The attenuation function of Dalbergia odorifera leaves on cerebral ischemia-reperfusion(I/R)is little known.The candidate targets for the Chinese herb were extracted from brain tissues through the high-affinity chroma...The attenuation function of Dalbergia odorifera leaves on cerebral ischemia-reperfusion(I/R)is little known.The candidate targets for the Chinese herb were extracted from brain tissues through the high-affinity chromatography.The molecular mechanism of D.odorifera leaves on cerebral I/R was investigated.Methods:Serial affinity chromatography based on D.odorifera leaves extract(DLE)affinity matrices were applied to find specific binding proteins in the brain tissues implemented on C57BL/6 mice by intraluminal middle cerebral artery occlusion for 1 h and reperfusion for 24 h.Specific binding proteins were subjected to mass-spectrometry to search for the differentially expressed proteins between control and DLE-affinity matrices.The hub genes were screened based on weighted gene co-expression network analysis(WGCNA).Then,predictive biology and potential experimental verification were performed for the candidate genes.The protective role of DLE in blood-brain barrier damage in cerebral I/R mice was evaluated by the leakage of Evans blue,western blotting,immunohistochemistry,and immunofluorescent staining.Results:952 differentially expressed proteins were classified into seven modules based on WGCNA under soft threshold 6.Based on WGCNA,AKT1,PIK3CA,NOS3,SMAD3,SMAD1,IL6,MAPK1,TGFBR2,TGFBR1,MAPK3,IGF1R,LRG1,mTOR,ROCK1,TGFB1,IL1B,SMAD2,and SMAD518 candidate hub proteins were involved in turquoise module.TGF-β,MAPK,focal adhesion,and adherens junction signaling pathway were associated with candidate hub proteins.Gene ontology analysis demonstrated that candidate hub proteins were related to the TGF-βreceptor signaling pathway,common-partner SMAD protein phosphorylation,etc.DLE could significantly reduce the leakage of Evans blue in mice with cerebral I/R,while attenuating the expression of occludin,claudin-5,and zonula occludens-1.Western blotting demonstrated that regulation of TGF-β/SMAD signaling pathway played an essential role in the protective effect of DLE.Conclusion:Thus,a number of candidate hub proteins were identified based on DLE affinity chromatography through WGCNA.DLE could attenuate the dysfunction of bloodbrain barrier in the TGF-β/SMAD signaling pathway induced by cerebral I/R.展开更多
Emerging evidence that Enterovirus A 71(EV-A71)infection closely related to apoptosis.The ZVAD is a caspase inhibitor that can prevent apoptosis.The aims of this project were to evaluate the mechanism of the ZVAD inhi...Emerging evidence that Enterovirus A 71(EV-A71)infection closely related to apoptosis.The ZVAD is a caspase inhibitor that can prevent apoptosis.The aims of this project were to evaluate the mechanism of the ZVAD inhibited EV-A71 virus and to provide experiment basis for finding new antiviral drugs.In this study,after treated with ZVAD in EV-A71 infected Vero cells,the viral replication was reduced,and the cell viability was higher than EV-A71 group.Additionally,ZVAD decreased the cell apoptosis and the level of inflammatory cytokines induced by EV-A71 in the infected Vero cells.ZVAD inhibited cell apoptosis by regulating ROS mediated signaling pathway and inflammation cytokines to achieve antiviral.展开更多
Through a variable transformation, the Whitham-Broer-Kaup system is transformed into a parameter Levi system. Based on the Lax pair of the parameter Levi system, the N-fold Darboux transformation with multi-parameters...Through a variable transformation, the Whitham-Broer-Kaup system is transformed into a parameter Levi system. Based on the Lax pair of the parameter Levi system, the N-fold Darboux transformation with multi-parameters is constructed. Then some new explicit solutions for the Whitham-Broer-Kaup system are obtained via the given Darboux transformation.展开更多
