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Integrative phosphoproteomics defines two biologically distinct groups of KMT2A rearranged acute myeloid leukaemia with different drug response phenotypes

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Signal Transduction and Targeted Therapy 2023年第3期8卷 1318-1331页

作者： Pedro Casado Ana Rio-Machin Juho JMiettinen Findlay Bewicke-Copley kevin rouault-pierre Szilvia Krizsan Alun Parsons Vinothini Rajeeve Farideh Miraki-Moud David CTaussig Csaba Bödör John Gribben Caroline Heckman Jude Fitzgibbon Pedro R.Cutillas Cell Signalling and Proteomics Group Centre for Genomics and Computational BiologyBarts Cancer InstituteQueen Mary University of LondonLondon EC1M6BQUK Centre for Genomics and Computational Biology Barts Cancer InstituteQueen Mary University of LondonLondon EC1M6BQUK Institute for Molecular Medicine Finland-FIMM HiLIFE-Helsinki Institute of Life ScienceiCAN Digital Precision Cancer Medicine FlagshipUniversity of HelsinkiHelsinkiFinland Centre for Haemato-Oncology Barts Cancer InstituteQueen Mary University of LondonLondon EC1M6BQUK HCEMM-SU Molecular Oncohematology Research Group 1st Department of Pathology and Experimental Cancer ResearchSemmelweis University BudapestBudapestHungary Cancer Research UK Cancer Therapeutics Unit Division of Cancer TherapeuticsThe Institute of Cancer ResearchSuttonUK a The Alan Turing Institute The British Library2QR96 Euston RdLondon NW12DBUK

Acute myeloid leukaemia(AML)patients harbouring certain chromosome abnormalities have particularly adverse *** these patients,targeted therapies have not yet made a significant clinical *** understand the molecular landscape of poor prognosis AML we profiled 74 patients from two different centres(in UK and Finland)at the proteomic,phosphoproteomic and drug response phenotypic *** data were complemented with transcriptomics analysis for 39 *** integration highlighted a phosphoproteomics signature that define two biologically distinct groups of KMT2A rearranged leukaemia,which we term MLLGA and *** presented increased DOT1L phosphorylation,HOXA gene expression,CDK1 activity and phosphorylation of proteins involved in RNA metabolism,replication and DNA damage when compared to MLLGB and no KMT2A rearranged *** was particularly sensitive to 15 compounds including genotoxic drugs and inhibitors of mitotic kinases and inosine-5-monosphosphate dehydrogenase(IMPDH)relative to other ***-risk KMT2A-MLLT3 cases were mainly represented in a third group closer to MLLGA than to *** expression of IMPDH2 and multiple nucleolar proteins was higher in MLLGA and correlated with the response to IMPDH inhibition in KMT2A rearranged leukaemia,suggesting a role of the nucleolar activity in sensitivity to *** summary,our multilayer molecular profiling of AML with poor prognosis and KMT2A-MLLT3 karyotypes identified a phosphoproteomics signature that defines two biologically and phenotypically distinct groups of KMT2A rearranged *** data provide a rationale for the potential development of specific therapies for AML patients characterised by the MLLGA phosphoproteomics signature identified in this study.

关键词： metabolism signature biologically

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The effect of landscape complexity and microclimate on the thermal tolerance of a pest insect

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Insect Science 2018年第5期25卷 905-915页

作者： Lucy Alford kevin Tougeron Jean-Sebastien pierre Francoise Burel Joan van Baaren UMR 6553 ECOBIO Centre National de la Recherche Scientitique Universite de Rennes I Rennes Cedex France Departement de Sciences Biologiques Insfitut de Recherche en Biologie Vegetale Universite de Montreal Montreal QC Canada Universite Europeenne de Bretagne (UEB) Rennes France

