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1. Spatially resolved multiomics of human cardiac niches

Author

Kazumasa Kanemaru, James Cranley, Daniele Muraro, Antonio M.A. Miranda, Jan Patrick Pett, Monika Litvinukova, Natsuhiko Kumasaka, Siew Yen Ho, Krzysztof Polanski, Laura Richardson, Lukas Mach, Monika Dabrowska, Nathan Richoz, Sam N. Barnett, Shani Perera, Anna Wilbrey-Clark, Carlos Talavera-López, Ilaria Mulas, Krishnaa T. Mahbubani, Liam Bolt, Lira Mamanova, Liz Tuck, Lu Wang, Margaret M. Huang, Martin Prete, Sophie Pritchard, John Dark, Kourosh Saeb-Parsy, Minal Patel, Menna R. Clatworthy, Norbert Hübner, Rasheda A. Chowdhury, Michela Noseda, and Sarah A. Teichmann

Abstract

A cell’s function is defined by its intrinsic characteristics and its niche: the tissue microenvironment in which it dwells. Here, we combine single-cell and spatial transcriptomic data to discover cellular niches within eight regions of the human heart. We map cells to micro-anatomic locations and integrate knowledge-based and unsupervised structural annotations. For the first time, we profile the cells of the human cardiac conduction system, revealing their distinctive repertoire of ion channels, G-protein coupled receptors, and cell interactions using a customCellPhoneDB.orgmodule. We show that the sinoatrial node is compartmentalised, with a core of pacemaker cells, fibroblasts and glial cells supporting paracrine glutamatergic signalling. We introduce a druggable target prediction tool, drug2cell, which leverages single-cell profiles and drug-target interactions, providing unexpected mechanistic insights into the chronotropic effects of drugs, including GLP-1 analogues. In the epicardium, we show enrichment of both IgG+ and IgA+ plasma cells forming immune niches which may contribute to infection defence. We define a ventricular myocardial-stress niche enriched for activated fibroblasts and stressed cardiomyocytes, cell states that are expanded in cardiomyopathies. Overall, we provide new clarity to cardiac electro-anatomy and immunology, and our suite of computational approaches can be deployed to other tissues and organs.

Published
2023
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2. Multi-organ functions of yolk sac during human early development

Author

Rachel A Botting, Issac Goh, Antony Rose, Simone Webb, Justin Engelbert, Yorick Gitton, Emily Stephenson, Mariana Quiroga Londoño, Michael Mather, Nicole Mende, Ivan Imaz-Rosshandler, Dave Horsfall, Daniela Basurto-Lozada, Nana-Jane Chipampe, Victoria Rook, Pavel Mazin, MS Vijayabaskar, Rebecca Hannah, Laure Gambardella, Kile Green, Stephane Ballereau, Megumi Inoue, Liz Tuck, Valentina Lorenzi, Kwasi Kwakwa, Clara Alsinet, Bayanne Olabi, Mohi Miah, Chloe Admane, Dorin-Mirel Popescu, Meghan Acres, David Dixon, Rowen Coulthard, Steven Lisgo, Deborah J Henderson, Emma Dann, Chenqu Suo, Sarah J Kinston, Jong-eun Park, Krzysztof Polanski, Stijn Van Dongen, Kerstin B Meyer, Marella de Bruijn, James Palis, Sam Behjati, Elisa Laurenti, Nicola K Wilson, Roser Vento-Tormo, Alain Chédotal, Omer Bayraktar, Irene Roberts, Laura Jardine, Berthold Göttgens, Sarah A Teichmann, and Muzlifah Haniffa

Abstract

The yolk sac (YS) represents an evolutionarily-conserved extraembryonic structure that ensures timely delivery of nutritional support and oxygen to the developing embryo. However, the YS remains ill-defined in humans. We therefore assemble a complete single cell 3D map of human YS from 3-8 post conception weeks by integrating multiomic protein and gene expression data. We reveal the YS as a site of primitive and definitive haematopoiesis including a YS-specific accelerated route to macrophage production, a source of nutritional/metabolic support and a regulator of oxygen-carrying capacity. We reconstruct the emergence of primitive haematopoietic stem and progenitor cells from YS hemogenic endothelium and their decline upon stromal support modulation as intraembryonic organs specialise to assume these functions. The YS therefore functions as ‘three organs in one’ revealing a multifaceted relay of vital organismal functions as pregnancy proceeds.One Sentence SummaryHuman yolk sac is a key staging post in a relay of vital organismal functions during human pregnancy.

