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Lipid nanovehicles overcome barriers to systemic RNA delivery: Lipid components, fabrication methods, and rational design

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Acta Pharmaceutica Sinica B 2024年第2期14卷 579-601页

作者： Jing yan Hao Zhang Guangfeng Li Jiacan su yan Wei Can Xu Institute of Translational Medicine Shanghai UniversityShanghai 200444China Institute of Medicine Shanghai UniversityShanghai 200444China Department of Orthopedics Xinhua HospitalShanghai Jiao Tong University School of MedicineShanghai 200092China Department of Orthopedics Shanghai Zhongye HospitalShanghai 200941China Organoid Research Center Shanghai UniversityShanghai 200444China Department of Gastroenterology Changhai HospitalShanghai 200433China

Lipid nanovehicles are currently the most advanced vehicles used for RNA delivery,as demonstrated by the approval of patisiran for amyloidosis therapy in 2018.To illuminate the unique superiority of lipid nanovehicles in RNA delivery,in this review,we first introduce various RNA therapeutics,describe systemic delivery barriers,and explain the lipid components and methods used for lipid nanovehicle preparation.Then,we emphasize crucial advances in lipid nanovehicle design for overcoming barriers to systemic RNA delivery.Finally,the current status and challenges of lipid nanovehicle-based RNA therapeutics in clinical applications are also discussed.Our objective is to provide a comprehensive overview showing how to utilize lipid nanovehicles to overcome multiple barriers to systemic RNA delivery,inspiring the development of more high-performance RNA lipid nanovesicles in the future.

关键词： Lipid nanovehicles RNAtherapeutics Barriers to systemicRNA delivery Lipid components Fabricationmethods Lipid nanovehicledesign Extrahepatictissue targeting Organ tropism

Resilient performance of self-centering hybrid rocking walls with curved interface under pseudo-static loading

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Earthquake Engineering and Engineering Vibration 2024年第1期23卷 65-85页

作者： su Xing yan Shi sun Xianglei Wang Tao School of Civil Engineering Shenyang Jianzhu UniversityShenyang 110168China PetroChina East China Design Institute Co. Ltd.Qingdao 266000China Qingdao Country Garden Bolin Real Estate Co. Ltd.Qingdao 266100China

Frame and rocking wall(FRW)structures have excellent resilient performance during earthquakes.However,the concrete at interfacial corners of rocking walls(RWs)is easily crushed due to local extreme compression during the rocking process.An innovative RW with a curved interface is proposed to prevent interfacial corners from producing local damage,enhancing its earthquake resilient performance(ERP).The precast wall panel with a curved interface is assembled into an integral self-centering hybrid rocking wall(SCRW)by two post-tensioned unbonded prestressed tendons.Moreover,two ordinary energy dissipation steel rebars and two shear reinforcements are arranged to increase the energy dissipation capacity and lateral resistance.Two SCRW specimens and one monolithic reinforced concrete(RC)shear wall(SW)were tested under pseudo-static loading to compare the ERPs of the proposed SCRW and the SW,focusing on studying the effect of the curved interface on the SCRW.The key resilient performance of rocking effects,failure modes,and hysteretic properties of the SCRW were explored.The results show that nonlinear deformations of the SCRW are concentrated along the interface between the SCRW and the foundation,avoiding damage within the SCRW.The restoring force provided by the prestressed tendons can effectively realize self-centering capacity with small residual deformation,and the resilient performance of the SCRW is better than that of monolithic SW.In addition,the curved interface of the SCRW makes the rocking center change and move inward,partially relieving the stress concentration and crush of concrete.The rocking range of the rocking center is about 41.4%of the width of the SCRW.

