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Scalable synthesis of lipid nanoparticles for nucleic acid drug delivery using an isometric channel-size enlarging strategy

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Nano Research 2024年第4期17卷 2899-2907页

作者： Zesen Ma Haiyang Tong Sijin Lin Li Zhou Demeng Sun Baoqing Li changlin tian Jiaru Chu Department of Precision Machinery and Precision Instrumentation University of Science and Technology of ChinaHefei 230027China Key Laboratory of Precision Scientific Instrumentation of Anhui Higher Education Institutes University of Science and Technology of ChinaHefei 230027China Science Island Branch Graduate SchoolUniversity of Science and Technology of ChinaHefei 230026China Anhui Provincial Key Laboratory of High Field Magnetic Resonance Imaging High Magnetic Field LaboratoryHefei Institute of Physical ScienceChinese Academy of SciencesHefei 230031China Anhui Provincial Engineering Laboratory of Peptide Drugs University of Science and Technology of ChinaHefei 230027China School of Biomedical Engineering Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaSuzhou 215127China

Lipid nanoparticles(LNPs)have emerged as highly effective delivery systems for nucleic acid-based therapeutics.However,the broad clinical translation of LNP-based drugs is hampered by the lack of robust and scalable synthesis techniques that can consistently produce formulations from early development to clinical application.In this work,we proposed a method to achieve scalable synthesis of LNPs by scaling inertial microfluidic mixers isometrically in three dimensions.Moreover,a theoretical predictive method,which controls the mixing time to be equal across different chips,is developed to ensure consistent particle size and size distribution of the synthesized LNPs.LNPs loaded with small interfering RNA(siRNA)were synthesized at different flow rates,exhibiting consistent physical properties,including particle size,size distribution and encapsulation efficiency.This work provides a practical approach for scalable synthesis of LNPs consistently,offering the potential to accelerate the transition of nucleic acid drug development into clinical application.

关键词： lipid nanoparticles nucleic acid delivery microfluidics scalable synthesis consistent particle size

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Recent advances in chemical protein synthesis:method developments and biological applications

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Science China Chemistry 2024年第4期67卷 1060-1096页

作者： Suwei Dong Ji-Shen Zheng Yiming Li Huan Wang Gong Chen Yongxiang Chen Gemin Fang Jun Guo Chunmao He Honggang Hu Xuechen Li Yanmei Li Zigang Li Man Pan Shan Tang changlin tian Ping Wang Bian Wu Chuanliu Wu Junfeng Zhao Lei Liu State Key Laboratory of Natural and Biomimetic Drugs and School of Pharmaceutical SciencesPeking UniversityBeijing 100191China Division of Life Sciences and Medicine University of Science and Technology of ChinaHefei 230027China School of Food and Biological Engineering Engineering Research Center of Bio-processMinistry of EducationHefei University of TechnologyHefei 230009China School of Chemistry and Chemical Engineering Nanjing UniversityNanjing 210023China State Key Laboratory of Elemento-Organic Chemistry Nankai UniversityTianjin 300071China Department of Chemistry Tsinghua UniversityBeijing 100084China Institute of Health Sciences Anhui UniversityHefei 230601China College of Chemistry Central China Normal UniversityWuhan 430079China School of Chemistry and Chemical Engineering South China University of TechnologyGuangzhou 510640China School of Medicine or Institute of Translational Medicine Shanghai UniversityShanghai 200444China Department of Chemistry The University of Hong KongHong Kong 999077China Shenzhen Graduate School Peking UniversityShenzhen 518055China School of Chemistry and Chemical Engineering Shanghai Jiao Tong UniversityShanghai 200240China School of Life Sciences University of Science and Technology of ChinaHefei 230026China Department of Chemical Biology Shanghai Jiao Tong UniversityShanghai 200240China Institute of Microbiology Chinese Academy of SciencesBeijing 100101China Department of Chemistry Xiamen UniversityXiamen 361005China School of Pharmaceutical Science Guangzhou Medical UniversityGuangzhou 511436China

