The repertoire of protein kinases encoded in the draft version of the human genome: atypical variations and uncommon domain combinations

Background: Phosphorylation by protein kinases is central to cellular signal transduction. Abnormal functioning of kinases has been implicated in developmental disorders and malignancies. Their activity is regulated by second messengers and by the binding of associated domains, which are also influential in translocating the catalytic component to their substrate sites, in mediating interaction with other proteins and carrying out their biological roles. Results: Using sensitive profile-search methods and manual analysis, the human genome has been surveyed for protein kinases. A set of 448 sequences, which show significant similarity to protein kinases and contain the critical residues essential for kinase function, have been selected for an analysis of domain combinations after classifying the kinase domains into subfamilies. The unusual domain combinations in particular kinases suggest their involvement in ubiquitination pathways and alternative modes of regulation for mitogen-activated protein kinase kinases (MAPKKs) and cyclin-dependent kinase (CDK)-like kinases. Previously unexplored kinases have been implicated in osteoblast differentiation and embryonic development on the basis of homology with kinases of known functions from other organisms. Kinases potentially unique to vertebrates are involved in highly evolved processes such as apoptosis, protein translation and tyrosine kinase signaling. In addition to coevolution with the kinase domain, duplication and recruitment of non-catalytic domains is apparent in signaling domains such as the PH, DAG-PE, SH2 and SH3 domains. Conclusions: Expansion of the functional repertoire and possible existence of alternative modes of regulation of certain kinases is suggested by their uncommon domain combinations. Experimental verification of the predicted implications of these kinases could enhance our understanding of their biological roles.

On the curvature ODE associated to the Ricci flow

In the vector space of algebraic curvature operators we study the reaction ODE which is associated to the evolution equation of the Riemann curvature operator along the Ricci flow. More precisely, we give a partial classification of the zeros of this ODE up to suitable normalization and analyze the stability of a special class of zeros of the same. In particular, we show that the ODE is unstable near the curvature operators of the Riemannian product spaces where is an Einstein (locally) symmetric space of compact type and not a spherical space form when .

Typical and atypical domain combinations in human protein kinases: functions, disease causing mutations and conservation in other primates

Ser/Thr and Tyr protein kinases orchestrate many signalling pathways and hence loss in this balance leads to many disease phenotypes. Due to their high abundance, diversity and importance, efforts have been made in the past to classify kinases and annotate their functions at both gross and fine levels. These kinases are conventionally classified into subfamilies based on the sequences of catalytic domains. Usually the domain architecture of a full-length kinase is consistent with the subfamily classification made based on the sequence of kinase domain. Important contributions of modular domains to the overall function of the kinase are well known. Recently occurrence of two kinds of outlier kinases-''Hybrid'' and ``Rogue'' has been reported. These show considerable deviations in their domain architectures from the typical domain architecture known for the classical kinase subfamilies. This article provides an overview of the different subfamilies of human kinases and the role of non-kinase domains in functions and diseases. Importantly this article provides analysis of hybrid and rogue kinases encoded in the human genome and highlights their conservation in closely related primate species. These kinases are examples of elegant rewiring to bring about subtle functional differences compared to canonical variants.

Generalized Burgers equations and Euler-Painleve transcendents. II

It was proposed earlier [P. L. Sachdev, K. R. C. Nair, and V. G. Tikekar, J. Math. Phys. 27, 1506 (1986)] that the Euler Painlevé equation yy[script `]+ay[script ']2+ f(x)yy[script ']+g(x) y2+by[script ']+c=0 represents the generalized Burgers equations (GBE's) in the same manner as Painlevé equations do the KdV type. The GBE was treated with a damping term in some detail. In this paper another GBE ut+uaux+Ju/2t =(gd/2)uxx (the nonplanar Burgers equation) is considered. It is found that its self-similar form is again governed by the Euler Painlevé equation. The ranges of the parameter alpha for which solutions of the connection problem to the self-similar equation exist are obtained numerically and confirmed via some integral relations derived from the ODE's. Special exact analytic solutions for the nonplanar Burgers equation are also obtained. These generalize the well-known single hump solutions for the Burgers equation to other geometries J=1,2; the nonlinear convection term, however, is not quadratic in these cases. This study fortifies the conjecture regarding the importance of the Euler Painlevé equation with respect to GBE's. Journal of Mathematical Physics is copyrighted by The American Institute of Physics.

