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Adeno-associated virus as a delivery vector for gene therapy of human diseases

Signal Transduction and Targeted Therapy 2024年第5期9卷 1808-1840页

作者： jiang-Hui wang Dominic j.Gessler wei zhan Thomas L.Gallagher Guangping Gao Horae Gene Therapy Center University of Massachusetts Chan Medical SchoolWorcesterMA01605USA Department of Microbiology and Physiological Systems University of Massachusetts Chan Medical SchoolWorcesterMA01605USA Centre for Eye Research Australia Royal Victorian Eye and Ear HospitalEast MelbourneVIC3002Australia Ophthalmology Department of SurgeryUniversity of MelbourneEast MelbourneVIC3002Australia Department of Neurological Surgery University of Massachusetts Chan Medical SchoolWorcesterMA01605USA Department of Neurosurgery University of MinnesotaMinneapolisMN55455USA Department of Medicine University of Massachusetts Chan Medical SchoolWorcesterMA01605USA Li weibo Institute for Rare Diseases Research University of Massachusetts Chan Medical SchoolWorcesterMA01605USA

Adeno-associated virus(AAV)has emerged as a pivotal delivery tool in clinical gene therapy owing to its minimal pathogenicity and ability to establish long-term gene expression in different *** AAV(rAAV)has been engineered for enhanced specificity and developed as a tool for treating various ***,as rAAV is being more widely used as a therapy,the increased demand has created challenges for the existing manufacturing *** rAAV-based gene therapy products have received regulatory approval,but there continue to be concerns about safely using high-dose viral therapies in humans,including immune responses and adverse effects such as genotoxicity,hepatotoxicity,thrombotic microangiopathy,and *** this review,we explore AAV biology with an emphasis on current vector engineering strategies and manufacturing *** discuss how rAAVs are being employed in ongoing clinical trials for ocular,neurological,metabolic,hematological,neuromuscular,and cardiovascular diseases as well as *** outline immune responses triggered by rAAV,address associated side effects,and discuss strategies to mitigate these *** hope that discussing recent advancements and current challenges in the field will be a helpful guide for researchers and clinicians navigating the ever-evolving landscape of rAAV-based gene therapy.

关键词： diseases specificity approval

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On the well-Posedness Problem of the Anisotropic Porous Medium Equation with a Variable Diffusion Coefficient

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journal of Partial Differential Equations 2024年第2期37卷 135-149页

作者： zhan Huashui School of Mathematics and Statistics Xiamen University of TechnologyXiamen 361024China

The initial-boundary value problem of an anisotropic porous medium equation■is *** with the usual porous medium equation,there are two different characteristics in this *** lies in its anisotropic property,another one is that there is a nonnegative variable diffusion coefficient a(x,t)*** a(x,t)may be degenerate on the parabolic boundary∂Ω×(0,T),instead of the boundedness of the gradient|∇u|for the usual porous medium,we can only show that∇u∈L^(∞)(0,T;L^(2)_(loc)(Ω)).Based on this property,the partial boundary value conditions matching up with the anisotropic porous medium equation are discovered and two stability theorems of weak solutions can be proved naturally.

关键词： Anisotropic porous medium equation variable diffusion coefficient stability partial boundary condition

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Application of a simplified ADM1 for full-scale anaerobic co-digestion of cattle slurry and grass silage:assessment of input variability

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Frontiers of Environmental Science & Engineering 2024年第4期18卷 125-139页

作者： Sofia Tisocco Sören weinrich Gary Lyons Michael wills Xinmin zhan Paul Crosson Civil Engineering College of Science and EngineeringUniversity of GalwayGalwayH91 TK33Ireland Teagasc Animal and Bioscience Research Department Animal and Grassland Research and Innovation CentreDunsanyC15 PW93Ireland Biochemical Conversion Department Deutsches Biomasseforschungszentrum gemeinnützige GmbHLeipzig 04347Germany Faculty of Energy·Building Services·Environmental Engineering Münster University of Applied SciencesSteinfurt 48565Germany Agri-Food and Biosciences Institute HillsboroughBT266DRUK Ryan Institute University of GalwayGalwayH91 TK33Ireland MaREI Research Centre for Energy Climate and MarineRyan InstituteUniversity of GalwayGalwayH91 TK33Ireland