Landscape changes are known to exacerbate the impacts of climate change. As such, understanding the combined effect of climate and landscape on agroecosystems is vital if we are to maintain the fimction of agroecosystems. This study aimed to elucidate the effects of agricultural landscape complexity on the microclimate and thermal tolerance of an aphid pest to better understand how landscape and climate may interact to affect the thermal tolerance of pest species within the context of global climate change. Meteo- rological data were measured at the landscape level, and cereal aphids （Sitobion avenae, Metopolophium dirhodum and Rhopalosiphum padi） sampled, from contrasting landscapes （simple and complex） in winter 2013/2014 and spring 2014 in cereal fields of Brittany, France. Aphids were returned to the laboratory and the effect of landscape of origin on aphid cold tolerance （as determined by CTmin） was investigated. Results revealed that local landscape complexity significantly affected microclimate, with simple homogenous landscapes being on average warmer, but with greater temperature variation. Landscape complexity was shown to impact aphid cold tolerance, with aphids from complex land- scapes being more cold tolerant than those from simple landscapes in both winter and spring, but with differences among species. This study highlights that future changes to land use could have implications for the thermal tolerance and adaptability of insects. Fur- thermore, not all insect species respond in a similar way to microhabitat and microclimate, which could disrupt important predator-prey relationships and the ecosystem service they provide.

关键词： agroecosystems biological control cereal aphids climate change coldtolerance landscape ecology

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Quantitative proteomic determination of diethylstilbestrol action on prostate cancer

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Asian Journal of Andrology 2013年第3期15卷 413-420页

作者： pierre Bigot kevin Mouzat Muriel Bahut Nora Benhabiles Geraldine Cancel Tassin Abdel-Rahmene Azzouzi Olivier Cussenot Department of Urology Angers University Hospital Angers 49933 France CeRePP Tenon Hospital Paris 75970 France Department of Biochemistry N'imes University Hospital NTmes 30029 France Plate-Forme Technologique de Biotechnologie Moleculaire Angers University Angers 49933 France 5CEA DSV IRCM SREIT Laboratoire de Cancerologie Experimentale Fontenay-aux-Roses 92265 France

Diethylstilbestrol （DES） has a direct cellular mechanism inhibition on prostate cancer. Its action is independent from the oestrogen receptors and is preserved after a first-line hormonal therapy. We aimed to identify proteins involved in the direct cellular inhibition effects of DES on prostate cancer. We used a clonogenic assay to establish the median lethal concentration of DES on 22RV1 cells. 22RV1 cells were exposed to standard and DES-enriched medium. After extraction, protein expression levels were obtained by two-dimensional differential in-gel electrophoresis （2D-DIGE） and isotope labelling tags for relative and absolute quantification （iTRAQ）. Proteins of interest were analysed by quantitative RT-PCR and western blotting. The differentially regulated proteins （P〈0.01） were interrogated against a global molecular network based on the ingenuity knowledge base. The 2D-DIGE analyses revealed DES-induced expression changes for 14 proteins （〉 1.3 fold; P〈0.05）. The iTRAQ analyses allowed the identification of 895 proteins. Among these proteins, 65 had a modified expression due to DES exposure （i.e., 23 overexpressed and 42 underexpressed）. Most of these proteins were implicated in apoptosis and redox processes and had a predicted mitochondrial expression. Additionally, ingenuity pathway analysis placed the OAT and HSBP1 genes at the centre of a highly significant network. RT-PCR confirmed the overexpression of OAT （P=0.006） and HSPB1 （P=0.046）.

关键词： cultured cells DES diethylstilbestrol ingenuity pathway analysis isotope labelling mass spectrometry prostate cancer proteomics

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Chemical reproductive traits of diploid Bombus terrestris males： Consequences on bumblebee conservation

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Insect Science 2017年第4期24卷 623-630页

作者： Thomas Lecocq Maxence Gerard kevin Maebe Nicolas Brasero Lauren Dehon Guy Smagghe Irena Valterova Thibaut De Meulemeester pierre Rasmont Denis Michez Laboratory of Zoology Research Institute of Biosciences University of Mons Mons France Research Unit Animal and Functionalities of Animal Products (URAFPA) University of Lorraine - INRA Avenue de la Foret de Haye BP 172 F-54505 Vandoeuvre-les-Nancy France Department of Crop Protection Faculty of Bioscience Engineering Ghent University Coupure links 653 B-9000 Ghent Belgium Academy of Sciences of the Czech Republic Institute of Organic Chemistry and Biochemistry Flamingovo nam 2 CZ 166 10 Prague Czech Republic Naturalis Biodiversity Center Darwinweg 2 Postbus 9517 2300 RA Leiden the Netherlands

