Cell–ECM adhesion is regulated by mechanical force. Quantitative imaging and mathematical modeling are used to elucidate how the intracellular adhesion complex of integrin-based adhesions responds to force, revealing the molecular mechanisms that allow the adhesion complex to respond to force to stabilize cell–ECM adhesion over development.

The development of three-dimensional tissue architecture requires precise control over the attachment of cells to the extracellular matrix (ECM). Integrins, the main ECM-binding receptors in animals, are regulated in multiple ways to modulate cell-ECM adhesion. One example is the conformational activation of integrins by extracellular signals ('outside-in activation') or by intracellular signals ('inside-out activation'), whereas another is the modulation of integrin turnover. We demonstrate that outside-in activation regulates integrin turnover to stabilize tissue architecture in vivo. Treating Drosophila embryos with Mg 2+ and Mn 2+, known to induce outside-in activation, resulted in decreased integrin turnover. Mathematical modeling combined with mutational analysis provides mechanistic insight into the stabilization of integrins at the membrane. We show that as tissues mature, outside-in activation is crucial for regulating the stabilization of integrin-mediated adhesions. This data identifies a new in vivo role for outside-in activation and sheds light on the key transition between tissue morphogenesis and maintenance.

No abstract

The development of three-dimensional tissue architecture requires precise control over the attachment of cells to the extracellular matrix (ECM). Integrins, the main ECM-binding receptors in animals, are regulated in multiple ways to modulate cell-ECM adhesion. One example is the conformational activation of integrins by extracellular signals ('outside-in activation') or by intracellular signals ('inside-out activation'), whereas another is the modulation of integrin turnover. We demonstrate that outside-in activation regulates integrin turnover to stabilize tissue architecture in vivo. Treating Drosophila embryos with Mg 2+ and Mn 2+, known to induce outside-in activation, resulted in decreased integrin turnover. Mathematical modeling combined with mutational analysis provides mechanistic insight into the stabilization of integrins at the membrane. We show that as tissues mature, outside-in activation is crucial for regulating the stabilization of integrin-mediated adhesions. This data identifies a new in vivo role for outside-in activation and sheds light on the key transition between tissue morphogenesis and maintenance.

During the SARS-CoV2 pandemic, epidemic models have been central to policy-making. Public health responses have been shaped by model-based projections and inferences, especially related to the impact of various non-pharmaceutical interventions. Accompanying this has been increased scrutiny over model performance, model assumptions, and the way that uncertainty is incorporated and presented. Here we consider a population-level model, focusing on how distributions representing host infectiousness and the infection-to-death times are modelled, and particularly on the impact of inferred epidemic characteristics if these distributions are misspecified. We introduce an SIR-type model with the infected population structured by 'infected age', i.e. the number of days since first being infected, a formulation that enables distributions to be incorporated that are consistent with clinical data. We show that inference based on simpler models without infected age, which implicitly misspecify these distributions, leads to substantial errors in inferred quantities relevant to policy-making, such as the reproduction number and the impact of interventions. We consider uncertainty quantification via a Bayesian approach, implementing this for both synthetic and real data focusing on UK data in the period 15 Feb-14 Jul 2020, and emphasising circumstances where it is misleading to neglect uncertainty.