A Gaussian network model study suggests that structural fluctuations are higher for inactive states than active states of protein kinases

We performed Gaussian network model based normal mode analysis of 3-dimensional structures of multiple active and inactive forms of protein kinases. In 14 different kinases, a more number of residues (1095) show higher structural fluctuations in inactive states than those in active states (525), suggesting that, in general, mobility of inactive states is higher than active states. This statistically significant difference is consistent with higher crystallographic B-factors and conformational energies for inactive than active states, suggesting lower stability of inactive forms. Only a small number of inactive conformations with the DFG motif in the ``in'' state were found to have fluctuation magnitudes comparable to the active conformation. Therefore our study reports for the first time, intrinsic higher structural fluctuation for almost all inactive conformations compared to the active forms. Regions with higher fluctuations in the inactive states are often localized to the aC-helix, aG-helix and activation loop which are involved in the regulation and/or in structural transitions between active and inactive states. Further analysis of 476 kinase structures involved in interactions with another domain/protein showed that many of the regions with higher inactive-state fluctuation correspond to contact interfaces. We also performed extensive GNM analysis of (i) insulin receptor kinase bound to another protein and (ii) holo and apo forms of active and inactive conformations followed by multi-factor analysis of variance. We conclude that binding of small molecules or other domains/proteins reduce the extent of fluctuation irrespective of active or inactive forms. Finally, we show that the perceived fluctuations serve as a useful input to predict the functional state of a kinase.

Improvements to the Froissart bound from AdS/CFT

In this paper we consider the issue of the Froissart bound on the high energy behaviour of total cross sections. This bound, originally derived using principles of analyticity of scattering amplitudes, is seen to be satisfied by all the available experimental data on total hadronic cross sections. At strong coupling, gauge/gravity duality has been used to provide some insights into this behaviour. In this work, we find the subleading terms to the so-derived Froissart bound from AdS/CFT. We find that a (ln s/s0) term is obtained, with a negative coefficient. We see that the fits to the currently available data confirm improvement in the fits due to the inclusion of such a term, with the appropriate sign. (C) 2015 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license.

Inner Bound on the GDOF of the K-User MIMO Gaussian Symmetric Interference Channel

The K-user multiple input multiple output (MIMO) Gaussian symmetric interference channel where each transmitter has M antennas and each receiver has N antennas is studied from a generalized degrees of freedom (GDOF) perspective. An inner bound on the GDOF is derived using a combination of techniques such as treating interference as noise, zero forcing (ZF) at the receivers, interference alignment (IA), and extending the Han-Kobayashi (HK) scheme to K users, as a function of the number of antennas and the log INR/log SNR level. Several interesting conclusions are drawn from the derived bounds. It is shown that when K > N/M + 1, a combination of the HK and IA schemes performs the best among the schemes considered. When N/M < K <= N/M + 1, the HK-scheme outperforms other schemes and is found to be GDOF optimal in many cases. In addition, when the SNR and INR are at the same level, ZF-receiving and the HK-scheme have the same GDOF performance.

Structures of substrate- and nucleotide-bound propionate kinase from Salmonella typhimurium: substrate specificity and phosphate-transfer mechanism

Kinases are ubiquitous enzymes that are pivotal to many biochemical processes. There are contrasting views on the phosphoryl-transfer mechanism in propionate kinase, an enzyme that reversibly transfers a phosphoryl group from propionyl phosphate to ADP in the final step of non-oxidative catabolism of L-threonine to propionate. Here, X-ray crystal structures of propionate- and nucleotide-bound Salmonella typhimurium propionate kinase are reported at 1.8-2.0 angstrom resolution. Although the mode of nucleotide binding is comparable to those of other members of the ASKHA superfamily, propionate is bound at a distinct site deeper in the hydrophobic pocket defining the active site. The propionate carboxyl is at a distance of approximate to 5 angstrom from the -phosphate of the nucleotide, supporting a direct in-line transfer mechanism. The phosphoryl-transfer reaction is likely to occur via an associative S(N)2-like transition state that involves a pentagonal bipyramidal structure with the axial positions occupied by the nucleophile of the substrate and the O atom between the - and the -phosphates, respectively. The proximity of the strictly conserved His175 and Arg236 to the carboxyl group of the propionate and the -phosphate of ATP suggests their involvement in catalysis. Moreover, ligand binding does not induce global domain movement as reported in some other members of the ASKHA superfamily. Instead, residues Arg86, Asp143 and Pro116-Leu117-His118 that define the active-site pocket move towards the substrate and expel water molecules from the active site. The role of Ala88, previously proposed to be the residue determining substrate specificity, was examined by determining the crystal structures of the propionate-bound Ala88 mutants A88V and A88G. Kinetic analysis and structural data are consistent with a significant role of Ala88 in substrate-specificity determination. The active-site pocket-defining residues Arg86, Asp143 and the Pro116-Leu117-His118 segment are also likely to contribute to substrate specificity.

