As a non-apoptotic cell death form,ferroptosis offers an alternative approach to overcome cancer chemotherapy resistance.However,accumulating evidence indicates cancer cells can develop ferroptosis resistance by evolv...As a non-apoptotic cell death form,ferroptosis offers an alternative approach to overcome cancer chemotherapy resistance.However,accumulating evidence indicates cancer cells can develop ferroptosis resistance by evolving antioxidative defense mechanisms.To address this issue,we prepared a Buthionine-(S,R)-sulfoximine(BSO)loaded metal organic framework(MOF)of BSO-MOF-HA(BMH)with the combination effect of boosting oxidative damage and inhibiting antioxidative defense.MOF nanoparticle was constructed by the photosensitizer of[4,4,4,4-(porphine-5,10,15,20-tetrayl)tetrakis(benzoic acid)](TCPP)and the metal ion of Zr6,which was further decorated with hyaluronic acid(HA)in order to impart active targeting to CD44 receptors overexpressed cancer cells.BMH exhibited a negative charge and spherical shape with average particle size about 162.5nm.BMH was found to restore the susceptibility of 4T1 cells to ferroptosis under irradiation.This was attributed to the combination of photodynamic therapy(PDT)andγ-glutamylcysteine synthetase inhibitor of BSO,shifting the redox balance to oxidative stress.Enhanced ferroptosis also induced the release of damage associated molecular patterns(DAMPs)to maturate dendritic cells and activated T lymphocytes,leading to superior anti-tumor performance in vivo.Taken together,our findings demonstrated that boosting oxidative damage with photosensitizer serves as an effective strategy to reverse ferroptosis resistance.展开更多
In this study, a p H-sensitive micelle self-assembled from poly(L-histidine) based triblock copolymers of poly(ethylene glycol)–poly(D,L-lactide)–poly(L-histidine)(mPEG-PLA-PHis) was prepared and used as the intrace...In this study, a p H-sensitive micelle self-assembled from poly(L-histidine) based triblock copolymers of poly(ethylene glycol)–poly(D,L-lactide)–poly(L-histidine)(mPEG-PLA-PHis) was prepared and used as the intracellular doxorubicin(Dox) delivery for cancer chemotherapy. Dox was loaded into the micelles by thin-film hydration method and a Box–Behnken design for three factors at three levels was used to optimize the preparations. The optimized mPEG-PLA-Phis/Dox micelles exhibited good encapsulation efficiency of 91.12%,a mean diameter of 45 nm and narrow size distribution with polydispersity index of 0.256.In vitro drug release studies demonstrated that Dox was released from the micelles in a p Hdependent manner. Furthermore, the cellular evaluation of Dox loaded micelles displayed that the micelles possessed high antitumor activity in vitro with an IC50 of 35.30 μg/ml against MCF-7/ADR cells. The confocal microscopy and flow cytometry experiments indicated that m PEG-PLA-Phis micelles mediated efficient cytoplasmic delivery of Dox with the aid of poly(Lhistidine) mediated endosomal escape. In addition, blank m PEG-PLA-Phis micelles were shown to be nontoxic to MCF-7/ADR cells even at a high concentration of 200 μg/ml. The pHsensitive mPEG-PLA-PHis micelles have been demonstrated to be a promising nanosystem for the intracellular delivery of Dox for MDR reversal.展开更多
Various biotin-modified liposomes incorporated with docetaxel(DTX) were prepared to study the effect of surface biotin density on the pharmacokinetic profile of the liposome. Four types of liposomes such as PEG modifi...Various biotin-modified liposomes incorporated with docetaxel(DTX) were prepared to study the effect of surface biotin density on the pharmacokinetic profile of the liposome. Four types of liposomes such as PEG modified liposome(PDL), 0.5%(mol) biotin modified liposome(0.5 BDL), 1%(mol) biotin modified liposome(1 BDL) and 2%(mol) biotin modified liposome(2 BDL) were prepared using thin film dispersion method. The prepared liposomes were characterized by measuring encapsulation efficiency(EE), particle size, Zeta-potential, physical stability and drug release profiles in vitro. MTT assay was performed to elevate the cytotoxicity of liposomes on MCF-7 cells. In vivo evaluation was further performed to investigate the effect of biotin surface density on the pharmacokinetic profiles. All the prepared liposomes exhibited high encapsulation efficiency, small particle size, narrow particle distribution and sustained release profiles in vitro. In MTT assay, 0.5 BDL showed largest tumor cell toxicity, compared with DTX solution. All liposomes containing DTX showed prolonged blood circulation in vivo, and 0.5 BDL showed the longest circulation time among the biotin modified liposome. Surface modification of liposome had a negative impact on the circulation of liposomes in the blood, which needs to be considered when designing the ligand mediated targeting delivery systems. A proper amount of biotin liposome with 0.5% molar ratio is expected to produce the best anti-tumor effect.展开更多
