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Sample records for nonlinear pde formulation

  1. Evolution Nonlinear Diffusion-Convection PDE Models for Spectrogram Enhancement

    NASA Astrophysics Data System (ADS)

    Dugnol, B.; Fernández, C.; Galiano, G.; Velasco, J.

    2008-09-01

    In previous works we studied the application of PDE-based image processing techniques applied to the spectrogram of audio signals in order to improve the readability of the signal. In particular we considered the implementation of the nonlinear diffusive model proposed by Álvarez, Lions and Morel [1](ALM) combined with a convective term inspired by the differential reassignment proposed by Chassandre-Mottin, Daubechies, Auger and Flandrin [2]-[3]. In this work we consider the possibility of replacing the diffusive model of ALM by diffusive terms in divergence form. In particular we implement finite element approximations of nonlinear diffusive terms studied by Chen, Levine, Rao [4] and Antontsev, Shmarev [5]-[8] with a convective term.

  2. Approximate optimal control design for nonlinear one-dimensional parabolic PDE systems using empirical eigenfunctions and neural network.

    PubMed

    Luo, Biao; Wu, Huai-Ning

    2012-12-01

    This paper addresses the approximate optimal control problem for a class of parabolic partial differential equation (PDE) systems with nonlinear spatial differential operators. An approximate optimal control design method is proposed on the basis of the empirical eigenfunctions (EEFs) and neural network (NN). First, based on the data collected from the PDE system, the Karhunen-Loève decomposition is used to compute the EEFs. With those EEFs, the PDE system is formulated as a high-order ordinary differential equation (ODE) system. To further reduce its dimension, the singular perturbation (SP) technique is employed to derive a reduced-order model (ROM), which can accurately describe the dominant dynamics of the PDE system. Second, the Hamilton-Jacobi-Bellman (HJB) method is applied to synthesize an optimal controller based on the ROM, where the closed-loop asymptotic stability of the high-order ODE system can be guaranteed by the SP theory. By dividing the optimal control law into two parts, the linear part is obtained by solving an algebraic Riccati equation, and a new type of HJB-like equation is derived for designing the nonlinear part. Third, a control update strategy based on successive approximation is proposed to solve the HJB-like equation, and its convergence is proved. Furthermore, an NN approach is used to approximate the cost function. Finally, we apply the developed approximate optimal control method to a diffusion-reaction process with a nonlinear spatial operator, and the simulation results illustrate its effectiveness.

  3. Adaptive wavelet collocation methods for initial value boundary problems of nonlinear PDE's

    NASA Technical Reports Server (NTRS)

    Cai, Wei; Wang, Jian-Zhong

    1993-01-01

    We have designed a cubic spline wavelet decomposition for the Sobolev space H(sup 2)(sub 0)(I) where I is a bounded interval. Based on a special 'point-wise orthogonality' of the wavelet basis functions, a fast Discrete Wavelet Transform (DWT) is constructed. This DWT transform will map discrete samples of a function to its wavelet expansion coefficients in O(N log N) operations. Using this transform, we propose a collocation method for the initial value boundary problem of nonlinear PDE's. Then, we test the efficiency of the DWT transform and apply the collocation method to solve linear and nonlinear PDE's.

  4. Distributed Proportional-spatial Derivative control of nonlinear parabolic systems via fuzzy PDE modeling approach.

    PubMed

    Wang, Jun-Wei; Wu, Huai-Ning; Li, Han-Xiong

    2012-06-01

    In this paper, a distributed fuzzy control design based on Proportional-spatial Derivative (P-sD) is proposed for the exponential stabilization of a class of nonlinear spatially distributed systems described by parabolic partial differential equations (PDEs). Initially, a Takagi-Sugeno (T-S) fuzzy parabolic PDE model is proposed to accurately represent the nonlinear parabolic PDE system. Then, based on the T-S fuzzy PDE model, a novel distributed fuzzy P-sD state feedback controller is developed by combining the PDE theory and the Lyapunov technique, such that the closed-loop PDE system is exponentially stable with a given decay rate. The sufficient condition on the existence of an exponentially stabilizing fuzzy controller is given in terms of a set of spatial differential linear matrix inequalities (SDLMIs). A recursive algorithm based on the finite-difference approximation and the linear matrix inequality (LMI) techniques is also provided to solve these SDLMIs. Finally, the developed design methodology is successfully applied to the feedback control of the Fitz-Hugh-Nagumo equation.

  5. A Comparison of PDE-based Non-Linear Anisotropic Diffusion Techniques for Image Denoising

    SciTech Connect

    Weeratunga, S K; Kamath, C

    2003-01-06

    PDE-based, non-linear diffusion techniques are an effective way to denoise images. In a previous study, we investigated the effects of different parameters in the implementation of isotropic, non-linear diffusion. Using synthetic and real images, we showed that for images corrupted with additive Gaussian noise, such methods are quite effective, leading to lower mean-squared-error values in comparison with spatial filters and wavelet-based approaches. In this paper, we extend this work to include anisotropic diffusion, where the diffusivity is a tensor valued function which can be adapted to local edge orientation. This allows smoothing along the edges, but not perpendicular to it. We consider several anisotropic diffusivity functions as well as approaches for discretizing the diffusion operator that minimize the mesh orientation effects. We investigate how these tensor-valued diffusivity functions compare in image quality, ease of use, and computational costs relative to simple spatial filters, the more complex bilateral filters, wavelet-based methods, and isotropic non-linear diffusion based techniques.

