Currently,human health due to corona virus disease 2019(COVID-19)pandemic has been seriously threatened.The coronavirus severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)spike(S)protein plays a crucial role i...Currently,human health due to corona virus disease 2019(COVID-19)pandemic has been seriously threatened.The coronavirus severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)spike(S)protein plays a crucial role in virus transmission and several S-based therapeutic approaches have been approved for the treatment of COVID-19.However,the efficacy is compromised by the SARS-CoV-2 evolvement and mutation.Here we report the SARS-CoV-2 S protein receptor-binding domain(RBD)inhibitor licorice-saponin A3(A3)could widely inhibit RBD of SARS-CoV-2 variants,including Beta,Delta,and Omicron BA.1,XBB and BQ1.1.Furthermore,A3 could potently inhibit SARS-CoV-2 Omicron virus in Vero E6 cells,with EC50 of 1.016μM.The mechanism was related to binding with Y453 of RBD determined by hydrogen-deuterium exchange mass spectrometry(HDX-MS)analysis combined with quantum mechanics/molecular mechanics(QM/MM)simulations.Interestingly,phosphoproteomics analysis and multi fluorescent immunohistochemistry(mIHC)respectively indicated that A3 also inhibits host inflammation by directly modulating the JNK and p38 mitogen-activated protein kinase(MAPK)pathways and rebalancing the corresponding immune dysregulation.This work supports A3 as a promising broad-spectrum small molecule drug candidate for COVID-19.展开更多
Obesity,caused by excessive energy,leads to body weight gain and various diseases,including cognitive impairment.Current studies suggest that diet restriction such as optimal fasting and regular exercise are crucial f...Obesity,caused by excessive energy,leads to body weight gain and various diseases,including cognitive impairment.Current studies suggest that diet restriction such as optimal fasting and regular exercise are crucial for improving cognitive capacity.However,further exploration is needed to understand the specific mechanisms of high fat diet(HFD)-induced cognitive decline in obesity.In the present study,4-month-old mice were subjected to HFD feeding for 18 weeks,followed by aerobic exercise and high-intensity intermittent exercise,regular diet feeding,and intermittent fasting for 8 weeks,and then used to evaluate cognitive capacity,inflammation,compromised insulin signaling pathway,and apoptosis in hippocampal tissue,as well as AMPK/SIRT1 and TLR4 signal pathways.Obese mice revealed impaired cognitive capacity as compared with mice fed with regular diets.In contrast,aerobic exercise,high-intensity intermittent exercise,regular diet,and intermittent fasting could inhibit apoptosis caused by inflammation-mediated compromised insulin signaling pathway in hippocampal tissues through activating the AMPK/SIRT1 signal pathway and suppressing the TLR4 signal pathway,thereby rescuing the cognitive impairment of obese mice.Therefore,diet restriction and exercise interventions may play a positive role in reverting obesity-induced cognitive impairment.展开更多
Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus closely related to the human pathogens including yellow fever virus, dengue virus and West Nile virus. There are currently no effective antiviral therap...Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus closely related to the human pathogens including yellow fever virus, dengue virus and West Nile virus. There are currently no effective antiviral therapies for all of the flavivirus and only a few highly effective vaccines are licensed for human use. In this paper, the E protein domain III (DIII) of six heterologous flaviviruses (DENV1-4, WNV and JEV) was expressed in Escherichia coli successfully. The proteins were purified after a solubilization and refolding procedure, characterized by SDS-PAGE and Western blotting. Competitive inhibition showed that all recombinant flavivirus DIII proteins blocked the entry of JEV into BHK-21 cells. Further studies indicated that antibodies induced by the soluble recombinant flavivirus DIII partially protected mice against lethal JEV challenge. These results demonstrated that recombinant flavivirus DIII proteins could inhibit JEV infection competitively, and immunization with proper folding flavivirus DIII induced cross-protection against JEV infection in mice, implying a possible role of DIII for the cross-protection among flavivirus as well as its use in antigens for immunization in animal models.展开更多
