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Novel Pt(IV) complex OAP2 induces STING activation and pyroptosis via mitochondrial membrane remodeling for synergistic chemo-immunotherapy

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Acta Pharmaceutica Sinica B 2024年第4期14卷 1742-1758页

作者： Renming Fan Ruizhuo Lin Shuo Zhang Aohua Deng Yongrui Hai Junyan Zhuang Yang Liu Maosheng Cheng Gaofei Wei Institute of Medical research Northwestern Polytechnical UniversityXi'an 710072China research&development Institute of Northwestern Polytechnical University in Shenzhen Shenzhen 518057China Key Laboratory of Structure-Based drug design and Discovery Ministry of EducationSchool of Pharmaceutical EngineeringShenyang Pharmaceutical UniversityShenyang 110016China

Mitochondrial membrane remodeling can trigger the release of mitochondrial DNA (mtDNA), leading to the activation of cellular oxidative stress and immune responses. While the role of mitochondrial membrane remodeling in promoting inflammation in hepatocytes is well-established, its effects on tumors have remained unclear. In this study, we designed a novel Pt(IV) complex, OAP2, which is composed of oxaliplatin (Oxa) and acetaminophen (APAP), to enhance its anti-tumor effects and amplify the immune response. Our findings demonstrate that OAP2 induces nuclear DNA damage, resulting in the production of nuclear DNA. Additionally, OAP2 downregulates the expression of mitochondrial Sam50, to promote mitochondrial membrane remodeling and trigger mtDNA secretion, leading to double-stranded DNA accumulation and ultimately synergistically activating the intracellular cGAS-STING pathway. The mitochondrial membrane remodeling induced by OAP2 overcomes the limitations of Oxa in activating the STING pathway and simultaneously promotes gasdermin-D-mediated cell pyroptosis. OAP2 also promotes dendritic cell maturation and enhances the quantity and efficacy of cytotoxic T cells, thereby inhibiting cancer cell proliferation and metastasis. Briefly, our study introduces the first novel small-molecule inhibitor that regulates mitochondrial membrane remodeling for active immunotherapy in anti-tumor research, which may provide a creative idea for targeting organelle in anti-tumor therapy.

关键词： Anti-tumor drug Prodrug Platinum Chemo-immunotherapy Mitochondrial membrane modeling STING Pyroptosis mtDNA

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Rapid discovery of two unprecedented meroterpenoids from Daphne altaica *** molecular networking integrated with MolNetEnhancer and Network Annotation Propagation

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Chinese Chemical Letters 2024年第8期35卷 294-298页

作者： Wei-Yu Zhou Zi-Han Xi Ning-Ning Du Li Ye Ming-Hao Jiang Jin-Le Hao Bin Lin Guo-Dong Yao Xiao-Xiao Huang Shao-Jiang Song Key Laboratory of Computational Chemistry-Based Natural Antitumor drug research&development Liaoning ProvinceEngineering Research Center of Natural Medicine Active Molecule Research&DevelopmentLiaoning ProvinceKey Laboratory of Natural Bioactive Compounds Discovery&ModificationShenyangSchool of Traditional Chinese Materia Medic1Shenyang Pharmaceutical UniversityShenyang 110016China Key Laboratory of Structure-Based drug design and Discovery of Ministry of Education Shenyang Pharmaceutical UniversityShenyang 110016China Wuya College of Innovation Shenyang Pharmaceutical UniversityShenyang 110016China

Under the guidance of the approach which integrates molecular networking,MolNetEnhancer and Net-work Annotation Propagation(NAP),daphnaltaicanoids A and B(1 and 2)with unprecedented 9-oxa-tetracyclo[6.***.1.0^(2,6).0^(8,13)]pentadecane and tetracyclo[5.***.0.1^(2,5).2^(4,11)]tridecane central frameworks were iso-lated from Daphne altaica Pall.,representing two types of unparalleled meroterpenoid *** struc-tures were elucidated by extensive spectroscopic analysis,nuclear magnetic resonance(NMR)calcula-tions,DP4+analysis and electronic circular dichroism(ECD)*** plausible biosynthetic path-ways for 1 and 2 were ***,2 exerted potent neuroprotective activities which were su-perior to trolox at 12.5 and 25μmol/***,1 and 2 exhibited more noticeable acetylcholinesterase inhibitory activities than *** docking simulations were performed to explore the inter-molecular interaction of compounds 1 and 2 with *** bioactivity evaluation results highlight the prospects of 1 and 2 as a novel category of neurological agents.

