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AZD1775 synergizes with SLC7A11 inhibition to promote ferroptosis

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Science China Life Sciences 2024年

作者： Chen Xiong Hong Ling Yingdan Huang Hanzhi Dong Bangxiang xie Qian Hao xiang Zhou Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences Fudan University Department of Oncology Shanghai Medical College Fudan University Department of Breast Surgery Fudan University Shanghai Cancer Center Fudan University Department of Oncology First Affiliated Hospital of Nanchang University Beijing Institute of Hepatology Beijing Youan Hospital Capital Medical University Beijing Engineering Research Center for Precision Medicine and Transformation of Hepatitis and Liver Cancer Key Laboratory of Breast Cancer in Shanghai Fudan University Shanghai Cancer Center Fudan University Shanghai Key Laboratory of Medical Epigenetics International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology) Institutes of Biomedical Sciences Fudan University

Tumor suppressor p53-mediated cell cycle arrest and DNA damage repair may exert cytoprotective effects against cancer therapies, including WEE1 inhibition. Considering that p53 activation can also lead to multiple types of cell death, the role of this tumor suppressor in WEE1 inhibitor-based therapies remains disputed. In this study, we reported that nucleolar stress-mediated p53 activation enhanced the WEE1 inhibitor AZD1775-induced ferroptosis to suppress lung cancer growth. Our findings showed that AZD1775 promoted ferroptosis by blocking cystine uptake, an action similar to that of Erastin. Meanwhile, inhibition of WEE1 by the WEE1 inhibitors or siRNAs induced compensatory upregulation of SLC7A11, which conferred resistance to ferroptosis. Mechanistically, AZD1775 prevented the enrichment of H3K9me3, a histone marker of transcriptional repression, on the SLC7A11 promoter by repressing the expression of the histone methyltransferase SETDB1, thereby enhancing NRF2-mediated SLC7A11 transcription. This finding was also validated using the H3K9me3 inhibitor BRD4770. Remarkably, we found that the nucleolar stress-inducing agent Actinomycin D(Act. D) inhibited SLC7A11 expression by activating p53, thus augmenting AZD1775-induced ferroptosis. Moreover, the combination of AZD1775 and Act. D synergistically suppressed wild-type p53-harboring lung cancer cell growth both in vitro and in vivo. Altogether, our study demonstrates that AZD1775promotes ferroptosis by targeting cystine uptake but also mediates the adaptive activation of SLC7A11 through the WEE1-SETDB1 cascade and NRF2-induced transcription, and inhibition of SLC7A11 by Act. D boosts the anti-tumor efficacy of AZD1775 by enhancing ferroptosis in cancers with wild-type p53.

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Literature overview of basic characteristics and flotation laws of flocs

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International Journal of Minerals,Metallurgy and Materials 2024年第5期31卷 943-958页

作者： Wanzhong Yin Yu xie Zhanglei Zhu School of Resources and Civil Engineering Northeastern UniversityShenyang 110819China College of Chemistry and Chemical Engineering Xi’an University of Science and TechnologyXi’an 710054China

Flocculation flotation is the most efficient method for recovering fine-grained minerals,and its essence lies in flotation and recovery of *** physical characteristics of flocs are mainly determined by their apparent particle size and structure(density and morphology).Substantial researches have been conducted regarding the effect of floc characteristics on particle settling and water ***,the influence of floc characteristics on flotation has not been widely *** on the floc formation and flocculation flotation,this study reviews the fundamental physical characteristics of flocs from the perspectives of floc particle size and structure,summarizing the interaction between floc particle size and ***,it thoroughly discusses the effect of floc particle size and structure on floc floatability,further revealing the influence of floc characteristics on bubble collision and adhesion and elucidating the mechanisms of interaction between flocs and ***,it is observed that floc particle size is not the only factor influencing flocculation *** the appropriate apparent particle size range,flocs with a compact structure exhibit higher efficiency in bubble collision and adhesion during flotation,thereby resulting in enhanced flotation *** study aims to provide a reference for flocculation flotation,targeting the development of more efficient and refined flocculation flotation processes in the future.

