Protein therap34 wherein therapeutic proteins are delivered to treat disorders, is considered the safest and most direct approach for treating diseases. However, its applications are highly limited by the paucity of e...Protein therap34 wherein therapeutic proteins are delivered to treat disorders, is considered the safest and most direct approach for treating diseases. However, its applications are highly limited by the paucity of efficient strategies for delivering proteins and the rapid clearance of therapeutic proteins in vivo after their administration. Here, we demonstrate a novel strategy that can significantly prolong the circulation time of therapeutic proteins as well as minimize their immunogenicity. This is achieved by encapsulating individual protein molecules with a thin layer of crosslinked phosphorylcholine polymer that resists protein adsorption. Through extensive cellular studies, we demonstrate that the crosslinked phosphorylcholine polymer shell effectively prevents the encapsulated protein from being phagocytosed by macrophages, which play an essential role in the clearance of nanoparfides in vivo. Moreover, the polymer shell prevents the encapsulated protein from being identified by immune cells. As a result, immune responses against the therapeutic protein are effectively suppressed. This work describes a feasible method to prolong the circulation time and reduce the immunogenicity of therapeutic proteins, which may promote the development and application of novel protein therapies in the treatment of diverse diseases.展开更多
The Indian and East Asian summer monsoons are two components of the whole Asian summer monsoon system. Previous studies have indicated in-phase and out-of-phase variations between Indian and East Asian summer rainfall...The Indian and East Asian summer monsoons are two components of the whole Asian summer monsoon system. Previous studies have indicated in-phase and out-of-phase variations between Indian and East Asian summer rainfall. The present study reviews the current understanding of the connection between Indian and East Asian summer rainfall. The review covers the relationship of northern China, southern Japan, and South Korean summer rainfall with Indian summer rainfall; the atmospheric circulation anomalies connecting Indian and East Asian summer rainfall variations; the long-term change in the connection between Indian and northern China rainfall and the plausible reasons for the change; and the influence of ENSO on the relationship between Indian and East Asian summer rainfall and its change. While much progress has been made about the relationship between Indian and East Asian summer rainfall variations, there are several remaining issues that need investigation. These include the processes involved in the connection between Indian and East Asian summer rainfall, the non-stationarity of the connection and the plausible reasons, the influences of ENSO on the relationship, the performance of climate models in simulating the relationship between Indian and East Asian summer rainfall, and the relationship between Indian and East Asian rainfall intraseasonal fluctuations.展开更多
To utilize themultiple functions and give full play of ginsenosides,a variety of ginsenosides with different structures were prepared into liposomes and evaluated for their effect on the stability,pharmacokinetics and...To utilize themultiple functions and give full play of ginsenosides,a variety of ginsenosides with different structures were prepared into liposomes and evaluated for their effect on the stability,pharmacokinetics and tumor targeting capability of liposomes.The results showed that the position and number of glycosyl groups of ginsenosides have significant effect on the in vitro and in vivo properties of their liposomes.The pharmacokinetics of ginsenosides liposomes indicated that the C-3 sugar group of ginsenosides is beneficial to their liposomes for longer circulation in vivo.The C-3 and C-6 glycosyls can enhance the uptake of their liposomes by 4T1 cells,and the glycosyls at C-3 position can enhance the tumor active targeting ability significantly,based on the specific binding capacity to Glut 1 expressed on the surface of 4T1 cells.According to the results in the study,ginsenoside Rg3 and ginsenoside Rh2 are potential for exploiting novel liposomes because of their cholesterol substitution,long blood circulation and tumor targeting capabilities.The results provide a theoretical basis for further development of ginsenoside based liposome delivery systems.展开更多
Using daily maximum temperature(Tmax)data from 516 observation stations in eastern China from 1981 to 2020,this study employed a relative threshold method to define short-and long-lived heat waves(HWs)by considering r...Using daily maximum temperature(Tmax)data from 516 observation stations in eastern China from 1981 to 2020,this study employed a relative threshold method to define short-and long-lived heat waves(HWs)by considering regional climate differences to investigate the spatial characteristics and evolution of large-scale circulation during summer HWs.The results demonstrated spatial disparities in the frequency distribution of HWs of different durations and differences in the magnitude of duration and intensity between short-and long-lived HWs.Empirical orthogonal function analysis revealed three dominant spatial modes for both short-and long-lived HWs.The first mode showed that short-lived HWs occur prominently in both northern and southern regions,whereas long-lived