Published
2022
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3. Mouse and cellular models of KPTN-related disorder implicate mTOR signalling in cognitive and progressive overgrowth phenotypes

Author

Maria O. Levitin, Lettie E Rawlins, Gabriela Sanchez-Andrade, Osama A. Arshad, Stephan C. Collins, Stephen J. Sawiak, Phillip H. Iffland, Malin H.L. Andersson, Caleb Bupp, Emma L. Cambridge, Eve L. Coomber, Ian Ellis, Johanna C. Herkert, Holly Ironfield, Logan Jory, Perrine F. Kretz, Sarina G. Kant, Alexandra Neaverson, Esther Nibbeling, Christine Rowley, Emily Relton, Mark Sanderson, Ethan M. Scott, Helen Stewart, Andrew Y. Shuen, John Schreiber, Liz Tuck, James Tonks, Thorkild Terkelsen, Conny van Ravenswaaij-Arts, Pradeep Vasudevan, Olivia Wenger, Michael Wright, Andrew Day, Adam Hunter, Minal Patel, Christopher J. Lelliott, Peter B. Crino, Binnaz Yalcin, Andrew Crosby, Emma L. Baple, Darren W. Logan, Matthew E. Hurles, and Sebastian S. Gerety

Abstract

KPTN-related disorder (KRD) is an autosomal recessive disorder associated with germline variants in KPTN (kaptin), a component of the mTOR regulatory complex KICSTOR. To gain further insights into the pathogenesis of KRD, we analysed mouse knockout and human stem cell KPTN loss-of-function models. Kptn−/− mice display many of the key KRD phenotypes, including brain overgrowth, behavioural abnormalities, and cognitive deficits. Assessment of affected individuals has identified concordant selectivity of cognitive deficits, postnatal onset of brain overgrowth, and a previously unrecognised KPTN dosage-sensitivity, resulting in increased head circumference in their heterozygous parents. Molecular and structural analysis of Kptn−/− mice revealed pathological changes, including differences in brain size, shape, and cell numbers primarily due to abnormal postnatal brain development. Both the mouse and differentiated iPSC models of the disorder display transcriptional and biochemical evidence for altered mTOR pathway signalling, supporting the role of KPTN in regulating mTORC1. Increased mTOR signalling downstream of KPTN is rapamycin sensitive, highlighting possible therapeutic avenues with currently available mTOR inhibitors. These findings place KRD in the broader group of mTORC1 related disorders affecting brain structure, cognitive function, and network integrity.

Published
2022
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4. A novel IgA plasma cell niche in the human airways

Author

Amanda Oliver, Elo Madissoon, Vitalii Kleshchevnikov, Anna Wilbrey-Clark, Kryzysztof Polanski, Ana Elisa Ribeiro Orsi, Lira Mamanova, Liam Bolt, J. Patrick Pett, Ni Huang, Rasa Elmentaite, Nathan Richoz, Peng He, Monika Dabrowska, Liz Tuck, Elena Prigmore, Andrew Knights, Agnes Oszlanczi, Adam Hunter, Sophie Pritchard, Sara Filipa Vieira, Minal Patel, Krishnaa Mahbubani, Nikitas Georgakapopoulos, Menna Clatworthy, Oliver Stegle, Kourosh Saeb-Parsy, Natsuhiko Kumasaka, Sarah Teichmann, and Kerstin Meyer

Published
2022
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5. A spatial multi-omics atlas of the human lung reveals a novel immune cell survival niche

Author

Anna Wilbrey-Clark, Vitalii Kleshchevnikov, Nathan Richoz, Ana Ribeiro Orsi, Liam Bolt, Lira Mamanova, Sophie Pritchard, Rasa Elmentaite, Natsuhiko Kumasaka, Minal Patel, Kourosh Saeb-Parsy, Sara F. Vieira, Adam Hunter, Menna R. Clatworthy, Elo Madissoon, Peng He, Monika Dabrowska, Agnes Oszlanczi, Elena Prigmore, Andrew J Knights, Oliver Stegle, Liz Tuck, Ni Huang, Nikitas Georgakopoulos, Omer Ali Bayraktar, Krzysztof Polanski, Kerstin B. Meyer, Krishnaa T. Mahbubani, J. Patrick Pett, Sarah A. Teichmann, and Amanda Oliver

Subjects
Transcriptome, Cell type, medicine.anatomical_structure, Immune system, Lineage (genetic), Cell, medicine, RNA, Context (language use), Pericyte, Biology, Cell biology
Abstract

SummaryMultiple distinct cell types of the human lung and airways have been defined by single cell RNA sequencing (scRNAseq). Here we present a multi-omics spatial lung atlas to define novel cell types which we map back into the macro- and micro-anatomical tissue context to define functional tissue microenvironments. Firstly, we have generated single cell and nuclei RNA sequencing, VDJ-sequencing and Visium Spatial Transcriptomics data sets from 5 different locations of the human lung and airways. Secondly, we define additional cell types/states, as well as spatially map novel and known human airway cell types, such as adult lung chondrocytes, submucosal gland (SMG) duct cells, distinct pericyte and smooth muscle subtypes, immune-recruiting fibroblasts, peribronchial and perichondrial fibroblasts, peripheral nerve associated fibroblasts and Schwann cells. Finally, we define a survival niche for IgA-secreting plasma cells at the SMG, comprising the newly defined epithelial SMG-Duct cells, and B and T lineage immune cells. Using our transcriptomic data for cell-cell interaction analysis, we propose a signalling circuit that establishes and supports this niche. Overall, we provide a transcriptional and spatial lung atlas with multiple novel cell types that allows for the study of specific tissue microenvironments such as the newly defined gland-associated lymphoid niche (GALN).

