Shape Changes of Self-Assembled Actin Bilayer Composite Membranes

We report the self-assembly of thin actin shells beneath the membranes of giant vesicles. Ion-carrier mediated influx of Mg2+ induces actin polymerization in the initially spherical vesicles. Buckling of the vesicles and the formation of blisters after thermally induced bilayer expansion is demonstrated. Bilayer flickering is dominated by tension generated by its coupling to the actin cortex. Quantitative flicker analysis suggests the bilayer and the actin cortex are separated by 0.4 \mum to 0.5 \mum due to undulation forces.Comment: pdf-file, has been accepted by PR

Structure formation in active networks

Structure formation and constant reorganization of the actin cytoskeleton are key requirements for the function of living cells. Here we show that a minimal reconstituted system consisting of actin filaments, crosslinking molecules and molecular-motor filaments exhibits a generic mechanism of structure formation, characterized by a broad distribution of cluster sizes. We demonstrate that the growth of the structures depends on the intricate balance between crosslinker-induced stabilization and simultaneous destabilization by molecular motors, a mechanism analogous to nucleation and growth in passive systems. We also show that the intricate interplay between force generation, coarsening and connectivity is responsible for the highly dynamic process of structure formation in this heterogeneous active gel, and that these competing mechanisms result in anomalous transport, reminiscent of intracellular dynamics

Solar Particle Acceleration at Reconnecting 3D Null Points

Context: The strong electric fields associated with magnetic reconnection in solar flares are a plausible mechanism to accelerate populations of high energy, non-thermal particles. One such reconnection scenario occurs at a 3D magnetic null point, where global plasma flows give rise to strong currents in the spine axis or fan plane. Aims: To understand the mechanism of charged particle energy gain in both the external drift region and the diffusion region associated with 3D magnetic reconnection. In doing so we evaluate the efficiency of resistive spine and fan models for particle acceleration, and find possible observables for each. Method: We use a full orbit test particle approach to study proton trajectories within electromagnetic fields that are exact solutions to the steady and incompressible magnetohydrodynamic equations. We study single particle trajectories and find energy spectra from many particle simulations. The scaling properties of the accelerated particles with respect to field and plasma parameters is investigated. Results: For fan reconnection, strong non-uniform electric drift streamlines can accelerate the bulk of the test particles. The highest energy gain is for particles that enter the current sheet, where an increasing "guide field" stabilises particles against ejection. The energy is only limited by the total electric potential energy difference across the fan current sheet. The spine model has both slow external electric drift speed and weak energy gain for particles reaching the current sheet. Conclusions: The electromagnetic fields of fan reconnection can accelerate protons to the high energies observed in solar flares, gaining up to 0.1 GeV for anomalous values of resistivity. However, the spine model, which gave a harder energy spectrum in the ideal case, is not an efficient accelerator after pressure constraints in the resistive model are included.Comment: 15 pages, 14 figures. Submitted to Astronomy and Astrophysic

Mathematical and Statistical Techniques for Systems Medicine: The Wnt Signaling Pathway as a Case Study

The last decade has seen an explosion in models that describe phenomena in systems medicine. Such models are especially useful for studying signaling pathways, such as the Wnt pathway. In this chapter we use the Wnt pathway to showcase current mathematical and statistical techniques that enable modelers to gain insight into (models of) gene regulation, and generate testable predictions. We introduce a range of modeling frameworks, but focus on ordinary differential equation (ODE) models since they remain the most widely used approach in systems biology and medicine and continue to offer great potential. We present methods for the analysis of a single model, comprising applications of standard dynamical systems approaches such as nondimensionalization, steady state, asymptotic and sensitivity analysis, and more recent statistical and algebraic approaches to compare models with data. We present parameter estimation and model comparison techniques, focusing on Bayesian analysis and coplanarity via algebraic geometry. Our intention is that this (non exhaustive) review may serve as a useful starting point for the analysis of models in systems medicine.Comment: Submitted to 'Systems Medicine' as a book chapte

In vitro characterisation of solid drug nanoparticle compositions of efavirenz in a brain endothelium cell line

The antiretroviral drug efavirenz displays many desirable pharmacokinetic properties such as a long half‐life enabling once daily dosing but suffers from central nervous system safety issues. Various nanotechnologies have been explored to mitigate some of the limitations with efavirenz. While there has been progress in increasing the bioavailability, there has been no attempt to assess the impact of increased exposure to efavirenz on central nervous system safety. The uptake of aqueous and solid drug nanoparticle (SDN) formulations of efavirenz was assessed in the human cerebral microvessel endothelial cells/D3 brain endothelial cell line. The mechanisms of uptake were probed using a panel of transport and endocytosis inhibitors. The cellular accumulation of an efavirenz aqueous solution was significantly reduced by amantadine, but this was not observed with SDNs. The uptake of efavirenz SDNs was reduced by dynasore, but concentrations of the efavirenz aqueous solution were not affected. These data indicate that efavirenz is a substrate for transporters in brain endothelial cells (amantadine is an inhibitor of organic cation transporters 1 and 2), and formation of SDNs may bypass this interaction in favour of a mechanism involving dynamin‐mediated endocytosis

Threat-sensitive anti-predator defence in precocial wader, the northern lapwing Vanellus vanellus