Lower-Bound Axisymmetric Formulation for Geomechanics Problems Using Nonlinear Optimization

A lower-bound limit analysis formulation, by using two-dimensional finite elements, the three-dimensional Mohr-Coulomb yield criterion, and nonlinear optimization, has been given to deal with an axisymmetric geomechanics stability problem. The optimization was performed using an interior point method based on the logarithmic barrier function. The yield surface was smoothened (1) by removing the tip singularity at the apex of the pyramid in the meridian plane and (2) by eliminating the stress discontinuities at the corners of the yield hexagon in the pi-plane. The circumferential stress (sigma(theta)) need not be assumed. With the proposed methodology, for a circular footing, the bearing-capacity factors N-c, N-q, and N-gamma for different values of phi have been computed. For phi = 0, the variation of N-c with changes in the factor m, which accounts for a linear increase of cohesion with depth, has been evaluated. Failure patterns for a few cases have also been drawn. The results from the formulation provide a good match with the solutions available from the literature. (C) 2014 American Society of Civil Engineers.

Bearing capacity of circular footings over rock mass by using axisymmetric quasi lower bound finite element limit analysis

The ultimate bearing capacity of a circular footing, placed over rock mass, is evaluated by using the lower bound theorem of the limit analysis in conjunction with finite elements and nonlinear optimization. The generalized Hoek-Brown (HB) failure criterion, but by keeping a constant value of the exponent, alpha = 0.5, was used. The failure criterion was smoothened both in the meridian and pi planes. The nonlinear optimization was carried out by employing an interior point method based on the logarithmic barrier function. The results for the obtained bearing capacity were presented in a non-dimensional form for different values of GSI, m(i), sigma(ci)/(gamma b) and q/sigma(ci). Failure patterns were also examined for a few cases. For validating the results, computations were also performed for a strip footing as well. The results obtained from the analysis compare well with the data reported in literature. Since the equilibrium conditions are precisely satisfied only at the centroids of the elements, not everywhere in the domain, the obtained lower bound solution will be approximate not true. (C) 2015 Elsevier Ltd. All rights reserved.

Lower Bound Axisymmetric Limit Analysis Using Drucker-Prager Yield Cone and Simulation with Mohr-Coulomb Pyramid

This paper presents a lower bound limit analysis approach for solving an axisymmetric stability problem by using the Drucker-Prager (D-P) yield cone in conjunction with finite elements and nonlinear optimization. In principal stress space, the tip of the yield cone has been smoothened by applying the hyperbolic approximation. The nonlinear optimization has been performed by employing an interior point method based on the logarithmic barrier function. A new proposal has also been given to simulate the D-P yield cone with the Mohr-Coulomb hexagonal yield pyramid. For the sake of illustration, bearing capacity factors N-c, N-q and N-gamma have been computed, as a function of phi, both for smooth and rough circular foundations. The results obtained from the analysis compare quite well with the solutions reported from literature.

Estimation of nonlinearities from pseudodynamic and dynamic responses of bridge structures using the Delay Vector Variance method

Analysis of the variability in the responses of large structural systems and quantification of their linearity or nonlinearity as a potential non-invasive means of structural system assessment from output-only condition remains a challenging problem. In this study, the Delay Vector Variance (DVV) method is used for full scale testing of both pseudo-dynamic and dynamic responses of two bridges, in order to study the degree of nonlinearity of their measured response signals. The DVV detects the presence of determinism and nonlinearity in a time series and is based upon the examination of local predictability of a signal. The pseudo-dynamic data is obtained from a concrete bridge during repair while the dynamic data is obtained from a steel railway bridge traversed by a train. We show that DVV is promising as a marker in establishing the degree to which a change in the signal nonlinearity reflects the change in the real behaviour of a structure. It is also useful in establishing the sensitivity of instruments or sensors deployed to monitor such changes. (C) 2015 Elsevier B.V. All rights reserved.

