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Development and Validation Of a Highly Sensitive and Specific Gene Expression Classifier To Prospectively Screen and Identify B-Precursor Acute Lymphoblastic Leukemia (ALL) Patients With a Philadelphia Chromosome-Like ("Ph-like" or "BCR-ABL1-Like") Signature For Therapeutic Targeting and Clinical Intervention

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BLOOD 2013年第21期122卷 826-826页

作者： Harvey, Richard C. Kang, Huining Roberts, Kathryn G. Chen, I-Ming L. Atlas, Susan R. Bedrick, Edward J. Gastier-Foster, Julie M. Zhang, Jinghui Gerhard, Daniels S. Smith, Malcolm A. Larsen, Eric C. Raetz, Elizabeth A. Winick, Naomi J. Carroll, William L. Stonerock, Eileen Heerema, Nyla A. Carroll, Andrew J. Chen, Shann-Ching Song, Guangchun Becksfort, Jared Rusch, Michael Li, Yongjin Ma, Jing Ell, Denise Reshmi, Shalini C. Loh, Mignon L. Davidas, Meenakshi Hunger, Stephen P. Mullighan, Charles G. Willman, Cheryl L. Pathology University of New Mexico Albuquerque NM USA Cancer Center University of New Mexico Albuquerque NM USA Pathology St. Jude Children's Research Hospital Memphis TN USA Cancer Center/Pathology University of New Mexico Albuquerque NM USA Physics and Astronomy University of New Mexico Albuquerque NM USA Internal Medicine University of New Mexico Cancer Center Albuquerque NM USA Ohio State University Laboratory Medicine/Pathology Nationwide Childrens Hospital Columbus OH USA Computational Biology St Jude Children's Research Hospital Memphis TN USA Office of Cancer Genomics National Cancer Institute Bethesda MD USA Maine Children's Cancer Program Scarborough ME USA Pedatrics New York University Langone Medical Center New York NY USA Department of Pediatrics University of Texas Southwestern Medical Center Dallas TX USA Cancer Institute New York University New York NY USA Nationwide Childrens Hospital Columbus OH USA Department of Pathology Wexner Medical Center at Ohio State University Columbus OH USA Department of Genetics University of Alabama at Birmingham Birmingham AL USA Department of Pathology St Jude Children's Research Hospital Memphis TN USA Information Sciences Research Informatics Bioinformatics St. Jude Children's Research Hospital Memphis TN USA

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Genome-Wide Promoter Methylation Profiling Of Splenic Marginal Zone Lymphoma (SMZL) Identifies Two Subgroups Of Patients With Distinct Genetic and Biologic Features and Different Outcomes

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BLOOD 2013年第21期122卷 77-77页

作者： Arribas, Alberto J. Rinaldi, Andrea Kwee, Ivo Mensah, Afua A. Cascione, Luciano Martinez-Climent, Jose A. Oscier, David Arcaini, Luca Baldini, Luca Marasca, Roberto Thieblemont, Catherine Soulier, Jean Forconi, Francesco Zamo, Alberto Bonifacio, Massimiliano Mollejo, Manuela Facchetti, Fabio Dirnhofer, Stephan Ponzoni, Maurilio Bhagat, Govind Piris, Miguel Angel A. Gaidano, Gianluca Zucca, Emanuele Rossi, Davide Bertoni, Francesco Lymphoma & Genomics Research Program IOR-Institute of Oncology Research Bellinzona Switzerland SIB Swiss Institute of Bioinformatics Lausanne Switzerland enter for Applied Medical Research (CIMA) University of Navarra Pamplona Spain Department of Pathology Royal Bournemouth Hospital Bournemouth United Kingdom Department of Hematology Oncology Fondazione IRCCS Policlinico San Matteo & Department of Molecular Medicine University of Pavia Pavia Italy Unità di Ematologia/CTMO Università di Milano Fondazione Ospedale Maggiore Policlinico MaRe IRCCS Milano Italy Division of Hematology Department of Oncology and Hematology University of Modena and Reggio Emilia Modena Italy Service Hémato-Oncologie Hôpital Saint- Louis Université Paris Diderot Paris France Hematology laboratory Saint-Louis Hospital Paris France Cancer Sciences Unit CRUK Clinical Centre University of Southampton Southampton United Kingdom Section of Pathological Anatomy Department of Pathology and Diagnostics University of Verona Verona Italy Department of Medicine Section of Hematology University of Verona Verona Italy Department of Pathology Hospital Virgen de la Salud Toledo Spain Divisions of Pathology Spedali Civili di Brescia Brescia Italy Institute of Pathology University of Basel Basel Switzerland Department of Pathology San Raffaele Scientific Institute Milano Italy Department of Pathology & Cell Biology Columbia University Medical Center and New York Presbyterian Hospital New York NY USA