Birds exhibit various forms of anti-predator behaviours to avoid reproductive failure, with mobbing—observation, approach and usually harassment of a predator—being one of the most commonly observed. Here, we investigate patterns of temporal variation in the mobbing response exhibited by a precocial species, the northern lapwing (Vanellus vanellus). We test whether brood age and self-reliance, or the perceived risk posed by various predators, affect mobbing response of lapwings. We quantified aggressive interactions between lapwings and their natural avian predators and used generalized additive models to test how timing and predator species identity are related to the mobbing response of lapwings. Lapwings diversified mobbing response within the breeding season and depending on predator species. Raven Corvus corax, hooded crow Corvus cornix and harriers evoked the strongest response, while common buzzard Buteo buteo, white stork Ciconia ciconia, black-headed gull Chroicocephalus ridibundus and rook Corvus frugilegus were less frequently attacked. Lapwings increased their mobbing response against raven, common buzzard, white stork and rook throughout the breeding season, while defence against hooded crow, harriers and black-headed gull did not exhibit clear temporal patterns. Mobbing behaviour of lapwings apparently constitutes a flexible anti-predator strategy. The anti-predator response depends on predator species, which may suggest that lapwings distinguish between predator types and match mobbing response to the perceived hazard at different stages of the breeding cycle. We conclude that a single species may exhibit various patterns of temporal variation in anti-predator defence, which may correspond with various hypotheses derived from parental investment theory

Collective dynamics of active cytoskeletal networks

Self organization mechanisms are essential for the cytoskeleton to adapt to the requirements of living cells. They rely on the intricate interplay of cytoskeletal filaments, crosslinking proteins and molecular motors. Here we present an in vitro minimal model system consisting of actin filaments, fascin and myosin-II filaments exhibiting pulsative collective long range dynamics. The reorganizations in the highly dynamic steady state of the active gel are characterized by alternating periods of runs and stalls resulting in a superdiffusive dynamics of the network's constituents. They are dominated by the complex competition of crosslinking molecules and motor filaments in the network: Collective dynamics are only observed if the relative strength of the binding of myosin-II filaments to the actin network allows exerting high enough forces to unbind actin/fascin crosslinks. The feedback between structure formation and dynamics can be resolved by combining these experiments with phenomenological simulations based on simple interaction rules

The proline-rich domain of tau plays a role in interactions with actin

<p>Abstract</p> <p>Background</p> <p>The microtubule-associated protein tau is able to interact with actin and serves as a cross-linker between the microtubule and actin networks. The microtubule-binding domain of tau is known to be involved in its interaction with actin. Here, we address the question of whether the other domains of tau also interact with actin.</p> <p>Results</p> <p>Several tau truncation and deletion mutants were constructed, namely N-terminal region (tauN), proline-rich domain (tauPRD), microtubule binding domain (tauMTBD) and C-terminal region (tauC) truncation mutants, and microtubule binding domain (tauΔMTBD) and proline-rich domain/microtubule binding domain (tauΔPRD&MTBD) deletion mutants. The proline-rich domain truncation mutant (tauPRD) and the microtubule binding domain deletion mutant (tauΔMTBD) promoted the formation of actin filaments. However, actin assembly was not observed in the presence of the N-terminal and C-terminal truncation mutants. These results indicate that the proline-rich domain is involved in the association of tau with G-actin. Furthermore, results from co-sedimentation, solid phase assays and electron microscopy showed that the proline-rich domain is also capable of binding to F-actin and inducing F-actin bundles. Using solid phase assays to analyze apparent dissociation constants for the binding of tau and its mutants to F-actin resulted in a sequence of affinity for F-actin: tau >> microtubule binding domain > proline-rich domain. Moreover, we observed that the proline-rich domain was able to associate with and bundle F-actin at physiological ionic strength.</p> <p>Conclusion</p> <p>The proline-rich domain is a functional structure playing a role in the association of tau with actin. This suggests that the proline-rich domain and the microtubule-binding domain of tau are both involved in binding to and bundling F-actin.</p

Force-Velocity Measurements of a Few Growing Actin Filaments

The authors propose a new mechanism for actin-based force generation based on results using chains of actin-grafted magnetic colloids

Falls and falls efficacy: the role of sustained attention in older adults

<p>Abstract</p> <p>Background</p> <p>Previous evidence indicates that older people allocate more of their attentional resources toward their gait and that the attention-related changes that occur during aging increase the risk of falls. The aim of this study was to investigate whether performance and variability in sustained attention is associated with falls and falls efficacy in older adults.</p> <p>Methods</p> <p>458 community-dwelling adults aged ≥ 60 years underwent a comprehensive geriatric assessment. Mean and variability of reaction time (RT), commission errors and omission errors were recorded during a fixed version of the Sustained Attention to Response Task (SART). RT variability was decomposed using the Fast Fourier Transform (FFT) procedure, to help characterise variability associated with the arousal and vigilance aspects of sustained attention.</p> <p>The number of self-reported falls in the previous twelve months, and falls efficacy (Modified Falls Efficacy Scale) were also recorded.</p> <p>Results</p> <p>Significant increases in the mean and variability of reaction time on the SART were significantly associated with both falls (p < 0.01) and reduced falls efficacy (p < 0.05) in older adults. An increase in omission errors was also associated with falls (p < 0.01) and reduced falls efficacy (p < 0.05). Upon controlling for age and gender affects, logistic regression modelling revealed that increasing variability associated with the vigilance (top-down) aspect of sustained attention was a retrospective predictor of falling (p < 0.01, OR = 1.14, 95% CI: 1.03 - 1.26) in the previous year and was weakly correlated with reduced falls efficacy in non-fallers (p = 0.07).</p> <p>Conclusions</p> <p>Greater variability in sustained attention is strongly correlated with retrospective falls and to a lesser degree with reduced falls efficacy. This cognitive measure may provide a novel and valuable biomarker for falls in older adults, potentially allowing for early detection and the implementation of preventative intervention strategies.</p