  6. PDE-based nonlinear diffusion techniques for denoising scientific and industrial images: an empirical study

    NASA Astrophysics Data System (ADS)

    Weeratunga, Sisira K.; Kamath, Chandrika

    2002-05-01

    Removing noise from data is often the first step in data analysis. Denoising techniques should not only reduce the noise, but do so without blurring or changing the location of the edges. Many approaches have been proposed to accomplish this; in this paper, we focus on one such approach, namely the use of non-linear diffusion operators. This approach has been studied extensively from a theoretical viewpoint ever since the 1987 work of Perona and Malik showed that non-linear filters outperformed the more traditional linear Canny edge detector. We complement this theoretical work by investigating the performance of several isotropic diffusion operators on test images from scientific domains. We explore the effects of various parameters such as the choice of diffusivity function, explicit and implicit methods for the discretization of the PDE, and approaches for the spatial discretization of the non-linear operator etc. We also compare these schemes with simple spatial filters and the more complex wavelet-based shrinkage techniques. Our empirical results show that, with an appropriate choice of parameters, diffusion-based schemes can be as effective as competitive techniques.

  7. Comparison of PDE-based non-linear anistropic diffusion techniques for image denoising

    NASA Astrophysics Data System (ADS)

    Weeratunga, Sisira K.; Kamath, Chandrika

    2003-05-01

    PDE-based, non-linear diffusion techniques are an effective way to denoise images.In a previous study, we investigated the effects of different parameters in the implementation of isotropic, non-linear diffusion. Using synthetic and real images, we showed that for images corrupted with additive Gaussian noise, such methods are quite effective, leading to lower mean-squared-error values in comparison with spatial filters and wavelet-based approaches. In this paper, we extend this work to include anisotropic diffusion, where the diffusivity is a tensor valued function which can be adapted to local edge orientation. This allows smoothing along the edges, but not perpendicular to it. We consider several anisotropic diffusivity functions as well as approaches for discretizing the diffusion operator that minimize the mesh orientation effects. We investigate how these tensor-valued diffusivity functions compare in image quality, ease of use, and computational costs relative to simple spatial filters, the more complex bilateral filters, wavelet-based methods, and isotropic non-linear diffusion based techniques.

  8. Nonlinear finite element analysis: An alternative formulation

    NASA Technical Reports Server (NTRS)

    Merazzi, S.; Stehlin, P.

    1980-01-01

    A geometrical nonlinear analysis based on an alternative definition of strain is presented. Expressions for strain are obtained by computing the change in length of the base vectors in the curvilinear element coordinate system. The isoparametric element formulation is assumed in the global Cartesian coordinate system. The approach is based on the minimization of the strain energy, and the resulting nonlinear equations are solved by the modified Newton method. Integration of the first and second variation of the strain energy is performed numerically in the case of two and three dimensional elements. Application is made to a simple long cantilever beam.

  9. Analysis and algorithms for a regularized Cauchy problem arising from a non-linear elliptic PDE for seismic velocity estimation

    SciTech Connect

    Cameron, M.K.; Fomel, S.B.; Sethian, J.A.

    2009-01-01

    In the present work we derive and study a nonlinear elliptic PDE coming from the problem of estimation of sound speed inside the Earth. The physical setting of the PDE allows us to pose only a Cauchy problem, and hence is ill-posed. However we are still able to solve it numerically on a long enough time interval to be of practical use. We used two approaches. The first approach is a finite difference time-marching numerical scheme inspired by the Lax-Friedrichs method. The key features of this scheme is the Lax-Friedrichs averaging and the wide stencil in space. The second approach is a spectral Chebyshev method with truncated series. We show that our schemes work because of (1) the special input corresponding to a positive finite seismic velocity, (2) special initial conditions corresponding to the image rays, (3) the fact that our finite-difference scheme contains small error terms which damp the high harmonics; truncation of the Chebyshev series, and (4) the need to compute the solution only for a short interval of time. We test our numerical scheme on a collection of analytic examples and demonstrate a dramatic improvement in accuracy in the estimation of the sound speed inside the Earth in comparison with the conventional Dix inversion. Our test on the Marmousi example confirms the effectiveness of the proposed approach.

  10. PDE-based Non-Linear Diffusion Techniques for Denoising Scientific and Industrial Images: An Empirical Study

    SciTech Connect

    Weeratunga, S K; Kamath, C

    2001-12-20

    Removing noise from data is often the first step in data analysis. Denoising techniques should not only reduce the noise, but do so without blurring or changing the location of the edges. Many approaches have been proposed to accomplish this; in this paper, they focus on one such approach, namely the use of non-linear diffusion operators. This approach has been studied extensively from a theoretical viewpoint ever since the 1987 work of Perona and Malik showed that non-linear filters outperformed the more traditional linear Canny edge detector. They complement this theoretical work by investigating the performance of several isotropic diffusion operators on test images from scientific domains. They explore the effects of various parameters such as the choice of diffusivity function, explicit and implicit methods for the discretization of the PDE, and approaches for the spatial discretization of the non-linear operator etc. They also compare these schemes with simple spatial filters and the more complex wavelet-based shrinkage techniques. The empirical results show that, with an appropriate choice of parameters, diffusion-based schemes can be as effective as competitive techniques.