The current bumblebee decline leads to inbreeding in populations that fosters a loss of allelic diversity and diploid male production. As diploid males are viable and their offspring are sterile, bumblebee populations can quickly fall in a vortex of extinction. In this article, we investigate for the first time a potential premating mechanism through a major chemical reproductive trait （male cephalic labial gland secretions） that could prevent monandrous virgin queens from mating with diploid males. We focus our study on the cephalic labial gland secretions of diploid and haploid males ofBombus terrestris （L.）. Contrary to initial expectations, our results do not show any significant differentiation of cephalic labial gland secretions between diploid and haploid specimens. Queens seem therefore to be unable to avoid mating with diploid males based on their compositions of cephalic labial gland secretions. This suggests that the vortex of extinction of diploid males could not be stopped through premating avoidance based on the cephalic labial gland secretions but other mechanisms could avoid mating between diploid males and queens.

关键词： bee decline bumblebees conservation diploid males premating recogni-tion reproductive traits

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TREM-1 multimerization is essential for its activation on monocytes and neutrophils

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Cellular & Molecular Immunology 2019年第5期16卷 460-472页

作者： kevin Carrasco Amir Boufenzer Lucie Jolly Helene Le Cordier Guanbo Wang Albert JR Heck Adelheid Cerwenka Emilie Vinolo Alexis Nazabal Alexandre Kriznik pierre Launay Sebastien Gibot Marc Derive INOTREM Vandœuvre-les-NancyFrance UMR-S 1116 Defaillance cardiovasculaire aigue et chroniqueVandœuvre-les-NancyFrance UMR7365 Ingénierie Moléculaire et Physiopathologie Articulaire(IMoPA)CNRS-Universitéde LorraineVandœuvre-les-NancyFrance Biomolecular Mass Spectrometry and Proteomics Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences and Netherlands Proteomics CenterUtrecht UniversityUtrechtThe Netherlands Innate Immunity German Cancer Research Center(DKFZ)HeidelbergGermany CovalX ZurichSwitzerland Service Commun de Biophysique Interactions Moléculaires(SCBIM) FR3209Biopole de l’Universitede LorraineVandœuvre-les-NancyFrance Inatherys Evry CedexFrance

The triggering receptor expressed on myeloid cells-1(TREM-1)is a receptor expressed on innate immune *** promoting the amplification of inflammatory signals that are initially triggered by Toll-like receptors(TLRs),TREM-1 has been characterized as a major player in the pathophysiology of acute and chronic inflammatory diseases,such as septic shock,myocardial infarction,atherosclerosis,and inflammatory bowel ***,the molecular events leading to the activation of TREM-1 in innate immune cells remain ***,we show that TREM-1 is activated by multimerization and that the levels of intracellular Ca 2+release,reactive oxygen species,and cytokine production correlate with the degree of TREM-1 ***-1 activation on primary human monocytes by LPS required a two-step process consisting of upregulation followed by clustering of TREM-1 at the cell surface,in contrast to primary human neutrophils,where LPS induced a rapid cell membrane reorganization of TREM-1,which confirmed that TREM-1 is regulated differently in primary human neutrophils and *** addition,we show that the ectodomain of TREM-1 is able to homooligomerize in a concentration-dependent manner,which suggests that the clustering of TREM-1 on the membrane promotes its *** further show that the adapter protein DAP12 stabilizes TREM-1 surface expression and ***-1 multimerization at the cell surface is also mediated by its endogenous ligand,a conclusion supported by the ability of the TREM-1 inhibitor LR12 to limit TREM-1 *** results provide evidence for ligand-induced,receptor-mediated dimerization of ***,our findings uncover the mechanisms necessary for TREM-1 activation in monocytes and neutrophils.

关键词： TREM-1 multimerization activation monocytes neutrophils

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High-finesse Fabry-Perot cavities with bidimensional Si_(3)N_(4) photonic-crystal slabs

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Light(Science & Applications) 2016年第1期5卷 320-327页

作者： Xu Chen Clément Chardin kevin Makles Charles Caër Sheon Chua Rémy Braive Isabelle Robert-Philip Tristan Briant pierre-François Cohadon Antoine Heidmann Thibaut Jacqmin Samuel Deléglise Laboratoire Kastler Brossel UPMC-Sorbonne UniversitésCNRSENS-PSL Research UniversityCollège de France4 place JussieuCase 74F75252 ParisFrance Current address:IBM Research-Zürich Säumerstrasse 48803 RüschlikonSwitzerland Laboratoire de Photonique et de Nanostructures LPN-CNRS/CNRS Route de Nozay91460 MarcoussisFrance UniversitéParis Diderot Sorbonne Paris Cité75207 ParisFrance

