Isothermal forging(IF)is an effective method for forming difficult-to-deform materials like P/M superalloys.Understanding the isothermal compression microstructural evolution mechanism of a novel P/M s-peralloy provid...Isothermal forging(IF)is an effective method for forming difficult-to-deform materials like P/M superalloys.Understanding the isothermal compression microstructural evolution mechanism of a novel P/M s-peralloy provides the basis for its optimized IF planning.In this study,the isothermal compression tests of a novel fine-grained P/M nickel-based superalloy were carried out at 1000-1150℃with strain rates of 0.001-0.01 s^(−1).The results indicated that the alloy exhibits three distinct flow characteristics:continuous softening after reaching the peak stress,near-steady superplastic flow,and discontinuous hardening,corresponding to different strain rate sensitivity exponent(m)values.Varied microstructural evolution mechanisms,including grain boundary sliding(GBS),dynamic recrystallization(DRX),and grain growth,are dominated in different m-value domains.Meanwhile,different roles of primaryγ’play in microstruc-tural evolution were clarified.A moderate fraction of primaryγ’with 8.5%-14.2%can well coordinate the GBS and hinder excessive grain growth at a high m value domain(m>0.4).When 0.2<m<0.4,the role of the primaryγ’is changed to promote dislocation accumulation,accelerating the nucleation of DRXed grains.As the primaryγ’is dissolved at 1150℃,obvious grain growth was observed after compression.Work hardening effect by overgrown grains competed with DRX softening results in the discontinuous rising stress.展开更多
Peptides that are composed of dextrorotary(D)-amino acids have gained increasing attention as a potential therapeutic class.However,our understanding of the in vivo fate of D-peptides is limited.This highlights the ne...Peptides that are composed of dextrorotary(D)-amino acids have gained increasing attention as a potential therapeutic class.However,our understanding of the in vivo fate of D-peptides is limited.This highlights the need for whole-body,quantitative tracking of D-peptides to better understand how they interact with the living body.Here,we used mouse models to track the movement of a programmed death-ligand 1(PD-L1)-targeting D-dodecapeptide antagonist(DPA)using positron emission tomography(PET).More specifically,we profiled the metabolic routes of[^(64)Cu]DPA and investigated the tumor engagement of[^(64)Cu/^(68)Ga]DPA in mouse models.Our results revealed that intact[^(64)Cu/^(68)Ga]DPA was primarily eliminated by the kidneys and had a notable accumulation in tumors.Moreover,a single dose of[^(64)Cu]DPA effectively delayed tumor growth and improved the survival of mice.Collectively,these results not only deepen our knowledge of the in vivo fate of D-peptides,but also underscore the utility of D-peptides as radiopharmaceuticals.展开更多
As a serine hydrolase,monoacylglycerol lipase(MAGL) is principally responsible for the metabolism of 2-arachidonoylglycerol(2-AG) in the central nervous system(CNS),leading to the formation of arachidonic acid(AA).Dys...As a serine hydrolase,monoacylglycerol lipase(MAGL) is principally responsible for the metabolism of 2-arachidonoylglycerol(2-AG) in the central nervous system(CNS),leading to the formation of arachidonic acid(AA).Dysfunction of MAGL has been associated with multiple CNS disorders and symptoms,including neuroinflammation,cognitive impairment,epileptogenesis,nociception and neurodegenerative diseases.Inhibition of MAGL provides a promising therapeutic direction for the treatment of these conditions,and a MAGL positron emission tomography(PET) probe would greatly facilitate preclinical and clinical development of MAGL inhibitors.Herein,we design and synthesize a small library of fluoropyridyl-containing MAGL inhibitor candidates.Pharmacological evaluation of these candidates by activity-based protein profiling identified 14 as a lead compound,which was then radiolabeled with fluorine-18 via a facile SNAr reaction to form 2-[^(18)F]fluoropyridine scaffold.Good blood-brain barrier permeability and high in vivo specific binding was demonstrated for radioligand [^(18)F]14(also named as [^(18)F]MAGL-1902).This work may serve as a roadmap for clinical translation and further design of potent 18F-labeled MAGL PET tracers.展开更多
基金supported by the National Natural Science Foundation of China(Nos.52175319 and 52090043)the Fundamental Research Funds for the Central Universities(No.YCJJ202202003)the National Science and Technology Major Project(No.2017-Ⅵ-0009-0080).