  11. Geometry of PDE's. IV

    NASA Astrophysics Data System (ADS)

    Prástaro, Agostino

    2008-02-01

    Following our previous results on this subject [R.P. Agarwal, A. Prástaro, Geometry of PDE's. III(I): Webs on PDE's and integral bordism groups. The general theory, Adv. Math. Sci. Appl. 17 (2007) 239-266; R.P. Agarwal, A. Prástaro, Geometry of PDE's. III(II): Webs on PDE's and integral bordism groups. Applications to Riemannian geometry PDE's, Adv. Math. Sci. Appl. 17 (2007) 267-285; A. Prástaro, Geometry of PDE's and Mechanics, World Scientific, Singapore, 1996; A. Prástaro, Quantum and integral (co)bordism in partial differential equations, Acta Appl. Math. (5) (3) (1998) 243-302; A. Prástaro, (Co)bordism groups in PDE's, Acta Appl. Math. 59 (2) (1999) 111-201; A. Prástaro, Quantized Partial Differential Equations, World Scientific Publishing Co, Singapore, 2004, 500 pp.; A. Prástaro, Geometry of PDE's. I: Integral bordism groups in PDE's, J. Math. Anal. Appl. 319 (2006) 547-566; A. Prástaro, Geometry of PDE's. II: Variational PDE's and integral bordism groups, J. Math. Anal. Appl. 321 (2006) 930-948; A. Prástaro, Th.M. Rassias, Ulam stability in geometry of PDE's, Nonlinear Funct. Anal. Appl. 8 (2) (2003) 259-278; I. Stakgold, Boundary Value Problems of Mathematical Physics, I, The MacMillan Company, New York, 1967; I. Stakgold, Boundary Value Problems of Mathematical Physics, II, Collier-MacMillan, Canada, Ltd, Toronto, Ontario, 1968], integral bordism groups of the Navier-Stokes equation are calculated for smooth, singular and weak solutions, respectively. Then a characterization of global solutions is made on this ground. Enough conditions to assure existence of global smooth solutions are given and related to nullity of integral characteristic numbers of the boundaries. Stability of global solutions are related to some characteristic numbers of the space-like Cauchy dataE Global solutions of variational problems constrained by (NS) are classified by means of suitable integral bordism groups too.

  12. Nonlinear/linear unified thermal stress formulations - Transfinite element approach

    NASA Technical Reports Server (NTRS)

    Tamma, Kumar K.; Railkar, Sudhir B.

    1987-01-01

    A new unified computational approach for applicability to nonlinear/linear thermal-structural problems is presented. Basic concepts of the approach including applicability to nonlinear and linear thermal structural mechanics are first described via general formulations. Therein, the approach is demonstrated for thermal stress and thermal-structural dynamic applications. The proposed transfinite element approach focuses on providing a viable hybrid computational methodology by combining the modeling versatility of contemporary finite element schemes in conjunction with transform techniques and the classical Bubnov-Galerkin schemes. Comparative samples of numerical test cases highlight the capabilities of the proposed concepts.

  13. Terascale Optimal PDE Simulations

    SciTech Connect

    David Keyes

    2009-07-28

    The Terascale Optimal PDE Solvers (TOPS) Integrated Software Infrastructure Center (ISIC) was created to develop and implement algorithms and support scientific investigations performed by DOE-sponsored researchers. These simulations often involve the solution of partial differential equations (PDEs) on terascale computers. The TOPS Center researched, developed and deployed an integrated toolkit of open-source, optimal complexity solvers for the nonlinear partial differential equations that arise in many DOE application areas, including fusion, accelerator design, global climate change and reactive chemistry. The algorithms created as part of this project were also designed to reduce current computational bottlenecks by orders of magnitude on terascale computers, enabling scientific simulation on a scale heretofore impossible.

  14. Nonlinear theoretical formulation of elastic stability criterion of crystal solids

    NASA Astrophysics Data System (ADS)

    Wang, Hao; Li, Mo

    2012-03-01

    An elastic stability criterion is generally formulated based on local elasticity, where the second-order elastic constants of a crystalline system in an arbitrary deformed state are required. While simple in formalism, such a formulation demands extensive computational effort in either an ab initio calculation or an atomistic simulation and often lacks clear physical interpretation. Here, we present a nonlinear theoretical formulation employing higher-order elastic constants beyond the second-order ones; the elastic constants needed in the theory are those at a zero stress state or in any arbitrary deformed state, many of which are now available. We use the published second- and higher-order elastic constants of several cubic crystals, including Au, Al, and Cu, as well as diamond-structure Si, with transcription under different coordinate frames, to test the stability conditions of these crystals under uniaxial and hydrostatic loading. The stability region, ideal strength, and potential bifurcation mode of those cubic crystals under loading are obtained using this theory. The results obtained are in good agreement with the results from the ab initio calculation or embedded atom method. The overall good quality of the results confirms the desired utility of this new approach to predict elastic stability and related properties of crystalline materials without involving intense computation.

  15. A penalty method for PDE-constrained optimization in inverse problems

    NASA Astrophysics Data System (ADS)

    van Leeuwen, T.; Herrmann, F. J.

