Filamentation Instability Research Articles

Myopalladin's Role in Cardiac Muscle Function and Disease

Decades of research have provided fundamental insight into the human heart's structure and function. Yet, most cardiac malformations remain a mystery as scientists and clinicians continue to examine how inherited mutations and aging affect the normal biological functions of proteins associated with cardiac dysfunction. Recently, mutations in the muscle protein myopalladin have been linked to the pathogenesis of cardiomyopathy. Myopalladin is a sarcomeric protein that is thought to have an important role in maintaining sarcomere structure, signaling and regulation of gene expression in response to muscle stress. Myopalladin and palladin belong to a family of closely related immunoglobulin (Ig)‐domain‐containing proteins that have essential, but unclear roles in organizing the actin cytoskeleton. Recent work in the Beck lab has shown that the C‐terminal Ig domains of palladin bind directly to actin and increases both the rate of actin polymerization and the stability of actin filaments. The fact that a number of mutations in myopalladin are located within the analogous actin‐binding region suggests that a disruption in actin regulation may occur in cardiomyopathy. Thus, we hypothesized that myopalldin also binds directly to actin and increases both the rate of actin polymerization and the stability of actin filaments. To study the capability of myopalladin to bind and crosslink actin filaments, co‐sedimentation assays were performed between purified F‐actin and myopalladin Ig domains at various concentrations. The results suggest that Ig3 domain of myopalladin is the minimal domain required for both the binding and bundling of F‐actin. Pyrene fluorescence was used to monitor the polymerization rate of G‐actin in the presence of increasing concentrations of the various Ig domain of myopalladin. Our data reveals that myopalladin increases both the rate and extent of actin polymerization. From our data, we propose that myopalladin is involved in sarcomere structure and function through regulation of actin dynamics. We suggest that myopalladin may act both as a scaffold, binding directly to actin and other actin binding proteins at the Z‐disc, and by regulating actin thin filament turnover.Support or Funding InformationThis project was supported by the Kansas INBRE under grant number P20 GM103418; The WSU Carl and Rozina Cassat Regional Institute on Aging Grant (2016); and Wichita State University.

Langmuir wave filamentation in the kinetic regime. I. Filamentation instability of Bernstein-Greene-Kruskal modes in multidimensional Vlasov simulations

A nonlinear Langmuir wave in the kinetic regime kλD≳0.2 may have a filamentation instability, where k is the wavenumber and λD is the Debye length. The nonlinear stage of that instability develops into the filamentation of Langmuir waves which in turn leads to the saturation of the stimulated Raman scattering in laser-plasma interaction experiments. Here, we study the linear stage of the filamentation instability of the particular family (H. A. Rose and D. A. Russell, Phys. Plasmas 8, 4784 (2001)) of Bernstein-Greene-Kruskal (BGK) modes (I. B. Bernstein et al., Phys. Rev. 108, 546 (1957)) that is a bifurcation of the linear Langmuir wave. Performing direct 2 + 2D Vlasov–Poisson simulations of collisionless plasma, we find the growth rates of oblique modes of the electric field as a function of BGK's amplitude, wavenumber, and the angle of the oblique mode's wavevector relative to the BGK's wavevector. Simulation results are compared to theoretical predictions.

Langmuir wave filamentation in the kinetic regime. II. Weak and strong pumping of nonlinear electron plasma waves as the route to filamentation

We consider two kinds of pumped Langmuir waves (LWs) in the kinetic regime, kλD≳0.2, where k is the LW wavenumber and λD is the Debye length, driven to finite amplitude by a coherent external potential whose amplitude is either weak or strong. These dynamically prepared nonlinear LWs develop a transverse (filamentation) instability whose nonlinear evolution destroys the LW's transverse coherence. Instability growth rates in the weakly pumped regime are the same as those of Bernstein-Greene-Kruskal modes considered in Part I (D. A. Silantyev et al., Phys. Plasmas 24, 042104 (2017)), while strongly pumped LWs have higher filamentation grow rates.

