Cytoskeleton最新文献

The nuclear lamina is widely recognized as the most crucial component in providing mechanical stability to the nucleus. However, it is still a significant challenge to model the mechanics of this multilayered protein network. We developed a constitutive model of the nuclear lamina network based on its microstructure, which accounts for the deformation phases at the dimer level, as well as the orientational arrangement and density of lamin filaments. Instead of relying on homology modeling in the previous studies, we conducted molecular simulations to predict the force-extension response of a highly accurate lamin dimer structure obtained through X-ray diffraction crystallography experimentation. Furthermore, we devised a semiflexible worm-like chain extension-force model of lamin dimer as a substitute, incorporating phases of initial stretching, uncoiling of the dimer coiled-coil, and transition of secondary structures. Subsequently, we developed a 2D network continuum model for the nuclear lamina by using our extension-force lamin dimer model and derived stress resultants. By comparing with experimentally measured lamina modulus, we found that the lamina network has sharp initial strain-hardening behavior. This also enabled us to carry out finite element simulations of the entire nucleus with an accurate microstructure-based nuclear lamina model. Finally, we conducted simulations of transendothelial transmigration of a nucleus and investigated the impact of varying network density and uncoiling constants on the critical force required for successful transmigration. The model allows us to incorporate the microstructure characteristics of the nuclear lamina into the nucleus model, thereby gaining insights into how laminopathies and mutations affect nuclear mechanics.

Although diverse actin network architectures found inside the cell have been individually reconstituted outside of the cell, how different types of actin architectures reorganize under applied forces is not entirely understood. Recently, bottom-up reconstitution has enabled studies where dynamic and phenotypic characteristics of various actin networks can be recreated in an isolated cell-like environment. Here, by creating a giant unilamellar vesicle (GUV)-based cell model encapsulating actin networks, we investigate how actin networks rearrange in response to localized stresses applied by micropipette aspiration. We reconstitute actin bundles and branched bundles in GUVs separately and mechanically perturb them. Interestingly, we find that, when aspirated, protrusive actin bundles that are otherwise randomly oriented in the GUV lumen collapse and align along the axis of the micropipette. However, when branched bundles are aspirated, the network remains intact and outside of the pipette while the GUV membrane is aspirated into the micropipette. These results reveal distinct responses in the rearrangement of actin networks in a network architecture-dependent manner when subjected to physical forces.

ON THE BACK COVER: Schematic illustration that shows: In pathology, Tau (in green) targets the tyrosine kinase Fyn (yellow) to dendritic spines, where it phosphorylates subunit NR2b of the NMDA receptor (NMDAR, dark blue at the postsynaptic density), which leads to recruitment of PSD-95 (light blue) and formation of NMDAR/PSD95 complexes. Aβ oligomers (orange, extracellular) induce excitotoxicity by signalling through NMDAR/PSD95 complexes.

Credit: Alison Carlisle, Queensland Brain Institute, The University of Queensland.

ON THE FRONT COVER: Localization of tau phosphorylated at S217 (a biomarker for early, presymptomatic Alzheimer's disease), MAP2 (neuronal soma and dendrite marker) and PSD95 (dendritic spine marker), in green, red and purple respectively.

Credit: Binita Rajbanshi (UCSF; formerly University of Virginia) and George Bloom (University of Virginia).

ON THE INNER FRONT COVER: Total internal reflection microscopy image of taxol-stabilized microtubules coated in tau envelopes composed of human 2N4R tau (magenta). Tau envelopes exclude the binding of human MAP4 (green), resulting in distinct MAP-covered domains along single microtubules in vitro.

Credit: Richard J. McKenney, University of California, Davis.

ON THE INNER BACK COVER: Distribution of tau in the adult rat hippocampus (CA3 region shown). The tissue section was dephosphorylated and then stained with Tau1 antibody (white), MAP2 (red) and DAPI (blue). Tau is normally found at abundant levels within the soma, dendrites, axons and some nuclei of neurons (pink indicates colocalization between Tau1 and MAP2 signal).

Credit: Nicholas Kanaan, PhD, Michigan State University

Cellular response to the topography of their environment, known as contact guidance, is a crucial aspect to many biological processes yet remains poorly understood. A prevailing model to describe cellular contact guidance involves the lateral confinement of focal adhesions (FA) by topography as an underlying mechanism governing how cells can respond to topographical cues. However, it is not clear how this model is consistent with the well-documented depth-dependent contact guidance responses in the literature. To investigate this model, we fabricated a set of contact guidance chips with lateral dimensions capable of confining focal adhesions and relaxing that confinement at various depths. We find at the shallowest depth of 330 nm, the model of focal adhesion confinement is consistent with our observations. However, the cellular response at depths of 725 and 1000 nm is inadequately explained by this model. Instead, we observe a distinct reorganization of F-actin at greater depths in which topographically induced cell membrane deformation alters the structure of the cytoskeleton. These results are consistent with an alternative curvature-hypothesis to explain cellular response to topographical cues. Together, these results indicate a confluence of two molecular mechanisms operating at increased induced membrane curvature that govern how cells sense and respond to topography.

The muscle is the principal tissue that is capable to transform potential energy into kinetic energy. This process is due to the transformation of chemical energy into mechanical energy to enhance the movements and all the daily activities. However, muscular tissues can be affected by some pathologies associated with genetic alterations that affect the expression of proteins. As the muscle is a highly organized structure in which most of the signaling pathways and proteins are related to one another, pathologies may overlap. Duchenne muscular dystrophy (DMD) is one of the most severe muscle pathologies triggering degeneration and muscle necrosis. Several mathematical models have been developed to predict muscle response to different scenarios and pathologies. The aim of this review is to describe DMD and Becker muscular dystrophy in terms of cellular behavior and molecular disorders and to present an overview of the computational models implemented to understand muscle behavior with the aim of improving regenerative therapy.