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DNA-delivered monoclonal antibodies targeting the p53 R175H mutant epitope inhibit tumor development in mice

Genes & Diseases 2024年第4期11卷 368-380页

作者： Dafei Chai Xu Wang Praveen Neeli Shan Zhou Xingfang Yu Kanaga Sabapathy Yong Li Department of Medicine Section of Epidemiology and Population SciencesDan L Duncan Comprehensive Cancer CenterBaylor College of MedicineHoustonTX 77030USA Division of Cellular&Molecular research Humphrey Oei Institute of Cancer ResearchNational Cancer Centre SingaporeSingapore 168583Singapore

tThe tumor suppressor p53 is the most common mutated gene in cancer,with the R175H as the most frequent p53 missense mutant.However,there are currently no approved targeted therapies or immunotherapies against mutant p53.Here,we characterized and inves-tigated a monoclonal antibody(mAb)that recognizes the mutant p53-R175H for its affinity,specificity,and activity against tumor cells in vitro.We then delivered DNA plasmids expres-sing the anti-R175H mAb or a bispecific antibody(BsAb)into mice to evaluate their therapeutic effects.Our results showed that the anti-R175H mAb specifically bound to the p53-R175H an-tigen with a high affinity and recognized the human mutant p53-R175H antigen expressed on HEK293T or MC38 cells,with no cross-reactivity with wild-type p53.In cultured cells,the anti-R175H mAb showed higher cytotoxicity than the control but did not induce antibody-dependent cellular cytotoxicity.We made a recombinant MC38 mouse cell line(MC38-p53-R175H)that overexpressed the human p53-R175H after knocking out the endogenous mutant p53 alleles.In vivo,administration of the anti-R175H mAb plasmid elicited a robust anti-tumor effect against MC38-p53-R175H in mice.The administration of the anti-R175H BsAb plasmid showed no therapeutic effects,yet potent anti-tumor activity was observed in combination with the anti-PD-1 antibody.These results indicate that targeting specific mutant epitopes using DNA-delivered mAbs or BsAbs presents a form of improved natural immunity derived from tumor-infiltrating B cells and plasma cells against intracellular tumor antigens.

关键词： BsAb Cytotoxicity mAb Mutant p53 PD-1 R175H

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Molybdenum and cadmium co-induce necroptosis through Th1/Th2 imbalance-mediated endoplasmic reticulum stress in duck ovaries

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Journal of Environmental Sciences 2024年第8期142卷 92-102页

作者： Ting Cui Xueyan Dai Huiling Guo Dianyun Wang Bingyan Huang Wenjing Pu Xuesheng Chu Caiying Zhang Jiangxi Provincial Key Laboratory for Animal Health Institute of Animal Population HealthCollege of Animal Science and TechnologyJiangxi Agricultural UniversityNanchang 330045China

Cadmium(Cd)and excess molybdenum(Mo)pose serious threats to animal health.Our previous study has determined that Cd and/or Mo exposure can cause ovarian damage of ducks,while the specific mechanism is still obscure.To further investigate the toxic mechanism of Cd and Mo co-exposure in the ovary,forty 8-day-old female ducks were randomly allocated into four groups for 16 weeks,and the doses of Cd and Mo in basic diet per kg were as follows:control group,Mo group(100 mg Mo),Cd group(4 mg Cd),and Mo+Cd group(100 mg Mo+4 mg Cd).Cadmium sulfate 8/3-hydrate(CdSO_(4)·8/3H_(2)O)and hexaammonium molybdate((NH_(4))_(6)Mo_(7)O_(24)·4H_(2)O)were the origins of Cd and Mo,respectively.At the 16th week of the experiment,all ovary tissues were collected for the detection of related indexes.The data indicated that Mo and/or Cd induced trace element disorders and Th1/Th2 balance to divert toward Th1 in the ovary,which activated endoplasmic reticulum(ER)stress and then provoked necroptosis through triggering RIPK1/RIPK3/MLKL signaling pathway,and eventually caused ovarian pathological injuries and necroptosis characteristics.The alterations of above indicators were most apparent in the joint group.Above all,this research illustrates that Mo and/or Cd exposure can initiate necroptosis through Th1/Th2 imbalance-modulated ER stress in duck ovaries,and Mo and Cd combined exposure aggravates ovarian injuries.This research explores the molecular mechanism of necroptosis caused by Mo and/or Cd,which reveals that ER stress attenuation may be a therapeutic target to alleviate necroptosis.