HWs mainly occur in the northern region.The second mode was characterized by a meridional dipole pattern in both cases.The third mode exhibited a quadrupole pattern for short-lived HWs and a tripole pattern for long-lived HWs.Differences in the center locations of anomalies in the 500-hPa geopotential height and 850-hPa wind fields significantly influenced the temperature and precipitation anomaly distribution of typical HWs by affecting the warm column in the lower troposphere,cloud distribution,and moisture transport.Moreover,the atmospheric circulation evolution processes of typical HWs associated with the different modes of long-and short-lived HWs were linked to distinct teleconnection patterns.During the three modes of long-lived(short-lived)HWs,there was stronger(weaker)wave flux activity with multiple(single)propagation paths.Stronger westward Atlantic wave train activity at 300 hPa triggered the synergistic action of meridional and zonal wave fluxes,favoring the strengthening and maintenance of positive anomalies in geopotential height of 500 hPa.This may have contributed to the formation of long-lived HWs.These findings provide valuable insights to enhance our understanding and prediction of summer HWs.展开更多
Short in vivo circulation is a major hindrance to the widespread adoption of protein therapeutics. Protein nanocapsules generated by encapsulating proteins with a thin layer of phosphorylcholine-based polymer via a tw...Short in vivo circulation is a major hindrance to the widespread adoption of protein therapeutics. Protein nanocapsules generated by encapsulating proteins with a thin layer of phosphorylcholine-based polymer via a two-step encapsulation process exhibited significantly prolonged plasma half-life. Furthermore, by constructing nanocapsules with similar sizes but different surface charges and chemistry, we demonstrated a generic strategy for prolonging the plasma half-life of therapeutic proteins. In an in vitro experiment, four types of bovine serum albumin （BSA） nanocapsules were incubated with fetal bovine serum （FBS） in phosphate buffer saline （PBS）; the cell uptake by HeLa cells was monitored to systematically evaluate the characteristics of the surface chemistry during drculation. Single positron emission tomography-computed tomography （SPECT） was employed to allow real-time observation of the BSA nanoparticle distribution in vivo, as well as quantification of the plasma concentration after intravenous administration. This study offers a practical method for translating a broad range of proteins for clinical use.展开更多
Enzyme therapeutics have great potential for the treatment of systemic disorders such as urolithiasis and nephrocalcinosis, which are caused by the excessive accumulation of oxalate. However, exogenous enzymes have sh...Enzyme therapeutics have great potential for the treatment of systemic disorders such as urolithiasis and nephrocalcinosis, which are caused by the excessive accumulation of oxalate. However, exogenous enzymes have short half-lives in vivo and elicit high immunogenicity, which largely limit the therapeutic outcomes. Herein, we report a delivery strategy whereby therapeutic enzymes are encapsulated within a thin zwitterionic polymer shell to form enzyme nanocapsules. The strategy is exemplified by the encapsulation of oxalate oxidase （OxO） for the treatment of hyperoxaluria, because as-synthesized OxO nanocapsules have a prolonged blood circulation half-life and elicit reduced immunogenicity. Our design of enzyme nanocapsules that enable the systemic delivery of therapeutic enzymes can be extended to various biomedical applications.展开更多
Tumor microenvironment has been widely utilized for advanced drug delivery in recent years,among which hypoxia-responsive drug delivery systems have become the research hotspot.Although hypoxia-responsive micelles or ...Tumor microenvironment has been widely utilized for advanced drug delivery in recent years,among which hypoxia-responsive drug delivery systems have become the research hotspot.Although hypoxia-responsive micelles or polymersomes have been successfully developed,a type of hypoxia-degradable nanogel has rarely been reported and the advantages of hypoxia-degradable nanogel over other kinds of degradable nanogels in tumor drug delivery remain unclear.Herein,we reported the synthesis of a novel hypoxia-responsive crosslinker and the fabrication of a hypoxia-degradable zwitterionic poly(phosphorylcholine)-based(HPMPC)nanogel for tumor drug delivery.The obtained HPMPC nanogel showed ultra-long blood circulation and desirable immune compatibility,which leads to high and long-lasting accumulation in tumor tissue.Furthermore,HPMPC nanogel could rapidly degrade into oligomers of low molecule weight owing to the degradation of azo bond in hypoxic environment,which leads to the effective release of the loaded drug.Impressively,HPMPC nanogel showed superior tumor inhibition effect both in vitro and in vivo compared to the reduction-responsive phosphorylcholine-based nanogel,owing to the more complete drug release.Overall,the drug-loaded HPMPC nanogel exhibits a pronounced tumor inhibition effect in a humanized subcutaneous liver cancer model with negligible side effects,which showed great potential as nanocarrier for advanced tumor drug delivery.展开更多
基金This work is supported by the National Natural Science Foundation of China （NSFC, Nos. 91127045, 51390483, 51473319, 51303025, 81401439 and 51343007）, YG2012MS38 and China Postdoctoral Science Foundation （No. 2014M551399）.
