Biology subjects

Brook, B. S.

Publications and source records attributed to Brook, B. S..

3 recordsLinked to original sources

bioRxiv2025

Model of integrin binding as a function of light-induced variations in forces exerted on cells via RGD-terminated, photoswitchable azobenzene surfaces

Photo-responsive biomaterials are attractive because of the ability to non-invasively alter and control the material properties, thus allowing control over the cell response at the interface with the bioamaterial surface. While in silico mathematical models have been implemented for simulating single-cell force spectroscopy (SCFS) experiments on static and some dynamic biomaterials, these models have yet to be extended to light-responsive biointerfaces. So here, we develop a mathematical model that describes and predicts the strength of integrin-mediated cell adhesions to a photoswitchable biomaterial surface. The fluctuating biomaterial comprises photoswitchable azobenzene attached to a glass surface and terminated with peptide c(RGDfK). Upon irradiation with light at 530 nm, the azobenzenes rapidly fluctuate between an extended and contracted conformation, leading to a change in the length of the azobenzene that stimulates integrins bound to c(RGDfK). The mathematical model mimics the nascent adhesion and spatial fluctuations in the extra-cellular matrix (ECM) and is calibrated using single-cell force microscopy retraction curves. It relies on spring-based mechanics to describe the stretch and deformation of a cell and ensembles of integrins when applied to a fluctuating biomaterial. We use the model to simulate retraction curves and the proportion of bound integrins on the surface as the material fluctuates. Additionally, we use the model to predict SCFS retraction curves for varying experimental conditions. This includes the length of time the cell (attached to the tip of the atomic force microscopy cantilever) is kept in contact with the biomaterial before retraction, and for varying frequency of light-induced movement of the azobenzene conformations. These model outcomes provide an attractive route to integrate and rigorously control certain experimental variables, thus accelerating experimental design of the study of cell adhesion to light-responsive biomaterials. Furthermore the model complements experiments by providing estimates of variables that are experimentally inaccessible. Thus, the outcomes of the model provide a valuable resource to aid in the interpretation and design of light-responsive biointerface functionalities.

biophysics↗

bioRxiv2022

Differential remodelling in small and large murine airways revealed by novel whole lung airway analysis.

Airway remodelling occurs in chronic asthma leading to increased airway smooth muscle (ASM) mass and extra-cellular matrix (ECM) deposition. Whilst extensively studied in murine airways; studies report only selected larger airways at one time point meaning the spatial distribution and resolution of remodelling are poorly understood. Here we use a new method allowing comprehensive assessment of the spatial and temporal changes in ASM, ECM and epithelium in large numbers of murine airways after allergen challenge. Using image processing to analyse 20-50 airways from a whole lung section revealed increases in ASM and ECM after allergen challenge were greater in small and large rather than intermediate airways. ASM predominantly accumulated adjacent to the basement membrane whereas ECM was distributed across the airway wall. Epithelial hyperplasia was most marked in small and intermediate airways. Post challenge, ASM changes resolved over seven days whereas ECM and epithelial changes persisted. The new method suggests large and small airways remodel differently and the long-term consequences of airway inflammation may depend more on ECM and epithelial changes than ASM. The method reduces the number of animals needed, reveals important spatial differences in remodelling and could set new analysis standards for murine asthma models.

physiology↗

bioRxiv2021

A dynamical model of TGF-β activation in asthmatic airways

Excessive activation of the regulatory cytokine transforming growth factor {beta} (TGF-{beta}) via contraction of airway smooth muscle (ASM) is associated with the development of asthma. In this study, we develop an ordinary differential equation model that describes the change in density of the key airway wall constituents, ASM and extracellular matrix (ECM), and their interplay with subcellular signalling pathways leading to the activation of TGF-{beta}. We identify bistable parameter regimes where there are two positive steady states, corresponding to either reduced or elevated TGF-{beta} concentration, with the latter leading additionally to increased ASM and ECM density. We associate the former with a healthy homeostatic state and the latter with a diseased (asthmatic) state. We demonstrate that external stimuli, inducing TGF-{beta} activation via ASM contraction (mimicking an asthmatic exacerbation), can perturb the system irreversibly from the healthy state to the diseased one. We show that the properties of the stimuli, such as their frequency or strength, and the clearance of surplus active TGF-{beta}, are important in determining the long-term dynamics and the development of disease. Finally we demonstrate the utility of this model in investigating temporal responses to bronchial thermoplasty, a therapeutic intervention in which ASM is ablated by applying thermal energy to the airway wall. The model predicts the parameter-dependent threshold damage required to obtain irreversible reduction in ASM content suggesting that certain asthma phenotypes are more likely to benefit from this intervention.

systems biology↗