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  • 11
    Publication Date: 2018-10-04
    Description: Risk assessment has always been an important part of safety risk research in tunnel and underground engineering. Owing to the characteristics of tunnel construction, to achieve an expected risk control effect, it is necessary to carry out accurate risk assessment research according to the risk assessment concept based on the entire tunnel construction process. At present, because of the frequent occurrences of safety accidents, a variety of risk assessment models have been proposed for different tunnel projects such as subways and railway tunnels, which can be roughly classified into two types: probability-based and fuzzy set theories. However, the existing models may be more suitable for the construction stage, and the design stage lacks a reliable and practical fuzzy risk assessment method. Therefore, based on fuzzy set theory and similarity measure theory, a risk assessment model is proposed to adapt to the characteristics that the risk information is difficult to quantify the fuzziness in the design phase. Firstly, new ideas of fuzzy risk analysis are proposed to overcome deficiencies in existing methods; secondly, a new similarity measure is constructed; then fusing multi-source fuzzy information based on evidence theory, the relationship between similarity measure and mass function is established. Finally, the new method is applied to the Yuelongmen tunnel. Results show that the concept of risk control and the risk assessment model are feasible.
    Keywords: civil engineering
    Electronic ISSN: 2054-5703
    Topics: Natural Sciences in General
    Published by Royal Society
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  • 12
    Publication Date: 2018-03-29
    Description: Respiratory syncytial virus (RSV) is the main cause of acute lower respiratory tract infection (ALRI) in children worldwide. Virus-host interactions affect the progression and prognosis of the infection. Autophagy plays important roles in virus-host interactions. Respiratory epithelial cells serve as the front line of host defense during RSV infection, However, it is still unclear how they interact with RSV. In this study, we found that RSV induced autophagy that favored RSV replication and exacerbated lung pathology in vivo . Mechanistically, RSV induced complete autophagy flux through reactive oxygen species (ROS) generation and activation of the AMP-activated protein kinase/mammalian target of rapamycin (AMPK-MTOR) signaling pathway in HEp-2 cells. Furthermore, we evaluated the functions of autophagy in RSV replication and found that RSV replication was increased in HEp-2 cells treated with rapamycin but decreased remarkably in cells treated with 3-methylademine (3-MA) or wortmannin. Knockdown key molecules in the autophagy pathway with short hairpinp RNA (shRNA) against autophagy-related gene 5 ( ATG5 ), autophagy-related gene 7 ( ATG7 ), or BECN1/Beclin 1 or treatment with ROS scavenger N-acetyl- l -cysteine (NAC) and AMPK inhibitor (compound C) suppressed RSV replication. 3-MA or sh ATG5/BECN1 significantly decreased cell viability and increased cell apoptosis at 48 hours postinfection (hpi). Blocking apoptosis with Z-VAD-FMK partially restored virus replication at 48 hpi. Those results provide strong evidence that autophagy may function as a proviral mechanism in a cell-intrinsic manner during RSV infection. IMPORTANCE An understanding of the mechanisms that respiratory syncytial virus utilizes to interact with respiratory epithelial cells is critical to the development of novel antiviral strategies. In this study, we found that RSV induces autophagy through a ROS-AMPK signaling axis, which in turn promotes viral infection. Autophagy favors RSV replication through blocking cell apoptosis at 48 hpi. Mechanistically, RSV induces mitophagy, which maintains mitochondrial homeostasis and therefore decreases cytochrome c release and apoptosis induction. This study provides a novel insight into this virus-host interaction, which may help to exploit new antiviral treatments targeting autophagy processes.
