The rapid cycling synchrotron(RCS)at the China spallation neutron source operates as a high-intensity proton accelerator.The coupled bunch instability was observed during RCS beam commissioning,which significantly lim...The rapid cycling synchrotron(RCS)at the China spallation neutron source operates as a high-intensity proton accelerator.The coupled bunch instability was observed during RCS beam commissioning,which significantly limited the beam power.To investigate the dynamics of instability under an increased beam power,a pulsed octupole magnet with a gradient of 900 T/m^(3) was developed.The magnet system integrated an octupole magnet with a pulsed power supply.The field was carefully measured to examine the performance before its installation into the tunnel.After the installation of the magnets,beam measurements were performed to confirm the effectiveness of the instability mitigation on an actual proton beam.The measurement results show that the instability can be suppressed using the pulsed octupole magnet,particularly at the highenergy stage in an acceleration cycle,meeting the requirements for stable operation of the accelerator.Additionally,when the instability is completely suppressed through chromaticity optimization,octupole magnets can significantly enhance the RCS transmission efficiency,which is crucial for controlling beam loss.The pulsed octupole magnet offers significant progress in beam stability in the RCS,providing valuable experience for further beam power enhancement.展开更多
Objective:Psoriasis is associated with lipid metabolism disorders,but the underlying mechanisms remain unclear.This study aims to investigate the role of trimethylamine Noxide(TMAO)in lipid metabolism dysregulation in...Objective:Psoriasis is associated with lipid metabolism disorders,but the underlying mechanisms remain unclear.This study aims to investigate the role of trimethylamine Noxide(TMAO)in lipid metabolism dysregulation in psoriasis.Methods:An imiquimod(IMQ)-induced psoriasis-like mouse model was used to assess lipid metabolism parameters,TMAO levels,and liver flavin monooxygenase 3(FMO3)mRNA expression.Blood samples from healthy individuals and psoriatic patients were collected to measure serum TMAO levels and lipid profiles.To clarify the role of TMAO in the lipid metabolism disorder of mice with psoriasis model,exogenous TMAO,choline,or 3,3-dimethyl-1-butanol(DMB)were administered via intraperitoneal injections or diet in IMQ-treated mice.Liver tissues from the mouse models were subjected to RNA sequencing to identify TMAO-regulated signaling pathways.Results:IMQ-induced psoriatic mice exhibited abnormal glucose,insulin,and lipid levels.IMQ treatment also downregulated the hepatic mRNA expression of glucose transporter 2(Glut2)and silence information regulator 1(Sirt1),while upregulating glucose transporter 4(Glut4)and peroxisome proliferator-activated receptor gamma(PPARγ).Elevated serum TMAO levels were observed in both psoriatic patients and IMQ-treated mice.Additionally,liver FMO3 mRNA expression was increased in the psoriatic mouse model.In patients,TMAO levels positively correlated with Psoriasis Area and Severity Index(PASI)scores,serum triglyceride(TG),and total cholesterol(TC)levels.The intraperitoneal injection of TMAO exacerbated lipid dysregulation in IMQ-treated mice.A choline-rich diet further aggravated lipid abnormalities and liver injury in psoriatic mice,whereas DMB treatment alleviated these effects.RNA-Seq analysis demonstrated that TMAO upregulated hepatic microRNA-122(miR-122),which may suppress the expression of gremlin 2(GREM2),thus contributing to lipid metabolism disorder.Conclusion:TMAO may promote lipid metabolism dysregulation in psoriasis by modulating the hepatic miR-122/GREM2 pathway.展开更多
Yeast-based models have become a powerful platform in pharmaceutical research,offering significant potential for producing complex drugs,vaccines,and therapeutic agents.While many current drugs were discovered before ...Yeast-based models have become a powerful platform in pharmaceutical research,offering significant potential for producing complex drugs,vaccines,and therapeutic agents.While many current drugs were discovered before fully understanding their molecular mechanisms,yeast systems now provide valuable insights for drug discovery and personalized medicine.Recent advancements in genetic engineering,metabolic engineering,and synthetic biology have improved the efficiency and scalability of yeast-based production systems,enabling more sustainable and cost-effective manufacturing processes.This paper reviews the latest developments in yeast-based technologies,focusing on their use as model organisms to study disease mechanisms,identify drug targets,and develop novel therapies.We highlight key platforms such as the yeast two-hybrid system,surface display technologies,and optimized expression systems.Additionally,we explore the future integration of yeast engineering with artificial intelligence(AI),machine learning(ML),and advanced genome editing technologies like CRISPR/Cas9,which are expected to accelerate drug discovery and enable personalized therapies.Furthermore,yeast-based systems are increasingly employed in largescale drug production,vaccine development,and therapeutic protein expression,offering promising applications in clinical and industrial settings.This paper discusses the practical implications of these systems and their potential to revolutionize drug development,paving the way for safer,more effective therapies.展开更多