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Correction to: A first species‑wide phylogenetic analysis of small mammals from Costa Rica using mitochondrial cytochrome b

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Mammal Research 2024年第4期69卷 621-621页

作者： Gómez‑Lépiz, Alexander Sampaio, Sara Hughes, Jonathan J. Valdés, Sara María Cáceres Alves, Paulo Célio Paupério, Joana Searle, Jeremy B. Centro de Investigação Em Biodiversidade E Recursos Genéticos InBIO Laboratório Associado CIBIO Vairão Portugal BIOPOLIS Program in Genomics Biodiversity and Land Planning Vairão Portugal Departamento de Biologia Faculdade de Ciências Universidade Do Porto Porto Portugal Department of Ecology and Evolutionary Biology Cornell University Ithaca USA Department of Evolution Ecology & Organismal Biology University of California Riverside Spieth Hall Riverside USA Estação Biológica de Mértola EBM Praça Luís de Camões Mértola Portugal European Molecular Biology Laboratory European Bioinformatics Institute Wellcome Genome Campus Hinxton UK

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Discovery of an Inherited Variant Associated with Susceptibility to Secondary Acute Lymphoblastic Leukemia (ALL) after Lenalidomide Maintenance and Autologous HCT for Multiple Myeloma (MM)

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Transplantation and Cellular Therapy 2024年第2期30卷 S99-S100页

作者： Zhu, Qianqian, PhD Herr, Megan, PhD Liang, Shuyi Hu, Qiang, MD, PhD Singh, Prashant K, PhD Gao, Xinyu Pasquini, Marcelo C. Leonard, Jessica T., MD Rosko, Ashley, MD Bayer, Ruthee-Lu, MD Krishnan, Amrita, MD Stadtmauer, Edward A., MD Maziarz, Richard T., MD McCarthy, Phillip L, MD Hahn, Theresa E., PhD Biostatistics & Bioinformatics Roswell Park Comprehensive Cancer Center Buffalo NY Department of Medicine Roswell Park Comprehensive Cancer Center Buffalo NY Cancer Genetics & Genomics Roswell Park Comprehensive Cancer Center Buffalo NY Center for International Blood and Marrow Transplant Research Medical College of Wisconsin Milwaukee WI Center for Hematologic Malignancies - Knight Cancer Institute Oregon Health & Science University Portland OR The Ohio State University Columbus OH Hematology/Oncology North Shore University Hospital Northwell Health Lake Success NY City of Hope Duarte CA Blood and Marrow Transplantation Program Abramson Cancer Center and the Division of Hematology and Oncology Hospital of the University of Pennsylvania Philadelphia PA Cancer Prevention & Control Roswell Park Comprehensive Cancer Center Buffalo NY

