94 Publications

Independently paced Ca2+ oscillations in progenitor and differentiated cells in an ex vivo epithelial organ

Ann A. Kim, Amanda Nguyen, X. Du, et al.

Cytosolic Ca2+ is a highly dynamic, tightly regulated and broadly conserved cellular signal. Ca2+ dynamics have been studied widely in cellular monocultures, yet organs in vivo comprise heterogeneous populations of stem and differentiated cells. Here, we examine Ca2+ dynamics in the adult Drosophila intestine, a self-renewing epithelial organ in which stem cells continuously produce daughters that differentiate into either enteroendocrine cells or enterocytes. Live imaging of whole organs ex vivo reveals that stem-cell daughters adopt strikingly distinct patterns of Ca2+ oscillations after differentiation: enteroendocrine cells exhibit single-cell Ca2+ oscillations, whereas enterocytes exhibit rhythmic, long-range Ca2+ waves. These multicellular waves do not propagate through immature progenitors (stem cells and enteroblasts), of which the oscillation frequency is approximately half that of enteroendocrine cells. Organ-scale inhibition of gap junctions eliminates Ca2+ oscillations in all cell types – even, intriguingly, in progenitor and enteroendocrine cells that are surrounded only by enterocytes. Our findings establish that cells adopt fate-specific modes of Ca2+ dynamics as they terminally differentiate and reveal that the oscillatory dynamics of different cell types in a single, coherent epithelium are paced independently.

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Active Microphase Separation in Mixtures of Microtubules and Tip-Accumulating Molecular Motors

Bezia Lemma , Noah P. Mitchell, D. Needleman, et al.

Mixtures of filaments and molecular motors form active materials with diverse dynamical behaviors that vary based on their constituents’ molecular properties. To develop a multiscale of these materials, we map the nonequilibrium phase diagram of microtubules and tip-accumulating kinesin-4 molecular motors. We find that kinesin-4 can drive either global contractions or turbulent like extensile dynamics, depending on the concentrations of both microtubules and a bundling agent. We also observe a range of spatially heterogeneous nonequilibrium phases, including finite-sized radial asters, 1D wormlike chains, extended 2D bilayers, and system-spanning 3D active foams. Finally, we describe intricate kinetic pathways that yield microphase-separated structures and arise from the inherent frustration between the orientational order of filamentous microtubules and the positional order of tip-accumulating molecular motors. Our work reveals a range of novel active states. It also shows that the form of active stresses is not solely dictated by the properties of individual motors and filaments, but is also contingent on the constituent concentrations and spatial arrangement of motors on the filaments.

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Stability selection enables robust learning of differential equations from limited noisy data

S. Maddu, Bevan L. Cheeseman , Ivo F. Sbalzarini, C. Müller

We present a statistical learning framework for robust identification of differential equations from noisy spatio-temporal data. We address two issues that have so far limited the application of such methods, namely their robustness against noise and the need for manual parameter tuning, by proposing stability-based model selection to determine the level of regularization required for reproducible inference. This avoids manual parameter tuning and improves robustness against noise in the data. Our stability selection approach, termed PDE-STRIDE, can be combined with any sparsity-promoting regression method and provides an interpretable criterion for model component importance. We show that the particular combination of stability selection with the iterative hard-thresholding algorithm from compressed sensing provides a fast and robust framework for equation inference that outperforms previous approaches with respect to accuracy, amount of data required, and robustness. We illustrate the performance of PDE-STRIDE on a range of simulated benchmark problems, and we demonstrate the applicability of PDE-STRIDE on real-world data by considering purely data-driven inference of the protein interaction network for embryonic polarization in Caenorhabditis elegans. Using fluorescence microscopy images of C. elegans zygotes as input data, PDE-STRIDE is able to learn the molecular interactions of the proteins.

