[Objectives] This study was conducted to elucidate the mechanism of action of total glucosides of paeony （TGP） against the liver injury induced by isoniazid （INH） and rifampicin （RFP）, and to provide experimenta...[Objectives] This study was conducted to elucidate the mechanism of action of total glucosides of paeony （TGP） against the liver injury induced by isoniazid （INH） and rifampicin （RFP）, and to provide experimental evidence for rational use of anti-tuberculosis drugs.[Methods] Liver injury in mice was induced by the combination of INH and RFP in mice. After the mice were given different doses of Total Glucosides of White Paeony Capsules （TGP） for 10 d, the hepatosomatic index, biochemical indices in serum and liver homogenate were measured, and histopathological changes in liver tissue were observed. Glucurolactone was used as the positive control, and 0.9% sodium chloride was used as the negative control in the experiment.[Results] TGP reduced the activities of alanine transaminase （ALT） and aspartate transferase （AST） in serum and the level of malondialdehyde （MDA） in liver tissue, and increased the level of glutathione （GSH） and the activity of superoxidase dismutase （SOD） in liver tissue.[Conclusions] TAP has a protective effect against the liver injury induced by INH and RFP.展开更多
门控循环单元(gated recurrent unit, GRU)是一种有代表性的深度神经网络,它在众多序列学习任务中达到了国际领先的水平.然而,在门控循环单元的每个时间步之间,输入信息与隐含状态信息缺乏交互,这对更好地挖掘上下文语义信息带来了挑战...门控循环单元(gated recurrent unit, GRU)是一种有代表性的深度神经网络,它在众多序列学习任务中达到了国际领先的水平.然而,在门控循环单元的每个时间步之间,输入信息与隐含状态信息缺乏交互,这对更好地挖掘上下文语义信息带来了挑战.针对这个问题,本文提出了一个新颖的序列学习通用的语义特征提取模型:交互门控循环单元(interactive gated recurrent unit, InterGRU),可以让输入与隐含状态向量在各时间步间进行多轮充分的交互.并且,在到达时间估计(estimated time of arrival, ETA)这个有代表性、有挑战的时空序列预测任务上,本文提出了一套基于交互门控循环单元的深度学习框架(InterGRU-ETA).本文在来自滴滴出行平台真实场景下的海量数据集上充分地实验验证了InterGRU-ETA.结果表明,我们的框架在预测准确率上优于目前国际上最先进的方法.这反映了交互门控循环单元在捕获序列语义信息上的性能优势和广阔前景.展开更多
Plant leucine-rich repeat(LRR)receptor-like kinases(RLKs)and LRR receptor-like proteins(RLPs)comprise a large family of cell surface receptors that play critical roles in signal perception and transduction.Both LRR-RL...Plant leucine-rich repeat(LRR)receptor-like kinases(RLKs)and LRR receptor-like proteins(RLPs)comprise a large family of cell surface receptors that play critical roles in signal perception and transduction.Both LRR-RLKs and LRR-RLPs rely on regulatory LRR-RLKs to initiate downstream signaling pathways.BRASSINOSTEROID INSENSITIVE 1-ASSOCIATED KINASE 1/SOMATIC EMBRYOGENESIS RECEPTOR KINASE 3(BAK1/SERK3)and SUPPRESSOR OF BIR1-1(SOBIR1)are important and extensively studied regulatory LRR-RLKs with distinct functions.Although the regulatory mechanism of BAK1 activation has been studied in detail,the activation mechanism of SOBIR1 remains poorly understood.Here,the crystal structures of the catalytically inactive kinase domain of SOBIR1(SOBIR1-KD)from Arabidopsis thaliana were determined in complexes with AMP-PNP and Mg^(2+).The results show that SOBIR1-KD contains a uniquely long β3-αC loop and adopts an Src-like inactive conformation with an unusual architecture at the activation segment,which comprises three helices.Biochemical studies revealed that SOBIR1 is transphosphorylated by BAK1 following its autophosphorylation via an intermolecular mechanism,and the phosphorylation of Thr529 in the activation segment and the β3-αC loop are critical for SOBIR1 phosphorylation.Further functional analysis confirmed the importance of Thr529 and the β3-αC loop for the SOBIR1-induced cell death response in Nicotiana benthamiana.Taken together,these findings provide a structural basis for the regulatory mechanism of SOBIR1 and reveal the important elements and phosphorylation events in the special stepwise activation of SOBIR1-KD,the first such processes found in regulatory LRR-RLKs.展开更多
