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Targeting autophagy overcomes cancer-intrinsic resistance to CAR-T immunotherapy in B-cell malignancies

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Cancer Communications 2024年第3期44卷 408-432页

作者： Lu Tang huan Zhang Fen Zhou Qiuzhe Wei Mengyi Du Jianghua Wu Chenggong Li Wenjing Luo Jie Zhou Xindi Wang Zhaozhao Chen Yinqiang Zhang Zhongpei huang Zhuolin Wu yuxi Wen huiwen Jiang Danying Liao Haiming Kou Wei Xiong Heng Mei yu hu Institute of Hematology Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiP.R.China hubei Clinical Medical Center of Cell Therapy For Neoplastic Disease WuhanHubeiP.R.China Key Laboratory of Biological Targeted Therapy the Ministry of EducationWuhanHubeiP.R.China Department of Thoracic Surgery Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiP.R.China Department of Pediatrics Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiP.R.China hubei Key Laboratory of Biological Targeted Therapy Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubeiP.R.China

Background:Chimeric antigen receptor T(CAR-T)therapy has substantially revolutionized the clinical outcomes of patients with hematologic malignan-cies,but the cancer-intrinsic mechanisms underlying resistance to CAR-T cells remain yet to be fully understood.This study aims to explore the molecular deter-minants of cancer cell sensitivity to CAR-T cell-mediated killing and to provide a better understanding of the underlying mechanisms and potential modulation to improve clinical efficacy.Methods:The human whole-genome CRISPR/Cas9-based knockout screening was conducted to identify key genes that enable cancer cells to evade CD19 CAR-T-cell-mediated killing.The in vitro cytotoxicity assays and evaluation of tumor tissue and bone marrow specimens were further conducted to confirm the role of the key genes in cancer cell susceptibility to CAR-T cells.In addition,the specific mechanisms influencing CAR-T cell-mediated cancer clearance were elucidated in mouse and cellular models.Results:The CRISPR/Cas9-based knockout screening showed that the enrich-ment of autophagy-related genes(ATG3,BECN1,and RB1CC1)provided protec-tion of cancer cells from CD19 CAR-T cell-mediated cytotoxicity.These findings were further validated by in vitro cytotoxicity assays in cells with genetic and pharmacological inhibition of autophagy.Notably,higher expression of the three autophagy-related proteins in tumor samples was correlated with poorer respon-siveness and worse survival in patients with relapsed/refractory B-cell lymphoma after CD19 CAR-T therapy.Bulk RNA sequencing analysis of bone marrow samples from B-cell leukemia patients also suggested the clinical relevance of autophagy to the therapeutic response and relapse after CD19 CAR-T cell ther-apy.Pharmacological inhibition of autophagy and knockout of RB1CC1 could dramatically sensitize tumor cells to CD19 CAR-T cell-mediated killing in mouse models of both B-cell leukemia and lymphoma.Moreover,our study revealed that cancer-intrinsic autophagy mediates evasion of CAR-T cells via th

关键词： CAR-T resistance Autophagy Immune evasion Apoptosis Chemotaxis

Evolution and conservation genetics of pangolins

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Integrative Zoology 2024年第3期19卷 426-441页

作者： Tongtong GU Jingyang hu Li yu State Key Laboratory for Conservation and Utilization of Bio-Resource in yunnan School of Life SciencesYunnan UniversityKunmingChina

Pangolins(Pholidota,Manidae)are classified as an evolutionarily distinct and globally endangered mammal due to their unique morphology(nail-like scales and a myrmecophagous diet)and being the victim of heavy poaching and worldwide trafficking.As such,pangolins serve as a textbook example for studying the special phenotypic evolutionary adaptations and conservation genetics of an endangered species.Recent years have demonstrated significant advancements in the fields of molecular genetics and genomics,which have translated to a series of important research achievements and breakthroughs concerning the evolution and conservation genetics of pangolins.This review comprehensively presents the hitherto advances in phylogeny,adaptive evolution,conservation genetics,and conservation genomics that are related to pangolins,which will provide an ample understanding of their diversity,molecular adaptation mechanisms,and evolutionary potentials.In addition,we highlight the priority of investigating species/population diversity among pangolins and suggest several avenues of research that are highly relevant for future pangolin conservation.