Fluorescent carbon dots(CDs)have been identified as potential nanosensors and attracted tremendous research interests in wide areas including anti-counterfeiting,environmental and biological sensing and imaging in con...Fluorescent carbon dots(CDs)have been identified as potential nanosensors and attracted tremendous research interests in wide areas including anti-counterfeiting,environmental and biological sensing and imaging in considering of the attractive optical properties.In this work,we present a CDs based fluorescent sensor from polyvinylpyrrolidone,citric acid,and methionine as precursors by hydrothermal approach.The selective quantifying of Fe^(3+)and ascorbic acid(AA)are based on the fluorescent on-off-on process,in which the fluorescent quenching is induced by the coordination of the Fe^(3+)on the surface of the CDs,while the fluorescence recovery is mainly attributed to redox reaction between Fe^(3+)and AA,breaking the coordination and bringing the fluorescence back.Inspired by the good water solubility and biocompatibility,significant photostability,superior photobleaching resistance as well as high selectivity,sensitivity,and interference immunity,which are constructed mainly from the N,S-doping and methionine surface functionalization,the CDs have not only been employed as fluorescence ink in multiple anticounterfeiting printing and confidential document writing or transmitting,but also been developed as promising fluorescence sensors in solution and solid by CDs doped test strips and hydrogels for effectively monitoring and removing of Fe^(3+)and AA in environmental aqueous solution.The CDs have been also implemented as effective diagnostic candidates for imaging and tracking of Fe^(3+)and AA in living cells,accelerating the understanding of their function and importance in related biological processes for the prevention and treatment specific diseases.展开更多
Antibody leads must fulfill multiple desirable properties to be clinical candidates.Primarily due to the low throughput in the experimental procedure,the need for such multiproperty optimization causes the bottleneck ...Antibody leads must fulfill multiple desirable properties to be clinical candidates.Primarily due to the low throughput in the experimental procedure,the need for such multiproperty optimization causes the bottleneck in preclinical antibody discovery and development,because addressing one issue usually causes another.We developed a reinforcement learning(RL)method,named AB-Gen,for antibody library design using a generative pre-trained transformer(GPT)as the policy network of the RL agent.We showed that this model can learn the antibody space of heavy chain complementarity determining region 3(CDRH3)and generate sequences with similar property distributions.Besides,when using human epidermal growth factor receptor-2(HER2)as the target,the agent model of AB-Gen was able to generate novel CDRH3 sequences that fulfill multi-property constraints.Totally,509 generated sequences were able to pass all property filters,and three highly conserved residues were identified.The importance of these residues was further demonstrated by molecular dynamics simulations,consolidating that the agent model was capable of grasping important information in this complex optimization task.Overall,the ABGen method is able to design novel antibody sequences with an improved success rate than the traditional propose-then-filter approach.It has the potential to be used in practical antibody design,thus empowering the antibody discovery and development process.The source code of AB-Gen is freely available at Zenodo(https://doi.org/10.5281/zenodo.7657016)and BioCode(https://ngdc.cncb.ac.cn/biocode/tools/BT007341).展开更多
RNA interference(RNAi)is one of the most promising methods for the treatment of malignant tumors.However,developing an efficient biocompatible delivery vector for small interfering RNA(siRNA)remains a challenging issu...RNA interference(RNAi)is one of the most promising methods for the treatment of malignant tumors.However,developing an efficient biocompatible delivery vector for small interfering RNA(siRNA)remains a challenging issue.This study aimed to prepare a non-viral tumor-targeted carrier,named RGDfC-modified functionalized selenium nanoparticles(RGDfC-SeNPs).RGDfC-SeNPs were used to selectively deliver siSox2 to HepG2 liver cancer cells and tissues for the treatment of hepatocellular carcinoma(HCC).In the current study,RGDfC-SeNPs were successfully synthesized and characterized.It was shown that RGDfC-SeNPs could effectively load siSox2 to prepare an antitumor prodrug RGDfC-Se@siSox2.RGDfC-Se@siSox2 exhibited