Ischemic stroke is currently the second leading cause of death worldwide,and insufficient endogenous neurogenesis is the greatest cause of post-stroke disability.MicroRNAs have been proven to hold therapeutic potentia...Ischemic stroke is currently the second leading cause of death worldwide,and insufficient endogenous neurogenesis is the greatest cause of post-stroke disability.MicroRNAs have been proven to hold therapeutic potential,unfortunately,they have a low stability that hinders their clinical usage.Our earlier work revealed that Panax notoginseng derived exosome like nanoparticles,namely PDNs have potential to bypass BBB and reduce the cerebral ischemia/reperfusion(CI/R)damage.In this study,we employed microRNA-124 as a model therapeutic gene,utilizing its engineered variant Agomir-124(Ago124)to optimize loading efficiency.The therapeutic effects of Ago124@R-PDN were further assessed in several sets of experiments.Pharmacokinetic study showed that erythrocyte membrane extended the half-life of PDNs from 7 min to 11.3 h,and the loading efficiency of Ago124 reached 40%.In an in vitro oxygen-glucose deprivation/reperfusion(OGD/R)model,Ago124@R-PDN enhanced IL-10 production in microglia by 67%(vs 11.7%with free Ago124),and promoted Tuj1+neuronal differentiation by 2.23-fold compared with vehicle.Also,Ago124@R-PDN brought gene cargo into the brain,alleviated infarct volume,and improved functional behaviors in model mice.At last,we demonstrated that surface glycosyl of PDN facilitated its brain-entering ability by being recognized by sodium-glucose linked transporter-1 protein.In conclusion,our erythrocyte fused PDNs offer a promising strategy for delivering biomacromolecule to treat brain diseases.展开更多
Ultra-high strain rate impact tests were conducted by Split-Hopkinson pressure bar to investigate the microstructure evolution and impact deformation mechanism of a solution treated casting AM80 Mg alloy at 25, 150 an...Ultra-high strain rate impact tests were conducted by Split-Hopkinson pressure bar to investigate the microstructure evolution and impact deformation mechanism of a solution treated casting AM80 Mg alloy at 25, 150 and 250 ℃ with a strain rate of 5000 s^(-1). The microcrack and dynamic recrystallization(DRX) preferentially nucleate at grain boundary(GB) and twin boundary(TB), especially at the intersections between GBs and TBs, and then propagate along twin direction. In contrast, the adiabatic shear bands preferentially occur at high-density twined regions. At 25 ℃, the dominated deformation mechanisms are basal slip and twinning. As deformation temperature increases to 150and 250℃, the deformation gradually shifts to be dominated by a coordinated mechanism among non-basal slip, twinning and DRX. The flow stress behavior and deformation mechanism indicate that the degree of decrease in flow stress with temperature is associated with the change of deformation mode.展开更多
In the current study,high strain-rate rolling(≥10 s-1) has been successfully employed to produce Mg-3 A1-1 Zn alloy sheets to a high reduction of 82% with a fine grain structure in a single pass.The underlying mechan...In the current study,high strain-rate rolling(≥10 s-1) has been successfully employed to produce Mg-3 A1-1 Zn alloy sheets to a high reduction of 82% with a fine grain structure in a single pass.The underlying mechanism of forming primary and secondary edge cracks has been investigated.It is found that dynamic recrystallization(DRX) induced by subgrains tends to blunt cracks,while twinning-induced D RX is mainly observed around sharp crack tips.The motion of emitted dislocations from blunted cracks is inhibited by the DRX grain boundaries.This,on one hand,increases local work hardening,and on the other hand,causes stress concentration alo ng grain boundaries especially in the triple junctions leading to the formation of secondary cracks.展开更多
To clarify the mechanical behavior and deformation mechanism of rare earth magnesium(Mg)alloy WE43 under extreme service loads,high-speed impact tests under various deformation temperatures and loading paths were cond...To clarify the mechanical behavior and deformation mechanism of rare earth magnesium(Mg)alloy WE43 under extreme service loads,high-speed impact tests under various deformation temperatures and loading paths were conducted using a split Hopkinson pressure bar.The flow stress along extrusion direction(ED)and extrusion radial direction(ERD)decreases apparently with deformation temperature.Compared with conventional Mg alloys,it exhibits a slight anisotropy and an unusual C-shaped characteristic.Cellular dislocation,mechanical twin and fine grain that occur after high-speed impact deformation are insensitive to the loading direction,but strongly dependent on the deformation temperature,especially superimposed with adiabatic temperature rise.As a result,dynamic recrystallization(DRX)occurs even at an ambient temperature of 25℃.Double twinning and prismatic slip or pyramidal slip are the dominant deformation mechanisms at 25℃.These twins induce mechanical cutting refinement to form some fine-grained structures,accompanied by a small number of fine grains by twinning induced DRX.In contrast,the deformation at 250℃is mainly controlled by prismatic slip and pyramidal slip,accompanied by various types of twinning in early deformation stage.Compared with 25℃,more fine-grained microstructures are formed at 150 and 250℃through a synergy mechanism of twinning induced mechanical cutting and twinning induced DRX.展开更多
