The emergence of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variants capable of evading both convalescent and vaccine-triggered antibody responses has underscored the pivotal role of T-cell immunity in...The emergence of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variants capable of evading both convalescent and vaccine-triggered antibody responses has underscored the pivotal role of T-cell immunity in antiviral defense.Here,we develop the ConFormer network for epitope prediction,which couples convolutional neural network(CNN)local features with Transformer global representations to enhance binding prediction performance,and employ the deep learning algorithm and bioinformatics workflows to identify conserved T-cell epitopes within the SARS-CoV-2 proteome.Five epitopes are identified as potential inducers of T-cell immune responses.Notably,the multi-valent vaccine composed of these five peptides significantly activates cluster of differentiation(CD)8^(+)and CD4^(+)T cells both in vitro and in vivo.The serum of mice immunized with this vaccine is able to neutralize the five major SARS-CoV-2 variants of concern.This study provides a candidate peptide vaccine with the potential to trigger antiviral T-cell responses,thereby offering the prospect of immune protection against SARS-CoV-2 variants.展开更多
This paper estimates the population to be influenced by China's policy of postponed retirement age and provides design strategies and suggestions in the workplace for the ageing workforce from the perspective of i...This paper estimates the population to be influenced by China's policy of postponed retirement age and provides design strategies and suggestions in the workplace for the ageing workforce from the perspective of inclusive design.First,the literature review about western design principles and practices for the ageing workforce is conducted.It is estimated that China would face approximately 100 million elderly workers in the near future with diverse physical conditions and demands.However,the design research and practices dedicated to ageing workforce in the workplace are comparatively weak in China.Inclusive design,one of the design approaches mainly focusing on ageing problems in developed countries,as well as its theory and methodology,could act as a good reference for Chinese policymakers and designers.Then based on the concept of inclusive design,a human-centered design model is established and design suggestions from four aspects are presented.Finally,two cases are further discussed to illustrate the idea of inclusive design.展开更多
The traditional robust controller is designed to meet the requirement considering both the disturbance and the plant uncertainty while the controller uncertainty is always neglected.The structural optimal robustness o...The traditional robust controller is designed to meet the requirement considering both the disturbance and the plant uncertainty while the controller uncertainty is always neglected.The structural optimal robustness of the closed-loop system is proposed based on the analysis of the robust radii of both the plant and the controller.The subspace angle is introduced to measure the "distance" of two subspaces,and its metric is equivalent to the gap metric.The optimal robust controller based on gap metric is designed to control the rate of the line of sight for an electromechancial target tracking system.It is shown from simulations that the optimal robust controller with the biggest robust radius is superior on the ability of disturbance rejection,and high tracking performance when additive uncertainty exists compared with the robust controller with smaller robust radius.展开更多
In this review, we retrospect our progress in biological active naphthalimide and analogues as antitumor agents in the past 20 years. On one hand, various derivations in naphthalimide pharmacophores were developed to ...In this review, we retrospect our progress in biological active naphthalimide and analogues as antitumor agents in the past 20 years. On one hand, various derivations in naphthalimide pharmacophores were developed to enhance their DNA binding affinity and antitumor property thereby. Heterocyclic fused naphthalimides, bis-naphthalimides, non-fused substituted naphthalimides and the carboxamide derivatives were synthesized. For example, thio-heterocyclic fused-naphthalimides were designed and evaluated in comparison with their oxo-heterocyclic fused analogues. Extended or created heterocyclebased skeleton were also developed as antitumor agents. On the other hand, we broaden the design strategy of naphthalimide antitumor agents besides DNA intercalation and topo II poison. We have introduced more drug design methods, such as prodrugs, multitarget drugs, computer-aided drug design,photodynamic therapy. For example, we have got naphthalimide derivatives which inhibited topo II and induced LMP by introducing long alkyl chain and polyamines. Several representative compounds were clarified of their antitumor mechanism of action. In all, our research improves the structure diversity of naphthalimide antitumor agents and distinct variances of antitumor targets and mechanism of action.展开更多