An increased risk of ALL second primary malignancy (SPM) has been observed with lenalidomide maintenance therapy after autologous HCT (len-post-autoHCT) for MM. Lenalidomide exerts its therapeutic effects via cereblon-mediated downregulation of the transcription factors Ikaros ( IKZF1) and Aiolos ( IKZF3). Inherited susceptibility variants in IKZF1 have been described for de novo ALL. We performed a case-control germline targeted sequencing study of the entire IKZF1 and IKZF3 genes with mean coverage ∼2,200X to investigate inherited susceptibility to ALL SPM risk. All cases and controls had a primary diagnosis of MM and received len-post-autoHCT with melphalan; sequencing was performed on an aliquot of the apheresis product or peripheral blood sample that was collected before autoHCT for MM. Cases of ALL SPMs were contributed by 4 individual centers and one national trial (BMT CTN 0702); each case had a maximum of 4 controls per case, sampled with replacement and matched on age, sex, race/ethnicity and duration of lenalidomide exposure (controls had longer duration of lenalidomide maintenance than cases). An additional control group of Acute Myeloid Leukemia/Myelodysplastic Syndrome (AML/MDS) SPMs after len-post-autoHCT were contributed by one center (Table). Multivariate logistic regression of case-control status, adjusted by age at HCT, sex, race/ethnicity, duration of lenalidomide maintenance, was performed for: 1) ALL SPM, 2) AML/MDS SPM, 3) ALL and AML/MDS SPM. We found the risk allele A of rs62447181 in IKZF1 had an OR=2.51 P=9.53 × 10 −3 for ALL SPM, OR=4.18 P=0.09 for AML/MDS SPM and OR=2.57 P=4.98 × 10 −3 for ALL&AML/MDS SPM. rs62447181 is a cis-expression quantitative trait loci (eQTL) of IKZF1 in blood (p=3.88 × 10 −55 in eQTLGen Consortium data) and resides in a promoter-proximal enhancer predicted by the ENCODE project (Figure A). Our in silico analysis of transcription factor binding sites showed that rs62447181 disrupts the binding site of PLAGL2, a k

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Author Correction: Perspectives on ENCODE

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Nature 2022年第7909期605卷 E4页

作者： Michael P Snyder Thomas R Gingeras Jill E Moore Zhiping Weng Mark B Gerstein Bing Ren Ross C Hardison John A Stamatoyannopoulos Brenton R Graveley Elise A Feingold Michael J Pazin Michael Pagan Daniel A Gilchrist Benjamin C Hitz J Michael Cherry Bradley E Bernstein Eric M Mendenhall Daniel R Zerbino Adam Frankish Paul Flicek Richard M Myers Department of Genetics School of Medicine Stanford University Palo Alto CA USA. mpsnyder@stanford.edu. Cardiovascular Institute Stanford School of Medicine Stanford CA USA. mpsnyder@stanford.edu. Functional Genomics Cold Spring Harbor Laboratory Cold Spring Harbor NY USA. University of Massachusetts Medical School Program in Bioinformatics and Integrative Biology Worcester MA USA. Department of Thoracic Surgery Clinical Translational Research Center Shanghai Pulmonary Hospital The School of Life Sciences and Technology Tongji University Shanghai China. Bioinformatics Program Boston University Boston MA USA. Yale University New Haven CT USA. Ludwig Institute for Cancer Research University of California San Diego La Jolla CA USA. Center for Epigenomics University of California San Diego La Jolla CA USA. Department of Biochemistry and Molecular Biology The Pennsylvania State University University Park PA USA. Altius Institute for Biomedical Sciences Seattle WA USA. Department of Genome Sciences University of Washington Seattle WA USA. Department of Medicine University of Washington Seattle WA USA. Department of Genetics and Genome Sciences Institute for Systems Genomics UConn Health Farmington CT USA. National Human Genome Research Institute National Institutes of Health Bethesda MD USA. Department of Genetics School of Medicine Stanford University Palo Alto CA USA. Broad Institute and Department of Pathology Massachusetts General Hospital and Harvard Medical School Boston MA USA. Biological Sciences University of Alabama in Huntsville Huntsville AL USA. HudsonAlpha Institute for Biotechnology Huntsville AL USA. European Molecular Biology Laboratory European Bioinformatics Institute Wellcome Genome Campus Cambridge UK.