Similar to that of other enteroviruses, the replication of enterovirus 71(EV71) occurs on rearranged membranous structures called replication organelles(ROs). Phosphatidylinositol 4-kinase Ⅲ(PI4KB), which is required...Similar to that of other enteroviruses, the replication of enterovirus 71(EV71) occurs on rearranged membranous structures called replication organelles(ROs). Phosphatidylinositol 4-kinase Ⅲ(PI4KB), which is required by enteroviruses for RO formation, yields phosphatidylinositol-4-phosphate(PI4P) on ROs. PI4P then binds and induces conformational changes in the RNA-dependent RNA polymerase(Rd Rp) to modulate Rd Rp activity. Here, we targeted 3D polymerase, the core enzyme of EV71 ROs, and found that the host factor Annexin A2(ANXA2) can interact with 3 D polymerase and promote the replication of EV71. Then, an experiment showed that the annexin domain of ANXA2, which possesses membranebinding capacity, mediates the interaction of ANXA2 with EV71 3 D polymerase. Further research showed that ANXA2 is localized on ROs and interacts with PI4KB. Overexpression of ANXA2 stimulated the formation of PI4P, and the level of PI4P was decreased in ANXA2-knockout cells. Furthermore, ANXA2, PI4KB, and 3D were shown to be localized to the viral RNA replication site, where they form a higher-order protein complex, and the presence of ANXA2 promoted the PI4 KB-3D interaction. Altogether, our data provide new insight into the role of ANXA2 in facilitating formation of the EV71 RNA replication complex.展开更多
Influenza causes seasonal outbreaks yearly and unpredictable pandemics with high morbidity and mortality rates.Despite significant efforts to address influenza,it remains a major threat to human public health.This iss...Influenza causes seasonal outbreaks yearly and unpredictable pandemics with high morbidity and mortality rates.Despite significant efforts to address influenza,it remains a major threat to human public health.This issue is partially due to the lack of antiviral drugs with potent antiviral activity and broad reactivity against all influenza virus strains and the rapid emergence of drug-resistant variants.Moreover,designing a universal influenza vaccine that is sufficiently immunogenic to induce universal antibodies is difficult.Some novel epitopes hidden in the hemagglutinin(HA)trimeric interface have been discovered recently,and a number of antibodies targeting these epitopes have been found to be capable of neutralizing a broad range of influenza isolates.These findings may have important implications for the development of universal influenza vaccines and antiviral drugs.In this review,we focused on the antibodies targeting these newly discovered epitopes in the HA domain of the influenza virus to promote the development of universal anti-influenza antibodies or vaccines and extend the discovery to other viruses with similar conformational changes in envelope proteins.展开更多
Introduction:Community-based services for psychosis are an important part of mental health services in China.We analyzed community-based follow-up and treatment services for psychosis in China in 2019 to provide evide...Introduction:Community-based services for psychosis are an important part of mental health services in China.We analyzed community-based follow-up and treatment services for psychosis in China in 2019 to provide evidence for policymaking and services delivering.Methods:Data from the National Information System for Psychosis were used to analyze usage of the information system and the registration,management,and treatment situation of patients with psychosis in China in 2019 and compared the results of 2019 with that of 2018.Results:In 2019,100%of cities and counties used the information system and 6,230,157 patients were registered.In 2019,there were 5,944,724 registered patients(94.05%)in China under community-based follow-up services and 5,375,252 patients(85.04%)had regular follow-ups;5,295,657 patients(83.78%)were treated by taking antipsychotics and 3,354,251(53.07%)patients took medication regularly;4,974,314 patients at home(87.81%)were in stable condition;and there was a significant difference in patients’stable condition and medication-taking rates among eastern,central,and western regions(p<0.05).Compared with 2018,the nationwide regular management rate,medication-taking rate,regular medication-taking rate,and patients’stable rate increased by 2.35%,2.48%,11.29%,and 7.21%respectively.Conclusions and Implications for Public Health Practice:Compared with 2018,the level of management and treatment improved significantly but still needs to be further strengthened,especially in western China.展开更多
