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Novel spontaneous myelodysplastic syndrome mouse model

Animal Models and experimental Medicine 2021年第2期4卷 169-180,I0002页

作者： Weisha Li Lin Cao Mengyuan Li Xingjiu Yang Wenlong Zhang Zhiqi Song Xinpei Wang Lingyan Zhang Grant Morahan Chuan Qin Ran Gao NHC Key laboratory of Human Disease comparative Medicine Beijing Engineering Research Center for Experimental Animal Models of Human Critical DiseasesInstitute of Laboratory Animal SciencesChinese Academy of Medical Sciences(CAMS)and Comparative Medicine CenterPeking Union Medical College(PUMC)BeijingChina

Background:Myelodysplastic syndrome(MDS)is a group of disorders involving he-mopoietic dysfunction leading to leukemia.Although recently progress has been made in identifying underlying genetic mutations,many questions still remain.Animal models of MDS have been produced by introduction of specific mutations.However,there is no spontaneous mouse model of MDS,and an animal model to simulate natu-ral MDS pathogenesis is urgently needed.Methods:In characterizing the genetically diverse mouse strains of the Collaborative Cross(CC)we observed that one,designated JUN,had abnormal hematological traits.This strain was thus further analyzed for phenotypic and pathological iden-tification,comparing the changes in each cell population in peripheral blood and in bone marrow.Results:In a specific-pathogen free environment,mice of the JUN strain are rela-tively thin,with healthy appearance.However,in a conventional environment,they become lethargic,develop wrinkled yellow hair,have loose and light stools,and are prone to infections.We found that the mice were cytopenic,which was due to abnor-mal differentiation of multipotent bone marrow progenitor cells.These are common characteristics of MDS.Conclusions:A mouse strain,JUN,was found displaying spontaneous myelodysplas-tic syndrome.This strain has the advantage over existing models in that it develops MDS spontaneously and is more similar to human MDS than genetically modified mouse models.JUN mice will be an important tool for pathogenesis research of MDS and for evaluation of new drugs and treatments.

关键词： myelodysplastic syndrome(MDS) spontaneous mouse model The Collaborative Cross Mice

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Agent-based models reveal limits of mark-release-recapture estimates for the rare butterfly, Bhutanitis thaidina (Lepidoptera: Papilionidae)

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Insect Science 2022年第2期29卷 550-566页

作者： Zhengyang Wang Yuanheng Li Anuj Jain Naomi E.Pierce Department of Organismic and Evolutionary Biology and Museum of comparative Zoology Harvard UniversityCambridgeMA 02138 USA

Insect diversity and abundance are in drastic decline worldwide,but quantifying insect populations to better conserve them is a difficult task.Mark-release-recapture(MRR)is widely used as an ecological indicator for insect populations,but the accuracy of MRR estimates can vary with factors such as spatial scale,sampling effort and models of inference.We conducted a 3-year MRR study of B.thaidina in Yanzigou valley,Mt.Gongga but failed to obtain sufficient data for a robust population estimate.This prompted us to integrate B.thaidina life history information to parameterize agent-based models and evaluate the conditions under which successful MRR studies could be conducted.We evaluated:(1)the performance of MRR models under different landscape types,and(2)the influence of experimental design on the accuracy and variance of MRR-based estimates.Our simulations revealed systematic underestimates of true population parameters by MRR models when sampling effort was insufficient.In a total of 2772 simulations,subjective decisions in sampling protocol(e.g.,frequency,number of sampling locations,use of spatially explicit models,type of estimands)accounted for nearly half of the variation in estimates.We conclude that MRR-based estimates could be improved with the addition of more field-specific parameters.

关键词： agent-based simulation Aristolochia moupinensis habitat hostplant landscape Mt.Gongga program MARK spatially explicit capture-recapture(SECR)

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Anti-apoptotic protein BCL-XL as a therapeutic vulnerability in gastric cancer

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Animal Models and experimental Medicine 2023年第3期6卷 245-254页

作者： Yumin Wei Liping Zhang Chao Wang Zefeng Li Mingjie Luo Guomin Xie Xingjiu Yang Mengyuan Li Shuyue Ren Dongbing Zhao Ran Gao Jia-Nan Gong National Human Diseases Animal Model Resource Center The Institute of Laboratory Animal ScienceChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijingChina NHC Key laboratory of Human Disease comparative Medicine Beijing Engineering Research Center for Experimental Animal Models of Human Critical DiseasesBeijingChina Beijing Engineering Research Center for experimental Animal Models of Human Critical Diseases BeijingChina Department of Pancreatic and Gastric Surgical Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina State Key laboratory of Ophthalmology Zhongshan Ophthalmic CenterSun Yat-Sen UniversityGuangzhouChina

