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  • 1
    Publication Date: 2018-10-05
    Description: Investigation of spontaneous mutations by next-generation sequencing technology has attracted extensive attention lately due to the fundamental roles of spontaneous mutations in evolution and pathological processes. However, these studies only focused on the mutations accumulated through many generations during long-term (possibly be years of) culturing, but not the freshly generated mutations that occur at very low frequencies. In this study, we established a molecularly barcoded deep sequencing strategy to detect low abundant spontaneous mutations in genomes of bacteria cell cultures. Genome-wide spontaneous mutations in 15 Escherichia coli cell culture samples were defined with a high confidence ( P 〈 0.01). We also developed a hotspot-calling approach based on the run-length encoding algorithm to find the genomic regions that are vulnerable to the spontaneous mutations. The hotspots for the mutations appeared to be highly conserved across the bacteria samples. Further biological annotation of these regions indicated that most of the spontaneous mutations were located at the repeat domains or nonfunctional domains of the genomes, suggesting the existence of mechanisms that could somehow prevent the occurrence of mutations in crucial genic areas. This study provides a more faithful picture of mutation occurrence and spectra in a single expansion process without long-term culturing.
    Print ISSN: 0016-6731
    Topics: Biology
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  • 2
    Publication Date: 2018-06-28
    Description: The photodegradation of benzothiazole (BTH) in wastewater with the coexistence of iron oxides and oxalic acid under UV light irradiation was investigated. Results revealed that an effective heterogeneous photo-Fenton-like system could be set up for BTH abatement in wastewater under UV irradiation without additional H 2 O 2 , and 88.1% BTH was removed with the addition of 2.0 mmol l –1 oxalic acid and 0.2 g l –1 α-Fe 2 O 3 using a 500 W high-pressure mercury lamp (365 nm). The degradation of BTH in the photo-Fenton-like system followed the first-order kinetic model. The photoproduction of hydroxyl radicals (·OH) in different systems was determined by high-performance liquid chromatography. Identification of transformation products by using liquid chromatography coupled with high resolution tandem mass spectrometry provided information about six transformation products formed during the photodegradation of BTH. Further insight was obtained by monitoring concentrations of the sulfate ion (SO42–) and nitrate ion (NO3–) , which demonstrated that the intermediate products of BTH could be decomposed ultimately. Based on the results, the potential photodegradation pathway of BTH was also proposed.
    Keywords: environmental chemistry
    Electronic ISSN: 2054-5703
    Topics: Natural Sciences in General
    Published by Royal Society
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  • 3
    Abstract: Importance: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. Objective: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. Data Sources: Genomewide association studies (GWAS) published up to January 15, 2015. Study Selection: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. Data Extraction and Synthesis: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. Main Outcomes and Measures: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. Results: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420081 cases (median cases, 2526 per disease) and 1093105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]). Conclusions and Relevance: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.
    Type of Publication: Journal article published
    PubMed ID: 28241208
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  • 4
    Publication Date: 2018-09-05
    Description: One of the most clinically relevant molecular aberrations in breast cancer is overexpression of human epidermal growth factor receptor type 2 (HER2). We aimed to develop a radiolabeled tyrosine kinase inhibitor for HER2-targeted breast cancer imaging. In this study, a radioiodinated analog ( 125/131 I-IBA-CP) of the HER2-selective inhibitor CP724,714 was prepared and evaluated in HER2-positive or -negative subcutaneous human breast cancer xenografts. Methods: The CP724,714 analog IBA-CP was synthesized and assayed for its inhibitory activities against HER2 and 6 other tyrosine kinases. 125/131 I-IBA-CP was prepared using a copper-mediated radioiodination method with enhanced labeling yield and molar activity. In vitro biologic activity, including specific and nonspecific binding of 131 I-IBA-CP to its HER2 kinase target, was assessed in different cell lines. In vivo small-animal 125 I-IBA-CP SPECT imaging and biodistribution studies were conducted on mice bearing HER2-positive, HER2-negative, or epidermal growth factor receptor (EGFR)-positive tumors. Nonradioactive IBA-CP and the EGFR inhibitor erlotinib were used as blocking agents to investigate the binding specificity and selectivity of 125/131 I-IBA-CP toward HER2 in vitro and in vivo. Additionally, 125/131 I-ICP was prepared by direct radioiodination of CP724,714 for comparison with 125/131 I-IBA-CP. Results: IBA-CP displayed superior in vitro inhibitory activity (half-maximal inhibitory concentration, 16 nM) and selectivity for HER2 over 6 other cancer-related tyrosine kinases. 125/131 I-IBA-CP was prepared in a typical radiochemical yield of about 65% (decay-corrected), radiochemical purity of more than 98%, and molar activity of 42 GBq/μmol at the end of synthesis. SPECT imaging revealed significantly higher uptake of 125 I-IBA-CP than of 125 I-ICP in the HER2-positive MDA-MB-453 tumors. Uptake in the HER2-negative MCF-7 tumors was much lower. Binding of 125 I-IBA-CP in the MDA-MB-453 tumors was blocked by coinjection with an excess amount of IBA-CP, but not by erlotinib. Conclusion: The radiolabeled HER2-selective inhibitor 125/131 I-IBA-CP is a promising probe for in vivo detection of HER2-positive tumors.