Mathematical modeling of anaerobic digestion is a powerful tool to predict gas yields and optimize the *** Anaerobic Digestion Model No.1(ADM1)is a widely implemented model for this ***,modeling full-scale biogas plants is challenging due to the extensive substrate and parameter characterization *** study describes the modification of the ADM1 through a simplification of individual process phases,characteristic components and required ***,the ability of the simplified model to simulate the co-digestion of grass silage and cattle slurry was evaluated using data from a full-scale biogas *** impacts of substrate composition(crude carbohydrate,protein and lipid concentration)and variability of carbohydrate degradability on simulation results were assessed to identify the most influential *** indicated that the simplified version was able to depict biogas and biomethane production with average model efficiencies,according to the Nash-Sutcliffe efficiency(NSE)coefficient,of 0.70 and 0.67,respectively,and was comparable to the original ADM1(average model efficiencies of 0.71 and 0.63,respectively).The variability of crude carbohydrate,protein and lipid concentration did not significantly impact biogas and biomethane output for the data sets *** contrast,carbohydrate degradability seemed to explain much more of the variability in the biogas and methane ***,the application of simplified models provides a reliable basis for the process simulation and optimization of full-scale agricultural biogas plants.

关键词： ADM1 Agricultural feedstocks Biogas technology Input variability Parameter estimation

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The modulatory effect of oolong tea polyphenols on intestinal flora and hypothalamus gene expression in a circadian rhythm disturbance mouse model

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Food Science and Human wellness 2024年第2期13卷 748-764页

作者： Ruonan Yan Chi-Tang Ho Yanan Liu Shengnan zhan Zufang wu Xin zhang Department of Food Science and Engineering Ningbo UniversityNingbo 315211China Department of Food Science Rutgers UniversityNew BrunswickNew Jersey 08901USA

The interaction between host circadian rhythm and gut microbes through the gut-brain axis provides new clues for tea polyphenols to improve host *** present research showed that oolong tea polyphenols(OTP)improved the structural disorder of the intestinal flora caused by continuous darkness,thereby modulating the production of metabolites related to pyruvate metabolism,glycolysis/gluconeogenesis,and tryptophan metabolism to alleviate the steady-state *** fecal microbiota transplantation from the OTP group,the single-cell transcriptomic analysis revealed that OTP significantly increased the number of hypothalamus cell clusters,up-regulated the number of astrocytes and fibroblasts,and enhanced the expression of circadian rhythm genes Cry2,Per3,Bhlhe41,Nr1d1,Nr1d2,Dbp and Rorb in hypothalamic *** results confirmed that OTP can actively improve the intestinal environmental state as well as internal/peripheral circadian rhythm disorders and cognitive impairment,with potential prebiotic functional characteristics to notably contribute to host health.

关键词： Gut microbiota Circadian rhythm Oolong tea polyphenols Single-cell sequencing Metabolism

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Spin order and dynamics in the topological rare-earth germanide semimetals

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Science China(Physics,Mechanics & Astronomy) 2024年第10期67卷 113-127页

作者： Yuhao wang Zhixuan Zhen jing Meng Igor Plokhikh Delong wu Dariusz j.Gawryluk Yang Xu Qingfeng zhan Ming Shi Ekaterina Pomjakushina Toni Shiroka Tian Shang Key Laboratory of Polar Materials and Devices(MOE) School of Physics and Electronic ScienceEast China Normal UniversityShanghai 200241China Laboratory for Multiscale Materials and Experiments Paul Scherrer InstitutVilligen PSI CH-5232Switzerland Center for Correlated Matter and School of Physics Zhejiang UniversityHangzhou 310058China Laboratory for Muon-Spin Spectroscopy Paul Scherrer InstitutVilligen PSI CH-5232Switzerland Laboratorium für Festkörperphysik ETH ZürichZürich CH-8093Switzerland