Published
2021
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6. Late Breaking Abstract - A multiomic micro- and macro-anatomical cell atlas of the human lungs and airways

Author

Rasa Elmentaite, Andrew P. Knights, Sophie Pritchard, Adam Hunter, Ana Ribeiro Orsi, Monika Dabrowska, Krzysztof Polanski, Vitalii Kleshchevnikov, Kerstin B. Meyer, Jan Patrick Pett, Liam Bolt, Anna Wilbrey-Clark, Lira Mamanova, Sarah Vieira, Juliana Weller, Nikitas Georgakopoulos, Krishnaa Muhbubani, Liz Tuck, Ni Huang, Elena Prigmore, Kourosh Saeb-Parsy, Oliver Stegle, Peng He, Sarah A. Teichmann, Amanda Oliver, Elo Madisoon, Natsuhiko Kumasaka, and Minal Patel

Subjects
Atlas (topology), business.industry, Medicine, Anatomy, Macro, business
Published
2021
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7. Cross-tissue immune cell analysis reveals tissue-specific adaptations and clonal architecture in humans

Author

Louisa K. James, Lorna B. Jarvis, Campos L, Krzysztof Polanski, Kerstin B. Meyer, Krishnaa T. Mahbubani, Martin Prete, Zewen K. Tuong, Liz Tuck, Ni Huang, Omer Ali Bayraktar, Eirini S. Fasouli, Edward Needham, Joanne L. Jones, Lira Mamanova, Tong Li, Hamish W King, Sarah Howlett, Dan Rainbow, C Xu, Nathan Richoz, O Suchanek, Hani S Mousa, Rasa Elmentaite, Sophie Pritchard, Kourosh Saeb-Parsy, Tomás Gomes, David K. Menon, Clatworthy, Jong-Eun Park, C Domínguez Conde, and Sarah A. Teichmann

Subjects
Cell type, medicine.anatomical_structure, Immune system, T-cell receptor, Cell, medicine, Somatic hypermutation, Biology, Memory B cell, Receptor, Isotype, Cell biology
Abstract

Despite their crucial role in health and disease, our knowledge of immune cells within human tissues, in contrast to those circulating in the blood, remains limited. Here, we surveyed the immune compartment of lymphoid and non-lymphoid tissues of six adult donors by single-cell RNA sequencing, including alpha beta T-cell receptor (αβ TCR), gamma delta (γδ) TCR and B-cell receptor (BCR) variable regions. To aid systematic cell type identification we developed CellTypist, a tool for automated and accurate cell type annotation. Using this approach combined with manual curation, we determined the tissue distribution of finely phenotyped immune cell types and cell states. This revealed tissue-specific features within cell subsets, such as a subtype of activated dendritic cells in the airways expressing CSF2RA, GPR157, CRLF2, ITGAD-expressing γδ T cells in spleen and liver, and ITGAX+ splenic memory B cells. Single cell paired chain TCR analysis revealed cell type-specific biases in VDJ usage, and BCR analysis revealed characteristic patterns of somatic hypermutation and isotype usage in plasma and memory B cell subsets. In summary, our multi-tissue approach lays the foundation for identifying highly resolved immune cell types by leveraging a common reference dataset, tissue-integrated expression analysis and antigen receptor sequencing.

Published
2021
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8. Cells and gene expression programs in the adult human heart

Author

Joshua M. Gorham, Christine E. Seidman, Krishnaa T. Mahbubani, Jon G. Seidman, Krzysztof Polanski, Eric L. Lindberg, Daniel M. DeLaughter, Kenny Roberts, Hongbo Zhang, Eirini S. Fasouli, Emily R. Nadelmann, Catherine L. Worth, Michela Noseda, Daniel Reichart, Norbert Hubner, Hiroko Wakimoto, Barbara McDonough, Matthias Heinig, Giannino Patone, Gavin Y. Oudit, Liz Tuck, Sarah A. Teichmann, Omer Ali Bayraktar, Carlos Talavera-López, Monika Litviňuková, Anissa Viveiros, Kourosh Saeb-Parsy, Hao Zhang, Henrike Maatz, Sara Samari, Masatoshi Kanda, and Joseph J. Boyle

Subjects
education.field_of_study, government.form_of_government, Cell, Population, Skeletal muscle, Biology, Phenotype, Transcriptome, Lymphatic Endothelium, medicine.anatomical_structure, Cardiovascular and Metabolic Diseases, medicine, government, cardiovascular system, Interventricular septum, education, Neuroscience, Homeostasis
Abstract

SummaryCardiovascular disease is the leading cause of death worldwide. Advanced insights into disease mechanisms and strategies to improve therapeutic opportunities require deeper understanding of the molecular processes of the normal heart. Knowledge of the full repertoire of cardiac cells and their gene expression profiles is a fundamental first step in this endeavor. Here, using large-scale single cell and nuclei transcriptomic profiling together with state-of-the-art analytical techniques, we characterise the adult human heart cellular landscape covering six anatomical cardiac regions (left and right atria and ventricles, apex and interventricular septum). Our results highlight the cellular heterogeneity of cardiomyocytes, pericytes and fibroblasts, revealing distinct subsets in the atria and ventricles indicative of diverse developmental origins and specialized properties. Further we define the complexity of the cardiac vascular network which includes clusters of arterial, capillary, venous, lymphatic endothelial cells and an atrial-enriched population. By comparing cardiac cells to skeletal muscle and kidney, we identify cardiac tissue resident macrophage subsets with transcriptional signatures indicative of both inflammatory and reparative phenotypes. Further, inference of cell-cell interactions highlight a macrophage-fibroblast-cardiomyocyte network that differs between atria and ventricles, and compared to skeletal muscle. We expect this reference human cardiac cell atlas to advance mechanistic studies of heart homeostasis and disease.

