The search and development of anti-HIV drugs is currently one of the most urgent tasks of pharmacological studies. In this work, a quantitative structure-activity relationship （QSAR） model based on some new norm ind...The search and development of anti-HIV drugs is currently one of the most urgent tasks of pharmacological studies. In this work, a quantitative structure-activity relationship （QSAR） model based on some new norm indexes, was obtained to a series of more than 150 HEPT derivatives （1-[（2-hydroxyethoxy）methyl]-6-（phenylthio）thymine） to find their pEC50 （the required effective concentration to achieve 50% protection of MT-4 cells against the cytopathic effect of virus） and pCC50 （the required cytotoxic concentration to reduce visibility of 50% mock infected cell） activities. The model efficiencies were then validated using the leave-one-out cross validation （LOO-CV） and y- randomization test. Results indicated that this new model was efficient and could provide satisfactory results for prediction of pECso and pCC50 with the higher R2 train and the higher Rt2est. By using the leverage approach, the applicability domain of this model was further investigated and no response outlier was detected for HEFT derivatives involved in this work. Comparison results with reference methods demonstrated that this new method could result in significant improvements for predicting pEC50 and pCC50 of anti-HIV HEPT derivatives. Moreover, results shown in this present study suggested that these two absolutely different activities pECso and pCC50 of anti-HIV HEPT derivatives could be predicted well with a totally similar QSAR model, which indicated that this model mizht have the potential to be further utilized for other biological activities of HEFT derivatives.展开更多
An accurate and convenient method is essential for measuring the terminal velocity of seeds dispersed by wind.Systematic and random errors produced by existing methods lower the accuracy and convenience in determining...An accurate and convenient method is essential for measuring the terminal velocity of seeds dispersed by wind.Systematic and random errors produced by existing methods lower the accuracy and convenience in determining seed terminal velocity.In this study,a video camera was used to record the falling process of forty-one species of wind-borne seed with eight appendage structures and seven aerodynamic behaviors in a settling tower at a speed of 50 frames per second(fps).The videos were analyzed by Quick Time Player to determine seed acceleration height,acceleration time,and terminal velocity.The results showed that acceleration height and time,terminal velocity,and the diff erence between terminal velocity and descent velocity(DTD)increased with wing loading.Compared with dropping methods,the camera recording method eliminated the eff ect of acceleration and corrected seed terminal velocity.Based on wing loading,release heights were determined for accurate measurement of terminal velocity of diff erent seeds.This method,due to its inexpensive equipment,high accuracy,easy observation and operation,can be applied to measure the terminal velocity of wind dispersed seeds,and provides a promising method in exploring the dispersal process of seeds.展开更多
We construct a sovereign default network by employing high-dimensional vector autoregressions obtained by analyzing connectedness in sovereign credit default swap markets.We develop four measures of centrality,namely,...We construct a sovereign default network by employing high-dimensional vector autoregressions obtained by analyzing connectedness in sovereign credit default swap markets.We develop four measures of centrality,namely,degree,betweenness,closeness,and eigenvector centralities,to detect whether network properties drive the currency risk premia.We observe that closeness and betweenness centralities can negatively drive currency excess returns but do not exhibit a relationship with forward spread.Thus,our developed network centralities are independent of an unconditional carry trade risk factor.Based on our findings,we develop a trading strategy by taking a long position on peripheral countries’currencies and a short position on core coun-tries’currencies.The aforementioned strategy generates a higher Sharpe ratio than the currency momentum strategy.Our proposed strategy is robust to foreign exchange regimes and the coronavirus disease 2019 pandemic.展开更多
Purinostat Mesylate(PM)is a novel highly selective and active HDAC I/IIb inhibitor,and the injectable formulation of PM(PMF)based on the compound prescription containing cyclodextrin completely can overcome PM’s poor...Purinostat Mesylate(PM)is a novel highly selective and active HDAC I/IIb inhibitor,and the injectable formulation of PM(PMF)based on the compound prescription containing cyclodextrin completely can overcome PM’s poor solubility and improves its stability and pharmacokinetic properties.Here,we showed that PM effectively repressed the survival of Ph+leukemia cells and CD34+leukemia cells from CML patients in vitro.In vivo studies demonstrated that PMF significantly prevented BCR-ABL(T315I)induced CML progression by restraining leukemia stem cells(LSCs),which are insensitive to chemotherapy and responsible for CML relapse.Mechanism studies revealed that targeting HDAC I/IIb repressed several important factors for LSCs survival including c-Myc,β-Catenin,E2f,Ezh2,Alox5,and mTOR,as well as interrupted some critical biologic processes.Additionally,PMF increased glutamate metabolism in LSCs by increasing GLS1.The combination of PMF and glutaminase inhibitor BPTES synergistically eradicated LSCs by altering multiple key proteins and signaling pathways which are critical for LSC survival and self-renewal.Overall,our findings represent a new therapeutic strategy for eliminating LSCs by targeting HDAC I/IIb and glutaminolysis,which potentially provides a guidance for PMF clinical trials in the future for TKI resistance CML patients.展开更多
