Anomalous dynamics of a passive droplet in active turbulence.

Motion of a passive deformable object in an active environment serves as a representative of both in-vivo systems such as intracellular particle motion in Acanthamoeba castellanii, or in-vitro systems such as suspension of beads inside dense swarms of Escherichia coli. Theoretical modeling of such systems is challenging due to the requirement of well resolved hydrodynamics which can explore the spatiotemporal correlations around the suspended passive object in the active fluid. We address this critical lack of understanding using coupled hydrodynamic equations for nematic liquid crystals with finite active stress to model the active bath, and a suspended nematic droplet with zero activity. The droplet undergoes deformation fluctuations and its movement shows periods of "runs" and "stays". At relatively low interfacial tension, the droplet begins to break and mix with the outer active bath. We establish that the motion of the droplet is influenced by the interplay of spatial correlations of the flow and the size of the droplet. The mean square displacement shows a transition from ballistic to normal diffusion which depends on the droplet size. We discuss this transition in relation to spatiotemporal scales associated with velocity correlations of the active bath and the droplet.

Homopolymer and heteropolymer translocation through patterned pores under fluctuating forces.

We investigate the translocation of a semiflexible polymer through extended patterned pores using Langevin dynamics simulations, specifically focusing on the influence of a time-dependent driving force. Our findings reveal that, akin to its flexible counterpart, a rigid chain-like molecule translocates faster when subjected to an oscillating force than a constant force of equivalent average magnitude. The enhanced translocation is strongly correlated with the stiffness of the polymer and the stickiness of the pores. The arrangement of the pores plays a pivotal role in translocation dynamics, deeply influenced by the interplay between polymer stiffness and pore-polymer interactions. For heterogeneous polymers with periodically varying stiffness, the oscillating force introduces significant variations in the translocation time distributions based on segment sizes and orientations. On the basis of these insights, we propose a sequencing approach that harnesses distinct pore surface properties that are capable of accurately predicting sequences in heteropolymers with diverse bending rigidities.

Emergence of slip-ideal-slip behavior in tip-links serve as force filters of sound in hearing.

Tip-links in the inner ear convey force from sound and trigger mechanotransduction. Here, we present evidence that tip-links (collectively as heterotetrameric complexes of cadherins) function as force filters during mechanotransduction. Our force-clamp experiments reveal that the tip-link complexes show slip-ideal-slip bond dynamics. At low forces, the lifetime of the tip-link complex drops monotonically, indicating slip-bond dynamics. The ideal bond, rare in nature, is seen in an intermediate force regime where the survival of the complex remains constant over a wide range. At large forces, tip-links follow a slip bond and dissociate entirely to cut-off force transmission. In contrast, the individual tip-links (heterodimers) display slip-catch-slip bonds to the applied forces. While with a phenotypic mutant, we showed the importance of the slip-catch-slip bonds in uninterrupted hearing, our coarse-grained Langevin dynamics simulations demonstrated that the slip-ideal-slip bonds emerge as a collective feature from the slip-catch-slip bonds of individual tip-links.

Gain reversal in the translocation dynamics of a semiflexible polymer through a flickering pore.

We study the driven translocation of a semiflexible polymer through an attractive extended pore with a periodically oscillating width. Similar to its flexible counterpart, a stiff polymer translocates through an oscillating pore more quickly than a static pore whose width is equal to the oscillating pore's mean width. This efficiency quantified as a gain in the translocation time, highlights a considerable dependence of the translocation dynamics on the stiffness of the polymer and the attractive nature of the pore. The gain characteristics for various polymer stiffness exhibit a trend reversal when the stickiness of the pore is changed. The gain reduces with increasing stiffness for a lower attractive strength of the pore, whereas it increases with increasing stiffness for higher attractive strengths. Such a dependence leads to the possibility of a high degree of robust selectivity in the translocation process.

Stochastic resonance in a model of a periodically driven DNA: Multiple transitions, scaling, and sequence dependence.

We numerically study stochastic resonance in the unzipping of a model double-stranded DNA by a periodic force. We observe multiple peaks in stochastic resonance in the output signal as the driving force frequency is varied for different force amplitudes, temperature, chain length, and chain heterogeneity. Multiple peaks point to the existence of multiple stable and metastable states, which correspond to dynamical states of partially zipped and unzipped conformations and transitions between them. We quantify such transitions by looking at the time evolution of the fraction of bound base pairs. We obtain phase diagrams in the force amplitude-temperature plane both in the resonance frequency of the primary peak and the output signal at the peak value. We further obtain an excellent scaling behavior of the output signal for changing lengths of the DNA. Resonance behavior is also affected by chain heterogeneity as it depends strongly on which base pair the periodic forcing is applied.