Vibrations of a Beam in Variable Contact With a Flat Surface

We study small vibrations of cantilever beams contacting a rigid surface. We study two cases: the first is a beam that sags onto the ground due to gravity, and the second is a beam that sticks to the ground through reversible adhesion. In both cases, the noncontacting length varies dynamically. We first obtain the governing equations and boundary conditions, including a transversality condition involving an end moment, using Hamilton's principle. Rescaling the variable length to a constant value, we obtain partial differential equations with time varying coefficients, which, upon linearization, give the natural frequencies of vibration. The natural frequencies for the first case (gravity without adhesion) match that of a clamped-clamped beam of the same nominal length; frequencies for the second case, however, show no such match. We develop simple, if atypical, single degree of freedom approximations for the first modes of these two systems, which provide insights into the role of the static deflection profile, as well as the end moment condition, in determining the first natural frequencies of these systems. Finally, we consider small transverse sinusoidal forcing of the first case and find that the governing equation contains both parametric and external forcing terms. For forcing at resonance, w find that either the internal or the external forcing may dominate.

Generalized Burgers equations and Euler-Painlev transcendents. I

Initial-value problems for the generalized Burgers equation (GBE) ut+u betaux+lambdaualpha =(delta/2)uxx are discussed for the single hump type of initial data both continuous and discontinuous. The numerical solution is carried to the self-similar ``intermediate asymptotic'' regime when the solution is given analytically by the self-similar form. The nonlinear (transformed) ordinary differential equations (ODE's) describing the self-similar form are generalizations of a class discussed by Euler and Painlevé and quoted by Kamke. These ODE's are new, and it is postulated that they characterize GBE's in the same manner as the Painlev equations categorize the Kortweg-de Vries (KdV) type. A connection problem for some related ODE's satisfying proper asymptotic conditions at x=±[infinity], is solved. The range of amplitude parameter is found for which the solution of the connection problem exists. The other solutions of the above GBE, which display several interesting features such as peaking, breaking, and a long shelf on the left for negative values of the damping coefficient lambda, are also discussed. The results are compared with those holding for the modified KdV equation with damping. Journal of Mathematical Physics is copyrighted by The American Institute of Physics.

Occurrence, divergence and evolution of intrinsic terminators across Eubacteria

In Escherichia coli, the canonical intrinsic terminator of transcription includes a palindrome followed by a U-trail on the transcript. The apparent underrepresentation of such terminators in eubacterial genomes led us to develop a rapid and accurate algorithm, GeSTer, to predict putative intrinsic terminators. Now, we have analyzed 378 genome sequences with an improved version of GeSTer. Our results indicate that the canonical E. coli type terminators are not overwhelmingly abundant in eubacteria. The atypical structures, having stem-loop structures but lacking ‘U’ trail, occur downstream of genes in all the analyzed genomes but different phyla show conserved preference for different types of terminators. This propensity correlates with genomic GC content and presence of the factor, Rho. 60–70% of identified terminators in all the genomes show “optimized” stem-length and ΔG. These results provide evidence that eubacteria extensively rely on the mechanism of intrinsic termination, with a considerable divergence in their structure, positioning and prevalence. The software and detailed results for individual genomes are freely available on request