The current COVID-19 pandemic has heavily burdened the global public health system and may keep simmering for years.The frequent emergence of immune escape variants have spurred the search for prophylactic vaccines an...The current COVID-19 pandemic has heavily burdened the global public health system and may keep simmering for years.The frequent emergence of immune escape variants have spurred the search for prophylactic vaccines and therapeutic antibodies that confer broad protection against SARS-CoV-2 variants.Here we show that the bivalency of an affinity maturated fully human singledomain antibody(n3113.1-Fc)exhibits exquisite neutralizing potency against SARS-CoV-2 pseudovirus,and confers effective prophylactic and therapeutic protection against authentic SARS-CoV-2 in the host cell receptor angiotensin-converting enzyme 2(ACE2)humanized mice.The crystal structure of n3113 in complex with the receptor-binding domain(RBD)of SARS-CoV-2,combined with the cryo-EM structures of n3113 and spike ecto-domain,reveals that n3113 binds to the side surface of up-state RBD with no competition with ACE2.The binding of n3113 to this novel epitope stabilizes spike in up-state conformations but inhibits SARS-CoV-2 S mediated membrane fusion,expanding our recognition of neutralization by antibodies against SARS-CoV-2.Binding assay and pseudovirus neutralization assay show no evasion of recently prevalent SARS-CoV-2 lineages,including Alpha(B.1.1.7),Beta(B.1.351),Gamma(P.1),and Delta(B.1.617.2)for n3113.1-Fc with Y58L mutation,demonstrating the potential of n3113.1-Fc(Y58L)as a promising candidate for clinical development to treat COVID-19.展开更多
High density and uniform distribution of the gold nanoparticles functionalized single-stranded DNA modified reduced graphene oxide nanocomposites were obtained by non-covalent interaction.The positive gold nanoparticl...High density and uniform distribution of the gold nanoparticles functionalized single-stranded DNA modified reduced graphene oxide nanocomposites were obtained by non-covalent interaction.The positive gold nanoparticles prepared by phase inversion method exhibited good dimensional homogeneity and dispersibility,which could readily combine with single-stranded DNA modified reduced graphene oxide nanocomposites by electrostatic interactions.The modification of single-stranded DNA endowed the reduced graphene oxide with favorable biocompatibility and provided the preferable surface with negative charge for further assembling of gold nanoparticles to obtain gold nanoparticles/single-stranded DNA modified reduced graphene oxide nanocomposites with better conductivity,larger specific surface area,biocompatibility and electrocatalytic characteristics.The as-prepared nanocomposites were applied as substrates for the construction of cholesterol oxidase modified electrode and well realized the direct electron transfer between the enzyme and electrode.The modified gold nanoparticles could further catalyze the products of cholesterol oxidation catalyzed by cholesterol oxidase,which was beneficial to the enzyme-catalyzed reaction.The as-fabricated bioelectrode exhibited excellent electrocatalytic performance for the cholesterol with a linear range of 7.5–280.5μmol·L^(−1),a low detection limit of 2.1μmol·L^(−1),good stability and reproducibility.Moreover,the electrochemical biosensor showed good selectivity and acceptable accuracy for the detection of cholesterol in human serum samples.展开更多
基金Supported by Student Research Training Program of Jiaxing University(85171737)
文摘[Objectives] This study was conducted to elucidate the mechanism of action of total glucosides of paeony （TGP） against the liver injury induced by isoniazid （INH） and rifampicin （RFP）, and to provide experimental evidence for rational use of anti-tuberculosis drugs.[Methods] Liver injury in mice was induced by the combination of INH and RFP in mice. After the mice were given different doses of Total Glucosides of White Paeony Capsules （TGP） for 10 d, the hepatosomatic index, biochemical indices in serum and liver homogenate were measured, and histopathological changes in liver tissue were observed. Glucurolactone was used as the positive control, and 0.9% sodium chloride was used as the negative control in the experiment.[Results] TGP reduced the activities of alanine transaminase （ALT） and aspartate transferase （AST） in serum and the level of malondialdehyde （MDA） in liver tissue, and increased the level of glutathione （GSH） and the activity of superoxidase dismutase （SOD） in liver tissue.[Conclusions] TAP has a protective effect against the liver injury induced by INH and RFP.