Light scattering by a two-dimensional photonic-crystal slab(PCS)can result in marked interference effects associated with Fano *** devices offer appealing alternatives to distributed Bragg reflectors and filters for various applications,such as optical wavelength and polarization filters,reflectors,semiconductor lasers,photodetectors,bio-sensors and non-linear optical *** PCS also have natural applications in the field of optomechanics,where the mechanical modes of a suspended slab interact via radiation pressure with the optical field of a high-finesse *** reflectivity and transmission properties of a defect-free suspended PCS around normal incidence can be used to couple out-of-plane mechanical modes to an optical field by integrating it in a free-space *** we demonstrate the successful implementation of a PCS reflector on a high-tensile stress Si_(3)N_(4) *** illustrate the physical process underlying the high reflectivity by measuring the photonic-crystal band ***,we introduce a clear theoretical description of the membrane scattering properties in the presence of optical *** embedding the PCS inside a high-finesse cavity,we fully characterize its optical *** spectrally,angular-and polarization-resolved measurements demonstrate the wide tunability of the membrane’s reflectivity,from nearly 0 to 99.9470±0.0025%,and show that material absorption is not the main source of optical ***,the cavity storage time demonstrated in this work exceeds the mechanical period of low-order mechanical drum *** so-called resolved-sideband condition is a prerequisite to achieve quantum control of the mechanical resonator with light.

关键词： Fano resonance high-reflectivity membrane low-loss optical reflector nanomembrane resonator photonic-crystal slab quantum optomechanics

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The role of photovaporization of the prostate in small volume benign prostatic hyperplasia and review of the literature

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Asian Journal of Urology 2019年第4期6卷 353-358页

作者： Dominique Thomas kevin C.Zorn Malek Meskawi Ramy Goueli pierre-Alain Hueber Lesa Deonarine Vincent Misrai Alexis Te Bilal Chughtai Department of Urology Weill Cornell Medical College/New York PresbyterianNew YorkNYUSA Section of Urology Department of SurgeryUniversity of Montreal Hospital CenterMontrealQCCanada

Objective:Our objective was to characterize the safety and efficacy of the 180 W XPS-GreenLight laser in men with lower urinary tract symptoms secondary to a small volume benign prostatic hyperplasia(BPH).Methods:A retrospective analysis was performed for all patients who underwent 180 W XPSlaser photoselective vaporization of the prostate(PVP)vaporization of the prostate between 2012 and 2016 at two-tertiary medical *** collection included baseline comorbidities,disease-specific quality of life scores,maximum urinary flow rate(Qmax),postvoid residual(PVR),complications,prostate volume and prostate-specific antigen(PSA).The secondary endpoints were the incidence of intraoperative and postoperative adverse *** were stratified using the Clavien-Dindo grading system up to 90 days after ***:Mean age of men was 67.8 years old,with a mean body mass index of 29.7 kg/*** prostate volume as measured by transrectal ultrasound was 29 *** use was 47%and urinary retention with catheter at time of surgery was 17%.Mean hospital stay and catheter time were 0.5 *** follow-up time was 6 months with the longest duration of follow-up being 22.5 months(interquartile range,3-22.5 months).The International Prostate Symptom Score improved from 22.8±7.0 at baseline to 10.7±7.4(p<0.01)and 6.3±4.4(p<0.01)at 1 and 6 months,*** Qmax improved from 7.70±4.46 mL/s at baseline to 17.25±9.30 mL/s(p<0.01)and 19.14±7.19 mL/s(p<0.001)at 1 and 6 months,respectively,while the PVR improved from 216.0±271.0 mL preoperatively to 32.8±45.3 mL(p<0.01)and 26.2±46.0 mL(p<0.01)at 1 and 6 months,*** PSA dropped from 1.97±1.76 ng/mL preoperatively to 0.71±0.61 ng/mL(p<0.01)and 0.74±0.63 ng/mL at 1 and 6 months,*** patient had a bladder neck contracture postoperatively and no capsular perforations were noted ***:The 180 W GreenLight XPS system is safe and effective for men with small volume