We report herein that TSPAN32 is a key node factor for Philadelphia (Ph+) leukemia pathogenesis. We found that TSPAN32expression was repressed by BCR-ABL and ectopic TSPAN32 expression upon Imatinib treatment inhibite...We report herein that TSPAN32 is a key node factor for Philadelphia (Ph+) leukemia pathogenesis. We found that TSPAN32expression was repressed by BCR-ABL and ectopic TSPAN32 expression upon Imatinib treatment inhibited the proliferation of Ph+cell lines. Tspan32 overexpression significantly prevented BCR-ABL induced leukemia progression in a murine model and impairedleukemia stem cell (LSC) proliferation. LSCs represent an obstacle for chronic myeloid leukemia (CML) elimination, which continuallyreplenish leukemia cells and are associated with disease relapse. Therefore, the identification of essential targets that contribute tothe survival and self-renewal of LSCs is important for novel curative CML. Mechanistically, TSPAN32 was shown to interact withPTEN, increased its protein level and caused a reduction in PI3K-AKT signaling activity. We also found that TSPAN32 was repressedby BCR-ABL via the suppression of an important transcription factor, TAL1. Ectopic expression of TAL1 significantly increasedTSPAN32 mRNA and protein level, which indicated that BCR-ABL repressed TSPAN32 transcription by decreasing TAL1 expression.Overall, we identified a new signaling axis composed of “BCR-ABL-TAL1-TSPAN32-PTEN-PI3K-AKT”. Our findings furthercomplement the known mechanisms underlying the transformation potential of BCR-ABL in CML pathogenesis. This new signalingaxis also provides a potential means to target PI3K-AKT for CML treatment.展开更多
基金Supported by the National Natural Science Foundation of China(21306137)
文摘The search and development of anti-HIV drugs is currently one of the most urgent tasks of pharmacological studies. In this work, a quantitative structure-activity relationship （QSAR） model based on some new norm indexes, was obtained to a series of more than 150 HEPT derivatives （1-[（2-hydroxyethoxy）methyl]-6-（phenylthio）thymine） to find their pEC50 （the required effective concentration to achieve 50% protection of MT-4 cells against the cytopathic effect of virus） and pCC50 （the required cytotoxic concentration to reduce visibility of 50% mock infected cell） activities. The model efficiencies were then validated using the leave-one-out cross validation （LOO-CV） and y- randomization test. Results indicated that this new model was efficient and could provide satisfactory results for prediction of pECso and pCC50 with the higher R2 train and the higher Rt2est. By using the leverage approach, the applicability domain of this model was further investigated and no response outlier was detected for HEFT derivatives involved in this work. Comparison results with reference methods demonstrated that this new method could result in significant improvements for predicting pEC50 and pCC50 of anti-HIV HEPT derivatives. Moreover, results shown in this present study suggested that these two absolutely different activities pECso and pCC50 of anti-HIV HEPT derivatives could be predicted well with a totally similar QSAR model, which indicated that this model mizht have the potential to be further utilized for other biological activities of HEFT derivatives.
基金the National Natural Science Foundation of China(41571270).
文摘An accurate and convenient method is essential for measuring the terminal velocity of seeds dispersed by wind.Systematic and random errors produced by existing methods lower the accuracy and convenience in determining seed terminal velocity.In this study,a video camera was used to record the falling process of forty-one species of wind-borne seed with eight appendage structures and seven aerodynamic behaviors in a settling tower at a speed of 50 frames per second(fps).The videos were analyzed by Quick Time Player to determine seed acceleration height,acceleration time,and terminal velocity.The results showed that acceleration height and time,terminal velocity,and the diff erence between terminal velocity and descent velocity(DTD)increased with wing loading.Compared with dropping methods,the camera recording method eliminated the eff ect of acceleration and corrected seed terminal velocity.Based on wing loading,release heights were determined for accurate measurement of terminal velocity of diff erent seeds.This method,due to its inexpensive equipment,high accuracy,easy observation and operation,can be applied to measure the terminal velocity of wind dispersed seeds,and provides a promising method in exploring the dispersal process of seeds.