关键词： adaptive evolution conservation genetics conservation genomics pangolins phylogeny

Numerical simulation study on the hygrothermal performance of building exterior walls under dynamic wind-driven rain condition

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Building Simulation 2024年第2期17卷 207-221页

作者： Xing hu huibo Zhang hui yu School of Design Shanghai Jiao Tong UniversityShanghai200240China

Wind-driven rain(WDR)has a significant influence on the hygrothermal performance,durability,and energy consumption of building components.The calculation of WDR loads using semi-empirical models has been incorporated into the boundary conditions of coupled heat and moisture transfer models.However,prior research often relied on fixed WDR absorption ratio,which fail to accurately capture the water absorption characteristics of porous building materials under rainfall scenarios.Therefore,this study aims to investigate the coupled heat and moisture transfer of exterior walls under dynamic WDR boundary conditions,utilizing an empirically obtained WDR absorption ratio model based on field measurements.The developed coupled heat and moisture transfer model is validated against the HAMSTAD project.The findings reveal that the total WDR flux calculated with the dynamic WDR boundary is lower than that obtained with the fixed WDR boundary,with greater disparities observed in orientations experiencing higher WDR loads.The variations in moisture flow significantly impact the surface temperature and relative humidity of the walls,influencing the calculation of cooling and heating loads by different models.Compared to the transient heat transfer model,the coupled heat and moisture transfer model incorporating dynamic WDR boundary exhibits maximum increases of 17.6%and 16.2%in cooling and heating loads,respectively.The dynamic WDR boundary conditions provide more precise numerical values for surface moisture flux,offering valuable insights for the thermal design of building enclosures and load calculations for HVAC systems.

关键词： wind-driven rain building component hygrothermal model transient simulation cooling and heating loads

Trial application of the envelope method to the potential ambiguity problem

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Nuclear Science and Techniques 2024年第1期35卷 73-80页

作者： Li-yuan hu yu-Shou Song Fundamental Science on Nuclear Safety and Simulation Technology Laboratory Harbin Engineering UniversityHarbin 150001China College of Nuclear Science and Technology Harbin Engineering UniversityHarbin 150001China Key Laboratory of Nuclear Safety and Advanced Nuclear Energy Technology Ministry of Industry and Information TechnologyHarbin 150001China

The optical potential ambiguity is a long-standing problem in the analysis of elastic scattering data.For a specific collid-ing system,ambiguous potential families can lead to different behaviors in the nearside and farside scattering components.By contrast,the envelope method can decompose the experimental data into two components with negative and positive deflection angles,respectively.Hence,a question arises as to whether the comparison between the calculated nearside(or farside)component and the derived positive-deflection-angle(or negative-deflection-angle)component can help analyze the potential ambiguity problem.In this study,we conducted a trial application of the envelope method to the potential ambiguity problem.The envelope method was improved by including uncertainties in the experimental data.The colliding systems of 16O+28Si at 215.2 MeV and 12C+12C at 1016 MeV were considered in the analyses.For each colliding system,the angular distribution experimental data were described nearly equally well by two potential sets,one of which is“surface transpar-ent”and the other is refractive.The calculated angular distributions were decomposed into nearside and farside scattering components.Using the improved envelope method,the experimental data were decomposed into the positive-deflection-angle and negative-deflection-angle components,which were then compared with the calculated nearside and farside components.The capability of the envelope method to analyze the potential ambiguities was also discussed.

关键词： Elastic scattering Optical potential ambiguities Envelope method Nearside/farside decomposition

Efficient degradation of aqueous dichloromethane by an enhanced microbial electrolysis cell:Degradation kinetics,microbial community and metabolic mechanisms

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Journal of Environmental Sciences 2024年第5期139卷 150-159页

作者： Meng Wu Di Zhao Bing Gu ZiruWang Jun hu Zhiliang yu Jianming yu College of Environment College of Biotechnology and BioengineeringCollaborative Innovation Center of Yangtze River Delta Region Green PharmaceuticalsZhejiang University of TechnologyHangzhou 310014China Shentuo Environment(Hangzhou)Co.Ltd. Hangzhou 311121China Zhejiang Tianyi Environmental Co.Ltd. Hangzhou 310000China

