Biology subjects

Davies, G. E.

Publications and source records attributed to Davies, G. E..

3 recordsLinked to original sources

bioRxiv2023

A spatial human thymus cell atlas mapped to a continuous tissue axis

T cells develop from circulating precursors, which enter the thymus and migrate throughout specialised sub-compartments to support maturation and selection. This process starts already in early fetal development and is highly active until the involution of the thymus in adolescence. To map the micro-anatomical underpinnings of this process in pre- vs. post-natal states, we undertook a spatially resolved analysis and established a new quantitative morphological framework for the thymus, the Cortico-Medullary Axis. Using this axis in conjunction with the curation of a multimodal single-cell, spatial transcriptomics and high-resolution multiplex imaging atlas, we show that canonical thymocyte trajectories and thymic epithelial cells are highly organised and fully established by post-conception week 12, pinpoint TEC progenitor states, find that TEC subsets and peripheral tissue genes are associated with Hassalls Corpuscles and uncover divergence in the pace and drivers of medullary entry between CD4 vs. CD8 T cell lineages. These findings are complemented with a holistic toolkit for spatial analysis and annotation, providing a basis for a detailed understanding of T lymphocyte development.

immunology↗

bioRxiv2021

Complement Regulator Factor H is a Cofactor for Thrombin in both Pro- and Anticoagulant Roles

BackgroundComplement FH (FH) is a key regulator of complement activity whereas thrombin (FIIa) is central to hemostasis with both pro- and anticoagulant functions. Both have separately been shown to have auxiliary activities across the two systems. The purpose of this study was to determine the effect of FH on pro- and anti-coagulant functions and investigate the interaction between FH and thrombin. MethodsTail bleeding time and hemolysis were measured in FH-deficient mice (CFH-/-). Activated partial thromboplastin time (aPTT) was determined in FH-depleted human plasma. FH effect on fibrin clot generation was investigated in turbidity assays and on activated protein C (APC) generation. Binding affinity of thrombin with FH was determined using surface plasmon resonance (SPR). ResultsTail bleeding time in CFH-/- mice was significantly prolonged compared to wild type mice. The aPTT in FH-depleted human plasma was elevated compared to normal plasma and restored by adding back FH to depleted plasma. Accordingly, FH enhanced thrombin-mediated fibrin clot generation by shortening lag time, increasing rate of clot formation and maximum turbidity, and affected clot structure. Despite this, FH also increased the rate of thrombin-mediated protein C (PC) activation, both in the presence and absence of soluble recombinant thrombomodulin (TM). Nanomolar affinity binding of FH with thrombin, but not prothrombin, was confirmed. ConclusionComplement FH binds thrombin with strong affinity and acts as a novel cofactor that enhances both pro- and anticoagulant actions of thrombin. These data highlight an important role for FH in hemostasis. Key pointsO_LIAbsence of FH prolongs tail bleeding time in CFH-/- mice and activated partial thromboplastin time (aPTT) is elevated in human FH-depleted plasma. C_LIO_LIFH acts a cofactor for thrombin by enhancing fibrin generation, altering fibrin clot structure and enhancing TM-thrombin mediated protein C activation C_LI

immunology↗

bioRxiv2019

Intergenerational transmission of education and ADHD: Effects of parental genotypes

It is challenging to study whether children resemble their parents due to nature, nurture, or a mixture of both. Here we used a novel design that employs the fact that parents transmit 50% of their alleles to their offspring. The combined effect of these transmitted and non-transmitted alleles on a trait are summarized in a polygenic score (PGS). The non-transmitted PGS can only affect offspring through the environment, via genetically influenced behaviours in the parents, called genetic nurturing. For genotyped mother-father-offspring trios (1,120-2,518 per analysis) we calculated transmitted and non-transmitted PGSs for adult educational attainment (EA) and childhood ADHD and tested if these predicted outcomes in offspring. In adults, both transmitted (R2 = 7.6%) and non-transmitted (R2 = 1.7%) EA PGSs predicted offspring EA, evidencing genetic nurturing. In children around age 12, academic achievement was predicted only by transmitted EA PGSs (R2 = 5.7%), but we did not find genetic nurturing (R2 [~] 0.1%). The ADHD PGSs did not significantly predict academic achievement (R2 [~] 0.6%). ADHD symptoms in children were predicted by transmitted EA PGSs and ADHD PGSs (R2 = 1-2%). Based on these results, we conclude that previously reported associations between parent characteristics and offspring outcomes seem to be mainly a marker of genetic effects shared by parents and children.

genomics↗