The AZ91 D magnesium alloy containing rare earth Gd was prepared in this study, and the effect of semi-solid isothermal heat treatment on the microstructure of the alloy was investigated to obtain an optimum semi-soli...The AZ91 D magnesium alloy containing rare earth Gd was prepared in this study, and the effect of semi-solid isothermal heat treatment on the microstructure of the alloy was investigated to obtain an optimum semi-solid structure. Results show that Gd can refine the microstructure of AZ91 D magnesium alloy, and the optimum semi-solid AZ91 D microstructure can be achieved by adding 1.5wt.% Gd. After treated at 585 °C for 30 min, the well distributed rose-shaped and near-spherical semi-solid microstructures of AZ91D+1.5wt.%Gd alloy can be obtained. The liquid phase of the semi-solid alloy consists of three components, namely, the molten pool, the "entrapped liquid" pool and the liner liquid film which separates two neighbor particles. The solid phase is composed of two phases, the primary α-Mg particles and the α-Mg phase formed in the second stage of solidification. With the increase of holding time, melting which causes the decrease of the primary α-Mg particle size is the dominant mechanism in the initial stage while coalescence and Ostwald ripening tend to be the principles later.展开更多
The behaviors of time-dependent interaction between two buoyancy-driven in-line deformable drops rising in pure glycerin at Re 〈 1 were studied, where the diameter for the leading drops ranged from 9.51 mm to 12.6 mm...The behaviors of time-dependent interaction between two buoyancy-driven in-line deformable drops rising in pure glycerin at Re 〈 1 were studied, where the diameter for the leading drops ranged from 9.51 mm to 12.6 mm and for trailing drops from 12.7 mm to 15.8 mm. The situation while a larger drop chasing a smaller one was specifically considered which typically led to the smaller drop ＂coating＂ the larger one. Two approaches, the geometric feature approach and the energy change one, were used to judge the starting and ending times of the interaction between two drops. Based on a conical wake model, the drag coefficient of two approaching drops was calculated. Due to the approaching effect of the trailing drop, the leading drop was accelerated and the average drag coefficient was smaller than that for a free rising single drop. The frequency spectrums of the lateral oscillation of two drops during the interaction were obtained by using Fourier analysis. The oscillation frequency of the interactional drops was also different from that for a free rising single drop because of the wake effect produced by the leading drop. Due to a superposition of the drop shape oscillation and the drop internal circulation, the transverse oscillation frequencies of two drops have the same trend during the approaching process.展开更多
In the realm of drug discovery,recent advancements have paved the way for innovative approaches and methodologies.This comprehensive review encapsulates six distinct yet interrelated mini-reviews,each shedding light o...In the realm of drug discovery,recent advancements have paved the way for innovative approaches and methodologies.This comprehensive review encapsulates six distinct yet interrelated mini-reviews,each shedding light on novel strategies in drug development.(a)The resurgence of covalent drugs is highlighted,focusing on the targeted covalent inhibitors(TCIs)and their role in enhancing selectivity and affinity.(b)The potential of the quantum mechanics-based computational aid drug design(CADD)tool,Cov_DOX,is introduced for predicting protein-covalent ligand binding structures and affinities.(c)The scaffolding function of proteins is proposed as a new avenue for drug design,with a focus on modulating protein-protein interactions through small molecules and proteolysis targeting chimeras(PROTACs).(d)The concept of pro-PROTACs is explored as a promising strategy for cancer therapy,combining the principles of prodrugs and PROTACs to enhance specificity and reduce toxicity.(e)The design of prodrugs through carbon-carbon bond cleavage is discussed,offering a new perspective for the activation of drugs with limited modifiable functional groups.(f)The targeting of programmed cell death pathways in cancer therapies with small molecules is reviewed,emphasizing the induction of autophagy-dependent cell death,ferroptosis,and cuproptosis.These insights collectively contribute to a deeper understanding of the dynamic landscape of drug discovery.展开更多
基金supported by the Guangdong Basic and Applied Basic Research Foundation,China(No.2021B1515140007).
