Search

Living cells can leverage correlations in environmental fluctuations to predict the future environment and mount a response ahead of time. To this end, cells need to encode the past signal into the output of the intracellular network from which the future input is predicted. Yet, storing information is costly while not all features of the past signal are equally informative on the future input signal. Here, we show for two classes of input signals that cellular networks can reach the fundamental bound on the predictive information as set by the information extracted from the past signal: Push–pull networks can reach this information bound for Markovian signals, while networks that take a temporal derivative can reach the bound for predicting the future derivative of non-Markovian signals. However, the bits of past information that are most informative about the future signal are also prohibitively costly. As a result, the optimal system that maximizes the predictive information for a given resource cost is, in general, not at the information bound. Applying our theory to the chemotaxis network of Escherichia coli reveals that its adaptive kernel is optimal for predicting future concentration changes over a broad range of background concentrations, and that the system has been tailored to predicting these changes in shallow gradients. [ABSTRACT FROM AUTHOR]

The article discusses the concept of kinetic proofreading, which is a mechanism that allows biochemical processes to discriminate between different ligands. The authors argue that increasing the number of proofreading steps does not necessarily improve ligand discrimination when stochasticity is taken into account. However, they also suggest that if the discrimination time is allowed to vary, the proofreading performance can actually improve with more steps. This finding opens up new avenues for studying the relationship between discrimination time, discrimination accuracy, and signaling activity. [Extracted from the article]

Active matter systems can generate highly ordered structures, avoiding equilibrium through the consumption of energy by individual constituents. How the microscopic parameters that characterize the active agents are translated to the observed mesoscopic properties of the assembly has remained an open question. These active systems are prevalent in living matter; for example, in cells, the cytoskeleton is organized into structures such as the mitotic spindle through the coordinated activity of many motor proteins walking along microtubules. Here, we investigate how the microscopic motor-microtubule interactions affect the coherent structures formed in a reconstituted motor-microtubule system. This question is of deeper evolutionary significance as we suspect motor and microtubule type contribute to the shape and size of resulting structures. We explore key parameters experimentally and theoretically, using a variety of motors with different speeds, processivities, and directionalities. We demonstrate that aster size depends on the motor used to create the aster, and develop a model for the distribution of motors and microtubules in steady-state asters that depends on parameters related to motor speed and processivity. Further, we show that network contraction rates scale linearly with the single-motor speed in quasi-one- dimensional contraction experiments. In all, this theoretical and experimental work helps elucidate how microscopic motor properties are translated to the much larger scale of collective motor-microtubule assemblies. [ABSTRACT FROM AUTHOR]

During cell division, the spindle generates force to move chromosomes. In mammals, microtubule bundles called kinetochore-fibers (k-fibers) attach to and segregate chromosomes. To do so, k-fibers must be robustly anchored to the dynamic spindle. We previously developed microneedle manipulation to mechanically challenge k-fiber anchorage, and observed spatially distinct response features revealing the presence of heterogeneous anchorage (Suresh et al., 2020). How anchorage is precisely spatially regulated, and what forces are necessary and sufficient to recapitulate the k-fiber's response to force remain unclear. Here, we develop a coarse-grained k-fiber model and combine with manipulation experiments to infer underlying anchorage using shape analysis. By systematically testing different anchorage schemes, we find that forces solely at k-fiber ends are sufficient to recapitulate unmanipulated k-fiber shapes, but not manipulated ones for which lateral anchorage over a 3 µm length scale near chromosomes is also essential. Such anchorage robustly preserves k-fiber orientation near chromosomes while allowing pivoting around poles. Anchorage over a shorter length scale cannot robustly restrict pivoting near chromosomes, while anchorage throughout the spindle obstructs pivoting at poles. Together, this work reveals how spatially regulated anchorage gives rise to spatially distinct mechanics in the mammalian spindle, which we propose are key for function. [ABSTRACT FROM AUTHOR]

Key enzymatic processes use the nonequilibrium error correction mechanism called kinetic proofreading to enhance their specificity. The applicability of traditional proofreading schemes, however, is limited because they typically require dedicated structural features in the enzyme, such as a nucleotide hydrolysis site or multiple intermediate conformations. Here, we explore an alternative conceptual mechanism that achieves error correction by having substrate binding and subsequent product formation occur at distinct physical locations. The time taken by the enzyme-substrate complex to diffuse from one location to another is leveraged to discard wrong substrates. This mechanism does not have the typical structural requirements, making it easier to overlook in experiments. We discuss how the length scales of molecular gradients dictate proofreading performance, and quantify the limitations imposed by realistic diffusion and reaction rates. Our work broadens the applicability of kinetic proofreading and sets the stage for studying spatial gradients as a possible route to specificity. [ABSTRACT FROM AUTHOR]

Experiments on the acoustic vibrations of elastic nanostructures in fluid media have been used to study the mechanical properties of materials, as well as for mechanical and biological sensing. The medium surrounding the nanostructure is typically modeled as a Newtonian fluid. A recent experiment however suggested that high-frequency longitudinal vibration of bipyramidal nanoparticles could trigger a viscoelastic response in water-glycerol mixtures [Pelton et al., "Viscoelastic flows in simple liquids generated by vibrating nanostructures," Phys. Rev. Lett. 111, 244502 (2013)]. Motivated by these experimental studies, we first revisit a classical continuum mechanics problem of the purely radial vibration of an elastic sphere, also called the breathing mode, in a compressible viscous fluid and then extend our analysis to a viscoelastic medium using the Maxwell fluid model. The effects of fluid compressibility and viscoelasticity are discussed. Although in the case of longitudinal vibration of bipyramidal nanoparticles, the effects of fluid compressibility were shown to be negligible, we demonstrate that it plays a significant role in the breathing mode of an elastic sphere. On the other hand, despite the different vibration modes, the breathing mode of a sphere triggers a viscoelastic response in water-glycerol mixtures similar to that triggered by the longitudinal vibration of bipyramidal nanoparticles. We also comment on the effect of fluid viscoelasticity on the idea of destroying virus particles by acoustic resonance. [ABSTRACT FROM AUTHOR]

