β-elemene,a bioactive compound derived from traditional Chinese medicine(TCM),has been clinically used in cancer therapy.However,its molecular physicochemical properties require further optimization,and its precise a...β-elemene,a bioactive compound derived from traditional Chinese medicine(TCM),has been clinically used in cancer therapy.However,its molecular physicochemical properties require further optimization,and its precise anticancer mechanisms remain unknown.In modern drug development,structure-based drug design(SBDD)has significantly conserved resources,with computer-aided techniques such as molecular docking and molecule generation playing essential roles.A comprehensive review of existing molecular biology studies and virtual docking experiments led to the hypothesis that methyltransferaselike 3(METTL3)may serve as a potential target ofβ-elemene.This discovery establishes a scientific foundation for integrating advanced,rational drug design strategies withβ-elemene to enhance the therapeutic efficacy of TCM.Moreover,current artificial intelligence(AI)-based molecular generation models were examined,focusing on de novo molecular generation and lead optimization models.Their applications in the rational drug design ofβ-elemene were preliminarily explored to identify potential strategies for developing more potent anticancer derivatives by analyzing ligand-receptor interactions.展开更多
Mycobacterium tuberculosis FabH, an essential enzyme in mycolic acids biosynthetic pathway, is an attractive target for novel anti-tuberculosis agents. Structure-based design, synthesis of novel inhibitors of mtFabH w...Mycobacterium tuberculosis FabH, an essential enzyme in mycolic acids biosynthetic pathway, is an attractive target for novel anti-tuberculosis agents. Structure-based design, synthesis of novel inhibitors of mtFabH was reported in this paper. A novel scaffold structure was designed, and 12 candidate compounds that displayed favorable binding with the active site were identified and synthesized. 2009 Song Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.展开更多
Based upon the crystal structure of a previously reported fragment hit that binds to Corresponding author. β-secretase, a novel series of non-peptidic small-molecule β-secretase inhibitors, namely hexahydropyrimidin...Based upon the crystal structure of a previously reported fragment hit that binds to Corresponding author. β-secretase, a novel series of non-peptidic small-molecule β-secretase inhibitors, namely hexahydropyrimidin-5-ols, along with two series of their analogues, were rationally designed through structural modification. The CADD study was performed and revealed good expectation. Inhibitory activities of the corresponding structural cores were tested, which provided further support for our design approach.展开更多
A series of 7-azaindol derivatives were designed based on the homologous 3D model of human acrosin.These compounds were synthesized and evaluated for their human acrosin inhibitory activities in vitro.Compounds 7a,7i,...A series of 7-azaindol derivatives were designed based on the homologous 3D model of human acrosin.These compounds were synthesized and evaluated for their human acrosin inhibitory activities in vitro.Compounds 7a,7i,7j,7k and 7n showed highly inhibitory activity against human acrosin.The three-dimensional structure-activity relationship was investigated through a CoMFA model,which provided valuable information to further study of potential human acrosin inhibitors.展开更多
The mammalian target of rapamycin(mTOR) is a critical component of the PI3K-AKT signaling pathway. It is highly activated in cervical cancer, which continues to pose an important clinical challenge with an urgent need...The mammalian target of rapamycin(mTOR) is a critical component of the PI3K-AKT signaling pathway. It is highly activated in cervical cancer, which continues to pose an important clinical challenge with an urgent need for new and improved therapeutic approaches. Herein, we describe the structure-based drug discovery and biological evaluation of a series of m TOR kinase inhibitors as potential anti-cervical cancer agents. The results of enzymatic activity assays supported C3 as a potential m TOR inhibitor, which exhibited high inhibitory activity with an IC50 of 1.57 μM. Molecular docking and dynamics simulation were conducted to predict the binding patterns, suggesting relationships between structure and activity. The anti-proliferative assay against diverse cancer cell lines was displayed subsequently, revealing that C3 exhibited significant proliferation inhibition against cervical cancer cell He La(IC50=0.38μM) compared with other cell lines. Moreover, C3 could effectively reduce the expression of phospho-ribosomal S6 protein(p-S6) in He La cells in a dose-dependent manner. Noteworthily, m TOR signaling and other cellular pathways might contribute to the significant effect of C3 against cervical cancer simultaneously. These data indicated that C3 represented a good lead molecule for further development as a therapeutic agent for cervical cancer treatment.展开更多
There is a great need for new vaccine development against influenza A viruses due to the drawbacks of traditional vaccines that are mainly prepared using embryonated eggs.The main component of the current split influe...There is a great need for new vaccine development against influenza A viruses due to the drawbacks of traditional vaccines that are mainly prepared using embryonated eggs.The main component of the current split influenza A virus vaccine is viral hemagglutinin(HA)which induces a strong antibody-mediated immune response.To develop a modern vaccine against influenza A viruses,the current research has been focused on the universal vaccines targeting viral M2,NP and HA proteins.Crystallographic studies have shown that HA forms a trimer embedded on the viral envelope surface,and each monomer consists of a globular head(HA1)and a“rod-like”stalk region(HA2),the latter being more conserved among different HA subtypes and being the primary target for universal vaccines.In this study,we rationally designed the HA head based on the crystal structure of the 2009-pandemic influenza A(H1N1)virus HA as a model,tested its immunogenicity in mice,solved its crystal structure and further examined its immunological characteristics.The results show that the HA globular head can be easily prepared by in vitro refolding in an E.coli expression system,which maintains its intact structure and allows for the stimulation of a strong immune response.Together with recent reports on some similar HA globular head preparations we conclude that structure-based rational design of the HA globular head can be used for subtype-specific vaccines against influenza viruses.展开更多
