Receptor binding profiles of avian influenza virus hemagglutinin subtypes on human cells as a predictor of pandemic potential

The host adaptation of influenza virus is partly dependent on the sialic acid (SA) isoform bound by the viral hemagglutinin (HA). Avian influenza viruses preferentially bind the α-2,3 SA and human influenza viruses the α-2,6 isoform. Each isoform is predominantly associated with different surface epithelial cell types of the human upper airway. Using recombinant HAs and human tracheal airway epithelial cells in vitro and ex vivo, we show that many avian HA subtypes do not adhere to this canonical view of SA specificity. The propensity of avian viruses to adapt to human receptors may thus be more widespread than previously supposed.

Thermodynamic derivation of the fluctuation theorem and Jarzynski equality

A thermodynamic expression for the analog of the canonical ensemble for nonequilibrium systems is described based on a purely information theoretical interpretation of entropy. It is shown that this nonequilibrium canonical distribution implies some important results from nonequilibrium thermodynamics, specifically, the fluctuation theorem and the Jarzynski equality. Those results are therefore expected to be more widely applicable, for example, to macroscopic systems.

A note on an integration by parts formula for the generators of uniform translations on configuration space

An integration by parts formula is derived for the first order differential operator corresponding to the action of translations on the space of locally finite simple configurations of infinitely many points on Rd. As reference measures, tempered grand canonical Gibbs measures are considered corresponding to a non-constant non-smooth intensity (one-body potential) and translation invariant potentials fulfilling the usual conditions. It is proven that such Gibbs measures fulfill the intuitive integration by parts formula if and only if the action of the translation is not broken for this particular measure. The latter is automatically fulfilled in the high temperature and low intensity regime.

Adeno-associated virus-8-Mediated intravenous transfer of myostatin propeptide leads to systemic functional improvements of slow but not fast muscle

Myostatin is a member of the transformating growth factor-_ (TGF-_) superfamily of proteins and is produced almost exclusively in skeletal muscle tissue, where it is secreted and circulates as a serum protein. Myostatin acts as a negative regulator of muscle mass through the canonical SMAD2/3/4 signaling pathway. Naturally occurring myostatin mutants exhibit a ‘double muscling’ phenotype in which muscle mass is dramatically increased as a result of both hypertrophy and hyperplasia. Myostatin is naturally inhibited by its own propeptide; therefore, we assessed the impact of adeno associated virus-8 (AAV8) myostatin propeptide vectors when systemically introduced in MF-1 mice. We noted a significant systemic increase in muscle mass in both slow and fast muscle phenotypes, with no evidence of hyperplasia; however, the nuclei-to- cytoplasm ratio in all myofiber types was significantly reduced. An increase in muscle mass in slow (soleus) muscle led to an increase in force output; however, an increase in fast (extensor digitorum longus [EDL]) muscle mass did not increase force output. These results suggest that the use of gene therapeutic regimens of myostatin inhibition for age-related or disease-related muscle loss may have muscle-specific effects.

Oppositely charged polyelectrolytes: complex formation and effects of chain asymmetry

The formation of complexes in solutions of oppositely charged polyions has been studied by Monte Carlo simulations. The amount as well as the length, and thus, the absolute charge of one of the polyions have been varied. There is an increasing tendency to form large clusters as the excess of one kind of polyion decreases. When all polyions have the same length, this tendency reaches a maximum near, but off, equivalent amounts of the two types of polyions. When one kind of polyion is made shorter, the propensity to form large clusters decreases and the fluctuations in cluster charge increases. Simple free-energy expressions have been formulated on the basis of a set of simple rules that help rationalize the observations. By calculating cluster distributions in both grand canonical and canonical ensembles, it has been possible to show the extent of finite-size effects in the simulations.

The Life of Galileo and Brechtian television drama

Bertolt Brecht's dramaturgy was as influential upon the development of British drama on television between the 1950s and the 1970s as it was in the theatre. His influence was made manifest through the work of writers, directors and producers such as Tony Garnett, Ken Loach, John McGrath and Dennis Potter, whose attempts to create original Brechtian forms of television drama were reflected in the frequent reference to Brecht in contemporary debate concerning the political and aesthetic direction and value of television drama. While this discussion has been framed thus far around how Brechtian techniques and theory were applied to the newer media of television, this article examines these arguments from another perspective. Through detailed analysis of a 1964 BBC production of The Life of Galileo, I assess how the primary, canonical sources of Brecht's stage plays were realised on television during this period, locating Brecht's drama in the wider context of British television drama in general during the 1960s and 1970s. I pay particular attention to the use of the television studio as a site that could replicate or reinvent the theatrical space of the stage, and the responsiveness of the television audience towards Brechtian dramaturgy.