    2016-01-01

    Many inverse and parameter estimation problems can be written as PDE-constrained optimization problems. The goal is to infer the parameters, typically coefficients of the PDE, from partial measurements of the solutions of the PDE for several right-hand sides. Such PDE-constrained problems can be solved by finding a stationary point of the Lagrangian, which entails simultaneously updating the parameters and the (adjoint) state variables. For large-scale problems, such an all-at-once approach is not feasible as it requires storing all the state variables. In this case one usually resorts to a reduced approach where the constraints are explicitly eliminated (at each iteration) by solving the PDEs. These two approaches, and variations thereof, are the main workhorses for solving PDE-constrained optimization problems arising from inverse problems. In this paper, we present an alternative method that aims to combine the advantages of both approaches. Our method is based on a quadratic penalty formulation of the constrained optimization problem. By eliminating the state variable, we develop an efficient algorithm that has roughly the same computational complexity as the conventional reduced approach while exploiting a larger search space. Numerical results show that this method indeed reduces some of the nonlinearity of the problem and is less sensitive to the initial iterate.

  16. A numerical formulation for nonlinear ultrasonic waves propagation in fluids.

    PubMed

    Vanhille, C; Campos-Pozuelo, C

    2004-08-01

    A finite-difference algorithm is developed for analysing the nonlinear propagation of pulsed and harmonic ultrasonic waves in fluid media. The time domain model allows simulations from linear to strongly nonlinear plane waves including weak shock. Effects of absorption are included. All the harmonic components are obtained from only one solving process. The evolution of any original signal can be analysed. The nonlinear solution is obtained by the implicit scheme via a fast linear solver. The numerical model is validated by comparison to analytical data. Numerical experiments are presented and commented. The effect of the initial pulse shape on the evolution of the pressure waveform is especially analysed.

  17. Partial differential equation transform - Variational formulation and Fourier analysis.

    PubMed

    Wang, Yang; Wei, Guo-Wei; Yang, Siyang

    2011-12-01

    Nonlinear partial differential equation (PDE) models are established approaches for image/signal processing, data analysis and surface construction. Most previous geometric PDEs are utilized as low-pass filters which give rise to image trend information. In an earlier work, we introduced mode decomposition evolution equations (MoDEEs), which behave like high-pass filters and are able to systematically provide intrinsic mode functions (IMFs) of signals and images. Due to their tunable time-frequency localization and perfect reconstruction, the operation of MoDEEs is called a PDE transform. By appropriate selection of PDE transform parameters, we can tune IMFs into trends, edges, textures, noise etc., which can be further utilized in the secondary processing for various purposes. This work introduces the variational formulation, performs the Fourier analysis, and conducts biomedical and biological applications of the proposed PDE transform. The variational formulation offers an algorithm to incorporate two image functions and two sets of low-pass PDE operators in the total energy functional. Two low-pass PDE operators have different signs, leading to energy disparity, while a coupling term, acting as a relative fidelity of two image functions, is introduced to reduce the disparity of two energy components. We construct variational PDE transforms by using Euler-Lagrange equation and artificial time propagation. Fourier analysis of a simplified PDE transform is presented to shed light on the filter properties of high order PDE transforms. Such an analysis also offers insight on the parameter selection of the PDE transform. The proposed PDE transform algorithm is validated by numerous benchmark tests. In one selected challenging example, we illustrate the ability of PDE transform to separate two adjacent frequencies of sin(x) and sin(1.1x). Such an ability is due to PDE transform's controllable frequency localization obtained by adjusting the order of PDEs. The

  18. Partial differential equation transform — Variational formulation and Fourier analysis

    PubMed Central

    Wang, Yang; Wei, Guo-Wei; Yang, Siyang

    2011-01-01

    Nonlinear partial differential equation (PDE) models are established approaches for image/signal processing, data analysis and surface construction. Most previous geometric PDEs are utilized as low-pass filters which give rise to image trend information. In an earlier work, we introduced mode decomposition evolution equations (MoDEEs), which behave like high-pass filters and are able to systematically provide intrinsic mode functions (IMFs) of signals and images. Due to their tunable time-frequency localization and perfect reconstruction, the operation of MoDEEs is called a PDE transform. By appropriate selection of PDE transform parameters, we can tune IMFs into trends, edges, textures, noise etc., which can be further utilized in the secondary processing for various purposes. This work introduces the variational formulation, performs the Fourier analysis, and conducts biomedical and biological applications of the proposed PDE transform. The variational formulation offers an algorithm to incorporate two image functions and two sets of low-pass PDE operators in the total energy functional. Two low-pass PDE operators have different signs, leading to energy disparity, while a coupling term, acting as a relative fidelity of two image functions, is introduced to reduce the disparity of two energy components. We construct variational PDE transforms by using Euler-Lagrange equation and artificial time propagation. Fourier analysis of a simplified PDE transform is presented to shed light on the filter properties of high order PDE transforms. Such an analysis also offers insight on the parameter selection of the PDE transform. The proposed PDE transform algorithm is validated by numerous benchmark tests. In one selected challenging example, we illustrate the ability of PDE transform to separate two adjacent frequencies of sin(x) and sin(1.1x). Such an ability is due to PDE transform’s controllable frequency localization obtained by adjusting the order of PDEs. The

  19. Variational formulation for weakly nonlinear perturbations of ideal magnetohydrodynamics

    NASA Astrophysics Data System (ADS)

    Hirota, M.