DEK is required for homologous recombination repair of DNA breaks

DEK is a highly conserved chromatin-bound protein whose upregulation across cancer types correlates with genotoxic therapy resistance. Loss of DEK induces genome instability and sensitizes cells to DNA double strand breaks (DSBs), suggesting defects in DNA repair. While these DEK-deficiency phenotypes were thought to arise from a moderate attenuation of non-homologous end joining (NHEJ) repair, the role of DEK in DNA repair remains incompletely understood. We present new evidence demonstrating the observed decrease in NHEJ is insufficient to impact immunoglobulin class switching in DEK knockout mice. Furthermore, DEK knockout cells were sensitive to apoptosis with NHEJ inhibition. Thus, we hypothesized DEK plays additional roles in homologous recombination (HR). Using episomal and integrated reporters, we demonstrate that HR repair of conventional DSBs is severely compromised in DEK-deficient cells. To define responsible mechanisms, we tested the role of DEK in the HR repair cascade. DEK-deficient cells were impaired for γH2AX phosphorylation and attenuated for RAD51 filament formation. Additionally, DEK formed a complex with RAD51, but not BRCA1, suggesting a potential role regarding RAD51 filament formation, stability, or function. These findings define DEK as an important and multifunctional mediator of HR, and establish a synthetic lethal relationship between DEK loss and NHEJ inhibition.

Current filamentation instability of warm diluted electron beam in collisional weakly ionized plasma system

Fluid description is employed to investigate the collisional current-filamentation instability (CFI) in a weakly ionized warm-beam/return current system, taking into account both thermal pressure and space charge effects. Describing the equilibrium configuration and using the local approximation method, the dispersion relation (DR) is obtained in the presence of binary collision terms between charged and neutral particles. Analyzing the obtained DR for a warm-beam cold-plasma system shows increment of thermal effects, consisting of collision and thermal pressure, by electron beam temperature and plasma ionization degree decreases the unstable wavelength region as well as the maximum growth rate of CFI, called thermal-driven stabilization. On the other hand, increasing the beam current density is toward the destabilization (called current-driven destabilization) by broadening the unstable wavelength region and increasing the maximum growth rate of CFI. One can deduce that competition between thermal-driven stabilization and current-driven destabilization determines the stability degree of weakly ionized systems.

TaADF4, an actin-depolymerizing factor from wheat, is required for resistance to the stripe rust pathogen Puccinia striiformis f. sp. tritici.

Actin filament assembly in plants is a dynamic process, requiring the activity of more than 75 actin-binding proteins. Central to the regulation of filament assembly and stability is the activity of a conserved family of actin-depolymerizing factors (ADFs), whose primarily function is to regulate the severing and depolymerization of actin filaments. In recent years, the activity of ADF proteins has been linked to a variety of cellular processes, including those associated with response to stress. Herein, a wheat ADF gene, TaADF4, was identified and characterized. TaADF4 encodes a 139-amino-acid protein containing five F-actin-binding sites and two G-actin-binding sites, and interacts with wheat (Triticum aestivum) Actin1 (TaACT1), in planta. Following treatment of wheat, separately, with jasmonic acid, abscisic acid or with the avirulent race, CYR23, of the stripe rust pathogen Puccinia striiformis f. sp. tritici, we observed a rapid induction in accumulation of TaADF4 mRNA. Interestingly, accumulation of TaADF4 mRNA was diminished in response to inoculation with a virulent race, CYR31. Silencing of TaADF4 resulted in enhanced susceptibility to CYR23, demonstrating a role for TaADF4 in defense signaling. Using a pharmacological-based approach, coupled with an analysis of host response to pathogen infection, we observed that treatment of plants with the actin-modifying agent latrunculin B enhanced resistance to CYR23, including increased production of reactive oxygen species and enhancement of localized hypersensitive cell death. Taken together, these data support the hypothesis that TaADF4 positively modulates plant immunity in wheat via the modulation of actin cytoskeletal organization.

OSCILLATING FILAMENTS. I. OSCILLATION AND GEOMETRICAL FRAGMENTATION

ABSTRACT We study the stability of filaments in equilibrium between gravity and internal as well as external pressure using the grid-based AMR code RAMSES. A homogeneous, straight cylinder below a critical line mass is marginally stable. However, if the cylinder is bent, such as with a slight sinusoidal perturbation, an otherwise stable configuration starts to oscillate, is triggered into fragmentation, and collapses. This previously unstudied behavior allows a filament to fragment at any given scale, as long as it has slight bends. We call this process “geometrical fragmentation.” In our realization, the spacing between the cores matches the wavelength of the sinusoidal perturbation, whereas up to now, filaments were thought to be only fragmenting on the characteristic scale set by the mass-to-line ratio. Using first principles, we derive the oscillation period as well as the collapse timescale analytically. To enable a direct comparison with observations, we study the line-of-sight velocity for different inclinations. We show that the overall oscillation pattern can hide the infall signature of cores.