Published
2020

9. Single-cell sequencing of developing human gut reveals transcriptional links to childhood Crohn’s disease

Author

Omer Ali Bayraktar, Daniel Ortmann, Liz Tuck, Komal Nayak, Robert Heuschkel, Ludovic Vallier, Rasa Elmentaite, Matthias Zilbauer, Tomás Gomes, Kenny Roberts, Sarah A. Teichmann, Alexander Ross, and Kylie R. James

Subjects
0303 health sciences, Cell type, Cellular differentiation, Mesenchymal stem cell, Biology, Cell biology, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Single cell sequencing, Precursor cell, Organoid, Stem cell, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

SummaryHuman gut development requires the orchestrated interaction of various differentiating cell types. Here we generate an in-depth single-cell map of the developing human intestine at 6–10 weeks post-conception, a period marked by crypt-villus formation. Our analysis reveals the transcriptional profile of cycling epithelial precursor cells, which are distinct from LGR5-expressing cells. We use computational analyses to show that these cells contribute to differentiated cell subsets directly and indirectly via the generation of LGR5-expressing stem cells and receive signals from the surrounding mesenchymal cells. Furthermore, we draw parallels between the transcriptomes ofex vivotissues andin vitrofetal organoids, revealing the maturation of organoid cultures in a dish. Lastly, we compare scRNAseq profiles from paediatric Crohn’s disease epithelium alongside matched healthy controls to reveal disease associated changes in epithelial composition. Contrasting these with the fetal profiles reveals re-activation of fetal transcription factors in Crohn’s disease epithelium. Our study provides a unique resource, available atwww.gutcellatlas.org, and underscores the importance of unravelling fetal development in understanding disease.

Published
2020
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10. Cells of the adult human heart

Author

Monika Litviňuková, Carlos Talavera-López, Henrike Maatz, Daniel Reichart, Catherine L. Worth, Eric L. Lindberg, Masatoshi Kanda, Krzysztof Polanski, Matthias Heinig, Michael Lee, Emily R. Nadelmann, Kenny Roberts, Liz Tuck, Eirini S. Fasouli, Daniel M. DeLaughter, Barbara McDonough, Hiroko Wakimoto, Joshua M. Gorham, Sara Samari, Krishnaa T. Mahbubani, Kourosh Saeb-Parsy, Giannino Patone, Jose

Published
2020
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11. Embedding and freezing fresh human tissue in OCT using isopentane v3

Author

Kenny Roberts and Liz Tuck

Abstract

For many cutting-edge spatial transcriptomic analysis methods, it is essential to prepare and store tissue in a manner that preserves RNA integrity, tissue morphology, and spatial orientation. This protocol describes the process of freezing fresh or fixed and cryoprotected tissues in optimal cutting temperature compound (OCT) using an isopentane-dry ice slurry. Rapid controlled freezing preserves RNA and mimises ice damage, while embedding in OCT prepares tissues for future cryosectioning.

Published
2019
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12. Embedding and freezing fresh human tissue in OCT using isopentane v2

Author

Kenny Roberts and Liz Tuck

Abstract

For many cutting-edge spatial transcriptomic analysis methods, it is essential to prepare and store tissue in a manner that preserves RNA integrity, tissue morphology, and spatial orientation. This protocol describes the process of freezing fresh or fixed and cryoprotected tissues in optimal cutting temperature compound (OCT) using an isopentane-dry ice slurry. Rapid controlled freezing preserves RNA and mimises ice damage, while embedding in OCT prepares tissues for future cryosectioning.

Published
2019
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13. Embedding and freezing fresh human tissue in OCT using isopentane v1

Author

Kenny Roberts and Liz Tuck

Subjects
Isopentane, chemistry.chemical_compound, Chromatography, Chemistry, Fresh frozen, Embedding
Abstract

For many cutting-edge spatial transcriptomic analysis methods, it is essential to prepare and store tissue in a manner that preserves RNA integrity, tissue morphology, and spatial orientation. This protocol describes the process of freezing fresh or fixed and cryoprotected tissues in optimal cutting temperature compound (OCT) using an isopentane-dry ice slurry. Rapid controlled freezing preserves RNA and mimises ice damage, while embedding in OCT prepares tissues for future cryosectioning.

Published
2019
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14. (EN) Freezing Tissue in OCT using Isopentane - (FR) Congélation de tissus dans de l'OCT avec l'isopentane v2

Author

Liz Tuck and Heather Etchevers

Abstract

Introduction This protocol describes how to freeze tissues in OCT using dry-ice cooled isopentane (for downstream cryo-sectioning). In this new version we add that it is also possible to use liquid nitrogen to cool the isopentane, but it's more complicated. Ce protocole décrit comment congéler des tissus ou embryons dans du OCT / Tissue-Tek ou autre milieu de congélation pour faire des coupes cryostat. Dans cette version, on ajoute qu'on peut également refroidir l'iso-pentane dans de l'azote liquide mais il y a plus de contraintes.