The abnormal activation of JAK2 kinase is closely related to the occurrence and progression of myeloproliferative neoplasms(MPNs).At present,there is still an obvious unmet medical need for selective JAK2 inhibitors i...The abnormal activation of JAK2 kinase is closely related to the occurrence and progression of myeloproliferative neoplasms(MPNs).At present,there is still an obvious unmet medical need for selective JAK2 inhibitors in clinic.In this paper,a class of 2-aminopyridine derivatives as potent and selective JAK2 inhibitors was obtained by combining drug design,synthesis and structure-activity relationship studies based on the previously identified lead Crizotinib.Among them,21 b exhibited high inhibitory activity against JAK2 with an IC_(50)of 9 nmol/L,moreover,it showed 276-and 184-fold selectivity over JAK1 and JAK3,respectively.Besides,21 b had a significant antiproliferative activity against HEL cells,and also inhibited the phosphorylation of JAK2 and its down-stream signaling pathway.These results indicated that2-aminopyridine compound 21 b had the potential to be developed as a selective JAK2 inhibitor for further study.展开更多
Through the analysis on the current situation of the souvenirs in Jiangxi red revolutionary museums, the new design positioning of the souvenirs is discussed, and also the development direction of the souvenirs is stu...Through the analysis on the current situation of the souvenirs in Jiangxi red revolutionary museums, the new design positioning of the souvenirs is discussed, and also the development direction of the souvenirs is studied from culture connotation excavation, buying motivation, buying groups, the combination of design with technology, and pre-sale, in-sale, and after-sale services. On the basis of preserving the traditional revolutionary culture, the revolutionary stories are reshaped using modem design language and science and technology, so that new living space and development direction are given to the souvenirs of red revolution, the sales of the souvenirs are promoted, the economic benefits of the red revolutionary museums are improved, the red tourism is more effectively promoted, and Jiangxi red revolutionary culture is developed and expanded.展开更多
Resistance to malaria parasites has quickly developed to almost all used antimalarial drugs. Cysteine protease falcipain-2(FP-2) and Plasmodium falciparum dihydrofolate reductase(PfDHFR) have crucial roles, which are ...Resistance to malaria parasites has quickly developed to almost all used antimalarial drugs. Cysteine protease falcipain-2(FP-2) and Plasmodium falciparum dihydrofolate reductase(PfDHFR) have crucial roles, which are absolutely necessary, in the parasite life cycle. In this study, based on the uniform pharmacophores of reported PfDHFR inhibitors and the first-generation dual inhibitors against FP-2 and PfDHFR, we identified a novel series of dual inhibitors through fragments assembly. Lead optimization led to the identification of 14, which showed potent inhibition against FP-2 and PfDHFR enzyme(IC_(50)= 6.8 + 1.8 mmol/L and IC_(50)= 8.8 + 0.3 mmol/L) and P. falciparum 3D7 strain(IC50= 2.9mmol/L).Additionally, 14 exhibited more potent inhibition to the proliferation of chloroquine-resistant P.falciparum Dd2 strain(IC_(50)= 1.1 mmol/L) than pyrimethamine(IC_(50)>10 mmol/L), and 14 displayed micromolar inhibitory activities against two clinical isolated strains Fab9(IC_(50)= 2.6 mmol/L) and GB4(IC_(50)= 1.0 mmol/L). Collectively, these data demonstrated that 14 might be a good lead compound for the treatment of malaria.展开更多