A comparative study of the filamentation and two-stream instabilities in weakly relativistic counter-streaming plasmas

Counter-streaming plasma structures are ubiquitous in astrophysical sources of non-thermal radiations. We discuss the dispersion properties and the stability of this non-thermal particle distribution, which is modeled on the basis of the relativistic Jüttner-Maxwell distribution function in the correct laboratory frame of reference. In this work, we aim to construct analytical solutions of the dispersion relations and investigate the properties of the growth rate of the filamentation and two-stream instabilities in an unmagnetized and homogeneous counter-propagating plasma. The Maxwell and the relativistic Vlasov equations are used to derive the covariant dispersion relations that are valid in any (conveniently chosen) reference frame. Aperiodic solutions (ℜ(ω)≃0) to the covariant dispersion relations of the growing modes (ℑ(ω)>0) are demonstrated with the aid of analytical calculations. The dependence of the growth rate on the normalized bulk velocity β0=V0/c and thermal parameter μ=mc2/KBT is shown in graphic illustrations. We found that for both kinds of instabilities, growth rates are decreased by increasing the temperature and decreasing the bulk velocity. Therefore, the electrons at sufficiently low temperatures and with relativistic streams are capable of increasing the range of unstable wave numbers and consequently prevent the instability to cease at small wave numbers. The results indicate that under the same condition and in contrast to the non-relativistic regime, the filamentation instability has the largest growth rate and the electrostatic two-stream instability is in the next place.

Coarse-grained molecular dynamics studies of the structure and stability of peptide-based drug amphiphile filaments.

Peptide-based supramolecular filaments, in particular filaments self-assembled by drug amphiphiles (DAs), possess great potential in the field of drug delivery. These filaments possess one hundred percent drug loading, with a release mechanism that can be tuned based on the dissociation of the supramolecular filaments and the degradation of the DAs [Cheetham et al., J. Am. Chem. Soc., 2013, 135(8), 2907]. Recently, much attention has been drawn to the competing intermolecular interactions that drive the self-assembly of peptide-based amphiphiles into supramolecular filaments. Recently, we reported on long-time atomistic molecular dynamics simulations to characterize the structure and growth of chiral filaments by the self-assembly of a DA containing the aromatic anti-cancer drug camptothecin [Kang et al., Macromolecules, 2016, 49(3), 994]. We found that the π-π stacking of the aromatic drug governs the early stages of the self-assembly process, while also contributing towards the chirality of the self-assembled filament. Based on these all-atomistic simulations, we now build a chemically accurate coarse-grained model that can capture the structure and stability of these supramolecular filaments at long time-scales (microseconds). These coarse-grained models successfully recapitulate the growth of the molecular clusters (and their elongation trends) compared with previously reported atomistic simulations. Furthermore, the interfacial structure and the helicity of the filaments are conserved. Next, we focus on characterization of the disassembly process of a 0.675 μm DA filament at microsecond time-scales. These results provide very useful tools for the rational design of functional supramolecular filaments, in particular supramolecular filaments for drug delivery applications.

Biochemical and Cellular Determinants of Renal Glomerular Elasticity.