Rodents have been widely used in the production of cerebral ischemia models. However, successful therapies have been proven on experimental rodent stroke model, and they have often failed to be effective when tested c...Rodents have been widely used in the production of cerebral ischemia models. However, successful therapies have been proven on experimental rodent stroke model, and they have often failed to be effective when tested clinically. Therefore, nonhuman primates were recommended as the ideal alternatives, owing to their similarities with the human cerebrovascular system, brain metabolism, grey to white matter ratio and even their rich behavioral repertoire. The present review is a thorough summary of ten methods that establish nonhuman primate models of focal cerebral ischemia; electrocoagulation, endothelin-1-induced occlusion, microvascular clip occlusion, autologous blood clot embolization, balloon inflation, microcatheter embolization, coil embolization, surgical suture embolization, suture, and photochemical induction methods. This review addresses the advantages and disadvantages of each method, as well as precautions for each model, compared nonhuman primates with rodents, different species of nonhuman primates and different modeling methods. Finally it discusses various factors that need to be considered when modelling and the method of evaluation after modelling. These are critical for understanding their respective strengths and weaknesses and underlie the selection of the optimum model.展开更多
This paper presents a novel neural-fuzzy-based adaptive sliding mode automatic steering control strategy to improve the driving performance of vision-based unmanned electric vehicles with time-varying and uncertain pa...This paper presents a novel neural-fuzzy-based adaptive sliding mode automatic steering control strategy to improve the driving performance of vision-based unmanned electric vehicles with time-varying and uncertain parameters.Primarily,the kinematic and dynamic models which accurately express the steering behaviors of vehicles are constructed,and in which the relationship between the look-ahead time and vehicle velocity is revealed.Then,in order to overcome the external disturbances,parametric uncertainties and time-varying features of vehicles,a neural-fuzzy-based adaptive sliding mode automatic steering controller is proposed to supervise the lateral dynamic behavior of unmanned electric vehicles,which includes an equivalent control law and an adaptive variable structure control law.In this novel automatic steering control system of vehicles,a neural network system is utilized for approximating the switching control gain of variable structure control law,and a fuzzy inference system is presented to adjust the thickness of boundary layer in real-time.The stability of closed-loop neural-fuzzy-based adaptive sliding mode automatic steering control system is proven using the Lyapunov theory.Finally,the results illustrate that the presented control scheme has the excellent properties in term of error convergence and robustness.展开更多
Flaviviral NS2B is a required cofactor for NS3 serine protease activity and plays an important role in promoting functional NS2B-NS3 protease configuration and maintaining critical interactions with protease catalysis...Flaviviral NS2B is a required cofactor for NS3 serine protease activity and plays an important role in promoting functional NS2B-NS3 protease configuration and maintaining critical interactions with protease catalysis substrates. The residues D80DDG in West Nile virus (WNV) NS2B are important for protease activity. To investigate the effects of D80DDG in NS2B on protease activity and viral replication, the negatively charged region D80DD and the conserved residue G83 of NS2B were mutated (D80DD/E80EE, D80DD/K80KK, D80DD/A80AA, G83F, G83S, G83D, G83K, and G83A), and NS3 D75A was designated as the negative control. The effects of the mutations on NS2B-NS3 activity, viral translation, and viral RNA replication were analyzed using kinetic analysis of site-directed enzymes and a transient replicon assay. All substitutions resulted in significantly decreased enzyme activity and blocked RNA replication. The negative charge of D80DD is not important for maintaining NS2B function, but side chain changes in G83 have dramatic effects on protease activity and RNA replication. These results demonstrate that NS2B is important for viral replication and that D80DD and G83 substitutions prevent replication; they will be useful for understanding the relationship between NS2B and NS3.展开更多
Dengue virus(DENV) nonstructural protein 1(NS1) is a highly conserved 46-kDa protein that contains 2 glycosylation sites(Asn-130 and Asn-207) and 12 conserved cysteine(Cys) residues. Here, we performed site-directed m...Dengue virus(DENV) nonstructural protein 1(NS1) is a highly conserved 46-kDa protein that contains 2 glycosylation sites(Asn-130 and Asn-207) and 12 conserved cysteine(Cys) residues. Here, we performed site-directed mutagenesis to generate systematic mutants of viral strain TSV01. The results of the subsequent analysis showed that an alanine substitution at the second N-linked glycan Asn-207 in NS1 delayed viral RNA synthesis, reduced virus plaque size, and weakened the cytopathic effect. Three mutants at Cys sites(Cys-4, Cys-55, Cys-291) and a C-terminal deletion(ΔC) mutant significantly impaired RNA synthesis, and consequently abolished viral growth, whereas alanine mutations at Asn-130 and Glu-173 resulted in phenotypes that were similar to the wild-type(WT) virus. Further analysis showed that the Asn-207 mutation slightly delayed viral replication. These results suggest that the three conserved disulfide bonds and the second N-linked glycan in NS1 are required for DENV-2 replication.展开更多