关键词： flocs basic characteristics particle size and structure flotation laws bubbles

A midgut transcriptional regulatory loop favors an insect host to withstand a bacterial pathogen

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The Innovation 2024年第5期5卷 36-45,35页

作者： Zhaojiang guo Liuhong Zhu Zhouqiang Cheng Lina Dong Le guo Yang Bai Qingjun Wu Shaoli Wang Xin Yang Wen xie Neil Crickmore Xuguo Zhou RenéLafont Youjun Zhang State Key Laboratory of Vegetable Biobreeding Department of Plant ProtectionInstitute of Vegetables and FlowersChinese Academy of Agricultural SciencesBeijing 100081China School of Life Sciences University of SussexBrighton BN19QEUK Department of Entomology School of Integrative BiologyCollege of Liberal Arts&SciencesUniversity of Illinois Urbana-ChampaignUrbanaIL 61801-3795USA Sorbonne Université CNRS-IBPS(BIOSIPE)75005 ParisFrance

Mounting evidence suggests that insect hormones associated with growth and development also participate in pathogen *** have discovered a previously undescribed midgut transcriptional control pathway that modulates the availability of 20-hydroxyecdysone(20E)in a worldwide insect pest(Plutella xylostella),allowing it to defeat the major virulence factor of an insect pathogen Bacillus thuringiensis(Bt).A reduction of the transcriptional inhibitor(PxDfd)increases the expression of a midgut microRNA(miR-8545),which in turn represses the expression of a newly identified ecdysteroid-degrading glucose dehydrogenase(PxGLD).Downregulation of PxGLD reduces 20E degradation to increase 20E titer and concurrently triggers a transcriptional negative feedback loop to mitigate 20E *** moderately elevated 20E titer in the midgut activates a MAPK signaling pathway to increase Bt tolerance/*** findings deepen our understanding of the functions attributed to these classical insect hormones and help inform potential future strategies that can be employed to control insect pests.

关键词： elevated transcriptional loop

Automated detection of myopic maculopathy from color fundus photographs using deep convolutional neural networks

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Eye and Vision 2024年第4期10卷 11-22页

作者： Jun Li Lilong Wang Yan Gao Qianqian Liang Lingzhi Chen Xiaolei Sun Huaqiang Yang Zhongfang Zhao Lina Meng Shuyue Xue Qing Du zhichun Zhang Chuanfeng LV Haifeng Xu Zhen guo guotong xie Lixin xie Qingdao Eye Hospital of Shandong First Medical University 5 Yanerdao RoadQingdao 266071China State Key Laboratory Cultivation Base Shandong Provincial Key Laboratory of OphthalmologyShandong Eye InstituteShandong First Medical University&Shandong Academy of Medical SciencesQingdao 266071China Ping An Healthcare Technology 9F Building BPingAn IFCNo.1-3 Xinyuan South RoadBejing 100027China Shandong Eye Hospital of Shandong First Medical University Jinan 250021China Rongcheng Eye Hospital Weihai 264200China Hospital of PLA Navy Qingdao 266071China Qilu Hospital of Shandong University(Qingdao) Qingdao 266035China Ping An Healthcare and Technology Company Limited hanghai 200030China ping An International Smart City Technology Company Limited Shenzhen 518000China.