Published
2019
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15. (EN) Freezing Tissue in OCT using Isopentane - (FR) Congélation de tissus dans de l'OCT avec l'isopentane v1

Author

Liz Tuck and Heather Etchevers

Subjects
Chemistry, Histology, Molecular biology
Abstract

Introduction This protocol describes how to freeze tissues in OCT using dry-ice cooled isopentane (for downstream cryo-sectioning). Ce protocole décrit comment congéler des tissus ou embryons dans du OCT / Tissue-Tek ou autre milieu de congélation pour faire des coupes cryostat

Published
2019
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16. Freezing Tissue in OCT using Isopentane v1

Author

Liz Tuck

Subjects
Isopentane, chemistry.chemical_compound, Chromatography, chemistry
Abstract

Introduction This protocol describes how to freeze tissues in OCT using dry-ice cooled isopentane (for downstream cryo-sectioning). Related Documents Risk assessment: WTSI-3200_ Freezing Tissue using Isopentane

Published
2019
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17. Preoperative risk factors for conversion from laparoscopic to open cholecystectomy: a validated risk score derived from a prospective U.K. database of 8820 patients

Author

Robert P. Sutcliffe, Marianne Hollyman, James Hodson, Glenn Bonney, Ravi S. Vohra, Ewen A. Griffiths, Stephen Fenwick, Mohamed Elmasry, Quentin Nunes, David Kennedy, Raja B. Khan, Muhammad A.S. Khan, Conor J. Magee, Steven M. Jones, Denise Mason, Ciny P. Parappally, Pawan Mathur, Michael Saunders, Sara Jamel, Samer U.l. Haque, Sara Zafar, Muhammad H. Shiwani, Nehemiah Samuel, Farooq Dar, Andrew Jackson, Bryony Lovett, Shiva Dindyal, Hannah Winter, Saquib Rahman, Kevin Wheatley, Tom Nieto, Soofiyah Ayaani, Haney Youssef, Rajwinder S. Nijjar, Helen Watkin, David Naumann, Sophie Emeshi, Piyush B. Sarmah, Kathryn Lee, Nikita Joji, Jonathan Heath, Rebecca L. Teasdale, Chamindri Weerasinghe, Paul J. Needham, Hannah Welbourn, Luke Forster, David Finch, Jane M. Blazeby, William Robb, Angus G.K. McNair, Alex Hrycaiczuk, Alexandros Charalabopoulos, Sritharan Kadirkamanathan, Cheuk-Bong Tang, Naga V.G. Jayanthi, Nigel Noor, Brian Dobbins, Andrew J. Cockbain, April Nilsen-Nunn, Jonathan de Siqueira, Mike Pellen, Jonathan B. Cowley, Wei-Min Ho, Victor Miu, Timothy J. White, Kathryn A. Hodgkins, Alison Kinghorn, Matthew G. Tutton, Yahya A. Al-Abed, Donald Menzies, Anwar Ahmad, Joanna Reed, Shabuddin Khan, David Monk, Louis J. Vitone, Ghulam Murtaza, Abraham Joel, Stephen Brennan, David Shier, Catherine Zhang, Thusidaran Yoganathan, Steven J. Robinson, Iain J.D. McCallum, Michael J. Jones, Mohammed Elsayed, Liz Tuck, John Wayman, Kate Carney, Somaiah Aroori, Kenneth B. Hosie, Adam Kimble, David M. Bunting, Adeshina S. Fawole, Mohammed Basheer, Rajiv V. Dave, Janahan Sarveswaran, Elinor Jones, Chris Kendal, Michael P. Tilston, Martin Gough, Tom Wallace, Shailendra Singh, Justine Downing, Katherine A. Mockford, Eyad Issa, Nayab Shah, Neal Chauhan, Timothy R. Wilson, Amir Forouzanfar, Jonathan R.L. Wild, Emma Nofal, Catherine Bunnell, Khaliel Madbak, Sudhindra T.V. Rao, Laurence Devoto, Najaf Siddiqi, Zechan Khawaja, James C. Hewes, Laura Gould, Alice Chambers, Daniel U. Rodriguez, Gourab Sen, Stuart Robinson, Francis Bartlett, David M. Rae, Thomas E.J. Stevenson, Kas Sarvananthan, Simon J. Dwerryhouse, Simon M. Higgs, Oliver J. Old, Thomas J. Hardy, Reena Shah, Steve T. Hornby, Ken Keogh, Lucinda Frank, Musallam Al-Akash, Emma A. Upchurch, Richard J. Frame, Michael Hughes, Clare Jelley, Simon Weaver, Sudipta Roy, Toritseju O. Sillo, Giorgios Galanopoulos, Tamzin Cuming, Pedro Cunha, Salim Tayeh, Sarantos Kaptanis, Mohamed