Biology subjects

Reynolds, G.

Publications and source records attributed to Reynolds, G..

24 records · Page 2Linked to original sources

bioRxiv2020

Poised cell circuits in human skin are activated in disease

The human skin confers biophysical and immunological protection through a complex cellular network that is established early in development. We profiled ~500,000 single cells using RNA-sequencing from healthy adult and developing skin, and skin from patients with atopic dermatitis and psoriasis. Our findings reveal a predominance of innate lymphoid cells and macrophages in developing skin in contrast to T cells and migratory dendritic cells in adult skin. We demonstrate dual keratinocyte differentiation trajectories and activated cellular circuits comprising vascular endothelial cells mediating immune cell trafficking, disease-specific clonally expanded IL13/IL22 and IL17A/F-expressing lymphocytes, epidermal IL23-expressing dendritic cells and inflammatory keratinocytes in disease. Our findings provide key insights into the dynamic cellular landscape of human skin in health and disease. One Sentence SummarySingle cell atlas of human skin reveals cell circuits which are quantitatively and qualitatively reconfigured in inflammatory skin disease.

immunology↗

bioRxiv2020

A cell atlas of human thymic development defines T cell repertoire formation

The thymus provides a nurturing environment for the differentiation and selection of T cells, a process orchestrated by their interaction with multiple thymic cell types. We utilised single-cell RNA-sequencing (scRNA-seq) to create a cell census of the human thymus and to reconstruct T-cell differentiation trajectories and T-cell receptor (TCR) recombination kinetics. Using this approach, we identified and located in situ novel CD8+ T-cell populations, thymic fibroblast subtypes and activated dendritic cell (aDC) states. In addition, we reveal a bias in TCR recombination and selection, which is attributed to genomic position and suggests later commitment of the CD8+ T-cell lineage. Taken together, our data provide a comprehensive atlas of the human thymus across the lifespan with new insights into human T-cell development.

immunology↗

bioRxiv2019

Donor monocyte-derived macrophages promote human acute graft versus host disease

Myelopoiesis is invariably present, and contributes to pathology, in animal models of graft versus host disease (GVHD). In humans, a rich inflammatory infiltrate bearing macrophage markers has also been described in histological studies. In order to determine the origin, functional properties and role in pathogenesis of these cells, we isolated single cell suspensions from acute cutaneous GVHD and subjected them to genotype, transcriptome and in vitro functional analysis. A donor-derived population of CD11c+CD14+ cells was the dominant population of all leukocytes in GVHD. Surface phenotype and nanostring gene expression profiling indicated the closest steady-state counterpart of these cells to be monocyte-derived macrophages. In GVHD, however, there was upregulation of monocyte antigens SIRP and S100A8/9, and transcripts associated with leukocyte trafficking, pattern recognition, antigen presentation, and co-stimulation. Isolated GVHD macrophages stimulated greater proliferation and activation of allogeneic T cells, and secreted higher levels of inflammatory cytokines than their steady-state counterparts. In HLA-matched mixed leukocyte reactions, we also observed differentiation of activated macrophages with a similar phenotype. These exhibited cytopathicity to a cell line and mediated pathological damage to skin explants, independently of T cells. Together, these results define the origin, functional properties and potential pathogenic roles of human GVHD macrophages.

immunology↗

bioRxiv2019

The mechanical stability of the worlds tallest broadleaf trees

The factors that limit the maximum height of trees, whether ecophysiological or mechanical, are the subject of longstanding debate. Here we examine the role of mechanical stability in limiting tree height and focus on trees from the tallest tropical forests on Earth, in Sabah, Malaysian Borneo, including the recently discovered tallest tropical tree, a 100.8 m Shorea faguetiana. We use terrestrial laser scans, in situ strain gauge data and finite-element simulations to map the architecture of tall broadleaf trees and monitor their response to wind loading. We demonstrate that a trees risk of breaking due to gravity or self-weight decreases with tree height and is much more strongly affected by tree architecture than by material properties. In contrast, wind damage risk increases with tree height despite the larger diameters of tall trees, resulting in a U-shaped curve of mechanical risk with tree height. The relative rarity of extreme wind speeds in north Borneo may be the reason it is home to the tallest trees in the tropics.

ecology↗

bioRxiv2019

Decoding the development of the blood and immune systems during human fetal liver haematopoiesis

Definitive haematopoiesis in the fetal liver supports self-renewal and differentiation of haematopoietic stem cells/multipotent progenitors (HSC/MPPs), yet remains poorly defined in humans. Using single cell transcriptome profiling of ~133,000 fetal liver and ~65,000 fetal skin and kidney cells, we identify the repertoire of blood and immune cells in first and early second trimesters of development. From this data, we infer differentiation trajectories from HSC/MPPs, and evaluate the impact of tissue microenvironment on blood and immune cell development. We predict coupling of mast cell differentiation with erythro-megakaryopoiesis and identify physiological erythropoiesis in fetal skin. We demonstrate a shift in fetal liver haematopoietic composition during gestation away from being erythroid-predominant, accompanied by a parallel change in HSC/MPP differentiation potential, which we functionally validate. Our integrated map of fetal liver haematopoiesis provides a blueprint for the study of paediatric blood and immune disorders, and a valuable reference for understanding and harnessing the therapeutic potential of HSC/MPPs.

developmental biology↗

bioRxiv2019

PPPred: Classifying Protein-phenotype Co-mentions Extracted from Biomedical Literature

The MEDLINE database provides an extensive source of scientific articles and heterogeneous biomedical information in the form of unstructured text. One of the most important knowledge present within articles are the relations between human proteins and their phenotypes, which can stay hidden due to the exponential growth of publications. This has presented a range of opportunities for the development of computational methods to extract these biomedical relations from the articles. However, currently, no such method exists for the automated extraction of relations involving human proteins and human phenotype ontology (HPO) terms. In our previous work, we developed a comprehensive database composed of all co-mentions of proteins and phenotypes. In this study, we present a supervised machine learning approach called PPPred (Protein-Phenotype Predictor) for classifying the validity of a given sentence-level co-mention. Using an in-house developed gold standard dataset, we demonstrate that PPPred significantly outperforms several baseline methods. This two-step approach of co-mention extraction and classification constitutes a complete biomedical relation extraction pipeline for extracting protein-phenotype relations.\n\nCCS CONCEPTS*Computing methodologies [->] Information extraction; Supervised learning by classification; *Applied computing [->]Bioinformatics;

bioinformatics↗