关键词： Benign prostatic hyperplasia Photovaporization of the prostate GreenLight XPS Lower urinary tract symptoms Small prostate

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Determination of the Genetic Structure of the Oleaginous <i>Lagenaria siceraria</i>of the Nangui Abrogoua University Germplasm Collection

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American Journal of Plant Sciences 2015年第19期6卷 3231-3243页

作者： Ahou Anique Gbotto Kouamé kevin Koffi Jean-pierre Baudoin Irié Arsène Zoro Bi Laboratoire de Génomique Fonctionnelle et Amélioration Génétique (LaGeFAGe) UFR-SN Université Nangui Abrogoua Abidjan C&ocirc te d’Ivoire Unité de Phytotechnie Tropicale et d’Horticulture Gembloux Agro Bio Tech Université de Liège Gembloux Belgium

Thirty accessions of Lagenaria siceraria from the Nangui Abrogoua University germplasm collection were analyzed using three microsatellite markers. The average Polymorphism Information Content (PIC) value was 0.61. The average observed heterozygosity value (H0 = 0.631) compared to the average expected heterozygosity value (He = 0.645) did not show significant differences in the selected accessions, which suggested random mating in the set of accessions. Within accession inbreeding estimate (FIS), was 40% and was not significantly different from zero. The reduction of heterozygotes was likely the result of presence of null alleles. Analysis of Molecular Variance (AMOVA) within and among 30 accessions of L. siceraria revealed that 39% of the total variation resides among accessions and 61% within accessions. Accession structuring pattern derived from Bayesian clustering analysis revealed two clusters. Based on the genetic structure of the accessions analyzed, a sampling strategy to collect and conserve genetic resources of L. siceraria was suggested.

关键词： Genetic Structure Lagenaria siceraria Null Alleles Oleaginous SSR

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Genomic stability at the coding regions of the multidrug transporter gene ABCB1: insights into the development of alternative drug resistance mechanisms in human leukemia cells

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Cancer Drug Resistance 2020年第4期3卷 959-979页

作者： kevin G.Chen George E.Duran Mark J.Mogul Yan C.Wang kevin L.Ross Jean-pierre Jaffrézou Lyn M.Huff Kory R.Johnson Tito Fojo Norman J.Lacayo Branimir I.Sikic Division of Oncology Department of MedicineStanford University School of MedicineStanfordCA 94305USA Current Address:NIH Stem Cell Unit National Institute of Neurological Disorders and StrokeNational Institutes of HealthBethesdaMD 20892USA Current Address:Medical Affairs U.S. Servier PharmaceuticalsBostonMA 02210USA Current Address:Ross BioPharm Group Rocky PointNY 11778USA Current Address:French National Centre for Scientific Research Paris 75016France Medicine Branch National Cancer InstituteNational Institutes of HealthBethesdaMD 20892USA Current Address Laboratory of Cell BiologyNational Cancer InstituteNational Institutes of HealthBethesdaMD 20892USA Intramural IT and Bioinformatics Program National Institute of Neurological Disorders and StrokeNational Institutes of HealthBethesdaMD 20892USA Current Address:Herbert Irving Comprehensive Cancer Center Columbia University Medical Center/New York-Presbyterian HospitalNew YorkNY 10032USA Division of Pediatric Hematology-Oncology-Stem Cell Transplantation and Cancer Biology Stanford University School of Medicine and Stanford Cancer InstitutePalo AltoCA 94305USA

