Increasing evidence showed that histone deacetylase 6(HDAC6)dysfunction is directly associated with the onset and progression of various diseases,especially cancers,making the development of HDAC6-targeted anti-tumor ...Increasing evidence showed that histone deacetylase 6(HDAC6)dysfunction is directly associated with the onset and progression of various diseases,especially cancers,making the development of HDAC6-targeted anti-tumor agents a research hotspot.In this study,artificial intelligence(AI)technology and molecular simulation strategies were fully integrated to construct an efficient and precise drug screening pipeline,which combined Voting strategy based on compound-protein interaction(CPI)prediction models,cascade molecular docking,and molecular dynamic(MD)simulations.The biological potential of the screened compounds was further evaluated through enzymatic and cellular activity assays.Among the identified compounds,Cmpd.18 exhibited more potent HDAC6 enzyme inhibitory activity(IC_(50)=5.41 nM)than that of tubastatin A(TubA)(IC_(50)=15.11 nM),along with a favorable subtype selectivity profile(selectivity index z 117.23 for HDAC1),which was further verified by the Western blot analysis.Additionally,Cmpd.18 induced G2/M phase arrest and promoted apoptosis in HCT-116 cells,exerting desirable antiproliferative activity(IC_(50)=2.59 mM).Furthermore,based on long-term MD simulation trajectory,the key residues facilitating Cmpd.18's binding were identified by decomposition free energy analysis,thereby elucidating its binding mechanism.Moreover,the representative conformation analysis also indicated that Cmpd.18 could stably bind to the active pocket in an effective conformation,thus demonstrating the potential for in-depth research of the 2-(2-phenoxyethyl)pyridazin-3(2H)-one scaffold.展开更多
The commercial ZK 60 magnesium alloy with extruded state experienced aging heat treatment(T 6)was dynamically loaded at strain rate of 3000 s−1 by means of the split Hopkinson pressure bar(SHPB)in this paper.Transmiss...The commercial ZK 60 magnesium alloy with extruded state experienced aging heat treatment(T 6)was dynamically loaded at strain rate of 3000 s−1 by means of the split Hopkinson pressure bar(SHPB)in this paper.Transmission electron microscopy(TEM)observations showed that the precipitatedβ′_(1) phases partially dissolved(spheroidized)with blurred interfaces within 160μs at 3000 s^(−1).The average length and diameter of the rod-shapedβ′_(1) phase particles were 48.5 and 9.8 nm after the T 6 heat treatment;while the average diameter of the sphericalβ′_(1) phases changed to 8.8 nm after loading.The deformedβ′_(1) phase generated larger lattice distortion energy than Mg matrix under high strain rate loading.Therefore,the difference of free energy(the driving force of dissolution)between theβ′_(1) phase and the matrix increased,making the instantaneous dissolution of theβ′_(1) phase thermodynamically feasible.The dissolution(spheroidization)of theβ′_(1) phase particles was kinetically promoted because the diffusion rate of the solute Zn atoms was accelerated by combined actions of adiabatic temperature rise,high density of dislocations(vacancies)and high deviatoric stresses during high strain rate loading.The increase in hardness of ZK 60-T 6 alloy could be attributed to solid solution strengthening,dislocation strengthening and second phase particle strengthening.展开更多
The dynamic fracture behaviors of Ti-6Al-4V alloy at high strain rate loading were investigated systemically through Taylor impact test, over the range of impact velocities from 145 m/s to 306 m/s. The critical impact...The dynamic fracture behaviors of Ti-6Al-4V alloy at high strain rate loading were investigated systemically through Taylor impact test, over the range of impact velocities from 145 m/s to 306 m/s. The critical impact velocity of fracture ranges from 217 m/s to 236 m/s. Smooth surfaces and ductile dimple areas were observed on the fracture surfaces. As the impact velocity reached 260 m/s, the serious melting regions were also observed on the fracture surfaces. Self-organization of cracks emerges when the impact velocity reaches 260 m/s, while some special cracks whose ＂tips＂ are not sharp but arc and smooth, and without any evidence of deformation or adiabatic shear band were also observed on the impact end surfaces. Examination of the sections of these special cracks reveals that the cracks expand along the two maximum shear stress directions respectively, and finally intersect as a tridimensional ＂stagger ridge＂ structure.展开更多