This paper first defines the concept of interactive teaching,then discusses the current research status of interactive education in China and abroad,identifies the outstanding problems of interactive teaching,and then...This paper first defines the concept of interactive teaching,then discusses the current research status of interactive education in China and abroad,identifies the outstanding problems of interactive teaching,and then constructs a useful model of interactive teaching.展开更多
1.Introduction As an important resource,forests not only provide irreplaceable economic benefits,but also yield ecological benefits that maintain the balance of terrestrial ecosystems.In addition,forests are an energy...1.Introduction As an important resource,forests not only provide irreplaceable economic benefits,but also yield ecological benefits that maintain the balance of terrestrial ecosystems.In addition,forests are an energy base of the biosphere.With the development of information-based technologies and globalization,accurate information regarding individual trees and standing forests in forest resource investigations is increasingly needed in order to achieve sustainable development of forestry[1–6].As an important means of obtaining information,unmanned aerial vehicles(UAVs)are becoming increasingly popular in a wide range of fields,given their developmental trends of miniaturization and diversification[7–9].Moreover,geographic information system(GIS)technology,as another type of core technology in the digital world,is undergoing rapid development.展开更多
The deve lopment of c ros s-borde r e-commerce cannot be separated from the support of policy,and policy formulation must conform to the law of cross-border e-commerce development,which needs to understand the theory ...The deve lopment of c ros s-borde r e-commerce cannot be separated from the support of policy,and policy formulation must conform to the law of cross-border e-commerce development,which needs to understand the theory of cross-border e-commerce development,clarify the factors and mechanisms affecting the development of cross-border e-commerce,on this basis,the policy formulated can have synergies,but also for the development of e-commerce to play a better role.On the basis of theoretical discussion,this paper puts forward the problem of the synergy of policy formulation.展开更多
The levels of six perfluoroalkyl substances(PFASs) in surface sediment and their vertical variations in dated sediment cores from the Haihe River were investigated; studied substances included perfluorooctanoic acid(P...The levels of six perfluoroalkyl substances(PFASs) in surface sediment and their vertical variations in dated sediment cores from the Haihe River were investigated; studied substances included perfluorooctanoic acid(PFOA),perfluorononanoic acid(PFNA),perfluorooctane sulfonate(PFOS),perfluorodecanoic acid(PFDA),perfluoroundecanoic acid(PFUnA),and perfluorododecanoic acid(PFDoA). Results showed that the total PFAS concentration in surface sediment ranged between 0.52 and 16.33 ng/g dry weight(dw) with an average of3.47 ng/g dw,with PFOS and PFOA as the dominant PFASs. In general,the PFAS concentrations in the mainstream increased from the upper to the lower reaches,except that a drop occurred downstream of the Erdao dam. Although the PFASs in the sediment cores did not show a clear decreasing or increasing trend with depth,the three cores had a similar vertical variation.The PFAS levels were relatively low in the surface sediment,and reached the first high point at8–20 cm as a result of the wide use of PFASs from 1990 to 2000. After that the PFAS levels decreased,and then increased to a second high point at about 40–48 cm,which might be caused by the leaching of PFASs in sediment. Because PFASs have hydrophilic groups and relatively high solubility,the PFASs will transfer from the upper to lower layers of sediment when water infiltration occurs,leading to the fluctuation of PFAS levels in sediment cores. This study suggests that both the temporal variation of sources and transfer processes of PFASs in sediments are important factors influencing the vertical variation of PFASs in sediment cores.展开更多
Amplifying“eat me signal”during tumor immunogenic cell death(ICD)cascade is crucial for tumor immunotherapy.Inspired by the indispensable role of adenosine triphosphate(ATP,a necessary“eat me signal”for ICD),a ver...Amplifying“eat me signal”during tumor immunogenic cell death(ICD)cascade is crucial for tumor immunotherapy.Inspired by the indispensable role of adenosine triphosphate(ATP,a necessary“eat me signal”for ICD),a versatile ICD amplifier was developed for chemotherapy-sensitized immunotherapy.Doxorubicin(DOX),ATP and ferrous ions(Fe^(2+))were co-assembled into nanosized amplifier(ADO-Fe)throughπ‒πstacking and coordination effect.Meanwhile,phenylboric acid-polyethylene glycol-phenylboric acid(PBA-PEG-PBA)was modified on the surface of ADO-Fe(denoted as PADO-Fe)by the virtue of d-ribose unit of ATP.PADO-Fe could display active targetability against tumor cells via sialic acid/PBA interaction.In acidic microenvironment,PBA-PEG-PBA would dissociate from amplifier.Moreover,high H_(2)O_(2)concentration would induce hydroxyl radical(·OH)and oxygen(O_(2))generation through Fenton reaction by Fe^(2+).DOX and ATP would be released from the amplifier,which could induce ICD effect and“ICD adjuvant”to amplify this process.Together with programmed death ligands 1(PD-L1)checkpoint blockade immunotherapy,PADO-Fe could not only activate immune response against primary tumor,but also strong abscopal effect against distant tumor.Our simple and multifunctional ICD amplifier opens a new window for enhancing ICD effect and immune checkpoint blockade therapy.展开更多
