The Kirsten rat sarcoma virus—son of sevenless 1(KRAS-SOS1)axis drives tumor growth preferentially in pancreatic,colon,and lung cancer.Now,KRAS G12C mutated tumors can be successfully treated with inhibitors that cov...The Kirsten rat sarcoma virus—son of sevenless 1(KRAS-SOS1)axis drives tumor growth preferentially in pancreatic,colon,and lung cancer.Now,KRAS G12C mutated tumors can be successfully treated with inhibitors that covalently block the cysteine of the switch II binding pocket of KRAS.However,the range of other KRAS mutations is not amenable to treatment and the G12C-directed agents Sotorasib and Adragrasib show a response rate of only approximately 40%,lasting for a mean period of 8 months.One approach to increase the efficacy of inhibitors is their inclusion into proteolysis-targeting chimeras(PROTACs),which degrade the proteins of interest and exhibit much higher antitumor activity through multiple cycles of activity.Accordingly,PROTACs have been developed based on KRAS-or SOS1-directed inhibitors coupled to either von Hippel-Lindau(VHL)or Cereblon(CRBN)ligands that invoke the proteasomal degradation.Several of these PROTACs show increased activity in vitro and in vivo compared to their cognate inhibitors but their toxicity in normal tissues is not clear.The CRBN PROTACs containing thalidomide derivatives cannot be tested in experimental animals.Resistance to such PROTACS arises through downregulation or inactivation of CRBN or factors of the functional VHL E3 ubiquitin ligase.Although highly active KRAS and SOS1 PROTACs have been formulated their clinical application remains difficult.展开更多
Increasing soil salinization seriously impairs plant growth and development,resulting in crop loss.The Salt-Overly-Sensitive(SOS)pathway is indispensable to the mitigation of Na+toxicity in plants under high salinity....Increasing soil salinization seriously impairs plant growth and development,resulting in crop loss.The Salt-Overly-Sensitive(SOS)pathway is indispensable to the mitigation of Na+toxicity in plants under high salinity.However,whether natural variations of SOS2 contribute to salt tolerance has not been reported.Here a natural variation in the SlSOS2 promoter region was identified to be associated with root Na+/K+ratio and the loss of salt resistance during tomato domestication.This natural variation contains an ABI4-binding cis-element and plays an important role in the repression of SlSOS2 expression.Genetic evidence revealed that SlSOS2 mutations increase root Na+/K+ratio under salt stress conditions and thus attenuate salt resistance in tomato.Together,our findings uncovered a critical but previously unknown natural variation of SOS2 in salt resistance,which provides valuable natural resources for genetic breeding for salt resistance in cultivated tomatoes and other crops.展开更多
IEEE Serious Open Source for the Benefit of Humanity (SOSH) is hosted by the IEEE Standards Association, which gathers industry experts, innovators, and engineering leaders from around the world to explore the profoun...IEEE Serious Open Source for the Benefit of Humanity (SOSH) is hosted by the IEEE Standards Association, which gathers industry experts, innovators, and engineering leaders from around the world to explore the profound benefits of open source technology for industries and their customers.展开更多
文摘The Kirsten rat sarcoma virus—son of sevenless 1(KRAS-SOS1)axis drives tumor growth preferentially in pancreatic,colon,and lung cancer.Now,KRAS G12C mutated tumors can be successfully treated with inhibitors that covalently block the cysteine of the switch II binding pocket of KRAS.However,the range of other KRAS mutations is not amenable to treatment and the G12C-directed agents Sotorasib and Adragrasib show a response rate of only approximately 40%,lasting for a mean period of 8 months.One approach to increase the efficacy of inhibitors is their inclusion into proteolysis-targeting chimeras(PROTACs),which degrade the proteins of interest and exhibit much higher antitumor activity through multiple cycles of activity.Accordingly,PROTACs have been developed based on KRAS-or SOS1-directed inhibitors coupled to either von Hippel-Lindau(VHL)or Cereblon(CRBN)ligands that invoke the proteasomal degradation.Several of these PROTACs show increased activity in vitro and in vivo compared to their cognate inhibitors but their toxicity in normal tissues is not clear.The CRBN PROTACs containing thalidomide derivatives cannot be tested in experimental animals.Resistance to such PROTACS arises through downregulation or inactivation of CRBN or factors of the functional VHL E3 ubiquitin ligase.Although highly active KRAS and SOS1 PROTACs have been formulated their clinical application remains difficult.
基金This work was supported by the National Natural Science Foun-dation of China(grant 32000206 to Z.W.)the Natural Science Foundation of Anhui Province(grant 2208085Y08 to Z.W.).
文摘Increasing soil salinization seriously impairs plant growth and development,resulting in crop loss.The Salt-Overly-Sensitive(SOS)pathway is indispensable to the mitigation of Na+toxicity in plants under high salinity.However,whether natural variations of SOS2 contribute to salt tolerance has not been reported.Here a natural variation in the SlSOS2 promoter region was identified to be associated with root Na+/K+ratio and the loss of salt resistance during tomato domestication.This natural variation contains an ABI4-binding cis-element and plays an important role in the repression of SlSOS2 expression.Genetic evidence revealed that SlSOS2 mutations increase root Na+/K+ratio under salt stress conditions and thus attenuate salt resistance in tomato.Together,our findings uncovered a critical but previously unknown natural variation of SOS2 in salt resistance,which provides valuable natural resources for genetic breeding for salt resistance in cultivated tomatoes and other crops.
文摘IEEE Serious Open Source for the Benefit of Humanity (SOSH) is hosted by the IEEE Standards Association, which gathers industry experts, innovators, and engineering leaders from around the world to explore the profound benefits of open source technology for industries and their customers.