In polycrystalline Mg-RE magnesium alloys,the lattice parameter,dislocation dynamics and critical resolved shear stress(CRSS)for various deformation modes are altered with the addition of RE atom,finally affecting def...In polycrystalline Mg-RE magnesium alloys,the lattice parameter,dislocation dynamics and critical resolved shear stress(CRSS)for various deformation modes are altered with the addition of RE atom,finally affecting deformation mode and strain accommodation mechanism among neighboring grains.Uniaxial compression tests were performed on as-extruded AZ81-La Mg alloy samples with the c-axis of the majority of crystals vertical to the compression direction.Twin variants and dominant slip systems were examined by electron backscattered diffraction(EBSD)technique.It is found by in-grain misoriention axis(IGMA)analysis that the plastic deformation is mainly accommodated by a combination of the pyramidal slip and the basal slip.The dominant twin variant is{0112}<0111>and{1102}<1101>.Here,we applied a modified displacement gradient accommodation(m-DGA)method to evaluate the selection mechanism of twin/slip in neighbour grain stimulated by{1012}extension twin.It is found that the activated slip system and/or twin variant in the neighbouring grain is determined by the accommodation of the major shear strain induced by{1012}extension twin in such a way that strain concentration along grain boundaries can be relaxed.展开更多
MED25 has been implicated as a negative regulator of the abscisic acid(ABA)signaling pathway.However,it is unclear whether other Mediator subunits could associate with MED25 to participate in the ABA response.Here,we ...MED25 has been implicated as a negative regulator of the abscisic acid(ABA)signaling pathway.However,it is unclear whether other Mediator subunits could associate with MED25 to participate in the ABA response.Here,we used affinity purification followed by mass spectrometry to uncover Mediator subunits that associate with MED25 in transgenic plants.We found that at least26 Mediator subunits,belonging to the head,middle,tail,and CDK8 kinase modules,were copurified with MED25 in vivo.Interestingly,the tail module subunit MED16 was identified to associate with MED25 under both mock and ABA treatments.We further showed that the disruption of MED16 led to reduced ABA sensitivity compared to the wild type.Transcriptomic analysis revealedthattheexpressionofseveral ABA-responsive genes was significantly lower in med16 than those in wild type.Furthermore,we discovered that MED16 may possibly compete with MED25 to interact with the key transcription factor ABA INSENSITIVE 5(ABI5)to positively regulate ABA signaling.Consistently,med16 and med25 mutants displayed opposite phenotypes in ABA response,cuticle permeability,and differential ABI5-mediated EM1 and EM6 expression.Together,our data indicate that MED16 and MED25 differentially regulate ABA signaling byantagonisticallyaffectingABI5-mediated transcription in Arabidopsis.展开更多
Despite exciting achievements with some malignancies,immunotherapy for hypoimmunogenic cancers,especially glioblastoma(GBM),remains a formidable clinical challenge.Poor immunogenicity and deficient immune infiltrates ...Despite exciting achievements with some malignancies,immunotherapy for hypoimmunogenic cancers,especially glioblastoma(GBM),remains a formidable clinical challenge.Poor immunogenicity and deficient immune infiltrates are two major limitations to an effective cancer-specific immune response.Herein,we propose that an injectable signal-amplifying nanocomposite/hydrogel system consisting of granulocyte-macrophage colony-stimulating factor and imiquimod-loaded antigen-capturing nanoparticles can simultaneously amplify the chemotactic signal of antigen-presenting cells and the"danger"signal of GBM.We demonstrated the feasibility of this strategy in two scenarios of GBM.In the first scenario,we showed that this simultaneous amplification system,in conjunction with local chemotherapy,enhanced both the immunogenicity and immune infiltrates in a recurrent GBM model;thus,ultimately making a cold GBM hot and suppressing postoperative relapse.Encouraged by excellent efficacy,we further exploited this signal-amplifying system to improve the efficiency of vaccine lysate in the treatment of refractory multiple GBM,a disease with limited clinical treatment options.In general,this biomaterial-based immune signal amplification system represents a unique approach to restore GBM-specific immunity and may provide a beneficial preliminary treatment for other clinically refractorymalignancies.展开更多
基金supported by National Natural Science Foundation of China(82374296,82271965,62331021)Development Project of Shanghai Peak Disciplines-Integrated Medicine(201801)+1 种基金Shanghai Municipal Science and Technology Major Project(2018SHZDZX01)Shanghai Municipal Science and Technology Explorer Project(23TS1400500).