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Towards the cellular-scale simulation of motor-driven cytoskeletal assemblies

W. Yan, Saad Ansari, A. Lamson, Matthew A. Glaser, Meredith Betterton, M. Shelley

The cytoskeleton -- a collection of polymeric filaments, molecular motors, and crosslinkers -- is a foundational example of active matter, and in the cell assembles into organelles that guide basic biological functions. Simulation of cytoskeletal assemblies is an important tool for modeling cellular processes and understanding their surprising material properties. Here we present aLENS, a novel computational framework to surmount the limits of conventional simulation methods. We model molecular motors with crosslinking kinetics that adhere to a thermodynamic energy landscape, and integrate the system dynamics while efficiently and stably enforcing hard-body repulsion between filaments -- molecular potentials are entirely avoided in imposing steric constraints. Utilizing parallel computing, we simulate different mixtures of tens to hundreds of thousands of cytoskeletal filaments and crosslinking motors, recapitulating self-emergent phenomena such as bundle formation and buckling, and elucidating how motor type, thermal fluctuations, internal stresses, and confinement determine the evolution of active matter aggregates.

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May 26, 2022

Studying Interstellar Turbulence Driving Scales using the Bispectrum

M.J. O'Brien, B. Burkart, M. Shelley

We demonstrate the utility of the bispectrum, the Fourier three-point correlation function, for studying driving scales of magnetohydrodynamic (MHD) turbulence in the interstellar medium. We calculate the bispectrum by implementing a parallelized Monte Carlo direct measurement method, which we have made publicly available. In previous works, the bispectrum has been used to identify non-linear scaling correlations and break degeneracies in lower-order statistics like the power spectrum. We find that the bicoherence, a related statistic which measures phase coupling of Fourier modes, identifies turbulence driving scales using density and column density fields. In particular, it shows that the driving scale is phase-coupled to scales present in the turbulent cascade. We also find that the presence of an ordered magnetic field at large-scales enhances phase coupling as compared to a pure hydrodynamic case. We, therefore, suggest the bispectrum and bicoherence as tools for searching for non-locality for wave interactions in MHD turbulence.

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March 24, 2022

Thermodynamically consistent coarse-graining of polar active fluids

Scott Weady, D. Stein, M. Shelley

We introduce a closure model for coarse-grained kinetic theories of polar active fluids. Based on a thermodynamically consistent, quasi-equilibrium approximation of the particle distribution function, the model closely captures important analytical properties of the kinetic theory, including its linear stability and the balance of entropy production and dissipation. Nonlinear simulations show the model reproduces the qualitative behavior and nonequilibrium statistics of the kinetic theory, unlike commonly used closure models. We use the closure model to simulate highly turbulent suspensions in both two and three dimensions in which we observe complex multiscale dynamics, including large concentration fluctuations and a proliferation of polar and nematic defects.

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March 11, 2022

Enhanced clamshell swimming with asymmetric beating at low Reynolds number

Shiyuan Hu, Jun Zhang, M. Shelley

A single flexible filament can be actuated to escape from the scallop theorem and generate net propulsion at low Reynolds number. In this work, we study the dynamics of a simple boundary-driven multi-filament swimmer, a two-arm clamshell actuated at the hinged point, using a nonlocal slender body approximation with full hydrodynamic interactions. We first consider an elastic clamshell consisted of flexible filaments with intrinsic curvature, and then build segmental models consisted of rigid segments connected by different mechanical joints with different forms of response torques. The simplicity of the system allows us to fully explore the effect of various parameters on the swimming performance. Optimal included angles and elastoviscous numbers are identified. The segmental models capture the characteristic dynamics of the elastic clamshell. We further demonstrate how the swimming performance can be significantly enhanced by the asymmetric beating patterns induced by biased torques.

