Propensity to Form Amyloid Fibrils Is Encoded as Excitations in the Free Energy Landscape of Monomeric Proteins

Protein aggregation, linked to many of diseases, is initiated when monomers access rogue conformations that are poised to form amyloid fibrils. We show, using simulations of src SH3 domain, that mechanical force enhances the population of the aggregation-prone (N*) states, which are rarely populated under force free native conditions but are encoded in the spectrum of native fluctuations. The folding phase diagrams of SH3 as a function of denaturant concentration (C]), mechanical force (f), and temperature exhibit an apparent two-state behavior, without revealing the presence of the elusive N* states. Interestingly, the phase boundaries separating the folded and unfolded states at all C] and f fall on a master curve, which can be quantitatively described using an analogy to superconductors in a magnetic field. The free energy profiles as a function of the molecular extension (R), which are accessible in pulling experiments, (R), reveal the presence of a native-like N* with a disordered solvent-exposed amino-terminal beta-strand. The structure of the N* state is identical with that found in Fyn SH3 by NMR dispersion experiments. We show that the timescale for fibril formation can be estimated from the population of the N* state, determined by the free energy gap separating the native structure and the N* state, a finding that can be used to assess fibril forming tendencies of proteins. The structures of the N* state are used to show that oligomer formation and likely route to fibrils occur by a domain-swap mechanism in SH3 domain. (C) 2014 Elsevier Ltd. All rights reserved.

Ising model on a random network with annealed or quenched disorder

We study the equilibrium properties of an Ising model on a disordered random network where the disorder can be quenched or annealed. The network consists of fourfold coordinated sites connected via variable length one-dimensional chains. Our emphasis is on nonuniversal properties and we consider the transition temperature and other equilibrium thermodynamic properties, including those associated with one-dimensional fluctuations arising from the chains. We use analytic methods in the annealed case, and a Monte Carlo simulation for the quenched disorder. Our objective is to study the difference between quenched and annealed results with a broad random distribution of interaction parameters. The former represents a situation where the time scale associated with the randomness is very long and the corresponding degrees of freedom can be viewed as frozen, while the annealed case models the situation where this is not so. We find that the transition temperature and the entropy associated with one-dimensional fluctuations are always higher for quenched disorder than in the annealed case. These differences increase with the strength of the disorder up to a saturating value. We discuss our results in connection to physical systems where a broad distribution of interaction strengths is present.

Desingularization of the Milne Universe

Resolution of cosmological singularities is an important problem in any full theory of quantum gravity. The Milne orbifold is a cosmology with a big-bang/big-crunch singularity, but being a quotient of flat space it holds potential for resolution in string theory. It is known, however, that some perturbative string amplitudes diverge in the Milne geometry. Here we show that flat space higher spin theories can effect a simple resolution of the Milne singularity when one embeds the latter in 2 + 1 dimensions. We explain how to reconcile this with the expectation that non-perturbative string effects are required for resolving Milne. Along the way, we introduce a Grassmann realization of the inonfi-Wigner contraction to export much of the AdS technology to -our flat space computation. (C) 2014 The Authors. Published by Elsevier BAT.

Conductivity noise study of the insulator-metal transition and phase coexistence in epitaxial samarium nickelate thin films

Interaction between the lattice and the orbital degrees of freedom not only makes rare-earth nickelates unusually ``bad metal,'' but also introduces a temperature-driven insulator-metal phase transition. Here we investigate this insulator-metal phase transition in thin films of SmNiO3 using the slow time-dependent fluctuations (noise) in resistivity. The normalized magnitude of noise is found to be extremely large, being nearly eight orders of magnitude higher than thin films of common disordered metallic systems, and indicates electrical conduction via classical percolation in a spatially inhomogeneous medium. The higher-order statistics of the fluctuations indicate a strong non-Gaussian component of noise close to the transition, attributing the inhomogeneity to the coexistence of the metallic and insulating phases. Our experiment offers insight into the impact of lattice-orbital coupling on the microscopic mechanism of electron transport in the rare-earth nickelates.

