The von Hippel-Lindau tumor suppressor(VHL)has been extensively used to develop degraders targeting numerous proteins of interest.However,studies on the rational design of VHL-proteolysis-targeting chimeras(PROTACs)re...The von Hippel-Lindau tumor suppressor(VHL)has been extensively used to develop degraders targeting numerous proteins of interest.However,studies on the rational design of VHL-proteolysis-targeting chimeras(PROTACs)remain scarce.This study aimed to develop strategies to investigate VHL-recruiting PROTACs connecting with varying attachment sites on VHL ligands,which could be utilized for KRAS^(G12C) degraders development and expanded to additional targets.We developed a molecular dynamics(MD)-based strategy to explore the stability of ternary complexes induced by KRAS^(G12C) PROTACs with four distinct attachment sites of VH032.We found a potent degrader namely YN14-H,linked to hydroxyl group on VH032 benzene ring,exhibited the most superior ability of inducing ternary complexes,reflected by the lowest dissociation constant(Kd)for ternary complex induction and the highest AlphaScreen(AS)-based interaction.YN14-H inhibited cell growth with low nanomolar half maximal inhibitory concentration(IC_(50))and half maximal degradation concentration(DC_(50))values as well as>98%of maximum degradation(D_(max))in NCI-H358 and MIA PaCa-2 cells harboring KRAS^(G12C)-mutation.Mechanistically,YN14-H significantly induced apoptosis and inhibited the migratory capacity.Notably,YN14-H demonstrated favorable pharmacokinetic properties and excellent antitumor activity in vivo.Furthermore,bromodomain-containing protein 7(BRD7)and Bruton tyrosine kinase(BTK)degraders attached to distinct sites on VH032 further verified the rationality and universality of our MD-based strategies.Our findings demonstrated that YN14-H could serve as a promising candidate for the treatment of tumors with KRAS^(G12C)-mutation and present a strategy for the rational design of VHL-recruiting PROTACs that target additional proteins at distinct attachment sites.展开更多
Design patterns are micro architectures that have proved to be reliable, robust and easy to implement. Detecting design pattern from source code of object-oriented system can help a designer, a developer or a maintain...Design patterns are micro architectures that have proved to be reliable, robust and easy to implement. Detecting design pattern from source code of object-oriented system can help a designer, a developer or a maintainer to understand the software system. In this paper, a new method is provided which can detect design patterns from source code combining both static and dynamic analysis. To acquire the run-time dynamic information of software systems, a code instrumentation method is adopted. At the same time, all static and dynamic information is presented in UML diagrams format. The pattern detection process and its detection results are visual and interactive. This method is tested on a call center and a traffic simulation system. Experimental results prove that the method is effective in design patterns detection.展开更多
An orthogonal design was used to optimize SSR-PCR amplification system using Panax ginseng genomic DNA as template. Four levels of five factors （DNA template, Taq DNA polymerase, Mg^2＋, primer, and dNTP） and anneal...An orthogonal design was used to optimize SSR-PCR amplification system using Panax ginseng genomic DNA as template. Four levels of five factors （DNA template, Taq DNA polymerase, Mg^2＋, primer, and dNTP） and annealing temperature have been tested separately in this system. The results demonstrated the reaction efficiency was affected by these factors. Based on the results, a stable, productive and reproducible PCR system and cycling program for amplifying a ginseng SSR locus were obtained： 20 μL system containing 1.0 U Taq DNA polymerase, 2.0 mmol·L^-1 Mg^2＋, 0.2 mmol·L^-1 dNTPs, 0.3 μmol·L^-1 SSR primer, 60 ng· μla^-1 DNA template, performed with a program of 94℃ for 5 min, 94℃ for 30 s, annealing at 56.3℃ for 30 s, 72℃ for 1 min, 37 cycles, finishing at 72℃ for 7 min, and storing at 4℃.展开更多
C4 components are useful in industry and should be separated as individuals. A new process was proposed to separate them by extractive distillation, with the advantages of low equipment investment, energy consumption...C4 components are useful in industry and should be separated as individuals. A new process was proposed to separate them by extractive distillation, with the advantages of low equipment investment, energy consumption and liquid load in the columns. One principle to improve the extractive distillation process was put forward. Moreover, the analysis of operation state of the new process was done. There were eight operation states found for the whole process, but only one operation state was desirable. This work provides a way to effectively separate C4 mixtures and helps the reasonable utilization of C4 resource.展开更多