Background: New therapeutic targets are needed to improve the outcomes for gastric cancer(GC) patients with advanced disease. Evasion of programmed cell death(apoptosis) is a hallmark of cancer cells and direct induction of apoptosis by targeting the pro-survival BCL2 family proteins represents a promising therapeutic strategy for cancer treatment. Therefore, understanding the molecular mechanisms underpinning cancer cell survival could provide a molecular basis for potential therapeutic interventions. Method: Here we explored the role of BCL2L1 and the encoded anti-apoptotic BCL-XL in GC. Using Droplet Digital PCR(ddPCR) technology to investigate the DNA amplification of BCL2L1 in GC samples and GC cell lines, the sensitivity of GC cell lines to selective BCL-XL inhibitors A1155463 and A1331852, pan-inhibitor ABT-263, and VHL-based PROTAC-BCL-XL was analyzed using(CellTiter-Glo) CTG assay in vitro. Western Blot(WB) was used to detect the protein expression of BCL2 family members in GC cell lines and the manner in which PROTAC-BCL-XL kills GC cells. Coimmunoprecipitation(Co-IP) was used to investigate the mechanism of A1331852 and ABT-263 kills GC cell lines. DDPCR, WB, and real-time PCR(RTPCR) were used to investigate the correlation between DNA, RNA, protein levels, and drug activity. Results: The functional assay showed that a subset of GC cell lines relies on BCL-XL for survival. In gastric cancer cell lines, BCL-XL inhibitors A1155463 and A1331852 are more sensitive than the pan BCL2 family inhibitor ABT-263, indicating that ABT-263 is not an optimal inhibitor of BCL-XL. VHL-based PROTAC-BCL-XL DT2216 appears to be active in GC cells. DT2216 induces apoptosis of gastric cancer cells in a time-and dose-dependent manner through the proteasome pathway. Statistical analysis showed that the BCL-XL protein level predicts the response of GC cells to BCL-XL targeting therapy and BCL2L1 gene CNVs do not reliably predict BCL-XL expression.Conclusion: We identified BCL-XL as a promising therapeutic target in a subset o

关键词： apoptosis BCL2L1(BCL-XL) gastric cancer(GC) PROTAC-BCL-XL selective BCL-XL inhibitors

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Morphine analgesia in male inbred genetic diversity mice recapitulates the among-individual variance in response to morphine in humans

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Animal Models and experimental Medicine 2022年第3期5卷 288-296页

作者： Yin Yang Bowen Guan Qiang Wei Wei Wang Aimin Meng Key laboratory of Human Disease comparative Medicine Ministry of HealthBeijing Engineering Research Center for Laboratory Animal Models of Human Critical DiseasesInstitute of Laboratory Animal SciencesChinese Academy of Medical Sciences(CAMS)and Peking Union Medical College(PUMC)BeijingChina Department of Physiology and Neurobiology School of Basic Medical SciencesZhengzhou UniversityZhengzhouChina

Morphine is a widely used analgesic, but its use in clinical precision medicine is limited by the variance in response among individuals. Although previous studies have shown that individual differences in morphine can be explained in terms of pharmacodynamics and pharmacokinetics, genetic polymorphisms also play an important role. However, the genetic basis of different sensitivity and tolerance susceptibility to morphine remains ambiguous. Using 15 strains of inbred Genetic Diversity(GD) mice,a new resource with wide genetic and phenotypic variation, we demonstrated great variance in sensitivity to morphine analgesia and susceptibility to morphine tolerance between different GD strains. Among-i ndividual variance in response to morphine analgesia in the population can be modeled in GD mice. Two loci respectively may be associated with the among-i ndividual variance in morphine sensitivity and tolerance,confirming the role of genetic factors in among-i ndividual different responses to morphine. These results indicate that GD mice may be a potential tool for the identification of new biomarkers to improve the clinical administration of morphine.