Driven translocation of a semiflexible polymer through a conical channel in the presence of attractive surface interactions.

We study the translocation of a semiflexible polymer through a conical channel with attractive surface interactions and a driving force which varies spatially inside the channel. Using the results of the translocation dynamics of a flexible polymer through an extended channel as control, we first show that the asymmetric shape of the channel gives rise to non-monotonic features in the total translocation time as a function of the apex angle of the channel. The waiting time distributions of individual monomer beads inside the channel show unique features strongly dependent on the driving force and the surface interactions. Polymer stiffness results in longer translocation times for all angles of the channel. Further, non-monotonic features in the translocation time as a function of the channel angle changes substantially as the polymer becomes stiffer, which is reflected in the changing features of the waiting time distributions. We construct a free energy description of the system incorporating entropic and energetic contributions in the low force regime to explain the simulation results.

Effectiveness of Arsenicum album 30C in Prevention of COVID-19 in Individuals Residing in Containment Zones of Delhi-A Prospective, Community-based, Parallel Cohort Study.

OBJECTIVE: This work was undertaken to evaluate the protective effect of Arsenicum album 30C against COVID-19. DESIGN: The work was designed as a prospective parallel cluster cohort study. INTERVENTION: Participants were enrolled in a homeopathy intervention (HI) cohort (who received Arsenicum album) or in a non-intervention (NI) cohort (who received no systematic intervention) from COVID-19 containment areas of Delhi. Individuals of age 5 years or above were given four medicated pills of Arsenicum album 30C, while those from 1 to 5 years old were given two medicated pills in each dose. RESULTS: The analysis included 10,180 individuals residing in 11 COVID-19 containment areas in Delhi, out of which 6,590 individuals were in the HI cohort and 3,590 individuals were in the NI cohort. The overall protective effect of Arsenicum album 30C was 83.43% (95% confidence interval [CI], 76.77 to 88.17): 45 cases per 6,590 (8.34 per 10,000 person-weeks) in the Arsenicum album 30C group versus 143 cases per 3,590 (45.01 per 10,000 person-weeks) in the NI cohort. The protective effect of Arsenicum album 30C against laboratory confirmed COVID-19 was 74.40% (95% CI, 55.08 to 85.41): 18 cases per 6,590 (3.32 per 10,000 person-weeks) in the Arsenicum album 30C group versus 38 cases per 3,590 (11.85 per 10,000 person-weeks) in the NI cohort. CONCLUSION: The use of Arsenicum album 30C was associated with some protection against probable and laboratory-confirmed COVID-19 in a containment-zone setting. Randomized controlled trials are needed to confirm or refute these results.

Deconstructing the role of myosin contractility in force fluctuations within focal adhesions.

Force fluctuations exhibited in focal adhesions that connect a cell to its extracellular environment point to the complex role of the underlying machinery that controls cell migration. To elucidate the explicit role of myosin motors in the temporal traction force oscillations, we vary the contractility of these motors in a dynamical model based on the molecular clutch hypothesis. As the contractility is lowered, effected both by changing the motor velocity and the rate of attachment/detachment, we show analytically in an experimentally relevant parameter space, that the system goes from decaying oscillations to stable limit cycle oscillations through a supercritical Hopf bifurcation. As a function of the motor activity and the number of clutches, the system exhibits a rich array of dynamical states. We corroborate our analytical results with stochastic simulations of the motor-clutch system. We obtain limit cycle oscillations in the parameter regime as predicted by our model. The frequency range of oscillations in the average clutch and motor deformation compares well with experimental results.

A semiflexible polymer in a gliding assay: reentrant transition, role of turnover and activity.

We consider a model of an extensible semiflexible filament moving in two dimensions on a motility assay of motor proteins represented explicitly as active harmonic linkers. Their heads bind stochastically to polymer segments within a capture radius, and extend along the filament in a directed fashion before detaching. Both the extension and detachment rates are load-dependent and generate an active drive on the filament. The filament undergoes a first order phase transition from the open chain to spiral conformation and shows a reentrant behavior in both the active extension and the turnover, defined as the ratio of attachment-detachment rates. Associated with the phase transition, the size and shape of the polymer change non-monotonically, and the relevant autocorrelation functions display a double-exponential decay. The corresponding correlation times show a maximum signifying the dominance of spirals. The orientational dynamics captures the rotation of spirals, and its correlation time decays with activity as a power law.

Morphological and dynamical properties of semiflexible filaments driven by molecular motors.