Temperature-dependent stability of stacking faults in Al, Cu and Ni: first-principles analysis

We present comparative analysis of microscopic mechanisms relevant to plastic deformation of the face-centered cubic (FCC) metals Al, Cu, and Ni, through determination of the temperature-dependent free energies of intrinsic and unstable stacking faults along 1 (1) over bar 0] and 1 (2) over bar 1] on the (1 1 1) plane using first-principles density-functional-theory-based calculations. We show that vibrational contribution results in significant decrease in the free energy of barriers and intrinsic stacking faults (ISFs) of Al, Cu, and Ni with temperature, confirming an important role of thermal fluctuations in the stability of stacking faults (SFs) and deformation at elevated temperatures. In contrast to Al and Ni, the vibrational spectrum of the unstable stacking fault (USF1 (2) over bar 1]) in Cu reveals structural instabilities, indicating that the energy barrier (gamma(usf)) along the (1 1 1)1 (2) over bar 1] slip system in Cu, determined by typical first-principles calculations, is an overestimate, and its commonly used interpretation as the energy release rate needed for dislocation nucleation, as proposed by Rice (1992 J. Mech. Phys. Solids 40 239), should be taken with caution.

Exploration of supersonic confined mixing layer: Effect of dissimilar gases at different temperatures

The growth rate of high-speed mixing layer between two dissimilar gases is explored through the model free simulation results. To analyse the cause for the higher mixing layer growth rate in comparison to the existing values reported in literature, the results were compared with the model free simulations of mixing of two high-speed streams of nitrogen (similar gas) at matched temperature and density. The analysis indicates that pressure and density fluctuations no longer remain correlated completely for the mixing layer formed between two dissimilar gases at different temperatures in contrast to the complete pressure density correlation for similar gases. It has been observed that the correlation between temperature and density fluctuations is near -1.0 for dissimilar gases in the mixing layer region and is much higher than for similar gases. It is concluded that mixing layer of similar gases shows a decrease in growth rate due to compressibility effect, while that of dissimilar gases shows a decrease due to dominant temperature effect on density.

Social insect colony as a biological regulatory system: modelling information flow in dominance networks

Social insects provide an excellent platform to investigate flow of information in regulatory systems since their successful social organization is essentially achieved by effective information transfer through complex connectivity patterns among the colony members. Network representation of such behavioural interactions offers a powerful tool for structural as well as dynamical analysis of the underlying regulatory systems. In this paper, we focus on the dominance interaction networks in the tropical social wasp Ropalidia marginata-a species where behavioural observations indicate that such interactions are principally responsible for the transfer of information between individuals about their colony needs, resulting in a regulation of their own activities. Our research reveals that the dominance networks of R. marginata are structurally similar to a class of naturally evolved information processing networks, a fact confirmed also by the predominance of a specific substructure-the `feed-forward loop'-a key functional component in many other information transfer networks. The dynamical analysis through Boolean modelling confirms that the networks are sufficiently stable under small fluctuations and yet capable of more efficient information transfer compared to their randomized counterparts. Our results suggest the involvement of a common structural design principle in different biological regulatory systems and a possible similarity with respect to the effect of selection on the organization levels of such systems. The findings are also consistent with the hypothesis that dominance behaviour has been shaped by natural selection to co-opt the information transfer process in such social insect species, in addition to its primal function of mediation of reproductive competition in the colony.

An experimental study on loading rate effect on acoustic emission based b-values related to reinforced concrete fracture

This article reports on analysis of fracture processes in reinforced concrete (RC) beams with acoustic emission (AE) technique. An emphasis was given to study the effect of loading rate on variation in AE based b-values with the development of cracks in RC structures. RC beams of length 3.2 m were tested under load control at a rate of 4 kN/s, 5 kN/s and 6 kN/s and the b-value analysis available in seismology was used to study the fracture process in RC structures. Moreover, the b-value is related to the strain in steel to assess the damage state. It is observed that when the loading rate is higher, quick cracking development lead to rapid fluctuations and drops in the b-values. Also it is observed that concrete behaves relatively more brittle at higher loading rates (or at higher strain rates). The average b-values are lower as a few but larger amplitudes of AE events occur in contrast to more number of low amplitude AE events occur at low loading rates (or at low strain rates). (C) 2014 Elsevier Ltd. All rights reserved.