Dichloromethane(DCM)has been listed as a toxic and harmful water pollutant,and its re moval needs attention.Microbial electrolysis cells(MECs)are viewed as a promising alterna tive for pollutant removal,which can be strengthened from two aspects:microbial inocula tion and acclimation.In this study,the MEC for DCM degradation was inoculated with the ac tive sludge enhanced by Methylobacterium rhodesianum H13(strain H13)and then acclimated in the form of a microbial fuel cell(MFC).Both the introduction of strain H13 and the initi ation in MFC form significantly promoted DCM degradation.The degradation kinetics were fitted by the Haldane model,with V_(max),K_(h),K_(i)and v_(max)values of 103.2 mg/L/hr,97.8 mg/L268.3 mg/L and 44.7 mg/L/hr/cm^(2),respectively.The cyclic voltammogram implies that DCM redox reactions became easier with the setup of MEC,and the electrochemical impedance spectrogram shows that the acclimated and enriched microbes reduced the charge transfe resistance from the electrode to the electrolyte.In the biofilm,the dominant genera shifted from Geobacter to Hyphomicrobium in acclimation stages.Moreover,Methylobacterium played an increasingly important role.DCM metabolism mainly occurred through the hydrolytic glutathione S-transferase pathway,given that the gene dcmA was identified rather than the dhlA and P450/MO.The exogenous electrons facilitated the reduction of GSSG,directly o indirectly accelerating the GSH-catalyzed dehalogenation.This study provides support fo the construction of an efficient and stable MEC for DCM removal in water environment.

关键词： Dichloromethane Microbial electrolysis cells Metabolic pathways Electron transfer Degradation kinetics

Prenatal amoxicillin exposure induces developmental toxicity in fetal mice and its characteristics

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Journal of Environmental Sciences 2024年第3期137卷 287-301页

作者： Yongguo Dai yu Peng Wen hu Yi Liu hui Wang Department of Pharmacology Wuhan University School of Basic Medical SciencesWuhan 430071China Department of Pharmacy Zhongnan Hospital of Wuhan UniversityWuhan 430071China hubei Provincial Key Laboratory of Developmentally Originated Disease Wuhan 430071China

Amoxicillin,a widely used antibiotic in human and veterinary pharmaceuticals,is now considered as an“emerging contaminant”because it exists widespreadly in the environment and brings a series of adverse outcomes.Currently,systematic studies about the developmental toxicity of amoxicillin are still lacking.We explored the potential effects of amoxicillin exposure on pregnancy outcomes,maternal/fetal serum phenotypes,and fetal multiple organ development in mice,at different doses(75,150,300 mg/(kg·day))during late-pregnancy,or at a dose of 300 mg/(kg·day)during different stages(mid-/latepregnancy)and courses(single-/multi-course).Results showed that prenatal amoxicillin exposure(PAmE)had no significant infuence on the body weights of dams,but it could inhibit the physical development and reduce the survival rate of fetuses,especially during the midpregnancy.Meanwhile,PAmE altered multiple maternal/fetal serum phenotypes,especially in fetuses.Fetal multi-organ function results showed that PAmE inhibited testicular/adrenal steroid synthesis,long bone/cartilage and hippocampal development,and enhanced ovarian steroid synthesis and hepatic glycogenesis/lipogenesis,and the order of severity might be gonad(testis,ovary)>liver>others.Further analysis found that PAmE-induced multiorgan developmental and functional alterations had differences in stages,courses and fetal gender,and the most obvious changes might be in high-dose,late-pregnancy and multicourse,but there was no typical rule of a dose-response relationship.In conclusion,this study confirmed that PAmE could cause abnormal development and multi-organ function alterations,which deepens our understanding of the risk of PAmE and provides an experimental basis for further exploration of the long-term harm.

关键词： Amoxicillin Prenatal exposure Fetal development Organ function Developmental toxicity

An Enhanced Multiview Transformer for Population Density Estimation Using Cellular Mobility Data in Smart City

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Computers, Materials & Continua 2024年第4期79卷 161-182页

作者： yu Zhou Bosong Lin Siqi hu Dandan yu College of Computer Science and Software Engineering Shenzhen UniversityShenzhen518060China College of Management Shenzhen UniversityShenzhen518060China Information Center The First Affiliated Hospital of Dalian Medical UniversityDalian116011China

