secretome level for low and high doses of ionizing radiation.
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Dynamics between cancer cell subpopulations reveals a model coordinating with both hierarchical and stochastic concepts.
PLoS ONE
PUBLISHED: 01-01-2014
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Tumors are often heterogeneous in which tumor cells of different phenotypes have distinct properties. For scientific and clinical interests, it is of fundamental importance to understand their properties and the dynamic variations among different phenotypes, specifically under radio- and/or chemo-therapy. Currently there are two controversial models describing tumor heterogeneity, the cancer stem cell (CSC) model and the stochastic model. To clarify the controversy, we measured probabilities of different division types and transitions of cells via in situ immunofluorescence. Based on the experiment data, we constructed a model that combines the CSC with the stochastic concepts, showing the existence of both distinctive CSC subpopulations and the stochastic transitions from NSCCs to CSCs. The results showed that the dynamic variations between CSCs and non-stem cancer cells (NSCCs) can be simulated with the model. Further studies also showed that the model can be used to describe the dynamics of the two subpopulations after radiation treatment. More importantly, analysis demonstrated that the experimental detectable equilibrium CSC proportion can be achieved only when the stochastic transitions from NSCCs to CSCs occur, indicating that tumor heterogeneity may exist in a model coordinating with both the CSC and the stochastic concepts. The mathematic model based on experimental parameters may contribute to a better understanding of the tumor heterogeneity, and provide references on the dynamics of CSC subpopulation during radiotherapy.
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Discovery of 1-Methyl-1H-imidazole Derivatives as Potent Jak2 Inhibitors.
J. Med. Chem.
PUBLISHED: 12-20-2013
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Structure based design, synthesis, and biological evaluation of a novel series of 1-methyl-1H-imidazole, as potent Jak2 inhibitors to modulate the Jak/STAT pathway, are described. Using the C-ring fragment from our first clinical candidate AZD1480 (24), optimization of the series led to the discovery of compound 19a, a potent, orally bioavailable Jak2 inhibitor. Compound 19a displayed a high level of cellular activity in hematopoietic cell lines harboring the V617F mutation and in murine BaF3 TEL-Jak2 cells. Compound 19a demonstrated significant tumor growth inhibition in a UKE-1 xenograft model within a well-tolerated dose range.
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Variants in glucose- and circadian rhythm-related genes affect the response of energy expenditure to weight-loss diets: the POUNDS LOST Trial.
Am. J. Clin. Nutr.
PUBLISHED: 12-11-2013
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Circadian rhythm has been shown to be related to glucose metabolism and risk of diabetes, probably through effects on energy balance. Recent genome-wide association studies identified variants in circadian rhythm-related genes (CRY2 and MTNR1B) associated with glucose homeostasis.
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Aggregation of sparse linear discriminant analyses for event-related potential classification in brain-computer interface.
Int J Neural Syst
PUBLISHED: 12-02-2013
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Two main issues for event-related potential (ERP) classification in brain-computer interface (BCI) application are curse-of-dimensionality and bias-variance tradeoff, which may deteriorate classification performance, especially with insufficient training samples resulted from limited calibration time. This study introduces an aggregation of sparse linear discriminant analyses (ASLDA) to overcome these problems. In the ASLDA, multiple sparse discriminant vectors are learned from differently l1-regularized least-squares regressions by exploiting the equivalence between LDA and least-squares regression, and are subsequently aggregated to form an ensemble classifier, which could not only implement automatic feature selection for dimensionality reduction to alleviate curse-of-dimensionality, but also decrease the variance to improve generalization capacity for new test samples. Extensive investigation and comparison are carried out among the ASLDA, the ordinary LDA and other competing ERP classification algorithms, based on different three ERP datasets. Experimental results indicate that the ASLDA yields better overall performance for single-trial ERP classification when insufficient training samples are available. This suggests the proposed ASLDA is promising for ERP classification in small sample size scenario to improve the practicability of BCI.
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The cytokine and chemokine profiles in patients with hand, foot and mouth disease of different severities in shanghai, china, 2010.
PLoS Negl Trop Dis
PUBLISHED: 12-01-2013
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Systemic upregulation of inflammatory cytokines is characteristic of critical severe hand, foot, and mouth disease (HFMD) with pulmonary edema. Thus, immunomodulatory medicines such as steroids, including methylprednisolone, have been proposed to treat patients with severe HFMD in China, because it is postulated that inflammatory cytokines play a role in the development of severe complications. This study is to further investigate the inflammatory response in the relatively mild HFMD patients, and whether steroid treatment has a beneficial effect on the suppression of inflammation in HFMD patients.