New Delhi metallo-β-lactamase 1(NDM-1) can hydrolyze most β-lactam antibiotics, which is the major factor for drug resistance of Gram-negative bacteria. The binding of most reversible inhibitors to NDM-1 is relative...New Delhi metallo-β-lactamase 1(NDM-1) can hydrolyze most β-lactam antibiotics, which is the major factor for drug resistance of Gram-negative bacteria. The binding of most reversible inhibitors to NDM-1 is relatively weak due to the shallow active pocket of NDM-1. Alternatively, irreversible covalent inhibitors can prevent their dissociation from the target, leading to permanent inactivation of the protein.Herein, we report a series of irreversible covalent inhibitors of NDM-1 targeting the conserved Lys211 in the active pocket. Several methods, including mass spectrometry, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, fluorescent labeling, and coumarin probe were used to demonstrate that pentafluorophenyl ester formed a covalent bond with Lys211. Moreover, our target inhibitor, in combination with meropenem, achieved an antibacterial effect on drug-resistant bacteria, along with an excellent safety profile. Our new strategy in designing lysine-targeted irreversible covalent NDM-1 inhibitors provides a potential option for the clinical treatment of Gram-negative bacteria.展开更多
A philosophy for the design of novel,lightweight,multi-layered armor,referred to as Composite Armor Philosophy(CAP),which can adapt to the passive protection of light-,medium-,and heavy-armored vehicles,is presented i...A philosophy for the design of novel,lightweight,multi-layered armor,referred to as Composite Armor Philosophy(CAP),which can adapt to the passive protection of light-,medium-,and heavy-armored vehicles,is presented in this study.CAP can serve as a guiding principle to assist designers in comprehending the distinct roles fulfilled by each component.The CAP proposal comprises four functional layers,organized in a suggested hierarchy of materials.Particularly notable is the inclusion of a ceramic-composite principle,representing an advanced and innovative solution in the field of armor design.This paper showcases real-world defense industry applications,offering case studies that demonstrate the effectiveness of this advanced approach.CAP represents a significant milestone in the history of passive protection,marking an evolutionary leap in the field.This philosophical approach provides designers with a powerful toolset with which to enhance the protection capabilities of military vehicles,making them more resilient and better equipped to meet the challenges of modern warfare.展开更多
基金supported in part by the National Natural Science Foundation of China(82150208 and 82425104)the National Key Research and Development Program of China(2022YFC3400501)the Shanghai Rising-Star Program(23QA1402800).
文摘The emergence of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variants capable of evading both convalescent and vaccine-triggered antibody responses has underscored the pivotal role of T-cell immunity in antiviral defense.Here,we develop the ConFormer network for epitope prediction,which couples convolutional neural network(CNN)local features with Transformer global representations to enhance binding prediction performance,and employ the deep learning algorithm and bioinformatics workflows to identify conserved T-cell epitopes within the SARS-CoV-2 proteome.Five epitopes are identified as potential inducers of T-cell immune responses.Notably,the multi-valent vaccine composed of these five peptides significantly activates cluster of differentiation(CD)8^(+)and CD4^(+)T cells both in vitro and in vivo.The serum of mice immunized with this vaccine is able to neutralize the five major SARS-CoV-2 variants of concern.This study provides a candidate peptide vaccine with the potential to trigger antiviral T-cell responses,thereby offering the prospect of immune protection against SARS-CoV-2 variants.
基金Supported by the Shanghai Education Science Research Program(C17067)
文摘This paper estimates the population to be influenced by China's policy of postponed retirement age and provides design strategies and suggestions in the workplace for the ageing workforce from the perspective of inclusive design.First,the literature review about western design principles and practices for the ageing workforce is conducted.It is estimated that China would face approximately 100 million elderly workers in the near future with diverse physical conditions and demands.However,the design research and practices dedicated to ageing workforce in the workplace are comparatively weak in China.Inclusive design,one of the design approaches mainly focusing on ageing problems in developed countries,as well as its theory and methodology,could act as a good reference for Chinese policymakers and designers.Then based on the concept of inclusive design,a human-centered design model is established and design suggestions from four aspects are presented.Finally,two cases are further discussed to illustrate the idea of inclusive design.