关键词： inbred genetic diversity mice morphine analgesia morphine tolerance quantitative trait loci mapping

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Abnormal gonad development in Kit^(W-2Bao) mice caused by a Kit gene missense mutation

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Chinese Science Bulletin 2010年第36期55卷 4143-4149页

作者： WU BaoJin YIN LiJing LU ZhengLan YIN YuShu YANG WeiWei YANG Rong KANG XiaoDong LIU GuiJie YIN HongPing YU LiPing Gu MeiEr WU PeiLin laboratory of experimental Animal Science Hangzhou Normal University Hangzhou 310036 China comparative Medicine Centre of Yangzhou University Yangzhou 225000 China

KitW-2Bao mice are single-gene autosomal dominant mutation mice with a B6 background that were bred in our laboratory. Heterozygotes had morphological characteristics including albinism of the abdomen, extremities, and tail, whereas the homozygotes had albinism of the body, black eyes, and infertility. The homozygous mutants showed small, structurally abnormal gonads, and lacked germ cells. Heterozygous male mice lacked germ cells in some contorted seminiferous tubules. This mutation has been mapped at 43.8 cM from the centromere in chromosome 5 by linkage analysis and Kit has been identified as the candidate gene. After Kit full-length mRNA amplification, it was found that a G to T conversion at position 1228 in the ORF changed the 410th amino acid from V to F. This amino acid change could affect the protein’s secondary structure. Heterozygous mutant mice were intercrossed and homozygous mutant mice were bred and genotyped. We found that no primordial germ cells (PGCs) appeared in the urogenital ridge area at fetus day 11.5 in the homozygotes. The number of PGCs also significantly decreased in heterozygotes. At fetus day 15.5, the differentiation of the testis tubule structure was unclear; as well, they contained no spermatogonia. Female homozygotes contained no primordial follicles in the ovary. The numbers of PGCs and primordial follicles were significantly decreased in heterozygous mice. W-2Bao is the only mutated site in the extracellular 4th Ig-like domain and this mutant mouse model provides new material for the study of the mechanism of reproductive system development.

关键词：突变小鼠结构异常单基因套件性腺原始生殖细胞工具包杂合子缺乏

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Factors associated with trabecular bone score in postmenopausal women with type 2 diabetes and normal bone mineral density

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World Journal of Diabetes 2022年第7期13卷 553-565页

作者： Olga N Fazullina Anton I Korbut Vadim V Klimontov laboratory of Endocrinology Research Institute of Clinical and Experimental Lymphology-Branch of the Institute of Cytology and GeneticsSiberian Branch of Russian Academy of SciencesNovosibirsk 630060Russia

BACKGROUND Osteoporosis and type 2 diabetes(T2D)have been recognized as a widespread comorbidity leading to excess mortality and an enormous healthcare burden.In T2D,bone mineral density(BMD)may underestimate the risk of low-energy fractures as bone quality is reduced.It was hypothesized that a decrease in the trabecular bone score(TBS),a parameter assessing bone microarchitecture,may be an early marker of impaired bone health in women with T2D.AIM To identify clinical and body composition parameters that affect TBS in postmenopausal women with T2D and normal BMD.METHODS A non-interventional cross-sectional comparative study was conducted.Potentially eligible subjects were screened at tertiary referral center.Postmenopausal women with T2D,aged 50-75 years,with no established risk factors for secondary osteoporosis,were included.BMD,TBS and body composition parameters were assessed by dual-energy X-ray absorptiometry.In women with normal BMD,a wide range of anthropometric,general and diabetes-related clinical and laboratory parameters were evaluated as risk factors for TBS decrease using univariate and multivariate regression analysis and analysis of receiver operating characteristic(ROC)curves.RESULTS Three hundred twelve women were initially screened,176 of them met the inclusion criteria and underwent dual X-ray absorptiometry.Those with reduced BMD were subsequently excluded;96 women with normal BMD were included in final analysis.Among them,43 women(44.8%)showed decreased TBS values(≤1.31).Women with TBS≤1.31 were taller and had a lower body mass index(BMI)when compared to those with normal TBS(Р=0.008 and P=0.007 respectively).No significant differences in HbA1c,renal function,calcium,phosphorus,alkaline phosphatase,PTH and 25(ОН)D levels were found.In a model of multivariate linear regression analysis,TBS was positively associated with gynoid fat mass,whereas the height and androgen fat mass were associated negatively(all P<0.001).In a multiple logistic regression,TBS≤1.31 was associated with lower gynoid f

关键词： Diabetes Osteoporosis Bone mineral density Trabecular bone score Obesity Body composition