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The co-expression of telomerase and ALT pathway in human breast cancer tissues.
Tumour Biol.
PUBLISHED: 11-01-2013
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Recently, telomerase-targeted therapy was studied intensively; however, many studies have verified the existence of alternative lengthening mechanisms of telomeres in vitro. In the present work, we explored the expression characteristic of the two kinds of telomere-prolonging mechanisms in the breast cancer tissues per se. Furthermore, we studied the relationship between Her-2 expression and ALT pathway. Ninety samples of breast cancer tissues were examined in this research. RT-PCR was used for the detection of the expression of human telomerase reverse transcriptase (hTERT); IHC was used for the detection of the expression of promyelocytic leukemia body (PML) bodies; the co-expression of PML bodies and hTERT was detected using the QDs-based immunofluorescence. The co-expression of PML body and hTERT was found in the same cell in breast cancer tissues, and ten samples expressed neither PML bodies nor hTERT. Additionally, the expression of PML bodies and Her-2 was statistically co-related (P?=?0.047). The two kinds of mechanisms of telomere extension can co-exist in the same cell in beast cancer tissues, and there may be other mechanisms of telomere extension functioning in human breast carcinoma.
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Activation of the JAK-STAT3 pathway is associated with the growth of colorectal carcinoma cells.
Oncol. Rep.
PUBLISHED: 09-26-2013
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Excessive activation of inflammatory signaling pathways facilitates colorectal carcinoma (CRC) malignancy. Continuous activation of the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathway plays a central role in the development and progression of CRC. With the intent to explore whether attenuation of the JAK-STAT3 signaling axis inhibits cancer cell proliferation or induces apoptosis, a sophisticated oncolytic adenoviral vector, AdCN305, carrying the SOCS3 gene was used to treat CRC cells. Our data revealed that i) in CRC cells, STAT3 was continuously activated by phosphorylation, and SOCS3 was at a relative low expression level; and ii) AdCN305-cppSOCS3 inhibited the continuous activation of the JAK/STAT3 pathway, suppressed CRC cell growth and induced apoptosis, in vitro and in vivo. We proved that SOCS3, a negative regulator of the JAK-STAT3 pathway, efficiently inhibited the activation of the pathway and decreased levels of downstream factors which regulate cell proliferation and the cell cycle.
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One-step generation of different immunodeficient mice with multiple gene modifications by CRISPR/Cas9 mediated genome engineering.
Int. J. Biochem. Cell Biol.
PUBLISHED: 09-14-2013
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Taking advantage of the multiplexable genome engineering feature of the CRISPR/Cas9 system, we sought to generate different kinds of immunodeficient mouse strains by embryo co-microinjection of Cas9 mRNA and multiple sgRNAs targeting mouse B2m, Il2rg, Prf1, Prkdc, and Rag1. We successfully achieved multiple gene modifications, fragment deletion, double knockout of genes localizing on the same chromosome, and got different kinds of immunodeficient mouse models with different heritable genetic modifications at once, providing a one-step strategy for generating different immunodeficient mice which represents significant time-, labor-, and money-saving advantages over traditional approaches. Meanwhile, we improved the technology by optimizing the concentration of Cas9 and sgRNAs and designing two adjacent sgRNAs targeting one exon for each gene, which greatly increased the targeting efficiency and bi-allelic mutations.
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IRS1 genotype modulates metabolic syndrome reversion in response to 2-year weight-loss diet intervention: the POUNDS LOST trial.
Diabetes Care
PUBLISHED: 09-05-2013
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Genetic variants near IRS1 are associated with features of the metabolic syndrome (MetS). We examined whether genetic variants near IRS1 might modulate the effects of diets varying in fat content on the MetS status in a 2-year weight-loss trial.
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Association between a genetic variant related to glutamic acid metabolism and coronary heart disease in individuals with type 2 diabetes.
JAMA
PUBLISHED: 08-29-2013
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Diabetes is associated with an elevated risk of coronary heart disease (CHD). Previous studies have suggested that the genetic factors predisposing to excess cardiovascular risk may be different in diabetic and nondiabetic individuals.
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Gene × physical activity interactions in obesity: combined analysis of 111,421 individuals of European ancestry.
