Biology subjects

Lyons, B.

Publications and source records attributed to Lyons, B..

5 recordsLinked to original sources

bioRxiv2025

Specific degrader for fusion oncokinase kills tumors and is augmented by bimodal degrader-siRNA

Oncogenic fusions of two native proteins are challenging to block without disturbing the parental proteins. A mRNA delivered peptide degrader, selectively eliminates the oncogenic fusions DNAJB1::PRKACA and ATP1B1::PRKACA in fibrolamellar carcinoma (FLC), cholangiocarcinoma and intraductal pancreatic neoplasm, without effect on native PRKACA. Specific degradation reflected structural properties of the fusion proteins. The degrader was lethal to FLC tumor cells in a preclinical model, with no effect on non-FLC cells. To enhance efficacy and speed, we modified the mRNA to simultaneously encode the degrader and an siRNA against the fusion transcript, reducing new protein synthesis which accelerated degradation of DNAJB1::PRKACA, offering a wide therapeutic index for mutation-driven disease.

cancer biology↗

bioRxiv2024

4D hybrid model interrogates agent-level rules and parameters driving hiPS cell colony dynamics

Iterating between data-driven research and generative computational models is a powerful approach for emulating biological systems, testing hypotheses, and gaining a deeper understanding of these systems. We developed a hybrid agent-based model (ABM) that integrates a Cellular Potts Model (CPM) designed to investigate cell shape and colony dynamics in human induced pluripotent stem cell (hiPS cell) colonies. This model aimed to first mimic and then explore the dynamics observed in real-world hiPS cell cultures. Initial outputs showed great potential, seeming to mimic small colony behaviors relatively well. However, longer simulations and quantitative comparisons revealed limitations, particularly with the CPM component, which lacked long-range interactions that might be necessary for accurate simulations. This challenge led us to thoroughly examine the hybrid models potential and limitations, providing insights and recommendations for systems where cell-wide mechanics play significant roles. The CPM supports 2D and 3D cell shapes using a Monte Carlo algorithm to prevent cell fragmentation. Basic "out of the box" CPM Hamiltonian terms of volume and adhesion were insufficient to match live cell imaging of hiPS cell cultures. Adding substrate adhesion resulted in flatter colonies, highlighting the need to consider environmental context in modeling. High-throughput parameter sweeps identified regimes that produced consistent simulated shapes and demonstrated the impact of specific model decisions on emergent dynamics. Full-scale simulations showed that while certain agent rules could form a hiPS cell monolayer in 3D, they could not maintain it over time. Our study underscores that "out of the box" 3D CPMs, which do not natively incorporate long-range cell mechanics like elasticity, may be insufficient for accurately simulating hiPS cell and colony dynamics. To address this limitation, future work could add mechanical constraints to the CPM Hamiltonian or integrate global agent rules. Alternatively, replacing the CPM with a methodology that directly represents cell mechanics might be necessary. Documenting and sharing our model development process fosters open team science and supports the broader research community in developing computational models of complex biological systems.

systems biology↗

bioRxiv2024

Longitudinal Fragility phenotyping predicts lifespan and age-associated morbidity in C57BL/6 and Diversity Outbred mice

Aging studies in mammalian models often depend on natural lifespan data as a primary outcome. Tools for lifespan prediction could accelerate these studies and reduce the need for veterinary intervention. Here, we leveraged large-scale longitudinal frailty and lifespan data on two genetically distinct mouse cohorts to evaluate noninvasive strategies to predict life expectancy in mice. We applied a modified frailty assessment, the Fragility Index, derived from existing frailty indices with additional deficits selected by veterinarians. We developed an ensemble machine learning classifier to predict imminent mortality (95% proportion of life lived [95PLL]). Our algorithm represented improvement over previous predictive criteria but fell short of the level of reliability that would be needed to make advanced prediction of lifespan and thus accelerate lifespan studies. Highly sensitive and specific frailty-based predictive endpoint criteria for aged mice remain elusive. While frailty-based prediction falls short as a surrogate for lifespan, it did demonstrate significant predictive power and as such must contain information that could be used to inform the conclusion of aging experiments. We propose a frailty-based measure of healthspan as an alternative target for aging research and demonstrate that lifespan and healthspan criteria reveal distinct aspects of aging in mice.

bioinformatics↗

bioRxiv2023

PhysiCell Studio: a graphical tool to make agent-based modeling more accessible

Defining a multicellular model can be challenging. There may be hundreds of parameters that specify the attributes and behaviors of objects. Hopefully the model will be defined using some format specification, e.g., a markup language, that will provide easy model sharing (and a minimal step toward reproducibility). PhysiCell is an open source, physics-based multicellular simulation framework with an active and growing user community. It uses XML to define a model and, traditionally, users needed to manually edit the XML to modify the model. PhysiCell Studio is a tool to make this task easier. It provides a graphical user interface that allows editing the XML model definition, including the creation and deletion of fundamental objects, e.g., cell types and substrates in the microenvironment. It also lets users build their model by defining initial conditions and biological rules, run simulations, and view results interactively. PhysiCell Studio has evolved over multiple workshops and academic courses in recent years which has led to many improvements. Its design and development has benefited from an active undergraduate and graduate research program. Like PhysiCell, the Studio is open source software and contributions from the community are encouraged.

bioinformatics↗

bioRxiv2020

Long title: The occurrence of tarsal injuries in male mice of C57BL/6N substrains in multiple international mouse facilities

Dislocation in hindlimb tarsals are being observed at a low, but persistent frequency in adult male mice from C57BL/6N substrains. Clinical signs included a sudden onset of mild to severe unilateral or bilateral tarsal abduction, swelling, abnormal hindlimb morphology and lameness. Contraction of digits and gait abnormalities were noted in multiple cases. Radiographical and histological examination revealed caudal dislocation of the calcaneus and partial dislocation of the calcaneoquartal (calcaneous-tarsal bone IV) joint. The detection, frequency, and cause of this pathology in five large mouse production and phenotyping centres (MRC Harwell, UK; The Jackson Laboratory, USA; The Centre for Phenogenomics, Canada; German Mouse Clinic, Germany; Baylor College of Medicine, USA) are discussed.

genetics↗