Macroclimate and viticultural zoning in Europe: observed trends and atmospheric forcing

Temperature and precipitation are major forcing factors influencing grapevine phenology and yield, as well as wine quality. Bioclimatic indices describing the suitability of a particular region for wine production are a commonly used tool for viticultural zoning. For this research these indices were computed for Europe by using the E-OBS gridded daily temperature and precipitation data set for the period from 1950 to 2009. Results showed strong regional contrasts based on the different index patterns and reproduced the wide diversity of local conditions that largely explain the quality and diversity of grapevines being grown across Europe. Owing to the strong inter-annual variability in the indices, a trend analysis and a principal component analysis were applied together with an assessment of their mean patterns. Significant trends were identified in the Winkler and Huglin indices, particularly for southwestern Europe. Four statistically significant orthogonal modes of variability were isolated for the Huglin index (HI), jointly representing 82% of the total variance in Europe. The leading mode was largely dominant (48% of variance) and mainly reflected the observed historical long-term changes. The other 3 modes corresponded to regional dipoles within Europe. Despite the relevance of local and regional climatic characteristics to grapevines, it was demonstrated via canonical correlation analysis that the observed inter-annual variability of the HI was strongly controlled by the large-scale atmospheric circulation during the growing season (April to September).

On Hamiltonian balanced dynamics and the slowest invariant manifold

The concept of a slowest invariant manifold is investigated for the five-component model of Lorenz under conservative dynamics. It is shown that Lorenz's model is a two-degree-of-freedom canonical Hamiltonian system, consisting of a nonlinear vorticity-triad oscillator coupled to a linear gravity wave oscillator, whose solutions consist of regular and chaotic orbits. When either the Rossby number or the rotational Froude number is small, there is a formal separation of timescales, and one can speak of fast and slow motion. In the same regime, the coupling is weak, and the Kolmogorov–Arnold-Moser theorem is shown to apply. The chaotic orbits are inherently unbalanced and are confined to regions sandwiched between invariant tori consisting of quasi-periodic regular orbits. The regular orbits generally contain free fast motion, but a slowest invariant manifold may be geometrically defined as the set of all slow cores of invariant tori (defined by zero fast action) that are smoothly related to such cores in the uncoupled system. This slowest invariant manifold is not global; in fact, its structure is fractal; but it is of nearly full measure in the limit of weak coupling. It is also nonlinearly stable. As the coupling increases, the slowest invariant manifold shrinks until it disappears altogether. The results clarify previous definitions of a slowest invariant manifold and highlight the ambiguity in the definition of “slowness.” An asymptotic procedure, analogous to standard initialization techniques, is found to yield nonzero free fast motion even when the core solutions contain none. A hierarchy of Hamiltonian balanced models preserving the symmetries in the original low-order model is formulated; these models are compared with classic balanced models, asymptotically initialized solutions of the full system and the slowest invariant manifold defined by the core solutions. The analysis suggests that for sufficiently small Rossby or rotational Froude numbers, a stable slowest invariant manifold can be defined for this system, which has zero free gravity wave activity, but it cannot be defined everywhere. The implications of the results for more complex systems are discussed.

Crooks' fluctuation theorem for a process on a two dimensional fluid field

We investigate the behavior of a two-dimensional inviscid and incompressible flow when pushed out of dynamical equilibrium. We use the two-dimensional vorticity equation with spectral truncation on a rectangular domain. For a sufficiently large number of degrees of freedom, the equilibrium statistics of the flow can be described through a canonical ensemble with two conserved quantities, energy and enstrophy. To perturb the system out of equilibrium, we change the shape of the domain according to a protocol, which changes the kinetic energy but leaves the enstrophy constant. We interpret this as doing work to the system. Evolving along a forward and its corresponding backward process, we find numerical evidence that the distributions of the work performed satisfy the Crooks relation. We confirm our results by proving the Crooks relation for this system rigorously.

Nonlinear stability and the saturation of instabilities to axisymmetric vortices

Nonlinear stability theorems are presented for axisymmetric vortices under the restriction that the disturbance is independent of either the azimuthal or the axial coordinate. These stability theorems are then used, in both cases, to derive rigorous upper bounds on the saturation amplitudes of instabilities. Explicit examples of such bounds are worked out for some canonical profiles. The results establish a minimum order for the dependence of saturation amplitude on supercriticality, and are thereby suggestive as to the nature of the bifurcation at the stability threshold.