PLoS Genet.
PUBLISHED: 07-01-2013
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Numerous obesity loci have been identified using genome-wide association studies. A UK study indicated that physical activity may attenuate the cumulative effect of 12 of these loci, but replication studies are lacking. Therefore, we tested whether the aggregate effect of these loci is diminished in adults of European ancestry reporting high levels of physical activity. Twelve obesity-susceptibility loci were genotyped or imputed in 111,421 participants. A genetic risk score (GRS) was calculated by summing the BMI-associated alleles of each genetic variant. Physical activity was assessed using self-administered questionnaires. Multiplicative interactions between the GRS and physical activity on BMI were tested in linear and logistic regression models in each cohort, with adjustment for age, age(2), sex, study center (for multicenter studies), and the marginal terms for physical activity and the GRS. These results were combined using meta-analysis weighted by cohort sample size. The meta-analysis yielded a statistically significant GRS × physical activity interaction effect estimate (Pinteraction ?=?0.015). However, a statistically significant interaction effect was only apparent in North American cohorts (n?=?39,810, Pinteraction ?=?0.014 vs. n?=?71,611, Pinteraction ?=?0.275 for Europeans). In secondary analyses, both the FTO rs1121980 (Pinteraction ?=?0.003) and the SEC16B rs10913469 (Pinteraction ?=?0.025) variants showed evidence of SNP × physical activity interactions. This meta-analysis of 111,421 individuals provides further support for an interaction between physical activity and a GRS in obesity disposition, although these findings hinge on the inclusion of cohorts from North America, indicating that these results are either population-specific or non-causal.
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Metabolomic profiling analysis reveals chamber-dependent metabolite patterns in the mouse heart.
Am. J. Physiol. Heart Circ. Physiol.
PUBLISHED: 06-21-2013
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Energy of the cardiac muscle largely depends on fatty acid oxidation. It is known that the atrium and ventricle have chamber-specific functions, structures, gene expressions, and pathologies. The left ventricle works as a high-pressure chamber to pump blood toward the body, and its muscle wall is thicker than those of the other chambers, suggesting that energy utilization in each of the chambers should be different. However, a chamber-specific pattern of metabolism remains incompletely understood. Recently, innovative techniques have enabled the comprehensive analysis of metabolites. Therefore, we aimed to clarify differences in metabolic patterns among the chambers. Male C57BL6 mice at 6 wk old were subject to a comprehensive measurement of metabolites in the atria and ventricles by capillary electrophoresis and mass spectrometry. We found that overall metabolic profiles, including nucleotides and amino acids, were similar between the right and left ventricles. On the other hand, the atria exhibited a distinct metabolic pattern from those of the ventricles. Importantly, the high-energy phosphate pool (the total concentration of ATP, ADP, and AMP) was higher in both ventricles. In addition, the levels of lactate, acetyl CoA, and tricarboxylic acid cycle contents were higher in the ventricles. Accordingly, the activities and/or expression levels of key enzymes were higher in the ventricles to produce more energy. The present study provides a basis for understanding the chamber-specific metabolism underlining pathophysiology in the heart.
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Elevated antigen-specific Th2 type response is associated with the poor prognosis of hand, foot and mouth disease.
Virus Res.
PUBLISHED: 06-13-2013
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The immunopathogenesis of severe hand, foot and mouth disease (HFMD) remains elusive. This study revealed that enterovirus 71 (EV71) epitope-specific CD4+ T cell responses of HFMD patients were skewed toward a Th2 cytokine profile. Patients that demonstrated higher levels of IL-4 expression in their CD4 T cells following antigen stimulation in vitro tended to have a more prolonged period of high fevers and a longer duration of illness. Thus, an increase of EV71 epitope-specific Th2 type response may portend the poor prognosis for some HFMD patients.
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Whole-exome sequencing of 2,000 danish individuals and the role of rare coding variants in type 2 diabetes.
Am. J. Hum. Genet.
PUBLISHED: 06-07-2013
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It has been hypothesized that, in aggregate, rare variants in coding regions of genes explain a substantial fraction of the heritability of common diseases. We sequenced the exomes of 1,000 Danish cases with common forms of type 2 diabetes (including body mass index > 27.5 kg/m(2) and hypertension) and 1,000 healthy controls to an average depth of 56×. Our simulations suggest that our study had the statistical power to detect at least one causal gene (a gene containing causal mutations) if the heritability of these common diseases was explained by rare variants in the coding regions of a limited number of genes. We applied a series of gene-based tests to detect such susceptibility genes. However, no gene showed a significant association with disease risk after we corrected for the number of genes analyzed. Thus, we could reject a model for the genetic architecture of type 2 diabetes where rare nonsynonymous variants clustered in a modest number of genes (fewer than 20) are responsible for the majority of disease risk.
