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  1. Article ; Online: Probing the rules of cell coordination in live tissues by interpretable machine learning based on graph neural networks.

    Yamamoto, Takaki / Cockburn, Katie / Greco, Valentina / Kawaguchi, Kyogo

    PLoS computational biology

    2022  Volume 18, Issue 9, Page(s) e1010477

    Abstract: Robustness in developing and homeostatic tissues is supported by various types of spatiotemporal cell-to-cell interactions. Although live imaging and cell tracking are powerful in providing direct evidence of cell coordination rules, extracting and ... ...

    Abstract Robustness in developing and homeostatic tissues is supported by various types of spatiotemporal cell-to-cell interactions. Although live imaging and cell tracking are powerful in providing direct evidence of cell coordination rules, extracting and comparing these rules across many tissues with potentially different length and timescales of coordination requires a versatile framework of analysis. Here we demonstrate that graph neural network (GNN) models are suited for this purpose, by showing how they can be applied to predict cell fate in tissues and utilized to infer the cell interactions governing the multicellular dynamics. Analyzing the live mammalian epidermis data, where spatiotemporal graphs constructed from cell tracks and cell contacts are given as inputs, GNN discovers distinct neighbor cell fate coordination rules that depend on the region of the body. This approach demonstrates how the GNN framework is powerful in inferring general cell interaction rules from live data without prior knowledge of the signaling involved.
    MeSH term(s) Animals ; Cell Tracking ; Machine Learning ; Mammals ; Neural Networks, Computer
    Language English
    Publishing date 2022-09-06
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2193340-6
    ISSN 1553-7358 ; 1553-734X
    ISSN (online) 1553-7358
    ISSN 1553-734X
    DOI 10.1371/journal.pcbi.1010477
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: LGN loss randomizes spindle orientation and accelerates tumorigenesis in PTEN-deficient epidermis.

    Viala, Sophie / Hadjadj, Charlotte / Nathan, Vandana / Guiot, Marie-Christine / McCaffrey, Luke / Cockburn, Katie / Bouchard, Maxime

    Molecular biology of the cell

    2023  Volume 35, Issue 2, Page(s) br5

    Abstract: Loss of cell polarity and disruption of tissue organization are key features of tumorigenesis that are intrinsically linked to spindle orientation. Epithelial tumors are often characterized by spindle orientation defects, but how these defects impact ... ...

    Abstract Loss of cell polarity and disruption of tissue organization are key features of tumorigenesis that are intrinsically linked to spindle orientation. Epithelial tumors are often characterized by spindle orientation defects, but how these defects impact tumor formation driven by common oncogenic mutations is not fully understood. Here, we examine the role of spindle orientation in adult epidermis by deleting a key spindle regulator, LGN, in normal tissue and in a PTEN-deficient mouse model. We report that LGN deficiency in PTEN mutant epidermis leads to a threefold increase in the likelihood of developing tumors on the snout, and an over 10-fold increase in tumor burden. In this tissue, loss of LGN alone increases perpendicular and oblique divisions of epidermal basal cells, at the expense of a planar orientation of division. PTEN loss alone does not significantly affect spindle orientation in these cells, but the combined loss of PTEN and LGN fully randomizes basal spindle orientation. A subset of LGN- and PTEN-deficient animals have increased amounts of proliferative spinous cells, which may be associated with tumorigenesis. These results indicate that loss of LGN impacts spindle orientation and accelerates epidermal tumorigenesis in a PTEN-deficient mouse model.
    MeSH term(s) Animals ; Mice ; Spindle Apparatus/genetics ; Epidermis ; Epidermal Cells ; Carcinogenesis ; Cell Polarity/genetics
    Language English
    Publishing date 2023-11-22
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1098979-1
    ISSN 1939-4586 ; 1059-1524
    ISSN (online) 1939-4586
    ISSN 1059-1524
    DOI 10.1091/mbc.E23-03-0111
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Flexibility sustains epithelial tissue homeostasis.

    Tai, Karen / Cockburn, Katie / Greco, Valentina

    Current opinion in cell biology

    2019  Volume 60, Page(s) 84–91

    Abstract: Epithelia surround our bodies and line most of our organs. Intrinsic homeostatic mechanisms replenish and repair these tissues in the face of wear and tear, wounds, and even the presence of accumulating mutations. Recent advances in cell biology, ... ...

