Recent progress in targeted metabolic therapy of cancer has been limited by the considerable toxicity associated with such drugs.To address this challenge,we developed a smart theranostic prodrug system that combines ...Recent progress in targeted metabolic therapy of cancer has been limited by the considerable toxicity associated with such drugs.To address this challenge,we developed a smart theranostic prodrug system that combines a fluorophore and an anticancer drug,specifically 6-diazo-5-oxo-L-norleucine(DON),using a thioketal linkage(TK).This system enables imaging,chemotherapy,photodynamic therapy,and on-demand drug release upon radiation exposure.The optimized prodrug,DON-TK-BM3,incorporating cyanine dyes as the fluorophore,displayed potent reactive oxygen species release and efficient tumor cell killing.Unlike the parent drug DON,DON-TK-BM3 exhibited no toxicity toward normal cells.Moreover,DON-TK-BM3 demonstrated high tumor accumulation and reduced side effects,including gastrointestinal toxicity,in mice.This study provides a practical strategy for designing prodrugs of metabolic inhibitors with significant toxicity stemming from their lack of tissue selectivity.展开更多
Trapping unstable intermediates for elucidating reaction mechanisms in chemistry presents a formidable challenge.There has long been a lack of direct evidence for key intermediates like the highly reactive phlorin lea...Trapping unstable intermediates for elucidating reaction mechanisms in chemistry presents a formidable challenge.There has long been a lack of direct evidence for key intermediates like the highly reactive phlorin leading to porphyrin.Here,we report a molecular-strain engineering(MSE)strategy that harnesses intramolecular strain to trap the native phlorin during porphyrin synthesis.By mechanically constraining its periphery,a phlorin stable towards oxidation was captured as an isolable intermediate and fully characterized.展开更多
Background:Anticoagulants are promising regimens for treating coronavirus disease 2019(COVID-19).However,whether prophylactic or intermediate-to-therapeutic dosage is optimal remains under active discussion.Methods:We...Background:Anticoagulants are promising regimens for treating coronavirus disease 2019(COVID-19).However,whether prophylactic or intermediate-to-therapeutic dosage is optimal remains under active discussion.Methods:We comprehensively searched PubMed,Embase,Scopus,Web of Science,Cochrane Library,ClinicalTrials,and MedRxiv databases on April 26,2022.Two independent researchers conducted literature selection and data extraction separately according to predetermined criteria.Notably,this is the first meta-analysis on COVID-19,taking serious consideration regarding the dosage overlap between the 2 comparison groups of prophylactic anticoagulation(PA)and intermediate-to-therapeutic anticoagulation(I-TA).Results:We included 11 randomized controlled trials(RCTs)and 36 cohort studies with 27,051 COVID-19 patients.By analyzing all the RCTs,there was no significant difference in mortality between the PA and I-TA groups,which was further confirmed by trial sequential analysis(TSA)(odds ratio[OR]:0.93;95%confidence interval[CI]:0.71–1.22;P=0.61;TSA adjusted CI:0.71–1.26).The rate of major bleeding was remarkably higher in the I-TA group than in the PA group,despite adjusting for TSA(OR:1.73;95%CI:1.15–2.60;P=0.009;TSA adjusted CI:1.09–2.58).RCTs have supported the beneficial effect of I-TA in reducing thrombotic events.After including all studies,mortality in the I-TA group was significantly higher than in the PA group(OR:1.38;95%CI:1.15–1.66;P=0.0005).The rate of major bleeding was similar to the analysis from RCTs(OR:2.24;95%CI:1.86–2.69;P<0.00001).There was no distinct difference in the rate of thrombotic events between the 2 regimen groups.In addition,in both critical and noncritical subgroups,I-TA failed to reduce mortality but increased major bleeding rate compared with PA,as shown in meta-analysis of all studies,as well as RCTs only.Meta-regression of all studies suggested that there was no relationship between the treatment effect and the overall risk of mortality or major bleeding(P=0.14,P=0.09,respective展开更多
Japanese encephalitis virus(JEV) is a leading cause of viral encephalitis in endemic regions of Asia. The neurotropism of JEV and its high-efficiency replication in neurons are the key events for pathogenesis. Reveali...Japanese encephalitis virus(JEV) is a leading cause of viral encephalitis in endemic regions of Asia. The neurotropism of JEV and its high-efficiency replication in neurons are the key events for pathogenesis. Revealing the interplay between virus and host cells in metabolic facet is of great importance both for unraveling the pathogenesis mechanisms and providing novel antiviral targets. This study took advantage of the integration analysis of metabolomics and transcriptomics to depict the metabolic profiles of neurons during the early stage of JEV infection. Increased glycolysis and its branched pentose phosphate pathway(PPP) flux and impaired oxidative phosphorylation(OXPHOS) in glucose utilization,and the catabolic patterns of lipid metabolism were created to facilitate the biosynthesis of precursors needed for JEV replication in neurons. Pharmacological inhibitions of both glycolysis pathway and PPP in neurons suggested its indispensable role in maintaining the optimal propagation of JEV. In addition, analysis of metabolomic-transcriptomic regulatory network showed the pivotal biological function of lipid metabolism during JEV infection. Several pro-inflammatory lipid metabolites were significantly up-regulated and might partially be responsible for the progression of encephalitis.These unique metabolic reprogramming features might give deeper insight into JEV infected neurons and provide promising antiviral approaches targeting metabolism.展开更多
Correction to:Virologica Sinica https://doi.org/10.1007/s12250-021-00445-0 In the original version of this article,one image in Fig.4 was accidently duplicated during figure layout and the dilution rate was mislabeled.