A general method for finding extremal states of Hamiltonian dynamical systems, with applications to perfect fluids

In addition to the Hamiltonian functional itself, non-canonical Hamiltonian dynamical systems generally possess integral invariants known as ‘Casimir functionals’. In the case of the Euler equations for a perfect fluid, the Casimir functionals correspond to the vortex topology, whose invariance derives from the particle-relabelling symmetry of the underlying Lagrangian equations of motion. In a recent paper, Vallis, Carnevale & Young (1989) have presented algorithms for finding steady states of the Euler equations that represent extrema of energy subject to given vortex topology, and are therefore stable. The purpose of this note is to point out a very general method for modifying any Hamiltonian dynamical system into an algorithm that is analogous to those of Vallis etal. in that it will systematically increase or decrease the energy of the system while preserving all of the Casimir invariants. By incorporating momentum into the extremization procedure, the algorithm is able to find steadily-translating as well as steady stable states. The method is applied to a variety of perfect-fluid systems, including Euler flow as well as compressible and incompressible stratified flow.

Early and late stimulus-evoked cortical hemodynamic responses provide insight into the neurogenic nature of neurovascular coupling

Understanding neurovascular coupling is a prerequisite for the interpretation of results obtained from modern neuroimaging techniques. This study investigated the hemodynamic and neural responses in rat somatosensory cortex elicited by 16 seconds electrical whisker stimuli. Hemodynamics were measured by optical imaging spectroscopy and neural activity by multichannel electrophysiology. Previous studies have suggested that the whisker-evoked hemodynamic response contains two mechanisms, a transient ‘backwards’ dilation of the middle cerebral artery, followed by an increase in blood volume localized to the site of neural activity. To distinguish between the mechanisms responsible for these aspects of the response, we presented whisker stimuli during normocapnia (‘control’), and during a high level of hypercapnia. Hypercapnia was used to ‘predilate’ arteries and thus possibly ‘inhibit’ aspects of the response related to the ‘early’ mechanism. Indeed, hemodynamic data suggested that the transient stimulus-evoked response was absent under hypercapnia. However, evoked neural responses were also altered during hypercapnia and convolution of the neural responses from both the normocapnic and hypercapnic conditions with a canonical impulse response function, suggested that neurovascular coupling was similar in both conditions. Although data did not clearly dissociate early and late vascular responses, they suggest that the neurovascular coupling relationship is neurogenic in origin.

GSHMC: an efficient method for molecular simulation

The hybrid Monte Carlo (HMC) method is a popular and rigorous method for sampling from a canonical ensemble. The HMC method is based on classical molecular dynamics simulations combined with a Metropolis acceptance criterion and a momentum resampling step. While the HMC method completely resamples the momentum after each Monte Carlo step, the generalized hybrid Monte Carlo (GHMC) method can be implemented with a partial momentum refreshment step. This property seems desirable for keeping some of the dynamic information throughout the sampling process similar to stochastic Langevin and Brownian dynamics simulations. It is, however, ultimate to the success of the GHMC method that the rejection rate in the molecular dynamics part is kept at a minimum. Otherwise an undesirable Zitterbewegung in the Monte Carlo samples is observed. In this paper, we describe a method to achieve very low rejection rates by using a modified energy, which is preserved to high-order along molecular dynamics trajectories. The modified energy is based on backward error results for symplectic time-stepping methods. The proposed generalized shadow hybrid Monte Carlo (GSHMC) method is applicable to NVT as well as NPT ensemble simulations.

Inhibition of LRRK2 kinase activity stimulates macroautophagy

Leucine Rich Repeat Kinase 2 (LRRK2) is one of the most important genetic contributors to Parkinson's disease. LRRK2 has been implicated in a number of cellular processes, including macroautophagy. To test whether LRRK2 has a role in regulating autophagy, a specific inhibitor of the kinase activity of LRRK2 was applied to human neuroglioma cells and downstream readouts of autophagy examined. The resulting data demonstrate that inhibition of LRRK2 kinase activity stimulates macroautophagy in the absence of any alteration in the translational targets of mTORC1, suggesting that LRRK2 regulates autophagic vesicle formation independent of canonical mTORC1 signaling. This study represents the first pharmacological dissection of the role LRRK2 plays in the autophagy/lysosomal pathway, emphasizing the importance of this pathway as a marker for LRRK2 physiological function. Moreover it highlights the need to dissect autophagy and lysosomal activities in the context of LRRK2 related pathologies with the final aim of understanding their aetiology and identifying specific target for disease modifying therapies in patients.

Mg/Ca partitioning between aqueous solution and aragonite mineral: a molecular dynamics study

We have calculated the concentrations of Mg in the bulk and surfaces of aragonite CaCO3 in equilibrium with aqueous solution, based on molecular dynamics simulations and grand-canonical statistical mechanics. Mg is incorporated in the surfaces, in particular in the (001) terraces, rather than in the bulk of aragonite particles. However, the total Mg content in the bulk and surface of aragonite particles was found to be too small to account for the measured Mg/Ca ratios in corals. We therefore argue that most Mg in corals is either highly metastable in the aragonite lattice, or is located outside the aragonite phase of the coral skeleton, and we discuss the implications of this finding for Mg/Ca paleothermometry.