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Targeting the“undruggable”cancer driver genes:Ras,myc,and tp53

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BIOCELL 2023年第7期47卷 1459-1472页

作者： xingbo wu DAN PAN SHOUYI TANG YINGQIANG SHEN State Key Laboratory of Oral Diseases National Clinical Research Center for Oral DiseasesResearch Unit of Oral Carcinogenesis and ManagementChinese Academy of Medical SciencesWest China Hospital of StomatologySichuan UniversityChengdu610041China

The term“undruggable”is to describe molecules that are not targetable or at least hard to target ***,some targets with potent oncogenic activity fall into this category,and currently little is known about how to solve this problem,which largely hampered drug research on human ***,as one of the most common oncogenes,was previously considered“undruggable”,but in recent years,a few small molecules like Sotorasib(AMG-510)have emerged and proved their targeted anti-cancer ***,myc,as one of the most studied oncogenes,and tp53,being the most common tumor suppressor genes,are both considered“undruggable”.Many attempts have been made to target these“undruggable”targets,but little progress has been made *** article summarizes the current progress of direct and indirect targeting approaches for ras,myc,two oncogenes,and tp53,a tumor suppressor *** are potential therapeutic targets but are considered“undruggable”.We conclude with some emerging research approaches like proteolysis targeting chimeras(PROTACs),cancer vaccines,and artificial intelligence(AI)-based drug discovery,which might provide new cues for cancer ***,this review sets out to clarify the current status of targeted anti-cancer drug research,and the insights gained from this review may be of assistance to learn from experience and find new ideas in developing new chemicals that directly target such“undruggable”molecules.

关键词： Ras Myc Tp53 Antineoplastic agents Pharmacology Oncogene proteins Antagonists and inhibitors

Genetic differentiation of grain, fodder and pod vegetable type cowpeas (Vigna unguiculata L.) identified through single nucleotide polymorphisms from genotyping-by-sequencing

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Molecular Horticulture 2022年第1期2卷 101-115页

作者： xingbo wu Andrés JCortés Matthew W.Blair Department of Agricultural and Environmental Sciences Tennessee State UniversityNashvilleTN 37209USA Tropical Research and Education Center Department of Environmental HorticulturalUniversity of Florida18905 SW 280th StHomesteadFL 33031USA Corporación Colombiana de Investigación Agropecuaria AGROSAVIA C.I.La SelvaKm 7 vía Rionegro–Las PalmasRionegroColombia Universidad Nacional de Colombia–Sede Medellín Facultad de Ciencias Agrarias–Departamento de Ciencias ForestalesMedellínColombia

The species Vigna unguiculata L.(Walp),commonly known as cowpea,is a multi-purpose legume that has been selected into three subspecies that are divided into grain,fodder and pod(yardlong bean)***,genetic bases for distinctions are not well *** purpose of this study was to apply genotyping-by-sequencing(GBS)and current reference genome for *** to distinguish three subspecies and identify signatures of *** collection of 130 accessions included 128 cultivated from:1)***,fodder type;2)***,pod vegetable type;and 3)***,grain *** wilds genotypes from *** and ***,were used to anchor phylogeny.A total of 11,083 highly informative single nucleotide polymorphisms(SNPs)were *** accessions showed distinct genetic fingerprints and were separated from cultivated *** component analysis showed closer relationship between *** and *** compared to *** differentiation of cultivated subspecies(with Fixation Index,FST)indicated the existence of discrete signatures of *** work clarifies the population structure,phylogeny,and domestication of cultivated ***,significant genetic differences between grain and pod vegetable types can provide valuable information for future breeding in three cowpea groups.

关键词： Genomic landscape of divergence Relative differentiation FST GBS-derived SNP markers

FlexPolh adaptive event polling for network-intensive applications

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Frontiers of Computer Science 2016年第3期10卷 532-542页

作者： xingbo wu Xiang LONG Lei WANG School of Computer Science and Engineering Beihang University Beijing 100191 China