Electromagnetic stir casting process of A357-Si C nanocomposite was discussed using the D-optimal design of experiment(DODOE) method. As the main objective, nine random experiments obtained by DX-7 software were perfo...Electromagnetic stir casting process of A357-Si C nanocomposite was discussed using the D-optimal design of experiment(DODOE) method. As the main objective, nine random experiments obtained by DX-7 software were performed. By this method, A357-Si C nanocomposites with 0.5, 1.0 and 1.5 wt.% Si C were fabricated at three different frequencies(10, 35 and 60 Hz) in the experimental stage. The microstructural evolution was characterized by scanning electron and optical microscopes, and the mechanical properties were investigated using hardness and roomtemperature uniaxial tensile tests. The results showed that the homogeneous distribution of Si C nanoparticles leads to the microstructure evolution from dendritic to non-dendritic form and a reduction of size by 73.9%. Additionally, based on DODOE, F-values of 44.80 and 179.64 were achieved for yield stress(YS) and ultimate tensile strength(UTS), respectively, implying that the model is significant and the variables(Si C fraction and stirring frequency) were appropriately selected. The optimum values of the Si C fraction and stirring frequency were found to be 1.5 wt.% and 60 Hz, respectively. In this case, YS and UTS for A357-Si C nanocomposites were obtained to be 120 and 188 MPa(57.7% and 57.9 % increase compared with those of the as-cast sample), respectively.展开更多
Today’s product creative design has rendered many fe atures and has brought a great change in our everyday life, there are many new c hallenges in its traditional theory and principle. According to the traditional de...Today’s product creative design has rendered many fe atures and has brought a great change in our everyday life, there are many new c hallenges in its traditional theory and principle. According to the traditional design theory, the FBS design model pays more attention to the function and stru cture of the product. But this model still couldn’t strengthen the relation bet ween product appearance design and human-machine design effectively. This paper adopt converse design thinking and presents an improved design thinking methodo logy based on C: FBS for product appearance design and give a general summarizat ion for the features, methods and technology based on human-machine interaction and interface. Meanwhile it also combines with the behavior design of product r elated IT fields and constructs a new outline to improve the design of product a ppearance supported by the technology of computer aided design. So the new metho d about design thinking for computer aided design, the new abstract product design model and the key problem of design thinking based on human-machine inte raction and interface are addressed in this paper. This kind of creative design theory that is driven by human-machine interaction and interface will help the development of CAD software system and the research of product design and manufa cture. Additionally, this paper gives some beneficial characters to address the theory based on human-machine interaction and interface. Meanwhile, combining with the developing of computer technology, the trends of design thinking based on t he technology of human-machine interaction and interface are also analyzed and discussed at the end of this paper.展开更多
Real-time monitoring of the 14-MeV D-T fusion neutron yield is urgently required for the triton burnup study on the Experimental Advanced Superconducting Tokamak (EAST). In this study, we developed an optimal design o...Real-time monitoring of the 14-MeV D-T fusion neutron yield is urgently required for the triton burnup study on the Experimental Advanced Superconducting Tokamak (EAST). In this study, we developed an optimal design of a fast-neutron detector based on the scintillating fiber (Sci-Fi) to provide D-T neutron yield through Geant4simulation. The effect on the detection performance is concerned when changing the number of the Sci-Fis embedded in the probe head, minimum distance between the fibers, length of the fibers, or substrate material of the probe head. The maximum number of scintillation photons generated by the n/γ source particles and output by the light guide within an event (event:the entire simulation process for one source particle) was used to quantify the n/γ resolution of the detector as the main basis. And the intrinsic detection efficiency was used as another evaluation criterion. The results demonstrate that the optimal design scheme is to use a 5 cm probe head whose substrate material is pure aluminum, in which 463 Sci-Fis with the same length of 5 cm are embedded, and the minimum distance between the centers of the two fibers is 2 mm. The optimized detector exhibits clear directionality in the simulation, which is in line with the expectation and experimental data provided in the literature. This study presents the variation trends of the performance of the SciFi detector when its main parameters change, which is beneficial for the targeted design and optimization of the Sci-Fi detector used in a specific radiation environment.展开更多
基金supported by National Natural Science Foundation of China(No.82404417)State Key Laboratory of National Security Specially Needed Medicines Program(No.LTMC2022Zz006).