The REAl(Si,Ge)(RE=rare earth)family,known to break both the inversion-and time-reversal symmetries,represents one of the most suitable platforms for investigating the interplay between correlated-electron phenomena and topologically nontrivial ***,we report on systematic magnetic,transport,and muon-spin rotation and relaxation(μSR)measurements on(Nd,Sm)AlGe single crystals,which exhibit antiferromagnetic(AFM)transitions at T_(N)=6.1 and 5.9 K,*** addition,NdAlGe undergoes also an incommensurate-to-commensurate ferrimagnetic transition at 4.5 *** transverse-fieldμSR measurements confirm the AFM transitions,featuring a~90%magnetic volume ***-field(ZF)μSR measurements reveal a more disordered internal field distribution in NdAlGe than in SmAlGe,reflected in a larger transverse muon-spin relaxation rateλTat Twhich undergoes a series of metamagnetic transitions in an external magnetic field,while SmAlGe shows only a robust AFM *** NdAlGe,the topological Hall effect(THE)appears between the first and the second metamagnetic transitions for H‖c,while it is absent in *** THE in NdAlGe is most likely attributed to the field-induced topological spin *** longitudinal muon-spin relaxation rateλL,diverges near the AFM order,followed by a clear drop at Tweyl semimetals.

关键词： magneticweyl semimetals topological Hall effect spin fluctuations μSR

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Modeling and Analysis of Risk Propagation and Loss Causing Capacity for Key Nodes in Cyber-Physical Coupled Power Network

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Complex System Modeling and Simulation 2024年第2期4卷 124-136页

作者： Dongqi Liu Qiong zhang Haolan Liang Tao zhan Rui wang National Key Laboratory of Disaster Prevention and Reduction for Power Grid Changsha University of Science and TechnologyChangsha 410114China the School of Electrical and Information Engineering Changsha University of Science and TechnologyChangsha 410114China the College of Electrical and Information Engineering Hunan Institute of EngineeringXiangtan 411104China the School of Systems Engineering National University of Defense TechnologyChangsha 410003China

The modern power system has evolved into a cyber-physical system with deep coupling of physical and information domains,which brings new security *** at the problem that the“information-physical”cross-domain attacks with key nodes as springboards seriously threaten the safe and stable operation of power grids,a risk propagation model considering key nodes of power communication coupling networks is proposed to study the risk propagation characteristics of malicious attacks on key nodes and the impact on the ***,combined with the complex network theory,a topological model of the power communication coupling network is established,and the key nodes of the coupling network are screened out by Technique for Order Preference by Similarity to Ideal Solution(TOPSIS)method under the comprehensive evaluation index based on topological characteristics and physical ***,a risk propagation model is established for malicious attacks on key nodes to study its propagation characteristics and analyze the state changes of each node in the coupled ***,two loss-causing factors:the minimum load loss ratio and transmission delay factor are constructed to quantify the impact of risk propagation on the coupled ***,simulation analysis based on the IEEE 39-node system shows that the probability of node being breached(α)and the security tolerance of the system(β)are the key factors affecting the risk propagation characteristics of the coupled network,as well as the criticality of the node is positively correlated with the damage-causing *** proposed methodological model can provide an effective exploration of the diffusion of security risks in control systems on a macro level.

关键词： cyber-physical system risk propagation complex network loss causative factor

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Generative AI for visualization: State of the art and future directions

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Visual Informatics 2024年第2期8卷 43-66页

作者： Yilin Ye jianing Hao Yihan Hou zhan wang Shishi Xiao Yuyu Luo wei Zeng The Hong Kong University of Science and Technology(Guangzhou) GuangzhouGuangdongChina The Hong Kong University of Science and TechnologyHong KongChina