Non-genetic mechanisms have recently emerged as important drivers of anticancer drug resistance.Among these,the drug tolerant persister(DTP)cell phenotype is attracting more and more attention and giving a predominant...Non-genetic mechanisms have recently emerged as important drivers of anticancer drug resistance.Among these,the drug tolerant persister(DTP)cell phenotype is attracting more and more attention and giving a predominant non-genetic role in cancer therapy resistance.The DTP phenotype is characterized by a quiescent or slow-cell-cycle reversible state of the cancer cell subpopulation and inert specialization to stimuli,which tolerates anticancer drug exposure to some extent through the interaction of multiple underlying mechanisms and recovering growth and proliferation after drug withdrawal,ultimately leading to treatment resistance and cancer recurrence.Therefore,targeting DTP cells is anticipated to provide new treatment opportunities for cancer patients,although our current knowledge of these DTP cells in treatment resistance remains limited.In this review,we provide a comprehensive overview of the formation characteristics and underlying drug tolerant mechanisms of DTP cells,investigate the potential drugs for DTP(including preclinical drugs,novel use for old drugs,and natural products)based on different medicine models,and discuss the necessity and feasibility of anti-DTP therapy,related application forms,and future issues that will need to be addressed to advance this emerging field towards clinical applications.Nonetheless,understanding the novel functions of DTP cells may enable us to develop new more effective anticancer therapy and improve clinical outcomes for cancer patients.展开更多
Adakitic rocks are intermediate-acid magmatic rocks characterized by enrichment in light rare-earth elements,depletion in heavy rare-earth elements,positive to negligible Eu and Sr anomalies,and high La/Yb and Sr/Y ra...Adakitic rocks are intermediate-acid magmatic rocks characterized by enrichment in light rare-earth elements,depletion in heavy rare-earth elements,positive to negligible Eu and Sr anomalies,and high La/Yb and Sr/Y ratios.Cenozoic adakitic rocks generated by partial melting of subducted oceanic crust(slab)under eclogite-facies conditions(i.e.,the original definition of“adakite”)occur mainly in Pacific Rim volcanic arcs(intra-oceanic,continental,and continental-margin island arcs),whereas those generated by partial melting of thickened lower crust occur mainly in Tethyan Tibetan collisional orogens.In volcanic arcs,adakitic melts derived from the melting of subducted oceanic crust metasomatize the mantle wedge to form a unique rock suite comprising adakite-adakite-type high-Mg andesite-Piip-type high-Mg andesite-Nb-rich basalt-boninite.This suite differs from the basalt-andesite-dacite-rhyolite suite formed from mantle wedge metasomatized by fluids derived from subducted oceanic crust.Previously published data indicate that partial melting of mafic rocks can generate adakitic magmas under pressure,temperature,and hydrous conditions of 1.2-3.0 GPa,800-1000℃,and 1.5-6.0 wt.%H_(2)O,respectively,leaving residual minerals of garnet and rutile with little or no plagioclase.Cenozoic Au and Cu deposits occur proximally to adakitic rocks,with host rocks of some deposits actually being adakitic rocks.Adakitic rocks thus have important implications for both deep-Earth dynamics and Cu-Au mineralization/exploration.Although studies of Cenozoic adakitic rocks have made many important advances,there remain weaknesses in some important areas such as their tectonic settings,petrogenesis,magma sources,melt-mantle interactions of pre-Cenozoic adakitic rocks,and their relationship with the onset of plate tectonics and crustal growth.Future research directions are likely to involve(1)the generation of adakitic magmas by experimental simulations of partial melting of different types of rock(including intermediate-acid rocks)and magma fractional crystallization at different temperatures and pressures,(2)the relationship between magma reservoir evolution and the formation of adakitic rocks,(3)the tectonic setting and petrogenesis of pre-Cenozoic adakitic rocks and related geodynamic processes,(4)interactions between slab melts and the mantle wedge,(5)the formation of Archean adakitic tonalite-trondhjemite-granodiorite and its link to the onset of plate tectonics and crustal growth,and(6)the relationship between the formation of adakitic rocks and metal mineralization in different tectonic settings.展开更多