This paper addresses the problem of predicting population density leveraging cellular station data.As wireless communication devices are commonly used,cellular station data has become integral for estimating population figures and studying their movement,thereby implying significant contributions to urban planning.However,existing research grapples with issues pertinent to preprocessing base station data and the modeling of population prediction.To address this,we propose methodologies for preprocessing cellular station data to eliminate any irregular or redundant data.The preprocessing reveals a distinct cyclical characteristic and high-frequency variation in population shift.Further,we devise a multi-view enhancement model grounded on the Transformer(MVformer),targeting the improvement of the accuracy of extended time-series population predictions.Comparative experiments,conducted on the above-mentioned population dataset using four alternate Transformer-based models,indicate that our proposedMVformer model enhances prediction accuracy by approximately 30%for both univariate and multivariate time-series prediction assignments.The performance of this model in tasks pertaining to population prediction exhibits commendable results.

关键词： Population density estimation smart city transformer multiview learning

GraphFlow+:Exploiting Conversation Flow in Conversational Machine Comprehension with Graph Neural Networks

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Machine Intelligence Research 2024年第2期21卷 272-282页

作者： Jing hu Lingfei Wu yu Chen Po hu Mohammed J.Zaki School of Computer Science Central China Normal UniversityWuhan 430079China Pinterest San Francisco 94016USA Meta Mountain View 94039USA Rensselaer Polytechnic Institute Troy 12180USA

The conversation machine comprehension(MC)task aims to answer questions in the multi-turn conversation for a single passage.However,recent approaches don’t exploit information from historical conversations effectively,which results in some references and ellipsis in the current question cannot be recognized.In addition,these methods do not consider the rich semantic relationships between words when reasoning about the passage text.In this paper,we propose a novel model GraphFlow+,which constructs a context graph for each conversation turn and uses a unique recurrent graph neural network(GNN)to model the temporal dependencies between the context graphs of each turn.Specifically,we exploit three different ways to construct text graphs,including the dynamic graph,static graph,and hybrid graph that combines the two.Our experiments on CoQA,QuAC and DoQA show that the GraphFlow+model can outperform the state-of-the-art approaches.

关键词： Conversational machine comprehension(MC) reading comprehension question answering graph neural networks(GNNs) natural language processing(NLP)

Impact of Polymer Matrix on Polymer Mechanochromism from Excited State Intramolecular Proton Transfer

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Chinese Journal of Chemistry 2024年第6期42卷 611-616页

作者： yu Wu Xin Cheng huan hu Shui hu Zhimin Ma Zhiyong Ma Beijing Advanced Innovation Center for Soft Matter Science and Engineering Beijing State Key Laboratory of Organic-Inorganic CompositesCollege of Chemical EngineeringBeijing University of Chemical TechnologyBeijing100029 China Center of Advanced Elastomer Materials College of Materials Science and EngineeringBeijing University of Chemical TechnologyBeijing100029 China College of Engineering Peking UniversityBeijing100871 China

Mechanochromic polymers based on non-covalent changes have attracted much attention recently.Herein,we report the impact of inter/intramolecular hydrogen bonds on polymer mechanochromism from the excited state intramolecular proton transfer (ESIPT) process.PhMz-NH2-OH and PhMz=2A are designed and obtained by simple and high-yield synthesis,and are connected into polyurethane and poly(methyl acrylate-co-2-ethylhexyl acrylate),respectively.In the initial state,the PhMz-NH2-OH@PU sample shows blue fluorescence from the excited enol form (E*) excitons,owing to intermolecular hydrogen bonds that interrupt the ESIPT reactions but the PhMz=2A@PMA-2-EA sample expresses cyan fluorescence belonging to the excited keto form (K*) emission,implying that the intramolecular hydrogen bonds matter.Furthermore,under stretching,external force can tune the emission of the PhMz=2A@PMA-2-EA sample from K* to E* state.Though external force can putatively still promote a bond rotation,ESIPT reactions remain equivalently interrupted in both the relaxed and stressed states in a hydrogen-bond donating environment.DFT calculation confirms the force-induced increase in dihedral angle for the transition of ESIPT-on/off.Thus,PhMz-NH2-OH@PU and PhMz=2A@PMA-2-EA showed disparate initial ESIPT states and further different responses/sensitivity to force.This study reports a novel and efficient strategy for enriching mechanochromic investigation and extending the applications of ESIPT reactions.

关键词： Polymer mechanochromism Excited state intramolecular proton transfer Hydrogen bonding Supramolecular chemistry Elastomers