The dynamic recrystallization（DRX） behavior of Ti-6Al-2Zr-1Mo-1V alloy was investigated at deformation temperature of 1000-1100 °C and strain rate of 10-3-1.0 s-1 by using compression test.The results show that...The dynamic recrystallization（DRX） behavior of Ti-6Al-2Zr-1Mo-1V alloy was investigated at deformation temperature of 1000-1100 °C and strain rate of 10-3-1.0 s-1 by using compression test.The results show that discontinuous dynamic recrystallization（DDRX） is the predominant recrystallization mechanism at temperature higher than 1050 °C and strain rate lower than 0.01 s-1.Meanwhile,continuous dynamic recrystallization is the main mechanism observed at temperature below 1050 °C and strain rate above 0.01 s-1,mixed with a few DDRX grains.In addition,decreasing strain rate and increasing deformation temperature are found to facilitate the progress of DRX and refinement of grains in the Ti alloy in β forging process.展开更多
The quasi-static and dynamic tensile behaviors in electron beam welded（EBW） Ti-6Al-4V alloy were investigated at strain rates of 10-3 and 103 s-1,respectively,by materials test system（MTS） and reconstructive Hopki...The quasi-static and dynamic tensile behaviors in electron beam welded（EBW） Ti-6Al-4V alloy were investigated at strain rates of 10-3 and 103 s-1,respectively,by materials test system（MTS） and reconstructive Hopkinson bars apparatus.The microstructures of the base metal（BM） and the welded metal（WM） were observed with optical microscope.The fracture characteristics of the BM and WM were characterized with scanning electronic microscope.In Ti-6Al-4V alloy joint,the flow stress of WM is higher than that of BM,while the fracture strain of WM is less than that of BM at strain rates of 103 and 10-3 s-1,respectively.The fracture strain of WM has apparent improvement when the strain rate rises from 10-3 to 103 s-1,while the fracture strain of BM almost has no change.At the same time,the fracture mode of WM alters from brittle to ductile fracture,which causes improvement of the fracture strain of WM.展开更多
基金funded by Central Guidance on Local Science and Technology Development Fund of Hebei Province,China(Grant No.:226Z2605G)the Key Project from Hebei Provincial Department of Science and Technology,China(Grant No.:21372601D)+6 种基金Graduate Student Innovation Grant Program of Hebei Medical University,China(Grant No.:XCXZZB202303)Science Research Project of Hebei Education Department,China(Grant Nos.:BJ2025046,and CYZD202501)Program for Young Scientists in the Field of Natural Science of Hebei Medical University,China(Program Nos.:CYCZ2023010,CYCZ2023011,CYQD2021011,CYQD2021015 and CYQD2023012)Traditional Chinese Medicine Administration Project of Hebei Province,China(Project No.:2025427)National Natural Science Foundation of China(Grant No.:32100771)the Hebei Provincial Medical Science Research Project Plan,China(Project Nos.:20240241 and 20220200)Shijiazhuang Science and Technology Bureau,China(Grant Nos.:241200487A,and 07202204).
文摘Increasing evidence showed that histone deacetylase 6(HDAC6)dysfunction is directly associated with the onset and progression of various diseases,especially cancers,making the development of HDAC6-targeted anti-tumor agents a research hotspot.In this study,artificial intelligence(AI)technology and molecular simulation strategies were fully integrated to construct an efficient and precise drug screening pipeline,which combined Voting strategy based on compound-protein interaction(CPI)prediction models,cascade molecular docking,and molecular dynamic(MD)simulations.The biological potential of the screened compounds was further evaluated through enzymatic and cellular activity assays.Among the identified compounds,Cmpd.18 exhibited more potent HDAC6 enzyme inhibitory activity(IC_(50)=5.41 nM)than that of tubastatin A(TubA)(IC_(50)=15.11 nM),along with a favorable subtype selectivity profile(selectivity index z 117.23 for HDAC1),which was further verified by the Western blot analysis.Additionally,Cmpd.18 induced G2/M phase arrest and promoted apoptosis in HCT-116 cells,exerting desirable antiproliferative activity(IC_(50)=2.59 mM).Furthermore,based on long-term MD simulation trajectory,the key residues facilitating Cmpd.18's binding were identified by decomposition free energy analysis,thereby elucidating its binding mechanism.Moreover,the representative conformation analysis also indicated that Cmpd.18 could stably bind to the active pocket in an effective conformation,thus demonstrating the potential for in-depth research of the 2-(2-phenoxyethyl)pyridazin-3(2H)-one scaffold.