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Erratum to 'Core Biopsies from Prostate Cancer Patients in Active Surveillance Protocols Harbor PTEN and MYC Alterations'[European Urology Oncology 2 (2019) 277-285]

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European urology oncology 2021年第1期4卷 129页

作者： Paolo Gandellini Nicola Casiraghi Tiziana Rancati Matteo Benelli Valentina Doldi Alessandro Romanel Maurizio Colecchia Cristina Marenghi Riccardo Valdagni Francesca Demichelis Nadia Zaffaroni Molecular Pharmacology Unit Fondazione IRCCS Istituto Nazionale dei Tumori Milan Italy. Laboratory of Computational and Functional Oncology Centre for Integrative Biology (CIBIO) University of Trento Trento Italy. Prostate Cancer Program Fondazione IRCCS Istituto Nazionale dei Tumori Milan Italy. Bioinformatics Unit Hospital of Prato Prato Italy. Laboratory of Bioinformatics and Computational Genomics Centre for Integrative Biology (CIBIO) University of Trento Trento Italy. Department of Pathology and Laboratory Medicine Fondazione IRCCS Istituto Nazionale dei Tumori Milan Italy. Department of Radiation Oncology 1 Fondazione IRCCS Istituto Nazionale dei Tumori Milan Italy. Department of Oncology and Hemato-oncology Università degli Studi di Milano Milan Italy. Laboratory of Computational and Functional Oncology Centre for Integrative Biology (CIBIO) University of Trento Trento Italy. Electronic address: f.demichelis@unitn.it. Molecular Pharmacology Unit Fondazione IRCCS Istituto Nazionale dei Tumori Milan Italy. Electronic address: nadia.zaffaroni@istitutotumori.mi.it.

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GREGoR: Accelerating genomics for Rare Diseases

arXiv

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arXiv 2024年

作者： Dawood, Moez Heavner, Ben Wheeler, Marsha M. Ungar, Rachel A. LoTempio, Jonathan Wiel, Laurens Berger, Seth Bernstein, Jonathan A. Chong, Jessica X. Délot, Emmanuèle C. Eichler, Evan E. Gibbs, Richard A. Lupski, James R. Shojaie, Ali Talkowski, Michael E. Wagner, Alex H. Wei, Chia-Lin Wellington, Christopher Wheeler, Matthew T. Carvalho, Claudia M.B. Gifford, Casey A. May, Susanne Miller, Danny E. Rehm, Heidi L. Sedlazeck, Fritz J. Vilain, Eric O'Donnell-Luria, Anne Posey, Jennifer E. Chadwick, Lisa H. Bamshad, Michael J. Montgomery, Stephen B. Human Genome Sequencing Center Baylor College of Medicine HoustonTX United States Department of Molecular and Human Genetics Baylor College of Medicine HoustonTX United States Medical Scientist Training Program Baylor College of Medicine HoustonTX United States Department of Biostatistics University of Washington SeattleWA United States Department of Genetics School of Medicine Stanford University StanfordCA United States Department of Pathology School of Medicine Stanford University Stanford CA United States Stanford Center for Biomedical Ethics School of Medicine Stanford University Stanford CA United States Institute for Clinical and Translational Science University of California IrvineCA United States Division of Cardiovascular Medicine School of Medicine Stanford University Stanford CA United States Division of Genetics and Metabolism Children’s National Rare Disease Institute WashingtonDC United States Center for Genetic Medicine Research Children’s National Rare Disease Institute WashingtonDC United States Department of Genomics and Precision Medicine George Washington University WashingtonDC United States Department of Pediatrics School of Medicine Stanford University Stanford CA United States Department of Pediatrics Dvision of Genetic Medicine University of Washington SeattleWA United States Brotman Baty Institute for Precision Medicine University of Washington SeattleWA United States Department of Genome Sciences University of Washington SeattleWA United States Howard Hughes Medical Institute University of Washington SeattleWA United States Department of Pediatrics Baylor College of Medicine HoustonTX United States Center for Genomic Medicine Massachusetts General Hospital BostonMA United States Program in Medical and Population Genetics Broad Institute of MIT and Harvard BostonMA United States Department of Neurology Massachusetts General Hospital Harvard Medical School BostonMA United States Stanley Center for

Rare diseases are collectively common, affecting approximately one in twenty individuals worldwide. In recent years, rapid progress has been made in rare disease diagnostics due to advances in DNA sequencing, development of new computational and experimental approaches to prioritize genes and genetic variants, and increased global exchange of clinical and genetic data. However, more than half of individuals suspected to have a rare disease lack a genetic diagnosis. The genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium was initiated to study thousands of challenging rare disease cases and families and apply, standardize, and evaluate emerging genomics technologies and analytics to accelerate their adoption in clinical practice. Further, all data generated, currently representing ~7500 individuals from ~3000 families, is rapidly made available to researchers worldwide via the Genomic Data Science Analysis, Visualization, and Informatics Lab-space (AnVIL) to catalyze global efforts to develop approaches for genetic diagnoses in rare diseases (https://***/data). The majority of these families have undergone prior clinical genetic testing but remained unsolved, with most being exome-negative. Here, we describe the collaborative research framework, datasets, and discoveries comprising GREGoR that will provide foundational resources and substrates for the future of rare disease genomics. © 2024, CC BY.