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A large-scale screen for coding variants predisposing to psoriasis.
Nat. Genet.
PUBLISHED: 06-07-2013
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To explore the contribution of functional coding variants to psoriasis, we analyzed nonsynonymous single-nucleotide variants (SNVs) across the genome by exome sequencing in 781 psoriasis cases and 676 controls and through follow-up validation in 1,326 candidate genes by targeted sequencing in 9,946 psoriasis cases and 9,906 controls from the Chinese population. We discovered two independent missense SNVs in IL23R and GJB2 of low frequency and five common missense SNVs in LCE3D, ERAP1, CARD14 and ZNF816A associated with psoriasis at genome-wide significance. Rare missense SNVs in FUT2 and TARBP1 were also observed with suggestive evidence of association. Single-variant and gene-based association analyses of nonsynonymous SNVs did not identify newly associated genes for psoriasis in the regions subjected to targeted resequencing. This suggests that coding variants in the 1,326 targeted genes contribute only a limited fraction of the overall genetic risk for psoriasis.
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Multimodal use of new coumarin-based fluorescent chemosensors: towards highly selective optical sensors for Hg(2+) probing.
Chemistry
PUBLISHED: 05-31-2013
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Despite several types of fluorescent sensing molecules have been proposed and examined to signal Hg(2+) ion binding, the development of fluorescence-based devices for in-field Hg(2+) detection and screening in environmental and industrial samples is still a challenging task. Herein, we report the synthesis and characterization of three new coumarin-based fluorescent chemosensors featuring mixed thia/aza macrocyclic framework as receptors units, that is, ligands L1-L3. These probes revealed an OFF-ON selective response to the presence of Hg(2+) ions in MeCN/H2 O 4:1 (v/v), which allowed imaging of this metal ion in Cos-7 cells in vitro. Once included in silica core-polyethylene glycol (PEG) shell nanoparticles or supported on polyvinyl chloride (PVC)-based polymeric membranes, ligands L1-L3 can also selectively sense Hg(2+) ions in pure water. In particular we have developed an optical sensing array tacking advantage of the fluorescent properties of ligand L3 and based on the computer screen photo assisted technique (CSPT). In the device ligand L3 is dispersed into PVC membranes and it quantitatively responds to Hg(2+) ions in natural water samples.
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Higher order partial least squares (HOPLS): a generalized multilinear regression method.
IEEE Trans Pattern Anal Mach Intell
PUBLISHED: 05-18-2013
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A new generalized multilinear regression model, termed the higher order partial least squares (HOPLS), is introduced with the aim to predict a tensor (multiway array) Y from a tensor X through projecting the data onto the latent space and performing regression on the corresponding latent variables. HOPLS differs substantially from other regression models in that it explains the data by a sum of orthogonal Tucker tensors, while the number of orthogonal loadings serves as a parameter to control model complexity and prevent overfitting. The low-dimensional latent space is optimized sequentially via a deflation operation, yielding the best joint subspace approximation for both X and Y. Instead of decomposing X and Y individually, higher order singular value decomposition on a newly defined generalized cross-covariance tensor is employed to optimize the orthogonal loadings. A systematic comparison on both synthetic data and real-world decoding of 3D movement trajectories from electrocorticogram signals demonstrate the advantages of HOPLS over the existing methods in terms of better predictive ability, suitability to handle small sample sizes, and robustness to noise.
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Transcriptome Profile Analysis of Sugarcane Responses to Sporisorium scitaminea Infection Using Solexa Sequencing Technology.
