Time?varying mesh stiffness(TVMS) and gear errors include short?term and long?term components are the two main internal dynamic excitations for gear transmission. The coupling relationship between the two factors is u...Time?varying mesh stiffness(TVMS) and gear errors include short?term and long?term components are the two main internal dynamic excitations for gear transmission. The coupling relationship between the two factors is usually neglected in the traditional quasi-static and dynamic behaviors analysis of gear system. This paper investigates the influence of short?term and long?term components of manufacturing errors on quasi?static and dynamic behaviors of helical gear system considering the coupling relationship between TVMS and gear errors. The TVMS, loaded static transmission error(LSTE) and loaded composite mesh error(LCMS) are determined using an improved loaded tooth contact analysis(LTCA) model. Considering the structure of shaft, as well as the direction of power flow and bearing location, a precise generalized finite element dynamic model of helical gear system is developed, and the dynamic responses of the system are obtained by numerical integration method. The results suggest that lighter loading conditions result in smaller mesh stiffness and stronger vibration, and the corresponding resonance speeds of the system become lower. Long?term components of manufacturing errors lead to the appearance of sideband frequency components in frequency spectrum of dynamic responses. The sideband frequency components are predominant under light loading conditions. With the increase of output torque, the mesh frequency and its harmonics components tend to be enhanced relative to sideband frequency components. This study can provide effective reference for low noise design of gear transmission.展开更多
Motivated by the Fermi observations of some γ-ray pulsars in which the phases of radio and γ-ray peaks are almost the same, we investigate the outer gap model in a retarded dipole with a current-induced magnetic fie...Motivated by the Fermi observations of some γ-ray pulsars in which the phases of radio and γ-ray peaks are almost the same, we investigate the outer gap model in a retarded dipole with a current-induced magnetic field and apply it to explain pulsed γ-ray properties of the Crab pulsar. Our results show that the observed γ-ray energy-dependent light curves, which almost align with the radio light curve and phase averaged spectrum for the Crab pulsar, are reproduced well.展开更多
On the basis of clarifying the teachers'Ethics internalization theory,this paper analyzes the typical dilemma in teachers'Ethics internalization.To resolve these problems,this paper construct an overall framew...On the basis of clarifying the teachers'Ethics internalization theory,this paper analyzes the typical dilemma in teachers'Ethics internalization.To resolve these problems,this paper construct an overall framework,including security mechanism,normative mechanism,education mechanism,evaluation mechanism and supervision mechanism,which the external conditions are used to constantly strengthen the moral needs of the subject,then enhance the consciousness of moral internalization,improve the effectiveness of teachers'moral construction.展开更多
Protein kinase Cα(PKCα)regulates diverse biological functions of cancer cells and is a promising therapeutic target.However,clinical trials of PKC-targeted therapies have not yielded satisfactory results.Recent stud...Protein kinase Cα(PKCα)regulates diverse biological functions of cancer cells and is a promising therapeutic target.However,clinical trials of PKC-targeted therapies have not yielded satisfactory results.Recent studies have also indicated a tumor-suppressive role of PKCs via unclear molecular mechanisms.In this study,we found that PKCαinhibition enhances CD8+T-cell-mediated tumor evasion and abolishes antitumor activity in immunocompetent mice.We further identified PKCαas a critical regulator of programmed cell death-ligand 1(PD-L1)and found that it enhances T-cell-dependent antitumor immunity in breast cancer by interacting with PD-L1 and suppressing PD-L1 expression.We demonstrated that PKCα-mediated PD-L1 phosphorylation promotes PD-L1 degradation throughβtransducin repeat-containing protein.Notably,the efficacy of PKCαinhibitors was intensified by synergizing with anti-PD-L1 mAb therapy to boost antitumor T-cell immunity in vivo.Clinical analysis revealed that PKCαexpression is positively correlated with T-cell function and the interferon-gamma signature in patients with breast cancer.This study demonstrated the antitumor capability of PKCα,identified potential therapeutic strategies to avoid tumor evasion via PKC-targeted therapies,and provided a proof of concept for targeting PKCαin combination with anti-PD-L1 mAb therapy as a potential therapeutic approach against breast cancer,especially TNBC.展开更多