Short stature is among the most common endocrinological disease phenotypes of childhood and may occur as an isolated finding or in conjunction with other clinical manifestations.Although the diagnostic utility of clin...Short stature is among the most common endocrinological disease phenotypes of childhood and may occur as an isolated finding or in conjunction with other clinical manifestations.Although the diagnostic utility of clinical genetic testing in short stature has been implicated,the genetic architecture and the utility of genomic studies such as exome sequencing(ES)in a sizable cohort of patients with short stature have not been investigated systematically.In this study,we recruited 561 individuals with short stature from two centers in China during a 4-year period.We performed ES for all patients and available parents.All patients were retrospectively divided into two groups:an isolated short stature group(group I,n=257)and an apparently syndromic short stature group(group II,n=304).Causal variants were identified in 135 of 561(24.1%)patients.In group I,29 of 257(11.3%)of the patients were solved by variants in 24 genes.In group II,106 of 304(34.9%)patients were solved by variants in 57 genes.Genes involved in fundamental cellularprocess played an important role in the genetic architecture of syndromic short stature.Distinct genetic architectures and pathophysiological processes underlie isolated and syndromic short stature.展开更多
文摘As a non-apoptotic cell death form,ferroptosis offers an alternative approach to overcome cancer chemotherapy resistance.However,accumulating evidence indicates cancer cells can develop ferroptosis resistance by evolving antioxidative defense mechanisms.To address this issue,we prepared a Buthionine-(S,R)-sulfoximine(BSO)loaded metal organic framework(MOF)of BSO-MOF-HA(BMH)with the combination effect of boosting oxidative damage and inhibiting antioxidative defense.MOF nanoparticle was constructed by the photosensitizer of[4,4,4,4-(porphine-5,10,15,20-tetrayl)tetrakis(benzoic acid)](TCPP)and the metal ion of Zr6,which was further decorated with hyaluronic acid(HA)in order to impart active targeting to CD44 receptors overexpressed cancer cells.BMH exhibited a negative charge and spherical shape with average particle size about 162.5nm.BMH was found to restore the susceptibility of 4T1 cells to ferroptosis under irradiation.This was attributed to the combination of photodynamic therapy(PDT)andγ-glutamylcysteine synthetase inhibitor of BSO,shifting the redox balance to oxidative stress.Enhanced ferroptosis also induced the release of damage associated molecular patterns(DAMPs)to maturate dendritic cells and activated T lymphocytes,leading to superior anti-tumor performance in vivo.Taken together,our findings demonstrated that boosting oxidative damage with photosensitizer serves as an effective strategy to reverse ferroptosis resistance.
文摘In this study, a p H-sensitive micelle self-assembled from poly(L-histidine) based triblock copolymers of poly(ethylene glycol)–poly(D,L-lactide)–poly(L-histidine)(mPEG-PLA-PHis) was prepared and used as the intracellular doxorubicin(Dox) delivery for cancer chemotherapy. Dox was loaded into the micelles by thin-film hydration method and a Box–Behnken design for three factors at three levels was used to optimize the preparations. The optimized mPEG-PLA-Phis/Dox micelles exhibited good encapsulation efficiency of 91.12%,a mean diameter of 45 nm and narrow size distribution with polydispersity index of 0.256.In vitro drug release studies demonstrated that Dox was released from the micelles in a p Hdependent manner. Furthermore, the cellular evaluation of Dox loaded micelles displayed that the micelles possessed high antitumor activity in vitro with an IC50 of 35.30 μg/ml against MCF-7/ADR cells. The confocal microscopy and flow cytometry experiments indicated that m PEG-PLA-Phis micelles mediated efficient cytoplasmic delivery of Dox with the aid of poly(Lhistidine) mediated endosomal escape. In addition, blank m PEG-PLA-Phis micelles were shown to be nontoxic to MCF-7/ADR cells even at a high concentration of 200 μg/ml. The pHsensitive mPEG-PLA-PHis micelles have been demonstrated to be a promising nanosystem for the intracellular delivery of Dox for MDR reversal.
