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Outcomes of combined mitochondria and mesenchymal stem cellsderived exosome therapy in rat acute respiratory distress syndrome and sepsis

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World Journal of Stem Cells 2024年第6期16卷 690-707页

作者： Kun-Chen lin Wen-Feng Fang Jui-Ning Yeh john Y Chiang Hsin-Ju Chiang Pei-lin Shao Pei-Hsun Sung Hon-Kan Yip Department of Anesthesiology Kaohsiung Chang Gung Memorial HospitalKaohsiung 83301TaiwanChina Division of Pulmonary and Critical Care Medicine Department of Internal MedicineKaohsiung Chang Gung Memorial HospitalChang Gung University College of MedicineKaohsiung 83301TaiwanChina Department of Cardiology The First Affiliated Hospital of Jinan UniversityGuangzhou 510630Guangdong ProvinceChina Department of Computer Science and Engineering National Sun Yat-sen UniversityKaohsiung 804201TaiwanChina Department of Healthcare Administration and Medical Informatics Kaohsiung Medical UniversityKaohsiung 80708TaiwanChina School of Medicine Chung Shan Medical UniversityTaichung 40201TaiwanChina Department of Nursing Asia UniversityTaichung 41354TaiwanChina Division of Cardiology Department of Internal MedicineKaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung 83301TaiwanChina Institute for Translational Research in Biomedicine Kaohsiung Chang Gung Memorial HospitalKaohsiung 83301TaiwanChina Center for Shockwave Medicine and Tissue Engineering Kaohsiung Chang Gung Memorial HospitalKaohsiung 83301TaiwanChina Department of Medical Research China Medical University HospitalChina Medical UniversityTaichung 40402TaiwanChina School of Medicine College of MedicineChang Gung UniversityTaoyuan 33302TaiwanChina

BACKGROUND The treatment of acute respiratory distress syndrome(ARDS)complicated by sepsis syndrome(SS)remains *** To investigate whether combined adipose-derived mesenchymal-stem-cells(ADMSCs)-derived exosome(EXAD)and exogenous mitochondria(mitoEx)protect the lung from ARDS complicated by *** In vitro study,including l2 cells treated with lipopolysaccharide(lPS)and in vivo study including male-adult-SD rats categorized into groups 1(sham-operated-control),2(ARDS-SS),3(ARDS-SS+EXAD),4(ARDS-SS+mitoEx),and 5(ARDS-SS+EXAD+mitoEx),were included in the present *** In vitro study showed an abundance of mitoEx found in recipient-l2 cells,resulting in significantly higher mitochondrial-cytochrome-C,adenosine triphosphate and relative mitochondrial DNA levels(Plevels of inflammation[interleukin(Il)-1β/tumor necrosis factor(TNF)-α/nuclear factor-κB/toll-like receptor(TlR)-4/matrix-metalloproteinase(MMP)-9/oxidative-stress(NOX-1/NOX-2)/apoptosis(cleaved-caspase3/cleaved-poly(ADP-ribose)polymerase)]were significantly attenuated in lipopolysaccharide(lPS)-treated l2 cells with EXAD treatment than without EXAD treatment,whereas the protein expressions of cellular junctions[occluding/β-catenin/zonula occludens(ZO)-1/E-cadherin]exhibited an opposite pattern of inflam-mation(all Pls were euthanized by 72 h post-48 h-ARDS induction,and lung tissues were *** 72 h,flow cytometric analysis of bronchoalveolar lavage fluid demonstrated that the levels of inflam-matory cells(ly6G+/CD14+/CD68+/CD11b/c+/myeloperoxidase+)and albumin were lowest in group 1,highest in group 2,and significantly higher in groups 3 and 4 than in group 5(all Pl oxygen-saturation(SaO2%)displayed an opposite pattern of albumin among the *** findings of lung injury/fibrosis area and inflammatory/DNA-damaged markers(CD68+/γ-H2AX)displayed an identical pattern of SaO2%among the groups(all P<0.0001).The pro

关键词： Acute respiratory distress syndrome Sepsis syndrome Exosomes Mitochondria Adipose tissue-derived mesenchymal stem cells Inflammation

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Associations between health-related fitness and patient-reported symptoms in newly diagnosed breast cancer patients

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Journal of Sport and Health Science 2024年第6期13卷 851-862页