关键词： Daphne altaica Pall. Molecular networking MolNetEnhancer NAP Unprecedented meroterpenoid frameworks Neuroprotective activities Acetylcholinesterase inhibitors

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A novel copper metabolism-related signature model for predicting the prognosis,target drugs,and immunotherapy in stomach adenocarcinoma

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Genes & Diseases 2024年第5期11卷 21-24页

作者： Kai Zhuang Siqi Tang Haixin Feng Jinying Zhang Ying Liu Yong Liu Yongjian Su Jiaqi Yu Zunnan Huang Key Laboratory of Computer-Aided drug design of Dongguan City The First Dongguan Affiliated HospitalGuangdong Medical UniversityDongguanGuangdong 523710China Key Laboratory of Big Data Mining and Precision drug design of Guangdong Medical University Key Laboratory for Research and Development of Natural Drugs of Guangdong ProvinceSchool of PharmacyGuangdong Medical UniversityDongguanGuangdong 523808China School of Public Health Guangdong Medical UniversityDongguanGuangdong 523808China Marine Biomedical research Institute of Guangdong Zhanjiang ZhanjiangGuangdong 524203China

Stomach adenocarcinoma(STAD)is one of the most common gastric neoplasms with a high death ***,there is an urgent need to propose an efficient therapy for *** plays key roles in regulating the distribution of immune cells and affecting the tumor immune escape,and may be a novel indicator of immunotherapy in ***,the specific impact of copper metabolism-related genes(CMRGs)on the patient’s prognosis,tumor microenvironment,and immunotherapeutic response remains unelucidated.

关键词： metabolism stomach adenocarcinoma

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Sludge composition and characteristics shaped microbial community and further determined process performance: A study on full-scale thermal hydrolysis-anaerobic digestion processes

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Journal of Environmental Sciences 2024年第3期137卷 96-107页

作者： Wei Liu Chenxiang Sun Wei Li Tianle Li Zhan Chen Jiawei Wang Zhengran Ren Xianghua Wen School of Environment Tsinghua UniversityBeijing 100084China Jinneng Holding group DatongShanxi 037000China research and development Center Beijing Drainage Group Co.Ltd.Beijing 100124China Beijing Dabeinong Science and Technology group Co. Ltd.Beijing 100080China

Anaerobic digestion (AD) with thermal hydrolysis (TH) pretreatment is a promising process for excess sludge treatment,while there lacks of the knowledge from full-scale process about the impact of sludge composition and characteristics on microbial community and *** sludge physiochemical indices,microbial community and performance data of four full-scale TH-AD plants were characterized,and their relationships was *** four plants were operated under almost similar total organic loading rate (OLR)but their methanogenesis performance differentiate into two groups,namely superior group(SupG) and the inferior group (Inf G).In both groups,TH effectively solubilized particulate organic compounds,meanwhile raised the ammonia nitrogen (NH_(4)^(+)-N) and volatile fatty acid (VFA) *** with the Sup G,thermal hydrolyzed sludge of Inf G had higher level of VFAs,NH_(4)^(+)-N and total chemical oxygen demand (t COD),which showed higher inhibition effect on microbes,leading to a community with lower diversity,lower abundance of carbohydrate degrading functional guild,higher protein degrading one,and methanogens that adapted to limited substrates,and further declined the methane production ***,it was recommended that OLR alone was not sufficient for controlling the system in design and operation,the concentration of VFAs,NH_(4)^(+)-N and t COD should be equally *** higher concentration,together with the higher abundance of Defluviitoga and Proteiniphilum were recommended as indicators for inferior running *** results proposed that microbial communities played a role of bridge between environmental factors and performance,provided implications for engineering ecology and operational regulation for full-scale sludge TH-AD process.

关键词： Thermal hydrolysis Anaerobic digestion Microbial community Full-scale

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Comparative Analysis of Reaction to Fire and Flammability of Hemp Shives Insulation Boards with Incorporated Microencapsulated Phase Change Materials

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Journal of Renewable Materials 2024年第3期12卷 603-613页

作者： Inga Zotova Edgars Kirilovs Laura Ziemele Institute of Architecture and design Riga Technical UniversityRigaLV-1048Latvia Forest and Wood Products research and development Institute JelgavaLV-3001Latvia

