Mitotic rounding alters cell geometry to ensure efficient bipolar spindle formation.

Accurate animal cell division requires precise coordination of changes in the structure of the microtubule-based spindle and the actin-based cell cortex. Here, we use a series of perturbation experiments to dissect the relative roles of actin, cortical mechanics, and cell shape in spindle formation. We find that, whereas the actin cortex is largely dispensable for rounding and timely mitotic progression in isolated cells, it is needed to drive rounding to enable unperturbed spindle morphogenesis under conditions of confinement. Using different methods to limit mitotic cell height, we show that a failure to round up causes defects in spindle assembly, pole splitting, and a delay in mitotic progression. These defects can be rescued by increasing microtubule lengths and therefore appear to be a direct consequence of the limited reach of mitotic centrosome-nucleated microtubules. These findings help to explain why most animal cells round up as they enter mitosis.

Stress, mental health, and burnout in national humanitarian aid workers in Gulu, northern Uganda.

This study examined the mental health of national humanitarian aid workers in northern Uganda and contextual and organizational factors predicting well-being. A cross-sectional survey was conducted among 376 national staff working for 21 humanitarian aid agencies. Over 50% of workers experienced 5 or more categories of traumatic events. Although, in the absence of clinical interviews, no clinical diagnoses were able to be confirmed, 68%, 53%, and 26% of respondents reported symptom levels associated with high risk for depression, anxiety disorders, and posttraumatic stress disorder (PTSD), respectively. Between one quarter and one half of respondents reported symptom levels associated with high risk regarding measured dimensions of burnout. Female workers reported significantly more symptoms of anxiety, depression, PTSD, and emotional exhaustion than males. Workers with the United Nations and related agencies reported fewest symptoms. Higher levels of social support, stronger team cohesion, and reduced exposure to chronic stressors were associated with improved mental health. National humanitarian staff members in Gulu have high exposure to chronic and traumatic stress and high risk of a range of poor mental health outcomes. Given that work-related factors appear to influence the relationship between the two strategies are suggested to support the well-being of national staff working in such contexts.

Live-cell delamination counterbalances epithelial growth to limit tissue overcrowding.

The development and maintenance of an epithelium requires finely balanced rates of growth and cell death. However, the mechanical and biochemical mechanisms that ensure proper feedback control of tissue growth, which when deregulated contribute to tumorigenesis, are poorly understood. Here we use the fly notum as a model system to identify a novel process of crowding-induced cell delamination that balances growth to ensure the development of well-ordered cell packing. In crowded regions of the tissue, a proportion of cells undergo a serial loss of cell-cell junctions and a progressive loss of apical area, before being squeezed out by their neighbours. This path of delamination is recapitulated by a simple computational model of epithelial mechanics, in which stochastic cell loss relieves overcrowding as the system tends towards equilibrium. We show that this process of delamination is mechanistically distinct from apoptosis-mediated cell extrusion and precedes the first signs of cell death. Overall, this analysis reveals a simple mechanism that buffers epithelia against variations in growth. Because live-cell delamination constitutes a mechanistic link between epithelial hyperplasia and cell invasion, this is likely to have important implications for our understanding of the early stages of cancer development.

Active process mediates species-specific tuning of Drosophila ears.

The courtship behavior of Drosophilid flies has served as a long-standing model for studying the bases of animal communication. During courtship, male flies flap their wings to send a complex pattern of airborne vibrations to the antennal ears of the females. These "courtship songs" differ in their spectrotemporal composition across species and are considered a crucial component of the flies' premating barrier. However, whether the species-specific differences in song structure are also reflected in the receivers of this communication system, i.e., the flies' antennal ears, has remained unexplored. Here we show for seven members of the melanogaster species group that (1) their ears are mechanically tuned to different best frequencies, (2) the ears' best frequencies correlate with high-frequency pulses of the conspecific courtship songs, and (3) the species-specific tuning relies on amplificatory mechanical feedback from the flies' auditory neurons. As a result of its level-dependent nature, the active mechanical feedback amplification is particularly useful for the detection of small stimuli, such as conspecific song pulses, and becomes negligible for sensing larger stimuli, such as the flies' own wingbeat during flight.