关键词： self-centering hybrid rocking wall(SCRW) monolithic shear wall(SW) earthquake resilient performance(ERP) curved interface rocking center

Research on Hepatocyte Regulation of PCSK9-LDLR and Its Related Drug Targets

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Chinese Journal of Integrative Medicine 2024年第7期30卷 664-672页

作者： LIU su-su YU Tong QIAO yan-fang GU Shu-xiao CHAI Xin-lou School of Traditional Chinese Medicine Beijing University of Chinese Medicine

The prevalence of hyperlipidemia has increased significantly due to genetic, dietary, nutritional and pharmacological factors, and has become one of the most common pathological conditions in humans. Hyperlipidemia can lead to a range of diseases such as atherosclerosis, stroke, coronary heart disease, myocardial infarction, diabetes, and kidney failure, etc. High circulating low-density lipoprotein cholesterol(LDL-C) is one of the causes of hyperlipidemia. LDL-C in the blood binds to LDL receptor(LDLR) and regulates cholesterol homeostasis through endocytosis. In contrast, proprotein convertase subtilisin/kexin type 9(PCSK9) mediates LDLR degradation via the intracellular and extracellular pathways, leading to hyperlipidemia. Targeting PCSK9-synthesizing transcription factors and downstream molecules are important for development of new lipid-lowering drugs. Clinical trials regarding PCSK9 inhibitors have demonstrated a reduction in atherosclerotic cardiovascular disease events. The purpose of this review was to explore the target and mechanism of intracellular and extracellular pathways in degradation of LDLR and related drugs by PCSK9 in order to open up a new pathway for the development of new lipid-lowering drugs.

关键词： hyperlipidemia proprotein convertase subtilisin/kexin type 9 low-density lipoprotein receptor intracellular pathway extracellular pathway

Cosmological Constraints on Neutrino Masses in Light of JWST Red and Massive Candidate Galaxies

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Research in Astronomy and Astrophysics 2024年第4期24卷 7-12页

作者： Jian-Qi Liu Zhi-Qi Huang yan su School of Physics and Astronomy Sun Yat-sen UniversityZhuhai 519082China CSST Science Center for the Guangdong-Hong Kong-Macao Greater Bay Area Zhuhai 519082China

The overabundance of the red and massive candidate galaxies observed by the James Webb Space Telescope(JWST)implies efficient structure formation or large star formation efficiency at high redshift z~10.In the scenario of a low or moderate star formation efficiency,because massive neutrinos tend to suppress the growth of structure of the universe,the JWST observation tightens the upper bound of the neutrino masses.Assuming A cold dark matter cosmology and a star formation efficiency∈[0.05,0.3](flat prior),we perform joint analyses of Planck+JWST and Planck+BAO+JWST,and obtain improved constraints∑m_(ν)sumptions,the inverted mass ordering,which implies ∑m_(ν)≥0.1 eV,is excluded by Planck+BAO+JWST at 92.7% confidence level.

关键词： (cosmology:)cosmological parameters galaxies:abundances galaxies:formation neutrinos

Mechanism of action of the bile acid receptor TGR5 in obesity

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Acta Pharmaceutica Sinica B 2024年第2期14卷 468-491页

作者： Weijun Lun Qihao yan Xinghua Guo Minchuan Zhou yan Bai Jincan He Hua Cao Qishi Che Jiao Guo Zhengquan su Guangdong Engineering Research Center of Natural Products and New Drugs Guangdong Provincial University Engineering Technology Research Center of Natural Products and DrugsGuangdong Pharmaceutical UniversityGuangzhou 510006China Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine Key Laboratory of Glucolipid Metabolic DisorderMinistry of Education of ChinaGuangdong TCM Key Laboratory for Metabolic DiseasesGuangdong Pharmaceutical UniversityGuangzhou 510006China School of Public Health Guangdong Pharmaceutical UniversityGuangzhou 510310China School of Chemistry and Chemical Engineering Guangdong Pharmaceutical UniversityZhongshan 528458China Guangzhou Rainhome Pharm&Tech Co. Ltd.Science CityGuangzhou 510663China