关键词： Genome

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Chronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts

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The Lancet Respiratory Medicine 2020年第7期8卷 696-708页

作者： Moll, Matthew Sakornsakolpat, Phuwanat Shrine, Nick Hobbs, Brian D DeMeo, Dawn L John, Catherine Guyatt, Anna L McGeachie, Michael J Gharib, Sina A Obeidat, Ma'en Lahousse, Lies Wijnant, Sara R A Brusselle, Guy Meyers, Deborah A Bleecker, Eugene R Li, Xingnan Tal-Singer, Ruth Manichaikul, Ani Rich, Stephen S Won, Sungho Kim, Woo Jin Do, Ah Ra Washko, George R Barr, R Graham Psaty, Bruce M Bartz, Traci M Hansel, Nadia N Barnes, Kathleen Hokanson, John E Crapo, James D Lynch, David Bakke, Per Gulsvik, Amund Hall, Ian P Wain, Louise Soler Artigas, María Jackson, Victoria E Strachan, David P Hui, Jennie James, Alan L Kerr, Shona M Polasek, Ozren Vitart, Veronique Marten, Jonathan Rudan, Igor Kähönen, Mika Surakka, Ida Gieger, Christian Karrasch, Stefan Rawal, Rajesh Schulz, Holger Deary, Ian J Harris, Sarah E Enroth, Stefan Gyllensten, Ulf Imboden, Medea Probst-Hensch, Nicole M Lehtimäki, Terho Raitakari, Olli T Langenberg, Claudia Luan, Jian'an Wareham, Nick Zhao, Jing Hua Hayward, Caroline Murray, Alison Porteous, David J Smith, Blair H Jarvelin, Marjo-Riitta Wielscher, Matthias Joshi, Peter K Kentistou, Katherine A Timmers, Paul RHJ Wilson, James F Cook, James P Lind, Lars Mahajan, Anubha Morris, Andrew P Ewert, Ralf Homuth, Georg Stubbe, Beate Weiss, Stefan Zeggini, Eleftheria Weiss, Scott T Silverman, Edwin K Dudbridge, Frank Tobin, Martin D Cho, Michael H Channing Division of Network Medicine Brigham and Women's Hospital Boston MA United States Division of Pulmonary and Critical Care Medicine Brigham and Women's Hospital Boston MA United States Department of Medicine Faculty of Medicine Siriraj Hospital Mahidol University Bangkok Thailand Genetic Epidemiology Group Department of Health Sciences University of Leicester Leicester United Kingdom Computational Medicine Core Center for Lung Biology Department of Medicine University of Washington Seattle WA United States Division of Pulmonary Critical Care and Sleep Medicine Department of Medicine University of Washington Seattle WA United States Cardiovascular Health Research Unit Department of Medicine University of Washington Seattle WA United States University of British Columbia Center for Heart Lung Innovation St Paul's Hospital Vancouver BC Canada Department of Epidemiology Erasmus Medical Centre Rotterdam Netherlands Department of Respiratory Medicine Erasmus Medical Centre Rotterdam Netherlands Department of Bioanalysis Faculty of Pharmaceutical Sciences Ghent University Ghent Belgium Department of Respiratory Medicine Ghent University Hospital Ghent Belgium Department of Medicine University of Arizona Tucson AZ United States GlaxoSmithKline Research and Development Collegeville PA United States Center for Public Health Genomics University of Virginia Charlottesville VA United States Department of Public Health Sciences University of Virginia Charlottesville VA United States Department of Public Health Sciences Graduate School of Public Health Seoul National University Seoul South Korea Interdisciplinary Program of Bioinformatics College of National Sciences Seoul National University Seoul South Korea Institute of Health and Environment Seoul National University Seoul South Korea Department of Internal Medicine Kangwon National University Chuncheon South Korea Department of Medicine and Department of Epidemiology Columbia Universit