The central dogma of modern biology underscores the pivotal roles proteins play in diverse biological processes,the study of which necessitates advanced methods to produce proteins with precision and versatility.Chemical protein synthesis,a powerful approach utilizing chemical reactions for the de novo construction of structurally accurate proteins,has emerged as a transformative tool for studying proteins and generating protein derivatives/mimics inaccessible by natural biological machinery,including post-translationally modified proteins,proteins comprised of unnatural amino acids,as well as mirror-image proteins.This review summarizes recent strides in synthetic method developments for chemical protein synthesis,including innovative techniques in solid-phase peptide synthesis,the challenges presented by difficult sequences in either synthesis or folding and the exploration of novel ligation reactions using both chemical and enzymatic methods.Furthermore,the review also delves into newly developed protocols for site-selective protein modifications and the generation of stapled or macrocyclized peptides/miniproteins,highlighting the power of chemical methods to make structurally diverse proteins.Recent applications of synthetic proteins in investigating post-translational modifications(phosphorylation,lipidation,glycosylation,ubiquitination,etc.),mirror-image biological processes and drug development are further discussed.Together,these topics provide a comprehensive overview of the current landscape of chemical protein synthesis.

关键词： chemical protein synthesis solid-phase peptide synthesis ligation reactions post-translational modifications mirror-image proteins peptide drugs

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Simultaneously enhancing the strength and ductility of as-extruded AlN/AZ91 composites via nano-precipitation and pyramidal slip

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Journal of Materials Science & Technology 2024年第5期172卷 240-254页

作者： Bin Zhang Yunxia Sun Tuo Liang Yunzhen Li tian Li Jingchao Wang Ruiru Cai changlin Yang State Key Laboratory of Solidification Processing Northwestern Polytechnical UniversityXi’an 710072China

Age hardening is often used to optimize the mechanical properties of as-deformed Mg-based materials in industry,whereas the improvement of strength is usually accompanied by the significant loss of ductility,which hinders the application of Mg-based materials in structural components.In the present work,high strength-ductility synergy(the yield strength of 263±9 MPa,ultimate tensile strength of 398±7 MPa and elongation to fracture of 34%±1%)was realized in as-extruded AlN/AZ91 composites after optimiz-ing aging processes.Microstructural characterization shows that AlN particles induced a large number of geometrically necessary dislocations around the AlN/Mg interface during extrusion,which decreased the nucleation barrier and provided more heterogeneous nucleation sites forγ-Mg 17 Al 12 continuous precipi-tation.Meanwhile,95%of residual dislocations in as-extruded AlN/AZ91 composites were annihilated dur-ing peak-aging,suppressing the growth and coarsening of continuous precipitates.Therefore,high density of nano-sizedγ-Mg 17 Al 12 continuous precipitates was produced in as-extruded AlN/AZ91 composites af-ter peak-aging.During tension,gliding dislocations bypassed sphericalγ-Mg 17 Al 12 nano-precipitates by Orowan looping rather than cutting mechanism,which induced a strong block on dislocation motion.So high yield strength was mainly attributed to the high density of non-shearableγ-Mg 17 Al 12 nano-precipitates with spherical morphology,which was different from other Mg-Al-based systems.The results of texture evolution and slip trace analysis demonstrated that the suppression of extension twinning and less basal slip was due to the enhanced activity of pyramidalc+aslip in as-extruded AlN/AZ91 com-posites after peak-aging during the room temperature tension,meanwhile,the dislocation density of as-extruded AlN/AZ91 composites was significantly decreased during peak-aging,then higher elongation to fracture was achieved.

关键词： Magnesium matrix composites Mechanical properties Precipitation Deformation mechanisms Non-basal slip

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Metabolic state oscillations in cerebral nuclei detected using two-photon fluorescence lifetime imaging microscopy

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Chinese Chemical Letters 2023年第1期34卷 300-303页

作者： Peng Zhou Jiawei Shen Jun Liang tian Xue Yuansheng Sun Longhua Zhang changlin tian High Magnetic Field Laboratory Hefei Institutes of Physical ScienceChinese Academy of SciencesHefei 230031China The First Affiliated Hospital of USTC Division of Life Sciences and Medicineand Center for BioAnalytical ChemistryUniversity of Science and Technology of ChinaHefei 230026China ISS Inc.ChampaignIL 61822United States

The fluorescence lifetime of nicotinamide adenine dinucleotide(NADH),a key endogenous coenzyme and metabolic biomarker,can reflect the metabolic state of cells.To implement metabolic imaging of brain tissue at high resolution,we assembled a two-photon fluorescence lifetime imaging microscopy(FLIM)platform and verified the feasibility and stability of NADH-based two-photon FLIM in paraformaldehydefixed mouse cerebral slices.Furthermore,NADH based metabolic state oscillation was observed in cerebral nuclei suprachiasmatic nucleus(SCN).The free NADH fraction displayed a relatively lower level in the daytime than at the onset of night,and an ultradian oscillation at night was observed.Through the combination of high-resolution imaging and immunostaining data,the metabolic tendency of different cell types was detected after the first two hours of the day and at night.Thus,two-photon FLIM analysis of NADH in paraformaldehyde-fixed cerebral slices provides a high-resolution and label-free method to explore the metabolic state of deep brain regions.