G protein-coupled receptors(GPCRs)are a large family of membrane protein receptors,and Takeda G protein-coupled receptor 5(TGR5)is a member of this family.As a membrane receptor,TGR5 is widely distributed in different parts of the human body and plays a vital role in regulating metabolism,including the processes of energy consumption,weight loss and blood glucose homeostasis.Recent studies have shown that TGR5 plays an important role in glucose and lipid metabolism disorders such as fatty liver,obesity and diabetes.With the global obesity situation becoming more and more serious,a comprehensive explanation of the mechanism of TGR5 and filling the gaps in knowledge concerning clinical ligand drugs are urgently needed.In this review,we mainly explain the anti-obesity mechanism of TGR5 to promote the further study of this target,and show the electron microscope structure of TGR5 and review recent studies on TGR5 ligands to illustrate the specific binding between TGR5 receptor binding sites and ligands,which can effectively provide new ideas for ligand research and promote drug research.

关键词： Obesity TGR5 Bile acids Ligand Appetite Metabolism GLP-1 Inflammation

Analysis of the Erosion-Corrosion Mechanism of the Air Cooler in a Hydrocracking Unit:A Numerical and Experimental Study

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China Petroleum Processing & Petrochemical Technology 2024年第1期26卷 126-138页

作者： su Guoqing Li yan Guo Hongli Zhang Jianwen College of Mechanical and Electrical Engineering Beijing University of Chemical TechnologyBeijing 100029China

Corrosion leakages often occur in the air cooler of a hydrocracking unit,with the failure sites mainly located in the entrance area of the tubes.An analysis of the macroscopic morphology and corrosion products confirmed that the damage was caused by erosion-corrosion(E-C).Numerical and experimental methods were applied to investigate the E-C mechanism in the air cooler.Computational fluid dynamics(CFD)was used to calculate the hydrodynamic parameters of the air cooler.The results showed that there was a biased flow in the air cooler,which led to a significant increase in velocity,turbulent kinetic energy and wall shear within 0.2 m of the tube entrance.A visualization experiment was then performed to determine the principles of migration and transformation of multiphase flow in the air cooler tubes.Various flow patterns(pure droplet flow,mist flow,and annular flow)and their evolutionary processes were clearly depicted experimentally.The initiation mechanism and processes leading to the development of E-C in the air cooler were also determined.This study provided a comprehensive explanation for the E-C failures that occur in air coolers during operation.

关键词： air cooler hydrocracking unit erosion-corrosion simulation visualization experiment multiphase flow

Engineered plant extracellular vesicles for autoimmune diseases therapy

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Nano Research 2024年第4期17卷 2857-2873页

作者： Ruina Han yan Wu Yafei Han Xiangfei Liu Han Liu Jiacan su Institute of Translational Medicine Shanghai UniversityShanghai 200444China Organoid Research Center Shanghai UniversityShanghai 200444China National Center for Translational Medicine(Shanghai)SHU Branch Shanghai UniversityShanghai 200444China Department of Orthopedics Shanghai Zhongye HospitalShanghai 200941China Department of Orthopedics Xinhua HospitalShanghai Jiao Tong University School of MedicineShanghai 200092China

Autoimmune diseases(AID)encompass a diverse array of conditions characterized by immune system dysregulation,resulting in aberrant responses of B cells and T cells against the body’s own healthy tissues.Plant extracellular vesicles(PEVs)are nanoscale particles enclosed by phospholipid bilayers,secreted by plant cells,which facilitate intercellular communication by transporting various bioactive molecules.Due to their nanoscale structure,safety,abundant sources,low immunogenicity,high yield,biocompatibility,and effective targeting of the colon and liver,PEVs are regarded as a promising platform for the treatment of AID.This review provides a comprehensive summary of PEV biogenesis,physicochemical and biological properties,internalization mechanisms,isolation methods,and their applications in various diseases,with a specific focus on their potential roles in AID.Additionally,we propose engineering approaches and administration methods for PEVs.Finally,we present an overview of the advantages and challenges associated with utilizing PEVs for the treatment of AID.By gaining a comprehensive understanding of PEVs,we anticipate the development of innovative therapeutic strategies for AID.Natural and engineered PEVs hold substantial promise as a valuable resource for innovative technologies in AID treatment.