Background: Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes. Methods: We constructed a polygenic risk score using a genome-wide association study of lung function (FEV₁ and FEV₁/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV₁/FVC <0·7 and FEV₁ <80% of predicted). Associations were tested using logistic regression models, adjusting for age, sex, height, smoking pack-years, and principal components of genetic ancestry. We assessed predictive performance of models by area under the curve. In a subset of studies, we also studied quantitative and qualitative CT imaging phenotypes that reflect parenchymal and airway pathology, and patterns of reduced lung growth. Findings: The polygenic risk score was associated with COPD in European (odds ratio [OR] per SD 1·81 [95% CI 1·74–1·88] and non-European (1·42 [1·34–1·51]) populations. Compared with the first decile, the tenth decile of the polygenic risk score was associated with COPD, with an OR of 7·99 (6·56–9·72) in European ancestry and 4·83 (3·45–6·77) in non-European ancestry cohorts. The polygenic risk score was superior to previously described genetic risk scores and, when combined with clinical risk factors (ie, age, sex, and smoking pack-years), showed improved prediction for COPD compared with a model comprising clinical risk factors alone (AUC 0·80 [0·79–0·81] vs 0·76 [0·75–0·76]). The polygenic risk score was associated with CT imaging phenotypes, including wall area percent, quantitative and qualitative measures of emphysema, local histogram emphysema patterns, and destructive emphysema subtypes. The po

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Data integration of bulk and single-cell transcriptomics from cerebral organoids and post-mortem brains to identify cell types and cell type specific driver genes in autism

Research Square

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Research Square 2020年

作者： Lim, Elaine T. Chan, Yingleong Burns, Mannix J. Guo, Xiaoge Erdin, Serkan Tai, Derek J.C. Reichert, Julia M. Chan, Ying Kai Chiang, Jessica J. Meyers, Katharina Zhang, Xiaochang Walsh, Christopher A. Yankner, Bruce A. Raychaudhuri, Soumya Hirschhorn, Joel N. Gusella, James F. Talkowski, Michael E. Church, George M. DZNE Germany Program in Bioinformatics and Integrative Biology Departments of Neurology and Molecular Cell and Cancer Biology University of Massachusetts Medical School WorcesterMA01605 United States Department of Genetics Harvard Medical School BostonMA02115 United States Wyss Institute for Biologically Inspired Engineering Harvard University BostonMA02115 United States Stanley Center for Psychiatric Research Broad Institute of MIT and Harvard CambridgeMA02115 United States Center for Genomic Medicine Massachusetts General Hospital BostonMA02115 United States Department of Neurology Massachusetts General Hospital BostonMA02115 United States Department of Human Genetics The Grossman Institute for Neuroscience Quantitative Biology and Human Behavior The University of Chicago ChicagoIL60637 United States Division of Genetics and Genomics Manton Center for Orphan Disease Research Howard Hughes Medical Institute Boston Children’s Hospital BostonMA02115 United States Departments of Pediatrics and Neurology Harvard Medical School BostonMA02115 United States Divisions of Genetics and Rheumatology Brigham and Women's Hospital Harvard Medical School BostonMA02115 United States Partners Center for Personalized Genetic Medicine BostonMA02115 United States Faculty of Medical and Human Sciences University of Manchester ManchesterM13 9PL United Kingdom Division of Endocrinology Boston Children's Hospital BostonMA02115 United States Center for Basic and Translational Obesity Research Boston Children's Hospital BostonMA02115 United States