Nowadays buildings contain innovative materials,materials from local resources,production surpluses and rapidly renewable natural *** Change Materials(PCM)are one such group of novel materials which reduce building energy *** the wider availability of microencapsulated PCM,there is an opportunity to develop a new type of insulating materials,combinate PCM with traditional insulation materials for latent heat energy *** materials are typically flammable and are located on the interior wall finishing yet there has been no detailed assessment of their fire *** this research work prototypes of low-density insulating boards for indoor spaces from hemp shives using carbamide resin binder and cold pressing were ***-scale cone calorimeter tests were conducted to evaluate fire risk,with a focus on assessing material flammability properties and the influence of PCM on the *** this research,the amount of smoke,heat release rate,effective heat of combustion,specific extinction coefficient,mass loss,carbon dioxide yield,specific loss factor,ignition time of hemp straws samples and samples of hemp straws with 10%and without PCM admixture were *** is a risk of flammability for PCM and their fire reaction has not been evaluated when incorporating PCM into interior wall finishing *** obtained results can be used by designers to balance the potential energy savings of using PCM with a more complete understanding and predictability of the associated fire risk when using the proposed *** also allows for appropriate risk mitigation strategies.

关键词： Encapsuled phase change material renewable resources reaction to fire flammability

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Command filtered integrated estimation guidance and control for strapdown missiles with circular field of view

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Defence Technology（防务技术） 2024年第5期35卷 211-221页

作者： Wei Wang Jiaqi Liu Shiyao Lin Baokui Geng Zhongjiao Shi School of Aerospace Engineering Beijing Institute of TechnologyBeijing 10081China China research and development Academy of Machinery Equipment Beijing 100089China Northwest Industries group CO. Ltd.Xi'an 710043China

In this paper,an integrated estimation guidance and control(IEGC)system is designed based on the command filtered backstepping approach for circular field-of-view(FOV)strapdown *** threedimensional integrated estimation guidance and control nonlinear model with limited actuator deflection angle is established considering the seeker's FOV *** boundary time-varying integral barrier Lyapunov function(IBLF)is employed in backstepping design to constrain the body line-of-sight(BLOS)in IEGC system to fit a circular ***,the nonlinear adaptive controller is designed to estimate the changing aerodynamic *** generalized extended state observer(GESO)is designed to estimate the acceleration of the maneuvering targets and the unmatched time-varying disturbances for improving tracking ***,the command filters are used to solve the"differential expansion"problem during the backstepping *** Lyapunov theory is used to prove the stability of the overall closed-loop IEGC ***,the simulation results validate the integrated system's effectiveness,achieving high accuracy strikes against maneuvering targets.

关键词： Integrated estimation guidance and control Circular field-of-view Time-varying integral barrier Lyapunov function Command filtered backstepping control Nonlinear adaptive control Extended state observer

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Availability analysis of private cloud safety computer platform based on the Markov process

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Transportation Safety and Environment 2024年第1期6卷 103-108页

作者： Limin Fu Jiakun Wen Southwest Jiaotong University The School of Information Science&TechnologyChengduSichuan 610097China CRSC research&design Institute group Co. LtdBeijing 100070China

To ensure the correctness of train control system design and development,the ways of simulation,test and formalization were *** to the safe critical attribute of train control system,the characters related to system safety were propounded such as real time,hybrid,distribution(concurrence)and reactivity,and the specific formal methods associated with every character were introduced in *** analysis and classification of the methods were done based on their mathematical basis and applications,and their advantages and disadvantages were *** result indicates that every method has determinate limitations,which is determined by the essences of model checking and theory *** is pointed out that the presentation of new method,the expansion of existing methods and the integration of many methods will be the development trend of formalization in train control system.

关键词： safety computer Markov process cloud computing availability analysis

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Multi-omics Approach Reveals Influenza-A Virus Target Genes Associated Genomic,Clinical and Immunological Characteristics in Cancers

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Biomedical and Environmental Sciences 2024年第7期37卷 698-715页

作者： Jiaojiao Wang Yong Liao Pinglian Yang Weile Ye Yong Liu Chunxia Xiao Weixiong Liao Chunbo Chen Zhiping Liu Zunnan Huang Center of Scientific research Department of CardiologyMaoming People’s HospitalMaoming 525000GuangdongChina Department of Pharmacy Maoming People’s HospitalMaoming 525000GuangdongChina State Key Laboratory of Bioactive Molecules and druggability Assessment Jinan UniversityGuangzhou 510632GuangdongChina Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New drugs research College of PharmacyJinan UniversityGuangzhou 510632GuangdongChina Key Laboratory of Big Data Mining and Precision drug design of Guangdong Medical University Key Laboratory of Computer-Aided Drug Design of Dongguan CityKey Laboratory for Research and Development of Natural Drugs of Guangdong ProvinceSchool of PharmacyGuangdong Medical UniversityDongguan 523808GuangdongChina Department of Critical Care Medicine Maoming People’s HospitalMaoming 525000GuangdongChina