关键词： NADH Fluorescence lifetime imaging microscopy Brain metabolism Metabolic oscillation High resolution

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Overview and progress of X-nuclei magnetic resonance imaging in biomedical studies

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Magnetic Resonance Letters 2023年第4期3卷 327-343页

作者： Gengxin Wang Hongyi Yang Juan Li Jie Wen Kai Zhong changlin tian Institutes of Physical Science and Information Technology Anhui UniversityHefei230601China Anhui Provincial Key Laboratory of High Field Magnetic Resonance Imaging High Magnetic Field LaboratoryHefei Institute of Physical ScienceChinese Academy of SciencesHefei230031China School of Life Sciences Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefei230026China The First Affiliation Hospital Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefei230001China Division of Medicine Peking UniversityBeijing100101China

Proton nuclear(^(1)H)is the observed nucleus on which most magnetic resonance imaging(MRI)applications depend.Most traditional^(1)H MRI can provide structural and functional information about organisms,while various non-proton nuclei(X-nuclei)MRI can provide more metabolic information.However,due to the relatively poor signal-to-noise ratio(SNR)of X-nuclei MRI,their applications are quite rare compared to^(1)H.Benefit from the rapid developments of MRI hardware and software technologies,X-nuclei MRI has recently attracted increasing interests in biomedical research.This review firstly introduces some current methods to improve the SNR of X-nuclei MRI.Secondly,this review describes biomedical applications of X-nuclei MRI,especially focusing on the current use of X-nuclei(^(13)C,^(17)O,^(19)F,^(23)Na and^(31)P)MRI to study related diseases in different organs,including the brain,liver,kidney,heart and bone.Finally,perspectives studies on X-nuclei imaging and its potential applications are described in biomedical research.

关键词： Magnetic resonance imaging X-nuclei Biomedical ^(13)C ^(17)O ^(19)F ^(23)Na ^(31)P

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Allosteric conformational changes of G proteins upon its interaction with membrane and GPCR

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Chinese Chemical Letters 2022年第2期33卷 747-750页

作者： Longmei Li Jin Zhang Wenjing Sun Weimin Gong changlin tian Pan Shi Chaowei Shi Hefei National Laboratory of Physical Science at Microscale and School of Life Sciences University of Science and Technology of ChinaHefei 230027China Department of Chemical Physics at School of Chemistry and Materials Sciences University of Science and Technology of ChinaHefei 230027China

Current resolved structures of GPCRs and G protein complexes provided important insights into G protein activation. However, the binding or dissociation of GPCRs with G protein is instantaneous and highly dynamic in the intracellular environment. The conformational dynamic of G protein still needs to be addressed. In this study, we applied ^(19)F solution NMR spectroscopy to monitor the conformational changes of G protein upon interact with detergent mimicking membrane and receptor. Our results show that there are two states equilibria in the G_(α)in apo states. The interaction of G_(α)with detergents will accelerate this conformational transformation and induce a state that tends to bind to GPCRs. Finally, the G_(α)proteins presented a fully activation state when they coupled to GPCRs.

关键词： 19F solution NMR G protein-coupled receptors Conformational dynamics G protein

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A Blockchain-Based Access Control Scheme for Reputation Value Attributes of the Internet of Things

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Computers, Materials & Continua 2024年第1期78卷 1297-1310页

作者： Hongliang tian Junyuan tian College of Electrical Engineering Northeast Electric Power UniversityJilin132012China

The Internet of Things(IoT)access controlmechanism may encounter security issues such as single point of failure and data tampering.To address these issues,a blockchain-based IoT reputation value attribute access control scheme is proposed.Firstly,writing the reputation value as an attribute into the access control policy,and then deploying the access control policy in the smart contract of the blockchain system can enable the system to provide more fine-grained access control;Secondly,storing a large amount of resources fromthe Internet of Things in Inter Planetary File System(IPFS)to improve system throughput;Finally,map resource access operations to qualification tokens to improve the performance of the access control system.Complete simulation experiments based on the Hyperledger Fabric platform.Fromthe simulation experimental results,it can be seen that the access control system can achieve more fine-grained and dynamic access control while maintaining high throughput and low time delay,providing sufficient reliability and security for access control of IoT devices.

