HDAC7,a member of class IIa HDACs,plays a pivotal regulatory role in tumor,immune,fibrosis,and angiogenesis,rendering it a potential therapeutic target.Nevertheless,due to the high similarity in the enzyme active site...HDAC7,a member of class IIa HDACs,plays a pivotal regulatory role in tumor,immune,fibrosis,and angiogenesis,rendering it a potential therapeutic target.Nevertheless,due to the high similarity in the enzyme active sites of class IIa HDACs,inhibitors encounter challenges in discerning differences among them.Furthermore,the substitution of key residue in the active pocket of class IIa HDACs renders them pseudo-enzymes,leading to a limited impact of enzymatic inhibitors on their function.In this study,proteolysis targeting chimera(PROTAC)technology was employed to develop HDAC7 drugs.We developed an exceedingly selective HDAC7 PROTAC degrader B14 which showcased superior inhibitory effects on cell proliferation compared to TMP269 in various diffuse large B cell lymphoma(DLBCL)and acute myeloid leukemia(AML)cells.Subsequent investigations unveiled that B14 disrupts BCL6 forming a transcriptional inhibition complex by degrading HDAC7,thereby exerting proliferative inhibition in DLBCL.Our study broadened the understanding of the non-enzymatic functions of HDAC7 and underscored the importance of HDAC7 in the treatment of hematologic malignancies,particularly in DLBCL and AML.展开更多
Surface fractures have a great impact on ice shelf stability in Antarctica and can be considered precursors of ice shelf calving.However,our understanding of the spatial distribution and temporal evolution of surface ...Surface fractures have a great impact on ice shelf stability in Antarctica and can be considered precursors of ice shelf calving.However,our understanding of the spatial distribution and temporal evolution of surface fractures on the Antarctic ice shelf is limited.In this study,a ResUNet model was implemented on the Moderate Resolution Imaging Spectroradiometer(MODIS)-based Mosaic of Antarctica(MOA)to identify the spatial distribution of Antarctic ice shelf surface fractures in 2004,2009,and 2014.The accuracy of identification had an F1 value of 0.771.Our model identified 44744.59±2619.61 km^(2)of surface fractures in 2004,43737.15±2644.60 km^(2)in 2009,and 42978.67±2639.33 km^(2)in 2014.The reduction is primarily attributed to the variation in surface fractures within 20 km of the ice front,paratactically in the Amundsen and Wilkes sectors.Ice shelves in the Amundsen sector typically have a widespread distribution of surface fractures,with particularly high concentrations found in the Thwaites Ice Shelf,Crosson Ice Shelf and Getz Ice Shelf.The Brunt Ice Shelf also exhibits numerous surface fractures.This study provides comprehensive and detailed information about surface fractures on Antarctic ice shelves,carrying implications for evaluating ice shelf vulnerability.展开更多
基金support from the National Natural Science Foundation of China(Nos.82173660,82103975)Zhejiang Provincial Key Research&Development Plan(No.2023C03111,China)+1 种基金the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province(Nos.LR21H300003,LR22H310002,China)the Natural Science Foundation of Zhejiang Province(No.LQ21H300005,China).
文摘HDAC7,a member of class IIa HDACs,plays a pivotal regulatory role in tumor,immune,fibrosis,and angiogenesis,rendering it a potential therapeutic target.Nevertheless,due to the high similarity in the enzyme active sites of class IIa HDACs,inhibitors encounter challenges in discerning differences among them.Furthermore,the substitution of key residue in the active pocket of class IIa HDACs renders them pseudo-enzymes,leading to a limited impact of enzymatic inhibitors on their function.In this study,proteolysis targeting chimera(PROTAC)technology was employed to develop HDAC7 drugs.We developed an exceedingly selective HDAC7 PROTAC degrader B14 which showcased superior inhibitory effects on cell proliferation compared to TMP269 in various diffuse large B cell lymphoma(DLBCL)and acute myeloid leukemia(AML)cells.Subsequent investigations unveiled that B14 disrupts BCL6 forming a transcriptional inhibition complex by degrading HDAC7,thereby exerting proliferative inhibition in DLBCL.Our study broadened the understanding of the non-enzymatic functions of HDAC7 and underscored the importance of HDAC7 in the treatment of hematologic malignancies,particularly in DLBCL and AML.
基金supported by the National Natural Science Foundation of China(grant no.41830536,41925027)the Innovation Group Project of Southern Marine Science and Engineering Guangdong Laboratory(Zhuhai)(grant no.311022003)the Fundamental Research Funds for the Central Universities,Sun Yat-sen University(23ptpy99,231GBJ022).
文摘Surface fractures have a great impact on ice shelf stability in Antarctica and can be considered precursors of ice shelf calving.However,our understanding of the spatial distribution and temporal evolution of surface fractures on the Antarctic ice shelf is limited.In this study,a ResUNet model was implemented on the Moderate Resolution Imaging Spectroradiometer(MODIS)-based Mosaic of Antarctica(MOA)to identify the spatial distribution of Antarctic ice shelf surface fractures in 2004,2009,and 2014.The accuracy of identification had an F1 value of 0.771.Our model identified 44744.59±2619.61 km^(2)of surface fractures in 2004,43737.15±2644.60 km^(2)in 2009,and 42978.67±2639.33 km^(2)in 2014.The reduction is primarily attributed to the variation in surface fractures within 20 km of the ice front,paratactically in the Amundsen and Wilkes sectors.Ice shelves in the Amundsen sector typically have a widespread distribution of surface fractures,with particularly high concentrations found in the Thwaites Ice Shelf,Crosson Ice Shelf and Getz Ice Shelf.The Brunt Ice Shelf also exhibits numerous surface fractures.This study provides comprehensive and detailed information about surface fractures on Antarctic ice shelves,carrying implications for evaluating ice shelf vulnerability.