Objective To examine the precise function of influenza A virus target genes(IATGs)in *** Using multi-omics data from the TCGA and TCPA datasets,33 tumor types were evaluated for *** expression in cancer cells was analyzed using transcriptome *** number variation(CNV)was assessed using GISTICS ***’s analysis was used to correlate mRNA expression with methylation *** was used for the enrichment ***’s correlation analysis was used to examine the association between IATG mRNA expression and *** ImmuCellAI algorithm was used to calculate the infiltration scores of 24 immune cell *** In 13 solid tumors,IATG mRNA levels were atypically *** for UCS,UVM,KICH,PCPG,THCA,CHOL,LAMI,and MESO,most cancers contained somatic IATG *** main types of CNVs in IATGs are heterozygous amplifications and *** most tumors,IATG mRNA expression is adversely associated with ***-PCR demonstrated that EGFR,ANXA5,CACNA1C,CD209,UVRAG were upregulated and CLEC4M was downregulated in KIRC cell lines,consistent with the TCGA and GTEx *** Genomic changes and clinical characteristics of IATGs were identified,which may offer fresh perspectives linking the influenza A virus to cancer.

关键词： Genomic changes Immune microenvironment Prognosis drug resistance Experimental validation

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Adaptive battery thermal management systems in unsteady thermal application contexts

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Journal of Energy Chemistry 2024年第10期97卷 650-668页

作者： Kailong Liu Qiao Peng Zhuoran Liu Wei Li Naxin Cui Chenghui Zhang School of Control Science and Engineering Shandong University Information Technology Analytics & Operations Group Queen's University Belfast College of design and Engineering National University of Singapore

With the increasing attention paid to battery technology,the microscopic reaction mechanism and macroscopic heat transfer process of lithium-ion batteries have been further studied and understood from both academic and industrial ***,as one of the key parameters in the physical fra mework of batteries,affects the performa nce of the multi-physical fields within the battery,a nd its effective control is *** the heat generation in the battery is determined by the real-time operating conditions,the battery temperature is essentially controlled by the real-time heat dissipation conditions provided by the battery thermal management *** battery thermal management systems have basic temperature control capabilities for most conventional application ***,with the current development of la rge-scale,integrated,and intelligent battery technology,the adva ncement of battery thermal management technology will pay more attention to the effective control of battery temperature under sophisticated situations,such as high power and widely varied operating *** this context,this paper presents the latest advances and representative research related to battery thermal management ***,starting from battery thermal profile,the mechanism of battery heat generation is discussed in ***,the static characteristics of the traditional battery thermal management system are ***,considering the dynamic requirements of battery heat dissipation under complex operating conditions,the concept of adaptive battery thermal management system is proposed based on specific research ***,the main challenges for battery thermal management system in practice are identified,and potential future developments to overcome these challenges are presented and discussed.

关键词： Battery safety Battery thermal management system Cooling methods Heat generation mechanism Lithium-ion batteries

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Seismic effectiveness evaluation and optimized design of tie up method for securing museum collections

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Earthquake Engineering and Engineering Vibration 2024年第3期23卷 741-763页

作者： Wang Meng Yan Yi Yang Weiguo Liu Pei Ge Jiaqi Ma Botao School of Civil Engineering Beijing Jiaotong UniversityBeijing 100044China Beijing’s Key Laboratory of Structural Wind Engineering and Urban Wind Environment Beijing 100044China Beijing General Municipal Engineering design&research Institute Co. LtdBeijing 100082China China Aviation Planning and design Institute(group)Co.Ltd. Beijing 100120China

To quantify the seismic effectiveness of the most commonly used fishing line tie up method for securing museum collections and optimize fixed strategies for exhibitions,shaking table tests of the seismic systems used for typical museum collection replicas have been carried *** influence of body shape and fixed measure parameters on the seismic responses of replicas and the interaction behavior between replicas and fixed measures have been *** on the results,seismic effectiveness evaluation indexes of the tie up method are *** suggestions for fixed strategies are given,which provide a basis for the exhibition of delicate museum collections considering the principle of minimizing seismic responses and *** analysis results show that a larger ratio of height of mass center to bottom diameter led to more intense rocking *** the initial pretension of fishing lines was conducive to reducing the seismic responses and stress variation of the *** comprehensive consideration of the interaction forces and effective securement,it is recommended to apply 20%of breaking stress as the initial *** specific museum collections that cannot be effectively protected by the independent tie up method,an optimized strategy of a combination of fishing lines and fasteners is recommended.

关键词： tie up method museum collections shaking table test seismic effectiveness optimized design

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