Aim:Despite considerable efforts to reverse clinical multidrug resistance(MDR),targeting the predominant multidrug transporter ABCB1/P-glycoprotein(P-gp)using small molecule inhibitors has been unsuccessful,possibly due to the emergence of alternative drug resistance ***,the non-specific P-gp inhibitor cyclosporine(CsA)showed significant clinical benefits in patients with acute myeloid leukemia(AML),which likely represents the only proof-of-principle clinical trial using several generations of MDR ***,the mutational mechanisms that may underlie unsuccessful MDR modulation by CsA are not elucidated because of the absence of CsA-relevant cellular *** this study,our aims were to establish CsA-resistant leukemia models and to examine the presence or absence of ABCB1 exonic mutations in these models as well as in diverse types of human cancer samples including ***:Drug-resistant lines were established by stepwise drug co-selection and characterized by drug sensitivity assay,rhodamine-123 accumulation,[3H]-labeled drug export,ABCB1 cDNA sequencing,and RNase protection *** genomic stability of the ABCB1 coding regions was evaluated by exome sequencing analysis of variant allele frequencies in human ***,the mutational spectrum of ABCB1 was further assessed in diverse types of cancer samples including AMLs in the Cancer Genome Atlas(TCGA)at the National Cancer ***:We report the development of two erythroleukemia variants,RVC and RDC,which were derived by stepwise co-selection of K562/R7 drug-resistant leukemia cells with the etoposide-CsA and doxorubicin-CsA drug combinations,***,both RVC and RDC cell lines,which retained P-gp expression,showed altered multidrug-resistant phenotypes that were resistant to CsA ***,no mutations were found in the ABCB1 coding regions in these variant cells even under long-term stringent drug ***,ABCB1

关键词： Cancer leukemia multidrug resistance ABCB1 P-glycoprotein cyclosporine mutation

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Annual Maps of Forests in Australia from Analyses of Microwave and Optical Images with FAO Forest Definition

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Journal of Remote Sensing 2021年第1期2021卷 134-144页

作者： Yuanwei Qin Xiangming Xiao Jean-pierre Wigneron Philippe Ciais Josep G.Canadell Martin Brandt Xiaojun Li Lei Fan Xiaocui Wu Hao Tang Ralph Dubayah Russell Doughty Qing Chang Sean Crowell Bo Zheng kevin Neal Jorge A.Celis Berrien MooreⅢ Department of Microbiology and Plant Biology Center for Earth Observation and ModelingUniversity of OklahomaNormanOK 73019USA ISPA UMR 1391INRA Nouvelle-AquitaineBordeaux Villenave d’OrnonFrance Laboratoire des Sciences du Climat et de l'Environnement LSCE/IPSLCEA-CNRS-UVSQUniversitéParis-Saclay91191 Gif-sur-YvetteFrance CSIRO Oceans and Atmosphere CanberraACTAustralia Department of Geosciences and Natural Resource Management University of CopenhagenCopenhagenDenmark Chongqing Jinfo Mountain Karst Ecosystem National Observation and Research Station School of Geographical SciencesSouthwest UniversityChongqing 400715China Department of Geography National University of Singapore1 Arts LinkKent RidgeSingapore 117570 Department of Geographical Sciences University of MarylandCollege ParkMDUSA Division of Geological and Planetary Sciences California Institute of TechnologyPasadenaCA 91125USA O’Neill School of Public and Environmental Affairs Indiana University Bloomington702 N Walnut Grove AveBloomingtonIN 47405USA College of Atmospheric and Geographic Sciences University of OklahomaNormanOK 73019USA Institute of Environment and Ecology Tsinghua Shenzhen International Graduate SchoolTsinghua UniversityShenzhen 518055China

The Australian governmental agencies reported a total of 149 million ha forest in the Food and Agriculture Organization of the United Nations(FAO)in 2010,ranking sixth in the world,which is based on a forest definition with tree height>2 ***,we report a new forest cover data product that used the FAO forest definition(tree cover>10%and tree height>5 meters at observation time or mature)and was derived from microwave(Phased Array type L-band Synthetic Aperture Radar,PALSAR)and optical(Moderate Resolution Imaging Spectroradiometer,MODIS)images and validated with very high spatial resolution images,Light Detection and Ranging(LiDAR)data from the Ice,Cloud,and land Elevation Satellite(ICESat),and in situ field survey *** new PALSAR/MODIS forest map estimates 32 million ha of forest in 2010 over ***/MODIS forest map has an overall accuracy of~95%based on the reference data derived from visual interpretation of very high spatial resolution images for forest and nonforest cover *** with the canopy height and canopy coverage data derived from ICESat LiDAR strips,PALSAR/MODIS forest map has 73%of forest pixels meeting the FAO forest definition,much higher than the other four widely used forest maps(ranging from 36%to 52%).PALSAR/MODIS forest map also has a reasonable spatial consistency with the forest map from the National Vegetation Information *** new annual map of forests in Australia could support cross-country comparison when using data from the FAO Forest Resource Assessment Reports.

关键词： forest Forest PALSAR

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