    2011-10-01

    A new equation of motion that governs weakly nonlinear phenomena in ideal magnetohydrodynamics (MHDs) is derived as a natural extension of the well-known linearized equation of motion for the displacement field. This derivation is made possible by expanding the MHD Lagrangian explicitly up to third order with respect to the displacement of plasma, which necessitates an efficient use of the Lie series expansion. The resultant equation of motion (i.e. the Euler-Lagrange equation) includes a new quadratic force term which is responsible for various mode-mode coupling due to the MHD nonlinearity. The third-order potential energy serves to quantify the coupling coefficient among resonant three modes and its cubic symmetry proves the Manley-Rowe relations. In contrast to earlier works, the coupling coefficient is expressed only by the displacement vector field, which is already familiar in the linear MHD theory, and both the fixed and free boundary cases are treated systematically.

  20. Proper formulation of viscous dissipation for nonlinear waves in solids.

    PubMed

    Destrade, Michel; Saccomandi, Giuseppe; Vianello, Maurizio

    2013-03-01

    To model nonlinear viscous dissipative motions in solids, acoustical physicists usually add terms linear in Ė, the material time derivative of the Lagrangian strain tensor E, to the elastic stress tensor σ derived from the expansion to the third (sometimes fourth) order of the strain energy density E=E(tr E,tr E(2),tr E(3)). Here it is shown that this practice, which has been widely used in the past three decades or so, is physically wrong for at least two reasons and that it should be corrected. One reason is that the elastic stress tensor σ is not symmetric while Ė is symmetric, so that motions for which σ+σ(T)≠0 will give rise to elastic stresses that have no viscous pendant. Another reason is that Ė is frame-invariant, while σ is not, so that an observer transformation would alter the elastic part of the total stress differently than it would alter the dissipative part, thereby violating the fundamental principle of material frame indifference. These problems can have serious consequences for nonlinear shear wave propagation in soft solids as seen here with an example of a kink in almost incompressible soft solids.

  1. /N = 2 super W∞ algebra and its nonlinear realization through super KP formulation

    NASA Astrophysics Data System (ADS)

    Ghosh, Sasanka; Paul, Samir K.

    1995-01-01

    A nonlinear realizations of super W∞ algebra is shown to exist through a consistent superLax formulation of super KP hierarchy. The reduction of the superLax operator gives rise to the Lax operators for N = 2 generalized super KdV hierarchies, proposed by Inami and Kanno. The Lax equations are shown to be Hamiltonian and the associated Poisson bracket algebra among the superfields, consequently, gives rise to a realization of nonlinear super W∞ algebra.

  2. Optical wave turbulence: Towards a unified nonequilibrium thermodynamic formulation of statistical nonlinear optics

    NASA Astrophysics Data System (ADS)

    Picozzi, A.; Garnier, J.; Hansson, T.; Suret, P.; Randoux, S.; Millot, G.; Christodoulides, D. N.

    2014-09-01

    The nonlinear propagation of coherent optical fields has been extensively explored in the framework of nonlinear optics, while the linear propagation of incoherent fields has been widely studied in the framework of statistical optics. However, these two fundamental fields of optics have been mostly developed independently of each other, so that a satisfactory understanding of statistical nonlinear optics is still lacking. This article is aimed at reviewing a unified theoretical formulation of statistical nonlinear optics on the basis of the wave turbulence theory, which provides a nonequilibrium thermodynamic description of the system of incoherent nonlinear waves. We consider the nonlinear Schrödinger equation as a representative model accounting either for a nonlocal or a noninstantaneous nonlinearity, as well as higher-order dispersion effects. Depending on the amount of nonlocal (noninstantaneous) nonlinear interaction and the amount of inhomogeneous (nonstationary) statistics of the incoherent wave, different types of kinetic equations are derived and discussed. In the spatial domain, when the incoherent wave exhibits inhomogeneous statistical fluctuations, different forms of the (Hamiltonian) Vlasov equation are obtained depending on the amount of nonlocality. This Vlasov approach describes the processes of incoherent modulational instability and localized incoherent soliton structures. In the temporal domain, the causality property inherent to the response function leads to a kinetic formulation analogous to the weak Langmuir turbulence equation, which describes nonlocalized spectral incoherent solitons. In the presence of a highly noninstantaneous response, this formulation reduces to a family of singular integro-differential kinetic equations (e.g., Benjamin-Ono equation), which describe incoherent dispersive shock waves. Conversely, a non-stationary statistics leads to a (non-Hamiltonian) long-range Vlasov formulation, whose self-consistent potential is

  3. Ergodicity for Nonlinear Stochastic Equations in Variational Formulation

    SciTech Connect

    Barbu, Viorel Da Prato, Giuseppe

    2006-03-15

    This paper is concerned with nonlinear partial differential equations of the calculus of variation (see [13]) perturbed by noise. Well-posedness of the problem was proved by Pardoux in the seventies (see [14]), using monotonicity methods.The aim of the present work is to investigate the asymptotic behaviour of the corresponding transition semigroup P{sub t}. We show existence and, under suitable assumptions, uniqueness of an ergodic invariant measure {nu}. Moreover, we solve the Kolmogorov equation and prove the so-called 'identite du carre du champs'. This will be used to study the Sobolev space W{sup 1,2}(H,{nu}) and to obtain information on the domain of the infinitesimal generator of P{sub t}.