Biomed Res Int
PUBLISHED: 05-09-2013
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To understand the molecular basis of sugarcane-smut interaction, it is important to identify sugarcane genes that respond to the pathogen attack. High-throughput tag-sequencing (tag-seq) analysis by Solexa technology was performed on sugarcane infected with Sporisorium scitaminea, which should have massively increased the amount of data available for transcriptome profile analysis. After mapping to sugarcane EST databases in NCBI, we obtained 2015 differentially expressed genes, of which 1125 were upregulated and 890 downregulated by infection. Gene ontology (GO) analysis revealed that the differentially expressed genes involve in many cellular processes. Pathway analysis revealed that metabolic pathways and ribosome function are significantly affected, where upregulation of expression dominates over downregulation. Differential expression of three candidate genes involved in MAP kinase signaling pathway, ScBAK1 (GenBank Accession number: KC857629), ScMapkk (GenBank Accession number: KC857627), and ScGloI (GenBank Accession number: KC857628), was confirmed by reverse transcription polymerase chain reaction (RT-PCR). Real-time quantitative PCR (qRT-PCR) analysis concluded that the expression of these genes were all up-regulated after the infection of S. scitaminea and may play a role in pathogen response in sugarcane. The present study provides insights into the molecular mechanism of sugarcane defense to S. scitaminea infection, leading to a more comprehensive understanding of sugarcane-smut interaction.
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Design of assistive wheelchair system directly steered by human thoughts.
Int J Neural Syst
PUBLISHED: 04-23-2013
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Integration of brain-computer interface (BCI) technique and assistive device is one of chief and promising applications of BCI system. With BCI technique, people with disabilities do not have to communicate with external environment through traditional and natural pathways like peripheral nerves and muscles, and could achieve it only by their brain activities. In this paper, we designed an electroencephalogram (EEG)-based wheelchair which can be steered by users own thoughts without any other involvements. We evaluated the feasibility of BCI-based wheelchair in terms of accuracies and real-world testing. The results demonstrate that our BCI wheelchair is of good performance not only in accuracy, but also in practical running testing in a real environment. This fact implies that people can steer wheelchair only by their thoughts, and may have a potential perspective in daily application for disabled people.
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The two-faced T cell epitope: examining the host-microbe interface with JanusMatrix.
Hum Vaccin Immunother
PUBLISHED: 04-12-2013
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Advances in the field of T cell immunology have contributed to the understanding that cross-reactivity is an intrinsic characteristic of the T cell receptor (TCR), and that each TCR can potentially interact with many different T cell epitopes. To better define the potential for TCR cross-reactivity between epitopes derived from the human genome, the human microbiome, and human pathogens, we developed a new immunoinformatics tool, JanusMatrix, that represents an extension of the validated T cell epitope mapping tool, EpiMatrix. Initial explorations, summarized in this synopsis, have uncovered what appear to be important differences in the TCR cross-reactivity of selected regulatory and effector T cell epitopes with other epitopes in the human genome, human microbiome, and selected human pathogens. In addition to exploring the T cell epitope relationships between human self, commensal and pathogen, JanusMatrix may also be useful to explore some aspects of heterologous immunity and to examine T cell epitope relatedness between pathogens to which humans are exposed (Dengue serotypes, or HCV and Influenza, for example). In Hand-Foot-Mouth disease (HFMD) for example, extensive enterovirus and human microbiome cross-reactivity (and limited cross-reactivity with the human genome) seemingly predicts immunodominance. In contrast, more extensive cross-reactivity with proteins contained in the human genome as compared to the human microbiome was observed for selected Treg epitopes. While it may be impossible to predict all immune response influences, the availability of sequence data from the human genome, the human microbiome, and an array of human pathogens and vaccines has made computationally-driven exploration of the effects of T cell epitope cross-reactivity now possible. This is the first description of JanusMatrix, an algorithm that assesses TCR cross-reactivity that may contribute to a means of predicting the phenotype of T cells responding to selected T cell epitopes. Whether used for explorations of T cell phenotype or for evaluating cross-conservation between related viral strains at the TCR face of viral epitopes, further JanusMatrix studies may contribute to developing safer, more effective vaccines.
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HCV J6/JFH1 Tilts the Capability of Myeloid-Derived Dendritic Cells to Favor the Induction of Immunosuppression and Th17-Related Inflammatory Cytokines.
Pharm. Res.