The elastic properties of renal glomeruli and their capillaries permit them to maintain structural integrity in the presence of variable hemodynamic forces. Measured by micro-indentation, glomeruli have an elastic modulus (E, Young’s modulus) of 2.1 kPa, and estimates from glomerular perfusion studies suggest that the E of glomeruli is between 2 and 4 kPa. F-actin depolymerization by latrunculin, inhibition of acto-myosin contractility by blebbistatin, reduction in ATP synthesis, and reduction of the affinity of adhesion proteins by EDTA reduced the glomerular E to 1.26, 1.7, 1.5, and 1.43 kPa, respectively. Actin filament stabilization with jasplakinolide and increasing integrin affinity with Mg2+ increased E to 2.65 and 2.87 kPa, respectively. Alterations in glomerular E are reflected in commensurate changes in F/G actin ratios. Disruption of vimentin intermediate filaments by withaferin A reduced E to 0.92 kPa. The E of decellularized glomeruli was 0.74 kPa, indicating that cellular components of glomeruli have dominant effects on their elasticity. The E of glomerular basement membranes measured by magnetic bead displacement was 2.4 kPa. Podocytes and mesangial cells grown on substrates with E values between 3 and 5 kPa had actin fibers and focal adhesions resembling those of podocytes in vivo. Renal ischemia and ischemia-reperfusion reduced the E of glomeruli to 1.58 kPa. These results show that the E of glomeruli is between 2 and 4 kPa. E of the GBM, 2.4 kPa, is consistent with this value, and is supported by the behavior of podocytes and mesangial cells grown on variable stiffness matrices. The podocyte cytoskeleton contributes the major component to the overall E of glomeruli, and a normal E requires ATP synthesis. The reduction in glomerular E following ischemia and in other diseases indicates that reduced glomerular E is a common feature of many forms of glomerular injury and indicative of an abnormal podocyte cytoskeleton.

Actin activates Pseudomonas aeruginosa ExoY nucleotidyl cyclase toxin and ExoY-like effector domains from MARTX toxins.

The nucleotidyl cyclase toxin ExoY is one of the virulence factors injected by the Pseudomonas aeruginosa type III secretion system into host cells. Inside cells, it is activated by an unknown eukaryotic cofactor to synthesize various cyclic nucleotide monophosphates. ExoY-like adenylate cyclases are also found in Multifunctional-Autoprocessing Repeats-in-ToXin (MARTX) toxins produced by various Gram-negative pathogens. Here we demonstrate that filamentous actin (F-actin) is the hitherto unknown cofactor of ExoY. Association with F-actin stimulates ExoY activity more than 10,000 fold in vitro and results in stabilization of actin filaments. ExoY is recruited to actin filaments in transfected cells and alters F-actin turnover. Actin also activates an ExoY-like adenylate cyclase MARTX effector domain from Vibrio nigripulchritudo. Finally, using a yeast genetic screen, we identify actin mutants that no longer activate ExoY. Our results thus reveal a new sub-group within the class II adenylyl cyclase family, namely actin-activated nucleotidyl cyclase (AA-NC) toxins.

The stability of 1-D soliton in transverse direction

The complete characterization of the exact 1-D solitary wave solutions (both stationary and propagating) for light plasma coupled system have been studied extensively in the parameter space of light frequency and the group speed [Poornakala et al., Phys. Plasmas 9(5), 1820 (2002)]. It has been shown in 1-D that solutions with single light wave peak and paired structures are stable and hence long lived. However, solutions having multiple peaks of light wave are unstable due to Raman scattering instability [Saxena et al., Phys. Plasmas 14, 072307 (2007)]. Here, we have shown with the help of 2-D fluid simulation that single peak and paired solutions too get destabilized by the transverse filamentation instability. The numerical growth rates obtained from simulations is seen to compare well with the analytical values. It is also shown that multiple peaks solitons first undergo the regular 1-D forward Raman scattering instability. Subsequently, they undergo a distinct second phase of destabilization through t...

Interplay of multiple synaptic plasticity features in filamentary memristive devices for neuromorphic computing.

Bio-inspired computing represents today a major challenge at different levels ranging from material science for the design of innovative devices and circuits to computer science for the understanding of the key features required for processing of natural data. In this paper, we propose a detail analysis of resistive switching dynamics in electrochemical metallization cells for synaptic plasticity implementation. We show how filament stability associated to joule effect during switching can be used to emulate key synaptic features such as short term to long term plasticity transition and spike timing dependent plasticity. Furthermore, an interplay between these different synaptic features is demonstrated for object motion detection in a spike-based neuromorphic circuit. System level simulation presents robust learning and promising synaptic operation paving the way to complex bio-inspired computing systems composed of innovative memory devices.