The irregularities of the sunspot cycle and their theoretical modelling

The 11-year sunspot cycle has many irregularities, the most prominent amongst them being the grand minima when sunspots may not be seen for several cycles. After summarizing the relevant observational data about the irregularities, we introduce the flux transport dynamo model, the currently most successful theoretical model for explaining the 11-year sunspot cycle. Then we analyze the respective roles of nonlinearities and random fluctuations in creating the irregularities. We also discuss how it has recently been realized that the fluctuations in meridional circulation also can be a source of irregularities. We end by pointing out that fluctuations in the poloidal field generation and fluctuations in meridional circulation together can explain the occurrences of grand minima.

Cavitation in brittle metallic glasses - Effects of stress state and distributed weak zones

Experimental studies and atomistic simulations have shown that brittle metallic glasses fail by a cavitation mechanism whose origin has been traced to the presence of intrinsic atomic density fluctuations which give rise to weak zones with reduced yield strength. It has been shown recently through continuum analysis that the presence of these zones can lower the cavitation stress considerably under equibiaxial loading. The objective of the present work is to study the effect of the applied stress state on the cavitation behavior of such a heterogeneous plastic solid with distributed weak zones. To this end, 2D plane strain finite element simulations are performed by subjecting a unit cell containing a weak zone to different (biaxiality) stress ratios. The volume fraction and yield strength of the weak zone are varied over a wide range. The results show that unlike in a homogeneous plastic solid, the cavitation stress of the heterogeneous aggregate does not reduce appreciably as the stress ratio decreases from unity when the yield strength of the weak zone is low. It is found that a non-dimensional parameter characterizing the stress state prevailing in the weak zone and its yield properties uniquely control the cavitation stress. The nature of cavitation bifurcation may change from unstable bifurcation to the left at sufficiently low stress ratio to one involving snap cavitation at high stress ratio. (C) 2014 Elsevier Ltd. All rights reserved.

An integral fluctuation theorem for systems with unidirectional transitions

The fluctuations of a Markovian jump process with one or more unidirectional transitions, where R-ij > 0 but R-ji = 0, are studied. We find that such systems satisfy an integral fluctuation theorem. The fluctuating quantity satisfying the theorem is a sum of the entropy produced in the bidirectional transitions and a dynamical contribution, which depends on the residence times in the states connected by the unidirectional transitions. The convergence of the integral fluctuation theorem is studied numerically and found to show the same qualitative features as systems exhibiting microreversibility.

Noise Detected NMR Spectroscopy

Spin noise phenomenon was predicted way back in 1946. However, experimental investigations regarding spin noise became possible only recently with major technological improvements in NMR hardware. These experiments have several potential novel applications and also demand refinements in the existing theoretical framework to explain the phenomenon. Elegance of noise spectroscopy in gathering information about the properties of a system lies in the fact that it does not require external perturbation, and the system remains in thermal equilibrium. Spin noise is intrinsic magnetic fluctuations, and both longitudinal and transverse components have been detected independently in many systems. Detection of fluctuating longitudinal magnetization leads to field of Magnetic Resonance Force Microscopy (MRFM) that can efficiently probe very few spins even down to the level of single spin utilizing ultrasensitive cantilevers. Transverse component of spin noise, which can simultaneously monitor different resonances over a given frequency range enabling one to distinguish between different chemical environments, has also received considerable attention, and found many novel applications. These experiments demand a detailed understanding of the underlying spin noise phenomenon in order to perform perturbation-free magnetic resonance and widen the highly promising application area. Detailed investigations of noise magnetization have been performed recently using force microscopy on equilibrium ensemble of paramagnetic alkali atoms. It was observed that random fluctuations generate spontaneous spin coherences which has similar characteristics as generated by macroscopic magnetization of polarized ensemble in terms of precession and relaxation properties. Several other intrinsic properties like g-factors, isotope-abundance ratios, hyperfine splitting, spin coherence lifetimes etc. also have been achieved without having to excite the sample. In contrast to MRFM-approaches, detection of transverse spin noise also offers novel applications, attracting considerable attention. This has unique advantage as different resonances over a given frequency range enable one to distinguish between different chemical environments. Since these noise signatures scale inversely with sample size, these approaches lead to the possibility of non-perturbative magnetic resonance of small systems down to nano-scale. In this review, these different approaches will be highlighted with main emphasis on transverse spin noise investigations.