Objective To investigate the associations between eight serum per-and polyfluoroalkyl substances(PFASs)and regional fat depots,we analyzed the data from the National Health and Nutrition Examination Survey(NHANES)2011...Objective To investigate the associations between eight serum per-and polyfluoroalkyl substances(PFASs)and regional fat depots,we analyzed the data from the National Health and Nutrition Examination Survey(NHANES)2011-2018 cycles.Methods Multiple linear regression models were developed to explore the associations between serum PFAS concentrations and six fat compositions along with a fat distribution score created by summing the concentrations of the six fat compositions.The associations between structurally grouped PFASs and fat distribution were assessed,and a prediction model was developed to estimate the ability of PFAS exposure to predict obesity risk.Results Among females aged 39-59 years,trunk fat mass was positively associated with perfluorooctane sulfonate(PFOS).Higher concentrations of PFOS,perfluorohexane sulfonate(PFHxS),perfluorodecanoate(PFDeA),perfluorononanoate(PFNA),and n-perfluorooctanoate(n-PFOA)were linked to greater visceral adipose tissue in this group.In men,exposure to total perfluoroalkane sulfonates(PFSAs)and long-chain PFSAs was associated with reductions in abdominal fat,while higher abdominal fat in women aged 39-59 years was associated with short-chain PFSAs.The prediction model demonstrated high accuracy,with an area under the curve(AUC)of 0.9925 for predicting obesity risk.Conclusion PFAS exposure is associated with regional fat distribution,with varying effects based on age,sex,and PFAS structure.The findings highlight the potential role of PFAS exposure in influencing fat depots and obesity risk,with significant implications for public health.The prediction model provides a highly accurate tool for assessing obesity risk related to PFAS exposure.展开更多
Purpose-Interface management is the process of managing communications,responsibilities and coordination of project parties,phases or physical entities which are dependent on one another.Interface management is a cruc...Purpose-Interface management is the process of managing communications,responsibilities and coordination of project parties,phases or physical entities which are dependent on one another.Interface management is a crucial part of managing any construction project-but particularly important for high-speed railway projects that often have several contractual parties and stakeholders,very long project timelines and huge upfront cost overlays.This paper discusses how various project interfaces were managed during the design and construction of the civil engineering infrastructure for the High Speed Two(HS2)project in the United Kingdom.Design/methodology/approach-The paper uses the case study methodology.Key interfaces on the HS2 project are grouped into various categories and the paper discusses how they were managed within the Area North Integrated Project Team(IPT)of the HS2 project made up of contractor Balfour Beatty VINCI(BBV),the Mott MacDonald SYSTRA Design Joint Venture(DJV)and client HS2 Ltd.3 different case studies drawn from across the IPT are used,each of them highlighting different interfaces and how these interfaces were managed.Findings-The paper shows how innovative technical designs and modern methods of construction were used to address some of the unique and peculiar challenges of designing a brand-new railway in the United Kingdom.Addressing the contrasting and often competing requirements of different stakeholders,coupled with challenging physical constraints of the very limited land available for the project and the use of a rarely used Act of Parliament in the delivery of the project required different approach to interface management.Collaboration and proactive stakeholder engagement are necessary for successful interface management on megaprojects.The authors posit that adopting an integrated approach to engineering and construction management is an essential ingredient for the successful delivery of high-speed railway projects.Originality/value-With many high-speed railway projects around the world coming up in the next few years,understanding the context and challenges for each country will help engineering and design managers adopt appropriate approaches for their projects.The lessons learned on the HS2 project are also transferable to other mega infrastructure projects with complex project interfaces.展开更多
Against the backdrop of escalating global climate change and energy crises,the resource utilization of carbon dioxide(CO_(2)),a major greenhouse gas,has become a crucial pathway for achieving carbon peaking and carbon...Against the backdrop of escalating global climate change and energy crises,the resource utilization of carbon dioxide(CO_(2)),a major greenhouse gas,has become a crucial pathway for achieving carbon peaking and carbon neutrality goals.The hydrogenation of CO_(2)to methanol not only enables carbon sequestration and recycling,but also provides a route to produce high value-added fuels and basic chemical feedstocks,holding significant environmental and economic potential.However,this conversion process is thermodynamically and kinetically limited,and traditional catalyst systems(e.g.,Cu/ZnO/Al_(2)O_(3))exhibit inadequate activity,selectivity,and stability under mild conditions.Therefore,the development of novel high-performance catalysts with precisely tunable structures and functionalities is imperative.Metal-organic frameworks(MOFs),as crystalline porous materials with high surface area,tunable pore structures,and diverse metal-ligand compositions,have the great potential in CO_(2)hydrogenation catalysis.Their structural design flexibility allows for the construction of well-dispersed active sites,tailored electronic environments,and enhanced metal-support interactions.This review systematically summarizes the recent advances in MOF-based and MOF-derived catalysts for CO_(2)hydrogenation to methanol,focusing on four design strategies:(1)spatial confinement and in situ construction,(2)defect engineering and ion-exchange,(3)bimetallic synergy and hybrid structure design,and(4)MOF-derived nanomaterial synthesis.These approaches significantly improve CO_(2)conversion and methanol selectivity by optimizing metal dispersion,interfacial structures,and reaction pathways.The reaction mechanism is further explored by focusing on the three main reaction pathways:the formate pathway(HCOO*),the RWGS(Reverse Water Gas Shift reaction)+CO*hydrogenation pathway,and the trans-COOH pathway.In situ spectroscopic studies and density functional theory(DFT)calculations elucidate the formation and transformation of key intermediates,as well as the roles of active sites,metal-support interfaces,oxygen vacancies,and promoters.Additionally,representative catalytic performance data for MOFbased systems are compiled and compared,demonstrating their advantages over traditional catalysts in terms of CO_(2)conversion,methanol selectivity,and space-time yield.Future perspectives for MOF-based CO_(2)hydrogenation catalysts will prioritize two main directions:structural design and mechanistic understanding.The precise construction of active sites through multi-metallic synergy,defect engineering,and interfacial electronic modulation should be made to enhance catalyst selectivity and stability.In addition,advanced in situ characterization techniques combined with theoretical modeling are essential to unravel the detailed reaction mechanisms and intermediate behaviors,thereby guiding rational catalyst design.Moreover,to enable industrial application,challenges related to thermal/hydrothermal stability,catalyst recyclability,and cost-effective large-scale synthesis must be addressed.The development of green,scalable preparation methods and the integration of MOF catalysts into practical reaction systems(e.g.,flow reactors)will be crucial for bridging the gap between laboratory research and commercial deployment.Ultimately,multi-scale structure-performance optimization and catalytic system integration will be vital for accelerating the industrialization of MOF-based CO_(2)-to-methanol technologies.展开更多