PUBLISHED: 04-02-2013
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PURPOSE: How HCV virus affects the function of dendritic cells (DCs) and their ability to induce CD4+ T cell response remains not fully understood. This study was done to elucidate the impact of HCV on the function of DCs and on DCs capability to induce CD4+ T-cell response. METHODS: Monocyte-derived DCs (MoDCs) were treated with cell-culture HCV (HCVcc). The effects of HCVcc on DC maturation, CD40L-induced DC maturation, and cytokine production and the capacity of DCs to induce Th cytokine production of allogeneic CD4+ T cells were evaluated. RESULTS: HCVcc exposure increased expression of both IL-6 and IL-10 by MoDCs. HCV-exposed MoDCs also selectively facilitated allogeneic CD4+ T cells to further produce Th17-related cytokines interleukin 1 (IL-1), IL-6, and IL-17A. Pretreatment of IL-17A inhibited HCV production in Huh7.5 cells, suggesting that induction of Th17 cells may be beneficial to host anti-HCV immunity. Paradoxically, induction of IL-10 expression and the failure of HCV-exposed MoDCs to facilitate other Th cell development may hinder the anti-viral immunity. CONCLUSIONS: This study highlights both the therapeutic potential of IL-17A in treating HCV infection and the cautious consideration of HCV-induced immunosuppression in DC-based therapy.
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Mitochondrial genome sequences of Artemia tibetiana and Artemia urmiana: assessing molecular changes for high plateau adaptation.
Sci China Life Sci
PUBLISHED: 03-19-2013
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Brine shrimps, Artemia (Crustacea, Anostraca), inhabit hypersaline environments and have a broad geographical distribution from sea level to high plateaus. Artemia therefore possess significant genetic diversity, which gives them their outstanding adaptability. To understand this remarkable plasticity, we sequenced the mitochondrial genomes of two Artemia tibetiana isolates from the Tibetan Plateau in China and one Artemia urmiana isolate from Lake Urmia in Iran and compared them with the genome of a low-altitude Artemia, A. franciscana. We compared the ratio of the rate of nonsynonymous (Ka) and synonymous (Ks) substitutions (Ka/Ks ratio) in the mitochondrial protein-coding gene sequences and found that atp8 had the highest Ka/Ks ratios in comparisons of A. franciscana with either A. tibetiana or A. urmiana and that atp6 had the highest Ka/Ks ratio between A. tibetiana and A. urmiana. Atp6 may have experienced strong selective pressure for high-altitude adaptation because although A. tibetiana and A. urmiana are closely related they live at different altitudes. We identified two extended termination-associated sequences and three conserved sequence blocks in the D-loop region of the mitochondrial genomes. We propose that sequence variations in the D-loop region and in the subunits of the respiratory chain complexes independently or collectively contribute to the adaptation of Artemia to different altitudes.
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Spatial-temporal discriminant analysis for ERP-based brain-computer interface.
IEEE Trans Neural Syst Rehabil Eng
PUBLISHED: 03-12-2013
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Linear discriminant analysis (LDA) has been widely adopted to classify event-related potential (ERP) in brain-computer interface (BCI). Good classification performance of the ERP-based BCI usually requires sufficient data recordings for effective training of the LDA classifier, and hence a long system calibration time which however may depress the system practicability and cause the users resistance to the BCI system. In this study, we introduce a spatial-temporal discriminant analysis (STDA) to ERP classification. As a multiway extension of the LDA, the STDA method tries to maximize the discriminant information between target and nontarget classes through finding two projection matrices from spatial and temporal dimensions collaboratively, which reduces effectively the feature dimensionality in the discriminant analysis, and hence decreases significantly the number of required training samples. The proposed STDA method was validated with dataset II of the BCI Competition III and dataset recorded from our own experiments, and compared to the state-of-the-art algorithms for ERP classification. Online experiments were additionally implemented for the validation. The superior classification performance in using few training samples shows that the STDA is effective to reduce the system calibration time and improve the classification accuracy, thereby enhancing the practicability of ERP-based BCI.
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Multi-domain feature extraction for small event-related potentials through nonnegative multi-way array decomposition from low dense array EEG.
Int J Neural Syst
PUBLISHED: 03-03-2013
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Non-negative Canonical Polyadic decomposition (NCPD) and non-negative Tucker decomposition (NTD) were compared for extracting the multi-domain feature of visual mismatch negativity (vMMN), a small event-related potential (ERP), for the cognitive research. Since signal-to-noise ratio in vMMN is low, NTD outperformed NCPD. Moreover, we proposed an approach to select the multi-domain feature of an ERP among all extracted features and discussed determination of numbers of extracted components in NCPD and NTD regarding the ERP context.
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The Genome of the Netherlands: design, and project goals.
Eur. J. Hum. Genet.
