All Publications

  • Image-based axon model highlights heterogeneity in initiation of damage. Biophysical journal Wang, L. M., Goodman, M. B., Kuhl, E. 2022


    Head injury simulations predict the occurrence of traumatic brain injury by placing a threshold on the calculated strains for axon tracts within the brain. However, a current roadblock to accurate injury prediction is the selection of an appropriate axon damage threshold. While several computational studies have used models of the axon cytoskeleton to investigate damage initiation, these models all employ an idealized, homogeneous axonal geometry. This homogeneous geometry with regularly spaced microtubules, evenly distributed throughout the model, overestimates axon strength because in reality, the axon cytoskeleton is heterogeneous. In the heterogeneous cytoskeleton, the weakest cross section determines the initiation of failure, but these weak spots are not present in a homogeneous model. Addressing one source of heterogeneity in the axon cytoskeleton, we present a new semi-automated image analysis pipeline for using serial section transmission electron micrographs (ssTEM) to reconstruct the microtubule geometry of an axon. The image analysis procedure locates microtubules within the images, traces them throughout the image stack, and reconstructs the microtubule structure as a finite element mesh. We demonstrate the image analysis approach using a C. elegans touch receptor neuron due to the availability of high-quality ssTEM datasets. The results of the analysis highlight the heterogeneity of the microtubule structure in the spatial variation of both microtubule number and length. Simulations comparing this image-based geometry to homogeneous geometries show that structural heterogeneity in the image-based model creates significant spatial variation in deformation. The homogeneous geometries, on the other hand, deform more uniformly. Since no single homogeneous model can replicate the mechanical behavior of the image-based model, our results argue that heterogeneity in axon microtubule geometry should be considered in determining accurate axon failure thresholds.

    View details for DOI 10.1016/j.bpj.2022.11.2946

    View details for PubMedID 36461640

  • Mechanics of axon growth and damage: A systematic review of computational models. Seminars in cell & developmental biology Wang, L. M., Kuhl, E. 2022


    Normal axon development depends on the action of mechanical forces both generated within the cytoskeleton and outside the cell, but forces of large magnitude or rate cause damage instead. Computational models aid scientists in studying the role of mechanical forces in axon growth and damage. These studies use simulations to evaluate how different sources of force generation within the cytoskeleton interact with each other to regulate axon elongation and retraction. Furthermore, mathematical models can help optimize externally applied tension to promote axon growth without causing damage. Finally, scientists also use simulations of axon damage to investigate how forces are distributed among different components of the axon and how the tissue surrounding an axon influences its susceptibility to injury. In this review, we discuss how computational studies complement experimental studies in the areas of axon growth, regeneration, and damage.

    View details for DOI 10.1016/j.semcdb.2022.04.019

    View details for PubMedID 35474150

  • Mechanical stress compromises multicomponent efflux complexes in bacteria PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Genova, L. A., Roberts, M. F., Wong, Y., Harper, C. E., Santiago, A., Fu, B., Srivastava, A., Jung, W., Wang, L. M., Krzeminski, L., Mao, X., Sun, X., Hui, C., Chen, P., Hernandez, C. J. 2019; 116 (51): 25462–67


    Physical forces have a profound effect on growth, morphology, locomotion, and survival of organisms. At the level of individual cells, the role of mechanical forces is well recognized in eukaryotic physiology, but much less is known about prokaryotic organisms. Recent findings suggest an effect of physical forces on bacterial shape, cell division, motility, virulence, and biofilm initiation, but it remains unclear how mechanical forces applied to a bacterium are translated at the molecular level. In Gram-negative bacteria, multicomponent protein complexes can form rigid links across the cell envelope and are therefore subject to physical forces experienced by the cell. Here we manipulate tensile and shear mechanical stress in the bacterial cell envelope and use single-molecule tracking to show that octahedral shear (but not hydrostatic) stress within the cell envelope promotes disassembly of the tripartite efflux complex CusCBA, a system used by Escherichia coli to resist copper and silver toxicity. By promoting disassembly of this protein complex, mechanical forces within the cell envelope make the bacteria more susceptible to metal toxicity. These findings demonstrate that mechanical forces can inhibit the function of cell envelope protein assemblies in bacteria and suggest the possibility that other multicomponent, transenvelope efflux complexes may be sensitive to mechanical forces including complexes involved in antibiotic resistance, cell division, and translocation of outer membrane components. By modulating the function of proteins within the cell envelope, mechanical stress has the potential to regulate multiple processes required for bacterial survival and growth.

    View details for DOI 10.1073/pnas.1909562116

    View details for Web of Science ID 000503281500023

    View details for PubMedID 31772020

    View details for PubMedCentralID PMC6925999

  • Viscoelasticity of the axon limits stretch-mediated growth COMPUTATIONAL MECHANICS Wang, L. M., Kuhl, E. 2019