Biology subjects

Covert, M. W.

Publications and source records attributed to Covert, M. W..

4 recordsLinked to original sources

bioRxiv2026

Antibody Fc receptor CD16a mediates natural killer cell activation via mechanotransduction of piconewton forces

Natural Killer(NK) cells eliminate target cells through antibody-dependent cell-mediated cytotoxicity(ADCC), initiated by CD16a(Fc{gamma}RIIIa) recognizing the Fc region of antibodies bound to the target cell surface. While the recognition is considered to be driven by CD16a-Fc binding avidity, it fails to explain why Fc multimers inhibit ADCC rather than trigger it. Here, we reveal that CD16a transduces piconewton forces, and acts as a mechanosensor to facilitate NK activation. We demonstrate that CD16a force and the actin foci formation associated with it are essential for the phosphorylation of mechanosensitive adaptor Cas-L and signaling adaptor LAT, reshaping NK cell cytoskeletal dynamics and signaling. Our findings show that NK activation is an intricate process that integrates both biochemical and biophysical information, and provides new mechanistic insight for immunoengineering.

biophysics↗

bioRxiv2022

A dynamic HIF1alpha-PPARgamma circuit controls a paradoxical adipocyte regulatory landscape

Hypoxia-induced upregulation of HIF1 triggers adipose tissue dysfunction and insulin resistance in obese patients. HIF1 closely interacts with PPAR{gamma}, the master regulator of adipocyte differentiation and lipid accumulation, but there are conflicting results how this co-regulation controls the excessive lipid accumulation that drives adipocyte dysfunction. Using single-cell imaging and modeling, we find that, surprisingly, HIF1 both promotes and represses lipid accumulation during adipogenesis. We show that the opposing roles of HIF1 are isolated from each other and depend on when HIF1 increases relative to the positive-feedback mediated upregulation of PPAR{gamma} that drives adipocyte differentiation. A theoretical model incorporating our findings resolves conflicting prior results and suggests that three network nodes before and after the isolation step have to be synergistically targeted in therapeutic strategies to revert hypoxia-mediated adipose tissue dysfunction in obesity. TeaserA systems biology approach detangles the effect of hypoxic and adipogenic regulators on lipid accumulation in adipocytes.

systems biology↗

bioRxiv2021

Vivarium: an interface and engine for integrative multiscale modeling in computational biology

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSMotivationC_ST_ABSThis paper introduces Vivarium - software born of the idea that it should be as easy as possible for computational biologists to define any imaginable mechanistic model, combine it with existing models, and execute them together as an integrated multiscale model. Integrative multiscale modeling confronts the complexity of biology by combining heterogeneous datasets and diverse modeling strategies into unified representations. These integrated models are then run to simulate how the hypothesized mechanisms operate as a whole. But building such models has been a labor-intensive process that requires many contributors, and they are still primarily developed on a case-by-case basis with each project starting anew. New software tools that streamline the integrative modeling effort and facilitate collaboration are therefore essential for future computational biologists. ResultsVivarium is a Pythonic software for building integrative multiscale models. It provides an interface that makes individual models into modules that can be wired together in large composite models, parallelized across multiple CPUs, and run with Vivariums simulation engine. Vivariums utility is demonstrated by building composite models that combine several modeling frameworks: agent based models, ordinary differential equations, stochastic reaction systems, constraint-based models, solid-body physics, and spatial diffusion. This demonstrates just the beginning of what is possible - future efforts can integrate many more types of models and at many more biological scales. AvailabilityThe models, simulation pipelines, and notebooks developed for this paper are available at the vivarium-notebooks repository: https://github.com/vivarium-collective/vivarium-notebooks. Vivarium-core is available at https://github.com/vivarium-collective/vivarium-core, and has been released on PyPI. The Vivarium Collective (https://vivarium-collective.github.io) is a repository of freely-available Vivarium processes and composites, including the processes used in Section 3. Supplementary materials provide with an extensive methodology section, with several code listings that demonstrate the basic interfaces.

systems biology↗

bioRxiv2021

Whole-Colony Modeling of Escherichia coli

Bacterial behavior is the outcome of both molecular mechanisms within each cell and interactions between cells in the context of their environment. Whereas whole-cell models simulate a single cells behavior using molecular mechanisms, agent-based models simulate many agents independently acting and interacting to generate complex collective phenomena. To synthesize agent-based and whole-cell modeling, we used a novel model integration software, called Vivarium, to construct an agent-based model of E. coli colonies where each agent is represented by a current source code snapshot from the E. coli Whole-Cell Modeling Project and interacts with other cells in a shared spatial environment. The result is the first "whole-colony" computational model that mechanistically links expression of individual proteins to a population-level phenotype. Simulated colonies exhibit heterogeneous effects on their environments, heterogeneous gene expression, and media-dependent growth. Extending the cellular model with mechanisms of antibiotic susceptibility and resistance, our model also suggested that variation in the expression level of the betalactamase AmpC, and not of the multi-drug efflux pump AcrAB-TolC, was the key mechanistic driver of survival in the presence of nitrocefin. We see this as a significant step forward in the creation of more comprehensive multi-scale models, and it broadens the range of phenomena that can be modeled in mechanistic terms. Author summaryThis work combines several models of molecular and physical processes that impact the physiology and behavior of the common microbe Escherichia coli into a multiscale model. Colonies comprised of multiple individual cells are simulated as they grow and divide--each with complex internal mechanisms, and with physical interactions and molecular diffusion in their environments. The integrative modeling methodology supports the addition of new submodels. The flexibility of this methodology is demonstrated by adding models of antibiotic resistance and simulating the colonys response to antibiotic treatment.

systems biology↗