文摘The von Hippel-Lindau tumor suppressor(VHL)has been extensively used to develop degraders targeting numerous proteins of interest.However,studies on the rational design of VHL-proteolysis-targeting chimeras(PROTACs)remain scarce.This study aimed to develop strategies to investigate VHL-recruiting PROTACs connecting with varying attachment sites on VHL ligands,which could be utilized for KRAS^(G12C) degraders development and expanded to additional targets.We developed a molecular dynamics(MD)-based strategy to explore the stability of ternary complexes induced by KRAS^(G12C) PROTACs with four distinct attachment sites of VH032.We found a potent degrader namely YN14-H,linked to hydroxyl group on VH032 benzene ring,exhibited the most superior ability of inducing ternary complexes,reflected by the lowest dissociation constant(Kd)for ternary complex induction and the highest AlphaScreen(AS)-based interaction.YN14-H inhibited cell growth with low nanomolar half maximal inhibitory concentration(IC_(50))and half maximal degradation concentration(DC_(50))values as well as>98%of maximum degradation(D_(max))in NCI-H358 and MIA PaCa-2 cells harboring KRAS^(G12C)-mutation.Mechanistically,YN14-H significantly induced apoptosis and inhibited the migratory capacity.Notably,YN14-H demonstrated favorable pharmacokinetic properties and excellent antitumor activity in vivo.Furthermore,bromodomain-containing protein 7(BRD7)and Bruton tyrosine kinase(BTK)degraders attached to distinct sites on VH032 further verified the rationality and universality of our MD-based strategies.Our findings demonstrated that YN14-H could serve as a promising candidate for the treatment of tumors with KRAS^(G12C)-mutation and present a strategy for the rational design of VHL-recruiting PROTACs that target additional proteins at distinct attachment sites.
基金Project supported by the National Natural Science Foundation of China（Grant No.60473063）
文摘Design patterns are micro architectures that have proved to be reliable, robust and easy to implement. Detecting design pattern from source code of object-oriented system can help a designer, a developer or a maintainer to understand the software system. In this paper, a new method is provided which can detect design patterns from source code combining both static and dynamic analysis. To acquire the run-time dynamic information of software systems, a code instrumentation method is adopted. At the same time, all static and dynamic information is presented in UML diagrams format. The pattern detection process and its detection results are visual and interactive. This method is tested on a call center and a traffic simulation system. Experimental results prove that the method is effective in design patterns detection.
基金This research was supported by Department of Wildlife Conservation, State Forestry Administration, P. R. China.
文摘An orthogonal design was used to optimize SSR-PCR amplification system using Panax ginseng genomic DNA as template. Four levels of five factors （DNA template, Taq DNA polymerase, Mg^2＋, primer, and dNTP） and annealing temperature have been tested separately in this system. The results demonstrated the reaction efficiency was affected by these factors. Based on the results, a stable, productive and reproducible PCR system and cycling program for amplifying a ginseng SSR locus were obtained： 20 μL system containing 1.0 U Taq DNA polymerase, 2.0 mmol·L^-1 Mg^2＋, 0.2 mmol·L^-1 dNTPs, 0.3 μmol·L^-1 SSR primer, 60 ng· μla^-1 DNA template, performed with a program of 94℃ for 5 min, 94℃ for 30 s, annealing at 56.3℃ for 30 s, 72℃ for 1 min, 37 cycles, finishing at 72℃ for 7 min, and storing at 4℃.