文摘The rapid cycling synchrotron(RCS)at the China spallation neutron source operates as a high-intensity proton accelerator.The coupled bunch instability was observed during RCS beam commissioning,which significantly limited the beam power.To investigate the dynamics of instability under an increased beam power,a pulsed octupole magnet with a gradient of 900 T/m^(3) was developed.The magnet system integrated an octupole magnet with a pulsed power supply.The field was carefully measured to examine the performance before its installation into the tunnel.After the installation of the magnets,beam measurements were performed to confirm the effectiveness of the instability mitigation on an actual proton beam.The measurement results show that the instability can be suppressed using the pulsed octupole magnet,particularly at the highenergy stage in an acceleration cycle,meeting the requirements for stable operation of the accelerator.Additionally,when the instability is completely suppressed through chromaticity optimization,octupole magnets can significantly enhance the RCS transmission efficiency,which is crucial for controlling beam loss.The pulsed octupole magnet offers significant progress in beam stability in the RCS,providing valuable experience for further beam power enhancement.
基金supported by the National Natural Science Foundation(82173426)the Natural Science Foundation of Hunan Province(2023JJ30984),China。
文摘Objective:Psoriasis is associated with lipid metabolism disorders,but the underlying mechanisms remain unclear.This study aims to investigate the role of trimethylamine Noxide(TMAO)in lipid metabolism dysregulation in psoriasis.Methods:An imiquimod(IMQ)-induced psoriasis-like mouse model was used to assess lipid metabolism parameters,TMAO levels,and liver flavin monooxygenase 3(FMO3)mRNA expression.Blood samples from healthy individuals and psoriatic patients were collected to measure serum TMAO levels and lipid profiles.To clarify the role of TMAO in the lipid metabolism disorder of mice with psoriasis model,exogenous TMAO,choline,or 3,3-dimethyl-1-butanol(DMB)were administered via intraperitoneal injections or diet in IMQ-treated mice.Liver tissues from the mouse models were subjected to RNA sequencing to identify TMAO-regulated signaling pathways.Results:IMQ-induced psoriatic mice exhibited abnormal glucose,insulin,and lipid levels.IMQ treatment also downregulated the hepatic mRNA expression of glucose transporter 2(Glut2)and silence information regulator 1(Sirt1),while upregulating glucose transporter 4(Glut4)and peroxisome proliferator-activated receptor gamma(PPARγ).Elevated serum TMAO levels were observed in both psoriatic patients and IMQ-treated mice.Additionally,liver FMO3 mRNA expression was increased in the psoriatic mouse model.In patients,TMAO levels positively correlated with Psoriasis Area and Severity Index(PASI)scores,serum triglyceride(TG),and total cholesterol(TC)levels.The intraperitoneal injection of TMAO exacerbated lipid dysregulation in IMQ-treated mice.A choline-rich diet further aggravated lipid abnormalities and liver injury in psoriatic mice,whereas DMB treatment alleviated these effects.RNA-Seq analysis demonstrated that TMAO upregulated hepatic microRNA-122(miR-122),which may suppress the expression of gremlin 2(GREM2),thus contributing to lipid metabolism disorder.Conclusion:TMAO may promote lipid metabolism dysregulation in psoriasis by modulating the hepatic miR-122/GREM2 pathway.
基金funded by 2024 Scientific Research Project of Chongqing Medical and Pharmaceutical College(No.ygzrc2024101)Chongqing Education Commission Natural Science Foundation(No.KJQN202402821)+2 种基金Chongqing Shapingba District Science and Technology Bureau Project(No.2024071)2024 Chongqing Medical and Pharmaceutical College Innovation Research Group Project(No.ygz2024401)Chongqing Science and Health Joint Medical Research Project(No.2024SQKWLHMS051),respectively.