    Print ISSN: 0022-538X
    Electronic ISSN: 1098-5514
    Topics: Medicine
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  • 13
    Publication Date: 2018-03-14
    Description: Cresol is a prototype molecule in understanding intermolecular interactions in material and biological systems, because it offers different binding sites with various solvents and protonation states under different pH values. It is found that the UV/Vis absorption spectra of o -cresol in aromatic solvents (benzene, toluene) are characterized by a sharp peak, unlike the broad double-peaks in 11 non-aromatic solvents. Both molecular dynamics simulations and electronic structure calculations revealed the formation of intermolecular -complexation between o -cresol and aromatic solvents. The thermal movements of solvent and solute molecules render the conformations of o -cresol changing between trans and cis isomers. The -interaction makes the cis configuration a dominant isomer, hence leading to the single keen-edged UV/Vis absorption peak at approximately 283 nm. The free conformation changes between trans and cis in aqueous solution rationalize the broader absorption peaks in the range of 260–280 nm. The pH dependence of the UV/Vis absorption spectra in aqueous solutions is also rationalized by different protonation states of o -cresol. The explicit solvent model with long-ranged interactions is vital to describe the effects of -complexation and electrostatic interaction on the UV/Vis absorption spectra of o -cresol in toluene and alkaline aqueous (pH 〉 10.3) solutions, respectively.
    Keywords: computational chemistry
    Electronic ISSN: 2054-5703
    Topics: Natural Sciences in General
    Published by Royal Society
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  • 14
    Publication Date: 2018-03-29
    Description: The equine infectious anemia virus (EIAV) attenuated vaccine was developed by long-term passaging of a field-isolated virulent strain in cross-species hosts, followed by successive cultivation in cells in vitro . To explore the molecular mechanism underlying the evolution of the EIAV attenuated vaccine, a systematic study focusing on long-terminal-repeat (LTR) variation in numerous virus strains ranging from virulent EIAV to attenuated EIAV was performed over time both in vitro and in vivo . Two hypervariable regions were identified within the U3 region in the enhancer region (EHR) and the negative regulatory element (NRE) and within the R region in the transcription start site (TSS) and the Tat-activating region (TAR). Among these sites, variation in the U3 region resulted in the formation of additional transcription factor binding sites; this variation of the in vitro -adapted strains was consistent with the loss of pathogenicity. Notably, the same LTR variation pattern was observed both in vitro and in vivo . Generally, the LTR variation in both the attenuated virus and the virulent strain fluctuated over time in vivo . Interestingly, the attenuated-virus-specific LTR variation was also detected in horses infected with the virulent strain, supporting the hypothesis that the evolution of an attenuated virus might have involved branching from EIAV quasispecies. This hypothesis was verified by phylogenetic analysis. The present systematic study examining the molecular evolution of attenuated EIAV from EIAV quasispecies may provide an informative model reflecting the evolution of similar lentiviruses. IMPORTANCE The attenuated EIAV vaccine was the first lentiviral vaccine used to successfully control for equine infectious anemia in China. This vaccine provides an important reference for studying the relationship between EIAV gene variation and changes in biological characteristics. Importantly, the vaccine provides a model for the investigation of lentiviral quasispecies evolution. This study followed the "natural" development of the attenuated EIAV vaccine by use of a systematic analysis of LTR evolution in vitro and in vivo . The results revealed that the increase in LTR variation with passaging was accompanied by a decrease in virulence, which indicated that LTR variability might parallel the attenuation of virulence. Interestingly, the attenuated-virus-specific LTR variation was also detected in virulent-strain-infected horses, a finding consistent with those of previous investigations of gp90 and S2 evolution. Therefore, we present a hypothesis that the evolution of the attenuated virus may involve branching from EIAV quasispecies present in vivo .
    Print ISSN: 0022-538X
    Electronic ISSN: 1098-5514
    Topics: Medicine
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  • 15
    Publication Date: 2018-03-06
    Description: Cholesterol 25-hydroxylase (CH25H) catalyzes the production of 25-hydroxycholesterol (25-HC), an oxysterol that can play an important role in different biological processes. However, the mechanisms regulating CH25H expression have not been fully elucidated. In this study, we determined that CH25H is highly expressed in mouse liver and peritoneal macrophages. We identified several liver X receptor (LXR) response elements (LXREs) in the human CH25H promoter. In HepG2 cells, activation of LXR by 25-HC or other oxysterols and synthetic ligands [T0901317 (T317) and GW3965] induced CH25H protein expression, which was associated with increased CH25H mRNA expression. 25-HC or T317 activated CH25H transcription in an LXRE-dependent manner. Thus, high-expressing LXRα or LXRβ activated CH25H expression, and the activation was further enhanced by LXR ligands. In contrast, inhibition of LXRα/β expression attenuated 25-HC or T317-induced CH25H expression. Deficiency of interferon expression reduced, but did not block, LXR ligand-induced hepatic CH25H expression. Activation of LXR also substantially induced macrophage CH25H expression. In vivo, administration of GW3965 to mice increased CH25H expression in both liver and peritoneal macrophages. Taken together, our study demonstrates that 25-HC can activate CH25H expression in an LXR-dependent manner, which may be an important mechanism to exert the biological actions of 25-HC.