基金Projects(51871243,51574290)supported by the National Natural Science Foundation of ChinaProject(ASSIKFJJ202304001)supported by the Open Fund of the National Key Laboratory of Strength and Structural Integrity,China+3 种基金Project(HT-CSNS-DG-CD-0092/2021)supported by the Guangdong-Hong Kong-Macao Joint Laboratory for Neutron Scattering Science and Technology,ChinaProject(2022KF-08)supported by the Hubei Longzhong Laboratory,ChinaProject(22kfgk06)supported by the Shock and Vibration of Engineering Materials and Structures Key Laboratory of Sichuan Province,ChinaProject(PBSKL2022C01)supported by the State Key Laboratory of Precision Blasting and Hubei Key Laboratory of Blasting Engineering,China。
文摘The commercial ZK 60 magnesium alloy with extruded state experienced aging heat treatment(T 6)was dynamically loaded at strain rate of 3000 s−1 by means of the split Hopkinson pressure bar(SHPB)in this paper.Transmission electron microscopy(TEM)observations showed that the precipitatedβ′_(1) phases partially dissolved(spheroidized)with blurred interfaces within 160μs at 3000 s^(−1).The average length and diameter of the rod-shapedβ′_(1) phase particles were 48.5 and 9.8 nm after the T 6 heat treatment;while the average diameter of the sphericalβ′_(1) phases changed to 8.8 nm after loading.The deformedβ′_(1) phase generated larger lattice distortion energy than Mg matrix under high strain rate loading.Therefore,the difference of free energy(the driving force of dissolution)between theβ′_(1) phase and the matrix increased,making the instantaneous dissolution of theβ′_(1) phase thermodynamically feasible.The dissolution(spheroidization)of theβ′_(1) phase particles was kinetically promoted because the diffusion rate of the solute Zn atoms was accelerated by combined actions of adiabatic temperature rise,high density of dislocations(vacancies)and high deviatoric stresses during high strain rate loading.The increase in hardness of ZK 60-T 6 alloy could be attributed to solid solution strengthening,dislocation strengthening and second phase particle strengthening.
基金Project (51001014) supported by the Young Scientists Fund of the National Natural Science Foundation of China
文摘The dynamic fracture behaviors of Ti-6Al-4V alloy at high strain rate loading were investigated systemically through Taylor impact test, over the range of impact velocities from 145 m/s to 306 m/s. The critical impact velocity of fracture ranges from 217 m/s to 236 m/s. Smooth surfaces and ductile dimple areas were observed on the fracture surfaces. As the impact velocity reached 260 m/s, the serious melting regions were also observed on the fracture surfaces. Self-organization of cracks emerges when the impact velocity reaches 260 m/s, while some special cracks whose ＂tips＂ are not sharp but arc and smooth, and without any evidence of deformation or adiabatic shear band were also observed on the impact end surfaces. Examination of the sections of these special cracks reveals that the cracks expand along the two maximum shear stress directions respectively, and finally intersect as a tridimensional ＂stagger ridge＂ structure.
基金Project (2007CB613803) supported by the National Basic Research Program of ChinaProject (2010GQC0170) supported by the Natural Science Foundation of Jiangxi Province,ChinaProject (GJJ11159) supported by the Educational Committee of Jiangxi Province,China
文摘The dynamic recrystallization（DRX） behavior of Ti-6Al-2Zr-1Mo-1V alloy was investigated at deformation temperature of 1000-1100 °C and strain rate of 10-3-1.0 s-1 by using compression test.The results show that discontinuous dynamic recrystallization（DDRX） is the predominant recrystallization mechanism at temperature higher than 1050 °C and strain rate lower than 0.01 s-1.Meanwhile,continuous dynamic recrystallization is the main mechanism observed at temperature below 1050 °C and strain rate above 0.01 s-1,mixed with a few DDRX grains.In addition,decreasing strain rate and increasing deformation temperature are found to facilitate the progress of DRX and refinement of grains in the Ti alloy in β forging process.
文摘The quasi-static and dynamic tensile behaviors in electron beam welded（EBW） Ti-6Al-4V alloy were investigated at strain rates of 10-3 and 103 s-1,respectively,by materials test system（MTS） and reconstructive Hopkinson bars apparatus.The microstructures of the base metal（BM） and the welded metal（WM） were observed with optical microscope.The fracture characteristics of the BM and WM were characterized with scanning electronic microscope.In Ti-6Al-4V alloy joint,the flow stress of WM is higher than that of BM,while the fracture strain of WM is less than that of BM at strain rates of 103 and 10-3 s-1,respectively.The fracture strain of WM has apparent improvement when the strain rate rises from 10-3 to 103 s-1,while the fracture strain of BM almost has no change.At the same time,the fracture mode of WM alters from brittle to ductile fracture,which causes improvement of the fracture strain of WM.