Human-derived cerebral organoids demonstrate great promise for identifying cell types and cell type specific molecular processes perturbed by genetic variants associated with neuropsychiatric and neurodevelopmental disorders, which are notoriously challenging to study using animal models. However, considerable challenges remain in achieving robust, scalable and generalizable phenotyping of organoids to discover cell types and cell type specific genes. We perform RNA sequencing on 71 samples comprising 1,420 cerebral organoids from 25 donors, and describe a framework (Orgo-Seq) to integrate bulk RNA and single-cell RNA sequence data from human post-mortem brains and cerebral organoids, for the identification of cell types and cell type specific individual genes. We apply Orgo-Seq for two autism-associated loci: 16p11.2 deletions and 15q11-13 duplications, and identify neuroepithelial cells as critical cell types for 16p11.2 deletions, and discover novel and previously reported cell type specific driver genes. Finally, we validated our results that mutations in the KCTD13 gene in the 16p11.2 locus lead to imbalances in the proportion of neuroepithelial cells, using CRISPR/Cas9-edited mosaic organoids. Our work presents a quantitative technological framework to integrate multiple transcriptomics datasets to identify cell types and cell type specific driver genes associated with complex diseases using cerebral organoids. © 2020, CC BY.

关键词： Genes

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Small Molecule Mediated Intervention of NF-kB or TGF-β Signaling Reverses Age-Related Phenotypes in Satellite Cells and Enhances Muscle Repair

SSRN

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SSRN 2018年

作者： Cerletti, Massimiliano Rao, Tata Nageswara Cole, Deepti A. Moore, John T. Chuang, Tsu T. Becherer, Dave J. Sheckler, Lauren R. Stimpson, Stephen A. Schroeder, Joshua J. Inlay, Matthew A. Rossi, Derrick J. Weissman, Irving L. Wagers, Amy J. Paul F. Glenn Laboratories for the Biological Mechanisms of Aging Harvard Medical School BostonMA02115 United States Department of Stem Cell and Regenerative Biology Harvard University Harvard Stem Cell Institute CambridgeMA02138 United States Section on Islet Cell and Regenerative Biology Joslin Diabetes Center BostonMA02215 United States UCL Department of Nanotechnology University College London LondonNW3 2QG United Kingdom UCL Institute for Immunity and Transplantation Royal Free Campus University College London LondonNW3 2QG United Kingdom UCL Institute of Orthopaedic and Musculoskeletal Science University College London LondonHA7 4LP United Kingdom DERC Bioinformatics Core Joslin Diabetes Center BostonMA02215 United States Target and Pathway Validation Unit GlaxoSmithKline RTPNC27709 United States Regenerative Medicine Discovery Performance Unit GlaxoSmithKline StevenageSG1 2NY United Kingdom Metabolism Discovery Performance Unit GlaxoSmithKline RTP NC13398 United States Metabolic Pathways and Cardiovascular Therapeutic Area Unit GlaxoSmithKline RTPNC27709 United States DERC Genomics Core Joslin Diabetes Center BostonMA02215 United States Institute for Stem Cell Biology and Regenerative Medicine Stanford University StanfordCA94305 United States Program in Cellular and Molecular Medicine Children's Hospital Boston BostonMA02115 United States

Skeletal muscle normally exhibits robust regenerative potential in youth;however, myogenic activity declines with age, resulting in defective muscle repair after injury. In this study, we identified signaling pathways in mouse muscle stem cells that are altered with aging and contribute to age-dependent decline in muscle regenerative potential. By analyzing the transcriptional profile of highly purified muscle satellite cells, we identified a unique set of genes whose expression changes with chronological time. This set contains genes regulating inflammatory processes, cell adhesion and matrix interactions, proteolysis, extracellular matrix remodeling, skeletal muscle development, cancer and connective tissue disorders. Ingenuity Pathway Analysis (IPA) of these transcripts indicated a central role for the NF-κB pathway in muscle satellite cell dysfunction. In addition, we noted altered expression of extracellular matrix genes, a signature that could be linked to changes in TGF-β-like signaling activity. Pharmacological modulation of either the NF-κB or TGF-β-like signaling pathways with small molecule inhibitors targeting IKK2 kinase or ALK4/5 receptor-like kinase enhanced regenerative potential in aged muscle, altering both the kinetics and magnitude of the response. These results identify key pathways underlying age-related muscle dysfunction and demonstrate the potential therapeutic relevance of small molecules that target them. © 2018, The Authors. All rights reserved.

关键词： Muscle

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