文摘C4 components are useful in industry and should be separated as individuals. A new process was proposed to separate them by extractive distillation, with the advantages of low equipment investment, energy consumption and liquid load in the columns. One principle to improve the extractive distillation process was put forward. Moreover, the analysis of operation state of the new process was done. There were eight operation states found for the whole process, but only one operation state was desirable. This work provides a way to effectively separate C4 mixtures and helps the reasonable utilization of C4 resource.
文摘Electromagnetic stir casting process of A357-Si C nanocomposite was discussed using the D-optimal design of experiment(DODOE) method. As the main objective, nine random experiments obtained by DX-7 software were performed. By this method, A357-Si C nanocomposites with 0.5, 1.0 and 1.5 wt.% Si C were fabricated at three different frequencies(10, 35 and 60 Hz) in the experimental stage. The microstructural evolution was characterized by scanning electron and optical microscopes, and the mechanical properties were investigated using hardness and roomtemperature uniaxial tensile tests. The results showed that the homogeneous distribution of Si C nanoparticles leads to the microstructure evolution from dendritic to non-dendritic form and a reduction of size by 73.9%. Additionally, based on DODOE, F-values of 44.80 and 179.64 were achieved for yield stress(YS) and ultimate tensile strength(UTS), respectively, implying that the model is significant and the variables(Si C fraction and stirring frequency) were appropriately selected. The optimum values of the Si C fraction and stirring frequency were found to be 1.5 wt.% and 60 Hz, respectively. In this case, YS and UTS for A357-Si C nanocomposites were obtained to be 120 and 188 MPa(57.7% and 57.9 % increase compared with those of the as-cast sample), respectively.
文摘Today’s product creative design has rendered many fe atures and has brought a great change in our everyday life, there are many new c hallenges in its traditional theory and principle. According to the traditional design theory, the FBS design model pays more attention to the function and stru cture of the product. But this model still couldn’t strengthen the relation bet ween product appearance design and human-machine design effectively. This paper adopt converse design thinking and presents an improved design thinking methodo logy based on C: FBS for product appearance design and give a general summarizat ion for the features, methods and technology based on human-machine interaction and interface. Meanwhile it also combines with the behavior design of product r elated IT fields and constructs a new outline to improve the design of product a ppearance supported by the technology of computer aided design. So the new metho d about design thinking for computer aided design, the new abstract product design model and the key problem of design thinking based on human-machine inte raction and interface are addressed in this paper. This kind of creative design theory that is driven by human-machine interaction and interface will help the development of CAD software system and the research of product design and manufa cture. Additionally, this paper gives some beneficial characters to address the theory based on human-machine interaction and interface. Meanwhile, combining with the developing of computer technology, the trends of design thinking based on t he technology of human-machine interaction and interface are also analyzed and discussed at the end of this paper.
基金supported by the Users with Excellence Program of Hefei Science Center CAS(No.2020HSC-UE012)the Comprehensive Research Facility for Fusion Technology Program of China(No.2018-000052-73-01-001228)the Institute of Energy,Hefei Comprehensive National Science Center(No.21KZS205,21KZL401).
文摘Real-time monitoring of the 14-MeV D-T fusion neutron yield is urgently required for the triton burnup study on the Experimental Advanced Superconducting Tokamak (EAST). In this study, we developed an optimal design of a fast-neutron detector based on the scintillating fiber (Sci-Fi) to provide D-T neutron yield through Geant4simulation. The effect on the detection performance is concerned when changing the number of the Sci-Fis embedded in the probe head, minimum distance between the fibers, length of the fibers, or substrate material of the probe head. The maximum number of scintillation photons generated by the n/γ source particles and output by the light guide within an event (event:the entire simulation process for one source particle) was used to quantify the n/γ resolution of the detector as the main basis. And the intrinsic detection efficiency was used as another evaluation criterion. The results demonstrate that the optimal design scheme is to use a 5 cm probe head whose substrate material is pure aluminum, in which 463 Sci-Fis with the same length of 5 cm are embedded, and the minimum distance between the centers of the two fibers is 2 mm. The optimized detector exhibits clear directionality in the simulation, which is in line with the expectation and experimental data provided in the literature. This study presents the variation trends of the performance of the SciFi detector when its main parameters change, which is beneficial for the targeted design and optimization of the Sci-Fi detector used in a specific radiation environment.