关键词： Molybdenum Cadmium Th1/Th2 imbalance Endoplasmic reticulum stress Necroptosis Ovary

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Statement on Establishment of Public Health Protection Guideline for Cold Spells—China

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China CDC weekly 2024年第5期6卷 92-94页

作者： Tiantian Li Qinghua Sun Chen Chen Qing Wang Jie Ban Runmei Ma Yi Zhang Lijun Pan Yuanyuan Liu Qiutong Li Leyao Chang Hanshuo Zhang Yirong Liu Miaoyou Niu Xiangxiang Wei Lin Wang China CDC Key Laboratory of Environment and population Health National Institute of Environmental HealthChinese Center for Disease Control and PreventionBeijingChina

Cold spells are extreme weather events characterized by the invasion of cold air from high latitudes into the middle and low latitudes,resulting in significant cooling.Cold spells have various adverse health effects,including epidermal damage,respiratory tract spasms,respiratory immune abnormalities,acute cardiopulmonary diseases,and exacerbation of urinary and endocrine disorders.In response to the frequent cold spells in recent years.

关键词： respiratory invasion acute

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Impact of apolipoprotein E isoforms on sporadic Alzheimer's disease:beyond the role of amyloid beta

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Neural Regeneration research 2024年第1期19卷 80-83页

作者： Madia Lozupone Francesco Panza Neurodegenerative Disease Unit Department of Basic MedicineNeuroscienceand Sense OrgansUniversity of Bari Aldo MoroBariItaly Unit of research Methodology and Data Sciences for population Health National Institute of Gastroenterology“Saverio de Bellis”Research HospitalCastellana GrotteBariItaly

The impact of apolipoprotein E(ApoE)isoforms on sporadic Alzheimer's disease has long been studied;however,the influences of apolipoprotein E gene(APOE)on healthy and pathological human brains are not fully understood.ApoE exists as three common isoforms(ApoE2,ApoE3,and ApoE4),which differ in two amino acid residues.Traditionally,ApoE binds cholesterol and phospholipids and ApoE isoforms display diffe rent affinities for their receptors,lipids transport and distribution in the brain and periphery.The role of ApoE in the human depends on ApoE isoforms,brain regions,aging,and neural injury.APOE E4 is the strongest genetic risk factor for sporadic Alzheimer's disease,considering its role in influencing amyloid-beta metabolism.The exact mechanisms by which APOE gene variants may increase or decrease Alzheimer's disease risk are not fully understood,but APOE was also known to affect directly and indirectly tau-mediated neurodegeneration,lipids metabolism,neurovascular unit,and microglial function.Consistent with the biological function of ApoE,ApoE4 isoform significantly alte red signaling pathways associated with cholesterol homeostasis,transport,and myelination.Also,the rare protective APOE variants confirm that ApoE plays an important role in Alzheimer's disease pathogenesis.The objectives of the present mini-review were to describe classical and new roles of various ApoE isoforms in Alzheimer's disease pathophysiology beyond the deposition of amyloid-beta and to establish a functional link between APOE,brain function,and memory,from a molecular to a clinical level.APOE genotype also exerted a heterogeneous effect on clinical Alzheimer's disease phenotype and its outcomes.Not only in learning and memory but also in neuro psychiatric symptoms that occur in a premorbid condition.Cla rifying the relationships between Alzheimer's disease-related pathology with neuropsychiatric symptoms,particularly suicidal ideation in Alzheimer's disease patients,may be useful for elucidating also the underlying pathophysiological pro

关键词： Alzheimer's disease amyloid-beta apolipoprotein E dementia glymphatic transport lipids neuropsychiatric symptoms neurovascular unit tau protein

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Uncovering the dominant contribution of intermediate volatility compounds in secondary organic aerosol formation from biomass-burning emissions

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National Science Review 2024年第3期11卷 150-158页

作者： Kun Li Jun Zhang David M.Bell Tiantian Wang Houssni Lamkaddam Tianqu Cui Lu Qi Mihnea Surdu Dongyu Wang Lin Du Imad El Haddad Jay G.Slowik Andre S.H.Prevot Environment research institute Shandong University Laboratory of Atmospheric Chemistry Paul Scherrer Institute

Organic vapors from biomass burning are a major source of secondary organic aerosols(SOAs). Previous smog chamber studies found that the SOA contributors in biomass-burning emissions are mainly volatile organic compounds(VOCs). While intermediate volatility organic compounds(IVOCs) are efficient SOA precursors and contribute a considerable fraction of biomass-burning emissions, their contribution to SOA formation has not been directly observed. Here, by deploying a newly-developed oxidation flow reactor to study SOA formation from wood burning, we find that IVOCs can contribute ～70% of the formed SOA, i.e.>2 times more than VOCs. This previously missing SOA fraction is interpreted to be due to the high wall losses of semi-volatile oxidation products of IVOCs in smog chambers. The finding in this study reveals that SOA production from biomass burning is much higher than previously thought, and highlights the urgent need for more research on the IVOCs from biomass burning and potentially other emission sources.