基金Sponsored by the Science and Technology Project of the Department of Education of Heilongjiang Province(Grant No.12511015)the Defense Pre-Research Project of China (Grant No.51309040201)
文摘The traditional robust controller is designed to meet the requirement considering both the disturbance and the plant uncertainty while the controller uncertainty is always neglected.The structural optimal robustness of the closed-loop system is proposed based on the analysis of the robust radii of both the plant and the controller.The subspace angle is introduced to measure the "distance" of two subspaces,and its metric is equivalent to the gap metric.The optimal robust controller based on gap metric is designed to control the rate of the line of sight for an electromechancial target tracking system.It is shown from simulations that the optimal robust controller with the biggest robust radius is superior on the ability of disturbance rejection,and high tracking performance when additive uncertainty exists compared with the robust controller with smaller robust radius.
基金the financial supports from the National Natural Science Foundation of China(No.20536010)National Key Project for Basic Research(No.2003CB114400)the Program of Shanghai Subject Chief Scientist and the Science and Technology Foundation of Shanghai
文摘In this review, we retrospect our progress in biological active naphthalimide and analogues as antitumor agents in the past 20 years. On one hand, various derivations in naphthalimide pharmacophores were developed to enhance their DNA binding affinity and antitumor property thereby. Heterocyclic fused naphthalimides, bis-naphthalimides, non-fused substituted naphthalimides and the carboxamide derivatives were synthesized. For example, thio-heterocyclic fused-naphthalimides were designed and evaluated in comparison with their oxo-heterocyclic fused analogues. Extended or created heterocyclebased skeleton were also developed as antitumor agents. On the other hand, we broaden the design strategy of naphthalimide antitumor agents besides DNA intercalation and topo II poison. We have introduced more drug design methods, such as prodrugs, multitarget drugs, computer-aided drug design,photodynamic therapy. For example, we have got naphthalimide derivatives which inhibited topo II and induced LMP by introducing long alkyl chain and polyamines. Several representative compounds were clarified of their antitumor mechanism of action. In all, our research improves the structure diversity of naphthalimide antitumor agents and distinct variances of antitumor targets and mechanism of action.
基金the National Key Research and Development Program(No.2016YFA0502304)the National Natural Science Foundation of China(No.81825020)+3 种基金the Shanghai Committee of Science and Technology(No.20S11901000)the Fundamental Research Funds for the Central Universitiessponsored by the National Program for Special Supports of Eminent Professionalsthe National Program for Support of Top-Notch Young Professionals。
文摘The abnormal activation of JAK2 kinase is closely related to the occurrence and progression of myeloproliferative neoplasms(MPNs).At present,there is still an obvious unmet medical need for selective JAK2 inhibitors in clinic.In this paper,a class of 2-aminopyridine derivatives as potent and selective JAK2 inhibitors was obtained by combining drug design,synthesis and structure-activity relationship studies based on the previously identified lead Crizotinib.Among them,21 b exhibited high inhibitory activity against JAK2 with an IC_(50)of 9 nmol/L,moreover,it showed 276-and 184-fold selectivity over JAK1 and JAK3,respectively.Besides,21 b had a significant antiproliferative activity against HEL cells,and also inhibited the phosphorylation of JAK2 and its down-stream signaling pathway.These results indicated that2-aminopyridine compound 21 b had the potential to be developed as a selective JAK2 inhibitor for further study.
文摘Through the analysis on the current situation of the souvenirs in Jiangxi red revolutionary museums, the new design positioning of the souvenirs is discussed, and also the development direction of the souvenirs is studied from culture connotation excavation, buying motivation, buying groups, the combination of design with technology, and pre-sale, in-sale, and after-sale services. On the basis of preserving the traditional revolutionary culture, the revolutionary stories are reshaped using modem design language and science and technology, so that new living space and development direction are given to the souvenirs of red revolution, the sales of the souvenirs are promoted, the economic benefits of the red revolutionary museums are improved, the red tourism is more effectively promoted, and Jiangxi red revolutionary culture is developed and expanded.
