Biology subjects

Skalnik, C. J.

Publications and source records attributed to Skalnik, C. J..

3 recordsLinked to original sources

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↗

bioRxiv2020

Modular genetic control of social status in a cichlid fish

Social hierarchies are ubiquitous in social species and profoundly influence physiology and behavior. Androgens like testosterone have been strongly linked to social status, yet the molecular mechanisms regulating social status are not known. The African cichlid fish Astatotilapia burtoni is a powerful model species for elucidating the role of androgens in social status given their rich social hierarchy and genetic tractability. Dominant A. burtoni males possess large testes, bright coloration, and perform aggressive and reproductive behaviors while non-dominant males do not. Social status in A. burtoni is in flux, however, as males alter their status depending on the social environment. Due to a teleost-specific whole-genome duplication, A. burtoni possess two androgen receptor (AR) paralogs, ARα and ARβ, providing a unique opportunity to disentangle the role of gene duplication in the evolution of social systems. Here, we used CRISPR/Cas9 gene editing to generate AR mutant A. burtoni and performed a suite of experiments to interrogate the mechanistic basis of social dominance. We find that ARβ, but not ARα, is required for testes growth and bright coloration, while ARα, but not ARβ, is required for the performance of reproductive behavior and aggressive displays. Both receptors are required to reduce flees from females and either AR is sufficient for attacking males. Thus, social status in A. burtoni is inordinately dissociable and under the modular control of two AR paralogs. This type of non-redundancy may be important in facilitating social plasticity in A. burtoni and other species whose social status relies on social experience.Significance Statement Social rank along a hierarchy determines physiological state and behavioral performance. A ubiquitous feature of social hierarchies is the communication of rank through non-physical signaling systems (e.g., coloration) and aggression, traits that correlate with the reproductive status of an individual. Despite the links identified between social status, physiology, and behavior, the molecular basis of social status is not known. Here, we genetically dissect social status in the African cichlid fish Astatotilapia burtoni using CRISPR/Cas9 gene editing. We show that two distinct androgen receptor (AR) genes control social status in a highly modular manner. This type of coordination of social status may be fundamental across species that rely on social information to optimally guide physiology and behavior.Competing Interest StatementThe authors have declared no competing interest.View Full Text

animal behavior and cognition↗