  4. ODE/PDE analysis of corneal curvature.

    PubMed

    Płociniczak, Lukasz; Griffiths, Graham W; Schiesser, William E

    2014-10-01

    The starting point for this paper is a nonlinear, two-point boundary value ordinary differential equation (BVODE) that defines corneal curvature according to a static force balance. A numerical solution to the BVODE is computed by first converting the BVODE to a parabolic partial differential equation (PDE) by adding an initial value (t, pseudo-time) derivative to the BVODE. A numerical solution to the PDE is then computed by the method of lines (MOL) with the calculation proceeding to a sufficiently large value of t such that the derivative in t reduces to essentially zero. The PDE solution at this point is also the solution for the BVODE. This procedure is implemented in R (an open source scientific programming system) and the programming is discussed in some detail. A series approximation to the solution is derived from which an estimate for the rate of convergence is obtained. This is compared to a fitted exponential model. Also, two linear approximations are derived, one of which leads to a closed form solution. Both provide solutions very close to that obtained from the full nonlinear model. An estimate for the cornea radius of curvature is also derived. The paper concludes with a discussion of the features of the solution to the ODE/PDE system.

  5. On high-continuity transfinite element formulations for linear-nonlinear transient thermal problems

    NASA Technical Reports Server (NTRS)

    Tamma, Kumar K.; Railkar, Sudhir B.

    1987-01-01

    This paper describes recent developments in the applicability of a hybrid transfinite element methodology with emphasis on high-continuity formulations for linear/nonlinear transient thermal problems. The proposed concepts furnish accurate temperature distributions and temperature gradients making use of a relatively smaller number of degrees of freedom; and the methodology is applicable to linear/nonlinear thermal problems. Characteristic features of the formulations are described in technical detail as the proposed hybrid approach combines the major advantages and modeling features of high-continuity thermal finite elements in conjunction with transform methods and classical Galerkin schemes. Several numerical test problems are evaluated and the results obtained validate the proposed concepts for linear/nonlinear thermal problems.

  6. SEACAS Theory Manuals: Part 1. Problem Formulation in Nonlinear Solid Mechancis

    SciTech Connect

    Attaway, S.W.; Laursen, T.A.; Zadoks, R.I.

    1998-08-01

    This report gives an introduction to the basic concepts and principles involved in the formulation of nonlinear problems in solid mechanics. By way of motivation, the discussion begins with a survey of some of the important sources of nonlinearity in solid mechanics applications, using wherever possible simple one dimensional idealizations to demonstrate the physical concepts. This discussion is then generalized by presenting generic statements of initial/boundary value problems in solid mechanics, using linear elasticity as a template and encompassing such ideas as strong and weak forms of boundary value problems, boundary and initial conditions, and dynamic and quasistatic idealizations. The notational framework used for the linearized problem is then extended to account for finite deformation of possibly inelastic solids, providing the context for the descriptions of nonlinear continuum mechanics, constitutive modeling, and finite element technology given in three companion reports.

  7. Model-based optimal design of experiments - semidefinite and nonlinear programming formulations.

    PubMed

    Duarte, Belmiro P M; Wong, Weng Kee; Oliveira, Nuno M C

    2016-02-15

    We use mathematical programming tools, such as Semidefinite Programming (SDP) and Nonlinear Programming (NLP)-based formulations to find optimal designs for models used in chemistry and chemical engineering. In particular, we employ local design-based setups in linear models and a Bayesian setup in nonlinear models to find optimal designs. In the latter case, Gaussian Quadrature Formulas (GQFs) are used to evaluate the optimality criterion averaged over the prior distribution for the model parameters. Mathematical programming techniques are then applied to solve the optimization problems. Because such methods require the design space be discretized, we also evaluate the impact of the discretization scheme on the generated design. We demonstrate the techniques for finding D-, A- and E-optimal designs using design problems in biochemical engineering and show the method can also be directly applied to tackle additional issues, such as heteroscedasticity in the model. Our results show that the NLP formulation produces highly efficient D-optimal designs but is computationally less efficient than that required for the SDP formulation. The efficiencies of the generated designs from the two methods are generally very close and so we recommend the SDP formulation in practice.

  8. Nonlinear consider covariance analysis using a sigma-point filter formulation

    NASA Technical Reports Server (NTRS)

    Lisano, Michael E.

    2006-01-01

    The research reported here extends the mathematical formulation of nonlinear, sigma-point estimators to enable consider covariance analysis for dynamical systems. This paper presents a novel sigma-point consider filter algorithm, for consider-parameterized nonlinear estimation, following the unscented Kalman filter (UKF) variation on the sigma-point filter formulation, which requires no partial derivatives of dynamics models or measurement models with respect to the parameter list. It is shown that, consistent with the attributes of sigma-point estimators, a consider-parameterized sigma-point estimator can be developed entirely without requiring the derivation of any partial-derivative matrices related to the dynamical system, the measurements, or the considered parameters, which appears to be an advantage over the formulation of a linear-theory sequential consider estimator. It is also demonstrated that a consider covariance analysis performed with this 'partial-derivative-free' formulation yields equivalent results to the linear-theory consider filter, for purely linear problems.

  9. Model-based optimal design of experiments - semidefinite and nonlinear programming formulations

    PubMed Central

    Duarte, Belmiro P.M.; Wong, Weng Kee; Oliveira, Nuno M.C.