PUBLISHED: 02-28-2013
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Within the Netherlands a national network of biobanks has been established (Biobanking and Biomolecular Research Infrastructure-Netherlands (BBMRI-NL)) as a national node of the European BBMRI. One of the aims of BBMRI-NL is to enrich biobanks with different types of molecular and phenotype data. Here, we describe the Genome of the Netherlands (GoNL), one of the projects within BBMRI-NL. GoNL is a whole-genome-sequencing project in a representative sample consisting of 250 trio-families from all provinces in the Netherlands, which aims to characterize DNA sequence variation in the Dutch population. The parent-offspring trios include adult individuals ranging in age from 19 to 87 years (mean=53 years; SD=16 years) from birth cohorts 1910-1994. Sequencing was done on blood-derived DNA from uncultured cells and accomplished coverage was 14-15x. The family-based design represents a unique resource to assess the frequency of regional variants, accurately reconstruct haplotypes by family-based phasing, characterize short indels and complex structural variants, and establish the rate of de novo mutational events. GoNL will also serve as a reference panel for imputation in the available genome-wide association studies in Dutch and other cohorts to refine association signals and uncover population-specific variants. GoNL will create a catalog of human genetic variation in this sample that is uniquely characterized with respect to micro-geographic location and a wide range of phenotypes. The resource will be made available to the research and medical community to guide the interpretation of sequencing projects. The present paper summarizes the global characteristics of the project.European Journal of Human Genetics advance online publication, 29 May 2013; doi:10.1038/ejhg.2013.118.
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Genetic determinant for amino acid metabolites and changes in body weight and insulin resistance in response to weight-loss diets: the Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST) trial.
Circulation
PUBLISHED: 02-27-2013
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Circulating branched-chain amino acids and aromatic amino acids were recently related to insulin resistance and diabetes mellitus in prospective cohorts. We tested the effects of a genetic determinant of branched-chain amino acid/aromatic amino acid ratio on changes in body weight and insulin resistance in a 2-year diet intervention trial.
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Interaction between a common variant in FADS1 and erythrocyte polyunsaturated fatty acids on lipid profile in Chinese Hans.
J. Lipid Res.
PUBLISHED: 02-08-2013
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Little is known about the associations of FADS1 genetic variants with circulating levels of PUFA and lipids in Asian populations who have a different dietary pattern and dyslipidemia prevalence compared with Western populations. In a population-based sample of 3,210 unrelated Han Chinese living in Beijing and Shanghai, we examined a FADS1 genetic variant, rs174550, in relation to blood PUFA and lipid levels. C-allele of rs174550 was significantly associated with levels of erythrocyte PUFAs in upstream and downstream pathways of delta-5 desaturase (D5D) (P ? 0.003). Moreover, rs174550 C-allele was associated with a lower HDL cholesterol level (P = 0.02) in total population and a higher triglyceride level (P = 0.0002) in Beijing residents. Interestingly, erythrocyte levels of 18:2n-6 and 18:3n-3 modified the effect of rs174550 on HDL cholesterol level: stronger associations between rs174550 C-allele and lower HDL cholesterol levels were exhibited when erythrocyte 18:2n-6 or 18:3n-3 level was low (P for interaction = 0.02 and 0.03, respectively). These data suggested that FADS1 genetic variant was associated with circulating PUFA and lipid levels and that its effect on HDL cholesterol might depend on PUFA status in the Han Chinese population.
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Novel locus including FGF21 is associated with dietary macronutrient intake.
Hum. Mol. Genet.
PUBLISHED: 01-30-2013
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Dietary intake of macronutrients (carbohydrate, protein, and fat) has been associated with risk of chronic conditions such as obesity and diabetes. Family studies have reported a moderate contribution of genetics to variation in macronutrient intake. In a genome-wide meta-analysis of a population-based discovery cohort (n = 33 533), rs838133 in FGF21 (19q13.33), rs197273 near TRAF family member-associated NF-kappa-B activator (TANK) (2p24.2), and rs10163409 in FTO (16q12.2) were among the top associations (P < 10(-5)) for percentage of total caloric intake from protein and carbohydrate. rs838133 was replicated in silico in an independent sample from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE) Nutrition Working Group (n = 38 360) and attained genome-wide significance in combined analysis (Pjoint = 7.9 × 10(-9)). A cytokine involved in cellular metabolism, FGF21 is a potential susceptibility gene for obesity and type 2 diabetes. Our results highlight the potential of genetic variation for determining dietary macronutrient intake.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.