As unmanned underwater vehicles (UUVs) are increasingly designed to perform long-duration missions in highly complex and often extreme environments, traditional design methods face significant and growing challenges^(...As unmanned underwater vehicles (UUVs) are increasingly designed to perform long-duration missions in highly complex and often extreme environments, traditional design methods face significant and growing challenges^([1,2]).展开更多
Compact size,high brightness,and wide field of view(FOV)are key requirements for long-wave infrared imagers used in military surveillance or night navigation.However,to meet the imaging requirements of high resolution...Compact size,high brightness,and wide field of view(FOV)are key requirements for long-wave infrared imagers used in military surveillance or night navigation.However,to meet the imaging requirements of high resolution and wide FOV,infrared optical systems often adopt complex optical lens groups,which will increase the size and weight of the optical system.In this paper,a strategy based on wavefront coding(WFC)is proposed to design a compact wide-FOV infrared imager.A cubic phase mask is inserted into the pupil plane of the infrared imager to correct the aberration.The simulated results show that,the WFC infrared imager has good imaging quality in a wide FOV of±16°.In addition,the WFC infrared imager achieves compactness with its 40 mm×40 mm×40 mm size.A fast focal ratio of 1 combined with an entrance pupil diameter of 25 mm ensures brightness.This work is of significance for designing a compact wide-FOV infrared imager.展开更多
In recent years,the use of deep learning to replace traditional numerical methods for electromagnetic propagation has shown tremendous potential in the rapid design of photonic devices.However,most research on deep le...In recent years,the use of deep learning to replace traditional numerical methods for electromagnetic propagation has shown tremendous potential in the rapid design of photonic devices.However,most research on deep learning has focused on single-layer grating couplers,and the accuracy of multi-layer grating couplers has not yet reached a high level.This paper proposes and demonstrates a novel deep learning network-assisted strategy for inverse design.The network model is based on a multi-layer perceptron(MLP)and incorporates convolutional neural networks(CNNs)and transformers.Through the stacking of multiple layers,it achieves a high-precision design for both multi-layer and single-layer raster couplers with various functionalities.The deep learning network exhibits exceptionally high predictive accuracy,with an average absolute error across the full wavelength range of 1300–1700 nm being only 0.17%,and an even lower predictive absolute error below 0.09%at the specific wavelength of 1550 nm.By combining the deep learning network with the genetic algorithm,we can efficiently design grating couplers that perform different functions.Simulation results indicate that the designed single-wavelength grating couplers achieve coupling efficiencies exceeding 80%at central wavelengths of 1550 nm and 1310 nm.The performance of designed dual-wavelength and broadband grating couplers also reaches high industry standards.Furthermore,the network structure and inverse design method are highly scalable and can be applied not only to multi-layer grating couplers but also directly to the prediction and design of single-layer grating couplers,providing a new perspective for the innovative development of photonic devices.展开更多
In this study,an inverse design framework was established to find lightweight honeycomb structures(HCSs)with high impact resistance.The hybrid HCS,composed of re-entrant(RE)and elliptical annular re-entrant(EARE)honey...In this study,an inverse design framework was established to find lightweight honeycomb structures(HCSs)with high impact resistance.The hybrid HCS,composed of re-entrant(RE)and elliptical annular re-entrant(EARE)honeycomb cells,was created by constructing arrangement matrices to achieve structural lightweight.The machine learning(ML)framework consisted of a neural network(NN)forward regression model for predicting impact resistance and a multi-objective optimization algorithm for generating high-performance designs.The surrogate of the local design space was initially realized by establishing the NN in the small sample dataset,and the active learning strategy was used to continuously extended the local optimal design until the model converged in the global space.The results indicated that the active learning strategy significantly improved the inference capability of the NN model in unknown design domains.By guiding the iteration direction of the optimization algorithm,lightweight designs with high impact resistance were identified.The energy absorption capacity of the optimal design reached 94.98%of the EARE honeycomb,while the initial peak stress and mass decreased by 28.85%and 19.91%,respectively.Furthermore,Shapley Additive Explanations(SHAP)for global explanation of the NN indicated a strong correlation between the arrangement mode of HCS and its impact resistance.By reducing the stiffness of the cells at the top boundary of the structure,the initial impact damage sustained by the structure can be significantly improved.Overall,this study proposed a general lightweight design method for array structures under impact loads,which is beneficial for the widespread application of honeycomb-based protective structures.展开更多
In recent years,there have been fewer missions to detect neutrons in low Earth orbits(LEO),and the data obtained have been extremely limited.Studying the distribution of the neutron energy spectrum in LEO satellites t...In recent years,there have been fewer missions to detect neutrons in low Earth orbits(LEO),and the data obtained have been extremely limited.Studying the distribution of the neutron energy spectrum in LEO satellites through detection can help solve three major scientific problems:the source of particles in the inner radiation belt,information on solar-accelerated particles,and the proportion of neutrons from different sources in near-Earth space.The detection efficiency and accuracy of neutrons are affected by charged and primary particles in the environment and secondary neutrons produced by the spacecraft itself,which has been a hot research topic.The neutron spectrometer developed in this study adopts two combinations of 15 silicon detectors in terms of detector type and arrangement,which are used for neutron detection via the nuclear reaction method and recoil proton method,respectively,in which a 27μm-thick^(6)LiF conversion layer is used for thermal neutron detection up to 0.4 eV and a 300μm-thick high-density polyethylene conversion layer is used for fast-neutron detection up to 14 MeV and below.The design of the detector set can also remove the influence of primary charged particles and secondary neutrons in the detection environment to a certain extent,thereby improving the accuracy of neutron detection.In this study,the neutron spectrometer hardware,firmware,software design,and basic performance of the front-end readout chip SKIROC2A were tested.The readout circuit of each channel baseline ADC code was less than 17;thus,the channel consistency was good.The RMS noise of the channel baseline was only 7.1 mV and exhibited good stability.The maximum number of events that could be processed per second is 75.The overall power consumption was 3 W,the weight was 792 g,and the volume was less than 1 dm^(3).Furthermore,the neutron spectrometer was tested for principle and detection efficiency using various neutron sources,such as ^(241)Am-Be neutron source,2.5 MeV neutron beam,and 14 MeV neutron beam,and the experiments were analyzed with corresponding simulations.The experimental data and simulation results were in good agreement and met the design requirements.The intrinsic detection efficiency of the probes used in the neutron spectrometer was 1.05%for 14 MeV fast neutrons.展开更多