文摘Isothermal forging(IF)is an effective method for forming difficult-to-deform materials like P/M superalloys.Understanding the isothermal compression microstructural evolution mechanism of a novel P/M s-peralloy provides the basis for its optimized IF planning.In this study,the isothermal compression tests of a novel fine-grained P/M nickel-based superalloy were carried out at 1000-1150℃with strain rates of 0.001-0.01 s^(−1).The results indicated that the alloy exhibits three distinct flow characteristics:continuous softening after reaching the peak stress,near-steady superplastic flow,and discontinuous hardening,corresponding to different strain rate sensitivity exponent(m)values.Varied microstructural evolution mechanisms,including grain boundary sliding(GBS),dynamic recrystallization(DRX),and grain growth,are dominated in different m-value domains.Meanwhile,different roles of primaryγ’play in microstruc-tural evolution were clarified.A moderate fraction of primaryγ’with 8.5%-14.2%can well coordinate the GBS and hinder excessive grain growth at a high m value domain(m>0.4).When 0.2<m<0.4,the role of the primaryγ’is changed to promote dislocation accumulation,accelerating the nucleation of DRXed grains.As the primaryγ’is dissolved at 1150℃,obvious grain growth was observed after compression.Work hardening effect by overgrown grains competed with DRX softening results in the discontinuous rising stress.
基金financial support from the JSPS KAKENHI grant Nos.19K17156,21H02873,21K07659,and 20H03635,Japansupported by QST President’s Strategic Grant(Exploratory Research,Japan)+3 种基金financial support from the National Natural Science Foundation of China(82003532)General Project of Science and Technology Development Fund of Nanjing Medical University(NMUB2019154,China)the second round of Nanjing Clinical Medical Center"Nanjing Nuclear Medicine Center"the China Postdoctoral Science Foundation(2019M650302)。
文摘Peptides that are composed of dextrorotary(D)-amino acids have gained increasing attention as a potential therapeutic class.However,our understanding of the in vivo fate of D-peptides is limited.This highlights the need for whole-body,quantitative tracking of D-peptides to better understand how they interact with the living body.Here,we used mouse models to track the movement of a programmed death-ligand 1(PD-L1)-targeting D-dodecapeptide antagonist(DPA)using positron emission tomography(PET).More specifically,we profiled the metabolic routes of[^(64)Cu]DPA and investigated the tumor engagement of[^(64)Cu/^(68)Ga]DPA in mouse models.Our results revealed that intact[^(64)Cu/^(68)Ga]DPA was primarily eliminated by the kidneys and had a notable accumulation in tumors.Moreover,a single dose of[^(64)Cu]DPA effectively delayed tumor growth and improved the survival of mice.Collectively,these results not only deepen our knowledge of the in vivo fate of D-peptides,but also underscore the utility of D-peptides as radiopharmaceuticals.
基金the financial support from the NIH grants (DA038000 and DA043507 to S. H. L. and DA033760 to B. F. C.)the Swiss National Science Foundation for a postdoctoral fellowship to Michael A. Schafroth (Grant No. P2EZP3_175137, Switzerland)。
文摘As a serine hydrolase,monoacylglycerol lipase(MAGL) is principally responsible for the metabolism of 2-arachidonoylglycerol(2-AG) in the central nervous system(CNS),leading to the formation of arachidonic acid(AA).Dysfunction of MAGL has been associated with multiple CNS disorders and symptoms,including neuroinflammation,cognitive impairment,epileptogenesis,nociception and neurodegenerative diseases.Inhibition of MAGL provides a promising therapeutic direction for the treatment of these conditions,and a MAGL positron emission tomography(PET) probe would greatly facilitate preclinical and clinical development of MAGL inhibitors.Herein,we design and synthesize a small library of fluoropyridyl-containing MAGL inhibitor candidates.Pharmacological evaluation of these candidates by activity-based protein profiling identified 14 as a lead compound,which was then radiolabeled with fluorine-18 via a facile SNAr reaction to form 2-[^(18)F]fluoropyridine scaffold.Good blood-brain barrier permeability and high in vivo specific binding was demonstrated for radioligand [^(18)F]14(also named as [^(18)F]MAGL-1902).This work may serve as a roadmap for clinical translation and further design of potent 18F-labeled MAGL PET tracers.