The Experts below are selected from a list of 252 Experts worldwide ranked by ideXlab platform
Yoke Fun Chan - One of the best experts on this subject based on the ideXlab platform.
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Rosmarinic acid exhibits broad anti-enterovirus A71 activity by inhibiting the interaction between the five-Fold Axis of capsid VP1 and cognate sulfated receptors
Emerging microbes & infections, 2020Co-Authors: Chung-fan Hsieh, Jia-rong Jheng, Guan-hua Lin, Yu-li Chen, Chien-jou Liu, Kuei-yang Hsu, Yuan-siao Chen, Yoke Fun ChanAbstract:Enterovirus A71 (EV-A71), a positive-stranded RNA virus of the Picornaviridae family, may cause neurological complications or fatality in children. We examined specific factors responsible for this virulence using a chemical genetics approach. Known compounds from an anti-EV-A71 herbal medicine, Salvia miltiorrhiza (Danshen), were screened for anti-EV-A71. We identified a natural product, rosmarinic acid (RA), as a potential inhibitor of EV-A71 by cell-based antiviral assay and in vivo mouse model. Results also show that RA may affect the early stage of viral infection and may target viral particles directly, thereby interfering with virus-P-selectin glycoprotein ligand-1 (PSGL1) and virus-heparan sulfate interactions without abolishing the interaction between the virus and scavenger receptor B2 (SCARB2). Sequencing of the plaque-purified RA-resistant viruses revealed a N104K mutation in the five-Fold Axis of the structural protein VP1, which contains positively charged amino acids reportedly associated with virus-PSGL1 and virus-heparan sulfate interactions via electrostatic attraction. The plasmid-derived recombinant virus harbouring this mutation was confirmed to be refractory to RA inhibition. Receptor pull-down showed that this non-positively charged VP1-N104 is critical for virus binding to heparan sulfate. As the VP1-N104 residue is conserved among different EV-A71 strains, RA may be useful for inhibiting EV-A71 infection, even for emergent virus variants. Our study provides insight into the molecular mechanism of virus-host interactions and identifies a promising new class of inhibitors based on its antiviral activity and broad spectrum effects against a range of EV-A71.
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VP1 residues around the five-Fold Axis of enterovirus A71 mediate heparan sulfate interaction
Virology, 2016Co-Authors: Chee Wah Tan, I-ching Sam, Vannajan Sanghiran Lee, Hui Vern Wong, Yoke Fun ChanAbstract:Enterovirus A71 (EV-A71) is a neurotropic enterovirus that uses heparan sulfate as an attachment receptor. The molecular determinants of EV-A71-heparan sulfate interaction are unknown. With In silico heparin docking and mutagenesis of all possible lysine residues in VP1, we identified that K162, K242 and K244 are responsible for heparin interaction and inhibition. EV-A71 mutants with K242A and K244A rapidly acquired compensatory mutations, T100K or E98A, and Q145R-T237N respectively, which restored the heparin-binding phenotype. Both VP1-98 and VP1-145 modulates heparin binding. Heparin-binding phenotype was completely abolished with VP1-E98-E145, but was restored by an E98K or E145Q substitution. During cell culture adaptation, EV-A71 rapidly acquired K98 or Q/G145 to restore the heparin-binding phenotype. Together with next-generation sequencing analysis, our results implied that EV-A71 has high genetic plasticity by modulating positively-charged residues at the five-Fold Axis during in vitro heparin adaptation. Our finding has impact on EV-A71 vaccine production, evolutionary studies and pathogenesis.
Jiashi Yang - One of the best experts on this subject based on the ideXlab platform.
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Thickness vibration of piezoelectric plates of 6 mm crystals with tilted six-Fold Axis and two-layered thick electrodes
Ultrasonics, 2008Co-Authors: Kai Xian, Ji Wang, Jiashi YangAbstract:We perform a theoretical analysis of thickness vibrations in piezoelectric plates of crystals with 6mm symmetry. The six-Fold Axis is tilted with respect to the plate surfaces. The major surfaces of the plate are covered with two layers of electrodes of different metals. The equations of linear piezoelectricity are used for the crystal plate. The electrodes are modeled by the equations of elasticity. Thickness vibrations frequencies and modes as well as impedance are calculated and examined.