Effect of network topology on neuronal encoding based on spatiotemporal patterns of spikes.

Despite significant progress in our understanding of the brain at both microscopic and macroscopic scales, the mechanisms by which low-level neuronal behavior gives rise to high-level mental processes such as memory still remain unknown. In this paper, we assess the plausibility and quantify the performance of polychronization, a newly proposed mechanism of neuronal encoding, which has been suggested to underlie a wide range of cognitive phenomena. We then investigate the effect of network topology on the reliability with which input stimuli can be distinguished based on their encoding in the form of so-called polychronous groups or spatiotemporal patterns of spikes. We find that small-world networks perform an order of magnitude better than random ones, enabling reliable discrimination between inputs even when prompted by increasingly incomplete recall cues. Furthermore, we show that small-world architectures operate at significantly reduced energetic costs and that their memory capacity scales favorably with network size. Finally, we find that small-world topologies introduce biologically realistic constraints on the optimal input stimuli, favoring especially the topographic inputs known to exist in many cortical areas. Our results suggest that mammalian cortical networks, by virtue of being both small-world and topographically organized, seem particularly well-suited to information processing through polychronization. This article addresses the fundamental question of encoding in neuroscience. In particular, evidence is presented in support of an emerging model of neuronal encoding in the neocortex based on spatiotemporal patterns of spikes.

Simulation of cell motility that reproduces the force-velocity relationship.

Many cells crawl by extending an actin-rich pseudopod. We have devised a simulation that describes how the polymerization kinetics of a branched actin filament network, coupled with excluded volume effects, powers the motility of crawling cells such as amoebae and fish keratocytes. Our stochastic simulation is based on the key fundamental properties of actin polymerization, namely growth, shrinkage, capping, branching, and nucleation, and also includes contributions from the creation and breaking of adhesive contacts with the substrate together with excluded volume effects related to filament packing. When reasonable values for appropriate constants were employed, this simulation generated a force-velocity relationship that resembled closely that observed experimentally. Our simulations indicated that excluded volume effects associated with actin filament branching lead to a decreased packing efficiency and resultant swelling of the cytoskeleton gel that contributes substantially to lamellipod protrusion.

Controlled assembly for well-defined 3D bioarchitecture using two active enzymes.

This paper reports that a bioarchitecture with two different active enzymes can be fabricated conveniently on a prepatterned surface by highly selective surface-templated layer-by-layer (LBL) assembly by coupling a bilayer of avidin/biotin-lactate oxidase (biotin-LOD) with a bilayer of avidin/biotin-horseradish peroxidase (biotin-HRP). The two different active enzymes can be utilized as excellent building blocks for the fabrication of well-defined 3D nanostructures with precise control of the position and height on the surface. In addition, the LBL assembled bienzyme structures are highly functional, and bioarchitectures based on LOD and HRP-mediated coupling reaction can be employed in a number of viable biosensing applications.

Equilibrium mechanisms of receptor clustering.

Receptor clustering is a well-established feature of transmembrane signalling. In some cellular systems, clusters form dynamically in response to activation by an extracellular ligand; in others, extensive 2-dimensional arrays of receptors persist for long periods of time on the cell surface. Compelling evidence has accumulated that the interactions between receptors within a cluster play an important role in the signalling process. Here, we review statistical mechanical models that describe how clusters may be generated and maintained by the equilibrium thermodynamic interactions between receptors, the extracellular ligands that bind to their periplasmic domains, and cytosolic 'adaptor proteins' that bind to the cytoplasmic domains of the receptors. We discuss how adaptor proteins might permit cells to exert control over the propensity of cluster formation, and to target clusters to specific locations on the cell surface. We further outline how differential interactions between active and inactive receptors can enhance the sensitivity of the cellular response through the mechanism of 'conformational spread'.

Frequency clustering in spontaneous otoacoustic emissions from a lizard's ear.