Self-interrupted regenerative metal cutting in turning

A new approach is used to study the global dynamics of regenerative metal cutting in turning. The cut surface is modeled using a partial differential equation (PDE) coupled, via boundary conditions, to an ordinary differential equation (ODE) modeling the dynamics of the cutting tool. This approach automatically incorporates the multiple-regenerative effects accompanying self-interrupted cutting. Taylor's 3/4 power law model for the cutting force is adopted. Lower dimensional ODE approximations are obtained for the combined tool–workpiece model using Galerkin projections, and a bifurcation diagram computed. The unstable solution branch off the subcritical Hopf bifurcation meets the stable branch involving self-interrupted dynamics in a turning point bifurcation. The tool displacement at that turning point is estimated, which helps identify cutting parameter ranges where loss of stability leads to much larger self-interrupted motions than in some other ranges. Numerical bounds are also obtained on the parameter values which guarantee global stability of steady-state cutting, i.e., parameter values for which there exist neither unstable periodic motions nor self-interrupted motions about the stable equilibrium.

Self-interrupted regenerative turning

A preliminary study of self-interrupted regenerative turning is performed in this paper. To facilitate the analysis, a new approach is proposed to model the regenerative effect in metal cutting. This model automatically incorporates the multiple-regenerative effects accompanying self-interrupted cutting. Some lower dimensional ODE approximations are obtained for this model using Galerkin projections. Using these ODE approximations, a bifurcation diagram of the regenerative turning process is obtained. It is found that the unstable branch resulting from the subcritical Hopf bifurcation meets the stable branch resulting from the self-interrupted dynamics in a turning point bifurcation. Using a rough analytical estimate of the turning point tool displacement, we can identify regions in the cutting parameter space where loss of stability leads to much greater amplitude self-interrupted motions than in some other regions.

Exact nonlinear travelling hydromagnetic wave solutions

Exact travelling wave solutions for hydromagnetic waves in an exponentially stratified incompressible medium are obtained. With the help of two integrals it becomes possible to reduce the system of seven nonlinear PDE's to a second order nonlinear ODE which describes an one dimensional harmonic oscillator with a nonlinear friction term. This equation is studied in detail in the phase plane. The travelling waves are periodic only when they propagate either horizontally or vertically. The reduced second order nonlinear differential equation describing the travelling waves in inhomogeneous conducting media has rather ubiquitous nature in that it also appears in other geophysical systems such as internal waves, Rossby waves and topographic Rossby waves in the ocean.

Computation of restoration of ligand response in the random kinetics of a prostate cancer cell signaling pathway

Mutation and/or dysfunction of signaling proteins in the mitogen activated protein kinase (MAPK) signal transduction pathway are frequently observed in various kinds of human cancer. Consistent with this fact, in the present study, we experimentally observe that the epidermal growth factor (EGF) induced activation profile of MAP kinase signaling is not straightforward dose-dependent in the PC3 prostate cancer cells. To find out what parameters and reactions in the pathway are involved in this departure from the normal dose-dependency, a model-based pathway analysis is performed. The pathway is mathematically modeled with 28 rate equations yielding those many ordinary differential equations (ODE) with kinetic rate constants that have been reported to take random values in the existing literature. This has led to us treating the ODE model of the pathways kinetics as a random differential equations (RDE) system in which the parameters are random variables. We show that our RDE model captures the uncertainty in the kinetic rate constants as seen in the behavior of the experimental data and more importantly, upon simulation, exhibits the abnormal EGF dose-dependency of the activation profile of MAP kinase signaling in PC3 prostate cancer cells. The most likely set of values of the kinetic rate constants obtained from fitting the RDE model into the experimental data is then used in a direct transcription based dynamic optimization method for computing the changes needed in these kinetic rate constant values for the restoration of the normal EGF dose response. The last computation identifies the parameters, i.e., the kinetic rate constants in the RDE model, that are the most sensitive to the change in the EGF dose response behavior in the PC3 prostate cancer cells. The reactions in which these most sensitive parameters participate emerge as candidate drug targets on the signaling pathway. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

A characteristic based numerical method with tracking for nonlinear wave equations