Background:Myopic maculopathy(MM)has become a major cause of visual impairment and blindness worldwide,especially in East Asian *** learning approaches such as deep convolutional neural networks(DCNN)have been successfully applied to identify some common retinal diseases and show great potential for the intelligent analysis of *** study aimed to build a reliable approach for automated detection of MM from retinal fundus images using DCNN ***:A dual-stream DCNN(DCNN-DS)model that perceives features from both original images and corresponding processed images by color histogram distribution optimization method was designed for classification of no MM,tessellated fundus(TF),and pathologic myopia(PM).A total of 36,515 gradable images from four hospitals were used for DCNN model development,and 14,986 gradable images from the other two hospitals for external *** also compared the performance of the DCNN-DS model and four ophthalmologists on 3000 randomly sampledfundus ***:The DCNN-DS model achieved sensitivities of 93.3%and 91.0%,specificities of 99.6%and 98.7%,areas under the receiver operating characteristic curves(AUCs)of 0.998 and 0.994 for detecting PM,whereas sensitivities of 98.8%and 92.8%,specificities of 95.6%and 94.1%,AUCs of 0.986 and 0.970 for detecting TF in two external testing *** the sampled testing dataset,the sensitivities of four ophthalmologists ranged from 88.3%to 95.8%and 81.1%to 89.1%,and the specificities ranged from 95.9%to 99.2%and 77.8%to 97.3%for detecting PM and TF,***,the DCNN-DS model achieved sensitivities of 90.8%and 97.9%and specificities of 99.1%and 94.0%for detecting PMand T,***:The proposed DCNN-DS approach demonstrated reliable performance with high sensitivity,specificity,and AUC to classify different MM levels on fundus photographs sourced from *** can help identify MM automatically among the large myopic groups and show great potenti

关键词： Myopic maculopathy Tessellated fundus Pathologic myopia Deep convolutional neural network Color fundus image

Investigating the causal associations between five anthropometric indicators and nonalcoholic fatty liver disease:Mendelian randomization study

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World Journal of Clinical Cases 2024年第7期12卷 1215-1226页

作者： Xian-Pei Xiao Yong-Jun Dai Yu Zhang Meng Yang Jian xie guo Chen Zheng-Jun Yang Department of Oncology Luojiang District People's Hospital of Deyang CityDeyang 618000Sichuan ProvinceChina Department of Orthopaedics Luojiang District People's Hospital of Deyang CityDeyang 618000Sichuan ProvinceChina Department of Infectious Diseases Hospital of Chengdu University of Traditional Chinese MedicalChengdu 610500Sichuan ProvinceChina

BACKGROUND Although the etiology of nonalcoholic fatty liver disease(NAFLD)has not been thoroughly understood,the emerging roles of anthropometric indicators in assessing and predicting the risk of NAFLD have been highlighted by accumulating *** To evaluate the causal relationships between five anthropometric indicators and NAFLD employing Mendelian randomization(MR)*** The Anthropometric Consortium provided genetic exposure data for five anthropometric indicators,including hip circumference(HC),waist circumference(WC),waist-to-hip ratio(WHR),body mass index(BMI),and body fat percentage(BF).Genetic outcome data for NAFLD were obtained from the United Kingdom Biobank and FinnGen ***-wide significant single nucleotide polymorphisms were chosen as instrumental *** MR(UVMR)and multivariable MR(MVMR)designs with analytical approaches,including inverse variance weighted(IVW),MR-Egger,weighted median(WM),and weighted mode methods,were used to assess the causal relationships between anthropometric indicators and *** Causal relationships were revealed by UVMR,indicating that a higher risk of NAFLD was associated with a perunit increase in WC[IVW:odds ratio(OR)=2.67,95%CI:1.42-5.02,P=2.25×10^(−3)],and BF was causally associated with an increased risk of NAFLD(WM:OR=2.23,95%CI:1.07-4.66,P=0.033).The presence of causal effects of WC on the decreased risk of NAFLD was supported by MVMR after adjusting for BMI and ***,no causal association between BF and NAFLD was *** addition,other causal relationships of HC,WHR(BMI adjusted),and BMI with the risk of NAFLD were not retained after FDR *** This study establishes a causal relationship,indicating that an increase in WC is associated with a higher risk of *** demonstrates that a suitable decrease in WC is advantageous for preventing NAFLD.

关键词： Anthropometric indicator Waist circumference Nonalcoholic fatty liver disease Mendelian randomization Genetic variant

Optimal Coordination of Transportable Power Sources and Repair Crews for Service Restoration of Distribution Networks Considering Uncertainty of Traffic Congestion

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Journal of Modern Power Systems and Clean Energy 2024年第1期12卷 189-201页

作者： Zhao Shi Yan Xu Dunjian xie Shiwei xie Amer M.Y.M.Ghias Nanyang Technological University Singapore the School of Electrical Engineering and Automation Fuzhou UniversityFuzhou 350108China