文摘门控循环单元(gated recurrent unit, GRU)是一种有代表性的深度神经网络,它在众多序列学习任务中达到了国际领先的水平.然而,在门控循环单元的每个时间步之间,输入信息与隐含状态信息缺乏交互,这对更好地挖掘上下文语义信息带来了挑战.针对这个问题,本文提出了一个新颖的序列学习通用的语义特征提取模型:交互门控循环单元(interactive gated recurrent unit, InterGRU),可以让输入与隐含状态向量在各时间步间进行多轮充分的交互.并且,在到达时间估计(estimated time of arrival, ETA)这个有代表性、有挑战的时空序列预测任务上,本文提出了一套基于交互门控循环单元的深度学习框架(InterGRU-ETA).本文在来自滴滴出行平台真实场景下的海量数据集上充分地实验验证了InterGRU-ETA.结果表明,我们的框架在预测准确率上优于目前国际上最先进的方法.这反映了交互门控循环单元在捕获序列语义信息上的性能优势和广阔前景.
基金This work was supported by the National Natural Science Foundation of China(31571963).
文摘Plant leucine-rich repeat(LRR)receptor-like kinases(RLKs)and LRR receptor-like proteins(RLPs)comprise a large family of cell surface receptors that play critical roles in signal perception and transduction.Both LRR-RLKs and LRR-RLPs rely on regulatory LRR-RLKs to initiate downstream signaling pathways.BRASSINOSTEROID INSENSITIVE 1-ASSOCIATED KINASE 1/SOMATIC EMBRYOGENESIS RECEPTOR KINASE 3(BAK1/SERK3)and SUPPRESSOR OF BIR1-1(SOBIR1)are important and extensively studied regulatory LRR-RLKs with distinct functions.Although the regulatory mechanism of BAK1 activation has been studied in detail,the activation mechanism of SOBIR1 remains poorly understood.Here,the crystal structures of the catalytically inactive kinase domain of SOBIR1(SOBIR1-KD)from Arabidopsis thaliana were determined in complexes with AMP-PNP and Mg^(2+).The results show that SOBIR1-KD contains a uniquely long β3-αC loop and adopts an Src-like inactive conformation with an unusual architecture at the activation segment,which comprises three helices.Biochemical studies revealed that SOBIR1 is transphosphorylated by BAK1 following its autophosphorylation via an intermolecular mechanism,and the phosphorylation of Thr529 in the activation segment and the β3-αC loop are critical for SOBIR1 phosphorylation.Further functional analysis confirmed the importance of Thr529 and the β3-αC loop for the SOBIR1-induced cell death response in Nicotiana benthamiana.Taken together,these findings provide a structural basis for the regulatory mechanism of SOBIR1 and reveal the important elements and phosphorylation events in the special stepwise activation of SOBIR1-KD,the first such processes found in regulatory LRR-RLKs.