基金supported by the Natural Science Foundation of Guangdong Province,Grant No.2023A1515030221.
文摘We construct a sovereign default network by employing high-dimensional vector autoregressions obtained by analyzing connectedness in sovereign credit default swap markets.We develop four measures of centrality,namely,degree,betweenness,closeness,and eigenvector centralities,to detect whether network properties drive the currency risk premia.We observe that closeness and betweenness centralities can negatively drive currency excess returns but do not exhibit a relationship with forward spread.Thus,our developed network centralities are independent of an unconditional carry trade risk factor.Based on our findings,we develop a trading strategy by taking a long position on peripheral countries’currencies and a short position on core coun-tries’currencies.The aforementioned strategy generates a higher Sharpe ratio than the currency momentum strategy.Our proposed strategy is robust to foreign exchange regimes and the coronavirus disease 2019 pandemic.
基金Fundamental Research Funds for the Central Universities(2021SCU12022 to L.Yang)the 1.3.5 Project for Disciplines of Excellence(to Z.Li and L.Chen)+1 种基金West China Hospital,Sichuan University,the National Natural Science Foundation of China(82104211 to L.Yang)National Natural Science Foundation of China(81541092 and 81770103 to Y.Hu).
文摘Purinostat Mesylate(PM)is a novel highly selective and active HDAC I/IIb inhibitor,and the injectable formulation of PM(PMF)based on the compound prescription containing cyclodextrin completely can overcome PM’s poor solubility and improves its stability and pharmacokinetic properties.Here,we showed that PM effectively repressed the survival of Ph+leukemia cells and CD34+leukemia cells from CML patients in vitro.In vivo studies demonstrated that PMF significantly prevented BCR-ABL(T315I)induced CML progression by restraining leukemia stem cells(LSCs),which are insensitive to chemotherapy and responsible for CML relapse.Mechanism studies revealed that targeting HDAC I/IIb repressed several important factors for LSCs survival including c-Myc,β-Catenin,E2f,Ezh2,Alox5,and mTOR,as well as interrupted some critical biologic processes.Additionally,PMF increased glutamate metabolism in LSCs by increasing GLS1.The combination of PMF and glutaminase inhibitor BPTES synergistically eradicated LSCs by altering multiple key proteins and signaling pathways which are critical for LSC survival and self-renewal.Overall,our findings represent a new therapeutic strategy for eliminating LSCs by targeting HDAC I/IIb and glutaminolysis,which potentially provides a guidance for PMF clinical trials in the future for TKI resistance CML patients.
基金the State Key Laboratory of Biotherapy&Collaborative Innovation Center for Biotherapy for supportthe staff of the core facility and the animal facility of the State Key Laboratory of Biotherapy and West China Hospital.This work was supported by grants from the National Natural Science Foundation of China(82200152,81770103)+3 种基金National Clinical Research Center for Geriatrics,West China Hospital,Sichuan University(Z20201008)West China Hospital 1.3.5 Project for Disciplines of Excellence(ZYJC18025)Guizhou Provincial Science&Technology Support Program(NO[2020]4Y061)The Guizhou Innovation and Entrepreneurship Foundation for High-level Overseas Talent(NO.[2019]03).
文摘We report herein that TSPAN32 is a key node factor for Philadelphia (Ph+) leukemia pathogenesis. We found that TSPAN32expression was repressed by BCR-ABL and ectopic TSPAN32 expression upon Imatinib treatment inhibited the proliferation of Ph+cell lines. Tspan32 overexpression significantly prevented BCR-ABL induced leukemia progression in a murine model and impairedleukemia stem cell (LSC) proliferation. LSCs represent an obstacle for chronic myeloid leukemia (CML) elimination, which continuallyreplenish leukemia cells and are associated with disease relapse. Therefore, the identification of essential targets that contribute tothe survival and self-renewal of LSCs is important for novel curative CML. Mechanistically, TSPAN32 was shown to interact withPTEN, increased its protein level and caused a reduction in PI3K-AKT signaling activity. We also found that TSPAN32 was repressedby BCR-ABL via the suppression of an important transcription factor, TAL1. Ectopic expression of TAL1 significantly increasedTSPAN32 mRNA and protein level, which indicated that BCR-ABL repressed TSPAN32 transcription by decreasing TAL1 expression.Overall, we identified a new signaling axis composed of “BCR-ABL-TAL1-TSPAN32-PTEN-PI3K-AKT”. Our findings furthercomplement the known mechanisms underlying the transformation potential of BCR-ABL in CML pathogenesis. This new signalingaxis also provides a potential means to target PI3K-AKT for CML treatment.