基金Financial support for this research provided by the National Natural Science Foundation of China (Nos. 21372001 and 21672064)the "Shu Guang" Project supported by the Shanghai Municipal Education Commission and Shanghai Education Development Foundation (No. 14SG28)
文摘Resistance to malaria parasites has quickly developed to almost all used antimalarial drugs. Cysteine protease falcipain-2(FP-2) and Plasmodium falciparum dihydrofolate reductase(PfDHFR) have crucial roles, which are absolutely necessary, in the parasite life cycle. In this study, based on the uniform pharmacophores of reported PfDHFR inhibitors and the first-generation dual inhibitors against FP-2 and PfDHFR, we identified a novel series of dual inhibitors through fragments assembly. Lead optimization led to the identification of 14, which showed potent inhibition against FP-2 and PfDHFR enzyme(IC_(50)= 6.8 + 1.8 mmol/L and IC_(50)= 8.8 + 0.3 mmol/L) and P. falciparum 3D7 strain(IC50= 2.9mmol/L).Additionally, 14 exhibited more potent inhibition to the proliferation of chloroquine-resistant P.falciparum Dd2 strain(IC_(50)= 1.1 mmol/L) than pyrimethamine(IC_(50)>10 mmol/L), and 14 displayed micromolar inhibitory activities against two clinical isolated strains Fab9(IC_(50)= 2.6 mmol/L) and GB4(IC_(50)= 1.0 mmol/L). Collectively, these data demonstrated that 14 might be a good lead compound for the treatment of malaria.
基金funded by the National Natural Science Foundation of China (No. 82073688 to X. Sun and No. 82103971 to Y. Liang)Science and Technology Commission of Shanghai Municipality (No. 21S11907300 to X. Sun)Shanghai Science and Technology Development Fund from Central Leading Local Government (No. YDZX20223100001004 to X. Sun)。
文摘New Delhi metallo-β-lactamase 1(NDM-1) can hydrolyze most β-lactam antibiotics, which is the major factor for drug resistance of Gram-negative bacteria. The binding of most reversible inhibitors to NDM-1 is relatively weak due to the shallow active pocket of NDM-1. Alternatively, irreversible covalent inhibitors can prevent their dissociation from the target, leading to permanent inactivation of the protein.Herein, we report a series of irreversible covalent inhibitors of NDM-1 targeting the conserved Lys211 in the active pocket. Several methods, including mass spectrometry, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, fluorescent labeling, and coumarin probe were used to demonstrate that pentafluorophenyl ester formed a covalent bond with Lys211. Moreover, our target inhibitor, in combination with meropenem, achieved an antibacterial effect on drug-resistant bacteria, along with an excellent safety profile. Our new strategy in designing lysine-targeted irreversible covalent NDM-1 inhibitors provides a potential option for the clinical treatment of Gram-negative bacteria.
基金co-financed by the European Regional Development Fund of the European UnionGreek national funds through the Operational Program Competitiveness,Entrepreneurship and Innovation,under the call RESEARCH-CREATE-INNOVATE(project code:T1EDK-04429)。
文摘A philosophy for the design of novel,lightweight,multi-layered armor,referred to as Composite Armor Philosophy(CAP),which can adapt to the passive protection of light-,medium-,and heavy-armored vehicles,is presented in this study.CAP can serve as a guiding principle to assist designers in comprehending the distinct roles fulfilled by each component.The CAP proposal comprises four functional layers,organized in a suggested hierarchy of materials.Particularly notable is the inclusion of a ceramic-composite principle,representing an advanced and innovative solution in the field of armor design.This paper showcases real-world defense industry applications,offering case studies that demonstrate the effectiveness of this advanced approach.CAP represents a significant milestone in the history of passive protection,marking an evolutionary leap in the field.This philosophical approach provides designers with a powerful toolset with which to enhance the protection capabilities of military vehicles,making them more resilient and better equipped to meet the challenges of modern warfare.