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短纤维插层对亚麻纤维增强复合材料层间增韧效果的实验与数值仿真研究

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Acta Mechanica Sinica 2024年第1期40卷 183-196页

作者：于本泽李岩涂昊昀章中森 School of Aerospace Engineering and Applied Mechanics Tongji UniversityShanghai 200092China Key laboratory of Advanced Civil Engineering Materials Ministry of EducationTongji University Shanghai 200092China

本文分别通过双悬臂梁(DCB)实验与数值模拟,研究了不同短纤维插层(包括短纤维种类、短纤维长度与插层面密度)对亚麻纤维增强复合材料I型层间断裂韧性的影响规律.DCB试验结果表明,当插层为5mm长度、25g/m^(2)面密度的短碳纤维插层时,复... 详细信息

本文分别通过双悬臂梁(DCB)实验与数值模拟,研究了不同短纤维插层(包括短纤维种类、短纤维长度与插层面密度)对亚麻纤维增强复合材料I型层间断裂韧性的影响规律.DCB试验结果表明,当插层为5mm长度、25g/m^(2)面密度的短碳纤维插层时,复合材料1型层间断裂韧性达到2.322kJ/m^(2),取得最大提升幅度80.7%,短纤维桥联与亚麻连续纤维多层级破坏为其主要增韧机理。在此基础上,采用五参数控制的三线性内聚力单元,建立了数值仿真模型。实验与数值模拟结果的对比分析揭示了短纤维插层属性与内聚力模型参数之间的定量关系,可为植物纤维增强复合材料短纤维插层增韧设计提供参考依据.

关键词：纤维增强复合材料内聚力模型层间断裂韧性连续纤维增韧机理内聚力单元实验与数值模拟插层

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Strategies for generating mouse model resources of human disease

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Protein & Cell 2023年第12期14卷 866-870页

作者： Jirong Pan Ling Zhang Zhibing Huang Dalu Zhao He Li Yanan Fu Meng Wang Borui Chen Fuad A.Iraqi Grant Morahan Chuan Qin National Human Diseases Animal Model Resource Center NHC Key Laboratory of Human Disease Comparative MedicineBeijing Key Laboratory for Animal Models of Emerging and Reemerging Infectious DiseasesBeijing Engineering Research Center for Experimental Animal Models of Human Critical DiseasesInstitute of Laboratory Animal SciencesCAMS&PUMCNational Center of Technology Innovation for Animal ModelChangping National Laboratory(CPNL)Beijing 102206China Department of Clinical Microbiology and Immunology Sackler Faculty of MedicineTel-Aviv UniversityRamat AvivTel Aviv 69978Israel Harry Perkins Institute of Medical Research QEII Medical Centre and Centre for Medical ResearchUniversity of Western AustraliaNedlandsPerthWA 6009Australia

The number of genetically modified mouse models that mimic human disease is growing rapidly,but only a tiny fraction has been commonly used.According to The Knockout Mouse Program(Lloyd,2011),a public resource of mouse embryonic stem cells containing a null mutation in every gene in the mouse genome,8,916 mutant mice lines were phenotyped up to 19 July 2022.Due to the poor correlation between the genomic responses in the mouse models and those responses in human disease,and since humans differ significantly in their genetic vulnerability to common diseases,we still need better mouse models,especially for common and chronic human diseases,including cancer,pulmonary and cardiovascular diseases,obesity and diabetes,behavioral disorders,and neurodegenerative diseases.These new models will be placed into a public repository,The China National Human Disease Animal Model Resource Center(NAMR).This project is funded by Ministry of Science and Technology of China and specializes in the creation,introduction,collection,preservation,and supply of animal model resources forhuman diseases.

关键词： diseases cardiovascular generating

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A review of integrated surface-subsurface numerical hydrological models

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Science China Earth Sciences 2024年第5期67卷 1459-1479页

作者： Lele SHU Hao CHEN Xianhong MENG Yan CHANG Litang HU Wenke WANG Longcang SHU Xuan YU Christopher DUFFY Yingying YAO Donghai ZHENG Key laboratory of Cryospheric Science and Frozen Soil Engineering Northwest Institute of Eco-Environment and ResourcesChinese Academy of SciencesLanzhou 730000China College of Water Sciences Beijing Normal UniversityBeijing 100038China School of Water and Environment Chang’an UniversityXi’an 710064China College of Hydrology and Water Resources Hohai UniversityNanjing 210098China State Key laboratory of Soil and Sustainable Agriculture Institute of Soil ScienceChinese Academy of SciencesNanjing 210008China Department of Civil and Environmental Engineering Pennsylvania State UniversityState CollegePA 16801USA Department of Earth and Environmental Science School of Human Settlements and Civil EngineeringXi’an Jiaotong UniversityXi’an 710049China Institute of Tibetan Plateau Research Chinese Academy of SciencesBeijing 100101China

