Systematic analysis of distinct flow characteristics and underlying microstructural evolution mechanisms of a novel fine-grained P/M nickel-based superalloy during isothermal compression

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.

Whole-body PET tracking of a D-dodecapeptide and its radiotheranostic potential for PD-L1 overexpressing tumors

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.

Development of a highly-specific ^(18)F-labeled irreversible positron emission tomography tracer for monoacylglycerol lipase mapping

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.