selective uptake in HepG2 liver cancer cells and LO2 normal liver cells,indicating RGDfC-SeNPs could effectively deliver siSox2 to HepG2 liver cancer cells.RGDfC-Se@siSox2 entered HepG2 cells via clathrin-mediated endocytosis by firstly encircling the cytoplasm and then releasing siSox2 in the lysosomes.RGDfC-Se@siSox2 could effectively silence Sox2 and inhibit the proliferation,migration and invasion of HepG2 cells.RGDfC-Se@siSox2 induced HepG2 cells apoptosis most likely via overproduction of reactive oxygen species and disruption of the mitochondrial membrane potentials.Most importantly,RGDfC-Se@siSox2 significantly inhibited the tumor growth in HepG2 tumor-bearing mice without obvious toxic side effects.These studies indicated that RGDfC-SeNPs may be an ideal gene carrier for delivering siSox2 to HepG2 cells and that RGDfC-Se@siSox2 may be a novel and highly specific gene-targeted prodrug therapy for HCC.展开更多
Protein neddylation is catalyzed by a neddylation activating enzyme(NAE,E1),an E2 conjugating enzyme,and an E3 ligase.In various types of human cancers,the neddylation pathway is abnormally activated.Our previous stud...Protein neddylation is catalyzed by a neddylation activating enzyme(NAE,E1),an E2 conjugating enzyme,and an E3 ligase.In various types of human cancers,the neddylation pathway is abnormally activated.Our previous study validated that the neddylation E2 UBE2F is a promising therapeutic target in lung cancer.Although the NAE inhibitor MLN4924/pevonedistat is currently under clinical investigation as an anti-cancer agent,there are no small molecules available that selectively target UBE2F.Here,we report,for the first time,the discovery,via structure-based virtual screen and chemical optimization,of such a small molecule,designated as HA-9104.HA-9104 binds to UBE2F,reduces its protein levels,and consequently inhibits cullin-5 neddylation.Blockage of cullin-5 neddylation inactivates cullin-RING ligase-5(CRL5)activity,leading to accumulation of the CRL5 substrate,NOXA,to induce apoptosis.Moreover,HA-9104 appears to form the DNA adduct via its 7-azaindole group to induce DNA damage and G2/M arrest.Biologically,HA-9104 effectively suppresses the growth and survival of lung cancer cells and confers radiosensitization in both in vitro cell culture and in vivo xenograft tumor models.In summary,we discovered a small molecule,designated HA-9104,that targets the UBE2F-CRL5 axis with anti-cancer activity alone or in combination with radiation.展开更多
Protein neddylation is catalyzed by a three-enzyme cascade,namely an E1 NEDD8-activating enzyme(NAE),one of two E2 NEDD8 conjugation enzymes and one of several E3 NEDD8 ligases.The physiological substrates of neddylat...Protein neddylation is catalyzed by a three-enzyme cascade,namely an E1 NEDD8-activating enzyme(NAE),one of two E2 NEDD8 conjugation enzymes and one of several E3 NEDD8 ligases.The physiological substrates of neddylation are the family members of cullin,the scaffold component of cullin RING ligases(CRLs).Currently,a potent E1 inhibitor,MLN4924,also known as pevonedistat,is in several clinical trials for anti-cancer therapy.Here we report the discovery,through virtual screening and structural modifications,of a small molecule compound HA-1141 that directly binds to NAE in both in vitro and in vivo assays and effectively inhibits neddylation of cullins 1 e5.Surprisingly,unlike MLN4924,HA-1141 also triggers non-canonical endoplasmic reticulum(ER)stress and PKR-mediated terminal integrated stress response(ISR)to activate ATF4 at an early stage,and to inhibit protein synthesis and mTORC1 activity at a later stage,eventually leading to autophagy induction.Biologically,HA-1141 suppresses growth and survival of cultured lung cancer cells and tumor growth in in vivo xenograft lung cancer models at a well-tolerated dose.Taken together,our study has identified a small molecule compound with the dual activities of blocking neddylation and triggering ER stress,leading to growth suppression of cancer cells.展开更多
