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Hardy, O.

Publications and source records attributed to Hardy, O..

7 recordsLinked to original sources

Synovial lining expressed mechanosensor PIEZO1 drives inflammation-permissive macrophage phenotypes and joint inflammation

Synovial tissue-resident macrophages regulate immune homeostasis within the joint, but can adopt an inflammation-permissive phenotype that promotes immune cell infiltration in rheumatoid arthritis (RA). Understanding the factors that drive this phenotypic switch may help prevent the localisation of inflammation in the joints of individuals at-risk of RA. We identified the mechanosensitive ion channel PIEZO1 as a potential regulator of lining-layer synovial tissue macrophage (STM) function. PIEZO1 was highly expressed in homeostatic, tissue resident TREM2pos lining-layer STMs and in its pathogenic chemokine producing TREM2low phenotype that characterises the hyperplastic lining-layer in active RA. Intra-articular injection of a PIEZO1 agonist in mice induced neutrophil and monocyte infiltration, whereas inhibition of PIEZO1 signalling restored the protective macrophage phenotype. Thus, mechanosensing via PIEZO1 is a defining feature of the joint lining-layer, and its aberrant activation by mechanical stress may lead to the localisation of inflammation within the joint, facilitating a transition from asymptomatic autoimmunity of at-risk RA to clinical disease.

immunology↗

Human Fibroblast-Myeloid cell tissue atlas across lung, synovium, skin and heart

Single-cell RNA sequencing (scRNAseq) of human tissues has expanded our understanding of the complexity of cellular subsets and their changes in disease. The availability of scRNAseq data in different tissues and disease states provides an opportunity to compare cellular subsets and identify common and unique cellular activation. In this study, we aimed to characterize shared and tissue-specific myeloid and stromal phenotypes and uncover key cellular subtypes involved in pathogenic tissue activation. We analyzed scRNAseq data from 14 public datasets, comprising heart, lung, skin, and synovium in both healthy and diseased states. Our analysis identified distinct and overlapping myeloid and stromal cell populations in these tissues. Despite significant inter-individual variability, we were able to identify both shared and disease-specific changes in these cell populations. These findings provide insights into the conserved and tissue-specific roles of myeloid and stromal cells in health and disease and contribute to a better understanding of tissue pathology and potential therapeutic targets.

cell biology↗

Spatial transcriptomics reveals focal induction of molecular responses and cellular interactions in the small intestine during Heligmosomoides polygyrus infection.

The infective larvae of the helminth Heligmosomoides polygyrus bakeri migrate to the small intestine, invade the submucosa, and trigger granuloma formation around each parasite. Here, we employ spatial transcriptomics to elucidate the transcriptional intricacies and cell interactions in H. polygyrus-infected mice. We find a generalised reduction in expression of homeostatic genes such as Epcam, Pls1 (fimbrin) and Zg16, while cell adhesion (eg Cldn3, Cdh17) and immune-protective (Pla2g4c) loci are upregulated. Specific genes and cell types are associated with different spatial niches (lower crypt, upper crypt, villi and granuloma). Within the crypts, pathway analysis indicates activation of the osteopontin (Spp1) and pleiotrophin (Ptn) pathways that are poorly represented in steady-state tissues, whilst Wnt signalling within the crypts is abrogated by day 7 of infection. Granulomas contain concentrations of myeloid cells, NK and dendritic cells, with high expression levels of genes linked to M2 macrophages (Arg1, Retlna, Fcer1g) and wound repair pathways (Reg3b and Mxra7) as well as elevated Tmbx4 that has not previously been noted. Analysis of potential ligand-receptor pairs confirmed a major complementarity between granuloma-localised SPP1 and CD44 receptors in both crypt and granuloma, as well as TGF-{beta}/receptor interactions. Infected tissues also revealed abundant chemokine representation; among the latter category CCL6, CCL8 and MIF (macrophage migration inhibitory factor) dominated potential interactions. These results both enhance our understanding of the murine small intestines transcriptional landscape and also identify a new set of molecular interactions underpinning tissue-specific responses to infection that can be targeted for therapeutic intervention.

immunology↗

Spatially resolved single-cell atlas of the lung in fatal Covid19 in an African population reveals a distinct cellular signature and an interferon gamma dominated response

Postmortem single-cell studies have transformed understanding of lower respiratory tract diseases (LRTD) including Covid19 but there is almost no data from African settings where HIV, malaria and other environmental exposures may affect disease pathobiology and treatment targets. We used histology and high-dimensional imaging to characterise fatal lung disease in Malawian adults with (n=9) and without (n=7) Covid19, and generated single-cell transcriptomics data from lung, blood and nasal cells. Data integration with other cohorts showed a conserved Covid19 histopathological signature, driven by contrasting immune and inflammatory mechanisms: in the Malawi cohort, by response to interferon-gamma (IFN-{gamma}) in lung-resident alveolar macrophages, in USA, European and Asian cohorts by type I/III interferon responses, particularly in blood-derived monocytes. HIV status had minimal impact on histology or immunopathology. Our study provides data resources and highlights the importance of studying the cellular mechanisms of disease in underrepresented populations, indicating shared and distinct targets for treatment.

immunology↗

A large-scale species level dated angiosperm phylogeny for evolutionary and ecological analyses