    Print ISSN: 0022-3123
    Topics: Medicine
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  • 5
    Publication Date: 2018-10-06
    Description: High-energy lithium metal batteries (LMBs) are expected to play important roles in the next-generation energy storage systems. However, the uncontrolled Li dendrite growth in liquid electrolytes still impedes LMBs from authentic commercialization. Upgrading the traditional electrolyte system from liquid to solid and quasi-solid has therefore become a key issue for prospective LMBs. From this premise, it is particularly urgent to exploit facile strategies to accomplish this goal. We report that commercialized liquid electrolyte can be easily converted into a novel quasi-solid gel polymer electrolyte (GPE) via a simple and efficient in situ gelation strategy, which, in essence, is to use LiPF 6 to induce the cationic polymerization of the ether-based 1,3-dioxolane and 1,2-dimethoxyethane liquid electrolyte under ambient temperature. The newly developed GPE exhibits elevated protective effects on Li anodes and has universality for diversified cathodes including but not restricted to sulfur, olivine-type LiFePO 4 , and layered LiNi 0.6 Co 0.2 Mn 0.2 O 2 , revealing tremendous potential in promoting the large-scale application of future LMBs.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
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  • 6
    Publication Date: 2018-01-03
    Description: Autophagic impairment is implicated in nonalcoholic fatty liver disease (NAFLD), but the molecular mechanism is unclear. We found that autophagic flux was significantly inhibited in 3 murine models of NAFLD. Interestingly, the number of acidic organelles and the level of mature cathepsin D were reduced, suggesting defective lysosome acidification. Asparagine synthetase (ASNS) was induced by endoplasmic reticulum stress, leading to the generation of asparagine, which inhibited lysosome acidification. Both steatotic- and asparagine-treated hepatocytes showed reduced lysosomal acidity and retention of lysosomal calcium. Knockdown of ASNS in steatotic hepatocytes restored autophagic flux. As a potential biomarker, increased serum p62/sequestosome 1 (SQSTM1) level was an independent risk factor for patients with steatosis and lobular inflammation. Impaired autophagy in NAFLD is elicited by defective lysosome acidification, which is caused by ASNS-induced asparagine synthesis under endoplasmic reticulum stress and subsequent retention of lysosomal calcium. p62/SQSTM1 could be used as a noninvasive biomarker in the diagnosis of NAFLD patients.—Wang, X., Zhang, X., Chu, E. S. H., Chen, X., Kang, W., Wu, F., To, K.-F., Wong, V. W. S., Chan, H. L. Y., Chan, M. T. V., Sung, J. J. Y., Wu, W. K. K., Yu, J. Defective lysosomal clearance of autophagosomes and its clinical implications in nonalcoholic steatohepatitis.