In today＇s data centers supporting Internet-scale computing and input/output （I/0） services, increasingly more network-intensive applications are deployed on the network as a service. To this end, it is critical for the applications to quickly retrieve requests from the network and send their responses to the network. To facilitate this network func- tion, operating system usually provides an event notification mechanism so that the applications （or the library） know if the network is ready to supply data for them to read or to receive data for them to write. As a widely used and repre- sentative notification mechanism, epoll in Linux provides a scalable and high-performance implementation by allowing applications to specifically indicate which connections and what events on them need to be watched. As epoll has been used in some major systems, includ- ing key-value （KV） systems, such as Redis and Memcached, and web server systems such as NGINX, we have identified a substantial performance issue in its use. For the sake of efficiency, applications usually use epoll＇s system calls to inform the kernel exactly of what events they are interested in and always keep the information up-to-date. However, in a system with demanding network traffic, such a rigid main- tenance of the information is not necessary and the excess number of system calls for this purpose can substantially de- grade the system＇s performance. In this paper, we use Redis as an example to explore the issue. We propose a strategy of informing the kernel of the interest events in a manner adaptive to the current network load, so that the epoll system calls can be reduced and the events can be efficiently deliv- ered. We have implemented an event-polling library, named as FlexPoll, purely in user-level without modifying any ker- nel code. Our evaluation on Redis shows that the query through- put can be improved by up to 46.9% on micro-benchmarks, and even up to 67.8% on workloads emulating real-world a

关键词： operating systems performance evaluation andmodeling storage systems and networks workload characterization

Genome-wide association studies for inflorescence type and remontancy in Hydrangea macrophylla

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Horticulture Research 2020年第1期7卷 2477-2485页

作者： xingbo wu Lisa W.Alexander Oak Ridge Institute of Science and Technology Otis L.Floyd Nursery Research Center472 Cadillac LaneMcMinnvilleTNUSA U.S.Department of Agriculture Agricultural Research ServiceU.S.National ArboretumFloral and Nursery Plants Research UnitOtis L.Floyd Nursery Research Center472 Cadillac LaneMcMinnvilleTNUSA

Inflorescence type and remontancy are two valuable traits in bigleaf hydrangea(Hydrangea macrophylla L.)and both are recessively *** marker-assisted selection(MAS)can greatly reduce the time necessary to breed cultivars with desired *** this study,a genome-wide association study(GWAS)using 5803 single-nucleotide polymorphisms(SNPs)was performed using a panel of 82 bigleaf hydrangea *** SNP locus(Hy_CAPS_Inflo)associated with inflorescence type was identified with general linear model(GLM)and mixed linear model(MLM)methods that explained 65.5%and 36.1%of the phenotypic variations,***-three SNPs associated with remontancy were detected in GLM whereas no SNP was detected in *** SNP locus(Hy_CAPS_Inflo)was converted to a cleaved amplified polymorphic sequence(CAPS)marker that showed absolute identification accuracy(100%)of inflorescence type in a validation panel consisting of eighteen *** *** SNP was investigated in 341 F1 progenies using genotyping by sequencing(GBS)and co-segregated with inflorescence type(χ^(2)=0.12;P=0.73).The SNP was subsequently used for breeding selection using kompetitive allele specific PCR(KASP)*** directions for the use of genomics and MAS in hydrangea breeding improvement are *** results presented in this study provide insights for further research on understanding genetic mechanisms behind inflorescence type and remontancy in *** CAPS and KASP markers developed here will be immediately useful for applying MAS to accelerate breeding improvement in hydrangea.

关键词： breeding cultivar CAPS

Two haplotype-resolved genomes reveal important flower traits in bigleaf hydrangea(Hydrangea macrophylla)and insights into Asterid evolution

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Horticulture Research 2023年第12期10卷 45-57页

作者： xingbo wu Sheron A.Simpson Ramey C.Youngblood Xiaofen FLiu Brian E.Scheffler Timothy A.Rinehart Lisa W.Alexander Amanda M.Hulse-Kemp Department of Environmental Horticulture Tropical Research and Education CenterUniversity of FloridaHomesteadFL 33031United States Genomics and Bioinformatics Research Unit USDA-ARSRaleighNC 27695United States Genomics and Bioinformatics Research Unit USDA-ARSStonevilleMS 38776United States Institute for Genomics Biocomputing and BiotechnologyMississippi State UniversityStarkvilleMS 39762United States Crop Production and Protection USDA-ARSBeltsvilleMD 20705United States Floral and Nursery Plants Research Unit U.S.National ArboretumUSDA-ARSMcMinnvilleTN 37110United States Department of Crop and Soil Sciences North Carolina State UniversityRaleighNC 27695United States

The Hydrangea genus belongs to the Hydrangeaceae family,in the Cornales order of flowering plants,which early diverged among the Asterids,and includes several species that are commonly used ornamental *** them,Hydrangea macrophylla is one of the most valuable species in the nursery trade,yet few genomic resources are available for this crop or closely related Asterid *** high-quality haplotype-resolved reference genomes of hydrangea cultivars‘Veitchii’and‘Endless Summer’[highest quality at 2.22 gigabase pairs(Gb),396 contigs,N5022.8 megabase pairs(Mb)]were assembled and scaffolded into the expected 18 *** the newly developed high-quality reference genomes along with high-quality genomes of other related flowering plants,nuclear data were found to support a single divergence point in the Asterids clade where both the Cornales and Ericales diverged from the *** mapping with an F1 hybrid population demonstrated the power of linkage mapping combined with the new genomic resources to identify the gene for inflorescence shape,CYP78A5 located on chromosome 4,and a novel gene,BAM3 located on chromosome 17,for causing double *** developed in this study will not only help to accelerate hydrangea genetic improvement but also contribute to understanding the largest group of flowering plants,the Asterids.