Lithium-sulfur batteries(LSBs)represent a next-generation energy storage technology,but widespread applications are restricted by the shuttle of lithium polysulfides(LiPSs).The rational design of separators has been d...Lithium-sulfur batteries(LSBs)represent a next-generation energy storage technology,but widespread applications are restricted by the shuttle of lithium polysulfides(LiPSs).The rational design of separators has been demonstrated to be one of the most efficient and cost-effective strategies to curb the shuttle effect,and tremendous research progress has been achieved.The efficiency of a separator depends on its interaction with LiPSs,which is governed by the surface energy and binding strength.Despite several review works that have been reported to advance the separators,most of them primarily focus on active material innovation and construction.The most crucial issues of surface binding energy have not been systematically reviewed,limiting the precise design of efficient separators.In this review,fundamentals related to surface energy and binding interactions with LiPSs are comprehensively analyzed and discussed.With surface binding and energy main lines,the advancements in separator engineering strategies are elaborately summarized and discussed.Moreover,techniques for evaluating affinity to LiPSs are thoroughly analyzed to avoid any ambiguities in measurement.Based on the research context,valuable research directions are suggested to construct efficient separators.This work provides guidelines to regulate the surface binding and energy of separators for high-performance LSBs.展开更多
Machine learning(ML)is recognized as a potent tool for the inverse design of environmental functional material,particularly for complex entities like biochar-based catalysts(BCs).Thus,the tailored BCs can have a disti...Machine learning(ML)is recognized as a potent tool for the inverse design of environmental functional material,particularly for complex entities like biochar-based catalysts(BCs).Thus,the tailored BCs can have a distinct ability to trigger the nonradical pathway in advance oxidation processes(AOPs),promising a stable,rapid and selective degradation of persistent contaminants.However,due to the inherent“black box”nature and limitations of input features,results and conclusions derived from ML may not always be intuitively understood or comprehensively validated.To tackle this challenge,we linked the front-point interpretable analysis approaches with back-point density functional theory(DFT)calculations to form a chained learning strategy for deeper sight into the intrinsic activation mechanism of BCs in AOPs.At the front point,we conducted an easy-to-interpret meta-analysis to validate two strategies for enhancing nonradical pathways by increasing oxygen content and specific surface area(SSA),and prepared oxidized biochar(OBC500)and SSA-increased biochar(SBC900)by controlling pyrolysis conditions and modification methods.Subsequently,experimental results showed that OBC500 and SBC900 had distinct dominant degradation pathways for 1O2 generation and electron transfer,respectively.Finally,at the end point,DFT calculations revealed their active sites and degradation mechanisms.This chained learning strategy elucidates fundamental principles for BC inverse design and showcases the exceptional capacity to integrate computational techniques to accelerate catalyst inverse design.展开更多
From an engineering feasibility standpoint, what level of performance metrics can be ultimately achieved when designing a reactor using well-established nuclear fuels and structural materials that have already undergo...From an engineering feasibility standpoint, what level of performance metrics can be ultimately achieved when designing a reactor using well-established nuclear fuels and structural materials that have already undergone irradiation testing? The irradiation capability, which hinges on parameters like neutron flux level, irradiation channels' volume, and fuel cycle duration, is a core indicator for high-flux reactors. We propose a conceptual design of an ultra-high flux fast reactor(UFFR) with strong irradiation capability, which utilizes U-20Pu-10Zr alloy fuel and employs lead-bismuth as the coolant. The maximum neutron flux in the core reaches 1.32×10^(16) cm^(-2)s^(-1), while the average neutron flux in the irradiation channels attains 1.19×10^(16) cm^(-2)s^(-1). The volume of the central irradiation channel exceeds 10000 cm^(3), and the fuel cycle duration is 165 d, placing all its performance indicators among the top in the world. Based on the analyses of reactor physics and thermalhydraulics, it has been demonstrated that all reactivity coefficients are negative and all physical parameters meet the design criteria, ensuring the inherent safety of UFFR. An assessment of the irradiation capability has been carried out based on californium-252(^(252)Cf) production, indicating that the irradiation capability of UFFR surpasses that of the high flux isotope reactor(HFIR). The yield of ^(252)Cf from UFFR is 14.39 times that of HFIR, and its nuclei conversion rate is 3.21 times that of HFIR.展开更多
Cases of widespread bone hydatid infection are relatively rare in clinical practice.In this study,we reported for the first time a validated integrated repair therapy for multiple bone tissues,including the hip,femur,...Cases of widespread bone hydatid infection are relatively rare in clinical practice.In this study,we reported for the first time a validated integrated repair therapy for multiple bone tissues,including the hip,femur,and knee,caused by echinococ cosis.Artificial intelligence(AI)was used to develop a targeted surgical plan and to design a personalized prosthesis.Finite element analysis(FEA)was used to optimize the mechanical effectiveness of a customized integrated replacement prosthesis and to model stress distribution in the surrounding bone.Three-dimensional(3 D)printing was used to fabricate a customized prosthesis.With the assistance of AI,FEA,and 3 D printing technology,a personalized surgical plan and customized prosthesis were successfully constructed based on the patient’s disease.This approach achieved a successful therapeutic effect,demonstrating that AI-assisted personalized medicine holds great promise for the future.展开更多
基金Research Project of Hangzhou Normal University,China(Grant No.:2024JCXK06).