The Tibetan Plateau(TP)is an area sensitive to climate change,where the ozone distribution affects the atmospheric environment of the TP and its surrounding regions.The relatively low total column ozone over the TP in...The Tibetan Plateau(TP)is an area sensitive to climate change,where the ozone distribution affects the atmospheric environment of the TP and its surrounding regions.The relatively low total column ozone over the TP in boreal summer and its spatiotemporal variations have received extensive attention.In this study,five-year balloon-borne measurements of ozone over Lhasa in boreal summer are used to investigate the influences of the apparent heat source(Q1)on the ozone vertical structure over the plateau.The mechanisms for the above processes are also explored.The results show that the tropospheric ozone mixing ratio over Lhasa decreases when the total atmospheric Q1 in the troposphere over the TP is relatively high.Strengthened ascending motions are accompanied by enhanced Q1 over the main TP region.Consequently,the tropospheric ozone mixing ratio over Lhasa decreases when Q1 is higher in summer,which is attributed to the upward transport of the ozone-poor surface air.展开更多
A personalized recommendation for cloud services, which is based on usage history and the cooperative relationship of cloud services, is presented. According to service groups, a service group could be defined as seve...A personalized recommendation for cloud services, which is based on usage history and the cooperative relationship of cloud services, is presented. According to service groups, a service group could be defined as several services that were used together by one user at a time, and cooperative relationship between each two services can be calculated. In the process of recommendation, the services which are highly related to the service that the user has selected would be obtained firstly, the result should then take the QoS (Quality of Service) similarity between service’s QoS and user’s preference into account, so the final result combining the cooperative relationship and similarity will meet the functional needs of users and also meet the user’s personalized non-functional requirements. The simulation proves that the algorithm works effectively.展开更多
基金support from the National Natural Science Foundation of China(82072058,91859204,82073702)Natural Science Foundation of Jiangsu Province for Excellent Young Scientists(Grant BK20211580,China)Qinglan Project of Jiangsu Province of China.“Double First-Class”university project(CPUQNJC2205,China).
文摘Recent progress in targeted metabolic therapy of cancer has been limited by the considerable toxicity associated with such drugs.To address this challenge,we developed a smart theranostic prodrug system that combines a fluorophore and an anticancer drug,specifically 6-diazo-5-oxo-L-norleucine(DON),using a thioketal linkage(TK).This system enables imaging,chemotherapy,photodynamic therapy,and on-demand drug release upon radiation exposure.The optimized prodrug,DON-TK-BM3,incorporating cyanine dyes as the fluorophore,displayed potent reactive oxygen species release and efficient tumor cell killing.Unlike the parent drug DON,DON-TK-BM3 exhibited no toxicity toward normal cells.Moreover,DON-TK-BM3 demonstrated high tumor accumulation and reduced side effects,including gastrointestinal toxicity,in mice.This study provides a practical strategy for designing prodrugs of metabolic inhibitors with significant toxicity stemming from their lack of tissue selectivity.
基金from the National Natural Science Foundation of China(grant nos.22171232 and 21971211)the Natural Science Foundation of Zhejiang Province(grant no.2022XHSJJ007)the Qiantang River Talent Foundation(grant no.QJD1902029).
文摘Trapping unstable intermediates for elucidating reaction mechanisms in chemistry presents a formidable challenge.There has long been a lack of direct evidence for key intermediates like the highly reactive phlorin leading to porphyrin.Here,we report a molecular-strain engineering(MSE)strategy that harnesses intramolecular strain to trap the native phlorin during porphyrin synthesis.By mechanically constraining its periphery,a phlorin stable towards oxidation was captured as an isolable intermediate and fully characterized.
基金supported by the National Key R&D Program of China(2020YFC0846600,2020YFC1512700,2020YFC1512705,2020YFC1512703)National S&T Fundamental Resources Investigation Project(2018FY100600,2018FY100602)+2 种基金Taishan Pandeng Scholar Program of Shandong Province(tspd20181220)Taishan Young Scholar Program of Shandong Province(tsqn20161065,tsqn201812129)Youth Top-Talent Project of National Ten Thousand Talents Plan,and Qilu Young Scholar Program.