This paper proposes a new method for service restoration of distribution network with the support of transportable power sources(TPSs)and repair crews(RCs).Firstly,a coupling model of distribution networks and vehicle routing of TPSs and RCs is proposed,where the TPSs serve as emergency power supply sources,and the RCs are used to repair the faulted *** the uncertainty of traffic congestion,the probability distribution of the travel time spent on each road is derived based on the Nesterov user equilibrium model,and a two-stage stochastic program is formulated to determine the optimal routings of TPSs and *** efficiently solve the proposed stochastic mixed-integer linear program(MILP),a two-phase scenario reduction method is then developed to scale down the problem size,and an adaptive progressive hedging algorithm is used for an efficient *** effectiveness of the proposed methods and algorithms has been illustrated in a modified IEEE 33-bus system.

关键词： Service restoration distribution network traffic uncertainty transportable power source repair crew stochastic program

Analysis of a class of globally divergence-free HDG methods for stationary Navier-Stokes equations

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Science China Mathematics 2024年第5期67卷 1133-1158页

作者： Gang Chen Xiaoping xie School of Mathematics Sichuan University Chengdu 610064China

In this paper,we analyze a class of globally divergence-free(and therefore pressure-robust)hybridizable discontinuous Galerkin(HDG)finite element methods for stationary Navier-Stokes *** methods use the P_(k)/P_(k-1)(k≥1)discontinuous finite element combination for the velocity and pressure approximations in the interior of elements,piecewise Pm(m=k,k-1)for the velocity gradient approximation in the interior of elements,and piecewise P_(k)/P_(k) for the trace approximations of the velocity and pressure on the inter-element *** show that the uniqueness condition for the discrete solution is guaranteed by that for the continuous solution together with a sufficiently small mesh *** on the derived discrete HDG Sobolev embedding properties,optimal error estimates are *** experiments are performed to verify the theoretical analysis.

关键词： Navier-Stokes equations HDG methods divergence-free uniqueness condition error estimates

Method for Detecting Industrial Defects in Intelligent Manufacturing Using Deep Learning

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Computers, Materials & Continua 2024年第1期78卷 1329-1343页

作者： Bowen Yu Chunli xie College of Mechanical and Electrical Engineering Northeast Forestry UniversityHarbin150040China

With the advent of Industry 4.0,marked by a surge in intelligent manufacturing,advanced sensors embedded in smart factories now enable extensive data collection on equipment *** analysis of such data is pivotal for ensuring production safety,a critical factor in monitoring the health status of manufacturing *** defect detection techniques,typically limited to specific scenarios,often require manual feature extraction,leading to inefficiencies and limited versatility in the overall *** research presents an intelligent defect detection methodology that leverages deep learning techniques to automate feature extraction and defect localization *** proposed approach encompasses a suite of components:the high-level feature learning block(HLFLB),the multi-scale feature learning block(MSFLB),and a dynamic adaptive fusion block(DAFB),working in tandem to extract meticulously and synergistically aggregate defect-related characteristics across various scales and hierarchical *** have conducted validation of the proposed method using datasets derived from gearbox and bearing *** empirical outcomes underscore the superior defect detection capability of our *** demonstrates consistently high performance across diverse datasets and possesses the accuracy required to categorize defects,taking into account their specific locations and the extent of damage,proving the method’s effectiveness and reliability in identifying defects in industrial components.

关键词： Industrial defect detection deep learning intelligent manufacturing

Building the toolbox for in vivo glia-to-neuron reprogramming

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Neural Regeneration Research 2024年第6期19卷 1171-1172页

作者： Ye xie Bo Chen Departments of Ophthalmology and Neuroscience Icahn School of Medicine at Mount SinaiNew YorkNYUSA

Unlike regenerative-competent species that possess a remarkable intrinsic capacity to replenish lost neurons and restore neurocircuits spontaneously,the central nervous system in adult mammals lacks the ability to compensate for the neuronal loss caused by neurodegenerative diseases or traumatic injuries resulting in permanent loss of *** by earlier discoveries that radial glia or astrocytes isolated from the postnatal cortex can generate neurons.

关键词： injuries cortex diseases