Androgen receptor(AR) is a ligand-activated transcription factor that plays a pivotal role in the development and progression of many severe diseases such as prostate cancer, muscle atrophy, and osteoporosis. Binding ...Androgen receptor(AR) is a ligand-activated transcription factor that plays a pivotal role in the development and progression of many severe diseases such as prostate cancer, muscle atrophy, and osteoporosis. Binding of ligands to AR triggers the conformational changes in AR that may affect the recruitment of coactivators and downstream response of AR signaling pathway.Therefore, AR ligands have great potential to treat these diseases. In this study, we searched for novel AR ligands by performing a docking-based virtual screening(VS) on the basis of the crystal structure of the AR ligand binding domain(LBD) in complex with its agonist. A total of 58 structurally diverse compounds were selected and subjected to LBD affinity assay, with five of them(HBP1-3, HBP1-17, HBP1-38, HBP1-51, and HBP1-58) exhibiting strong binding to AR-LBD. The IC50 values of HBP1-51 and HBP1-58 are 3.96 m M and 4.92 m M, respectively, which are even lower than that of enzalutamide(Enz, IC50= 13.87 m M), a marketed second-generation AR antagonist. Further bioactivity assays suggest that HBP1-51 is an AR agonist, whereas HBP1-58 is an AR antagonist. In addition, molecular dynamics(MD) simulations and principal components analysis(PCA) were carried out to reveal the binding principle of the newlyidentified AR ligands toward AR. Our modeling results indicate that the conformational changes of helix 12 induced by the bindings of antagonist and agonist are visibly different. In summary,the current study provides a highly efficient way to discover novel AR ligands, which could serve as the starting point for development of new therapeutics for AR-related diseases.展开更多
Radiolarians form an important part of the planktonic realm in the ocean of Early Paleozoic, but their origin and evolutionary processes has long been enigmatic. The ancestral representatives of radiolarians have been...Radiolarians form an important part of the planktonic realm in the ocean of Early Paleozoic, but their origin and evolutionary processes has long been enigmatic. The ancestral representatives of radiolarians have been considered to belong to the order Archaeospicularia, whose unquestionable fossil records were dated back to the Middle Cambrian. Here we report ？Blastulospongia and unnamed spherical radiolarians in the Terreneuvian from the Yanjiabe Formation in Hubei Province, South China. Blastulospongia is an enigmatic siliceous microfossil genus, with affinities proposed amongst the radiolarian, sphinetozoan-grade sponges and uncertain protists. As for the newly discovered unnamed radiolarians, morphologically they possess latticed shell, spherical shape and are all small in size. Our discoveries support the idea that spherical radiolarians is an ancient representative, whose origin and diversification was probably much earlier than generally accepted. The hypothesis that the oldest radiolarians belong to the order Archaeospicularia needs to be re-examined.展开更多
Residue networks are constructed by defining the residues as the vertices and atom contacts between them as the edges. The residue network of a protein complex is divided into two types of networks, i.e. the hydrophob...Residue networks are constructed by defining the residues as the vertices and atom contacts between them as the edges. The residue network of a protein complex is divided into two types of networks, i.e. the hydrophobic and the hydrophilic residue networks. By analyzing the network parameters, it is found that the correct binding complex conformations are of both higher sum of the interface degree values and lower characteristic path length than those incorrect ones. These features reflect that the correct bind-ing complex conformations have better geometric and/or residue type complementarity, and the correct binding modes are very important for preserving the characteristic path lengths of native protein complexes. In addition, two scoring terms are proposed based on the network parameters, in which the characteristics of the entire complex shape and residue type complementarity are taken into account. These network-based scoring terms have also been used in conjunction with other scoring terms, and the new multi-term scoring HPNCscore is devised in this work. It can improve the discrimination of the combined scoring function of RosettaDock more than 12%. This work might enhance our knowledge of the mechanisms of protein-protein interactions and recognition.展开更多