We investigate the multichain version of the chemical master equation, when there are transitions between different states inside the long chains, as well as transitions between (a few) different chains. In the discrete version, such a model can describe the connected diffusion processes with jumps between different types. We apply the Hamilton-Jacobi equation to solve some aspects of the model. We derive exact (in the limit of infinite number of particles) results for the dynamic of the maximum of the distribution and the variance of distribution. [ABSTRACT FROM AUTHOR]

Summary Each time a cell divides, the microtubule cytoskeleton self-organizes into the metaphase spindle: an ellipsoidal steady-state structure that holds its stereotyped geometry despite microtubule turnover and internal stresses [ 1–6 ]. Regulation of microtubule dynamics, motor proteins, microtubule crosslinking, and chromatid cohesion can modulate spindle size and shape, and yet modulated spindles reach and hold a new steady state [ 7–11 ]. Here, we ask what maintains any spindle steady-state geometry. We report that clustering of microtubule ends by dynein and NuMA is essential for mammalian spindles to hold a steady-state shape. After dynein or NuMA deletion, the mitotic microtubule network is "turbulent"; microtubule bundles extend and bend against the cell cortex, constantly remodeling network shape. We find that spindle turbulence is driven by the homotetrameric kinesin-5 Eg5, and that acute Eg5 inhibition in turbulent spindles recovers spindle geometry and stability. Inspired by in vitro work on active turbulent gels of microtubules and kinesin [ 12, 13 ], we explore the kinematics of this in vivo turbulent network. We find that turbulent spindles display decreased nematic order and that motile asters distort the nematic director field. Finally, we see that turbulent spindles can drive both flow of cytoplasmic organelles and whole-cell movement—analogous to the autonomous motility displayed by droplet-encapsulated turbulent gels [ 12 ]. Thus, end-clustering by dynein and NuMA is required for mammalian spindles to reach a steady-state geometry, and in their absence Eg5 powers a turbulent microtubule network inside mitotic cells. Graphical Abstract Highlights • Mammalian spindles use microtubule end-clustering by dynein or NuMA to hold their shape • Dynein or NuMA knockout spindles are unstable and turbulent • The kinesin Eg5 expands turbulent spindle networks and drives shape change • Turbulent spindles reorganize cytoplasm and increase cell movement Hueschen et al. show that mitotic spindles use clustering of microtubule ends by the motor dynein to maintain a steady-state spindle network shape. After complete loss of dynein or its partner NuMA, spindles dynamically remodel their shape and microtubule organization, and these unstable turbulent spindles can drive cell movement. [ABSTRACT FROM AUTHOR]

The stochastic dynamics of reinforcement learning is studied using a master equation formalism. We consider two different problems-Q learning for a two-agent game and the multiarmed bandit problem with policy gradient as the learning method. The master equation is constructed by introducing a probability distribution over continuous policy parameters or over both continuous policy parameters and discrete state variables (a more advanced case). We use a version of the moment closure approximation to solve for the stochastic dynamics of the models. Our method gives accurate estimates for the mean and the (co)variance of policy variables. For the case of the two-agent game, we find that the variance terms are finite at steady state and derive a system of algebraic equations for computing them directly.

Key enzymatic processes use the nonequilibrium error correction mechanism called kinetic proofreading to enhance their specificity. The applicability of traditional proofreading schemes, however, is limited because they typically require dedicated structural features in the enzyme, such as a nucleotide hydrolysis site or multiple intermediate conformations. Here, we explore an alternative conceptual mechanism that achieves error correction by having substrate binding and subsequent product formation occur at distinct physical locations. The time taken by the enzyme-substrate complex to diffuse from one location to another is leveraged to discard wrong substrates. This mechanism does not have the typical structural requirements, making it easier to overlook in experiments. We discuss how the length scales of molecular gradients dictate proofreading performance, and quantify the limitations imposed by realistic diffusion and reaction rates. Our work broadens the applicability of kinetic proofreading and sets the stage for studying spatial gradients as a possible route to specificity., Competing Interests: VG, KH, FX, AM, RP No competing interests declared, (© 2020, Galstyan et al.)

Kinetic proofreading is an error correction mechanism present in the processes of the central dogma and beyond and typically requires the free energy of nucleotide hydrolysis for its operation. Though the molecular players of many biological proofreading schemes are known, our understanding of how energy consumption is managed to promote fidelity remains incomplete. In our work, we introduce an alternative conceptual scheme called "the piston model of proofreading" in which enzyme activation through hydrolysis is replaced with allosteric activation achieved through mechanical work performed by a piston on regulatory ligands. Inspired by Feynman's ratchet and pawl mechanism, we consider a mechanical engine designed to drive the piston actions powered by a lowering weight, whose function is analogous to that of ATP synthase in cells. Thanks to its mechanical design, the piston model allows us to tune the "knobs" of the driving engine and probe the graded changes and trade-offs between speed, fidelity, and energy dissipation. It provides an intuitive explanation of the conditions necessary for optimal proofreading and reveals the unexpected capability of allosteric molecules to beat the Hopfield limit of fidelity by leveraging the diversity of states available to them. The framework that we have built for the piston model can also serve as a basis for additional studies of driven biochemical systems.