    Abstract Epithelia surround our bodies and line most of our organs. Intrinsic homeostatic mechanisms replenish and repair these tissues in the face of wear and tear, wounds, and even the presence of accumulating mutations. Recent advances in cell biology, genetics, and live-imaging techniques have revealed that epithelial homeostasis represents an intrinsically flexible process at the level of individual epithelial cells. This homeostatic flexibility has important implications for how we think about the more dramatic cell plasticity that is frequently thought to be associated with pathological settings. In this review, we will focus on key emerging mechanisms and processes of epithelial homeostasis and elaborate on the known molecular mechanisms of epithelial cell interactions to illuminate how epithelia are maintained throughout an organism's lifetime.
    MeSH term(s) Animals ; Carcinogenesis/genetics ; Epithelium/physiology ; Homeostasis ; Humans ; Mutation/genetics ; Wound Healing
    Language English
    Publishing date 2019-05-29
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1026381-0
    ISSN 1879-0410 ; 0955-0674
    ISSN (online) 1879-0410
    ISSN 0955-0674
    DOI 10.1016/j.ceb.2019.04.009
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Gradual differentiation uncoupled from cell cycle exit generates heterogeneity in the epidermal stem cell layer.

    Cockburn, Katie / Annusver, Karl / Gonzalez, David G / Ganesan, Smirthy / May, Dennis P / Mesa, Kailin R / Kawaguchi, Kyogo / Kasper, Maria / Greco, Valentina

    Nature cell biology

    2022  Volume 24, Issue 12, Page(s) 1692–1700

    Abstract: Highly regenerative tissues continuously produce terminally differentiated cells to replace those that are lost. How they orchestrate the complex transition from undifferentiated stem cells towards post-mitotic, molecularly distinct and often spatially ... ...

    Abstract Highly regenerative tissues continuously produce terminally differentiated cells to replace those that are lost. How they orchestrate the complex transition from undifferentiated stem cells towards post-mitotic, molecularly distinct and often spatially segregated differentiated populations is not well understood. In the adult skin epidermis, the stem cell compartment contains molecularly heterogeneous subpopulations
    MeSH term(s) Cell Division ; Cell Cycle/genetics ; Stem Cells ; Cell Differentiation
    Language English
    Publishing date 2022-11-10
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1474722-4
    ISSN 1476-4679 ; 1465-7392
    ISSN (online) 1476-4679
    ISSN 1465-7392
    DOI 10.1038/s41556-022-01021-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Zeb2 drives the formation of CD11c

    Gao, Xin / Shen, Qian / Roco, Jonathan A / Dalton, Becan / Frith, Katie / Munier, C Mee Ling / Ballard, Fiona D / Wang, Ke / Kelly, Hannah G / Nekrasov, Maxim / He, Jin-Shu / Jaeger, Rebecca / Carreira, Patricia / Ellyard, Julia I / Beattie, Lynette / Enders, Anselm / Cook, Matthew C / Zaunders, John J / Cockburn, Ian A

    Science immunology

    2024  Volume 9, Issue 93, Page(s) eadj4748

    Abstract: ... ...

    Abstract CD11c
    MeSH term(s) Animals ; Humans ; Mice ; Germinal Center ; Immunization ; Persistent Infection ; Vaccination ; Zinc Finger E-box Binding Homeobox 2/genetics
    Chemical Substances Zinc Finger E-box Binding Homeobox 2 ; ZEB2 protein, human ; ZEB2 protein, mouse
    Language English
    Publishing date 2024-03-29
    Publishing country United States
    Document type Journal Article
    ISSN 2470-9468
    ISSN (online) 2470-9468
    DOI 10.1126/sciimmunol.adj4748
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Live imaging reveals chromatin compaction transitions and dynamic transcriptional bursting during stem cell differentiation in vivo.

    May, Dennis / Yun, Sangwon / Gonzalez, David G / Park, Sangbum / Chen, Yanbo / Lathrop, Elizabeth / Cai, Biao / Xin, Tianchi / Zhao, Hongyu / Wang, Siyuan / Gonzalez, Lauren E / Cockburn, Katie / Greco, Valentina

    eLife

    2023  Volume 12

    Abstract: Stem cell differentiation requires dramatic changes in gene expression and global remodeling of chromatin architecture. How and when chromatin remodels relative to the transcriptional, behavioral, and morphological changes during differentiation remain ... ...