文摘Protein therap34 wherein therapeutic proteins are delivered to treat disorders, is considered the safest and most direct approach for treating diseases. However, its applications are highly limited by the paucity of efficient strategies for delivering proteins and the rapid clearance of therapeutic proteins in vivo after their administration. Here, we demonstrate a novel strategy that can significantly prolong the circulation time of therapeutic proteins as well as minimize their immunogenicity. This is achieved by encapsulating individual protein molecules with a thin layer of crosslinked phosphorylcholine polymer that resists protein adsorption. Through extensive cellular studies, we demonstrate that the crosslinked phosphorylcholine polymer shell effectively prevents the encapsulated protein from being phagocytosed by macrophages, which play an essential role in the clearance of nanoparfides in vivo. Moreover, the polymer shell prevents the encapsulated protein from being identified by immune cells. As a result, immune responses against the therapeutic protein are effectively suppressed. This work describes a feasible method to prolong the circulation time and reduce the immunogenicity of therapeutic proteins, which may promote the development and application of novel protein therapies in the treatment of diverse diseases.
基金supported by the National Key Basic Research Program of China(Grant No.2014CB953902)the National Key Research and Development Program of China(Grant No.2016YFA0600603)the National Natural Science Foundation of China(Grant Nos.41475081,41275081 and 41530425)
文摘The Indian and East Asian summer monsoons are two components of the whole Asian summer monsoon system. Previous studies have indicated in-phase and out-of-phase variations between Indian and East Asian summer rainfall. The present study reviews the current understanding of the connection between Indian and East Asian summer rainfall. The review covers the relationship of northern China, southern Japan, and South Korean summer rainfall with Indian summer rainfall; the atmospheric circulation anomalies connecting Indian and East Asian summer rainfall variations; the long-term change in the connection between Indian and northern China rainfall and the plausible reasons for the change; and the influence of ENSO on the relationship between Indian and East Asian summer rainfall and its change. While much progress has been made about the relationship between Indian and East Asian summer rainfall variations, there are several remaining issues that need investigation. These include the processes involved in the connection between Indian and East Asian summer rainfall, the non-stationarity of the connection and the plausible reasons, the influences of ENSO on the relationship, the performance of climate models in simulating the relationship between Indian and East Asian summer rainfall, and the relationship between Indian and East Asian rainfall intraseasonal fluctuations.
基金supported by the National Natural Science Foundation of China (No. 82074277 and 81773911)the Development Project of Shanghai Peak Disciplines-Integrated Medicine (No. 20180101)
文摘To utilize themultiple functions and give full play of ginsenosides,a variety of ginsenosides with different structures were prepared into liposomes and evaluated for their effect on the stability,pharmacokinetics and tumor targeting capability of liposomes.The results showed that the position and number of glycosyl groups of ginsenosides have significant effect on the in vitro and in vivo properties of their liposomes.The pharmacokinetics of ginsenosides liposomes indicated that the C-3 sugar group of ginsenosides is beneficial to their liposomes for longer circulation in vivo.The C-3 and C-6 glycosyls can enhance the uptake of their liposomes by 4T1 cells,and the glycosyls at C-3 position can enhance the tumor active targeting ability significantly,based on the specific binding capacity to Glut 1 expressed on the surface of 4T1 cells.According to the results in the study,ginsenoside Rg3 and ginsenoside Rh2 are potential for exploiting novel liposomes because of their cholesterol substitution,long blood circulation and tumor targeting capabilities.The results provide a theoretical basis for further development of ginsenoside based liposome delivery systems.
基金Supported by the National Key Research and Development Program of China(2022YFF0801603).
文摘Using daily maximum temperature(Tmax)data from 516 observation stations in eastern China from 1981 to 2020,this study employed a relative threshold method to define short-and long-lived heat waves(HWs)by considering regional climate differences to investigate the spatial characteristics and evolution of large-scale circulation during summer HWs.The results demonstrated spatial disparities in the frequency distribution of HWs of different durations and differences in the magnitude of duration and intensity between short-and long-lived HWs.Empirical orthogonal function analysis revealed three dominant spatial modes for both short-and long-lived HWs.The first mode showed that short-lived HWs occur prominently in both northern and southern regions,whereas long-lived HWs mainly occur in the northern region.The second mode was characterized by a meridional dipole pattern in both cases.The third mode exhibited a quadrupole pattern for short-lived HWs and a tripole pattern for long-lived HWs.Differences in the center locations of anomalies in the 500-hPa geopotential height and 850-hPa wind fields significantly influenced the temperature and precipitation anomaly distribution of typical HWs by affecting the warm column in the lower troposphere,cloud distribution,and moisture transport.Moreover,the atmospheric circulation evolution processes of typical HWs associated with the different modes of long-and short-lived HWs were linked to distinct teleconnection patterns.During the three modes of long-lived(short-lived)HWs,there was stronger(weaker)wave flux activity with multiple(single)propagation paths.Stronger westward Atlantic wave train activity at 300 hPa triggered the synergistic action of meridional and zonal wave fluxes,favoring the strengthening and maintenance of positive anomalies in geopotential height of 500 hPa.This may have contributed to the formation of long-lived HWs.These findings provide valuable insights to enhance our understanding and prediction of summer HWs.