    Print ISSN: 0022-2275
    Electronic ISSN: 1539-7262
    Topics: Biology , Chemistry and Pharmacology , Medicine
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  • 16
    Publication Date: 2018-01-09
    Description: Three-component fermions with surface Fermi arcs in tungsten carbide Three-component fermions with surface Fermi arcs in tungsten carbide, Published online: 08 January 2018; doi:10.1038/s41567-017-0021-8 Triply degenerate electronic structure—three-component fermions—protected by crystal symmetries is observed in tungsten carbide. The observed Fermi arcs associated with the surface states provide evidence of the non-trivial topology of the states.
    Print ISSN: 1745-2473
    Electronic ISSN: 1745-2481
    Topics: Physics
    Published by Springer Nature
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  • 17
    Publication Date: 2018-02-23
    Description: Respiratory diseases, which are leading causes of mortality and morbidity in the world, are dysfunctions of the nasopharynx, the trachea, the bronchus, the lung and the pleural cavity. Symptoms of chronic respiratory diseases, such as cough, sneezing and difficulty breathing, may seriously affect the productivity, sleep quality and physical and mental well-being of patients, and patients with acute respiratory diseases may have difficulty breathing, anoxia and even life-threatening respiratory failure. Respiratory diseases are generally heterogeneous, with multifaceted causes including smoking, ageing, air pollution, infection and gene mutations. Clinically, a single pulmonary disease can exhibit more than one phenotype or coexist with multiple organ disorders. To correct abnormal function or repair injured respiratory tissues, one of the most promising techniques is to correct mutated genes by gene editing, as some gene mutations have been clearly demonstrated to be associated with genetic or heterogeneous respiratory diseases. Zinc finger nucleases (ZFN), transcription activator-like effector nucleases (TALEN) and clustered regulatory interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) systems are three innovative gene editing technologies developed recently. In this short review, we have summarised the structure and operating principles of the ZFNs, TALENs and CRISPR/Cas9 systems and their preclinical and clinical applications in respiratory diseases.
    Print ISSN: 0022-2593
    Electronic ISSN: 1468-6244
    Topics: Medicine
    Published by BMJ Publishing Group
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  • 18
    Publication Date: 2018-02-27
    Description: Feline immunodeficiency virus (FIV) infection in domestic cats is the smallest usable natural model for lentiviral infection studies. FLA-E*01801 was applied to FIV AIDS vaccine research. We determined the crystal structure of FLA-E*01801 complexed with a peptide derived from FIV (gag positions 40 to 48; RMANVSTGR [RMA9]). The A pocket of the FLA-E*01801 complex plays a valuable restrictive role in peptide binding. Mutation experiments and circular-dichroism (CD) spectroscopy revealed that peptides with Asp at the first position (P1) could not bind to FLA-E*01801. The crystal structure and in vitro refolding of the mutant FLA-E*01801 complex demonstrated that Glu 63 and Trp 167 in the A pocket play important roles in restricting P1D. The B pocket of the FLA-E*01801 complex accommodates M/T/A/V/I/L/S residues, whereas the negatively charged F pocket prefers R/K residues. Based on the peptide binding motif, 125 FLA-E*01801-restricted FIV nonapeptides (San Diego isolate) were identified. Our results provide the structural basis for peptide presentation by the FLA-E*01801 molecule, especially A pocket restriction on peptide binding, and identify the potential cytotoxic T lymphocyte (CTL) epitope peptides of FIV presented by FLA-E*01801. These results will benefit both the reasonable design of FLA-E*01801-restricted CTL epitopes and the further development of the AIDS vaccine. IMPORTANCE Feline immunodeficiency virus (FIV) is a viral pathogen in cats, and this infection is the smallest usable natural model for lentivirus infection studies. To examine how FLA I presents FIV epitope peptides, we crystallized and solved the first classic feline major histocompatibility complex class I (MHC-I) molecular structure. Surprisingly, pocket A restricts peptide binding. Trp 167 blocks the left side of pocket A, causing P1D to conflict with Glu 63 . We also identified the FLA-E*01801 binding motif X (except D)-(M/T/A/V/I/L/S)-X-X-X-X-X-X-(R/K) based on structural and biochemical experiments. We identified 125 FLA-E*01801-restricted nonapeptides from FIV. These results are valuable for developing peptide-based FIV and human immunodeficiency virus (HIV) vaccines and for studying how MHC-I molecules present peptides.