文摘β-elemene,a bioactive compound derived from traditional Chinese medicine(TCM),has been clinically used in cancer therapy.However,its molecular physicochemical properties require further optimization,and its precise anticancer mechanisms remain unknown.In modern drug development,structure-based drug design(SBDD)has significantly conserved resources,with computer-aided techniques such as molecular docking and molecule generation playing essential roles.A comprehensive review of existing molecular biology studies and virtual docking experiments led to the hypothesis that methyltransferaselike 3(METTL3)may serve as a potential target ofβ-elemene.This discovery establishes a scientific foundation for integrating advanced,rational drug design strategies withβ-elemene to enhance the therapeutic efficacy of TCM.Moreover,current artificial intelligence(AI)-based molecular generation models were examined,focusing on de novo molecular generation and lead optimization models.Their applications in the rational drug design ofβ-elemene were preliminarily explored to identify potential strategies for developing more potent anticancer derivatives by analyzing ligand-receptor interactions.
基金supported by the National Basic Research Program of China(No.2004CB518908)the National High Technology Research and Development Program of China(No.2006AA020601)
文摘Mycobacterium tuberculosis FabH, an essential enzyme in mycolic acids biosynthetic pathway, is an attractive target for novel anti-tuberculosis agents. Structure-based design, synthesis of novel inhibitors of mtFabH was reported in this paper. A novel scaffold structure was designed, and 12 candidate compounds that displayed favorable binding with the active site were identified and synthesized. 2009 Song Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
基金National Natural Science Foundation of China (Grant No.20772008 and 30772650)
文摘Based upon the crystal structure of a previously reported fragment hit that binds to Corresponding author. β-secretase, a novel series of non-peptidic small-molecule β-secretase inhibitors, namely hexahydropyrimidin-5-ols, along with two series of their analogues, were rationally designed through structural modification. The CADD study was performed and revealed good expectation. Inhibitory activities of the corresponding structural cores were tested, which provided further support for our design approach.
基金supported by the Shanghai Family Planning Commission Research Fund(No2007JG02)Shanghai Leading Academic Discipline Project(NoB906)
文摘A series of 7-azaindol derivatives were designed based on the homologous 3D model of human acrosin.These compounds were synthesized and evaluated for their human acrosin inhibitory activities in vitro.Compounds 7a,7i,7j,7k and 7n showed highly inhibitory activity against human acrosin.The three-dimensional structure-activity relationship was investigated through a CoMFA model,which provided valuable information to further study of potential human acrosin inhibitors.
基金National Natural Science Foundation of China(Grant No.21772005,81872730)the Beijing Natural Science Foundation(Grant No.7202088,7172118)。
文摘The mammalian target of rapamycin(mTOR) is a critical component of the PI3K-AKT signaling pathway. It is highly activated in cervical cancer, which continues to pose an important clinical challenge with an urgent need for new and improved therapeutic approaches. Herein, we describe the structure-based drug discovery and biological evaluation of a series of m TOR kinase inhibitors as potential anti-cervical cancer agents. The results of enzymatic activity assays supported C3 as a potential m TOR inhibitor, which exhibited high inhibitory activity with an IC50 of 1.57 μM. Molecular docking and dynamics simulation were conducted to predict the binding patterns, suggesting relationships between structure and activity. The anti-proliferative assay against diverse cancer cell lines was displayed subsequently, revealing that C3 exhibited significant proliferation inhibition against cervical cancer cell He La(IC50=0.38μM) compared with other cell lines. Moreover, C3 could effectively reduce the expression of phospho-ribosomal S6 protein(p-S6) in He La cells in a dose-dependent manner. Noteworthily, m TOR signaling and other cellular pathways might contribute to the significant effect of C3 against cervical cancer simultaneously. These data indicated that C3 represented a good lead molecule for further development as a therapeutic agent for cervical cancer treatment.
基金by the National Basic Research Program(973 Program)(Grant No.2011CB504703)We are grateful to Dr Christopher Vavricka and Dr Guangwen Lu for their help.GFG is a leading principal investigator of the Innovative Research Group of the National Natural Science Foundation of China(Grant No.81021003).
文摘There is a great need for new vaccine development against influenza A viruses due to the drawbacks of traditional vaccines that are mainly prepared using embryonated eggs.The main component of the current split influenza A virus vaccine is viral hemagglutinin(HA)which induces a strong antibody-mediated immune response.To develop a modern vaccine against influenza A viruses,the current research has been focused on the universal vaccines targeting viral M2,NP and HA proteins.Crystallographic studies have shown that HA forms a trimer embedded on the viral envelope surface,and each monomer consists of a globular head(HA1)and a“rod-like”stalk region(HA2),the latter being more conserved among different HA subtypes and being the primary target for universal vaccines.In this study,we rationally designed the HA head based on the crystal structure of the 2009-pandemic influenza A(H1N1)virus HA as a model,tested its immunogenicity in mice,solved its crystal structure and further examined its immunological characteristics.The results show that the HA globular head can be easily prepared by in vitro refolding in an E.coli expression system,which maintains its intact structure and allows for the stimulation of a strong immune response.Together with recent reports on some similar HA globular head preparations we conclude that structure-based rational design of the HA globular head can be used for subtype-specific vaccines against influenza viruses.
基金supported by the National Key R&D Program of China(No.2021YFC2700605)the National Natural Science Foundation of China(82071700 and 82101679)+4 种基金333 High-level Talent Training Project of the Jiangsu Province((2022)3-16-425)the Natural Science Foundation of Jiangsu Province(BK20220317)Jiangsu Funding Program for Excellent Postdoctoral Talent(2022ZB414)the Natural Science Foundation of the Jiangsu Higher Education Institutions of China(22KJB330001)China Postdoctoral Science Foundation(2022M711673).