Nonlinear evolution of the filamentation instability and chaos in laser–plasma interaction

AbstractFilamentation is one of the most common nonlinear phenomena taking place in the laser–plasma interaction that splits the laser beam into high-intensity spikes. The present study deals with the nonlinear evolution of filamentation instability in laser–plasma interaction and the development of chaos in contrast to linear growth as reported by Kaw et al. in 1973. We have considered a non-uniform perturbation superimposed on plane-wave pump such that due to non-uniformity of the perturbation a finite intensity gradient arises and gives rise to ponderomotive force. This causes filamentation of wave, which has been studied presently using numerical methods as well as analytical tools. The results reveal that the intensity of perturbation gets localized and delocalized with the distance of propagation. The numerical simulation results also reveal that the intensity of perturbation route from ordered to chaotic behavior depending upon the pump laser and perturbation parameters. To study the chaotic behavior, Lyapunov exponents has also been calculated. The semi-analytical method is also developed to have an insight into some of the features of simulation like the formation of localized structures.

Monoallelic Mutations in the Translation Initiation Codon of KLHL24 Cause Skin Fragility

The genetic basis of epidermolysis bullosa, a group of genetic disorders characterized by the mechanically induced formation of skin blisters, is largely known, but a number of cases still remain genetically unsolved. Here, we used whole-exome and targeted sequencing to identify monoallelic mutations, c.1A>G and c.2T>C, in the translation initiation codon of the gene encoding kelch-like protein 24 (KLHL24) in 14 individuals with a distinct skin-fragility phenotype and skin cleavage within basal keratinocytes. Remarkably, mutation c.1A>G occurred de novo and was recurrent in families originating from different countries. The striking similarities of the clinical features of the affected individuals point to a unique and very specific pathomechanism. We showed that mutations in the translation initiation codon of KLHL24 lead to the usage of a downstream translation initiation site with the same reading frame and formation of a truncated polypeptide. The pathobiology was examined in keratinocytes and fibroblasts of the affected individuals and via expression of mutant KLHL24, and we found mutant KLHL24 to be associated with abnormalities of intermediate filaments in keratinocytes and fibroblasts. In particular, KLHL24 mutations were associated with irregular and fragmented keratin 14. Recombinant overexpression of normal KLHL24 promoted keratin 14 degradation, whereas mutant KLHL24 showed less activity than the normal molecule. Thesefindings identify KLHL24 mutations as a cause of skin fragility and identify a role for KLHL24 in maintaining the balance between intermediate filament stability and degradation required for skin integrity.

Role of non-motile microtubule-associated proteins in virus trafficking.

Viruses are entirely dependent on their ability to infect a host cell in order to replicate. To reach their site of replication as rapidly and efficiently as possible following cell entry, many have evolved elaborate mechanisms to hijack the cellular transport machinery to propel themselves across the cytoplasm. Long-range movements have been shown to involve motor proteins along microtubules (MTs) and direct interactions between viral proteins and dynein and/or kinesin motors have been well described. Although less well-characterized, it is also becoming increasingly clear that non-motile microtubule-associated proteins (MAPs), including structural MAPs of the MAP1 and MAP2 families, and microtubule plus-end tracking proteins (+TIPs), can also promote viral trafficking in infected cells, by mediating interaction of viruses with filaments and/or motor proteins, and modulating filament stability. Here we review our current knowledge on non-motile MAPs, their role in the regulation of cytoskeletal dynamics and in viral trafficking during the early steps of infection.

A Polar and Nucleotide-Dependent Mechanism of Action for RAD51 Paralogs in RAD51 Filament Remodeling

SummaryCentral to homologous recombination in eukaryotes is the RAD51 recombinase, which forms helical nucleoprotein filaments on single-stranded DNA (ssDNA) and catalyzes strand invasion with homologous duplex DNA. Various regulatory proteins assist this reaction including the RAD51 paralogs. We recently discovered that a RAD51 paralog complex from C. elegans, RFS-1/RIP-1, functions predominantly downstream of filament assembly by binding and remodeling RAD-51-ssDNA filaments to a conformation more proficient for strand exchange. Here, we demonstrate that RFS-1/RIP-1 acts by shutting down RAD-51 dissociation from ssDNA. Using stopped-flow experiments, we show that RFS-1/RIP-1 confers this dramatic stabilization by capping the 5′ end of RAD-51-ssDNA filaments. Filament end capping propagates a stabilizing effect with a 5′→3′ polarity approximately 40 nucleotides along individual filaments. Finally, we discover that filament capping and stabilization are dependent on nucleotide binding, but not hydrolysis by RFS-1/RIP-1. These data define the mechanism of RAD51 filament remodeling by RAD51 paralogs.