    Print ISSN: 0022-538X
    Electronic ISSN: 1098-5514
    Topics: Medicine
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  • 19
    Publication Date: 2014-10-11
    Description: Cycloaddition is an essential tool in chemical synthesis. Instead of using light or heat as a driving force, marine sponges promote cycloaddition with a more versatile but poorly understood mechanism in producing pyrrole-imidazole alkaloids sceptrin, massadine, and ageliferin. Through de novo synthesis of sceptrin and massadine, we show that sponges may use single-electron oxidation as a central mechanism to promote three different types of cycloaddition. Additionally, we provide surprising evidence that, in contrast to previous reports, sceptrin, massadine, and ageliferin have mismatched chirality. Therefore, massadine cannot be an oxidative rearrangement product of sceptrin or ageliferin, as is commonly believed. Taken together, our results demonstrate unconventional chemical approaches to achieving cycloaddition reactions in synthesis and uncover enantiodivergence as a new biosynthetic paradigm for natural products.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4205478/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4205478/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ma, Zhiqiang -- Wang, Xiaolei -- Wang, Xiao -- Rodriguez, Rodrigo A -- Moore, Curtis E -- Gao, Shuanhu -- Tan, Xianghui -- Ma, Yuyong -- Rheingold, Arnold L -- Baran, Phil S -- Chen, Chuo -- R01 GM073949/GM/NIGMS NIH HHS/ -- R01 GM079554/GM/NIGMS NIH HHS/ -- R01-GM073949/GM/NIGMS NIH HHS/ -- R01-GM079554/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2014 Oct 10;346(6206):219-24. doi: 10.1126/science.1255677.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. ; Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA. ; Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093, USA. ; Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. chuo.chen@utsouthwestern.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25301624" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biosynthetic Pathways ; *Cycloaddition Reaction ; Molecular Structure ; Porifera/*metabolism ; Pyrroles/*chemical synthesis/chemistry/metabolism ; Stereoisomerism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 20
    Publication Date: 2015-07-15
    Description: Sherman et al. commented on the precedence of enantiodivergence, listing a number of congeneric natural products with opposite chirality. However, these "congeners" are not derived from enantiodivergent biosyntheses. Instead, they are antipodes arising from separate enantiomeric biosyntheses. A distinct feature of the biosynthesis of the cyclic pyrrole-imidazole dimers is the production of antipodal congeners without the corresponding enantiomers.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4536548/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4536548/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ma, Zhiqiang -- Wang, Xiaolei -- Wang, Xiao -- Rodriguez, Rodrigo A -- Moore, Curtis E -- Gao, Shuanhu -- Tan, Xianghui -- Ma, Yuyong -- Rheingold, Arnold L -- Baran, Phil S -- Chen, Chuo -- R01 GM073949/GM/NIGMS NIH HHS/ -- R01 GM079554/GM/NIGMS NIH HHS/ -- R01-GM073949/GM/NIGMS NIH HHS/ -- R01-GM079554/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Jul 10;349(6244):149. doi: 10.1126/science.aaa9626. Epub 2015 Jul 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. chuo.chen@utsouthwestern.edu. ; Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. ; Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA. ; Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26160939" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Cycloaddition Reaction ; Porifera/*metabolism ; Pyrroles/*chemical synthesis
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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