文摘Objective To investigate the associations between eight serum per-and polyfluoroalkyl substances(PFASs)and regional fat depots,we analyzed the data from the National Health and Nutrition Examination Survey(NHANES)2011-2018 cycles.Methods Multiple linear regression models were developed to explore the associations between serum PFAS concentrations and six fat compositions along with a fat distribution score created by summing the concentrations of the six fat compositions.The associations between structurally grouped PFASs and fat distribution were assessed,and a prediction model was developed to estimate the ability of PFAS exposure to predict obesity risk.Results Among females aged 39-59 years,trunk fat mass was positively associated with perfluorooctane sulfonate(PFOS).Higher concentrations of PFOS,perfluorohexane sulfonate(PFHxS),perfluorodecanoate(PFDeA),perfluorononanoate(PFNA),and n-perfluorooctanoate(n-PFOA)were linked to greater visceral adipose tissue in this group.In men,exposure to total perfluoroalkane sulfonates(PFSAs)and long-chain PFSAs was associated with reductions in abdominal fat,while higher abdominal fat in women aged 39-59 years was associated with short-chain PFSAs.The prediction model demonstrated high accuracy,with an area under the curve(AUC)of 0.9925 for predicting obesity risk.Conclusion PFAS exposure is associated with regional fat distribution,with varying effects based on age,sex,and PFAS structure.The findings highlight the potential role of PFAS exposure in influencing fat depots and obesity risk,with significant implications for public health.The prediction model provides a highly accurate tool for assessing obesity risk related to PFAS exposure.
文摘Purpose-Interface management is the process of managing communications,responsibilities and coordination of project parties,phases or physical entities which are dependent on one another.Interface management is a crucial part of managing any construction project-but particularly important for high-speed railway projects that often have several contractual parties and stakeholders,very long project timelines and huge upfront cost overlays.This paper discusses how various project interfaces were managed during the design and construction of the civil engineering infrastructure for the High Speed Two(HS2)project in the United Kingdom.Design/methodology/approach-The paper uses the case study methodology.Key interfaces on the HS2 project are grouped into various categories and the paper discusses how they were managed within the Area North Integrated Project Team(IPT)of the HS2 project made up of contractor Balfour Beatty VINCI(BBV),the Mott MacDonald SYSTRA Design Joint Venture(DJV)and client HS2 Ltd.3 different case studies drawn from across the IPT are used,each of them highlighting different interfaces and how these interfaces were managed.Findings-The paper shows how innovative technical designs and modern methods of construction were used to address some of the unique and peculiar challenges of designing a brand-new railway in the United Kingdom.Addressing the contrasting and often competing requirements of different stakeholders,coupled with challenging physical constraints of the very limited land available for the project and the use of a rarely used Act of Parliament in the delivery of the project required different approach to interface management.Collaboration and proactive stakeholder engagement are necessary for successful interface management on megaprojects.The authors posit that adopting an integrated approach to engineering and construction management is an essential ingredient for the successful delivery of high-speed railway projects.Originality/value-With many high-speed railway projects around the world coming up in the next few years,understanding the context and challenges for each country will help engineering and design managers adopt appropriate approaches for their projects.The lessons learned on the HS2 project are also transferable to other mega infrastructure projects with complex project interfaces.
基金Supported by the National Key Research and Development Program of China(2023YFB4104500,2023YFB4104502)the National Natural Science Foundation of China(22138013)the Taishan Scholar Project(ts201712020).
文摘Against the backdrop of escalating global climate change and energy crises,the resource utilization of carbon dioxide(CO_(2)),a major greenhouse gas,has become a crucial pathway for achieving carbon peaking and carbon neutrality goals.The hydrogenation of CO_(2)to methanol not only enables carbon sequestration and recycling,but also provides a route to produce high value-added fuels and basic chemical feedstocks,holding significant environmental and economic potential.However,this conversion process is thermodynamically and kinetically limited,and traditional catalyst systems(e.g.,Cu/ZnO/Al_(2)O_(3))exhibit inadequate activity,selectivity,and stability under mild conditions.Therefore,the development of novel high-performance catalysts with precisely tunable structures and functionalities is imperative.Metal-organic frameworks(MOFs),as crystalline porous materials with high surface area,tunable pore structures,and diverse metal-ligand compositions,have the great potential in CO_(2)hydrogenation catalysis.Their structural design flexibility allows for the construction of well-dispersed active sites,tailored electronic environments,and enhanced metal-support interactions.This review systematically summarizes the recent advances in MOF-based and MOF-derived catalysts for CO_(2)hydrogenation to methanol,focusing on four design strategies:(1)spatial confinement and in situ construction,(2)defect engineering and ion-exchange,(3)bimetallic synergy and hybrid structure design,and(4)MOF-derived nanomaterial synthesis.These approaches significantly improve CO_(2)conversion and methanol selectivity by optimizing metal dispersion,interfacial structures,and reaction pathways.The reaction mechanism is further explored by focusing on the three main reaction pathways:the formate pathway(HCOO*),the RWGS(Reverse Water Gas Shift reaction)+CO*hydrogenation pathway,and the trans-COOH pathway.In situ spectroscopic studies and density functional theory(DFT)calculations elucidate the formation and transformation of key intermediates,as well as the roles of active sites,metal-support interfaces,oxygen vacancies,and promoters.Additionally,representative catalytic performance data for MOFbased systems are compiled and compared,demonstrating their advantages over traditional catalysts in terms of CO_(2)conversion,methanol selectivity,and space-time yield.Future perspectives for MOF-based CO_(2)hydrogenation catalysts will prioritize two main directions:structural design and mechanistic understanding.The precise construction of active sites through multi-metallic synergy,defect engineering,and interfacial electronic modulation should be made to enhance catalyst selectivity and stability.In addition,advanced in situ characterization techniques combined with theoretical modeling are essential to unravel the detailed reaction mechanisms and intermediate behaviors,thereby guiding rational catalyst design.Moreover,to enable industrial application,challenges related to thermal/hydrothermal stability,catalyst recyclability,and cost-effective large-scale synthesis must be addressed.The development of green,scalable preparation methods and the integration of MOF catalysts into practical reaction systems(e.g.,flow reactors)will be crucial for bridging the gap between laboratory research and commercial deployment.Ultimately,multi-scale structure-performance optimization and catalytic system integration will be vital for accelerating the industrialization of MOF-based CO_(2)-to-methanol technologies.