作者： Ki-Yong An Fernanda Z.Arthuso Myriam Filion Spencer J.Allen Stephanie M.Ntoukas Gordon J.Bell Jessica McNeil Qinggang Wang Margaret l.McNeely Jeff K.Vallance lin Yang S.Nicole Culos-Reed leanne Dickau john R.Mackey Christine M.Friedenreich Kerry S.Courneya Faculty of Kinesiology Sportand RecreationCollege of Health SciencesUniversity of AlbertaEdmonton T6G 2H9Canada Department of Kinesiology School of Health and Human SciencesUniversity of North Carolina at GreensboroGreensboroNC 27412USA Department of Cancer Epidemiology and Prevention Research Cancer Care AlbertaAlberta Health ServicesCalgary T2S 3C3Canada Faculty of Rehabilitation Medicine University of AlbertaEdmonton T6G 2H9Canada Faculty of Health Disciplines Athabasca UniversityAthabasca T9S 3A3Canada Department of Oncology Cumming School of MedicineUniversity of CalgaryCalgary T2N 4N1Canada Faculty of Kinesiology University of CalgaryCalgary T2N 1N4Canada Faculty of Medicine and Dentistry University of AlbertaEdmonton T6G 2H9Canada

Background:Newly diagnosed breast cancer patients experience symptoms that may affect their quality of life,treatment outcomes,and *** and managing breast cancer-related symptoms soon after diagnosis is *** purpose of this study was to investigate the associations between health-related fitness(HRF)and patient-reported symptoms in newly diagnosed breast cancer ***:This study utilized baseline data from the Alberta Moving Beyond Breast Cancer Cohort Study that were collected within 90 days of *** measures included peak cardiopulmonary fitness(peak volume of oxygen consumption(VO_(2peak))),maximal muscular strength and endurance,flexibility,and body *** measures included depression,sleep quality,and *** multivariable logistic regression was performed for ***:Of 1458 participants,51.5%reported poor sleep quality,26.5%reported significant fatigue,and 10.4%reported moderate *** multivariable-adjusted models,lower relative VO_(2peak)was independently associated with a greater likelihood of all symptom measures,including moderate depression(pleep quality(p=0.009),significant fatigue(p=0.008),any symptom(pltiple symptoms(pld associations with all symptom measures such that all 3 lower quartiles exhibited similar elevated risk compared to the highest *** strength of the threshold associations varied by the symptom measure with odds ratios ranging from-1.5 for poor sleep quality to-3.0 for moderate depression and multiple ***,lower relative upper body muscular endurance was also independently associated with fatigue in a dose-response manner(p=0.001),and higher body weight was independently associated with poor sleep quality in an inverted U pattern(p=0.021).Conclusion:Relative VO_(2peak)appears to be a critical HRF component associated with multiple patient-reported symptoms in newly diag

关键词： Breast cancer Fatigue Depression Sleep quality Cardiorespiratory fitness

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植物凝集素类受体激酶研究进展

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热带亚热带植物学报 2024年

作者：熊圭 john Seymour HESlOP-HARRISON 刘青植物多样性与特色经济作物全国重点实验室广东省应用植物学重点实验室中国科学院华南植物园华南国家植物园中国科学院大学莱斯特大学遗传学和基因组生物学系

植物凝集素类受体激酶(lectin receptor-like kinases， lecRlKs)，隶属于植物膜蛋白类受体激酶，lecRlKs主要由胞外凝集素结构域、跨膜结构域和胞内激酶结构域组成，根据胞外结构域的特异性，分为G型、l型和C型，凝集素类受体激酶参与... 详细信息

植物凝集素类受体激酶(lectin receptor-like kinases， lecRlKs)，隶属于植物膜蛋白类受体激酶，lecRlKs主要由胞外凝集素结构域、跨膜结构域和胞内激酶结构域组成，根据胞外结构域的特异性，分为G型、l型和C型，凝集素类受体激酶参与植物的生长发育和环境响应调控。该文总结凝集素类受体激酶的研究历史、结构和分类，阐述植物lecRlKs的发育调控和胁迫响应功能，对功能明确的lecRlKs基因进行归类。提出凝集素类受体激酶研究中存在的不足之处，包括该家族演化历史研究极其缺乏、信号传导途径及其潜在配体亟待开展等方面。在此基础上，提出未来深入研究的方向，以期为植物凝集素类受体激酶基因家族的定向育种提供理论支持。