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March 4, 2022

Incompressible active phases at an interface. I. Formulation and axisymmetric odd flows

L. Jia, William T. M. Irvine, M. Shelley

Inspired by the recent realization of a 2D chiral fluid as an active monolayer droplet moving atop a 3D Stokesian fluid, we formulate mathematically its free-boundary dynamics. The surface droplet is described as a general 2D linear, incompressible, and isotropic fluid, having a viscous shear stress, an active chiral driving stress, and a Hall stress allowed by the lack of time-reversal symmetry. The droplet interacts with itself through its driven internal mechanics and by driving flows in the underlying 3D Stokes phase. We pose the dynamics as the solution to a singular integral-differential equation, over the droplet surface, using the mapping from surface stress to surface velocity for the 3D Stokes equations. Specializing to the case of axisymmetric droplets, exact representations for the chiral surface flow are given in terms of solutions to a singular integral equation, solved using both analytical and numerical techniques. For a disc-shaped monolayer, we additionally employ a semi-analytical solution that hinges on an orthogonal basis of Bessel functions and allows for efficient computation of the monolayer velocity field, which ranges from a nearly solid-body rotation to a unidirectional edge current depending on the subphase depth and the Saffman-Delbruck length. Except in the near-wall limit, these solutions have divergent surface shear stresses at droplet boundaries, a signature of systems with codimension one domains embedded in a three-dimensional medium. We further investigate the effect of a Hall viscosity, which couples radial and transverse surface velocity components, on the dynamics of a closing cavity

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February 28, 2022

Euchromatin activity enhances segregation and compaction of heterochromatin in the cell nucleus

Achal Mahajan, W. Yan, Alexandra Zidovska, D. Saintillan, M. Shelley

The large-scale organization of the genome inside the cell nucleus is critical for the cell’s function. Chromatin – the functional form of DNA in cells – serves as a substrate for active nuclear processes such as transcription, replication and DNA repair. Chromatin’s spatial organization directly affects its accessibility by ATP-powered enzymes, e.g., RNA polymerase II in the case of transcription. In differentiated cells, chromatin is spatially segregated into compartments – euchromatin and heterochromatin – the former being largely transcriptionally active and loosely packed, the latter containing mostly silent genes and densely compacted. The euchromatin/heterochromatin segregation is crucial for proper genomic function, yet the physical principles behind it are far from understood. Here, we model the nucleus as filled with hydrodynamically interacting active Zimm chains – chromosomes – and investigate how large heterochromatic regions form and segregate from euchromatin through their complex interactions. Each chromosome presents a block copolymer composed of heterochromatic blocks, capable of crosslinking that increases chromatin’s local compaction, and euchromatic blocks, subjected to stochastic force dipoles that capture the microscopic stresses exerted by nuclear ATPases. These active stresses lead to a dynamic self-organization of the genome, with its coherent motions driving the mixing of chromosome territories as well as large-scale heterochromatic segregation through crosslinking of distant genomic regions. We study the stresses and flows that arise in the nucleus during the heterochromatic segregation, and identify their signatures in Hi-C proximity maps. Our results reveal the fundamental role of active mechanical processes and hydrodynamic interactions in the kinetics of chromatin compartmentalization and in the emergent large-scale organization of the nucleus.

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February 22, 2022

Measuring errors over time: towards a quantitative theory of chromosome segregation error correction

G. Ha, P. Dieterle, H. Shen, D. Needleman

The mammalian mitotic spindle segregates an equal number of chromosomes to daughter cells. Over the course of spindle assembly, many initially erroneous attachments between kinetochores and microtubules are fixed through a process called error correction. Despite the importance of chromosome segregation errors in many human health conditions, we lack quantitative methods to characterize the dynamic error correction process and how it is impaired in disease states. We have developed a novel experimental method and analysis framework to quantify chromosome segregation error correction in human tissue culture cells with live cell confocal imaging of spindle assembly, timed premature chromosome separation, and automated counting of kinetochores after cell division. Using our assay we targeted Aurora B kinase, a key regulator of kinetochore-microtubule attachments, with two small molecules that either inhibited Aurora B activity or perturbed its localization. While both inhibitors increased the steady state error baseline over 10-fold from control, they differed in their initial error states and times to reach steady state. Our results indicate that error correction dynamics, and not just endpoint segregation errors, are important for understanding the involvement of proteins in error correction. Future work will focus on distinguishing the functional roles of different proteins in error correction, characterizing how kinetochore-microtubule affinity and microtubule stability determine error correction dynamics, and constructing and testing a mathematical theory of error correction.

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