In this paper,we design a friendly jammer selection scheme for the social Internet of Things(IoT).A typical social IoT is composed of a cellular network with underlaying Device-to-Device(D2D)communications.In our sche...In this paper,we design a friendly jammer selection scheme for the social Internet of Things(IoT).A typical social IoT is composed of a cellular network with underlaying Device-to-Device(D2D)communications.In our scheme,we consider signal characteristics over a physical layer and social attribute information of an application layer simultaneously.Using signal characteristics,one of the D2D gadgets is selected as a friendly jammer to improve the secrecy performance of a cellular device.In return,the selected D2D gadget is allowed to reuse spectrum resources of the cellular device.Using social relationship,we analyze and quantify the social intimacy degree among the nodes in IoT to design an adaptive communication time threshold.Applying an artificial intelligence forecasting model,we further forecast and update the intimacy degree,and then screen and filter potential devices to effectively reduce the detection and calculation costs.Finally,we propose an optimal scheme to integrate the virtual social relationship with actual communication systems.To select the optimal D2D gadget as a friendly jammer,we apply Kuhn-Munkres(KM)algorithm to solve the maximization problem of social intimacy and cooperative jamming.Comprehensive numerical results are presented to validate the performance of our scheme.展开更多
Whether arc magmatism occurs above oceanic subduction zones is the forefront of studies on convergent plate margins.The most important petrologic issue related to the evolution of arc systems is the origin of arc magm...Whether arc magmatism occurs above oceanic subduction zones is the forefront of studies on convergent plate margins.The most important petrologic issue related to the evolution of arc systems is the origin of arc magmatism,among which arc basalts are the most important one because they provide insights into mantle enrichment mechanism and crust-mantle interaction at oceanic subduction zones.Fluids or melts released either by dehydration or by melting of subducting oceanic slab infiltrate and metasomatize the overlying mantle wedge at varying depth,leading to the formation of source regions of arc basalts.Such processes make most of arc basalts commonly enriched in large ion lithosphile elements and light rare earth elements,but depleted in high-field strength elements and heavy rare earth elements.Small amounts of arc basalts are characterized by relatively high Nb contents or by Nb enrichment.Rare basalts with compositions similar to ocean island basalts or mid-ocean ridge basalt also occur in arc systems.For these peculiar rocks,it remains debated whether their source is affected by subduction-related components.During their ascent and before their eruption,arc basaltic magmas are subjected to crystal fractionation,mixing and crustal contamination.In addition to the contribution of subducting slab components to the mantle source of arc basalts,the materials above the subducting slab at forearc depths would have been transported either by drag or by subduction erosion into the subarc mantle and into the source of arc magmas.Heats and materials brought by corner flows also play important roles in the generation of arc basalts.Despite the important progresses made in recent studies of arc basalts,further efforts are needed to investigate subarc mantle metasomatism,material recycling,the formation of arc magma sources,geodynamic mechanism in generating arc basalts,and their implicationd s for the initiation of plate tectonics on Earth.展开更多
Small non-coding RNAs(sRNAs)have received much attention in recent years due to their unique biological properties,which can efficiently and specifically tune target gene expressions in bacteria.Inspired by natural sR...Small non-coding RNAs(sRNAs)have received much attention in recent years due to their unique biological properties,which can efficiently and specifically tune target gene expressions in bacteria.Inspired by natural sRNAs,recent works have proposed the use of artificial sRNAs(asRNAs)as genetic tools to regulate desired gene that has been applied in several fields,such as metabolic engineering and bacterial physiology studies.However,the rational design of asRNAs is still a challenge.In this study,we proposed structure and length as two criteria to implement rational visualized and precise design of asRNAs.T7 expression system was one of the most useful recombinant protein expression systems.However,it was deeply limited by the formation of inclusion body.To settle this problem,we designed a series of asRNAs to inhibit the T7 RNA polymerase(Gene1)expression to balance the rate between transcription and folding of recombinant protein.Based on the heterologous expression of Aspergillus oryzae Li-3 glucuronidase in E.coli,the asRNA-antigene1-17bp can effectively decrease the inclusion body and increase the enzyme activity by 169.9%.展开更多
基金supported by National Natural Science Foundation of China(Grant Nos.:81891010/81891011,81725023,82003614,82173950,31770192,32070187,32161133003 and 82003681)China Postdoctoral Science Foundation(Grant No:2022T150029).