关键词：凝集素类受体蛋白激酶生长发育生物/非生物胁迫免疫

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Geochemistry and mineralogy of beach sediments in the northern Gulf of Mexico,Tamaulipas state,Mexico:implication for provenance

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Journal of Palaeogeography 2024年第3期13卷 375-400页

作者： Mayank Shukla Sanjeet K.Verma Mayla A.Ramos-Vázquez john S.Armstrong-Altrin Karla R.Hernández-Martínez Sumit Mishra Vivek P.Malviya Héctor Hernández-Mendoza Posgrado de la Division de Geociencias Aplicadas Instituto Potosino de Investigacion Científica y Tecnologica(IPICYT)Camino a la Presa San José2055San Luis Potosí78216Mexico Division de Geociencias Aplicadas Instituto Potosino de Investigación Científica y Tecnologica(IPICYT)Camino a la Presa San Jose 2055San Luis Potosí78216Mexico Universidad Nacional Autonoma de México Instituto de Ciencias del Mar y LimnologíaUnidad de ProcesosOceanicos y CosterosCiudad UniversitariaCiudad de México 04510Mexico Department of Marine Sciences Bharathidasan UniversityTiruchirappalli620024Tamil NaduIndia Instituto de Geociencias Universidad Nacional Autonoma de MéxicoBoulevard Juriquilla 300176230JuriquillaQueretaroMexico Department of Applied Geology Dr.Harisingh Gour Central UniversitySagar470002Madhya PradeshIndia Instituto de Investigacion de Zonas Desérticas Universidad Autònoma de San Luis PotosíAltair 200CP 78377San LuisS.L.P.Mexico Universidad del Centro de Mexico Capitán Caldera 75CP 78250San LuisS.L.P.Mexico

Geochemical and mineralogical studies were performed in the la Pesca(lP)and Tesoro Altamira(TA)beach sediments,located in the Tamaulipas state,northern Gulf of *** main aim of this study is to infer the weathering history and provenance and to discriminate the tectonic environment of the beach *** sediments are composed of quartz with small amounts of accessory minerals such as plagioclase,calcite,orthoclase,microcline,and *** beach sediments are classified as fine-grained and very well sorted,however lP has coarse skewed and leptokurtic sediments,whereas TA has fine-skewed and very leptokurtic *** chemical index of weathering(CIW’)indicates intense weathering in the source *** quartz grain microtextures in the lP and TA are classified into mechanical,chemical,and mechanical/chemical *** features such as fractures,pits,percussion marks,abrasion fatigue,and V-shaped marks favor high-energy littoral,fluvial,subaqueous-marine,and aeolian *** chemical features indicate solution pits and crystalline overgrowth,which suggests a silica saturated marine *** mechanical/chemical features display adhering particles and elongated depressions suggest formation in a sub-aqueous nearshore marine *** and trace elements-based provenance discrimination diagrams indicate a felsic source derived from the Mesa Central(MC),Sierra Madre Oriental(SMOr)and Oaxaquia *** major and trace element concentrations imply a passive margin setting for the northern Gulf of Mexico,which is consistent with the general geology.

关键词： Beach sediments Geochemistry Mineralogy Provenance Tamaulipas Tectonic setting

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Integrative genomic and transcriptomic profiling of pulmonary sarcomatoid carcinoma identifies molecular subtypes associated with distinct immune features and clinical outcomes

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Cancer Innovation 2024年第3期3卷 81-94页