I-ching Sam - One of the best experts on this subject based on the ideXlab platform.
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Electrostatic interactions at the five-Fold Axis alter heparin-binding phenotype and drive enterovirus A71 virulence in mice.
PLoS pathogens, 2019Co-Authors: Han Kang Tee, Chee Wah Tan, Vannajan Sanghiran Lee, Thinesshwary Yogarajah, Michelle Hui Pheng Lee, Hann Juang Chai, Nur Aziah Hanapi, Siti R. Yusof, Kien Chai Ong, I-ching SamAbstract:Enterovirus A71 (EV-A71) causes hand, foot and mouth disease epidemics with neurological complications and fatalities. However, the neuropathogenesis of EV-A71 remains poorly understood. In mice, adaptation and virulence determinants have been mapped to mutations at VP2-149, VP1-145 and VP1-244. We investigate how these amino acids alter heparin-binding phenotype and shapes EV-A71 virulence in one-day old mice. We constructed six viruses with varying residues at VP1-98, VP1-145 (which are both heparin-binding determinants) and VP2-149 (based on the wild type 149K/98E/145Q, termed KEQ) to generate KKQ, KKE, KEE, IEE and IEQ variants. We demonstrated that the weak heparin-binder IEE was highly lethal in mice. The initially strong heparin-binding IEQ variant acquired an additional mutation VP1-K244E, which confers weak heparin-binding phenotype resulting in elevated viremia and increased virus antigens in mice brain, with subsequent high virulence. IEE and IEQ-244E variants inoculated into mice disseminated efficiently and displayed high viremia. Increasing polymerase fidelity and impairing recombination of IEQ attenuated the virulence, suggesting the importance of population diversity in EV-A71 pathogenesis in vivo. Combining in silico docking and deep sequencing approaches, we inferred that virus population diversity is shaped by electrostatic interactions at the five-Fold Axis of the virus surface. Electrostatic surface charges facilitate virus adaptation by generating poor heparin-binding variants for better in vivo dissemination in mice, likely due to reduced adsorption to heparin-rich peripheral tissues, which ultimately results in increased neurovirulence. The dynamic switching between heparin-binding and weak heparin-binding phenotype in vivo explained the neurovirulence of EV-A71.
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Electrostatic interactions at the five-Fold Axis alter heparin-binding phenotype and drive EV-A71 virulence in mice
2019Co-Authors: Han Kang Tee, Chee Wah Tan, Vannajan Sanghiran Lee, Thinesshwary Yogarajah, Michelle Hui Pheng Lee, Hann Juang Chai, Nur Aziah Hanapi, Siti R. Yusof, Kien Chai Ong, I-ching SamAbstract:Enterovirus A71 (EV-A71) causes hand, foot and mouth disease epidemics with neurological complications and fatalities. However, the neuropathogenesis of EV-A71 remains poorly understood. In mice, adaptation and virulence determinants have been mapped to mutations at VP1-145, VP1-244 and VP2-149. We constructed six viruses with varying residues at VP1-98, VP1-145 (which are both heparin-binding determinants) and VP2-149 (based on the wild type 98E/145Q/149K, termed EQK) to generate KQK, KEK, EEK, EEI and EQI variants. We hypothesize that heparin-binding phenotype shapes EV-A71 virulence in mice. We demonstrated that the weak heparin-binder EEI was highly lethal in mice. The initially strong heparin-binding EQI variant acquired an additional mutation VP1-K244E, which confers weak heparin-binding phenotype resulting in elevated viremia and increased brain inflammation and virus antigens in mice, with subsequent high virulence. EEI and EQI-K244E variants inoculated into mice disseminated efficiently and displayed high viremia. Increasing polymerase fidelity and impairing recombination of EQI attenuated virulence, suggesting the importance of population diversity in EV-A71 pathogenesis in vivo. Combining in silico docking and deep sequencing approaches, we inferred that virus population diversity is shaped by electrostatic interactions at the five-Fold Axis of the virus surface. Electrostatic surface charges facilitate virus adaptation by generating poor heparin-binding variants for better in vivo dissemination in mice, likely due to reduced adsorption to heparin-rich peripheral tissues, which ultimately results in increased neurovirulence. The dynamic switching from heparin-binding to weak heparin-binding phenotype in vivo explained the neurovirulence of EV-A71.
