Biology subjects

Cole, T.

Publications and source records attributed to Cole, T..

5 recordsLinked to original sources

bioRxiv2026

The cytokine structural homologs IL-1β and IL-1Ra have distinct dynamical character that potentially influence their roles in allosteric regulation of the IL-1 receptor.

Interleukin-1{beta} (IL-1{beta}) and the interleukin-1 receptor antagonist (IL-1Ra) share the {beta}-trefoil fold, engage the same receptor (IL-1R), but produce opposite biological outcomes. IL-1{beta} recruits the accessory protein IL-1RAcP to initiate inflammatory signaling while IL-1Ra occupies the receptor without supporting co-receptor recruitment. Seeking the origin of this divergence in properties not apparent from static structures, we used solution NMR relaxation to characterize fast internal motion in both proteins. Rigorous treatment of macromolecular tumbling shows both to be nearly maximally triaxial, which admits two near-degenerate axially symmetric solutions. This ambiguity was propagated throughout and found to have negligible impact. Complete replicate data sets from independently prepared IL-1{beta} samples establish the experimental precision directly. Backbone amide and methyl-bearing side chain order parameters are indistinguishable between the two proteins, the latter averaging 0.484 {+/-} 0.030 and 0.486 {+/-} 0.033, indicating essentially equivalent residual conformational entropy. Their spatial distributions are uncorrelated when projected onto the shared fold. Importantly, the difference between the proteins is concentrated at the receptor interface, where methyl probes lying on the IL-1{beta} footprint are considerably more mobile than those of IL-1Ra. It is therefore the agonist, not the antagonist, that presents an anomalously mobile binding surface. IL-1Ra also buries some 16% less surface while ostensibly binding IL-1R more tightly, the signature of an interface predisposed toward productive contact. Conformational entropy can thus distinguish protein function where structure and average flexibility are conserved, and the distinction resides not in how much entropy a protein has but in where it is kept.

biophysics↗

bioRxiv2024

Early regional lymph node activation drives influenza vaccine responses in an ancestrally diverse cohort

Early in vivo dynamics of human immune-cell activation across regionally activated lymphoid tissue sites upon immunisation are poorly characterised in ancestrally diverse individuals. Here, we profiled draining and non-draining axillary lymph nodes (dLNs and ndLNs) by ultrasound-guided fine-needle aspiration (FNA) in 13 Black and Asian ancestry individuals, before and 3-7 days after vaccination with adjuvanted influenza vaccine. Draining but not ndLNs rapidly increased in size post-vaccination, by day 3, with distinct cellular dynamics determined through single cell multiomics. Dissecting LN cellular diversity into 42 lymphoid and non-lymphoid cell states, post-vaccination cell abundance changes were observed across all LNs, but dLNs were specifically characterised by CD4+ T follicular helper (CD4+ Tfh) cell expansion. Gene expression analysis revealed a dLN post-vaccination hub of multicellular activity defined by CD4+ Tfh signalling, cross-compartmental activation, translation, and enhanced antigen-presentation capacity. Thus, robust responses to intramuscular immunisation transcending ancestral inter-individual variation are elicited through temporal, anatomical and cellular lymphatic co-ordination with implications for vaccine design in ancestrally diverse populations. SummaryIn this study of ancestrally diverse young adults, the temporarily co-ordinated response to an adjuvanted influenza vaccine at lymph nodes local to (draining) and distal from (non-draining) the injection site, reveals early regulation of cellular kinetics and anatomical hierarchy of the innate and adaptive immune responses.

immunology↗

bioRxiv2023

Ancient mitogenomes reveal evidence for the late Miocene dispersal of mergansers to the Southern Hemisphere