关键词： atmospheric chemistry biomass burning secondary organic aerosol intermediate volatility organic compounds

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Functional Optical Fiber Sensors Detecting Imperceptible Physical/Chemical Changes for Smart Batteries

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Nano-Micro Letters 2024年第8期16卷 268-308页

作者： Yiding Li Li Wang Youzhi Song Wenwei Wang Cheng Lin Xiangming He institute of Nuclear and New Energy Technology Tsinghua UniversityBeijing 100084People’s Republic of China National Engineering research Center of Electric Vehicles Beijing Institute of Technology(BIT)Beijing 100081People’s Republic of China Shenzhen Automotive research institute of BIT(Shenzhen research institute of National Engineering research Center of Electric Vehicles) Shenzhen 518118People’s Republic of China

The battery technology progress has been a contradictory process in which performance improvement and hidden risks coexist.Now the battery is still a“black box”,thus requiring a deep understanding of its internal state.The battery should“sense its internal physical/chemical conditions”,which puts strict requirements on embedded sensing parts.This paper summarizes the application of advanced optical fiber sensors in lithium-ion batteries and energy storage technologies that may be mass deployed,focuses on the insights of advanced optical fiber sensors into the processes of one-dimensional nano-micro-level battery material structural phase transition,electrolyte degradation,electrode-electrolyte interface dynamics to three-dimensional macro-safety evolution.The paper contributes to understanding how to use optical fiber sensors to achieve“real”and“embedded”monitoring.Through the inherent advantages of the advanced optical fiber sensor,it helps clarify the battery internal state and reaction mechanism,aiding in the establishment of more detailed models.These advancements can promote the development of smart batteries,with significant importance lying in essentially promoting the improvement of system consistency.Furthermore,with the help of smart batteries in the future,the importance of consistency can be weakened or even eliminated.The application of advanced optical fiber sensors helps comprehensively improve the battery quality,reliability,and life.

关键词： Smart battery Advanced embedded optical fiber sensor Battery internal physical/chemical state Quality-reliability-life characteristic

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Roles of neuronal lysosomes in the etiology of Parkinson’s disease

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Neural Regeneration research 2024年第9期19卷 1981-1983页

作者： Mattia Volta institute for Biomedicine Eurac ResearchBolzanoItaly

Therapeutic progress in neurodegenerative conditions such as Parkinson’s disease has been hampered by a lack of detailed knowledge of its molecular etiology.The advancements in genetics and genomics have provided fundamental insights into specific protein players and the cellular processes involved in the onset of disease.In this respect,the autophagy-lysosome system has emerged in recent years as a strong point of convergence for genetics,genomics,and pathologic indications,spanning both familial and idiopathic Parkinson’s disease.Most,if not all,genes linked to familial disease are involved,in a regulatory capacity,in lysosome function(e.g.,LRRK2,alpha-synuclein,VPS35,Parkin,and PINK1).Moreover,the majority of genomic loci associated with increased risk of idiopathic Parkinson’s cluster in lysosome biology and regulation(GBA as the prime example).Lastly,neuropathologic evidence showed alterations in lysosome markers in autoptic material that,coupled to the alpha-synuclein proteinopathy that defines the disease,strongly indicate an alteration in functionality.In this Brief Review article,I present a personal perspective on the molecular and cellular involvement of lysosome biology in Parkinson’s pathogenesis,aiming at a larger vision on the events underlying the onset of the disease.The attempts at targeting autophagy for therapeutic purposes in Parkinson’s have been mostly aimed at“indiscriminately”enhancing its activity to promote the degradation and elimination of aggregate protein accumulations,such as alpha-synuclein Lewy bodies.However,this approach is based on the assumption that protein pathology is the root cause of disease,while pre-pathology and pre-degeneration dysfunctions have been largely observed in clinical and pre-clinical settings.In addition,it has been reported that unspecific boosting of autophagy can be detrimental.Thus,it is important to understand the mechanisms of specific autophagy forms and,even more,the adjustment of specific lysosome functionalities.Indeed,lysosomes exert fine signa