文摘Ischemic stroke is currently the second leading cause of death worldwide,and insufficient endogenous neurogenesis is the greatest cause of post-stroke disability.MicroRNAs have been proven to hold therapeutic potential,unfortunately,they have a low stability that hinders their clinical usage.Our earlier work revealed that Panax notoginseng derived exosome like nanoparticles,namely PDNs have potential to bypass BBB and reduce the cerebral ischemia/reperfusion(CI/R)damage.In this study,we employed microRNA-124 as a model therapeutic gene,utilizing its engineered variant Agomir-124(Ago124)to optimize loading efficiency.The therapeutic effects of Ago124@R-PDN were further assessed in several sets of experiments.Pharmacokinetic study showed that erythrocyte membrane extended the half-life of PDNs from 7 min to 11.3 h,and the loading efficiency of Ago124 reached 40%.In an in vitro oxygen-glucose deprivation/reperfusion(OGD/R)model,Ago124@R-PDN enhanced IL-10 production in microglia by 67%(vs 11.7%with free Ago124),and promoted Tuj1+neuronal differentiation by 2.23-fold compared with vehicle.Also,Ago124@R-PDN brought gene cargo into the brain,alleviated infarct volume,and improved functional behaviors in model mice.At last,we demonstrated that surface glycosyl of PDN facilitated its brain-entering ability by being recognized by sodium-glucose linked transporter-1 protein.In conclusion,our erythrocyte fused PDNs offer a promising strategy for delivering biomacromolecule to treat brain diseases.
基金supported by the National Natural Science Foundation of China (Nos. 51975201 and 52071139)the Natural Science Foundation of Hunan Province (No.2019JJ50586)。
文摘Ultra-high strain rate impact tests were conducted by Split-Hopkinson pressure bar to investigate the microstructure evolution and impact deformation mechanism of a solution treated casting AM80 Mg alloy at 25, 150 and 250 ℃ with a strain rate of 5000 s^(-1). The microcrack and dynamic recrystallization(DRX) preferentially nucleate at grain boundary(GB) and twin boundary(TB), especially at the intersections between GBs and TBs, and then propagate along twin direction. In contrast, the adiabatic shear bands preferentially occur at high-density twined regions. At 25 ℃, the dominated deformation mechanisms are basal slip and twinning. As deformation temperature increases to 150and 250℃, the deformation gradually shifts to be dominated by a coordinated mechanism among non-basal slip, twinning and DRX. The flow stress behavior and deformation mechanism indicate that the degree of decrease in flow stress with temperature is associated with the change of deformation mode.
基金financially supported by the National Natural Science Foundation of China (Nos. 51601062, 51905166, 11872216 and 51605159)。
文摘In the current study,high strain-rate rolling(≥10 s-1) has been successfully employed to produce Mg-3 A1-1 Zn alloy sheets to a high reduction of 82% with a fine grain structure in a single pass.The underlying mechanism of forming primary and secondary edge cracks has been investigated.It is found that dynamic recrystallization(DRX) induced by subgrains tends to blunt cracks,while twinning-induced D RX is mainly observed around sharp crack tips.The motion of emitted dislocations from blunted cracks is inhibited by the DRX grain boundaries.This,on one hand,increases local work hardening,and on the other hand,causes stress concentration alo ng grain boundaries especially in the triple junctions leading to the formation of secondary cracks.
基金Project supported by the National Natural Science Foundation of China(52201074,52475344,52171115,U20A20275)the Natural Science Foundation of Hunan Province(2024JJ5644,2023JJ50109)。
文摘To clarify the mechanical behavior and deformation mechanism of rare earth magnesium(Mg)alloy WE43 under extreme service loads,high-speed impact tests under various deformation temperatures and loading paths were conducted using a split Hopkinson pressure bar.The flow stress along extrusion direction(ED)and extrusion radial direction(ERD)decreases apparently with deformation temperature.Compared with conventional Mg alloys,it exhibits a slight anisotropy and an unusual C-shaped characteristic.Cellular dislocation,mechanical twin and fine grain that occur after high-speed impact deformation are insensitive to the loading direction,but strongly dependent on the deformation temperature,especially superimposed with adiabatic temperature rise.As a result,dynamic recrystallization(DRX)occurs even at an ambient temperature of 25℃.Double twinning and prismatic slip or pyramidal slip are the dominant deformation mechanisms at 25℃.These twins induce mechanical cutting refinement to form some fine-grained structures,accompanied by a small number of fine grains by twinning induced DRX.In contrast,the deformation at 250℃is mainly controlled by prismatic slip and pyramidal slip,accompanied by various types of twinning in early deformation stage.Compared with 25℃,more fine-grained microstructures are formed at 150 and 250℃through a synergy mechanism of twinning induced mechanical cutting and twinning induced DRX.