Denote by Dm the dihedral group of order 2m. Let R（Dm） be its complex representation ring, and let △（Dm） be its augmentation ideal. In this paper, we determine the isomorphism class of the n-th augmentation quoti...Denote by Dm the dihedral group of order 2m. Let R（Dm） be its complex representation ring, and let △（Dm） be its augmentation ideal. In this paper, we determine the isomorphism class of the n-th augmentation quotient △^n（Dm）/△^n＋1（Dm） for each positive integer n.展开更多
The Ediacaran to Cambrian transition witnessed great biological and environmental turnovers from the Precambrian to Phanerozoic.These changes are also reflected by the fossil records during that time.However,the fossi...The Ediacaran to Cambrian transition witnessed great biological and environmental turnovers from the Precambrian to Phanerozoic.These changes are also reflected by the fossil records during that time.However,the fossil distribution was highly heterogenous.While diverse fossils were constantly found from the shallow shelf including restricted basins,reports from deep-water areas,which are characterized by chert-dominated formations straddling the Ediacaran-Cambrian boundary,were scarce.Among them was the Liuchapo Formation that has been considered barren.In this study,a fossiliferous assemblage was found from the Liuchapo Formation in east Guizhou Province,South China.This assemblage comprises Palaeopascichnus jiumenensis,Horodyskia minor,multicellular algae that possibly related with red algae,cyanobacteria,sponge spicules,small shelly fossils,membrane structures of uncertain affinity,and fossils with structures resemble the Ediacaran Megasphaera.Palaeopascichnus and Horodyskia have been widely reported and abundant in the Liuchapo Formation and equivalents,while the others have seldomly,or never,been found from this formation or,more widely,the deep-water chert of transitional interval.The discovery not only contributes to the rare paleontological records preserved in deep-water sediments,but also expanded the geographic distribution of the fossils,providing new materials of biological diversity during this critical interval.展开更多
基金Supported by Key Project of National Natural Science Foundation of China(Grant No.51535009)111 Project(Grant No.B13044)
文摘Time?varying mesh stiffness(TVMS) and gear errors include short?term and long?term components are the two main internal dynamic excitations for gear transmission. The coupling relationship between the two factors is usually neglected in the traditional quasi-static and dynamic behaviors analysis of gear system. This paper investigates the influence of short?term and long?term components of manufacturing errors on quasi?static and dynamic behaviors of helical gear system considering the coupling relationship between TVMS and gear errors. The TVMS, loaded static transmission error(LSTE) and loaded composite mesh error(LCMS) are determined using an improved loaded tooth contact analysis(LTCA) model. Considering the structure of shaft, as well as the direction of power flow and bearing location, a precise generalized finite element dynamic model of helical gear system is developed, and the dynamic responses of the system are obtained by numerical integration method. The results suggest that lighter loading conditions result in smaller mesh stiffness and stronger vibration, and the corresponding resonance speeds of the system become lower. Long?term components of manufacturing errors lead to the appearance of sideband frequency components in frequency spectrum of dynamic responses. The sideband frequency components are predominant under light loading conditions. With the increase of output torque, the mesh frequency and its harmonics components tend to be enhanced relative to sideband frequency components. This study can provide effective reference for low noise design of gear transmission.
基金partially supported by the National Natural Science Foundation of China(Grant Nos.11173020 and 11433004)the Top Talents Program of Yunnan Province
文摘Motivated by the Fermi observations of some γ-ray pulsars in which the phases of radio and γ-ray peaks are almost the same, we investigate the outer gap model in a retarded dipole with a current-induced magnetic field and apply it to explain pulsed γ-ray properties of the Crab pulsar. Our results show that the observed γ-ray energy-dependent light curves, which almost align with the radio light curve and phase averaged spectrum for the Crab pulsar, are reproduced well.