文摘Currently,human health due to corona virus disease 2019(COVID-19)pandemic has been seriously threatened.The coronavirus severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)spike(S)protein plays a crucial role in virus transmission and several S-based therapeutic approaches have been approved for the treatment of COVID-19.However,the efficacy is compromised by the SARS-CoV-2 evolvement and mutation.Here we report the SARS-CoV-2 S protein receptor-binding domain(RBD)inhibitor licorice-saponin A3(A3)could widely inhibit RBD of SARS-CoV-2 variants,including Beta,Delta,and Omicron BA.1,XBB and BQ1.1.Furthermore,A3 could potently inhibit SARS-CoV-2 Omicron virus in Vero E6 cells,with EC50 of 1.016μM.The mechanism was related to binding with Y453 of RBD determined by hydrogen-deuterium exchange mass spectrometry(HDX-MS)analysis combined with quantum mechanics/molecular mechanics(QM/MM)simulations.Interestingly,phosphoproteomics analysis and multi fluorescent immunohistochemistry(mIHC)respectively indicated that A3 also inhibits host inflammation by directly modulating the JNK and p38 mitogen-activated protein kinase(MAPK)pathways and rebalancing the corresponding immune dysregulation.This work supports A3 as a promising broad-spectrum small molecule drug candidate for COVID-19.
基金supported by the National Natural Science Foundation of China(32471186,31771318)the 14th Five-Year-Plan Advantageous and Characteristic Disciplines(Groups)of Colleges and Universities in Hubei Province for Exercise and Brain Science from Hubei Provincial Department of Education,and the Leading Talent Program Foundation from Wuhan Sports University to Ning Chen+3 种基金and the National Natural Science Foundation of China(81701391)the Natural Science Foundation of Hubei Province(2023AFB700)Key Project of Scientific Research of Education Department of Hubei Province(D20234101)Young and Middle aged Scientific Research Team Project of Wuhan Sports University(21KT08)to Jingjing Fan.
文摘Obesity,caused by excessive energy,leads to body weight gain and various diseases,including cognitive impairment.Current studies suggest that diet restriction such as optimal fasting and regular exercise are crucial for improving cognitive capacity.However,further exploration is needed to understand the specific mechanisms of high fat diet(HFD)-induced cognitive decline in obesity.In the present study,4-month-old mice were subjected to HFD feeding for 18 weeks,followed by aerobic exercise and high-intensity intermittent exercise,regular diet feeding,and intermittent fasting for 8 weeks,and then used to evaluate cognitive capacity,inflammation,compromised insulin signaling pathway,and apoptosis in hippocampal tissue,as well as AMPK/SIRT1 and TLR4 signal pathways.Obese mice revealed impaired cognitive capacity as compared with mice fed with regular diets.In contrast,aerobic exercise,high-intensity intermittent exercise,regular diet,and intermittent fasting could inhibit apoptosis caused by inflammation-mediated compromised insulin signaling pathway in hippocampal tissues through activating the AMPK/SIRT1 signal pathway and suppressing the TLR4 signal pathway,thereby rescuing the cognitive impairment of obese mice.Therefore,diet restriction and exercise interventions may play a positive role in reverting obesity-induced cognitive impairment.
基金supported by Important National Science & Technology Specific Projects (2012ZX10004403, 2012ZX10004219)National Natural Scientific Fund of China (81072675)
文摘Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus closely related to the human pathogens including yellow fever virus, dengue virus and West Nile virus. There are currently no effective antiviral therapies for all of the flavivirus and only a few highly effective vaccines are licensed for human use. In this paper, the E protein domain III (DIII) of six heterologous flaviviruses (DENV1-4, WNV and JEV) was expressed in Escherichia coli successfully. The proteins were purified after a solubilization and refolding procedure, characterized by SDS-PAGE and Western blotting. Competitive inhibition showed that all recombinant flavivirus DIII proteins blocked the entry of JEV into BHK-21 cells. Further studies indicated that antibodies induced by the soluble recombinant flavivirus DIII partially protected mice against lethal JEV challenge. These results demonstrated that recombinant flavivirus DIII proteins could inhibit JEV infection competitively, and immunization with proper folding flavivirus DIII induced cross-protection against JEV infection in mice, implying a possible role of DIII for the cross-protection among flavivirus as well as its use in antigens for immunization in animal models.