Untethered microrobots have attracted extensive attention due to their potential for biomedical applications and micromanipulation at the small scale.Soft microrobots are of great research importance because of their ...Untethered microrobots have attracted extensive attention due to their potential for biomedical applications and micromanipulation at the small scale.Soft microrobots are of great research importance because of their highly deformable ability to achieve not only multiple locomotion mechanisms but also minimal invasion to the environment.However,the existing microrobots are still limited in their ability to locomote and cross obstacles in unstructured environments compared to conventional legged robots.Nature provides much inspiration for developing miniature robots.Here,we propose a bionic quadruped soft thin-film microrobot with a nonmagnetic soft body and 4 magnetic flexible legs.The quadruped soft microrobot can achieve multiple controllable locomotion modes in the external magnetic field.The experiment demonstrated the robot’s excellent obstacle-crossing ability by walking on the surface with steps and moving in the bottom of a stomach model with gullies.In particular,by controlling the conical angle of the external conical magnetic field,microbeads gripping,transportation,and release of the microrobot were demonstrated.In the future,the quadruped microrobot with excellent obstacle-crossing and gripping capabilities will be relevant for biomedical applications and micromanipulation.展开更多
Prof. Tafu Yu (1901-1993)(Fig. 1) is a pioneering scientist of phytopathology and agricultural microbiology in China. Like most of the scientists of his generation, Prof. Yu gave up the attractive conditions abroad an...Prof. Tafu Yu (1901-1993)(Fig. 1) is a pioneering scientist of phytopathology and agricultural microbiology in China. Like most of the scientists of his generation, Prof. Yu gave up the attractive conditions abroad and went back to China with the determination to rescue the nation with his knowledge. He has devoted his entire life to the development of phytopathology in China since 1924. Prof. Yu is also a distinguished educator who has instructed and in spired several generations of talent students for the country and has made outstanding contributions to the development of the agricultural scienee and education in China.展开更多
Fire-induced pollutant dispersion under the influence of buoyancy in urban street canyons has attracted wide attention given its adverse impact on human health.This study analyzes the influences of fire source locatio...Fire-induced pollutant dispersion under the influence of buoyancy in urban street canyons has attracted wide attention given its adverse impact on human health.This study analyzes the influences of fire source location and crossflowing wind(perpendicular to the canyon centerline)on indoor and outdoor air pollutant dispersion in an idealized urban street canyon by employing large eddy simulation.Three fire scenarios are defined according to the transverse location of the fire source:near the windward building(scenario 1),in the middle of the canyon(scenario 2),and near the leeward building(scenario 3).Results show that a re-entrainment phenomenon appears when the wind velocity reaches a critical value in scenarios 1 and 2,but it doesn't occur in scenario 3.Fire source location significantly influences the critical re-entrainment velocity.The critical velocity in scenario 1 is approximate 1.2-1.5 m/s larger than that in scenario 2.When the heat release rate is large,the critical Fr numbers are less sensitive to changes in HRR,and remain approximately constant with values of 0.47(scenario 1)and 0.37(scenario 2).When the wind velocity is large,more compartments are expected to be affected in the upper floors in all of the three scenarios,and smoke is distributed in an inverted triangle within the buildings.The indoor/outdoor temperature and pollutant concentrations are also analyzed.Our findings can provide valuable information for both human and property safety in relation to urban street canyons and their surrounding buildings.展开更多
基金supported by National Natural Science Foundation of China(Nos.82100417,81760094,81760724)The Foundation of Jiangxi Provincial Department of Science and Technology Project(Nos.20202ACBL206001,20212BAB206022,20181BAB205026)+1 种基金Youth Project of Jiangxi Education Department(No.GJJ200217)Open Project of Key Laboratory of Modern of TCM,Ministry of Education Jiangxi University of Traditional Chinese Medicine(TCM-2019010).