Phylogenies are a central and indispensable tool for evolutionary and ecological research. Even though most angiosperm families are well investigated from a phylogenetic point of view, there are far less possibilities to carry out large-scale meta-analyses at order level or higher. Here, we reconstructed a large-scale dated phylogeny including nearly 1/8th of all angiosperm species based on two plastid barcoding genes, matK and rbcL. Novel sequences were generated for several species, while the rest of the data were mined from GenBank. The resulting tree was dated using 56 angiosperm fossils as calibration points. The resulting megaphylogeny is one of the largest dated phylogenetic tree of angiosperms yet, consisting of 36,101 sampled species, representing 8,399 genera, 426 families and all orders. This novel framework will be useful to investigate different broad scale research questions in ecological and evolutionary biology.

evolutionary biology↗

The Origin and Early Evolution of the Legumes are a Complex Paleopolyploid Phylogenomic Tangle closely associated with the Cretaceous-Paleogene (K-Pg) Boundary

The consequences of the Cretaceous-Paleogene (K-Pg) boundary (KPB) mass extinction for the evolution of plant diversity are poorly understood, even although evolutionary turnover of plant lineages at the KPB is central to understanding the assembly of the Cenozoic biota. One aspect that has received considerable attention is the apparent concentration of whole genome duplication (WGD) events around the KPB, which may have played a role in survival and subsequent diversification of plant lineages. In order to gain new insights into the origins of Cenozoic biodiversity, we examine the origin and early evolution of the legume family, one of the most important angiosperm clades that rose to prominence after the KPB and for which multiple WGD events are found to have occurred early in its evolution. The legume family (Leguminosae or Fabaceae), with c. 20.000 species, is the third largest family of Angiospermae, and is globally widespread and second only to the grasses (Poaceae) in economic importance. Accordingly, it has been intensively studied in botanical, systematic and agronomic research, but a robust phylogenetic framework and timescale for legume evolution based on large-scale genomic sequence data is lacking, and key questions about the origin and early evolution of the family remain unresolved. We extend previous phylogenetic knowledge to gain insights into the early evolution of the family, analysing an alignment of 72 protein-coding chloroplast genes and a large set of nuclear genomic sequence data, sampling thousands of genes. We use a concatenation approach with heterogeneous models of sequence evolution to minimize inference artefacts, and evaluate support and conflict among individual nuclear gene trees with internode certainty calculations, a multi-species coalescent method, and phylogenetic supernetwork reconstruction. Using a set of 20 fossil calibrations we estimate a revised timeline of legume evolution based on a selection of genes that are both informative and evolving in an approximately clock-like fashion. We find that the root of the family is particularly difficult to resolve, with strong conflict among gene trees suggesting incomplete lineage sorting and/or reticulation. Mapping of duplications in gene family trees suggest that a WGD event occurred along the stem of the family and is shared by all legumes, with additional nested WGDs subtending subfamilies Papilionoideae and Detarioideae. We propose that the difficulty of resolving the root of the family is caused by a combination of ancient polyploidy and an alternation of long and very short internodes, shaped respectively by extinction and rapid divergence. Our results show that the crown age of the legumes dates back to the Maastrichtian or Paleocene and suggests that it is most likely close to the KPB. We conclude that the origin and early evolution of the legumes followed a complex history, in which multiple nested polyploidy events coupled with rapid diversification are associated with the mass extinction event at the KPB, ultimately underpinning the evolutionary success of the Leguminosae in the Cenozoic.

evolutionary biology↗

Phylogenomics within the Anthonotha clade (Detarioideae, Leguminosae) reveals a high diversity in floral trait shifts and a general trend towards organ number reduction

Detarioideae is well known for its high diversity of floral traits, including flower symmetry, number of organs, and petal size and morphology. This diversity has been characterized and studied at higher taxonomic levels, but limited analyses have been performed among closely related genera with contrasting floral traits due to the lack of fully resolved phylogenetic relationships. Here, we used four representative transcriptomes to develop an exome capture bait for the entire subfamily and applied it to the Anthonotha clade using a complete data set (61 specimens) representing all extant floral diversity. Our phylogenetic analyses recovered congruent topologies using ML and Bayesian methods. The genus Anthonotha was recovered as monophyletic contrary to the remaining three genera (Englerodendron, Isomacrolobium and Pseudomacrolobium), which form a monophyletic group sister to Anthonotha. We inferred a total of 35 transitions for the seven floral traits (pertaining to flower symmetry, petals, stamens and staminodes) that we analyzed, suggesting that at least 30% of the species in this group display transitions from the ancestral condition reconstructed for the Anthonotha clade. The main transitions were towards a reduction in the number of organs (petals, stamens and staminodes). Despite the high number of transitions, our analyses indicate that the seven characters are evolving independently in these lineages. Petal morphology is the most labile floral trait with a total of seven independent transitions in number and seven independent transitions to modification in petal types. The diverse petal morphology along the dorsoventral axis of symmetry within the flower is not associated with differences at the micromorphology of petal surface, suggesting that in this group all petals within the flower might possess the same petal identity at the molecular level. Our results provide a solid evolutionary framework for further detailed analyses of the molecular basis of petal identity.

evolutionary biology↗