文摘On the basis of clarifying the teachers'Ethics internalization theory,this paper analyzes the typical dilemma in teachers'Ethics internalization.To resolve these problems,this paper construct an overall framework,including security mechanism,normative mechanism,education mechanism,evaluation mechanism and supervision mechanism,which the external conditions are used to constantly strengthen the moral needs of the subject,then enhance the consciousness of moral internalization,improve the effectiveness of teachers'moral construction.
基金supported by grants from the National Natural Science Foundation of China(82173853,82173379,82373914,82073892)Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(2022-I2M-2-002,2021-I2M-1e026 and 2021-I2M-1e016,China)+2 种基金CAMS Central Public-interest Scientific Institution Basal Research Fund(2018PT35004,China)Beijing Outstanding Young Scientist Program(BJJWZYJH01201910023028,China)Peking Union Medical College Graduate Innovation Fund(2019-1007-05,China).
文摘Protein kinase Cα(PKCα)regulates diverse biological functions of cancer cells and is a promising therapeutic target.However,clinical trials of PKC-targeted therapies have not yielded satisfactory results.Recent studies have also indicated a tumor-suppressive role of PKCs via unclear molecular mechanisms.In this study,we found that PKCαinhibition enhances CD8+T-cell-mediated tumor evasion and abolishes antitumor activity in immunocompetent mice.We further identified PKCαas a critical regulator of programmed cell death-ligand 1(PD-L1)and found that it enhances T-cell-dependent antitumor immunity in breast cancer by interacting with PD-L1 and suppressing PD-L1 expression.We demonstrated that PKCα-mediated PD-L1 phosphorylation promotes PD-L1 degradation throughβtransducin repeat-containing protein.Notably,the efficacy of PKCαinhibitors was intensified by synergizing with anti-PD-L1 mAb therapy to boost antitumor T-cell immunity in vivo.Clinical analysis revealed that PKCαexpression is positively correlated with T-cell function and the interferon-gamma signature in patients with breast cancer.This study demonstrated the antitumor capability of PKCα,identified potential therapeutic strategies to avoid tumor evasion via PKC-targeted therapies,and provided a proof of concept for targeting PKCαin combination with anti-PD-L1 mAb therapy as a potential therapeutic approach against breast cancer,especially TNBC.
基金supported by the National Key R&D Program of China (Grant Nos.2016YFA0501701 and 2016YFA0202900)the National Natural Science Foundation of China (Grant Nos.21575128,81773632,and 81302679)
文摘Androgen receptor(AR) is a ligand-activated transcription factor that plays a pivotal role in the development and progression of many severe diseases such as prostate cancer, muscle atrophy, and osteoporosis. Binding of ligands to AR triggers the conformational changes in AR that may affect the recruitment of coactivators and downstream response of AR signaling pathway.Therefore, AR ligands have great potential to treat these diseases. In this study, we searched for novel AR ligands by performing a docking-based virtual screening(VS) on the basis of the crystal structure of the AR ligand binding domain(LBD) in complex with its agonist. A total of 58 structurally diverse compounds were selected and subjected to LBD affinity assay, with five of them(HBP1-3, HBP1-17, HBP1-38, HBP1-51, and HBP1-58) exhibiting strong binding to AR-LBD. The IC50 values of HBP1-51 and HBP1-58 are 3.96 m M and 4.92 m M, respectively, which are even lower than that of enzalutamide(Enz, IC50= 13.87 m M), a marketed second-generation AR antagonist. Further bioactivity assays suggest that HBP1-51 is an AR agonist, whereas HBP1-58 is an AR antagonist. In addition, molecular dynamics(MD) simulations and principal components analysis(PCA) were carried out to reveal the binding principle of the newlyidentified AR ligands toward AR. Our modeling results indicate that the conformational changes of helix 12 induced by the bindings of antagonist and agonist are visibly different. In summary,the current study provides a highly efficient way to discover novel AR ligands, which could serve as the starting point for development of new therapeutics for AR-related diseases.