Many physical problems can be modeled by scalar, first-order, nonlinear, hyperbolic, partial differential equations (PDEs). The solutions to these PDEs often contain shock and rarefaction waves, where the solution becomes discontinuous or has a discontinuous derivative. One can encounter difficulties using traditional finite difference methods to solve these equations. In this paper, we introduce a numerical method for solving first-order scalar wave equations. The method involves solving ordinary differential equations (ODEs) to advance the solution along the characteristics and to propagate the characteristics in time. Shocks are created when characteristics cross, and the shocks are then propagated by applying analytical jump conditions. New characteristics are inserted in spreading rarefaction fans. New characteristics are also inserted when values on adjacent characteristics lie on opposite sides of an inflection point of a nonconvex flux function, Solutions along characteristics are propagated using a standard fourth-order Runge-Kutta ODE solver. Shocks waves are kept perfectly sharp. In addition, shock locations and velocities are determined without analyzing smeared profiles or taking numerical derivatives. In order to test the numerical method, we study analytically a particular class of nonlinear hyperbolic PDEs, deriving closed form solutions for certain special initial data. We also find bounded, smooth, self-similar solutions using group theoretic methods. The numerical method is validated against these analytical results. In addition, we compare the errors in our method with those using the Lax-Wendroff method for both convex and nonconvex flux functions. Finally, we apply the method to solve a PDE with a convex flux function describing the development of a thin liquid film on a horizontally rotating disk and a PDE with a nonconvex flux function, arising in a problem concerning flow in an underground reservoir.

Probing the Allosteric Mechanism in Pyrrolysyl-tRNA Synthetase Using Energy-Weighted Network Formalism

Pyrrolysyl-tRNA synthetase (PyIRS) is an atypical enzyme responsible for charging tRNA(Pyl) with pyrrolysine, despite lacking precise tRNA anticodon recognition. This dimeric protein exhibits allosteric regulation of function, like any other tRNA synthetases. In this study we examine the paths of allosteric communication at the atomic level, through energy-weighted networks of Desulfitobacterium hafniense PyIRS (DhPyIRS) and its complexes with tRNA(Pyl) and activated pyrrolysine. We performed molecular dynamics simulations of the structures of these complexes to obtain an ensemble conformation-population perspective. Weighted graph parameters relevant to identifying key players and ties in the context of social networks such as edge/node betweenness, closeness index, and the concept of funneling are explored in identifying key residues and interactions leading to shortest paths of communication in the structure networks of DhPylRS. Further, the changes in the status of important residues and connections and the costs of communication due to ligand induced perturbations are evaluated. The optimal, suboptimal, and preexisting paths are also investigated. Many of these parameters have exhibited an enhanced asymmetry between the two subunits of the dimeric protein, especially in the pretransfer complex, leading us to conclude that encoding of function goes beyond the sequence/structure of proteins. The local and global perturbations mediated by appropriate ligands and their influence on the equilibrium ensemble of conformations also have a significant role to play in the functioning of proteins. Taking a comprehensive view of these observations, we propose that the origin of many functional aspects (allostery rand half-sites reactivity in the case of DhPyIRS) lies in subtle rearrangements of interactions and dynamics at a global level.

Time Evolution of the Microstructure of VO2(B) Films Deposited on Glass by MOCVD

Thin films of VO2(B), a metastable polymorph of vanadium dioxide, have been grown on glass by low-pressure metalorganic chemical vapor deposition (MOCVD). The films grown for 90 minutes have atypical microstructure, comprising micrometer-sized, island-like entities made up of numerous small, single-crystalline platelets (≅1 μm) emerging orthogonally from larger ones at the center. Microstructure evolution as a function of deposition time has been examined by X-ray diffraction, scanning electron microscopy, and transmission electron microscopy. The metastable VO2(B) transforms to the stable rutile (R) phase at 550°C in inert ambient, which on cooling convert reversibly to M phase. Electron microscopy shows that annealing leads to the disintegration of the VO2(B) platelets into small crystallites of the rutile phase VO2(R), although the platelet morphology is retained. The magnitude of the jump in resistance at the semiconductor-to-metal, VO2(M)→VO2(R) phase transition depends on the arrangement of polycrystalline platelets in the films.