Generative AI(GenAI)has witnessed remarkable progress in recent years and demonstrated impressive performance in various generation tasks in different domains such as computer vision and computational *** researchers have attempted to integrate GenAI into visualization framework,leveraging the superior generative capacity for different ***,recent major breakthroughs in GenAI like diffusion models and large language models have also drastically increased the potential of *** a technical perspective,this paper looks back on previous visualization studies leveraging GenAI and discusses the challenges and opportunities for future ***,we cover the applications of different types of GenAI methods including sequence,tabular,spatial and graph generation techniques for different tasks of visualization which we summarize into four major stages:data enhancement,visual mapping generation,stylization and *** each specific visualization sub-task,we illustrate the typical data and concrete GenAI algorithms,aiming to provide in-depth understanding of the state-of-the-art GenAI4VIS techniques and their ***,based on the survey,we discuss three major aspects of challenges and research opportunities including evaluation,dataset,and the gap between end-to-end GenAI methods and *** summarizing different generation algorithms,their current applications and limitations,this paper endeavors to provide useful insights for future GenAI4VIS research.

关键词： Visualization Generative AI

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BMSC-derived Exosomes Ameliorate Peritoneal Dialysis-associated Peritoneal Fibrosis via the Mir-27a-3p/TP53 Pathway

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Current Medical Science 2024年第2期44卷 333-345页

作者： jun-li ZHAO Lin ZHAO Qiu-nan zhan Miao LIU Ting zhanG wen-wen CHU Department of Nephrology Shanghai University of Medicine&Health Sciences Affiliated Zhoupu HospitalShanghai 201318China Orthopedic Department Guangming Traditional Chinese Medicine Hospital of Pudong New AreaShanghai 201399China

Objective:Peritoneal fibrosis(PF)is the main cause of declining efficiency and ultrafiltration failure of the peritoneum,which restricts the long-term application of peritoneal dialysis(PD).This study aimed to investigate the therapeutic effects and mechanisms of bone marrow mesenchymal stem cells-derived exosomes(BMSC-Exos)on PF in response to ***:Small RNA sequencing analysis of BMSC-Exos was performed by second-generation sequencing.C57BL/6j mice were infused with 4.25%glucose-based peritoneal dialysis fluid(PDF)for 6 consecutive weeks to establish a PF model.A total of 36 mice were randomly divided into 6 groups:control group,1.5%PDF group,2.5%PDF group,4.25%PDF group,BMSC-Exos treatment group,and BMSC-Exos+TP53 treatment *** transcription quantitative polymerase chain reaction(RT-qPCR)was performed to measure the expression level of miR-27a-3p in BMSC-Exos and peritoneum of mice treated with different concentrations of *** and Masson staining were performed to evaluate the extent of *** therapeutic potential of BMSC-Exos for PF was examined through pathological examination,RT-qPCR,western blotting,and peritoneal function ***-mesenchymal transition(EMT)of HMrSV5 was induced with 4.25%*** were divided into control group,4.25%PDF group,BMSC-Exos treatment group,and BMSC-Exos+TP53 treatment *** Counting Kit-8 assay was used to measure cell viability,and transwell migration assay was used to verify the capacity of BMSC-Exos to inhibit EMT in HMrSV5 ***:Small RNA sequencing analysis showed that miR-27a-3p was highly expressed in BMSC-derived exosomes compared to *** RT-qPCR results showed that the expression of miR-27a-3p was upregulated in BMSC-Exos,but decreased in PD *** found that PF was glucose concentration-dependently enhanced in the peritoneum of the PD *** with the control mice,the PD mice showed high solute transport and decreased ultrafiltration volume as well as an obvious f

关键词： peritoneal fibrosis bone marrow mesenchymal stem cell-derived exosomes miR-27a-3p TP53 epithelialmesenchymal transition

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New insights into the correlations between circulating tumor cells and target organ metastasis

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Signal Transduction and Targeted Therapy 2024年第1期9卷 211-233页

作者： Qinru zhan Bixia Liu Xiaohua Situ Yuting Luo Tongze Fu Yanxia wang Zhongpeng Xie Lijuan Ren Ying Zhu weiling He Zunfu Ke Department of Pathology The First Affiliated Hospital of Sun Yat-sen University510000 GuangzhouGuangdongP.R.China Institute of Precision Medicine The First Affiliated Hospital of Sun Yat-sen University510000 GuangzhouGuangdongP.R.China Zhongshan School of Medicine Sun Yat-sen University510000 GuangzhouGuangdongP.R.China Department of Radiology The First Affiliated Hospital of Sun Yat-sen University510000 GuangzhouGuangdongP.R.China Department of Microbiology and Immunology Weill Cornell MedicineNew YorkNY 10065USA School of Medicine Xiang’an Hospital of Xiamen UniversityXiamen University361000 XiamenFujianP.R.China