关键词： autoimmune diseases plant extracellular vesicles extracellular vesicles engineering modification

Development of a prognostic scoring system for hepatic vena cava Budd-Chiari syndrome with hepatocellular carcinoma

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Hepatobiliary & Pancreatic Diseases International 2024年第4期23卷 370-375页

作者： Sheng-yan Liu Lu-Hao Li Zhao-Chen Liu su-Xin Li Xiao-Wei Dang Department of Hepatopancreatobiliary surgery the First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052China Budd-Chiari Syndrome Diagnosis and Treatment Center of Henan Province Zhengzhou 450052China

Background:Hepatocellular carcinoma(HCC)is a serious complication of hepatic vena cava Budd-Chiari syndrome(HVC-BCS)that significantly reduces the survival time of patients.Our study aimed to analyze the prognostic factors influencing the survival of HVC-BCS patients with HCC and to develop a prognostic scoring system.Methods:The clinical and follow-up data of 64 HVC-BCS patients with HCC who received invasive treatment at the First Affiliated Hospital of Zhengzhou University between January 2015 and December 2019 were retrospectively analyzed.Kaplan-Meier curves and log-rank tests were used to analyze the survival curve of patients and the difference in prognoses between the groups.Univariate and multivariate Cox regression analyses were performed to analyze the influence of biochemical,tumor,and etiological characteristics on the total survival time of patients,and a new prognostic scoring system was developed according to the regression coefficients of the independent predictors in the statistical model.The prediction efficiency was evaluated using the time-dependent receiver operating characteristics curve and concordance index.Results:Multivariate analysis showed that serum albumin level7 cm(HR=8.623,95%CI:3.771-19.715,Psurvival.A prognostic scoring system was developed according to the above-mentioned independent predictors,and patients were classified into grades A,B,C and D.Significant differences in survival were found among the four groups.Conclusions:This study successfully developed a prognostic scoring system for HVC-BCS patients with HCC,which is helpful for clinical evaluation of patient prognosis.

关键词： Budd-Chiari syndrome Hepatocellular carcinoma Prognostic factors Inferior vena cava stenosis Prognostic scoring system

Identification of key genes regulating the synthesis of quercetin derivatives in Rosa roxburghii through integrated transcriptomics and metabolomics

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Journal of Integrative Agriculture 2024年第3期23卷 876-887页

作者： Liyao su Min Wu Tian Zhang yan Zhong Zongming(Max) Cheng State Key Laboratory of Crop Genetics and Germplasm Enhancement College of HorticultureNanjing Agricultural UniversityNanjing210095China

Rosa roxburghii fruit is rich in flavonoids, but little is known about their biosynthetic pathways. In this study, we employed transcriptomics and metabolomics to study changes related to the flavonoids at five different stages of R. roxburghii fruit development. Flavonoids and the genes related to their biosynthesis were found to undergo significant changes in abundance across different developmental stages, and numerous quercetin derivatives were identified. We found three gene expression modules that were significantly associated with the abundances of the different flavonoids in R. roxburghii and identified three structural UDP-glycosyltransferase genes directly involved in the synthesis of quercetin derivatives within these modules. In addition, we found that RrBEH4, RrLBD1 and RrPIF8could significantly increase the expression of downstream quercetin derivative biosynthesis genes. Taken together,these results provide new insights into the metabolism of flavonoids and the accumulation of quercetin derivatives in R. roxburghii.

关键词： Rosa roxburghii quercetin derivatives weighted gene co-expression network analysis transcription factor transcriptome metabolome