基金supported by the National Natural Science Foundation of China (Grant No.52405033)。
文摘As unmanned underwater vehicles (UUVs) are increasingly designed to perform long-duration missions in highly complex and often extreme environments, traditional design methods face significant and growing challenges^([1,2]).
文摘Compact size,high brightness,and wide field of view(FOV)are key requirements for long-wave infrared imagers used in military surveillance or night navigation.However,to meet the imaging requirements of high resolution and wide FOV,infrared optical systems often adopt complex optical lens groups,which will increase the size and weight of the optical system.In this paper,a strategy based on wavefront coding(WFC)is proposed to design a compact wide-FOV infrared imager.A cubic phase mask is inserted into the pupil plane of the infrared imager to correct the aberration.The simulated results show that,the WFC infrared imager has good imaging quality in a wide FOV of±16°.In addition,the WFC infrared imager achieves compactness with its 40 mm×40 mm×40 mm size.A fast focal ratio of 1 combined with an entrance pupil diameter of 25 mm ensures brightness.This work is of significance for designing a compact wide-FOV infrared imager.
基金sponsored by the National Key Scientific Instrument and Equipment Development Projects of China(Grant No.62027823)the National Natural Science Foun-dation of China(Grant No.61775048).
文摘In recent years,the use of deep learning to replace traditional numerical methods for electromagnetic propagation has shown tremendous potential in the rapid design of photonic devices.However,most research on deep learning has focused on single-layer grating couplers,and the accuracy of multi-layer grating couplers has not yet reached a high level.This paper proposes and demonstrates a novel deep learning network-assisted strategy for inverse design.The network model is based on a multi-layer perceptron(MLP)and incorporates convolutional neural networks(CNNs)and transformers.Through the stacking of multiple layers,it achieves a high-precision design for both multi-layer and single-layer raster couplers with various functionalities.The deep learning network exhibits exceptionally high predictive accuracy,with an average absolute error across the full wavelength range of 1300–1700 nm being only 0.17%,and an even lower predictive absolute error below 0.09%at the specific wavelength of 1550 nm.By combining the deep learning network with the genetic algorithm,we can efficiently design grating couplers that perform different functions.Simulation results indicate that the designed single-wavelength grating couplers achieve coupling efficiencies exceeding 80%at central wavelengths of 1550 nm and 1310 nm.The performance of designed dual-wavelength and broadband grating couplers also reaches high industry standards.Furthermore,the network structure and inverse design method are highly scalable and can be applied not only to multi-layer grating couplers but also directly to the prediction and design of single-layer grating couplers,providing a new perspective for the innovative development of photonic devices.
基金the financial supports from National Key R&D Program for Young Scientists of China(Grant No.2022YFC3080900)National Natural Science Foundation of China(Grant No.52374181)+1 种基金BIT Research and Innovation Promoting Project(Grant No.2024YCXZ017)supported by Science and Technology Innovation Program of Beijing institute of technology under Grant No.2022CX01025。
文摘In this study,an inverse design framework was established to find lightweight honeycomb structures(HCSs)with high impact resistance.The hybrid HCS,composed of re-entrant(RE)and elliptical annular re-entrant(EARE)honeycomb cells,was created by constructing arrangement matrices to achieve structural lightweight.The machine learning(ML)framework consisted of a neural network(NN)forward regression model for predicting impact resistance and a multi-objective optimization algorithm for generating high-performance designs.The surrogate of the local design space was initially realized by establishing the NN in the small sample dataset,and the active learning strategy was used to continuously extended the local optimal design until the model converged in the global space.The results indicated that the active learning strategy significantly improved the inference capability of the NN model in unknown design domains.By guiding the iteration direction of the optimization algorithm,lightweight designs with high impact resistance were identified.The energy absorption capacity of the optimal design reached 94.98%of the EARE honeycomb,while the initial peak stress and mass decreased by 28.85%and 19.91%,respectively.Furthermore,Shapley Additive Explanations(SHAP)for global explanation of the NN indicated a strong correlation between the arrangement mode of HCS and its impact resistance.By reducing the stiffness of the cells at the top boundary of the structure,the initial impact damage sustained by the structure can be significantly improved.Overall,this study proposed a general lightweight design method for array structures under impact loads,which is beneficial for the widespread application of honeycomb-based protective structures.
基金supported by the National Natural Science Foundation of China(NSFC)(Nos.42225405 and U2106202)。
文摘In recent years,there have been fewer missions to detect neutrons in low Earth orbits(LEO),and the data obtained have been extremely limited.Studying the distribution of the neutron energy spectrum in LEO satellites through detection can help solve three major scientific problems:the source of particles in the inner radiation belt,information on solar-accelerated particles,and the proportion of neutrons from different sources in near-Earth space.The detection efficiency and accuracy of neutrons are affected by charged and primary particles in the environment and secondary neutrons produced by the spacecraft itself,which has been a hot research topic.The neutron spectrometer developed in this study adopts two combinations of 15 silicon detectors in terms of detector type and arrangement,which are used for neutron detection via the nuclear reaction method and recoil proton method,respectively,in which a 27μm-thick^(6)LiF conversion layer is used for thermal neutron detection up to 0.4 eV and a 300μm-thick high-density polyethylene conversion layer is used for fast-neutron detection up to 14 MeV and below.The design of the detector set can also remove the influence of primary charged particles and secondary neutrons in the detection environment to a certain extent,thereby improving the accuracy of neutron detection.In this study,the neutron spectrometer hardware,firmware,software design,and basic performance of the front-end readout chip SKIROC2A were tested.The readout circuit of each channel baseline ADC code was less than 17;thus,the channel consistency was good.The RMS noise of the channel baseline was only 7.1 mV and exhibited good stability.The maximum number of events that could be processed per second is 75.The overall power consumption was 3 W,the weight was 792 g,and the volume was less than 1 dm^(3).Furthermore,the neutron spectrometer was tested for principle and detection efficiency using various neutron sources,such as ^(241)Am-Be neutron source,2.5 MeV neutron beam,and 14 MeV neutron beam,and the experiments were analyzed with corresponding simulations.The experimental data and simulation results were in good agreement and met the design requirements.The intrinsic detection efficiency of the probes used in the neutron spectrometer was 1.05%for 14 MeV fast neutrons.