Organ-specific metastasis is the primary cause of cancer patient *** distant metastasis of tumor cells to specific organs depends on both the intrinsic characteristics of the tumor cells and extrinsic factors in their *** an intermediate stage of metastasis,circulating tumor cells(CTCs)are released into the bloodstream from primary and metastatic *** harboring aggressive or metastatic features can extravasate to remote sites for continuous colonizing growth,leading to further *** the past decade,numerous studies demonstrated that CTCs exhibited huge clinical value including predicting distant metastasis,assessing prognosis and monitoring treatment response et ***,increasingly numerous experiments are dedicated to identifying the key molecules on or inside CTCs and exploring how they mediate CTC-related organ-specific *** on the above molecules,more and more inhibitors are being developed to target CTCs and being utilized to completely clean CTCs,which should provide promising prospects to administer advanced ***,the application of various nanomaterials and microfluidic technologies in CTCs enrichment technology has assisted to improve our deep insights into the phenotypic characteristics and biological functions of CTCs as a potential therapy target,which may pave the way for us to make practical clinical *** the present review,we mainly focus on the role of CTCs being involved in targeted organ metastasis,especially the latest molecular mechanism research and clinical intervention strategies related to CTCs.

关键词： metastasis organs insight

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Synergistic induction of mitotic pyroptosis and tumor remission by inhibiting proteasome and wEE family kinases

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Signal Transduction and Targeted Therapy 2024年第8期9卷 3467-3482页

作者： zhan-Li Chen Chen Xie wei Zeng Rui-Qi Huang jin-E Yang jin-Yu Liu Ya-jing Chen Shi-Mei Zhuang MOE Key Laboratory of Gene Function and Regulation Guangdong Province Key Laboratory of Pharmaceutical Functional GenesSchool of Life SciencesState Key Laboratory of Oncology in Southern ChinaSun Yat-sen UniversityGuangzhouPR China Key Laboratory of Liver Disease of Guangdong Province The Third Affiliated HospitalSun Yat-sen UniversityGuangzhou 510630PR China

Mitotic catastrophe(MC),which occurs under dysregulated mitosis,represents a fascinating tactic to specifically eradicate tumor *** pyroptosis can be a death form of MC remains ***-mediated protein degradation is crucial for ***(BTZ),which inhibits the 20S catalytic particle of proteasome,is approved to treat multiple myeloma and mantle cell lymphoma,but not solid tumors due to primary *** date,whether and how proteasome inhibitor affected the fates of cells in M-phase remains ***,we show that BTZ treatment,or silencing of PSMC5,a subunit of 19S regulatory particle of proteasome,causes G2-and M-phase arrest,multi-polar spindle formation,and consequent caspase-3/GSDME-mediated pyroptosis in M-phase(designated as mitotic pyroptosis).Further investigations reveal that inhibitor of wEE1/PKMYT1(PD0166285),but not inhibitor of ATR,CHK1 or CHK2,abrogates the BTZ-induced G2-phase arrest,thus exacerbates the BTZ-induced mitotic arrest and *** BTZ and PD0166285 treatment(named BP-Combo)selectively kills various types of solid tumor cells,and significantly lessens the IC50 of both BTZ and PD0166285 compared to BTZ or PD0166285 *** using various mouse models show that BP-Combo has much stronger inhibition on tumor growth and metastasis than BTZ or PD0166285 monotreatment,and no obvious toxicity is observed in BP-Combo-treated *** findings disclose the effect of proteasome inhibitors in inducing pyroptosis in M-phase,characterize pyroptosis as a new death form of mitotic catastrophe,and identify dual inhibition of proteasome and wEE family kinases as a promising anti-cancer strategy to selectively kill solid tumor cells.

关键词： proteasome inhibiting catastrophe

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