    Print ISSN: 0892-6638
    Electronic ISSN: 1530-6860
    Topics: Biology
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  • 7
    Publication Date: 2018-03-09
    Description: Objective In previous studies using oesophageal squamous cells from patients with Barrett's oesophagus (normal oesophageal squamous (NES)-B cells) and from patients without Barrett's oesophagus (NES-G cells), we showed that acid and bile salts induced caudal-related homeobox transcription factor 2 (CDX2) expression only in NES-B cells. CDX2, a transcription factor required to form intestinal epithelium, is a target of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-B) signalling, which can be inhibited by aspirin. We explored mechanisms underlying differences between NES-B and NES-G cells in CDX2 expression and effects of aspirin on that CDX2 expression. Design We exposed NES-B and NES-G cells to acid and bile salts, with and without aspirin, and evaluated effects on IB-NF-B-PKAc complex activation, p65 NF-B subunit function, and CDX2 expression. Results In both NES-B and NES-G cells, acid and bile salts activated nicotinamide adenine dinucleotide phosphate oxidase to generate H 2 O 2 , which activated the IB-NF-B-PKAc complex. NES-B cells exhibited higher levels of phosphorylated IB and p65 and greater NF-B transcriptional activity than NES-G cells, indicating greater IB-NF-B-PKAc complex activation by acid and bile salts in NES-B cells, and p65 siRNA prevented their increased expression of CDX2. Aspirin blocked IB phosphorylation, p65 nuclear translocation, CDX2 promoter activation and CDX2 expression induced by acid and bile salts in NES-B cells. Conclusions Differences between NES-B and NES-G cells in NF-B activation by acid and bile salts can account for their differences in CDX2 expression, and their CDX2 expression can be blocked by aspirin. These findings might explain why some patients with GORD develop Barrett's oesophagus while others do not, and why aspirin might protect against development of Barrett's oesophagus.
    Print ISSN: 0017-5749
    Electronic ISSN: 1468-3288
    Topics: Medicine
    Published by BMJ Publishing Group
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  • 8
    Publication Date: 2018-03-28
    Description: A novel 65.8-kb multidrug resistance transposon, designated Tn 6450 , was characterized in a Proteus mirabilis isolate from chicken in China. Tn 6450 contains 18 different antimicrobial resistance genes, including cephalosporinase gene bla DHA-1 and fluoroquinolone resistance genes qnrA1 and aac(6 ' )-Ib-cr . It carries a class 1/2 hybrid integron composed of intI2 and a 3' conserved segment of the class 1 integron. Tn 6450 is derived from Tn 7 via acquisition of new mobile elements and resistance genes.
    Print ISSN: 0066-4804
    Electronic ISSN: 1098-6596
    Topics: Biology , Medicine
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  • 9
    Publication Date: 2018-03-06
    Description: Background/Aim: Prostate cancer (PCa) diagnosis using patient urine samples represents a non-invasive and more convenient method than the conventional biopsy and prostate-specific antigen (PSA) test. This study intended to identify a biomarker panel to distinguish PCa from benign prostate using urine samples. Materials and Methods: We identified six biomarkers with differential gene expression in 154 PCa and benign prostate specimens. We then determined mRNA expression signature and the diagnostic performance of the 6-biomarker panel in 156 urine samples from patients with PCa and benign disease. Results: The 6-biomarker panel distinguished PCa from benign prostate cases with sensitivity of 80.6%, specificity of 62.9% and area under the curve (AUC) of 0.803 (p〈0.0001), whereas serum PSA at 4 ng/ml cutoff had sensitivity of 95.5%, specificity of 20.2% and AUC of 0.521 (p〈0.0001). Conclusion: The 6-biomarker panel for use in urine samples was able to distinguish PCa from benign prostate with higher specificity and accuracy than PSA and may be useful in clinical settings.
    Print ISSN: 0250-7005
    Electronic ISSN: 1791-7530
    Topics: Medicine
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  • 10
    Publication Date: 2018-09-15
    Description: Air-stable, lightweight, and electrically conductive polymers are highly desired as the electrodes for next-generation electronic devices. However, the low electrical conductivity and low carrier mobility of polymers are the key bottlenecks that limit their adoption. We demonstrate that the key to addressing these limitations is to molecularly engineer the crystallization and morphology of polymers. We use oxidative chemical vapor deposition (oCVD) and hydrobromic acid treatment as an effective tool to achieve such engineering for conducting polymer poly(3,4-ethylenedioxythiophene) (PEDOT). We demonstrate PEDOT thin films with a record-high electrical conductivity of 6259 S/cm and a remarkably high carrier mobility of 18.45 cm 2 V –1 s –1 by inducing a crystallite-configuration transition using oCVD. Subsequent theoretical modeling reveals a metallic nature and an effective reduction of the carrier transport energy barrier between crystallized domains in these thin films. To validate this metallic nature, we successfully fabricate PEDOT-Si Schottky diode arrays operating at 13.56 MHz for radio frequency identification (RFID) readers, demonstrating wafer-scale fabrication compatible with conventional complementary metal-oxide semiconductor (CMOS) technology. The oCVD PEDOT thin films with ultrahigh electrical conductivity and high carrier mobility show great promise for novel high-speed organic electronics with low energy consumption and better charge carrier transport.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
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