Bearing capacity factors for a conical footing using lower- and upper-bound finite elements limit analysis

Bearing capacity factors, N-c, N-q, and N-gamma, for a conical footing are determined by using the lower and upper bound axisymmetric formulation of the limit analysis in combination with finite elements and optimization. These factors are obtained in a bound form for a wide range of the values of cone apex angle (beta) and phi with delta = 0, 0.5 phi, and phi. The bearing capacity factors for a perfectly rough (delta = phi) conical footing generally increase with a decrease in beta. On the contrary, for delta = 0 degrees, the factors N-c and N-q reduce gradually with a decrease in beta. For delta = 0 degrees, the factor N-gamma for phi >= 35 degrees becomes a minimum for beta approximate to 90 degrees. For delta = 0 degrees, N-gamma for phi <= 30 degrees, as in the case of delta = phi, generally reduces with an increase in beta. The failure and nodal velocity patterns are also examined. The results compare well with different numerical solutions and centrifuge tests' data available from the literature.

An Exponential Lower Bound for Homogeneous Depth Four Arithmetic Formulas

We show here a 2(Omega(root d.log N)) size lower bound for homogeneous depth four arithmetic formulas. That is, we give an explicit family of polynomials of degree d on N variables (with N = d(3) in our case) with 0, 1-coefficients such that for any representation of a polynomial f in this family of the form f = Sigma(i) Pi(j) Q(ij), where the Q(ij)'s are homogeneous polynomials (recall that a polynomial is said to be homogeneous if all its monomials have the same degree), it must hold that Sigma(i,j) (Number of monomials of Q(ij)) >= 2(Omega(root d.log N)). The above mentioned family, which we refer to as the Nisan-Wigderson design-based family of polynomials, is in the complexity class VNP. Our work builds on the recent lower bound results 1], 2], 3], 4], 5] and yields an improved quantitative bound as compared to the quasi-polynomial lower bound of 6] and the N-Omega(log log (N)) lower bound in the independent work of 7].

Upper bound on cubicity in terms of boxicity for graphs of low chromatic number

The boxicity (respectively cubicity) of a graph G is the least integer k such that G can be represented as an intersection graph of axis-parallel k-dimensional boxes (respectively k-dimensional unit cubes) and is denoted by box(G) (respectively cub(G)). It was shown by Adiga and Chandran (2010) that for any graph G, cub(G) <= box(G) log(2) alpha(G], where alpha(G) is the maximum size of an independent set in G. In this note we show that cub(G) <= 2 log(2) X (G)] box(G) + X (G) log(2) alpha(G)], where x (G) is the chromatic number of G. This result can provide a much better upper bound than that of Adiga and Chandran for graph classes with bounded chromatic number. For example, for bipartite graphs we obtain cub(G) <= 2(box(G) + log(2) alpha(G)] Moreover, we show that for every positive integer k, there exist graphs with chromatic number k such that for every epsilon > 0, the value given by our upper bound is at most (1 + epsilon) times their cubicity. Thus, our upper bound is almost tight. (c) 2015 Elsevier B.V. All rights reserved.

Reply to Discussion on ``Bearing capacity of circular footings over rock mass by using axisymmetric quasi lower bound finite element limit analysis'' Comput. Geotech. 70 (2015) 138-149]

A discussion has been provided for the comments raised by the discusser (Clausen, 2015)1] on the article recently published by the authors (Chakraborty and Kumar, 2015). The effect of exponent alpha for values of GSI approximately smaller than 30 becomes more critical. On the other hand, for greater values of GSI, the results obtained by the authors earlier remain primarily independent of alpha and can be easily used. (C) 2015 Elsevier Ltd. All rights reserved.

A Closer Look at Multiple Forking: Leveraging (In)Dependence for a Tighter Bound

Boldyreva, Palacio and Warinschi introduced a multiple forking game as an extension of general forking. The notion of (multiple) forking is a useful abstraction from the actual simulation of cryptographic scheme to the adversary in a security reduction, and is achieved through the intermediary of a so-called wrapper algorithm. Multiple forking has turned out to be a useful tool in the security argument of several cryptographic protocols. However, a reduction employing multiple forking incurs a significant degradation of , where denotes the upper bound on the underlying random oracle calls and , the number of forkings. In this work we take a closer look at the reasons for the degradation with a tighter security bound in mind. We nail down the exact set of conditions for success in the multiple forking game. A careful analysis of the cryptographic schemes and corresponding security reduction employing multiple forking leads to the formulation of `dependence' and `independence' conditions pertaining to the output of the wrapper in different rounds. Based on the (in)dependence conditions we propose a general framework of multiple forking and a General Multiple Forking Lemma. Leveraging (in)dependence to the full allows us to improve the degradation factor in the multiple forking game by a factor of . By implication, the cost of a single forking involving two random oracles (augmented forking) matches that involving a single random oracle (elementary forking). Finally, we study the effect of these observations on the concrete security of existing schemes employing multiple forking. We conclude that by careful design of the protocol (and the wrapper in the security reduction) it is possible to harness our observations to the full extent.