Biology subjects

Bogle, G.

Publications and source records attributed to Bogle, G..

3 recordsLinked to original sources

bioRxiv2026

RaDRI: A computational model for radiosensitisation by DNA double strand break repair inhibitors

Repair of radiation-induced DNA double strand breaks (DSB) is a major contributor to radioresistance and an important target for tumour radiosensitisation. DNA-dependent protein kinase (DNA-PK) plays key roles in non-homologous end-joining (NHEJ), the dominant DSB repair pathway in human cells, and DNA-PK inhibitors (DNA-PKi) are highly effective radiosensitisers. However, many questions remain concerning tumour selectivity, mechanisms of enhancement of cell killing, interaction with other repair pathways and cell cycle checkpoints and the required duration of DNA-PK inhibition. Here, we develop an agent-based computational model for Radiosensitisation by DSB Repair Inhibitors (RaDRI) with a level of complexity suitable for use in pharmacokinetic/pharmacodynamic models, and use it to investigate a potent and selective DNA-PKi, SN39536. RaDRI utilises analytical solutions for the spatial distribution of radiation-induced DSB, and their repair by NHEJ, from the Medras model (McMahon et al. Sci Rep 6:33290, 2016). Features include: (1) cell cycle progression and checkpoints are explicit; (2) probability of assignment of DSB to homologous recombination repair decreases with time post-replication, reflecting chromatin maturation, and is radiation dose-dependent; (3) Misjoining (ligation of ends from different DSBs), leading to chromosome aberrations, increases with time due to active DSB clustering. The model is parameterised using flow cytometry and clonogenic survival datasets for low-LET irradiation of HCT116 cells, with and without the DNA-PKi. Clonogenic survival is computed as a function of the number of remaining DSBs and misjoins at mitosis. RaDRI demonstrates known radiobiological features including a near linear-quadratic dose dependence for killing by radiation, almost exclusively due to DSB misjoining, but predicts a distinct mechanism of radiosensitisation by SN39536 in which failure to resolve DSBs before mitosis becomes a significant driver of radiosensitisation. The model predicts that exposure to the DNA-PKi is required for [~]9 hours to achieve 90% of maximal radiosensitisation of DSB repair-proficient human cells in log-phase growth.

cancer biology↗

bioRxiv2021

The chemical synthesis of knob domain antibody fragments

Cysteine-rich knob domains found in the ultralong complementarity determining regions of a subset of bovine antibodies, are capable of functioning autonomously as 3-6 kDa peptides. While they can be expressed recombinantly in cellular systems, in this paper we show that knob domains are also readily amenable to chemical synthesis, with a co-crystal structure of a chemically synthesised knob domain in complex with antigen showing structural equivalence to the biological product. For drug discovery, following immunisation of cattle, knob domain peptides can be synthesised directly from antibody sequence data, combining the power and diversity of the bovine immune repertoire with the ability to rapidly incorporate non-biological modifications. We demonstrate that, through rational design with non-natural amino acids, paratope diversity can be massively expanded, in this case improving the efficacy of an allosteric peptide. As a potential route to further improve stability, we also performed head-to-tail cyclisation, exploiting the unusual proximity of the N- and C-termini to synthesise functional, fully cyclic antibody fragments. Lastly, we highlight the stability of knob domains in plasma and, through pharmacokinetic studies, use palmitoylation as a route to extend the plasma half-life of knob domains in vivo. This study presents an antibody-derived medicinal chemistry platform, with protocols for solid-phase synthesis of knob domains; together with characterisation of their molecular structures, in vitro pharmacology and pharmacokinetics.

biochemistry↗

bioRxiv2019

High-resolution 3D imaging and topological mapping of the lymph node conduit system

The conduit network is a hallmark of lymph node microanatomy, but lack of suitable imaging technology has prevented comprehensive investigation of its topology. We employed an extended-volume imaging system to capture the conduit network of an entire murine lymph node ({approx}280,000 segments). The extensive 3D images provide a comprehensive overview of the regions supplied by conduits including perivascular sleeves, and distinctive \"follicular reservoirs\" within B cell follicles, surrounding follicular dendritic cells. A 3D topology map of conduits within the T cell zone showed homogeneous branching, but conduit density was significantly higher in the superficial T cell zone compared to the deep zone, where distances between segments are sufficient for T cells to lose contact with fibroblastic reticular cells. This topological mapping of the conduit anatomy can now aid modeling of its roles in lymph node function, as we demonstrate by simulating T cell motility in the different T cell zones.

immunology↗