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VP1 residues around the five-Fold Axis of enterovirus A71 mediate heparan sulfate interaction
Virology, 2016Co-Authors: Chee Wah Tan, I-ching Sam, Vannajan Sanghiran Lee, Hui Vern Wong, Yoke Fun ChanAbstract:Enterovirus A71 (EV-A71) is a neurotropic enterovirus that uses heparan sulfate as an attachment receptor. The molecular determinants of EV-A71-heparan sulfate interaction are unknown. With In silico heparin docking and mutagenesis of all possible lysine residues in VP1, we identified that K162, K242 and K244 are responsible for heparin interaction and inhibition. EV-A71 mutants with K242A and K244A rapidly acquired compensatory mutations, T100K or E98A, and Q145R-T237N respectively, which restored the heparin-binding phenotype. Both VP1-98 and VP1-145 modulates heparin binding. Heparin-binding phenotype was completely abolished with VP1-E98-E145, but was restored by an E98K or E145Q substitution. During cell culture adaptation, EV-A71 rapidly acquired K98 or Q/G145 to restore the heparin-binding phenotype. Together with next-generation sequencing analysis, our results implied that EV-A71 has high genetic plasticity by modulating positively-charged residues at the five-Fold Axis during in vitro heparin adaptation. Our finding has impact on EV-A71 vaccine production, evolutionary studies and pathogenesis.
Chee Wah Tan - One of the best experts on this subject based on the ideXlab platform.
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Electrostatic interactions at the five-Fold Axis alter heparin-binding phenotype and drive enterovirus A71 virulence in mice.
PLoS pathogens, 2019Co-Authors: Han Kang Tee, Chee Wah Tan, Vannajan Sanghiran Lee, Thinesshwary Yogarajah, Michelle Hui Pheng Lee, Hann Juang Chai, Nur Aziah Hanapi, Siti R. Yusof, Kien Chai Ong, I-ching SamAbstract:Enterovirus A71 (EV-A71) causes hand, foot and mouth disease epidemics with neurological complications and fatalities. However, the neuropathogenesis of EV-A71 remains poorly understood. In mice, adaptation and virulence determinants have been mapped to mutations at VP2-149, VP1-145 and VP1-244. We investigate how these amino acids alter heparin-binding phenotype and shapes EV-A71 virulence in one-day old mice. We constructed six viruses with varying residues at VP1-98, VP1-145 (which are both heparin-binding determinants) and VP2-149 (based on the wild type 149K/98E/145Q, termed KEQ) to generate KKQ, KKE, KEE, IEE and IEQ variants. We demonstrated that the weak heparin-binder IEE was highly lethal in mice. The initially strong heparin-binding IEQ variant acquired an additional mutation VP1-K244E, which confers weak heparin-binding phenotype resulting in elevated viremia and increased virus antigens in mice brain, with subsequent high virulence. IEE and IEQ-244E variants inoculated into mice disseminated efficiently and displayed high viremia. Increasing polymerase fidelity and impairing recombination of IEQ attenuated the virulence, suggesting the importance of population diversity in EV-A71 pathogenesis in vivo. Combining in silico docking and deep sequencing approaches, we inferred that virus population diversity is shaped by electrostatic interactions at the five-Fold Axis of the virus surface. Electrostatic surface charges facilitate virus adaptation by generating poor heparin-binding variants for better in vivo dissemination in mice, likely due to reduced adsorption to heparin-rich peripheral tissues, which ultimately results in increased neurovirulence. The dynamic switching between heparin-binding and weak heparin-binding phenotype in vivo explained the neurovirulence of EV-A71.