基金This study was supported by the National Science Foundation of China(81971976,81772236)Major Project of Technology Innovation Program of Hubei Province(2018ACA123)。
文摘Similar to that of other enteroviruses, the replication of enterovirus 71(EV71) occurs on rearranged membranous structures called replication organelles(ROs). Phosphatidylinositol 4-kinase Ⅲ(PI4KB), which is required by enteroviruses for RO formation, yields phosphatidylinositol-4-phosphate(PI4P) on ROs. PI4P then binds and induces conformational changes in the RNA-dependent RNA polymerase(Rd Rp) to modulate Rd Rp activity. Here, we targeted 3D polymerase, the core enzyme of EV71 ROs, and found that the host factor Annexin A2(ANXA2) can interact with 3 D polymerase and promote the replication of EV71. Then, an experiment showed that the annexin domain of ANXA2, which possesses membranebinding capacity, mediates the interaction of ANXA2 with EV71 3 D polymerase. Further research showed that ANXA2 is localized on ROs and interacts with PI4KB. Overexpression of ANXA2 stimulated the formation of PI4P, and the level of PI4P was decreased in ANXA2-knockout cells. Furthermore, ANXA2, PI4KB, and 3D were shown to be localized to the viral RNA replication site, where they form a higher-order protein complex, and the presence of ANXA2 promoted the PI4 KB-3D interaction. Altogether, our data provide new insight into the role of ANXA2 in facilitating formation of the EV71 RNA replication complex.
基金This work was supported by the National Natural Science Foundation of China(Nos.81822027 and 81630090)the National Key R&D Program of China(No.2019YFA0904400)+1 种基金the National Science and Technology Major Projects of Infectious Disease funds(No.2018ZX10301403)the grant from the Chinese Academy of Medical Sciences(No.2019PT350002).
文摘Influenza causes seasonal outbreaks yearly and unpredictable pandemics with high morbidity and mortality rates.Despite significant efforts to address influenza,it remains a major threat to human public health.This issue is partially due to the lack of antiviral drugs with potent antiviral activity and broad reactivity against all influenza virus strains and the rapid emergence of drug-resistant variants.Moreover,designing a universal influenza vaccine that is sufficiently immunogenic to induce universal antibodies is difficult.Some novel epitopes hidden in the hemagglutinin(HA)trimeric interface have been discovered recently,and a number of antibodies targeting these epitopes have been found to be capable of neutralizing a broad range of influenza isolates.These findings may have important implications for the development of universal influenza vaccines and antiviral drugs.In this review,we focused on the antibodies targeting these newly discovered epitopes in the HA domain of the influenza virus to promote the development of universal anti-influenza antibodies or vaccines and extend the discovery to other viruses with similar conformational changes in envelope proteins.
文摘Introduction:Community-based services for psychosis are an important part of mental health services in China.We analyzed community-based follow-up and treatment services for psychosis in China in 2019 to provide evidence for policymaking and services delivering.Methods:Data from the National Information System for Psychosis were used to analyze usage of the information system and the registration,management,and treatment situation of patients with psychosis in China in 2019 and compared the results of 2019 with that of 2018.Results:In 2019,100%of cities and counties used the information system and 6,230,157 patients were registered.In 2019,there were 5,944,724 registered patients(94.05%)in China under community-based follow-up services and 5,375,252 patients(85.04%)had regular follow-ups;5,295,657 patients(83.78%)were treated by taking antipsychotics and 3,354,251(53.07%)patients took medication regularly;4,974,314 patients at home(87.81%)were in stable condition;and there was a significant difference in patients’stable condition and medication-taking rates among eastern,central,and western regions(p<0.05).Compared with 2018,the nationwide regular management rate,medication-taking rate,regular medication-taking rate,and patients’stable rate increased by 2.35%,2.48%,11.29%,and 7.21%respectively.Conclusions and Implications for Public Health Practice:Compared with 2018,the level of management and treatment improved significantly but still needs to be further strengthened,especially in western China.
基金This work was supported by grants from the National Key R&D Program of China(2019YFA0904400)National Natural Science Foundation of China(32070938,82041003,81822027,81630090,81902108)+2 种基金Chinese Academy of Medical Sciences(2019PT350002)Shanghai Municipal Health Commission(GWV-10.2-YQ06,GWV-10.2-XD01)Science and Technology Commission of Shanghai Municipality(20411950402,20XD1401200,18DZ2210200,20DZ2254600,20DZ2261200).