作者： Sahil Seth Runzhe Chen Yang liu Junya Fujimoto lingzhi Hong Alexandre Reuben Susan Varghese Carmen Behrens Tina McDowell luisa Solis Soto Cara Haymaker Annikka Weissferdt Neda Kalhor Jia Wu Xiuning le Natalie I Vokes Chao Cheng john V.Heymach Don l.Gibbons P.Andrew Futreal Ignacio IWistuba Humam Kadara Jianhua Zhang Cesar Moran Jianjun Zhang Department of Genomic Medicine The University of Texas MD Anderson Cancer CenterHoustonTexasUSA TRACTION The University of Texas MD Anderson Cancer CenterHoustonTexasUSA Graduate School of Biomedical Sciences The University of Texas MD Anderson and the University of Texas Health Science CenterHoustonTexasUSA Department of Thoracic/Head and Neck Medical Oncology The University of Texas MD Anderson Cancer CenterHoustonTexasUSA Department of Translational Molecular Pathology The University of Texas MD Anderson Cancer CenterHoustonTexasUSA Department of Epidemiology The University of Texas MD Anderson Cancer CenterHoustonTexasUSA Department of Pathology The University of Texas MD Anderson Cancer CenterHoustonTexasUSA Department of Imaging Physics The University of Texas MD Anderson Cancer CenterHoustonTexasUSA Department of Medicine Baylor College of MedicineHoustonTexasUSA

Background:Pulmonary sarcomatoid carcinoma(PSC)is a rare and aggressive subtype of non-small cell lung cancer(NSClC),characterized by the presence of epithelial and sarcoma-like *** molecular and immune landscape of PSC has not been well ***:Multiomics profiling of 21 pairs of PSCs with matched normal lung tissues was performed through targeted high-depth DNA panel,whole-exome,and RNA *** describe molecular and immune features that define subgroups of PSC with disparate genomic and immunogenic features as well as distinct clinical ***:In total,27 canonical cancer gene mutations were identified,with TP53 the most frequently mutated gene,followed by ***,most TP53 and KRAS mutations were earlier genomic events mapped to the trunks of the tumors,suggesting branching evolution in most PSC *** identified two distinct molecular subtypes of PSC,driven primarily by immune infiltration and *** Immune High(IM-H)subtype was associated with superior survival,highlighting the impact of immune infiltration on the biological and clinical features of localized ***:We provided detailed insight into the mutational landscape of PSC and identified two molecular subtypes associated with ***-H tumors were associated with favorable recurrence-free survival and overall survival,highlighting the importance of tumor immune infiltration in the biological and clinical features of PSCs.

关键词： genomic immune pulmonary sarcomatoid carcinoma survival

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Effect of l-theanine combined with geniposide on depression-like behavior induced by the chronic unpredictable mild stress(CUMS) in mice

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Food Science and Human Wellness 2024年

作者： Qi-Ming Yu Yan Zhu Tao Jiang Ying Gao Nan ling Na Wang john Shi Wei-Chun Pan Qi-Zhen Du Jun-Feng Yin Tea Research Institute Chinese Academy of Agricultural Sciences Key laboratory of Tea Biology and Resources Utilization Ministry of Agriculture College of Food and Health Sciences Zhejiang A & F University Zhejiang Gongshang University Guelph Food Research Center Agriculture and Agri-Food Canada College of Public Health Guilin Medical University

Depression is a prevalent mental disorder with limited effective treatments， posing a significant global issue. This study explored l-theanine and geniposide， key components in "food-medicine homology" materials， to determine if their combination (TG) could alleviate depression-like behaviors and hippocampal neuronal damage in a chronic unpredictable mild stress (CUMS) mouse model. Male C57Bl/6J mice were divided into control， CUMS model， and CUMS+TG groups with varying doses. The CUMS group displayed depression-like behaviors， including reduced activity and sucrose preference. TG treatment partially reversed these changes， significantly increasing antioxidant enzyme activities， decreasing pro-inflammatory cytokine levels， and improving neuromodulator levels. RNA-seq analysis identified the transthyretin (TTR) gene， upregulated in the model group but downregulated after TG treatment. TG treatment modulated intestinal microbiota composition compared to the CUMS group， including increased Firmicutes， reduced Bacteroidetes and Prevotella， and variable changes in Bifidobacterium abundance. In conclusion， our study indicates that CUMS exposure upregulates stress hormones and TTR expression， associated with neuroinflammation， oxidative stress， monoamine depletion， depression-like behaviors， and intestinal microbiota dysbiosis. TG treatment alleviates these effects and modulates intestinal microbiota， suggesting l-theanine and geniposide’s potential as a novel depression therapy.