文摘Yeast-based models have become a powerful platform in pharmaceutical research,offering significant potential for producing complex drugs,vaccines,and therapeutic agents.While many current drugs were discovered before fully understanding their molecular mechanisms,yeast systems now provide valuable insights for drug discovery and personalized medicine.Recent advancements in genetic engineering,metabolic engineering,and synthetic biology have improved the efficiency and scalability of yeast-based production systems,enabling more sustainable and cost-effective manufacturing processes.This paper reviews the latest developments in yeast-based technologies,focusing on their use as model organisms to study disease mechanisms,identify drug targets,and develop novel therapies.We highlight key platforms such as the yeast two-hybrid system,surface display technologies,and optimized expression systems.Additionally,we explore the future integration of yeast engineering with artificial intelligence(AI),machine learning(ML),and advanced genome editing technologies like CRISPR/Cas9,which are expected to accelerate drug discovery and enable personalized therapies.Furthermore,yeast-based systems are increasingly employed in largescale drug production,vaccine development,and therapeutic protein expression,offering promising applications in clinical and industrial settings.This paper discusses the practical implications of these systems and their potential to revolutionize drug development,paving the way for safer,more effective therapies.
基金financially supported by the Natural Science Foundation of Jiangxi,China(grant No.:20142BAB216015)Jiangxi Key Laboratory for Advanced Copper and Tungsten Materials,China(grant No.:2013-KLP-07)
文摘The AZ91 D magnesium alloy containing rare earth Gd was prepared in this study, and the effect of semi-solid isothermal heat treatment on the microstructure of the alloy was investigated to obtain an optimum semi-solid structure. Results show that Gd can refine the microstructure of AZ91 D magnesium alloy, and the optimum semi-solid AZ91 D microstructure can be achieved by adding 1.5wt.% Gd. After treated at 585 °C for 30 min, the well distributed rose-shaped and near-spherical semi-solid microstructures of AZ91D+1.5wt.%Gd alloy can be obtained. The liquid phase of the semi-solid alloy consists of three components, namely, the molten pool, the "entrapped liquid" pool and the liner liquid film which separates two neighbor particles. The solid phase is composed of two phases, the primary α-Mg particles and the α-Mg phase formed in the second stage of solidification. With the increase of holding time, melting which causes the decrease of the primary α-Mg particle size is the dominant mechanism in the initial stage while coalescence and Ostwald ripening tend to be the principles later.
基金Supported by the National Natural Science Foundation of China(21376016,21506005)
文摘The behaviors of time-dependent interaction between two buoyancy-driven in-line deformable drops rising in pure glycerin at Re 〈 1 were studied, where the diameter for the leading drops ranged from 9.51 mm to 12.6 mm and for trailing drops from 12.7 mm to 15.8 mm. The situation while a larger drop chasing a smaller one was specifically considered which typically led to the smaller drop ＂coating＂ the larger one. Two approaches, the geometric feature approach and the energy change one, were used to judge the starting and ending times of the interaction between two drops. Based on a conical wake model, the drag coefficient of two approaching drops was calculated. Due to the approaching effect of the trailing drop, the leading drop was accelerated and the average drag coefficient was smaller than that for a free rising single drop. The frequency spectrums of the lateral oscillation of two drops during the interaction were obtained by using Fourier analysis. The oscillation frequency of the interactional drops was also different from that for a free rising single drop because of the wake effect produced by the leading drop. Due to a superposition of the drop shape oscillation and the drop internal circulation, the transverse oscillation frequencies of two drops have the same trend during the approaching process.
基金supported by grants from the National Natural Science Foundation of China(No.82273770)the Foundation for Innovative Research Groups of the National Natural Science Foundation of Sichuan Province(No.24NSFTD0051).
文摘In the realm of drug discovery,recent advancements have paved the way for innovative approaches and methodologies.This comprehensive review encapsulates six distinct yet interrelated mini-reviews,each shedding light on novel strategies in drug development.(a)The resurgence of covalent drugs is highlighted,focusing on the targeted covalent inhibitors(TCIs)and their role in enhancing selectivity and affinity.(b)The potential of the quantum mechanics-based computational aid drug design(CADD)tool,Cov_DOX,is introduced for predicting protein-covalent ligand binding structures and affinities.(c)The scaffolding function of proteins is proposed as a new avenue for drug design,with a focus on modulating protein-protein interactions through small molecules and proteolysis targeting chimeras(PROTACs).(d)The concept of pro-PROTACs is explored as a promising strategy for cancer therapy,combining the principles of prodrugs and PROTACs to enhance specificity and reduce toxicity.(e)The design of prodrugs through carbon-carbon bond cleavage is discussed,offering a new perspective for the activation of drugs with limited modifiable functional groups.(f)The targeting of programmed cell death pathways in cancer therapies with small molecules is reviewed,emphasizing the induction of autophagy-dependent cell death,ferroptosis,and cuproptosis.These insights collectively contribute to a deeper understanding of the dynamic landscape of drug discovery.
