CDEV Subgroup Contributed Talks

Tricity Andrew

North Carolina State University

"Computational modeling to gain insight into developmental processes shaping stomach curvature"

Many organs develop left-right (LR) asymmetrical shapes and positions internally. Failure to properly establish LR asymmetry causes common, severe birth defects. The leftward curvature of the stomach is one of the most recognized LR asymmetries in the body. During its development the left side of the stomach undergo a specialized type of cell rearrangement (radial intercalation) that expands the left layers of the tube, thus forcing it to curve. Experiments with frog embryos (X. Laevis), however, show that inhibiting these cell rearrangements alone is not sufficient to prevent curvature, indicating the presence of additional left- and/or right-specific mechanisms. To explore what these mechanisms may be, I am integrating 2D and 3D agent-based computational modeling and animal experimentation. Starting with stomach shapes derived from nano-CT tomography, I am exploring which combinations of LR mechanisms, such as radial intercalation, cell shape changes, and differential adhesion, can reproduce patterns of stomach curvature under different conditions. The knowledge gained will help prioritize and contextualize the study of candidate genes from our ongoing genomic sequencing of human LR birth defects patients. On a broader level, we will gain novel insights into the physical forces that shapes 3D tissues, revealing general “rules” of tubular morphogenesis.

Amjad Khan

Dalhousie University

"Modeling the transmission and loss of an important class of mobile genetic elements"

Horizontal gene transfer (HGT) allows the transmission of genetic information between microorganisms. Integrative Conjugative Elements (ICE) are segments of DNA that contain genes for insertion and excision from the genome, and transfer between microorganisms. ICE frequently contain antimicrobial resistance (AMR) genes and are significant contributors to the global increase in AMR incidence. Despite being widely distributed and contributing to the spread of AMR genes, their role, transfer rate, and impact on the fitness of the host are largely unexplored. In this study, we have developed a Partial Differential Equation model that considers the distribution of ICE across a population of bacteria. We assume that after a time step, this distribution may change due to four processes, each of which has a corresponding parameter in the model: excision, HGT, mutational degradation, and conference of a selective advantage. We fit this PDE to the data obtained from more than a thousand genomes from the genus Enterococcus, an opportunistic pathogen that is a frequent cause of hospital-derived infections. This will result in the estimation of transfer rate, conjugation rate, degradation rate, and selective advantage, which can be further utilized to study the genetic repertoire of ICEs.

Julio M Belmonte

North Carolina State University

"Non-Linear Mechanical Response Transforms a Graded Molecular Distribution into a Step-Wise Output in Cell Behavior"

The intrinsic genetic programme of a cell is not always sufficient to explain the cell's activities. External mechanical stimuli are increasingly being recognized as determinants of cell behavior. In the epithelial folding event that constitutes the beginning of gastrulation in Drosophila, the genetic programme of the future mesoderm leads to the establishment of a contractile actomyosin network that triggers apical constriction of cells, and thereby, furrow formation. However, some cells do not constrict but instead stretch, even though they share the same genetic programme as their constricting neighbors. We show here that tissue-wide interactions override the intrinsic programme of a subset of cells, forcing them to expand even when an otherwise sufficient amount and concentration of apical, active actomyosin has been accumulated. Models based on contractile forces and linear stress-strain responses are not sufficient to reproduce experimental observations, but simulations in which cells behave as materials with non-linear mechanical properties do. Our models also show that this behavior is an emergent property of supracellular actomyosin networks, in accordance with our experimental observations of actin reorganization within stretching cells, with this event being stochastic and rare in cells with high myosin levels, but reproducible in cells with lower concentrations.

Sarafa Iyaniwura

The University of British Columbia, Vancouver

"Oscillatory instabilities for a 2-D coupled ODE-PDE Model of Diffusion-Mediated Communication Between Small Signaling Compartments"

We analyze a class of cell-bulk coupled ODE-PDE models that characterize communication between localized spatially segregated dynamically active signaling compartments/cells. In this model, the cells are disks of a common radius coupled through a passive extracellular bulk diffusion field in a bounded 2-D domain. Each cell secretes a signaling chemical into the bulk region at a constant rate and receives bulk chemical feedback from the entire collection of cells. This global feedback, which activates signaling pathways within the cells, modifies their intracellular dynamics according to the external environment. In the limit of finite diffusion, the method of matched asymptotic expansions is used to construct steady-state solutions of the ODE-PDE model and to derive a globally coupled nonlinear matrix eigenvalue problem (GCEP) that characterizes the linear stability properties of the steady-states. We also used matched asymptotic analysis to derive a nonlinear ODE system from the coupled ODE-PDE model in the limit of asymptotically large bulk diffusivity. For Sel'kov reaction kinetics, we investigated oscillatory instabilities in the dynamics of the cells triggered by global coupling. We also studied quorum sensing and how coupling defective cells to a group of identical cells change the intracellular dynamics of the cells.