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Effects of a school-based karate intervention on academic achievement,psychosocial functioning,and physical fitness:A multi-country cluster randomized controlled trial

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Journal of Sport and Health Science 2024年第1期13卷 90-98页

作者： Tania Pinto-Escalona Erica Gobbi Pedro l.Valenzuela Simon J.Bennett Pierluigi Aschieri Manuel Martin-loeches Antonio Paoli Oscar Martinez-de-Quel Faculty of Education Complutense University of MadridMadrid 28040Spain Department of Biomolecular Sciences University of Urbino“Carlo Bo”Urbino 61029Italy Department of Systems Biology University of AlcaláMadrid 28805Spain Research Institute for Sport and Exercise Sciences Faculty of ScienceLiverpool John Moores UniversityLiverpoolL33AFUK Italian Judo WrestlingKarate and Martial Arts FederationRome 00122Italy Psychobiology&Methods for the Behavioural Sciences Department Complutense University of MadridMadrid 28040Spain Department of Biomedical Sciences University of PaduaPadua 35122Italy

Purpose:To examine the effects of a school-based karate intervention on academic achievement,psychosocial functioning,and physical fitness in children aged 7-8 ***:Twenty schools in 5 different European countries(2 second-grade classrooms per school)participated in a cluster randomized controlled trial(Sport at School trial).Participants were assigned to either a control group,which continued with their habitual physical education lessons,or to an intervention group,which replaced these lessons with a 1-year karate intervention(Karate Mind and Movement program).A total of 721 children(344 girls and 377 boys,7.4±0.5 years old,mean±SD)completed the study,of which 333 and 388 were assigned to the control group and intervention group,*** included academic performance(average grade),psychosocial functioning(Strengths and Difficulties Questionnaire for parents),and different markers of physical fitness(cardiorespiratory fitness,balance,and flexibility).Results:The intervention provided small but significant benefits compared to the control group for academic achievement(d=0.16;p=0.003),conduct problems(d=-0.28;p=0.003),cardiorespiratory fitness(d=0.36;plance(d=0.24;p=0.015).There was a trend towards significant benefits for flexibility(d=0.24;p=0.056).No significant benefits were observed for other variables,including psychosocial difficulties,emotional symptoms,hyperactivity/inattention,peer problems,or prosocial behaviour(all p>0.05).Conclusion:A 1-year school-based karate intervention was effective in improving academic achievement,conduct problems,and physical fitness in primary school *** results support the inclusion of karate during physical education lessons.

关键词： Academic performance Cardiorespiratory fitness Conduct problems Karate Physical fitness

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Analyzing neural degeneration of the retina with connectomics

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Neural Regeneration Research 2022年第1期17卷 113-114页

作者： Charles l.Zucker john E.Dowling Department of Molecular and Cellular Biology Harvard UniversityCambridgeMAUSA

Electron microscopy(EM)provides a unique ability to visualize structural detail with a resolution orders of magnitude better than other imaging *** conventionally,its limitation is that each acquired image represents a small area with a section thickness significantly less than 100 ***,techniques have been developed that allow thousands of relatively large serial-sections to be collected and efficiently imaged at full EM resolution,with the images then being stitched back together to produce a 3D volume.

关键词： neural image Applied

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Superior antibody and membrane protein‑specific T‑cell responses to CoronaVac by intradermal versus intramuscular routes in adolescents

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World Journal of Pediatrics 2024年第4期20卷 353-370页

作者： Jaime S.Rosa Duque Samuel M.S.Cheng Carolyn A.Cohen Daniel leung Xiwei Wang Xiaofeng Mu Yuet Chung Tsun Ming lau Manni Wang Wenyue Zhang Yanmei Zhang Howard H.W.Wong leo C.H.Tsang Sara Chaothai Tsz Chun Kwan john K.C.li Karl C.K.Chan leo l.H.luk Jenson C.H.Ho Wing Yan li Amos M.T.lee Jennifer H.Y.lam Sau Man Chan Wilfred H.S.Wong Issan Y.S.Tam Masashi Mori Sophie A.Valkenburg Malik Peiris Wenwei Tu Yu lung lau Department of Paediatrics and Adolescent Medicine The University of Hong KongHong KongChina School of Public Health The University of Hong KongHong KongChina HKU‑Pasteur Research Pole School of Public HealthThe University of Hong KongHong KongChina Research Institute for Bioresources and Biotechnology Ishikawa Prefectural UniversityNonoichiJapan Department of Microbiology and Immunology Peter Doherty Institute for Infectionand ImmunityUniversity of MelbourneMelbourneVICAustralia Center for Immunology and Infection C2i Hong KongChina