Spontaneous otoacoustic emissions (SOAEs) are indicators of an active process in the inner ear that enhances the sensitivity and frequency selectivity of hearing. They are particularly regular and robust in certain lizards, so these animals are good model organisms for studying how SOAEs are generated. We show that the published properties of SOAEs in the bobtail lizard are wholly consistent with a mathematical model in which active oscillators, with exponentially varying characteristic frequencies, are coupled together in a chain by visco-elastic elements. Physically, each oscillator corresponds to a small group of hair cells, covered by a tectorial sallet, so our theoretical analysis directly links SOAEs to the micromechanics of active hair bundles.

Adaptive reconfiguration of fractal small-world human brain functional networks.

Brain function depends on adaptive self-organization of large-scale neural assemblies, but little is known about quantitative network parameters governing these processes in humans. Here, we describe the topology and synchronizability of frequency-specific brain functional networks using wavelet decomposition of magnetoencephalographic time series, followed by construction and analysis of undirected graphs. Magnetoencephalographic data were acquired from 22 subjects, half of whom performed a finger-tapping task, whereas the other half were studied at rest. We found that brain functional networks were characterized by small-world properties at all six wavelet scales considered, corresponding approximately to classical delta (low and high), , alpha, beta, and gamma frequency bands. Global topological parameters (path length, clustering) were conserved across scales, most consistently in the frequency range 2-37 Hz, implying a scale-invariant or fractal small-world organization. Dynamical analysis showed that networks were located close to the threshold of order/disorder transition in all frequency bands. The highest-frequency gamma network had greater synchronizability, greater clustering of connections, and shorter path length than networks in the scaling regime of (lower) frequencies. Behavioral state did not strongly influence global topology or synchronizability; however, motor task performance was associated with emergence of long-range connections in both beta and gamma networks. Long-range connectivity, e.g., between frontal and parietal cortex, at high frequencies during a motor task may facilitate sensorimotor binding. Human brain functional networks demonstrate a fractal small-world architecture that supports critical dynamics and task-related spatial reconfiguration while preserving global topological parameters.

Balls and chains--a mesoscopic approach to tethered protein domains.

Many proteins contain regions of unstructured polypeptide chain that appear to be flexible and to undergo random thermal motion. In some cases the unfolded sequence acts as a flexible tether that restricts the diffusion of a globular protein domain for the purpose of catalysis or self-assembly. In this article, we present a stochastic model for tethered protein domains under various conditions and solve it numerically to deduce the general and dynamic properties of these systems. A critical domain size dependent on the length of the tether is presented, above which a spherical domain tethered to an impenetrable wall by a flexible chain displays a restricted localization between two concentric half-shells. Results suggest that the diffusion of such a spherical domain is effectively reduced in its dimensionality and able to explore the available space with high efficiency. It also becomes clear that the orientation of the ball is not independent of the distance from the tethering point but becomes more constrained as the linking tether is extended. The possible biological significance of these and other results is discussed.

The logical repertoire of ligand-binding proteins.

Proteins whose conformation can be altered by the equilibrium binding of a regulatory ligand are one of the main building blocks of signal-processing networks in cells. Typically, such proteins switch between an 'inactive' and an 'active' state, as the concentration of the regulator varies. We investigate the properties of proteins that can bind two different ligands and show that these proteins can individually act as logical elements: their 'output', quantified by their average level of activity, depends on the two 'inputs', the concentrations of both regulators. In the case where the two ligands can bind simultaneously, we show that all of the elementary logical functions can be implemented by appropriate tuning of the ligand-binding energies. If the ligands bind exclusively, the logical repertoire is more limited. When such proteins cluster together, cooperative interactions can greatly enhance the sharpness of the response. Protein clusters can therefore act as digital logical elements whose activity can be abruptly switched from fully inactive to fully active, as the concentrations of the regulators pass threshold values. We discuss a particular instance in which this type of protein logic appears to be used in signal transduction-the chemotaxis receptors of E. coli.

Conformational spread: the propagation of allosteric states in large multiprotein complexes.