Tuning the switching behavior of conductive-bridge resistive memory by the modulation of the cation-supplier alloys

Conductive bridge random access memory (CBRAM) represents a promising technology under consideration for future non-volatile memory. These devices rely on a reversible formation and dissolution of metallic filaments inside a dielectric that is sandwiched between two electrodes. The metal cations needed for the formation of the filament, are generally provided by one of the two electrodes whose chemical composition can affect the properties of the switching behavior. The impact of various layers acting as cations-supplier is investigated at the nanoscale by means of atomic force microscopy (AFM) in terms of filament's formation and stability for three different Cu-based electrodes. Three samples are investigated: pure Cu, C-doped Cu0.6Te0.4 and Cu2GeTe3. We show different effects on the conductive filaments when the Cu chemical composition approaches the 40at.% in the material. In particular, the observed switching behavior ranges from non-volatile to volatile by reducing the fraction of Cu inside the cation supplier electrode. A simple method based on AFM is demonstrated for the comparison of the filament stability across different samples. The latter can be applicable for the rapid assessment of the non-volatility of a given material system. We observe the appearance of unstable filaments using Cu2GeTe3 that represents the material containing the lowest Cu fraction among those screened. Finally, the AFM-based analysis is linked to the electrical behavior of CBRAM stacks showing volatile or a non-volatile operations depending on the selection of the cations-supplier electrode. Our results indicate that the selection of such electrodes can lead to the direct tuning of the electrical properties of the generated filaments and thus to the overall resistive switching (RS) operation.

Modulation and filamentation instability of ultrarelativistic electromagnetic waves in electron-positron-ion plasma

In this study, we have analytically investigated the effects of nonlinear Landau damping on the temporal growth rate of modulation and filamentation instabilities. Here, the nonlocal nonlinear Landau damping phenomena is appearing due to the nonlinear interaction between ultrarelativistic electromagnetic (UREM) wave (having wave vector normal to the beam) and electron-positron-ion plasma. We found that the ultrarelativistic ponderomotive force is linear, while usually it is nonlinear in relativistic case. We construct three dimensional kinetic nonlinear Schrödinger equation for a slowly varying spatio and temporal amplitude of UREM waves. The equations are then Fourier analyzed to obtain dispersion relation, which admit both modulation and filamentation instabilities. It is shown that nonlinear Landau damping is the main source of modulation instability, for a particular condition taking into account later one the maximum growth rate of modulation instability obtained as a function of amplitude of UREM waves and is displayed graphically. Further, it is shown that for an oscillating density profile, plane wave of uniform intensity becomes unstable and gets filamented. Growth rate of stationary state filament is found to be a function of amplitude of UREM waves and is emphasized that the maximum value of growth rate of filamentation instability is further increased in the presence of nonlinear Landau damping term. Finally, the growth rate of non stationary state filamentation instability is calculated and is shown that the characteristic growth length increases both with perpendicular wave vector and the amplitude of UREM waves.

SWAP70 Organizes the Actin Cytoskeleton and Is Essential for Phagocytosis

SummaryActin plays a critical role during the early stages of pathogenic microbe internalization by immune cells. In this study, we identified a key mechanism of actin filament tethering and stabilization to the surface of phagosomes in human dendritic cells. We found that the actin-binding protein SWAP70 is specifically recruited to nascent phagosomes by binding to the lipid phosphatidylinositol (3,4)-bisphosphate. Multi-color super-resolution stimulated emission depletion (STED) microscopy revealed that the actin cage surrounding early phagosomes is formed by multiple concentric rings containing SWAP70. SWAP70 colocalized with and stimulated activation of RAC1, a known activator of actin polymerization, on phagosomes. Genetic ablation of SWAP70 impaired actin polymerization around phagosomes and resulted in a phagocytic defect. These data show a key role for SWAP70 as a scaffold for tethering the peripheral actin cage to phagosomes.