We consider an explicit model of a semiflexible filament moving in two dimensions on a gliding assay of motor proteins, which attach to and detach from filament segments stochastically, with a detachment rate that depends on the local load experienced. Attached motor proteins move along the filament to one of its ends with a velocity that varies nonlinearly with the motor protein extension. The resultant force on the filament drives it out of equilibrium. The distance from equilibrium is reflected in the end-to-end distribution, modified bending stiffness, and a transition to spiral morphology of the polymer. The local stress dependence of activity results in correlated fluctuations in the speed and direction of the center of mass leading to a series of ballistic-diffusive crossovers in its dynamics.

Force-activated catalytic pathway accelerates bacterial adhesion against flow.

Mechanical cues often influence the factors affecting the transition states of catalytic reactions and alter the activation pathway. However, tracking the real-time dynamics of such activation pathways is limited. Using single-molecule trapping of reaction intermediates, we developed a method that enabled us to perform one reaction at one site and simultaneously study the real-time dynamics of the catalytic pathway. Using this, we showed single-molecule calligraphy at nanometer resolution and deciphered the mechanism of the sortase A enzymatic reaction that, counter-intuitively, accelerates bacterial adhesion under shear tension. Our method captured a force-induced dissociation of the enzyme-substrate bond that accelerates the forward reaction 100×, proposing a new mechano-activated catalytic pathway. In corroboration, our molecular dynamics simulations in the presence of force identified a force-induced conformational switch in the enzyme that accelerates proton transfer between CYS184 (acceptor) and HIS120 (donor) catalytic dyads by reducing the inter-residue distances. Overall, the present study opens up the possibility of studying the influence of factors affecting transition states in real time and paves the way for the rational design of enzymes with enhanced efficiency.

Sequencing of semiflexible polymers of varying bending rigidity using patterned pores.

We study the translocation of a semiflexible polymer through extended pores with patterned stickiness, using Langevin dynamics simulations. We find that the consequence of pore patterning on the translocation time dynamics is dramatic and depends strongly on the interplay of polymer stiffness and pore-polymer interactions. For heterogeneous polymers with periodically varying stiffness along their lengths, we find that variation of the block size of the sequences and the orientation results in large variations in the translocation time distributions. We show how this fact may be utilized to develop an effective sequencing strategy. This strategy involving multiple pores with patterned surface energetics can predict heteropolymer sequences having different bending rigidity to a high degree of accuracy.

Effect of catch bonding on transport of cellular cargo by dynein motors.

Recent experiments have demonstrated that dynein motors exhibit catch bonding behavior, in which the unbinding rate of a single dynein decreases with increasing force, for a certain range of force. Motivated by these experiments, we study the effect of catch bonding on unidirectional transport properties of cellular cargo carried by multiple dynein motors. We introduce a threshold force bond deformation (TFBD) model, consistent with the experiments, wherein catch bonding sets in beyond a critical applied load force. We find catch bonding can result in dramatic changes in the transport properties, which are in sharp contrast to kinesin-driven unidirectional transport, where catch bonding is absent. We predict that under certain conditions, the average velocity of the cellular cargo can actually increase as applied load is increased. We characterize the transport properties in terms of a velocity profile plot in the parameter space of the catch bond strength and the stall force of the motor. This plot yields predictions that may be experimentally accessed by suitable modifications of motor transport and binding properties.

Forced desorption of semiflexible polymers, adsorbed and driven by molecular motors.

We formulate and characterize a model to describe the dynamics of semiflexible polymers in the presence of activity due to motor proteins attached irreversibly to a substrate, and a transverse pulling force acting on one end of the filament. The stochastic binding-unbinding of the motor proteins and their ability to move along the polymer generate active forces. As the pulling force reaches a threshold value, the polymer eventually desorbs from the substrate. Performing underdamped Langevin dynamics simulation of the polymer, and with stochastic motor activity, we obtain desorption phase diagrams. The correlation time for fluctuations in the desorbed fraction increases as one approaches complete desorption, captured quantitatively by a power law spectral density. We present theoretical analysis of the phase diagram using mean field approximations in the weakly bending limit of the polymer and performing linear stability analysis. This predicts an increase in the desorption force with the polymer bending rigidity, active velocity and processivity of the motor proteins to capture the main features of the simulation results.

Translocation through environments with time dependent mobility.