Heshaishi, Abdalla Eisawi, Michael Abayomi, Wee S. Ngu, Katie Fleming, Dalvir S. Bajwa, Vivek Chitre, Kamal Aryal, Paul Ferris, Michael Silva, Simon Lammy, Sarah Mohamed, Amir Khawaja, Adnan Hussain, Mudassar A. Ghazanfar, Maria I. Bellini, Hamdi Ebdewi, Mohamed Elshaer, Gianpiero Gravante, Benjamin Drake, Arikoge Ogedegbe, Dipankar Mukherjee, Chanpreet Arhi, Lola Giwa, Nusrat Iqbal, Nicholas F. Watson, Smeer K. Aggarwal, Philippa Orchard, Eduardo Villatoro, Peter D. Willson, Kam W.J. Mok, Thomas Woodman, Jean Deguara, Giuseppe Garcea, Benoy I. Babu, Alistair R. Dennison, Deep Malde, David Lloyd, John P. Slavin, Robert P. Jones, Laura Ballance, Stratos Gerakopoulos, Periyathambi Jambulingam, Sami Mansour, Naomi Sakai, Vikas Acharya, Mohammed M. Sadat, Lawen Karim, David Larkin, Khalid Amin, Amarah Khan, Jennifer Law, Saurabh Jamdar, Stella R. Smith, Keerthika Sampat, Kathryn M. O'shea, Mangta Manu, Fotini M. Asprou, Nabeela S. Malik, Jessica Chang, Marianne Johnstone, Michael Lewis, Geoffrey P. Roberts, Babu Karavadra, Evangelos Photi, James Hewes, Dan Rodriguez, Derek A. O'Reilly, Anthony J. Rate, Hema Sekhar, Lucy T. Henderson, Benjamin Z. Starmer, Peter O. Coe, Sotonye Tolofari, Jenifer Barrie, Gareth Bashir, Jake Sloane, Suroosh Madanipour, Constantine Halkias, Alexander E.J. Trevatt, David W. Borowski, Jane Hornsby, Michael J. Courtney, Suvi Virupaksha, Keith Seymour, Sarah Robinson, Helen Hawkins, Sadiq Bawa, Paul V. Gallagher, Alistair Reid, Peter Wood, Jonathan G. Finch, J.Guy Finch, Jitesh Parmar, Euan Stirland, James Gardner-Thorpe, Ahmed Al-Muhktar, Mark Peterson, Ali Majeed, Farrukh M. Bajwa, Jack Martin, Alfred Choy, Andrew Tsang, Naresh Pore, David R. Andrew, Waleed Al-Khyatt, Christopher Taylor Santosh Bhandari, Adam Chambers, Dhivya Subramanium, Simon K.C. Toh, Nicholas C. Carter, Stuart J. Mercer, Benjamin Knight, Vardhini Vijay, Swethan Alagaratnam, Sidhartha Sinha, Shahab Khan, Shamsi S. El-Hasani, Abdulzahra A. Hussain, Vish Bhattacharya, Nisheeth Kansal, Tani Fasih, Claire Jackson, Midhat N. Siddiqui, Imran A. Chishti, Imogen J. Fordham, Zohaib Siddiqui, Harald Bausbacher, Ileana Geogloma, Kabita Gurung, George Tsavellas, Pradeep Basynat, Ashish K. Shrestha, Sanjoy Basu, Alok Chhabra, Mohan Harilingam, Mohamed Rabie, Mansoor Akhtar, Pradeep Kumar, Sadaf F. Jafferbhoy, Najam Hussain, Soulat Raza, Manzarul Haque, Imran Alam, Rabiya Aseem, Shakira Patel, Mehek Asad, Michael I. Booth, William R. Ball, Christopher P.J. Wood, Ana C. Pinho-Gomes, Ambareen Kausar, Mohammed Obeidallah, Joseph Varghase, Joshil Lodhia, Donal Bradley, Carla Rengifo, David Lindsay, Sivakumar Gopalswamy, Ian Finlay, Stacy Wardle, Naomi Bullen, Syed Y. Iftikhar, Altaf Awan, Javed Ahmed, Paul Leeder, Guiseppe Fusai, Giles Bond-Smith, Alicja Psica, Yogesh Puri, David Hou, Fergus Noble, Karoly Szentpali, Jack Broadhurst, Ravindra Date, Martin R. Hossack, Yan L. Goh, Paul Turner, Vinutha Shetty, Manel Riera, Christina A.W. Macano, Anisha Sukha, Shaun R. Preston, Jennifer R. Hoban, Daniel J. Puntis, Sophie V. Williams, Richard Krysztopik, James Kynaston, Jeremy Batt, Matthew Doe, Andrzej Goscimski, Gareth H. Jones, Claire Hall, Nick Carty, Jamil Ahmed, Sofoklis Panteleimonitis, Rohan T. Gunasekera, Andrea R.G. Sheel, Hannah Lennon, Caroline Hindley, Marcus Reddy, Ross Kenny, Natalie Elkheir, Emma R. McGlone, Rajasundaram Rajaganeshan, Kate Hancorn, Anita Hargreaves, Raj Prasad, David A. Longbotham, Dhakshinamoorthy Vijayanand, Imeshi Wijetunga, Paul Ziprin, Christopher R. Nicolay, Geoffrey Yeldham, Edward Read, James A. Gossage, Rachel C. Rolph, Husam Ebied, Manraj Phull, Mohammad A. Khan, Matthew Popplewell, Dimitrios Kyriakidis, Anwar Hussain, Natasha