    Abstract Stem cell differentiation requires dramatic changes in gene expression and global remodeling of chromatin architecture. How and when chromatin remodels relative to the transcriptional, behavioral, and morphological changes during differentiation remain unclear, particularly in an intact tissue context. Here, we develop a quantitative pipeline which leverages fluorescently-tagged histones and longitudinal imaging to track large-scale chromatin compaction changes within individual cells in a live mouse. Applying this pipeline to epidermal stem cells, we reveal that cell-to-cell chromatin compaction heterogeneity within the stem cell compartment emerges independent of cell cycle status, and instead is reflective of differentiation status. Chromatin compaction state gradually transitions over days as differentiating cells exit the stem cell compartment. Moreover, establishing live imaging of
    MeSH term(s) Animals ; Mice ; Chromatin ; Keratin-10/genetics ; Keratin-10/metabolism ; Histones/metabolism ; Cell Differentiation/genetics ; Stem Cells/metabolism
    Chemical Substances Chromatin ; Keratin-10 (147785-83-9) ; Histones
    Language English
    Publishing date 2023-03-07
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.83444
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  7. Article ; Online: Live imaging of stem cells: answering old questions and raising new ones.

    Park, Sangbum / Greco, Valentina / Cockburn, Katie

    Current opinion in cell biology

    2016  Volume 43, Page(s) 30–37

    Abstract: Stem cells are essential for both tissue maintenance and injury repair, but many aspects of stem cell biology remain incompletely understood. Recent advances in live imaging technology have allowed the direct visualization and tracking of a wide variety ... ...

    Abstract Stem cells are essential for both tissue maintenance and injury repair, but many aspects of stem cell biology remain incompletely understood. Recent advances in live imaging technology have allowed the direct visualization and tracking of a wide variety of tissue-resident stem cells in their native environments over time. Results from these studies have helped to resolve long-standing debates about stem cell regulation and function while also revealing previously unanticipated phenomena that raise new questions for future work. Here we review recent discoveries of both types, with a particular emphasis on how stem cells behave and interact with their niches during homeostasis, as well as how these behaviours change in response to wounding.
    MeSH term(s) Animals ; Carcinogenesis/pathology ; Cell Proliferation ; Humans ; Imaging, Three-Dimensional ; Stem Cell Niche ; Stem Cells/cytology ; Wound Healing
    Language English
    Publishing date 2016-12
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 1026381-0
    ISSN 1879-0410 ; 0955-0674
    ISSN (online) 1879-0410
    ISSN 0955-0674
    DOI 10.1016/j.ceb.2016.07.004
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: OpenSAFELY: The impact of COVID-19 on azathioprine, leflunomide and methotrexate monitoring, and factors associated with change in monitoring rate.

    Brown, Andrew D / Fisher, Louis / Curtis, Helen J / Wiedemann, Milan / Hulme, William J / Speed, Victoria / Hopcroft, Lisa E M / Cunningham, Christine / Costello, Ruth E / Galloway, James B / Russell, Mark D / Bechman, Katie / Kurt, Zeyneb / Croker, Richard / Wood, Chris / Walker, Alex J / Schaffer, Andrea L / Bacon, Seb C J / Mehrkar, Amir /
    Hickman, George / Bates, Chris / Cockburn, Jonathan / Parry, John / Hester, Frank / Harper, Sam / Goldacre, Ben / MacKenna, Brian

    British journal of clinical pharmacology

    2024  

    Abstract: Aims: The COVID-19 pandemic created unprecedented pressure on healthcare services. This study investigates whether disease-modifying antirheumatic drug (DMARD) safety monitoring was affected during the COVID-19 pandemic.: Methods: A population-based ... ...