基金This work is supported by the National Natural Science Foundation of China （NSFC, Nos. 51343007, 81271612 and 81401439）, Shanghai Pujiang Program （No. 13PJD022）, and Shanghai Health Bureau Fund （No. 20124016）.
文摘Short in vivo circulation is a major hindrance to the widespread adoption of protein therapeutics. Protein nanocapsules generated by encapsulating proteins with a thin layer of phosphorylcholine-based polymer via a two-step encapsulation process exhibited significantly prolonged plasma half-life. Furthermore, by constructing nanocapsules with similar sizes but different surface charges and chemistry, we demonstrated a generic strategy for prolonging the plasma half-life of therapeutic proteins. In an in vitro experiment, four types of bovine serum albumin （BSA） nanocapsules were incubated with fetal bovine serum （FBS） in phosphate buffer saline （PBS）; the cell uptake by HeLa cells was monitored to systematically evaluate the characteristics of the surface chemistry during drculation. Single positron emission tomography-computed tomography （SPECT） was employed to allow real-time observation of the BSA nanoparticle distribution in vivo, as well as quantification of the plasma concentration after intravenous administration. This study offers a practical method for translating a broad range of proteins for clinical use.
文摘目的采用p H梯度法制备重酒石酸长春瑞滨长循环脂质体并进行表征。方法以粒径为指标,考察水化温度和挤出次数对空白脂质体粒径的影响;以粒径及包封率为指标,考察孵化温度和孵化时间对载药脂质体粒径和包封率的影响。并采用Malvern粒度仪测定脂质体的粒径分布、多分散系数及Zeta电位,透射电镜考察其形态,并考察脂质体稳定性。结果重酒石酸长春瑞滨长循环脂质体粒径(96.4±27.2)nm,多分散系数(0.162±0.042),Zeta电位(-26.7±3.5)m V;透射电镜显示脂质体粒径均一,成单层膜球状分布;长期稳定性研究显示,脂质体在5℃条件下放置3个月稳定。结论 p H梯度法可以用于重酒石酸长春瑞滨长循环脂质体的制备。
文摘Enzyme therapeutics have great potential for the treatment of systemic disorders such as urolithiasis and nephrocalcinosis, which are caused by the excessive accumulation of oxalate. However, exogenous enzymes have short half-lives in vivo and elicit high immunogenicity, which largely limit the therapeutic outcomes. Herein, we report a delivery strategy whereby therapeutic enzymes are encapsulated within a thin zwitterionic polymer shell to form enzyme nanocapsules. The strategy is exemplified by the encapsulation of oxalate oxidase （OxO） for the treatment of hyperoxaluria, because as-synthesized OxO nanocapsules have a prolonged blood circulation half-life and elicit reduced immunogenicity. Our design of enzyme nanocapsules that enable the systemic delivery of therapeutic enzymes can be extended to various biomedical applications.
基金financially supported by the National Key Research and Development Program of China(No.2017YFA0205200)the National Natural Science Foundation of China(Grant No.81903165 and 81901857)the Chinese Postdoctoral Foundation(Grant No.2019M663361,China)
文摘Tumor microenvironment has been widely utilized for advanced drug delivery in recent years,among which hypoxia-responsive drug delivery systems have become the research hotspot.Although hypoxia-responsive micelles or polymersomes have been successfully developed,a type of hypoxia-degradable nanogel has rarely been reported and the advantages of hypoxia-degradable nanogel over other kinds of degradable nanogels in tumor drug delivery remain unclear.Herein,we reported the synthesis of a novel hypoxia-responsive crosslinker and the fabrication of a hypoxia-degradable zwitterionic poly(phosphorylcholine)-based(HPMPC)nanogel for tumor drug delivery.The obtained HPMPC nanogel showed ultra-long blood circulation and desirable immune compatibility,which leads to high and long-lasting accumulation in tumor tissue.Furthermore,HPMPC nanogel could rapidly degrade into oligomers of low molecule weight owing to the degradation of azo bond in hypoxic environment,which leads to the effective release of the loaded drug.Impressively,HPMPC nanogel showed superior tumor inhibition effect both in vitro and in vivo compared to the reduction-responsive phosphorylcholine-based nanogel,owing to the more complete drug release.Overall,the drug-loaded HPMPC nanogel exhibits a pronounced tumor inhibition effect in a humanized subcutaneous liver cancer model with negligible side effects,which showed great potential as nanocarrier for advanced tumor drug delivery.