文摘Background:Anticoagulants are promising regimens for treating coronavirus disease 2019(COVID-19).However,whether prophylactic or intermediate-to-therapeutic dosage is optimal remains under active discussion.Methods:We comprehensively searched PubMed,Embase,Scopus,Web of Science,Cochrane Library,ClinicalTrials,and MedRxiv databases on April 26,2022.Two independent researchers conducted literature selection and data extraction separately according to predetermined criteria.Notably,this is the first meta-analysis on COVID-19,taking serious consideration regarding the dosage overlap between the 2 comparison groups of prophylactic anticoagulation(PA)and intermediate-to-therapeutic anticoagulation(I-TA).Results:We included 11 randomized controlled trials(RCTs)and 36 cohort studies with 27,051 COVID-19 patients.By analyzing all the RCTs,there was no significant difference in mortality between the PA and I-TA groups,which was further confirmed by trial sequential analysis(TSA)(odds ratio[OR]:0.93;95%confidence interval[CI]:0.71–1.22;P=0.61;TSA adjusted CI:0.71–1.26).The rate of major bleeding was remarkably higher in the I-TA group than in the PA group,despite adjusting for TSA(OR:1.73;95%CI:1.15–2.60;P=0.009;TSA adjusted CI:1.09–2.58).RCTs have supported the beneficial effect of I-TA in reducing thrombotic events.After including all studies,mortality in the I-TA group was significantly higher than in the PA group(OR:1.38;95%CI:1.15–1.66;P=0.0005).The rate of major bleeding was similar to the analysis from RCTs(OR:2.24;95%CI:1.86–2.69;P<0.00001).There was no distinct difference in the rate of thrombotic events between the 2 regimen groups.In addition,in both critical and noncritical subgroups,I-TA failed to reduce mortality but increased major bleeding rate compared with PA,as shown in meta-analysis of all studies,as well as RCTs only.Meta-regression of all studies suggested that there was no relationship between the treatment effect and the overall risk of mortality or major bleeding(P=0.14,P=0.09,respective
基金This research was funded by the National Major Science and Technology Projects of China,grant number 2017ZX10202203-007-003.
文摘Japanese encephalitis virus(JEV) is a leading cause of viral encephalitis in endemic regions of Asia. The neurotropism of JEV and its high-efficiency replication in neurons are the key events for pathogenesis. Revealing the interplay between virus and host cells in metabolic facet is of great importance both for unraveling the pathogenesis mechanisms and providing novel antiviral targets. This study took advantage of the integration analysis of metabolomics and transcriptomics to depict the metabolic profiles of neurons during the early stage of JEV infection. Increased glycolysis and its branched pentose phosphate pathway(PPP) flux and impaired oxidative phosphorylation(OXPHOS) in glucose utilization,and the catabolic patterns of lipid metabolism were created to facilitate the biosynthesis of precursors needed for JEV replication in neurons. Pharmacological inhibitions of both glycolysis pathway and PPP in neurons suggested its indispensable role in maintaining the optimal propagation of JEV. In addition, analysis of metabolomic-transcriptomic regulatory network showed the pivotal biological function of lipid metabolism during JEV infection. Several pro-inflammatory lipid metabolites were significantly up-regulated and might partially be responsible for the progression of encephalitis.These unique metabolic reprogramming features might give deeper insight into JEV infected neurons and provide promising antiviral approaches targeting metabolism.
文摘Correction to:Virologica Sinica https://doi.org/10.1007/s12250-021-00445-0 In the original version of this article,one image in Fig.4 was accidently duplicated during figure layout and the dilution rate was mislabeled.
基金This research was supported by the second Tibetan Plateau Scientific Expedition and Research Program(STEP)[grant number 2019QZKK0604]the National Natural Science Foundation of China[grant numbers 91837311,41705025,and 41705021].
文摘The Tibetan Plateau(TP)is an area sensitive to climate change,where the ozone distribution affects the atmospheric environment of the TP and its surrounding regions.The relatively low total column ozone over the TP in boreal summer and its spatiotemporal variations have received extensive attention.In this study,five-year balloon-borne measurements of ozone over Lhasa in boreal summer are used to investigate the influences of the apparent heat source(Q1)on the ozone vertical structure over the plateau.The mechanisms for the above processes are also explored.The results show that the tropospheric ozone mixing ratio over Lhasa decreases when the total atmospheric Q1 in the troposphere over the TP is relatively high.Strengthened ascending motions are accompanied by enhanced Q1 over the main TP region.Consequently,the tropospheric ozone mixing ratio over Lhasa decreases when Q1 is higher in summer,which is attributed to the upward transport of the ozone-poor surface air.
文摘A personalized recommendation for cloud services, which is based on usage history and the cooperative relationship of cloud services, is presented. According to service groups, a service group could be defined as several services that were used together by one user at a time, and cooperative relationship between each two services can be calculated. In the process of recommendation, the services which are highly related to the service that the user has selected would be obtained firstly, the result should then take the QoS (Quality of Service) similarity between service’s QoS and user’s preference into account, so the final result combining the cooperative relationship and similarity will meet the functional needs of users and also meet the user’s personalized non-functional requirements. The simulation proves that the algorithm works effectively.