文摘The attenuation function of Dalbergia odorifera leaves on cerebral ischemia-reperfusion(I/R)is little known.The candidate targets for the Chinese herb were extracted from brain tissues through the high-affinity chromatography.The molecular mechanism of D.odorifera leaves on cerebral I/R was investigated.Methods:Serial affinity chromatography based on D.odorifera leaves extract(DLE)affinity matrices were applied to find specific binding proteins in the brain tissues implemented on C57BL/6 mice by intraluminal middle cerebral artery occlusion for 1 h and reperfusion for 24 h.Specific binding proteins were subjected to mass-spectrometry to search for the differentially expressed proteins between control and DLE-affinity matrices.The hub genes were screened based on weighted gene co-expression network analysis(WGCNA).Then,predictive biology and potential experimental verification were performed for the candidate genes.The protective role of DLE in blood-brain barrier damage in cerebral I/R mice was evaluated by the leakage of Evans blue,western blotting,immunohistochemistry,and immunofluorescent staining.Results:952 differentially expressed proteins were classified into seven modules based on WGCNA under soft threshold 6.Based on WGCNA,AKT1,PIK3CA,NOS3,SMAD3,SMAD1,IL6,MAPK1,TGFBR2,TGFBR1,MAPK3,IGF1R,LRG1,mTOR,ROCK1,TGFB1,IL1B,SMAD2,and SMAD518 candidate hub proteins were involved in turquoise module.TGF-β,MAPK,focal adhesion,and adherens junction signaling pathway were associated with candidate hub proteins.Gene ontology analysis demonstrated that candidate hub proteins were related to the TGF-βreceptor signaling pathway,common-partner SMAD protein phosphorylation,etc.DLE could significantly reduce the leakage of Evans blue in mice with cerebral I/R,while attenuating the expression of occludin,claudin-5,and zonula occludens-1.Western blotting demonstrated that regulation of TGF-β/SMAD signaling pathway played an essential role in the protective effect of DLE.Conclusion:Thus,a number of candidate hub proteins were identified based on DLE affinity chromatography through WGCNA.DLE could attenuate the dysfunction of bloodbrain barrier in the TGF-β/SMAD signaling pathway induced by cerebral I/R.
基金supported by the fund from Open Project of Guangdong Key Laboratory of Marine Materia Medica(LMM2020-7)the fund from Guangzhou Institute of Pediatrics/Guangzhou Women and Children’s Medical Center(Nos.Pre-NSFC-2019-016,YIP-2019-059,IP-2019-019)+3 种基金the Project of Traditional Chinese Medicine Bureau of Guangdong Province(No.20192075)the technology planning projects of Guangdong province(No.202102010202)The Guangdong Natural Science Foundation(2020A1515110648)the Open Fund of Guangdong Provincial Key Laboratory of Functional Supramolecular Coordination Materials and Applications(2020A03).
文摘Emerging evidence that Enterovirus A 71(EV-A71)infection closely related to apoptosis.The ZVAD is a caspase inhibitor that can prevent apoptosis.The aims of this project were to evaluate the mechanism of the ZVAD inhibited EV-A71 virus and to provide experiment basis for finding new antiviral drugs.In this study,after treated with ZVAD in EV-A71 infected Vero cells,the viral replication was reduced,and the cell viability was higher than EV-A71 group.Additionally,ZVAD decreased the cell apoptosis and the level of inflammatory cytokines induced by EV-A71 in the infected Vero cells.ZVAD inhibited cell apoptosis by regulating ROS mediated signaling pathway and inflammation cytokines to achieve antiviral.
文摘Through a variable transformation, the Whitham-Broer-Kaup system is transformed into a parameter Levi system. Based on the Lax pair of the parameter Levi system, the N-fold Darboux transformation with multi-parameters is constructed. Then some new explicit solutions for the Whitham-Broer-Kaup system are obtained via the given Darboux transformation.
基金supported by the National Natural Science Foundation of China(Nos.22171223,22179107,22077099,and 21807087)the Technology Innovation Leading Program of Shaanxi(No.2020TG−031)+2 种基金the Shaanxi Provincial Natural Science Fund Project(No.2018JQ2061)the Xi’an City Science and Technology Project(Nos.2020KJRC011 and 2019218214GXRC018CG019−GXYD18.4)the Outstanding Youth Science Fund of Xi’an University of Science and Technology(No.2018YQ3-14).