Henley, Jessica R. Packer, Laura Derbyshire, Jonathan Porter, Shaun Appleton, Marwan Farouk, Melvinder Basra, Neil A. Jennings, Shahda Ali, Venkatesh Kanakala, Haythem Ali, Risha Lane, Richard Dickson-Lowe, Prizzi Zarsadias, Darius Mirza, Sonia Puig, Khalid Al Amari, Deepak Vijayan, Robert Sutcliffe, Ravi Marudanayagam, Zayed Hamady, Abheesh R. Prasad, Abhilasha Patel, Damien Durkin, Parminder Kaur, Laura Bowen, James P. Byrne, Katherine L. Pearson, Theo G. Delisle, James Davies, Mark A. Tomlinson, Michelle A. Johnpulle, Corinna Slawinski, Andrew Macdonald, James Nicholson, Katy Newton, James Mbuvi, Ansar Farooq, Bhavani S. Mothe, Zakhi Zafrani, Daniel Brett, James Francombe, Philip Spreadborough, James Barnes, Melanie Cheung, Ahmed Z. Al-Bahrani, Giuseppe Preziosi, Tomas Urbonas, Justin Alberts, Mekhlola Mallik, Krashna Patel, Ashvina Segaran, Triantafyllos Doulias, Pratik A. Sufi, Caroline Yao, Sarah Pollock, Antonio Manzelli, Saj Wajed, Michail Kourkulos, Roberto Pezzuto, Martin Wadley, Emma Hamilton, Shameen Jaunoo, Robert Padwick, Mazin Sayegh, Richard C. Newton, Madhusoodhana Hebbar, Sameh F. Farag, Madhu Hebbar, John Spearman, Mohammed F. Hamdan, Conrad D'Costa, Christine Blane, Mathew Giles, Mark B. Peter, Natalie A. Hirst, Tanvir Hossain, Arslan Pannu, Yesar El-Dhuwaib, Tamsin E.M. Morrison, Greg W. Taylor, Ronald L.E. Thompson, Ken McCune, Paula Loughlin, Roger Lawther, Colman K. Byrnes, Duncan J. Simpson, Abi Mawhinney, Conor Warren, Damian McKay, Colin McIlmunn, Serena Martin, Matthew MacArtney, Tom Diamond, Phil Davey, Claire Jones, Joshua M. Clements, Ruairi Digney, Wei M. Chan, Stephen McCain, Sadaf Gull, Adam Janeczko, Emmet Dorrian, Andrew Harris, Suzanne Dawson, Dorothy Johnston, Barry McAree, Essam Ghareeb, George Thomas, Martin Connelly, Stephen McKenzie, Krzysztos Cieplucha, Gary Spence, William Campbell, Gareth Hooks, Neil Bradley, Arnold D.K. Hill, John T. Cassidy, Michael Boland, Paul Burke, Deirdre M. Nally, Elmoataz Khogali, Wael Shabo, Edrin Iskandar, Gerry P. McEntee, Maeve A. O'Neill, Colin Peirce, Emma M. Lyons, Adrian W. O'Sullivan, Rohan Thakkar, Paul Carroll, Ivan Ivanovski, Paul Balfe, Matthew Lee, Des C. Winter, Michael E. Kelly, Emir Hoti, Donal Maguire, Priyadarssini Karunakaran, Justin G. Geoghegan, Sean T. Martin, Keith S. Cross, Fiachra Cooke, Saquib Zeeshan, James O. Murphy, Ken Mealy, Helen M. Mohan, Yuwaraja Nedujchelyn, Muhammad F. Ullah, Irfan Ahmed, Francesco Giovinazzo, James Milburn, Sarah Prince, Eleanor Brooke, Joanna Buchan, Ahmed M. Khalil, Elizabeth M. Vaughan, Michael I. Ramage, Roland C. Aldridge, Simon Gibson, Gary A. Nicholson, David G. Vass, Alan J. Grant, David J. Holroyd, Angharad Jones, Cherith M.L.R. Sutton, Patrick O'Dwyer, Frida Nilsson, Beatrix Weber, Tracey K. Williamson, Kushik Lalla, Alice Bryant, Ross Carter, Craig R. Forrest, David I. Hunter, Ahmad H. Nassar, Mavis N. Orizu, Katrina Knight, Haitham Qandeel, Stuart Suttie, Rowena Belding, Andrew McClarey, Alan T. Boyd, Graeme J.K. Guthrie, Pei J. Lim, Andreas Luhmann, Angus J.M. Watson, Colin H. Richards, Laura Nicol, Marta Madurska, Ewen Harrison, Kathryn M. Boyce, Amanda Roebuck, Graeme Ferguson, Pradeep Pati, Michael S.J. Wilson, Faith Dalgaty, Laura Fothergill, Peter J. Driscoll, Kirsty L. Mozolowski, Victoria Banwell, Stephen P. Bennett, Paul N. Rogers, Brendan L. Skelly, Claire L. Rutherford, Ahmed K. Mirza, Taha Lazim, Henry C.C. Lim, Diana Duke, Talat Ahmed, William D. Beasley, Marc D. Wilkinson, Geta Maharaj, Cathy Malcolm, Timothy H. Brown, Guy M. Shingler, Nicholas Mowbray, Rami Radwan, Paul Morcous, Simon Wood, Abbas Kadhim, Duncan J. Stewart, Andrew L. Baker, Nicola Tanner, and Hrishikesh Shenoy