The phenomenon of allostery is conventionally described for small symmetrical oligomeric proteins such as hemoglobin. Here we review experimental evidence from a variety of systems-including bacterial chemotaxis receptors, muscle ryanodine receptors, and actin filaments-showing that conformational changes can also propagate through extended lattices of protein molecules. We explore the statistical mechanics of idealized linear and two-dimensional arrays of allosteric proteins and show that, as in the analogous Ising models, arrays of closely packed units can show large-scale integrated behavior. We also discuss proteins that undergo conformational changes driven by the hydrolysis of ATP and give examples in which these changes propagate through linear chains of molecules. We suggest that conformational spread could provide the basis of a solid-state "circuitry" in a living cell, able to integrate biochemical and biophysical events over hundreds of protein molecules.

Synchronization of active mechanical oscillators by an inertial load.

Motivated by the operation of myogenic (self-oscillatory) insect flight muscle, we study a model consisting of a large number of identical oscillatory contractile elements joined in a chain, whose end is attached to a damped mass-spring oscillator. When the inertial load is small, the serial coupling favors an antisynchronous state in which the extension of one oscillator is compensated by the contraction of another, in order to preserve the total length. However, a sufficiently massive load can synchronize the oscillators and can even induce oscillation in situations where isolated elements would be stable. The system has a complex phase diagram displaying quiescent, synchronous and antisynchronous phases, as well as an unusual asynchronous phase in which the total length of the chain oscillates at a different frequency from the individual active elements.

Instabilities in the transient response of muscle.

We investigate the isometric transient response of muscle using a quantitative stochastic model of the actomyosin cycle based on the swinging lever-arm hypothesis. We first consider a single pair of filaments, and show that when values of parameters such as the lever-arm displacement and the cross-bridge elasticity are chosen to provide effective energy transduction, the T(2) curve (the tension recovered immediately after a step displacement) displays a region of negative slope. If filament compliance and the discrete nature of the binding sites are taken into account, the negative slope is diminished, but not eliminated. This implies that there is an instability in the dynamics of individual half sarcomeres. However, when the symmetric nature of whole sarcomeres is taken into account, filament rearrangement becomes important during the transient: as tension is recovered, some half sarcomeres lengthen whereas others shorten. This leads to a flat T(2) curve, as observed experimentally. In addition, we investigate the isotonic transient response and show that for a range of parameter values the model displays damped oscillations, as recently observed in experiments on single muscle fibers. We conclude that it is essential to consider the collective dynamics of many sarcomeres, rather than the dynamics of a single pair of filaments, when interpreting the transient response of muscle.

Two adaptation processes in auditory hair cells together can provide an active amplifier.

The hair cells of the vertebrate inner ear convert mechanical stimuli to electrical signals. Two adaptation mechanisms are known to modify the ionic current flowing through the transduction channels of the hair bundles: a rapid process involves Ca(2+) ions binding to the channels; and a slower adaptation is associated with the movement of myosin motors. We present a mathematical model of the hair cell which demonstrates that the combination of these two mechanisms can produce "self-tuned critical oscillations", i.e., maintain the hair bundle at the threshold of an oscillatory instability. The characteristic frequency depends on the geometry of the bundle and on the Ca(2+) dynamics, but is independent of channel kinetics. Poised on the verge of vibrating, the hair bundle acts as an active amplifier. However, if the hair cell is sufficiently perturbed, other dynamical regimes can occur. These include slow relaxation oscillations which resemble the hair bundle motion observed in some experimental preparations.

Active traveling wave in the cochlea.

A sound stimulus entering the inner ear excites a deformation of the basilar membrane which travels along the cochlea towards the apex. It is well established that this wavelike disturbance is amplified by an active system. Recently, it has been proposed that the active system consists of a set of self-tuned critical oscillators which automatically operate at an oscillatory instability. Here, we show how the concepts of a traveling wave and of self-tuned critical oscillators can be combined to describe the nonlinear wave in the cochlea.

Electrodeless dielectrophoresis of single- and double-stranded DNA.

Dielectrophoretic trapping of molecules is typically carried out using metal electrodes to provide high field gradients. In this paper we demonstrate dielectrophoretic trapping using insulating constrictions at far lower frequencies than are feasible with metallic trapping structures because of water electrolysis. We demonstrate that electrodeless dielectrophoresis (EDEP) can be used for concentration and patterning of both single-strand and double-strand DNA. A possible mechanism for DNA polarization in ionic solution is discussed based on the frequency, viscosity, and field dependence of the observed trapping force.