文摘Radiolarians form an important part of the planktonic realm in the ocean of Early Paleozoic, but their origin and evolutionary processes has long been enigmatic. The ancestral representatives of radiolarians have been considered to belong to the order Archaeospicularia, whose unquestionable fossil records were dated back to the Middle Cambrian. Here we report ？Blastulospongia and unnamed spherical radiolarians in the Terreneuvian from the Yanjiabe Formation in Hubei Province, South China. Blastulospongia is an enigmatic siliceous microfossil genus, with affinities proposed amongst the radiolarian, sphinetozoan-grade sponges and uncertain protists. As for the newly discovered unnamed radiolarians, morphologically they possess latticed shell, spherical shape and are all small in size. Our discoveries support the idea that spherical radiolarians is an ancient representative, whose origin and diversification was probably much earlier than generally accepted. The hypothesis that the oldest radiolarians belong to the order Archaeospicularia needs to be re-examined.
基金supported by the National Natural Science Foundation of China (Grant Nos. 20773006, 30670497, 10974008)Beijing Natural Science Foundation (Grant No. 4102006) Specialized Research Fund for the Doctoral Program of Higher Education (Grant No. 200800050003)
文摘Residue networks are constructed by defining the residues as the vertices and atom contacts between them as the edges. The residue network of a protein complex is divided into two types of networks, i.e. the hydrophobic and the hydrophilic residue networks. By analyzing the network parameters, it is found that the correct binding complex conformations are of both higher sum of the interface degree values and lower characteristic path length than those incorrect ones. These features reflect that the correct bind-ing complex conformations have better geometric and/or residue type complementarity, and the correct binding modes are very important for preserving the characteristic path lengths of native protein complexes. In addition, two scoring terms are proposed based on the network parameters, in which the characteristics of the entire complex shape and residue type complementarity are taken into account. These network-based scoring terms have also been used in conjunction with other scoring terms, and the new multi-term scoring HPNCscore is devised in this work. It can improve the discrimination of the combined scoring function of RosettaDock more than 12%. This work might enhance our knowledge of the mechanisms of protein-protein interactions and recognition.
文摘Denote by Dm the dihedral group of order 2m. Let R（Dm） be its complex representation ring, and let △（Dm） be its augmentation ideal. In this paper, we determine the isomorphism class of the n-th augmentation quotient △^n（Dm）/△^n＋1（Dm） for each positive integer n.
基金supported by the Natural Science Foundation of China(No.41430101)。
文摘The Ediacaran to Cambrian transition witnessed great biological and environmental turnovers from the Precambrian to Phanerozoic.These changes are also reflected by the fossil records during that time.However,the fossil distribution was highly heterogenous.While diverse fossils were constantly found from the shallow shelf including restricted basins,reports from deep-water areas,which are characterized by chert-dominated formations straddling the Ediacaran-Cambrian boundary,were scarce.Among them was the Liuchapo Formation that has been considered barren.In this study,a fossiliferous assemblage was found from the Liuchapo Formation in east Guizhou Province,South China.This assemblage comprises Palaeopascichnus jiumenensis,Horodyskia minor,multicellular algae that possibly related with red algae,cyanobacteria,sponge spicules,small shelly fossils,membrane structures of uncertain affinity,and fossils with structures resemble the Ediacaran Megasphaera.Palaeopascichnus and Horodyskia have been widely reported and abundant in the Liuchapo Formation and equivalents,while the others have seldomly,or never,been found from this formation or,more widely,the deep-water chert of transitional interval.The discovery not only contributes to the rare paleontological records preserved in deep-water sediments,but also expanded the geographic distribution of the fossils,providing new materials of biological diversity during this critical interval.