关键词： Hydra traits resolved

Unveiling blood pressure-associated genes in aortic cells through integrative analysis of GWAS and RNA modification-associated variants

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Chronic Diseases and Translational Medicine 2024年第2期10卷 118-129页

作者： Huan Zhang Yuxi Chen Peng Xu Dan Liu Naqiong wu Laiyuan Wang xingbo Mo Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases Department of EpidemiologySchool of Public HealthMedical College of Soochow UniversitySuzhouJiangsuChina Cardiometabolic Center Fuwai HospitalNational Center for Cardiovascular DiseasesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina Key Laboratory of Cardiovascular Epidemiology&Department of Epidemiology State Key Laboratory of Cardiovascular DiseaseFuwai HospitalNational Center for Cardiovascular DiseasesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina MOE Key Laboratory of Geriatric Diseases and Immunology School of Public HealthCenter for Genetic Epidemiology and GenomicsMedical College of Soochow UniversitySuzhouJiangsuChina

Background Genome-wide association studies(GWAS)have identified more than a thousand loci for blood pressure(BP).Functional genes in these loci are cell-type *** aim of this study was to elucidate potentially functional genes associated with BP in the aorta through the utilization of RNA modification-associated single-nucleotide polymorphisms(RNAm-SNPs).Methods Utilizing large-scale genetic data of 757,601 individuals from the UK Biobank and International Consortium of Blood Pressure consortium,we identified associations between RNAm-SNPs and *** association between RNAm-SNPs,gene expression,and BP were *** A total of 355 RNAm-SNPs related to m6A,m1A,m5C,m7G,and A-to-I modification were associated with *** related genes were enriched in the pancreatic secretion pathway and renin secretion *** BP GWAS signals were significantly enriched with m6A-SNPs,highlighting the potential functional relevance of m6A in physiological processes influencing ***,m6A-SNPs in CYP11B1,PDE3B,HDAC7,ACE,SLC4A7,PDE1A,FRK,MTHFR,NPPA,CACNA1D,and HDAC9 were *** methylation and differential expression of the BP genes in FTO-overexpression and METTL14-knockdown vascular smooth muscle cells were ***-SNPs were associated with ascending and descending aorta diameter and the genes showed differential methylation between aortic dissection(AD)cases and *** scRNA-seq study,we identified ARID5A,HLA-DPB1,HLA-DRA,IRF1,LINC01091,MCL1,MLF1,MLXIPL,NAA16,NADK,RERG,SRM,and USP53 as differential expression genes for AD in aortic *** The present study identified RNAm-SNPs in BP loci and elucidated the associations between the RNAm-SNPs,gene expression,and *** identified BP-associated genes in aortic cells were associated with AD.

关键词： aortic dissection blood pressure genome-wide association study RNA modification single-cell

Comparison of basic features and origins of oolitic shoal reservoirs between carbonate platform interior and platform margin locations in the Lower Triassic Feixianguan Formation of the Sichuan Basin,southwest China

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Petroleum Science 2012年第4期9卷 417-428页

作者： Tan Xiucheng Zhao Luzi Luo Bing Jiang Xingfu Cao Jian Liu Hong Li Ling wu xingbo Nie Yong State Key Laboratory of Oil and Gas Geology and Exploitation Southwest Petroleum University Chengdu Sichuan610500 China School of Resource and Environment Southwest Petroleum University Chengdu Sichuan 610500 China Branch of Exploration Management PetroChina Southwest Oil and Gas Field Company Chengdu Sichuan 610051 China Branch Station in Research Institute of Petroleum Exploration and Development Post-doctoral Workstation of PetroChinaSouthwest Oil and Gas Field Company Chengdu Sichuan 610051 China Branch of Exploration Industry PetroChina Southwest Oil and Gas Field Company Chengdu Sichuan 610051 China Department of Earth Sciences Nanjing University Jiangsu 210093 China