基金supported by the National Natural Science Foundation of China (52172228)the Natural Science Foundation of Fujian Province (2024J01475 and 2023J05127)
文摘Lithium-sulfur batteries(LSBs)represent a next-generation energy storage technology,but widespread applications are restricted by the shuttle of lithium polysulfides(LiPSs).The rational design of separators has been demonstrated to be one of the most efficient and cost-effective strategies to curb the shuttle effect,and tremendous research progress has been achieved.The efficiency of a separator depends on its interaction with LiPSs,which is governed by the surface energy and binding strength.Despite several review works that have been reported to advance the separators,most of them primarily focus on active material innovation and construction.The most crucial issues of surface binding energy have not been systematically reviewed,limiting the precise design of efficient separators.In this review,fundamentals related to surface energy and binding interactions with LiPSs are comprehensively analyzed and discussed.With surface binding and energy main lines,the advancements in separator engineering strategies are elaborately summarized and discussed.Moreover,techniques for evaluating affinity to LiPSs are thoroughly analyzed to avoid any ambiguities in measurement.Based on the research context,valuable research directions are suggested to construct efficient separators.This work provides guidelines to regulate the surface binding and energy of separators for high-performance LSBs.
基金supported by Project of National and Local Joint Engineering Research Center for Biomass Energy Development and Utilization(Harbin Institute of Technology,No.2021A004).
文摘Machine learning(ML)is recognized as a potent tool for the inverse design of environmental functional material,particularly for complex entities like biochar-based catalysts(BCs).Thus,the tailored BCs can have a distinct ability to trigger the nonradical pathway in advance oxidation processes(AOPs),promising a stable,rapid and selective degradation of persistent contaminants.However,due to the inherent“black box”nature and limitations of input features,results and conclusions derived from ML may not always be intuitively understood or comprehensively validated.To tackle this challenge,we linked the front-point interpretable analysis approaches with back-point density functional theory(DFT)calculations to form a chained learning strategy for deeper sight into the intrinsic activation mechanism of BCs in AOPs.At the front point,we conducted an easy-to-interpret meta-analysis to validate two strategies for enhancing nonradical pathways by increasing oxygen content and specific surface area(SSA),and prepared oxidized biochar(OBC500)and SSA-increased biochar(SBC900)by controlling pyrolysis conditions and modification methods.Subsequently,experimental results showed that OBC500 and SBC900 had distinct dominant degradation pathways for 1O2 generation and electron transfer,respectively.Finally,at the end point,DFT calculations revealed their active sites and degradation mechanisms.This chained learning strategy elucidates fundamental principles for BC inverse design and showcases the exceptional capacity to integrate computational techniques to accelerate catalyst inverse design.
基金supported by the National Natural Science Foundation of China (Grant No.12575180)the Lingchuang Research Project of China National Nuclear Corporation (CNNC)。
文摘From an engineering feasibility standpoint, what level of performance metrics can be ultimately achieved when designing a reactor using well-established nuclear fuels and structural materials that have already undergone irradiation testing? The irradiation capability, which hinges on parameters like neutron flux level, irradiation channels' volume, and fuel cycle duration, is a core indicator for high-flux reactors. We propose a conceptual design of an ultra-high flux fast reactor(UFFR) with strong irradiation capability, which utilizes U-20Pu-10Zr alloy fuel and employs lead-bismuth as the coolant. The maximum neutron flux in the core reaches 1.32×10^(16) cm^(-2)s^(-1), while the average neutron flux in the irradiation channels attains 1.19×10^(16) cm^(-2)s^(-1). The volume of the central irradiation channel exceeds 10000 cm^(3), and the fuel cycle duration is 165 d, placing all its performance indicators among the top in the world. Based on the analyses of reactor physics and thermalhydraulics, it has been demonstrated that all reactivity coefficients are negative and all physical parameters meet the design criteria, ensuring the inherent safety of UFFR. An assessment of the irradiation capability has been carried out based on californium-252(^(252)Cf) production, indicating that the irradiation capability of UFFR surpasses that of the high flux isotope reactor(HFIR). The yield of ^(252)Cf from UFFR is 14.39 times that of HFIR, and its nuclei conversion rate is 3.21 times that of HFIR.
基金partially supported by the National Natural Science Foundation of China(Nos.32471474 and 82102574)the Precision Medicine Project of People’s Hospital of Xinjiang Uygur Autonomous Region(No.20220305)+4 种基金Chengdu Advanced Metal Materials Industry Technology Research Institute Co.,Ltd.Support Project(No.24H0802)Sichuan Science and Technology Program(Nos.2025YFHZ0086,2023YFS0053,2024YFHZ0125,and 2025ZNSFSC0381)Project of Tianfu Jincheng Laboratory(No.2025ZH009)Guangdong Basic and Applied Basic Research Foundation(No.2023A1515220102)Xinjiang Autonomous Region Science and Technology Support Project Plan(Directive)Project(No.2024E02049)。
文摘Cases of widespread bone hydatid infection are relatively rare in clinical practice.In this study,we reported for the first time a validated integrated repair therapy for multiple bone tissues,including the hip,femur,and knee,caused by echinococ cosis.Artificial intelligence(AI)was used to develop a targeted surgical plan and to design a personalized prosthesis.Finite element analysis(FEA)was used to optimize the mechanical effectiveness of a customized integrated replacement prosthesis and to model stress distribution in the surrounding bone.Three-dimensional(3 D)printing was used to fabricate a customized prosthesis.With the assistance of AI,FEA,and 3 D printing technology,a personalized surgical plan and customized prosthesis were successfully constructed based on the patient’s disease.This approach achieved a successful therapeutic effect,demonstrating that AI-assisted personalized medicine holds great promise for the future.