    2015-01-01

    We use mathematical programming tools, such as Semidefinite Programming (SDP) and Nonlinear Programming (NLP)-based formulations to find optimal designs for models used in chemistry and chemical engineering. In particular, we employ local design-based setups in linear models and a Bayesian setup in nonlinear models to find optimal designs. In the latter case, Gaussian Quadrature Formulas (GQFs) are used to evaluate the optimality criterion averaged over the prior distribution for the model parameters. Mathematical programming techniques are then applied to solve the optimization problems. Because such methods require the design space be discretized, we also evaluate the impact of the discretization scheme on the generated design. We demonstrate the techniques for finding D–, A– and E–optimal designs using design problems in biochemical engineering and show the method can also be directly applied to tackle additional issues, such as heteroscedasticity in the model. Our results show that the NLP formulation produces highly efficient D–optimal designs but is computationally less efficient than that required for the SDP formulation. The efficiencies of the generated designs from the two methods are generally very close and so we recommend the SDP formulation in practice. PMID:26949279

  10. A special case of the Poisson PDE formulated for Earth's surface and its capability to approximate the terrain mass density employing land-based gravity data, a case study in the south of Iran

    NASA Astrophysics Data System (ADS)

    AllahTavakoli, Yahya; Safari, Abdolreza; Vaníček, Petr

    2016-12-01

    This paper resurrects a version of Poisson's Partial Differential Equation (PDE) associated with the gravitational field at the Earth's surface and illustrates how the PDE possesses a capability to extract the mass density of Earth's topography from land-based gravity data. Herein, first we propound a theorem which mathematically introduces this version of Poisson's PDE adapted for the Earth's surface and then we use this PDE to develop a method of approximating the terrain mass density. Also, we carry out a real case study showing how the proposed approach is able to be applied to a set of land-based gravity data. In the case study, the method is summarized by an algorithm and applied to a set of gravity stations located along a part of the north coast of the Persian Gulf in the south of Iran. The results were numerically validated via rock-samplings as well as a geological map. Also, the method was compared with two conventional methods of mass density reduction. The numerical experiments indicate that the Poisson PDE at the Earth's surface has the capability to extract the mass density from land-based gravity data and is able to provide an alternative and somewhat more precise method of estimating the terrain mass density.

  11. Regional evaporation estimates in the eastern monsoon region of China: Assessment of a nonlinear formulation of the complementary principle

    NASA Astrophysics Data System (ADS)

    Liu, Xiaomang; Liu, Changming; Brutsaert, Wilfried

    2016-12-01

    The performance of a nonlinear formulation of the complementary principle for evaporation estimation was investigated in 241 catchments with different climate conditions in the eastern monsoon region of China. Evaporation (Ea) calculated by the water balance equation was used as the reference. Ea estimated by the calibrated nonlinear formulation was generally in good agreement with the water balance results, especially in relatively dry catchments. The single parameter in the nonlinear formulation, namely αe as a weak analog of the alpha parameter of Priestley and Taylor (), tended to exhibit larger values in warmer and humid near-coastal areas, but smaller values in colder, drier environments inland, with a significant dependency on the aridity index (AI). The nonlinear formulation combined with the equation relating the one parameter and AI provides a promising method to estimate regional Ea with standard and routinely measured meteorological data.

  12. An application of nonlinear programming to the design of regulators of a linear-quadratic formulation

    NASA Technical Reports Server (NTRS)

    Fleming, P.

    1983-01-01

    A design technique is proposed for linear regulators in which a feedback controller of fixed structure is chosen to minimize an integral quadratic objective function subject to the satisfaction of integral quadratic constraint functions. Application of a nonlinear programming algorithm to this mathematically tractable formulation results in an efficient and useful computer aided design tool. Particular attention is paid to computational efficiency and various recommendations are made. Two design examples illustrate the flexibility of the approach and highlight the special insight afforded to the designer. One concerns helicopter longitudinal dynamics and the other the flight dynamics of an aerodynamically unstable aircraft.

  13. A Green's function formulation for a nonlinear potential flow solution applicable to transonic flow

    NASA Technical Reports Server (NTRS)

    Baker, A. J.; Fox, C. H., Jr.

    1977-01-01

    Routine determination of inviscid subsonic flow fields about wing-body-tail configurations employing a Green's function approach for numerical solution of the perturbation velocity potential equation is successfully extended into the high subsonic subcritical flow regime and into the shock-free supersonic flow regime. A modified Green's function formulation, valid throughout a range of Mach numbers including transonic, that takes an explicit accounting of the intrinsic nonlinearity in the parent governing partial differential equations is developed. Some considerations pertinent to flow field predictions in the transonic flow regime are discussed.

  14. CAD of control systems: Application of nonlinear programming to a linear quadratic formulation

    NASA Technical Reports Server (NTRS)

    Fleming, P.

    1983-01-01

    The familiar suboptimal regulator design approach is recast as a constrained optimization problem and incorporated in a Computer Aided Design (CAD) package where both design objective and constraints are quadratic cost functions. This formulation permits the separate consideration of, for example, model following errors, sensitivity measures and control energy as objectives to be minimized or limits to be observed. Efficient techniques for computing the interrelated cost functions and their gradients are utilized in conjunction with a nonlinear programming algorithm. The effectiveness of the approach and the degree of insight into the problem which it affords is illustrated in a helicopter regulation design example.

  15. Implementation of Free-Formulation-Based Flat Shell Elements into NASA Comet Code and Development of Nonlinear Shallow Shell Element

    NASA Technical Reports Server (NTRS)

    Barut, A.; Madenci, Erdogan; Tessler, A.