文摘Fluorescent carbon dots(CDs)have been identified as potential nanosensors and attracted tremendous research interests in wide areas including anti-counterfeiting,environmental and biological sensing and imaging in considering of the attractive optical properties.In this work,we present a CDs based fluorescent sensor from polyvinylpyrrolidone,citric acid,and methionine as precursors by hydrothermal approach.The selective quantifying of Fe^(3+)and ascorbic acid(AA)are based on the fluorescent on-off-on process,in which the fluorescent quenching is induced by the coordination of the Fe^(3+)on the surface of the CDs,while the fluorescence recovery is mainly attributed to redox reaction between Fe^(3+)and AA,breaking the coordination and bringing the fluorescence back.Inspired by the good water solubility and biocompatibility,significant photostability,superior photobleaching resistance as well as high selectivity,sensitivity,and interference immunity,which are constructed mainly from the N,S-doping and methionine surface functionalization,the CDs have not only been employed as fluorescence ink in multiple anticounterfeiting printing and confidential document writing or transmitting,but also been developed as promising fluorescence sensors in solution and solid by CDs doped test strips and hydrogels for effectively monitoring and removing of Fe^(3+)and AA in environmental aqueous solution.The CDs have been also implemented as effective diagnostic candidates for imaging and tracking of Fe^(3+)and AA in living cells,accelerating the understanding of their function and importance in related biological processes for the prevention and treatment specific diseases.
基金supported in part by the Office of Research Administration(ORA),King Abdullah University of Science and Technology(KAUST),Saudi Arabia(Grant Nos.FCC/1/1976-44-01,FCC/1/1976-45-01,REI/1/5234-01-01,and URF/1/4352-01-01)the National Natural Science Foundation of China(Grant No.22273107).
文摘Antibody leads must fulfill multiple desirable properties to be clinical candidates.Primarily due to the low throughput in the experimental procedure,the need for such multiproperty optimization causes the bottleneck in preclinical antibody discovery and development,because addressing one issue usually causes another.We developed a reinforcement learning(RL)method,named AB-Gen,for antibody library design using a generative pre-trained transformer(GPT)as the policy network of the RL agent.We showed that this model can learn the antibody space of heavy chain complementarity determining region 3(CDRH3)and generate sequences with similar property distributions.Besides,when using human epidermal growth factor receptor-2(HER2)as the target,the agent model of AB-Gen was able to generate novel CDRH3 sequences that fulfill multi-property constraints.Totally,509 generated sequences were able to pass all property filters,and three highly conserved residues were identified.The importance of these residues was further demonstrated by molecular dynamics simulations,consolidating that the agent model was capable of grasping important information in this complex optimization task.Overall,the ABGen method is able to design novel antibody sequences with an improved success rate than the traditional propose-then-filter approach.It has the potential to be used in practical antibody design,thus empowering the antibody discovery and development process.The source code of AB-Gen is freely available at Zenodo(https://doi.org/10.5281/zenodo.7657016)and BioCode(https://ngdc.cncb.ac.cn/biocode/tools/BT007341).
基金supported by National Natural Science Foundation of China(81970507)Natural Science Foundation of Guangdong Province(2020A1515010100)+3 种基金Technology Planning Project of Guangzhou City(201904010132)Innovative Clinical Technique of Guangzhou(2019GX05)China Postdoctoral Science Foundation(2017M612632)Yu Xia thanks to Yuyan Huang and all the staff of Guangzhou First People’s Hospital for supporting this research.
