bioRxiv Science⌕ Search

Biology subjects

Miles, K.

Publications and source records attributed to Miles, K..

3 recordsLinked to original sources

Three-dimensional fossils of a Cretaceous collared carpet shark (Parascylliidae, Orectolobiformes) shed light on skeletal evolution in galeomorphs

A rich fossil record of teeth shows that many living shark families origins lie deep in the Mesozoic. Skeletal fossils of the sharks to whom these teeth belonged are far rarer and when they are preserved are often flattened, hindering understanding of the evolutionary radiation of living shark groups. Here we use computed tomography to describe two articulated Upper Cretaceous shark skeletons from the Chalk of the UK preserving three- dimensional neurocrania, visceral cartilages, pectoral skeletons and vertebrae. These fossils display skeletal anatomies characteristic of the Parascylliidae, a family of Orectolobiformes now endemic to Australia and the Indo Pacific. However, they differ in having a more heavily mineralised braincase and a tri-basal pectoral fin endoskeleton, while their teeth can be attributed to a new species of the problematic taxon Pararhincodon. Phylogenetic analysis of these new fossils confirms that Pararhincodon is a stem-group parascylliid, providing insight into the evolution of parascylliids distinctive anatomy during the late Mesozoic-Cenozoic shift in orectolobiform biodiversity from the Northern Atlantic to the Indo Pacific. Meanwhile both Pararhincodon and extant parascylliids have a distinctive vertebral morphology previously described only in Carcharhiniformes, contributing a skeletal perspective to the picture emerging from macroevolutionary analyses of coastal, small-bodied origins for galeomorphs.

paleontology↗

A comprehensive analysis of rheumatoid arthritis B cells reveals the importance of CD11c+ve double-negative-2 B cells as the major synovial plasma cell precursor.

B cells are key pathogenic drivers of chronic inflammation in rheumatoid arthritis (RA). There is limited understanding of the relationship between synovial B cell subsets and pathogenic antibody secreting cells (ASCs). This knowledge is crucial for the development of targeted therapies. Here, we combine flow cytometry of circulating B cells with single-cell RNA and paired repertoire sequencing of over 27,000 synovial B cells from patients with established RA. Twelve B cell clusters were identified including previously recognised subsets, and a novel cluster that strongly expressed heat shock proteins. All lineages identified by trajectory analysis contribute to the DN2 B cell population, which is the major precursor to synovial ASCs. This was further supported by B cell receptor (BCR) lineage analysis, which revealed clonal relationships between DN2 cells and ASCs. This study advances our understanding of B cells in RA and reveals the origin of pathogenic ASCs in the RA synovium.

immunology↗

Rheumatoid arthritis patients express a skewed repertoire of polyclonal, hypomutated B-cell receptors

ObjectivesThe success of B cell depletion therapy in rheumatoid arthritis (RA) therapy testifies to their importance in disease pathogenesis, but the precise B cells mediating this are unclear. For example, it is unknown if RA patients predominantly express a limited number of circulating clonally expanded populations of B cells with highly mutated B cell antigen receptors (BCRs) that would constitute a shared antigen driven response.\n\nMethodsTo address this, we have undertaken the largest study to date utilising next generation sequencing (NGS), to identify the full length of the peripheral blood BCR sequences from the antigen-binding heavy chain. Between 25,000 to 200,000 BCR sequences per patient were analysed from 127 newly diagnosed RA patients, 16 heathy controls, 16 RA patients with established disease and 8 paired blood and synovial samples. This was complemented with B cell subset analysis from an additional 64 RA patients and 22 healthy controls.\n\nResultsRA patients expressed a significantly higher percentage of circulating poorly mutated polyclonal IgG+ve variable heavy (IgG-Vh) BCR sequences, both at the time of diagnosis and following treatment. These sequences resided predominantly within TNF-alpha secreting IgG+veCD27-ve B cells, that were expanded in RA peripheral blood and enriched in the rheumatoid synovium. Surprisingly, peripheral and synovial B cell repertoires of RA patients are quite distinct, sharing very few IgG sequences.\n\nConclusionsThis is the first report to conclusively establish that a substantial component of the peripheral B cell repertoire in RA consists of polyclonal hypomutated IgG+ve BCRs that may play a critical role in driving an autoimmune mediated inflammation.

immunology↗