    Abstract Aims: The COVID-19 pandemic created unprecedented pressure on healthcare services. This study investigates whether disease-modifying antirheumatic drug (DMARD) safety monitoring was affected during the COVID-19 pandemic.
    Methods: A population-based cohort study was conducted using the OpenSAFELY platform to access electronic health record data from 24.2 million patients registered at general practices using TPP's SystmOne software. Patients were included for further analysis if prescribed azathioprine, leflunomide or methotrexate between November 2019 and July 2022. Outcomes were assessed as monthly trends and variation between various sociodemographic and clinical groups for adherence with standard safety monitoring recommendations.
    Results: An acute increase in the rate of missed monitoring occurred across the study population (+12.4 percentage points) when lockdown measures were implemented in March 2020. This increase was more pronounced for some patient groups (70-79 year-olds: +13.7 percentage points; females: +12.8 percentage points), regions (North West: +17.0 percentage points), medications (leflunomide: +20.7 percentage points) and monitoring tests (blood pressure: +24.5 percentage points). Missed monitoring rates decreased substantially for all groups by July 2022. Consistent differences were observed in overall missed monitoring rates between several groups throughout the study.
    Conclusion: DMARD monitoring rates temporarily deteriorated during the COVID-19 pandemic. Deterioration coincided with the onset of lockdown measures, with monitoring rates recovering rapidly as lockdown measures were eased. Differences observed in monitoring rates between medications, tests, regions and patient groups highlight opportunities to tackle potential inequalities in the provision or uptake of monitoring services. Further research should evaluate the causes of the differences identified between groups.
    Language English
    Publishing date 2024-04-08
    Publishing country England
    Document type Journal Article
    ZDB-ID 188974-6
    ISSN 1365-2125 ; 0306-5251 ; 0264-3774
    ISSN (online) 1365-2125
    ISSN 0306-5251 ; 0264-3774
    DOI 10.1111/bcp.16062
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: AIRE is a critical spindle-associated protein in embryonic stem cells.

    Gu, Bin / Lambert, Jean-Philippe / Cockburn, Katie / Gingras, Anne-Claude / Rossant, Janet

    eLife

    2017  Volume 6

    Abstract: Embryonic stem (ES) cells go though embryo-like cell cycles regulated by specialized molecular mechanisms. However, it is not known whether there are ES cell-specific mechanisms regulating mitotic fidelity. Here we showed that Autoimmune Regulator ( ...

    Abstract Embryonic stem (ES) cells go though embryo-like cell cycles regulated by specialized molecular mechanisms. However, it is not known whether there are ES cell-specific mechanisms regulating mitotic fidelity. Here we showed that Autoimmune Regulator (
    MeSH term(s) Animals ; Cell Division ; Embryonic Stem Cells/physiology ; Gene Knockout Techniques ; Mice ; Mouse Embryonic Stem Cells/physiology ; Protein Binding ; Spindle Apparatus/metabolism ; Transcription Factors/metabolism ; AIRE Protein
    Chemical Substances Transcription Factors
    Language English
    Publishing date 2017-07-25
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.28131
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  10. Article ; Online: Making the blastocyst: lessons from the mouse.

    Cockburn, Katie / Rossant, Janet

    The Journal of clinical investigation

    2010  Volume 120, Issue 4, Page(s) 995–1003

    Abstract: Mammalian preimplantation development, which is the period extending from fertilization to implantation, results in the formation of a blastocyst with three distinct cell lineages. Only one of these lineages, the epiblast, contributes to the embryo ... ...

    Abstract Mammalian preimplantation development, which is the period extending from fertilization to implantation, results in the formation of a blastocyst with three distinct cell lineages. Only one of these lineages, the epiblast, contributes to the embryo itself, while the other two lineages, the trophectoderm and the primitive endoderm, become extra-embryonic tissues. Significant gains have been made in our understanding of the major events of mouse preimplantation development, and recent discoveries have shed new light on the establishment of the three blastocyst lineages. What is less clear, however, is how closely human preimplantation development mimics that in the mouse. A greater understanding of the similarities and differences between mouse and human preimplantation development has implications for improving assisted reproductive technologies and for deriving human embryonic stem cells.
    MeSH term(s) Animals ; Blastocyst/physiology ; Cell Division ; Cell Lineage ; Cell Polarity ; Embryonic Development ; Endoderm/cytology ; Fibroblast Growth Factors/physiology ; Germ Layers/cytology ; Humans ; Mice ; Stem Cells/cytology ; Transcription Factors/physiology
    Chemical Substances Transcription Factors ; Fibroblast Growth Factors (62031-54-3)
    Language English
    Publishing date 2010-04-01
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 3067-3
    ISSN 1558-8238 ; 0021-9738
    ISSN (online) 1558-8238
    ISSN 0021-9738
    DOI 10.1172/JCI41229
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