基金supported by the National Natural Science Foundation of China,No.81000852 and 81301677the AHA Award,No.17POST32530004+1 种基金the Supporting Project of Science & Technology of Sichuan Province of China,No.2012SZ0140the Research Foundation of Zhejiang Province of China,No.201022896
文摘Rodents have been widely used in the production of cerebral ischemia models. However, successful therapies have been proven on experimental rodent stroke model, and they have often failed to be effective when tested clinically. Therefore, nonhuman primates were recommended as the ideal alternatives, owing to their similarities with the human cerebrovascular system, brain metabolism, grey to white matter ratio and even their rich behavioral repertoire. The present review is a thorough summary of ten methods that establish nonhuman primate models of focal cerebral ischemia; electrocoagulation, endothelin-1-induced occlusion, microvascular clip occlusion, autologous blood clot embolization, balloon inflation, microcatheter embolization, coil embolization, surgical suture embolization, suture, and photochemical induction methods. This review addresses the advantages and disadvantages of each method, as well as precautions for each model, compared nonhuman primates with rodents, different species of nonhuman primates and different modeling methods. Finally it discusses various factors that need to be considered when modelling and the method of evaluation after modelling. These are critical for understanding their respective strengths and weaknesses and underlie the selection of the optimum model.
基金Supported by National Basic Research Project of China(Grant No.2016YFB0100900)National Natural Science Foundation of China(Grant No.61803319)+2 种基金Shenzhen Municipal Science and Technology Projects of China(Grant No.JCYJ20180306172720364)Fundamental Research Funds for the Central Universities of China(Grant No.20720190015)State Key Laboratory of Automotive Safety and Energy of China(Grant No.KF2011).
文摘This paper presents a novel neural-fuzzy-based adaptive sliding mode automatic steering control strategy to improve the driving performance of vision-based unmanned electric vehicles with time-varying and uncertain parameters.Primarily,the kinematic and dynamic models which accurately express the steering behaviors of vehicles are constructed,and in which the relationship between the look-ahead time and vehicle velocity is revealed.Then,in order to overcome the external disturbances,parametric uncertainties and time-varying features of vehicles,a neural-fuzzy-based adaptive sliding mode automatic steering controller is proposed to supervise the lateral dynamic behavior of unmanned electric vehicles,which includes an equivalent control law and an adaptive variable structure control law.In this novel automatic steering control system of vehicles,a neural network system is utilized for approximating the switching control gain of variable structure control law,and a fuzzy inference system is presented to adjust the thickness of boundary layer in real-time.The stability of closed-loop neural-fuzzy-based adaptive sliding mode automatic steering control system is proven using the Lyapunov theory.Finally,the results illustrate that the presented control scheme has the excellent properties in term of error convergence and robustness.
基金Supported by Important National Science& Technology Specific Projects (2012ZX10004403,2012ZX10004219)
文摘Flaviviral NS2B is a required cofactor for NS3 serine protease activity and plays an important role in promoting functional NS2B-NS3 protease configuration and maintaining critical interactions with protease catalysis substrates. The residues D80DDG in West Nile virus (WNV) NS2B are important for protease activity. To investigate the effects of D80DDG in NS2B on protease activity and viral replication, the negatively charged region D80DD and the conserved residue G83 of NS2B were mutated (D80DD/E80EE, D80DD/K80KK, D80DD/A80AA, G83F, G83S, G83D, G83K, and G83A), and NS3 D75A was designated as the negative control. The effects of the mutations on NS2B-NS3 activity, viral translation, and viral RNA replication were analyzed using kinetic analysis of site-directed enzymes and a transient replicon assay. All substitutions resulted in significantly decreased enzyme activity and blocked RNA replication. The negative charge of D80DD is not important for maintaining NS2B function, but side chain changes in G83 have dramatic effects on protease activity and RNA replication. These results demonstrate that NS2B is important for viral replication and that D80DD and G83 substitutions prevent replication; they will be useful for understanding the relationship between NS2B and NS3.
基金supported by Important National Science & Technology Specific Projects (2012ZX10004219, 2012ZX10004403)the National Natural Scientific Fund of China (81072675)the Wuhan Key Laboratory on Emerging Infectious Diseases and Biosafety
文摘Dengue virus(DENV) nonstructural protein 1(NS1) is a highly conserved 46-kDa protein that contains 2 glycosylation sites(Asn-130 and Asn-207) and 12 conserved cysteine(Cys) residues. Here, we performed site-directed mutagenesis to generate systematic mutants of viral strain TSV01. The results of the subsequent analysis showed that an alanine substitution at the second N-linked glycan Asn-207 in NS1 delayed viral RNA synthesis, reduced virus plaque size, and weakened the cytopathic effect. Three mutants at Cys sites(Cys-4, Cys-55, Cys-291) and a C-terminal deletion(ΔC) mutant significantly impaired RNA synthesis, and consequently abolished viral growth, whereas alanine mutations at Asn-130 and Glu-173 resulted in phenotypes that were similar to the wild-type(WT) virus. Further analysis showed that the Asn-207 mutation slightly delayed viral replication. These results suggest that the three conserved disulfide bonds and the second N-linked glycan in NS1 are required for DENV-2 replication.