文摘RNA interference(RNAi)is one of the most promising methods for the treatment of malignant tumors.However,developing an efficient biocompatible delivery vector for small interfering RNA(siRNA)remains a challenging issue.This study aimed to prepare a non-viral tumor-targeted carrier,named RGDfC-modified functionalized selenium nanoparticles(RGDfC-SeNPs).RGDfC-SeNPs were used to selectively deliver siSox2 to HepG2 liver cancer cells and tissues for the treatment of hepatocellular carcinoma(HCC).In the current study,RGDfC-SeNPs were successfully synthesized and characterized.It was shown that RGDfC-SeNPs could effectively load siSox2 to prepare an antitumor prodrug RGDfC-Se@siSox2.RGDfC-Se@siSox2 exhibited selective uptake in HepG2 liver cancer cells and LO2 normal liver cells,indicating RGDfC-SeNPs could effectively deliver siSox2 to HepG2 liver cancer cells.RGDfC-Se@siSox2 entered HepG2 cells via clathrin-mediated endocytosis by firstly encircling the cytoplasm and then releasing siSox2 in the lysosomes.RGDfC-Se@siSox2 could effectively silence Sox2 and inhibit the proliferation,migration and invasion of HepG2 cells.RGDfC-Se@siSox2 induced HepG2 cells apoptosis most likely via overproduction of reactive oxygen species and disruption of the mitochondrial membrane potentials.Most importantly,RGDfC-Se@siSox2 significantly inhibited the tumor growth in HepG2 tumor-bearing mice without obvious toxic side effects.These studies indicated that RGDfC-SeNPs may be an ideal gene carrier for delivering siSox2 to HepG2 cells and that RGDfC-Se@siSox2 may be a novel and highly specific gene-targeted prodrug therapy for HCC.
基金National Key R&D Program of China(2021YFA1101000 to Y.S.,and 2018YFE0195100 to H.L.)Zhejiang Provincial Natural Science Foundation of China(LD22H300003 to Y.S.)+1 种基金A grant from Research Center for Life Science and Human Health,Binjiang Institute of Zhejiang University(ZY202205SMKY007 to Y.S.)National Natural Science Foundation of China(82020108030 for H.L.).
文摘Protein neddylation is catalyzed by a neddylation activating enzyme(NAE,E1),an E2 conjugating enzyme,and an E3 ligase.In various types of human cancers,the neddylation pathway is abnormally activated.Our previous study validated that the neddylation E2 UBE2F is a promising therapeutic target in lung cancer.Although the NAE inhibitor MLN4924/pevonedistat is currently under clinical investigation as an anti-cancer agent,there are no small molecules available that selectively target UBE2F.Here,we report,for the first time,the discovery,via structure-based virtual screen and chemical optimization,of such a small molecule,designated as HA-9104.HA-9104 binds to UBE2F,reduces its protein levels,and consequently inhibits cullin-5 neddylation.Blockage of cullin-5 neddylation inactivates cullin-RING ligase-5(CRL5)activity,leading to accumulation of the CRL5 substrate,NOXA,to induce apoptosis.Moreover,HA-9104 appears to form the DNA adduct via its 7-azaindole group to induce DNA damage and G2/M arrest.Biologically,HA-9104 effectively suppresses the growth and survival of lung cancer cells and confers radiosensitization in both in vitro cell culture and in vivo xenograft tumor models.In summary,we discovered a small molecule,designated HA-9104,that targets the UBE2F-CRL5 axis with anti-cancer activity alone or in combination with radiation.
基金National Key R&D Program of China(2016YFA0501800 to Yi Sun)for financial support。
文摘Protein neddylation is catalyzed by a three-enzyme cascade,namely an E1 NEDD8-activating enzyme(NAE),one of two E2 NEDD8 conjugation enzymes and one of several E3 NEDD8 ligases.The physiological substrates of neddylation are the family members of cullin,the scaffold component of cullin RING ligases(CRLs).Currently,a potent E1 inhibitor,MLN4924,also known as pevonedistat,is in several clinical trials for anti-cancer therapy.Here we report the discovery,through virtual screening and structural modifications,of a small molecule compound HA-1141 that directly binds to NAE in both in vitro and in vivo assays and effectively inhibits neddylation of cullins 1 e5.Surprisingly,unlike MLN4924,HA-1141 also triggers non-canonical endoplasmic reticulum(ER)stress and PKR-mediated terminal integrated stress response(ISR)to activate ATF4 at an early stage,and to inhibit protein synthesis and mTORC1 activity at a later stage,eventually leading to autophagy induction.Biologically,HA-1141 suppresses growth and survival of cultured lung cancer cells and tumor growth in in vivo xenograft lung cancer models at a well-tolerated dose.Taken together,our study has identified a small molecule compound with the dual activities of blocking neddylation and triggering ER stress,leading to growth suppression of cancer cells.