Hydrological modeling,leveraging mathematical formulations to represent the hydrological cycle,is a pivotal tool in representing the spatiotemporal dynamics and distribution patterns inherent in hydrology.These models serve a dual purpose:they validate theoretical robustness and applicability via observational data and project future trends,thereby bridging the understanding and prediction of natural processes.In rapid advancements in computational methodologies and the continuous evolution of observational and experimental techniques,the development of numerical hydrological models based on physicallybased surface-subsurface process coupling have accelerated.Anchored in micro-scale conservation principles and physical equations,these models employ numerical techniques to integrate surface and subsurface hydrodynamics,thus replicating the macro-scale hydrological responses of watersheds.Numerical hydrological models have emerged as a leading and predominant trend in hydrological modeling due to their explicit representation of physical processes,heightened by their spatiotemporal resolution and reliance on interdisciplinary integration.This article focuses on the theoretical foundation of surface-subsurface numerical hydrological models.It includes a comparative and analytical discussion of leading numerical hydrological models,encompassing model architecture,numerical solution strategies,spatial representation,and coupling algorithms.Additionally,this paper contrasts these models with traditional hydrological models,thereby delineating the relative merits,drawbacks,and future directions of numerical hydrological modeling.

关键词： Numerical Hydrological Models Surface-Subsurface Process Coupling Numerical Methods Hydrological Modeling

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A systematic study of Erzhu Erchen decoction against damp-heat internalized type 2 diabetes based on data mining and experimental verification

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Traditional Medicine Research 2024年第2期9卷 27-41页

作者： Peng-Yu Wang Jian-Fen Shen Shuo Zhang Qing Lan Guan-Di Ma Tong Wang You-Zhi Zhang School of Pharmacy Hubei Engineering Research Center of Traditional Chinese Medicine of South Hubei ProvinceXianning Medical CollegeHubei University of Science and TechnologyXianning 437100China Department of Central laboratory The First Affiliated Hospital of Jiaxing UniversityJiaxing 314000China

Background:Erzhu Erchen decoction(EZECD),which is based on Erchen decoction and enhanced with Atractylodes lancea and Atractylodes macrocephala,is widely used for the treatment of dampness and heat(The clinical manifestations of Western medicine include thirst,inability to drink more,diarrhea,yellow urine,red tongue,et al.)internalized disease.Nevertheless,the mechanism of EZECD on damp-heat internalized Type 2 diabetes(T2D)remains unknown.We employed data mining,pharmacology databases and experimental verification to study how EZECD treats damp-heat internalized T2D.Methods:The main compounds or genes of EZECD and damp-heat internalized T2D were obtained from the pharmacology databases.Succeeding,the overlapped targets of EZECD and damp-heat internalized T2D were performed by the Gene Ontology,kyoto encyclopedia of genes and genomes analysis.And the compound-disease targets-pathway network were constructed to obtain the hub compound.Moreover,the hub genes and core related pathways were mined with weighted gene co-expression network analysis based on Gene Expression Omnibus database,the capability of hub compound and genes was valid in AutoDock 1.5.7.Furthermore,and violin plot and gene set enrichment analysis were performed to explore the role of hub genes in damp-heat internalized T2D.Finally,the interactions of hub compound and genes were explored using comparative Toxicogenomics Database and quantitative polymerase chain reaction.Results:First,herb-compounds-genes-disease network illustrated that the hub compound of EZECD for damp-heat internalized T2D could be quercetin.Consistently,the hub genes were CASP8,CCL2,and AHR according to weighted gene co-expression network analysis.Molecular docking showed that quercetin could bind with the hub genes.Further,gene set enrichment analysis and Gene Ontology represented that CASP8,or CCL2,is negatively involved in insulin secretion response to the TNF or lipopolysaccharide process,and AHR or CCL2 positively regulated lipid and atherosclerosis,and/or including NOD-lik

关键词： data mining damp-heat internalized type 2 diabetes Erzhu Erchen decoction network pharmacology bioinformatics

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