文摘Non-genetic mechanisms have recently emerged as important drivers of anticancer drug resistance.Among these,the drug tolerant persister(DTP)cell phenotype is attracting more and more attention and giving a predominant non-genetic role in cancer therapy resistance.The DTP phenotype is characterized by a quiescent or slow-cell-cycle reversible state of the cancer cell subpopulation and inert specialization to stimuli,which tolerates anticancer drug exposure to some extent through the interaction of multiple underlying mechanisms and recovering growth and proliferation after drug withdrawal,ultimately leading to treatment resistance and cancer recurrence.Therefore,targeting DTP cells is anticipated to provide new treatment opportunities for cancer patients,although our current knowledge of these DTP cells in treatment resistance remains limited.In this review,we provide a comprehensive overview of the formation characteristics and underlying drug tolerant mechanisms of DTP cells,investigate the potential drugs for DTP(including preclinical drugs,novel use for old drugs,and natural products)based on different medicine models,and discuss the necessity and feasibility of anti-DTP therapy,related application forms,and future issues that will need to be addressed to advance this emerging field towards clinical applications.Nonetheless,understanding the novel functions of DTP cells may enable us to develop new more effective anticancer therapy and improve clinical outcomes for cancer patients.
基金the National Natural Science Foundation of China(Grant Nos.41630208 and 91855215)the Second Tibetan Plateau Scientific Expedition and Research Program(STEP)(Grant No.2019QZKK0702)+2 种基金the National Key R&D Program of China(Grant No.2016YFC0600407)the Strategic Priority Research Program(A)of the Chinese Academy of Sciences(Grant No.XDA2007030402),the Key Program of the Chinese Academy of Sciences(Grant No.QYZDJ-SSWDQC026)the Key Program of Guangzhou City(Grant No.201707020032).
文摘Adakitic rocks are intermediate-acid magmatic rocks characterized by enrichment in light rare-earth elements,depletion in heavy rare-earth elements,positive to negligible Eu and Sr anomalies,and high La/Yb and Sr/Y ratios.Cenozoic adakitic rocks generated by partial melting of subducted oceanic crust(slab)under eclogite-facies conditions(i.e.,the original definition of“adakite”)occur mainly in Pacific Rim volcanic arcs(intra-oceanic,continental,and continental-margin island arcs),whereas those generated by partial melting of thickened lower crust occur mainly in Tethyan Tibetan collisional orogens.In volcanic arcs,adakitic melts derived from the melting of subducted oceanic crust metasomatize the mantle wedge to form a unique rock suite comprising adakite-adakite-type high-Mg andesite-Piip-type high-Mg andesite-Nb-rich basalt-boninite.This suite differs from the basalt-andesite-dacite-rhyolite suite formed from mantle wedge metasomatized by fluids derived from subducted oceanic crust.Previously published data indicate that partial melting of mafic rocks can generate adakitic magmas under pressure,temperature,and hydrous conditions of 1.2-3.0 GPa,800-1000℃,and 1.5-6.0 wt.%H_(2)O,respectively,leaving residual minerals of garnet and rutile with little or no plagioclase.Cenozoic Au and Cu deposits occur proximally to adakitic rocks,with host rocks of some deposits actually being adakitic rocks.Adakitic rocks thus have important implications for both deep-Earth dynamics and Cu-Au mineralization/exploration.Although studies of Cenozoic adakitic rocks have made many important advances,there remain weaknesses in some important areas such as their tectonic settings,petrogenesis,magma sources,melt-mantle interactions of pre-Cenozoic adakitic rocks,and their relationship with the onset of plate tectonics and crustal growth.Future research directions are likely to involve(1)the generation of adakitic magmas by experimental simulations of partial melting of different types of rock(including intermediate-acid rocks)and magma fractional crystallization at different temperatures and pressures,(2)the relationship between magma reservoir evolution and the formation of adakitic rocks,(3)the tectonic setting and petrogenesis of pre-Cenozoic adakitic rocks and related geodynamic processes,(4)interactions between slab melts and the mantle wedge,(5)the formation of Archean adakitic tonalite-trondhjemite-granodiorite and its link to the onset of plate tectonics and crustal growth,and(6)the relationship between the formation of adakitic rocks and metal mineralization in different tectonic settings.