基金supported in part by National Key Re search and Development Project under Grant SQ2020YFB130100in part by the National Natural Science Foundation of China under Grants 62022087 and U22A2064+5 种基金in part by the Shenzhen Science and Technology Innovation Commission under Shenzhen Fundamental Research Program under Grant JCYJ20220818101611025in part by the Youth In novation Promotion Association of CAS,in part by the Special Support Project for Outstanding Young Scholars of Guangdong Province under Grant 2019TQ05X933in part by the CAS-Croucher Funding Scheme for Joint Laboratories under Grant 172644KYSB20200044the Croucher Foundation Grant with reference no.CAS20403in part by the Shenzhen Institute of Artificial Intelligence and Robotics for Society,in part by DMETKF2022008in part by SIAT-CUHK Joint Laboratory of Robotics and Intelligent Systems.
文摘Untethered microrobots have attracted extensive attention due to their potential for biomedical applications and micromanipulation at the small scale.Soft microrobots are of great research importance because of their highly deformable ability to achieve not only multiple locomotion mechanisms but also minimal invasion to the environment.However,the existing microrobots are still limited in their ability to locomote and cross obstacles in unstructured environments compared to conventional legged robots.Nature provides much inspiration for developing miniature robots.Here,we propose a bionic quadruped soft thin-film microrobot with a nonmagnetic soft body and 4 magnetic flexible legs.The quadruped soft microrobot can achieve multiple controllable locomotion modes in the external magnetic field.The experiment demonstrated the robot’s excellent obstacle-crossing ability by walking on the surface with steps and moving in the bottom of a stomach model with gullies.In particular,by controlling the conical angle of the external conical magnetic field,microbeads gripping,transportation,and release of the microrobot were demonstrated.In the future,the quadruped microrobot with excellent obstacle-crossing and gripping capabilities will be relevant for biomedical applications and micromanipulation.
文摘Prof. Tafu Yu (1901-1993)(Fig. 1) is a pioneering scientist of phytopathology and agricultural microbiology in China. Like most of the scientists of his generation, Prof. Yu gave up the attractive conditions abroad and went back to China with the determination to rescue the nation with his knowledge. He has devoted his entire life to the development of phytopathology in China since 1924. Prof. Yu is also a distinguished educator who has instructed and in spired several generations of talent students for the country and has made outstanding contributions to the development of the agricultural scienee and education in China.
基金This work was sponsored by the National Natural Science Foundation of Shandong Province(No.ZR2020QE279)Shandong Jianzhu University Doctoral Fund(No.X19055Z)Plan of Guidance and Cultivation for Young Innovative Talents of Shandong Province.
文摘Fire-induced pollutant dispersion under the influence of buoyancy in urban street canyons has attracted wide attention given its adverse impact on human health.This study analyzes the influences of fire source location and crossflowing wind(perpendicular to the canyon centerline)on indoor and outdoor air pollutant dispersion in an idealized urban street canyon by employing large eddy simulation.Three fire scenarios are defined according to the transverse location of the fire source:near the windward building(scenario 1),in the middle of the canyon(scenario 2),and near the leeward building(scenario 3).Results show that a re-entrainment phenomenon appears when the wind velocity reaches a critical value in scenarios 1 and 2,but it doesn't occur in scenario 3.Fire source location significantly influences the critical re-entrainment velocity.The critical velocity in scenario 1 is approximate 1.2-1.5 m/s larger than that in scenario 2.When the heat release rate is large,the critical Fr numbers are less sensitive to changes in HRR,and remain approximately constant with values of 0.47(scenario 1)and 0.37(scenario 2).When the wind velocity is large,more compartments are expected to be affected in the upper floors in all of the three scenarios,and smoke is distributed in an inverted triangle within the buildings.The indoor/outdoor temperature and pollutant concentrations are also analyzed.Our findings can provide valuable information for both human and property safety in relation to urban street canyons and their surrounding buildings.