The oolitic shoal reservoirs of the Lower Triassic Feixianguan Formation carbonates in the Sichuan Basin of southwest China are an important target for gas exploration in the *** occurrence,like other cases worldwide,can be divided into two locations in general,i.e.,platform interior and platform margin *** differences of reservoir features and origins,however,have not been investigated comprehensively due to different exploration *** issue is addressed in this paper,to provide basic data and information for the basin＇s hydrocarbon exploration and for the study of carbonate platform sedimentology and reservoir geology *** compared the features of these two types of reservoirs in detail,including the depositional and diagenetic features,pore types and petrophysical *** on the comparison,the origin of the reservoirs was further *** is shown that the reservoirs in platform interior and platform margin locations differ *** interior carbonates were deposited in moderate to high energy settings and the dominant lithologic type was limestone,which was weakly compacted and intensely cemented and has undergone meteoric *** types include intragranular dissolution and moldic pores,with low porosities（6%） and low permeabilities（0.1 mD）.By contrast,the platform margin carbonates were deposited in relatively high energy settings and mainly consisted of dolostones with some *** rocks were strongly compacted but incompletely *** a result,some primary intergranular pores were *** meteoric solution and burial solution have taken *** are various types of pore spaces including intergranular and intercrystalline solution pores and residual intergranular *** type of reservoir generally has better petrophysical properties（9% porosity and 0.1 mD permeability） and pore-throat structures than the interior *** differences were influenced by both primar

关键词： Carbonate platform oolitic shoal reservoir platform margin platform interior Lower Triassic Feixianguan Formation Sichuan Basin China

Ballistic performances of the hourglass lattice sandwich structures under high-velocity fragments

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Defence Technology（防务技术） 2024年第1期31卷 312-325页

作者： He-xiang wu Jia Qu Lin-zhi wu Key Laboratory of Advanced Ship Materials and Mechanics College of Aerospace and Civil EngineeringHarbin Engineering UniversityHarbin150001China School of Civil Engineering Northeast Forestry UniversityHarbin150040China

In this paper,the numerical simulation method is used to study the ballistic performances of hourglass lattice sandwich structures with the same mass under the vertical incidence of *** is paid to elucidating the influences of rod cross-section dimensions,structure height,structure layer,and rod inclination angle on the deformation mode,ballistic performances,and ability to change the ballistic direction of *** results show that the ballistic performances of hourglass lattice sandwich structures are mainly affected by their structural *** this respect,structural parameters optimization of the hourglass lattice sandwich structures enable one to effectively improve their ballistic limit velocity and,consequently,ballistic performances.

关键词： Hourglass lattice sandwich structures Ballistic performances high-velocity Finite element analysis

Resilience-incorporated seismic risk assessment of precast concrete frames with“dry”connections

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Earthquake Engineering and Engineering Vibration 2024年第2期23卷 403-425页

作者： wu Chenhao Tang Yuchuan Cao Xuyang wu Gang Key Laboratory of Concrete and Prestressed Concrete Structures of the Ministry of Education Nanjing 211102China Department of Civil and Environmental Engineering University of CaliforniaLos AngelesCA 90095USA School of Civil Engineering Southeast UniversityNanjing 211102China College of Civil and Transportation Engineering Hohai UniversityNanjing 210024China

A resilience-incorporated risk assessment framework is proposed and demonstrated in this study to manifest the advantageous seismic resilience of precast concrete frame(PCF)structures with“dry”connections in terms of their low damage and rapid *** framework integrates various uncertainties in the seismic hazard,fragility,capacity,demand,loss functions,and post-earthquake *** this study,the PCF structures are distinguished from ordinary reinforced concrete frame(RCF)structures by characterizing multiple limit states for the PCF based on its unique damage ***,probabilistic story-wise pushover analyses are performed to yield story-wise capacities for the predefined limit *** the seismic resilience analysis,a step-wise recovery model is proposed to idealize the functionality recovery process,with separate considerations of the repair and non-repair *** recovery model leverages the economic loss and downtime to delineate the stochastic post-earthquake recovery curves for the resilience loss *** such,contingencies in the probabilistic post-earthquake repairs are incorporated and the empirical judgments on the recovery parameters are largely *** proposed framework is demonstrated through a comparative study between two“dry”connected PCFs and one RCF designed as alternative structural systems for a prototype *** results from the risk quantification indicate that the PCFs show reduced loss hazards and lower expected losses relative to the ***,the PCF equipped with energy dissipation devices at the“dry”connections largely reduces the expected economic loss,downtime,and resilience loss by 29%,56%,and 60%,respectively,compared to the RCF.

关键词： precast concrete frame non-emulative precast system seismic resilience seismic risk functional recovery