Mergansers are riverine and coastal piscivorous ducks that are widespread throughout North America and Eurasia but uncommon in the Southern Hemisphere. One species occurs in South America and at least two extinct species from New Zealand. It has been proposed that Southern Hemisphere mergansers were founded by independent dispersal events from the Northern Hemisphere. However, some morphological and behavioural evidence suggests that Southern Hemisphere mergansers may be closely related to one another. They share several characteristics that differ from Northern Hemisphere mergansers (e.g., non-migratory vs. migratory, sexual monochromatism vs. sexual dichromatism, long vs. short pair bonds). We sequenced complete mitogenomes from the Brazilian merganser and an extinct merganser from New Zealand--the Auckland Island merganser. Our results show the Brazilian and Auckland Island mergansers form a monophyletic clade with the common merganser, and that a sister relationship between Southern Hemisphere mergansers cannot be rejected. We cannot exclude the possibility that the Brazilian and Auckland Island mergansers descend from a single dispersal event from the Northern Hemisphere at least seven million years ago. Nuclear (palaeo)genomic data may help to resolve the relationship between living and extinct mergansers, including merganser fossils from New Zealand that have not been subjected to palaeogenetic analysis.

genetics↗

bioRxiv2020

Rab10 Regulates Macropinocytosis in Phagocytes

Genetic variation in LRRK2 associates with susceptibility to Parkinsons disease, Crohns disease, and mycobacteria infection, with high expression of LRRK2, and the LRRK2 kinase substrate Rab10, in phagocytic cells in the immune system. In mouse and human primary monocyte-derived macrophages, dendritic cells, and microglia-like cells, we find that Rab10 specifically regulates a specialized form of endocytosis known as macropinocytosis, without affecting phagocytosis or clathrin-mediated endocytosis. LRRK2 phosphorylates cytoplasmic PI(3,4,5)P3-positive GTP-Rab10 early macropinosomes, before EEA1 and Rab5 recruitment occurs. Macropinosome cargo in macrophages includes CCR5, CD11b, and MHCII, with LRRK2-phosphorylation of Rab10 potently blocking EHBP1L1-mediated recycling tubules and cargo turnover. EHBP1L1 over-expression competitively inhibits LRRK2-phosphorylation of Rab10, mimicking the effects of LRRK2 kinase inhibition in promoting cargo recycling. Both Rab10 knockdown and LRRK2 kinase inhibition potently suppresses the maturation of macropinosome-derived CCR5-loaded signaling endosomes important for CCL5-induced AKT-activation and chemotaxis. These data support a novel axis in the endolysosomal system whereby LRRK2-mediated Rab10 phosphorylation stalls vesicle fast-recycling to promote PI3K-AKT signal transduction.

cell biology↗

bioRxiv2018

Complex Structural Variants Resolved by Short-Read and Long-Read Whole Genome Sequencing in Mendelian Disorders

Complex structural variants (cxSVs) are genomic rearrangements comprising multiple structural variants, typically involving three or more breakpoint junctions. They contribute to human genomic variation and can cause Mendelian disease, however they are not typically considered during genetic testing. Here, we investigate the role of cxSVs in Mendelian disease using short-read whole genome sequencing (WGS) data from 1,324 individuals with neurodevelopmental or retinal disorders from the NIHR BioResource project. We present four cases of individuals with a cxSV affecting Mendelian disease-associated genes. Three of the cxSVs are pathogenic: a de novo duplication-inversion-inversion-deletion affecting ARID1B in an individual with Coffin-Siris syndrome, a deletion-inversion-duplication affecting HNRNPU in an individual with intellectual disability and seizures, and a homozygous deletion-inversion-deletion affecting CEP78 in an individual with cone-rod dystrophy. Additionally, we identified a de novo duplication-inversion-duplication overlapping CDKL5 in an individual with neonatal hypoxic-ischaemic encephalopathy. Long-read sequencing technology used to resolve the breakpoints demonstrated the presence of both a disrupted and an intact copy of CDKL5 on the same allele; therefore, it was classified as a variant of uncertain significance. Analysis of sequence flanking all breakpoint junctions in all the cxSVs revealed both microhomology and longer repetitive sequences, suggesting both replication and homology based processes. Accurate resolution of cxSVs is essential for clinical interpretation, and here we demonstrate that long-read WGS is a powerful technology by which to achieve this. Our results show cxSVs are an important although rare cause of Mendelian disease, and we therefore recommend their consideration during research and clinical investigations.

genomics↗