基金Project supported by the National Natural Science Foundation of China(52071139,52075167,U21A20130,U20A20275)the Natural Science Foundation of Hunan(2023JJ30262,2023JJ30252)Natural Science Foundation of Chongqing(CSTB2023NSCQ-MSX0886)。
文摘In polycrystalline Mg-RE magnesium alloys,the lattice parameter,dislocation dynamics and critical resolved shear stress(CRSS)for various deformation modes are altered with the addition of RE atom,finally affecting deformation mode and strain accommodation mechanism among neighboring grains.Uniaxial compression tests were performed on as-extruded AZ81-La Mg alloy samples with the c-axis of the majority of crystals vertical to the compression direction.Twin variants and dominant slip systems were examined by electron backscattered diffraction(EBSD)technique.It is found by in-grain misoriention axis(IGMA)analysis that the plastic deformation is mainly accommodated by a combination of the pyramidal slip and the basal slip.The dominant twin variant is{0112}<0111>and{1102}<1101>.Here,we applied a modified displacement gradient accommodation(m-DGA)method to evaluate the selection mechanism of twin/slip in neighbour grain stimulated by{1012}extension twin.It is found that the activated slip system and/or twin variant in the neighbouring grain is determined by the accommodation of the major shear strain induced by{1012}extension twin in such a way that strain concentration along grain boundaries can be relaxed.
基金supported by the National Natural Science Foundation of China(NSFC 31900238 and NSFC 32070307)to Y.Z.
文摘MED25 has been implicated as a negative regulator of the abscisic acid(ABA)signaling pathway.However,it is unclear whether other Mediator subunits could associate with MED25 to participate in the ABA response.Here,we used affinity purification followed by mass spectrometry to uncover Mediator subunits that associate with MED25 in transgenic plants.We found that at least26 Mediator subunits,belonging to the head,middle,tail,and CDK8 kinase modules,were copurified with MED25 in vivo.Interestingly,the tail module subunit MED16 was identified to associate with MED25 under both mock and ABA treatments.We further showed that the disruption of MED16 led to reduced ABA sensitivity compared to the wild type.Transcriptomic analysis revealedthattheexpressionofseveral ABA-responsive genes was significantly lower in med16 than those in wild type.Furthermore,we discovered that MED16 may possibly compete with MED25 to interact with the key transcription factor ABA INSENSITIVE 5(ABI5)to positively regulate ABA signaling.Consistently,med16 and med25 mutants displayed opposite phenotypes in ABA response,cuticle permeability,and differential ABI5-mediated EM1 and EM6 expression.Together,our data indicate that MED16 and MED25 differentially regulate ABA signaling byantagonisticallyaffectingABI5-mediated transcription in Arabidopsis.
基金supported by the National Natural Science Foundation of China(No.81773911,81690263,and 81573616)the Development Project of Shanghai Peak Disciplines-Integrated Medicine(No.20180101).
文摘Despite exciting achievements with some malignancies,immunotherapy for hypoimmunogenic cancers,especially glioblastoma(GBM),remains a formidable clinical challenge.Poor immunogenicity and deficient immune infiltrates are two major limitations to an effective cancer-specific immune response.Herein,we propose that an injectable signal-amplifying nanocomposite/hydrogel system consisting of granulocyte-macrophage colony-stimulating factor and imiquimod-loaded antigen-capturing nanoparticles can simultaneously amplify the chemotactic signal of antigen-presenting cells and the"danger"signal of GBM.We demonstrated the feasibility of this strategy in two scenarios of GBM.In the first scenario,we showed that this simultaneous amplification system,in conjunction with local chemotherapy,enhanced both the immunogenicity and immune infiltrates in a recurrent GBM model;thus,ultimately making a cold GBM hot and suppressing postoperative relapse.Encouraged by excellent efficacy,we further exploited this signal-amplifying system to improve the efficiency of vaccine lysate in the treatment of refractory multiple GBM,a disease with limited clinical treatment options.In general,this biomaterial-based immune signal amplification system represents a unique approach to restore GBM-specific immunity and may provide a beneficial preliminary treatment for other clinically refractorymalignancies.