关键词： alpha-synuclein autophagy LRRK2 lysosome neuroprotection neurotransmission Parkinson’s disease Rit2 synapse

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Comparative study between three carbonaceous nanoblades and nanodarts for antimicrobial applications

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Journal of Environmental Sciences 2024年第2期136卷 594-605页

作者： Mohamed S.Selim Ahmed M.Azzam Mohamed A.Shenashen Shimaa A.Higazy Bayaumy B.Mostafa Sherif A.El-Safty National institute for Materials Science(NIMS) 1-2-1 SengenTsukuba-ShiIbaraki-Ken 305-0047Japan Petroleum Application Department Egyptian Petroleum Research InstituteNasr City 11727Egypt Department of Environmental research Theodor Bilharz Research InstituteGizaEgypt

The design of nanostructured materials occupies a privileged position in the development and management of affordable and effective technology in the antibacterial sector.Here,we discuss the antimicrobial properties of three carbonaceous nanoblades and nanodarts materials of graphene oxide(GO),reduced graphene oxide(RGO),and single-wall carbon nanotubes(SWCNTs)that have a mechano-bactericidal effect,and the ability to piercing or slicing bacterial membranes.To demonstrate the significance of size,morphology and composition on the antibacterial activity mechanism,the designed nanomaterials have been characterized.The minimum inhibitory concentration(MIC),standard agar well diffusion,and transmission electron microscopy were utilized to evaluate the antibacterial activity of GO,RGO,and SWCNTs.Based on the evidence obtained,the three carbonaceous materials exhibit activity against all microbial strains tested by completely encapsulating bacterial cells and causing morphological disruption by degrading the microbial cell membrane in the order of RGO>GO>SWCNTs.Because of the external cell wall structure and outer membrane proteins,the synthesized carbonaceous nanomaterials exhibited higher antibacterial activity against Gram-positive bacterial strains than Gram-negative and fungal microorganisms.RGO had the lowest MIC values(0.062,0.125,and 0.25 mg/mL against B.subtilis,S.aureus,and E.coli,respectively),as well as minimum fungal concentrations(0.5 mg/mL for both A.fumigatus and C.albicans).At 12 hr,the cell viability values against tested microbial strains were completely suppressed.Cell lysis and death occurred as a result of severe membrane damage caused by microorganisms perched on RGO nanoblades.Our work gives an insight into the design of effective graphene-based antimicrobial materials for water treatment and remediation.

关键词： Antimicrobial properties Nanoblades Mechano-bactericidal effect RGO nanosheets Gram-positive bacteria Cell viability

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Virus-like nanoparticle vaccines for inducing long-lasting immunity against infectious diseases

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National Science Review 2024年第4期11卷 13-15页

作者： Yi-Nan Zhang Sarah Auclair Jiang Zhu Department of Integrative Structural and Computational Biology The Scripps Research Institute Department of Immunology and Microbiology The Scripps Research Institute

Prophylactic vaccines that can generate long-lasting protective immune responses are needed for many infectious diseases. Efficient vaccination requires vaccine antigens to be retained and presented to B cells in lymp...

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Optimal search path planning of UUV in battlefeld ambush scene

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Defence Technology（防务技术） 2024年第2期32卷 541-552页

作者： Wei Feng Yan Ma Heng Li Haixiao Liu Xiangyao Meng Mo Zhou Naval research institute Beijing100161China

Aiming at the practical application of Unmanned Underwater Vehicle(UUV)in underwater combat,this paper proposes a battlefield ambush scene with UUV considering ocean current.Firstly,by establishing these mathematical models of ocean current environment,target movement,and sonar detection,the probability calculation methods of single UUV searching target and multiple UUV cooperatively searching target are given respectively.Then,based on the Hybrid Quantum-behaved Particle Swarm Optimization(HQPSO)algorithm,the path with the highest target search probability is found.Finally,through simulation calculations,the influence of different UUV parameters and target parameters on the target search probability is analyzed,and the minimum number of UUVs that need to be deployed to complete the ambush task is demonstrated,and the optimal search path scheme is obtained.The method proposed in this paper provides a theoretical basis for the practical application of UUV in the future combat.

关键词： Battlefield ambush Optimal search path planning UUV path Planning Probability of cooperative search

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