基金supported by the National Natural Science Foundation of China(Nos.61871023 and 61931001)Beijing Natural Science Foundation(No.4202054)。
文摘In this paper,we design a friendly jammer selection scheme for the social Internet of Things(IoT).A typical social IoT is composed of a cellular network with underlaying Device-to-Device(D2D)communications.In our scheme,we consider signal characteristics over a physical layer and social attribute information of an application layer simultaneously.Using signal characteristics,one of the D2D gadgets is selected as a friendly jammer to improve the secrecy performance of a cellular device.In return,the selected D2D gadget is allowed to reuse spectrum resources of the cellular device.Using social relationship,we analyze and quantify the social intimacy degree among the nodes in IoT to design an adaptive communication time threshold.Applying an artificial intelligence forecasting model,we further forecast and update the intimacy degree,and then screen and filter potential devices to effectively reduce the detection and calculation costs.Finally,we propose an optimal scheme to integrate the virtual social relationship with actual communication systems.To select the optimal D2D gadget as a friendly jammer,we apply Kuhn-Munkres(KM)algorithm to solve the maximization problem of social intimacy and cooperative jamming.Comprehensive numerical results are presented to validate the performance of our scheme.
基金State Ocean Bureau International Collaboration Program(Grant No.GASI-GEOGE-02)the National Natural Science Foundation of China(Grant Nos.91855215,41630208)CAS Strategy Program B(Grant No.XDB18000000).
文摘Whether arc magmatism occurs above oceanic subduction zones is the forefront of studies on convergent plate margins.The most important petrologic issue related to the evolution of arc systems is the origin of arc magmatism,among which arc basalts are the most important one because they provide insights into mantle enrichment mechanism and crust-mantle interaction at oceanic subduction zones.Fluids or melts released either by dehydration or by melting of subducting oceanic slab infiltrate and metasomatize the overlying mantle wedge at varying depth,leading to the formation of source regions of arc basalts.Such processes make most of arc basalts commonly enriched in large ion lithosphile elements and light rare earth elements,but depleted in high-field strength elements and heavy rare earth elements.Small amounts of arc basalts are characterized by relatively high Nb contents or by Nb enrichment.Rare basalts with compositions similar to ocean island basalts or mid-ocean ridge basalt also occur in arc systems.For these peculiar rocks,it remains debated whether their source is affected by subduction-related components.During their ascent and before their eruption,arc basaltic magmas are subjected to crystal fractionation,mixing and crustal contamination.In addition to the contribution of subducting slab components to the mantle source of arc basalts,the materials above the subducting slab at forearc depths would have been transported either by drag or by subduction erosion into the subarc mantle and into the source of arc magmas.Heats and materials brought by corner flows also play important roles in the generation of arc basalts.Despite the important progresses made in recent studies of arc basalts,further efforts are needed to investigate subarc mantle metasomatism,material recycling,the formation of arc magma sources,geodynamic mechanism in generating arc basalts,and their implicationd s for the initiation of plate tectonics on Earth.
基金The author would like to acknowledge the National Science Fund for Distinguished Young Scholars(21425624)the National Natural Science Foundation of China(21476026,21376028).
文摘Small non-coding RNAs(sRNAs)have received much attention in recent years due to their unique biological properties,which can efficiently and specifically tune target gene expressions in bacteria.Inspired by natural sRNAs,recent works have proposed the use of artificial sRNAs(asRNAs)as genetic tools to regulate desired gene that has been applied in several fields,such as metabolic engineering and bacterial physiology studies.However,the rational design of asRNAs is still a challenge.In this study,we proposed structure and length as two criteria to implement rational visualized and precise design of asRNAs.T7 expression system was one of the most useful recombinant protein expression systems.However,it was deeply limited by the formation of inclusion body.To settle this problem,we designed a series of asRNAs to inhibit the T7 RNA polymerase(Gene1)expression to balance the rate between transcription and folding of recombinant protein.Based on the heterologous expression of Aspergillus oryzae Li-3 glucuronidase in E.coli,the asRNA-antigene1-17bp can effectively decrease the inclusion body and increase the enzyme activity by 169.9%.