文摘Various biotin-modified liposomes incorporated with docetaxel(DTX) were prepared to study the effect of surface biotin density on the pharmacokinetic profile of the liposome. Four types of liposomes such as PEG modified liposome(PDL), 0.5%(mol) biotin modified liposome(0.5 BDL), 1%(mol) biotin modified liposome(1 BDL) and 2%(mol) biotin modified liposome(2 BDL) were prepared using thin film dispersion method. The prepared liposomes were characterized by measuring encapsulation efficiency(EE), particle size, Zeta-potential, physical stability and drug release profiles in vitro. MTT assay was performed to elevate the cytotoxicity of liposomes on MCF-7 cells. In vivo evaluation was further performed to investigate the effect of biotin surface density on the pharmacokinetic profiles. All the prepared liposomes exhibited high encapsulation efficiency, small particle size, narrow particle distribution and sustained release profiles in vitro. In MTT assay, 0.5 BDL showed largest tumor cell toxicity, compared with DTX solution. All liposomes containing DTX showed prolonged blood circulation in vivo, and 0.5 BDL showed the longest circulation time among the biotin modified liposome. Surface modification of liposome had a negative impact on the circulation of liposomes in the blood, which needs to be considered when designing the ligand mediated targeting delivery systems. A proper amount of biotin liposome with 0.5% molar ratio is expected to produce the best anti-tumor effect.
文摘This paper first defines the concept of interactive teaching,then discusses the current research status of interactive education in China and abroad,identifies the outstanding problems of interactive teaching,and then constructs a useful model of interactive teaching.
基金We are grateful to the staff of the Precision Forestry Key Laboratory of Beijing,Beijing Forestry University,and to acknowledge all the people who have contributed to this paperThis research was jointly supported by the Fundamental Research Funds for the Central Universities(2015ZCQ-LX-01)the National Natural Science Foundation of China(U1710123).
文摘1.Introduction As an important resource,forests not only provide irreplaceable economic benefits,but also yield ecological benefits that maintain the balance of terrestrial ecosystems.In addition,forests are an energy base of the biosphere.With the development of information-based technologies and globalization,accurate information regarding individual trees and standing forests in forest resource investigations is increasingly needed in order to achieve sustainable development of forestry[1–6].As an important means of obtaining information,unmanned aerial vehicles(UAVs)are becoming increasingly popular in a wide range of fields,given their developmental trends of miniaturization and diversification[7–9].Moreover,geographic information system(GIS)technology,as another type of core technology in the digital world,is undergoing rapid development.
文摘The deve lopment of c ros s-borde r e-commerce cannot be separated from the support of policy,and policy formulation must conform to the law of cross-border e-commerce development,which needs to understand the theory of cross-border e-commerce development,clarify the factors and mechanisms affecting the development of cross-border e-commerce,on this basis,the policy formulated can have synergies,but also for the development of e-commerce to play a better role.On the basis of theoretical discussion,this paper puts forward the problem of the synergy of policy formulation.
基金supported by the Major State Basic Research Development Program (No.2010CB951104)the National Science Foundation for Distinguished Young Scholars (No.51325902)+1 种基金the Specialized Research Fund for the Doctoral Program of Higher Education (No.20110003110030)the National Natural Science Foundation of China (No.51279010)
文摘The levels of six perfluoroalkyl substances(PFASs) in surface sediment and their vertical variations in dated sediment cores from the Haihe River were investigated; studied substances included perfluorooctanoic acid(PFOA),perfluorononanoic acid(PFNA),perfluorooctane sulfonate(PFOS),perfluorodecanoic acid(PFDA),perfluoroundecanoic acid(PFUnA),and perfluorododecanoic acid(PFDoA). Results showed that the total PFAS concentration in surface sediment ranged between 0.52 and 16.33 ng/g dry weight(dw) with an average of3.47 ng/g dw,with PFOS and PFOA as the dominant PFASs. In general,the PFAS concentrations in the mainstream increased from the upper to the lower reaches,except that a drop occurred downstream of the Erdao dam. Although the PFASs in the sediment cores did not show a clear decreasing or increasing trend with depth,the three cores had a similar vertical variation.The PFAS levels were relatively low in the surface sediment,and reached the first high point at8–20 cm as a result of the wide use of PFASs from 1990 to 2000. After that the PFAS levels decreased,and then increased to a second high point at about 40–48 cm,which might be caused by the leaching of PFASs in sediment. Because PFASs have hydrophilic groups and relatively high solubility,the PFASs will transfer from the upper to lower layers of sediment when water infiltration occurs,leading to the fluctuation of PFAS levels in sediment cores. This study suggests that both the temporal variation of sources and transfer processes of PFASs in sediments are important factors influencing the vertical variation of PFASs in sediment cores.