Subjects
Male, Databases, Factual, medicine.medical_treatment, 0302 clinical medicine, Risk Factors, Odds Ratio, Prospective Studies, Prospective cohort study, Framingham Risk Score, Gastroenterology, Age Factors, Gallbladder, Middle Aged, Conversion to Open Surgery, Treatment Outcome, Cholecystectomy, Laparoscopic, 030220 oncology & carcinogenesis, Predictive value of tests, 030211 gastroenterology & hepatology, Female, Original Article, Risk assessment, Dilatation, Pathologic, Adult, medicine.medical_specialty, Digestive System Diseases, MEDLINE, Risk Assessment, 03 medical and health sciences, Sex Factors, Predictive Value of Tests, medicine, Humans, Aged, Common Bile Duct, Chi-Square Distribution, Hepatology, Laparoscopyc cholecystectomy, business.industry, General surgery, Reproducibility of Results, Odds ratio, United Kingdom, Surgery, preoperative assessment, Logistic Models, Multivariate Analysis, Cholecystectomy, business, Chi-squared distribution, risk factors
Abstract

Laparoscopic cholecystectomy is commonly performed, and several factors increase the risk of open conversion, prolonging operating time and hospital stay. Preoperative stratification would improve consent, scheduling and identify appropriate training cases. The aim of this study was to develop a validated risk score for conversion for use in clinical practice.Preoperative patient and disease-related variables were identified from a prospective cholecystectomy database (CholeS) of 8820 patients, divided into main and validation sets. Preoperative predictors of conversion were identified by multivariable binary logistic regression. A risk score was developed and validated using a forward stepwise approach.Some 297 procedures (3.4%) were converted. The risk score was derived from six significant predictors: age (p = 0.005), sex (p 0.001), indication for surgery (p 0.001), ASA (p 0.001), thick-walled gallbladder (p = 0.040) and CBD diameter (p = 0.004). Testing the score on the validation set yielded an AUROC = 0.766 (p 0.001), and a score6 identified patients at high risk of conversion (7.1% vs. 1.2%).This validated risk score allows preoperative identification of patients at six-fold increased risk of conversion to open cholecystectomy.

Published
2016

18. Single-Cell Sequencing of Developing Human Gut Reveals Transcriptional Links to Childhood Crohn's Disease

Author

Kenny Roberts, Liz Tuck, Ludovic Vallier, Matthias Zilbauer, Robert Heuschkel, Daniel Ortmann, Komal Nayak, Kylie R. James, Sophie Pritchard, Rasa Elmentaite, Omer Ali Bayraktar, Tomás Gomes, Sarah A. Teichmann, Alexander Ross, Vallier, Ludovic [0000-0002-3848-2602], Teichmann, Sarah [0000-0002-6294-6366], Zilbauer, Matthias [0000-0002-7272-0547], and Apollo - University of Cambridge Repository

Subjects
Resource, Cell type, Adolescent, Cellular differentiation, Biology, Inflammatory bowel disease, General Biochemistry, Genetics and Molecular Biology, pediatric Crohn's disease, single-cell RNA sequencing, Receptors, G-Protein-Coupled, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Crohn Disease, inflammatory bowel disease, Precursor cell, villus formation, medicine, Humans, RNA-Seq, Intestinal Mucosa, Child, Molecular Biology, Cells, Cultured, 030304 developmental biology, intestinal stem cells, 0303 health sciences, Mesenchymal stem cell, Cell Biology, human fetal gut development, medicine.disease, 3. Good health, Cell biology, Single cell sequencing, intestinal organoids, Stem cell, Single-Cell Analysis, 030217 neurology & neurosurgery, Developmental Biology, Transcription Factors
Abstract

Summary Human gut development requires the orchestrated interaction of differentiating cell types. Here, we generate an in-depth single-cell map of the developing human intestine at 6–10 weeks post-conception. Our analysis reveals the transcriptional profile of cycling epithelial precursor cells; distinct from LGR5-expressing cells. We propose that these cells may contribute to differentiated cell subsets via the generation of LGR5-expressing stem cells and receive signals from surrounding mesenchymal cells. Furthermore, we draw parallels between the transcriptomes of ex vivo tissues and in vitro fetal organoids, revealing the maturation of organoid cultures in a dish. Lastly, we compare scRNA-seq profiles from pediatric Crohn’s disease epithelium alongside matched healthy controls to reveal disease-associated changes in the epithelial composition. Contrasting these with the fetal profiles reveals the re-activation of fetal transcription factors in Crohn’s disease. Our study provides a resource available at www.gutcellatlas.org, and underscores the importance of unraveling fetal development in understanding disease., Graphical Abstract, Highlights • Single-cell RNA-seq map of the developing and pediatric human intestine • Cycling BEX5+ epithelial precursors are distinct from adult LGR5+ stem cells • Human fetal intestinal organoids mature in culture • Fetal transcription factors are reactivated in the Crohn’s disease epithelium, Elmentaite and Ross et al. generated a detailed single-cell RNA-seq map of the developing human intestine. Data analyses revealed the presence of an early intestinal epithelial precursor cell and the re-activation of fetal transcription factors in the intestinal epithelium of children diagnosed with Crohn’s disease. The study provides a unique resource accessible to all researchers at www.gutcellatlas.org.

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