Background Optimising the immunogenicity of COVID-19 vaccines to improve their protection against disease is *** dosing by intradermal(ID)administration has been shown to be equally immunogenic as intramuscular(IM)administration for several vaccines,but the immunogenicity of ID inactivated whole severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)at the full dose is *** study(NCT04800133)investigated the superiority of antibody and T-cell responses of full-dose CoronaVac by ID over IM administration in *** Participants aged 11–17 years received two doses of IM or ID vaccine,followed by the 3rd dose 13–42 days *** and cellular immunogenicity outcomes were measured post-dose 2(IM-CC versus ID-CC)and post-dose 3(IMCCC versus ID-CCC).Doses 2 and 3 were administered to 173 and 104 adolescents,*** Spike protein(S)immunoglobulin G(IgG),S-receptor-binding domain(RBD)IgG,S IgG Fcγreceptor IIIa(FcγRIIIa)-binding,SNM[sum of individual(S),nucleocapsid protein(N),and membrane protein(M)peptide pool]-specific interleukin-2(Il-2)+CD4^(+),SNM-specific Il-2^(+)CD8^(+),S-specific Il-2^(+)CD8^(+),N-specific Il-2^(+)CD4^(+),N-specific Il-2^(+)CD8^(+)and M-specific Il-2^(+)CD4^(+)responses fulfilled the superior and non-inferior criteria for ID-CC compared to IM-CC,whereas IgG avidity was *** ID-CCC,S-RBD IgG,surrogate virus neutralisation test,90%plaque reduction neutralisation titre(PRNT90),PRNT50,S IgG avidity,S IgG FcγRIIIa-binding,M-specific Il-2^(+)CD4^(+),interferon-γ+CD8^(+)and Il-2^(+)CD8^(+)responses were superior and non-inferior to *** estimated vaccine efficacies were 49%,52%,66%and 79%for IM-CC,ID-CC,IM-CCC and ID-CCC,*** ID groups reported more local,mild adverse *** This is the first study to demonstrate superior antibody and M-specific T-cell responses by ID inactivated SARSCoV-2 vaccination and serves as the basis for future research to improve the

关键词： CoronaVac Coronavirus disease 2019 Immunity Intradermal Vaccine

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分支河流体系河网形态演变规律——以格尔木河流扇为例

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地质论评 2024年第3期70卷 1047-1060页

作者：王浩楠张昌民孙家惠张祥辉徐清海刘洪平 Adrian john HARTlEY 长江大学地球科学学院中国武汉430100 阿伯丁大学地球科学学院英国阿伯丁AB243UE

为了探索分支河流体系河网分布规律,为创建储层建模训练图像提供知识库信息。利用Google Earth、Global Mapper、91卫图助手等现代地理信息软件,系统测量了现代格尔木河流扇表面河道分叉特征,应用Horton定律和分形方法建立了河流扇的河... 详细信息

为了探索分支河流体系河网分布规律,为创建储层建模训练图像提供知识库信息。利用Google Earth、Global Mapper、91卫图助手等现代地理信息软件,系统测量了现代格尔木河流扇表面河道分叉特征,应用Horton定律和分形方法建立了河流扇的河网形态模型。结果表明:①格尔木河流扇从顶点到入湖段共识别出26级河道,882个节点和2162个河道段,泉线上、下的河道表现出不同的河网形态;②泉线上部共发育64个节点,每级河道数目增长是上一级河道的R_(B)=1.8900倍,每级河道平均长度是下一级河道的R_(l)=1.0095倍,即河网形态特征参数R_(B)=1.8900和R_(l)=1.0095;泉线下部共发育818个节点,每级河道数目增长是上一级河道的R_(B)=1.0279倍,每级河道平均长度是下一级河道的R_(l)=0.9899倍,即河网形态特征参数是R_(B)=1.0279和R_(l)=0.9899;③河网形态特征参数受坡度影响变化较大,坡度较大则河网形态特征参数较大,坡度较小则河网形态特征参数较小。河网形态特征参数定量表征促进了分支河流体系沉积学发展,为开展陆相盆地储层建模和砂体预测提供了新的知识库信息.

关键词：分支河流体系河网形态河网模型 Horton定律格尔木河流扇

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