关键词： Blockchain IoT access control Hyperledger Fabric

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Robust adaptive radar beamforming based on iterative training sample selection using kurtosis of generalized inner product statistics

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Journal of Systems Engineering and Electronics 2024年第1期35卷 24-30页

作者： tian Jing ZHANG Wei School of Information and Electronics Beijing Institute of TechnologyBeijing 100081China National Key Laboratory of Electromagnetic Space Security Chengdu 610036China

In engineering application,there is only one adaptive weights estimated by most of traditional early warning radars for adaptive interference suppression in a pulse reputation interval(PRI).Therefore,if the training samples used to calculate the weight vector does not contain the jamming,then the jamming cannot be removed by adaptive spatial filtering.If the weight vector is constantly updated in the range dimension,the training data may contain target echo signals,resulting in signal cancellation effect.To cope with the situation that the training samples are contaminated by target signal,an iterative training sample selection method based on non-homogeneous detector(NHD)is proposed in this paper for updating the weight vector in entire range dimension.The principle is presented,and the validity is proven by simulation results.

关键词： adaptive radar beamforming training sample selection non-homogeneous detector electronic jamming jamming suppression

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Transformer and GAN-Based Super-Resolution Reconstruction Network for Medical Images

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Tsinghua Science and Technology 2024年第1期29卷 197-206页

作者： Weizhi Du Shihao tian Arts&Sciences College Washington University in St.LouisSt.LouisMO 63130USA Department of Electric and Computing Engineering Cornell UniversityIthacaNY 14850USA

Super-resolution reconstruction in medical imaging has become more demanding due to the necessity of obtaining high-quality images with minimal radiation dose,such as in low-field magnetic resonance imaging(MRI).However,image super-resolution reconstruction remains a difficult task because of the complexity and high textual requirements for diagnosis purpose.In this paper,we offer a deep learning based strategy for reconstructing medical images from low resolutions utilizing Transformer and generative adversarial networks(T-GANs).The integrated system can extract more precise texture information and focus more on important locations through global image matching after successfully inserting Transformer into the generative adversarial network for picture reconstruction.Furthermore,we weighted the combination of content loss,adversarial loss,and adversarial feature loss as the final multi-task loss function during the training of our proposed model T-GAN.In comparison to established measures like peak signal-to-noise ratio(PSNR)and structural similarity index measure(SSIM),our suggested T-GAN achieves optimal performance and recovers more texture features in super-resolution reconstruction of MRI scanned images of the knees and belly.

关键词： super-resolution image reconstruction Transformer generative adversarial network(GAN)

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Revisiting East Asian monsoon change during the Last Glacial Maximum using PMIP4 simulations

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Atmospheric and Oceanic Science Letters 2024年第3期17卷 47-52页

作者： Zhiping tian Institute of Atmospheric Physics Chinese Academy of SciencesBeijingChina

利用PMIP4多模式试验数据,本文重新检查了末次冰盛期(距今约21000年)东亚季风变化.结果表明:相对于工业革命前期,所有5个模式一致模拟显示末次冰盛期东亚季风减弱,冬季和夏季减幅分别为1%-18%和2-32%;不同模式中东亚季风环流变化的空间... 详细信息

利用PMIP4多模式试验数据,本文重新检查了末次冰盛期(距今约21000年)东亚季风变化.结果表明:相对于工业革命前期,所有5个模式一致模拟显示末次冰盛期东亚季风减弱,冬季和夏季减幅分别为1%-18%和2-32%;不同模式中东亚季风环流变化的空间分布存在差异,这主要源于该时期大尺度变冷和海平面气压梯度变化的空间分布不同;由于模式之间的差异和重建记录之间的不确定性,未来有待开展更多模拟和重建工作以更好地理解冰期东亚季风变化.

关键词：末次冰盛期东亚冬季风东亚夏季风 PMIP4试验

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