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Electrostatic interactions at the five-Fold Axis alter heparin-binding phenotype and drive EV-A71 virulence in mice
2019Co-Authors: Han Kang Tee, Chee Wah Tan, Vannajan Sanghiran Lee, Thinesshwary Yogarajah, Michelle Hui Pheng Lee, Hann Juang Chai, Nur Aziah Hanapi, Siti R. Yusof, Kien Chai Ong, I-ching SamAbstract:Enterovirus A71 (EV-A71) causes hand, foot and mouth disease epidemics with neurological complications and fatalities. However, the neuropathogenesis of EV-A71 remains poorly understood. In mice, adaptation and virulence determinants have been mapped to mutations at VP1-145, VP1-244 and VP2-149. We constructed six viruses with varying residues at VP1-98, VP1-145 (which are both heparin-binding determinants) and VP2-149 (based on the wild type 98E/145Q/149K, termed EQK) to generate KQK, KEK, EEK, EEI and EQI variants. We hypothesize that heparin-binding phenotype shapes EV-A71 virulence in mice. We demonstrated that the weak heparin-binder EEI was highly lethal in mice. The initially strong heparin-binding EQI variant acquired an additional mutation VP1-K244E, which confers weak heparin-binding phenotype resulting in elevated viremia and increased brain inflammation and virus antigens in mice, with subsequent high virulence. EEI and EQI-K244E variants inoculated into mice disseminated efficiently and displayed high viremia. Increasing polymerase fidelity and impairing recombination of EQI attenuated virulence, suggesting the importance of population diversity in EV-A71 pathogenesis in vivo. Combining in silico docking and deep sequencing approaches, we inferred that virus population diversity is shaped by electrostatic interactions at the five-Fold Axis of the virus surface. Electrostatic surface charges facilitate virus adaptation by generating poor heparin-binding variants for better in vivo dissemination in mice, likely due to reduced adsorption to heparin-rich peripheral tissues, which ultimately results in increased neurovirulence. The dynamic switching from heparin-binding to weak heparin-binding phenotype in vivo explained the neurovirulence of EV-A71.
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VP1 residues around the five-Fold Axis of enterovirus A71 mediate heparan sulfate interaction
Virology, 2016Co-Authors: Chee Wah Tan, I-ching Sam, Vannajan Sanghiran Lee, Hui Vern Wong, Yoke Fun ChanAbstract:Enterovirus A71 (EV-A71) is a neurotropic enterovirus that uses heparan sulfate as an attachment receptor. The molecular determinants of EV-A71-heparan sulfate interaction are unknown. With In silico heparin docking and mutagenesis of all possible lysine residues in VP1, we identified that K162, K242 and K244 are responsible for heparin interaction and inhibition. EV-A71 mutants with K242A and K244A rapidly acquired compensatory mutations, T100K or E98A, and Q145R-T237N respectively, which restored the heparin-binding phenotype. Both VP1-98 and VP1-145 modulates heparin binding. Heparin-binding phenotype was completely abolished with VP1-E98-E145, but was restored by an E98K or E145Q substitution. During cell culture adaptation, EV-A71 rapidly acquired K98 or Q/G145 to restore the heparin-binding phenotype. Together with next-generation sequencing analysis, our results implied that EV-A71 has high genetic plasticity by modulating positively-charged residues at the five-Fold Axis during in vitro heparin adaptation. Our finding has impact on EV-A71 vaccine production, evolutionary studies and pathogenesis.
Kai Xian - One of the best experts on this subject based on the ideXlab platform.
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Thickness vibration of piezoelectric plates of 6 mm crystals with tilted six-Fold Axis and two-layered thick electrodes
Ultrasonics, 2008Co-Authors: Kai Xian, Ji Wang, Jiashi YangAbstract:We perform a theoretical analysis of thickness vibrations in piezoelectric plates of crystals with 6mm symmetry. The six-Fold Axis is tilted with respect to the plate surfaces. The major surfaces of the plate are covered with two layers of electrodes of different metals. The equations of linear piezoelectricity are used for the crystal plate. The electrodes are modeled by the equations of elasticity. Thickness vibrations frequencies and modes as well as impedance are calculated and examined.