A strongly coupled anisotropic fluid from dilaton driven holography

We consider a system consisting of 5 dimensional gravity with a negative cosmological constant coupled to a massless scalar, the dilaton. We construct a black brane solution which arises when the dilaton satisfies linearly varying boundary conditions in the asymptotically AdS(5) region. The geometry of this black brane breaks rotational symmetry while preserving translational invariance and corresponds to an anisotropic phase of the system. Close to extremality, where the anisotropy is big compared to the temperature, some components of the viscosity tensor become parametrically small compared to the entropy density. We study the quasi normal modes in considerable detail and find no instability close to extremality. We also obtain the equations for fluid mechanics for an anisotropic driven system in general, working upto first order in the derivative expansion for the stress tensor, and identify additional transport coefficients which appear in the constitutive relation. For the fluid of interest we find that the parametrically small viscosity can result in a very small force of friction, when the fluid is enclosed between appropriately oriented parallel plates moving with a relative velocity.

Absolute/Convective Instability Transition in a Backward Facing Step Combustor: Fundamental Mechanism and Influence of Density Gradient

Hydrodynamic instabilities of the flow field in lean premixed gas turbine combustors can generate velocity perturbations that wrinkle and distort the flame sheet over length scales that are smaller than the flame length. The resultant heat release oscillations can then potentially result in combustion instability. Thus, it is essential to understand the hydrodynamic instability characteristics of the combustor flow field in order to understand its overall influence on combustion instability characteristics. To this end, this paper elucidates the role of fluctuating vorticity production from a linear hydrodynamic stability analysis as the key mechanism promoting absolute/convective instability transitions in shear layers occurring in the flow behind a backward facing step. These results are obtained within the framework of an inviscid, incompressible, local temporal and spatio-temporal stability analysis. Vorticity fluctuations in this limit result from interaction between two competing mechanisms-(1) production from interaction between velocity perturbations and the base flow vorticity gradient and (2) baroclinic torque in the presence of base flow density gradients. This interaction has a significant effect on hydrodynamic instability characteristics when the base flow density and velocity gradients are colocated. Regions in the space of parameters characterizing the base flow velocity profile, i.e., shear layer thickness and ratio of forward to reverse flow velocity, corresponding to convective and absolute instability are identified. The implications of the present results on understanding prior experimental studies of combustion instability in backward facing step combustors and hydrodynamic instability in other flows such as heated jets and bluff body stabilized flames is discussed.

Strings vs. spins on the null orbifold

We study the null orbifold singularity in 2+1 d flat space higher spin theory as well as string theory. Using the Chern-Simons formulation of 2+1 d Einstein gravity, we first observe that despite the singular nature of this geometry, the eigenvalues of its Chern-Simons holonomy are trivial. Next, we construct a resolution of the singularity in higher spin theory: a Kundt spacetime with vanishing scalar curvature invariants. We also point out that the UV divergences previously observed in the 2-to-2 tachyon tree level string amplitude on the null orbifold do not arise in the at alpha' -> infinity limit. We find all the divergences of the amplitude and demonstrate that the ones remaining in the tensionless limit are physical IR-type divergences. We conclude with a discussion on the meaning and limitations of higher spin (cosmological) singularity resolution and its potential connection to string theory.