基金the financial support of Natural Science Foundation of China (Nos. 82104108, 82073797, 81874305 and 81773668)China Postdoctoral Science Foundation (2021M693869)Liaoning Natural Science Foundation for Planned Project (2021JH6/10500161, China)
文摘Amplifying“eat me signal”during tumor immunogenic cell death(ICD)cascade is crucial for tumor immunotherapy.Inspired by the indispensable role of adenosine triphosphate(ATP,a necessary“eat me signal”for ICD),a versatile ICD amplifier was developed for chemotherapy-sensitized immunotherapy.Doxorubicin(DOX),ATP and ferrous ions(Fe^(2+))were co-assembled into nanosized amplifier(ADO-Fe)throughπ‒πstacking and coordination effect.Meanwhile,phenylboric acid-polyethylene glycol-phenylboric acid(PBA-PEG-PBA)was modified on the surface of ADO-Fe(denoted as PADO-Fe)by the virtue of d-ribose unit of ATP.PADO-Fe could display active targetability against tumor cells via sialic acid/PBA interaction.In acidic microenvironment,PBA-PEG-PBA would dissociate from amplifier.Moreover,high H_(2)O_(2)concentration would induce hydroxyl radical(·OH)and oxygen(O_(2))generation through Fenton reaction by Fe^(2+).DOX and ATP would be released from the amplifier,which could induce ICD effect and“ICD adjuvant”to amplify this process.Together with programmed death ligands 1(PD-L1)checkpoint blockade immunotherapy,PADO-Fe could not only activate immune response against primary tumor,but also strong abscopal effect against distant tumor.Our simple and multifunctional ICD amplifier opens a new window for enhancing ICD effect and immune checkpoint blockade therapy.
基金funded in part by the Beijing Natural Science Foundation(JQ20032 to N.W.and to 7191007 to Z.W.)National Natural Science Foundation of China(81822030 and 82072391 to N.W.,81772299and 81930068 to Z.W.,81772301 and 81972132 to G.Q.,81672123and 81972037 to J.Z.)+7 种基金Capital's Funds for Health Improvement and Research(2020-4-40114 to N.W.)Tsinghua University-Peking Union Medical College Hospital Initiative Scientific Research ProgramNational Key Research and Development Program of China(2018YFC0910500 to N.W.and Z.W.,2016YFC0901501 to S.Z.)the PUMC Youth Fund and the Fundamental Research Funds for the Central Universities(3332019052 to Y.M.)the CAMS Initiative Fund for Medical Sciences(2016-I2M-3-003 to G.Q.and N.W.,2016-I2M-2-006 and 2017-I2M-2-001 to Z.W.)the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2019PT320025 to N.W.)sponsored by GeneScience Pharmaceuticals Co.,Ltd.(Changchun,China)funded by the United States National Institutes of Health(UM1HG006542 and K08 HG008986)。
文摘Short stature is among the most common endocrinological disease phenotypes of childhood and may occur as an isolated finding or in conjunction with other clinical manifestations.Although the diagnostic utility of clinical genetic testing in short stature has been implicated,the genetic architecture and the utility of genomic studies such as exome sequencing(ES)in a sizable cohort of patients with short stature have not been investigated systematically.In this study,we recruited 561 individuals with short stature from two centers in China during a 4-year period.We performed ES for all patients and available parents.All patients were retrospectively divided into two groups:an isolated short stature group(group I,n=257)and an apparently syndromic short stature group(group II,n=304).Causal variants were identified in 135 of 561(24.1%)patients.In group I,29 of 257(11.3%)of the patients were solved by variants in 24 genes.In group II,106 of 304(34.9%)patients were solved by variants in 57 genes.Genes involved in fundamental cellularprocess played an important role in the genetic architecture of syndromic short stature.Distinct genetic architectures and pathophysiological processes underlie isolated and syndromic short stature.