文摘The current COVID-19 pandemic has heavily burdened the global public health system and may keep simmering for years.The frequent emergence of immune escape variants have spurred the search for prophylactic vaccines and therapeutic antibodies that confer broad protection against SARS-CoV-2 variants.Here we show that the bivalency of an affinity maturated fully human singledomain antibody(n3113.1-Fc)exhibits exquisite neutralizing potency against SARS-CoV-2 pseudovirus,and confers effective prophylactic and therapeutic protection against authentic SARS-CoV-2 in the host cell receptor angiotensin-converting enzyme 2(ACE2)humanized mice.The crystal structure of n3113 in complex with the receptor-binding domain(RBD)of SARS-CoV-2,combined with the cryo-EM structures of n3113 and spike ecto-domain,reveals that n3113 binds to the side surface of up-state RBD with no competition with ACE2.The binding of n3113 to this novel epitope stabilizes spike in up-state conformations but inhibits SARS-CoV-2 S mediated membrane fusion,expanding our recognition of neutralization by antibodies against SARS-CoV-2.Binding assay and pseudovirus neutralization assay show no evasion of recently prevalent SARS-CoV-2 lineages,including Alpha(B.1.1.7),Beta(B.1.351),Gamma(P.1),and Delta(B.1.617.2)for n3113.1-Fc with Y58L mutation,demonstrating the potential of n3113.1-Fc(Y58L)as a promising candidate for clinical development to treat COVID-19.
基金support from the National Natural Science Foundation of China(Grant Nos.51773085,52071171)the Liaoning Province Doctor Start-up Fund(Grant No.20170520282)+8 种基金the Doctor Start-up Fund of Liaoning University(Grant No.a280008020)research fund pre-declaration project of Liaoning University(Grant No.LDGY2019001)teaching reform research project of Liaoning University(Grant Nos.JG2018YB20,LNDXJG20183013,JG2020ZSWT022)Liaoning Revitalization Talents Program-Pan Deng Scholars(Grant No.XLYC1802005)Liaoning BaiQianWan Talents Program(Grant No.LNBQW2018B0048)Natural Science Fund of Liaoning Province for Excellent Young Scholars(Grant No.2019-YQ-04)Key Project of Scientific Research of the Education Department of Liaoning Province(Grant No.LZD201902)the Young Scientific and Technological Talents Project of the Department of Education of Liaoning Province(Grant Nos.LQN201903 and LQN202008)the Foundation for Young Scholars of Liaoning University(Grant No.LDQN2019007).
文摘High density and uniform distribution of the gold nanoparticles functionalized single-stranded DNA modified reduced graphene oxide nanocomposites were obtained by non-covalent interaction.The positive gold nanoparticles prepared by phase inversion method exhibited good dimensional homogeneity and dispersibility,which could readily combine with single-stranded DNA modified reduced graphene oxide nanocomposites by electrostatic interactions.The modification of single-stranded DNA endowed the reduced graphene oxide with favorable biocompatibility and provided the preferable surface with negative charge for further assembling of gold nanoparticles to obtain gold nanoparticles/single-stranded DNA modified reduced graphene oxide nanocomposites with better conductivity,larger specific surface area,biocompatibility and electrocatalytic characteristics.The as-prepared nanocomposites were applied as substrates for the construction of cholesterol oxidase modified electrode and well realized the direct electron transfer between the enzyme and electrode.The modified gold nanoparticles could further catalyze the products of cholesterol oxidation catalyzed by cholesterol oxidase,which was beneficial to the enzyme-catalyzed reaction.The as-fabricated bioelectrode exhibited excellent electrocatalytic performance for the cholesterol with a linear range of 7.5–280.5μmol·L^(−1),a low detection limit of 2.1μmol·L^(−1),good stability and reproducibility.Moreover,the electrochemical biosensor showed good selectivity and acceptable accuracy for the detection of cholesterol in human serum samples.