We consider single particle and polymer translocation where the frictional properties experienced from the environment are changing in time. This work is motivated by the interesting frequency responsive behaviour observed when a polymer is passing through a pore with an oscillating width. In order to explain this better we construct general diffusive and non-diffusive frequency response of the gain in translocation time for a single particle in changing environments and look at some specific variations. For two state confinement, where the particle either has constant drift velocity or is stationary, we find exact expressions for both the diffusive and non-diffusive gain. We then apply this approach to polymer translocation under constant forcing through a pore with a sinusoidally varying width. We find good agreement for small polymers at low frequency oscillation with deviations occurring at longer lengths and higher frequencies. Unlike periodic forcing of a single particle at constant mobility, constant forcing with time dependent mobility is amenable to exact solution through manipulation of the Fokker-Planck equation.

Modified fluctuation-dissipation and Einstein relation at nonequilibrium steady states.

Starting from the pioneering work of Agarwal [G. S. Agarwal, Zeitschrift für Physik 252, 25 (1972)], we present a unified derivation of a number of modified fluctuation-dissipation relations (MFDR) that relate response to small perturbations around nonequilibrium steady states to steady-state correlations. Using this formalism we show the equivalence of velocity forms of MFDR derived using continuum Langevin and discrete master equation dynamics. The resulting additive correction to the Einstein relation is exemplified using a flashing ratchet model of molecular motors.

Active polymer translocation through flickering pores.

Single file translocation of a homopolymer through an active channel under the presence of a driving force is studied using Langevin dynamics simulation. It is shown that a channel with sticky walls and oscillating width could lead to significantly more efficient translocation as compared to a static channel that has a width equal to the mean width of the oscillating pore. The gain in translocation exhibits a strong dependence on the stickiness of the pore, which could allow the polymer translocation process to be highly selective.

Spatiotemporal regulation of chemical reactions by active cytoskeletal remodeling.

Efficient and reproducible construction of signaling and sorting complexes, both on the surface and within the living cell, is contingent on local regulation of biochemical reactions by the cellular milieu. We propose that in many cases this spatiotemporal regulation can be mediated by interaction with components of the dynamic cytoskeleton. We show how the interplay between active contractility and remodeling of the cytoskeleton can result in transient focusing of passive molecules to form clusters, leading to a dramatic increase in the reaction efficiency and output levels. The dynamic cytoskeletal elements that drive focusing behave as quasienzymes catalyzing the chemical reaction. These ideas are directly applicable to the cortical actin-dependent clustering of cell surface proteins such as lipid-tethered GPI-anchored proteins, Ras proteins, as well as many proteins that have domains that confer the ability to interact with the actin cytoskeleton. In general such cytoskeletal driven clustering of proteins could be a cellular mechanism to spatiotemporally regulate and amplify local chemical reaction rates in a variety of contexts such as signaling, transcription, sorting, and endocytosis.

The effect of interactions on the cellular uptake of nanoparticles.

We present a simple two-state model to understand the size-dependent endocytosis of nanoparticles. Using this model, we elucidate the relevant energy terms required to understand the size-dependent uptake mechanism and verify it by correctly predicting the behavior at large and small particle sizes. In the absence of interactions between the nanoparticles, we observe an asymmetric distribution of sizes with maximum uptake at intermediate sizes and a minimum size cut-off below which there can be no endocytosis. Including the effect of interactions in our model has remarkable effects on the uptake characteristics. Attractive interactions shift the minimum size cut-off and increase the optimal uptake while repulsive interactions make the distribution more symmetric lowering the optimal uptake.

Fluctuations at a constrained liquid-solid interface.

We study the interface between a solid trapped within a bath of liquid by a suitably shaped nonuniform external potential. Such a potential may be constructed using lasers, external electric or magnetic fields, or a surface template. We study a two-dimensional case where a thin strip of solid, created in this way, is surrounded on either side by a bath of liquid with which it can easily exchange particles. Since height fluctuations of the interface cost energy, this interface is constrained to remain flat at all length scales. However, when such a solid is stressed by altering the depth of the potential beyond a certain limit, it responds by relieving stress by novel interfacial fluctuations, which involve addition or deletion of entire lattice layers of the crystal. This "layering" transition is a generic feature of the system regardless of the details of the interaction potential. We show how such interfacial fluctuations influence mass, momentum, and energy transport across the interface. Tiny momentum impulses produce weak shock waves, which travel through the interface and cause the spallation of crystal layers into the liquid. Kinetic and energetic constraints prevent spallation of partial layers from the crystal, a fact which may be of some practical use. We also study heat transport through the liquid-solid interface and obtain the resistances in liquid, solid, and interfacial regions (Kapitza resistance) as the solid undergoes such layering transitions. Heat conduction, which shows strong signatures of the structural transformations, can be understood using a free volume calculation.