    1997-01-01

    This study presents a transient nonlinear finite element analysis within the realm of a multi-body dynamics formulation for determining the dynamic response of a moderately thick laminated shell undergoing a rapid and large rotational motion and nonlinear elastic deformations. Nonlinear strain measure and rotation, as well as 'the transverse shear deformation, are explicitly included in the formulation in order to capture the proper motion-induced stiffness of the laminate. The equations of motion are derived from the virtual work principle. The analysis utilizes a shear deformable shallow shell element along with the co-rotational form of the updated Lagrangian formulation. The shallow shell element formulation is based on the Reissner-Mindlin and Marguerre theory.

  16. A survey of the core-congruential formulation for geometrically nonlinear TL finite elements

    NASA Technical Reports Server (NTRS)

    Felippa, Carlos A.; Crivelli, Luis A.; Haugen, Bjorn

    1994-01-01

    This article presents a survey of the core-congruential formulation (CCF) for geometrically nonlinear mechanical finite elements based on the total Lagrangian (TL) kinematic description. Although the key ideas behind the CCF can be traced back to Rajasekaran and Murray in 1973, it has not subsequently received serious attention. The CCF is distinguished by a two-phase development of the finite element stiffness equations. The initial phase developed equations for individual particles. These equations are expressed in terms of displacement gradients as degrees of freedom. The second phase involves congruential-type transformations that eventually binds the element particles of an individual element in terms of its node-displacement degrees of freedom. Two versions of the CCF, labeled direct and generalized, are distinguished. The direct CCF (DCCF) is first described in general form and then applied to the derivation of geometrically nonlinear bar, and plane stress elements using the Green-Lagrange strain measure. The more complex generalized CCF (GCCF) is described and applied to the derivation of 2D and 3D Timoshenko beam elements. Several advantages of the CCF, notably the physically clean separation of material and geometric stiffnesses, and its independence with respect to the ultimate choice of shape functions and element degrees of freedom, are noted. Application examples involving very large motions solved with the 3D beam element display the range of applicability of this formulation, which transcends the kinematic limitations commonly attributed to the TL description.

  17. Nonlinear force-free coronal magnetic field extrapolation scheme based on the direct boundary integral formulation

    NASA Astrophysics Data System (ADS)

    He, Han; Wang, Huaning

    2008-05-01

    The boundary integral equation (BIE) method was first proposed by Yan and Sakurai (2000) and used to extrapolate the nonlinear force-free magnetic field in the solar atmosphere. Recently, Yan and Li (2006) improved the BIE method and proposed the direct boundary integral equation (DBIE) formulation, which represents the nonlinear force-free magnetic field by direct integration of the magnetic field on the bottom boundary surface. On the basis of this new method, we devised a practical calculation scheme for the nonlinear force-free field extrapolation above solar active regions. The code of the scheme was tested by the analytical solutions of Low and Lou (1990) and was applied to the observed vector magnetogram of solar active region NOAA 9077. The results of the calculations show that the improvement of the new computational scheme to the scheme of Yan and Li (2006) is significant, and the force-free and divergence-free constraints are well satisfied in the extrapolated fields. The calculated field lines for NOAA 9077 present the X-shaped structure and can be helpful for understanding the magnetic configuration of the filament channel as well as the magnetic reconnection process during the Bastille Day flare on 14 July 2000.

  18. Thermomechanical formulation of ductile damage coupled to nonlinear isotropic hardening and multiplicative viscoplasticity

    NASA Astrophysics Data System (ADS)

    Soyarslan, C.; Bargmann, S.

    2016-06-01

    In this paper, we present a thermomechanical framework which makes use of the internal variable theory of thermodynamics for damage-coupled finite viscoplasticity with nonlinear isotropic hardening. Damage evolution, being an irreversible process, generates heat. In addition to its direct effect on material's strength and stiffness, it causes deterioration of the heat conduction. The formulation, following the footsteps of Simó and Miehe (1992), introduces inelastic entropy as an additional state variable. Given a temperature dependent damage dissipation potential, we show that the evolution of inelastic entropy assumes a split form relating to plastic and damage parts, respectively. The solution of the thermomechanical problem is based on the so-called isothermal split. This allows the use of the model in 2D and 3D example problems involving geometrical imperfection triggered necking in an axisymmetric bar and thermally triggered necking of a 3D rectangular bar.

  19. A kinetic formulation of piezoresistance in N-type silicon: Application to non-linear effects

    NASA Astrophysics Data System (ADS)

    Charbonnieras, A. R.; Tellier, C. R.

    1999-07-01

    This paper is devoted to the theoretical study of the influence of the temperature and of the doping on the piezoresistance of N-type silicon. In the first step the fractional change in the resistivity caused by stresses is calculated in the framework of a multivalley model using a kinetic transport formulation based on the Boltzmann transport equation. In the second step shifts in the minima of the conduction band and the resulting shift of the Fermi level are expressed in terms of deformation potentials and of stresses. General expressions for the fundamental linear, π_{11} and π_{12}, and non-linear, π_{111}, π_{112}, π_{122} and π_{123}, piezoresistance coefficients are then derived. Plots of the non-linear piezoresistance coefficients against the reduced shift of the Fermi level or against temperature allow us to characterize the influence of doping and temperature. Finally some attempts are made to estimate the non-linearity for heavily doped semiconductor gauges. Cette publication est consacrée à l'étude théorique de l'influence de la température et du dopage sur la piezorésistivité du silicium type N. Dans une première étape nous adoptons le modèle de vallées et nous utilisons une formulation cinétique du transport électronique faisant appel à l'équation de transport de Boltzmann pour calculer la variation de la résistivité du semiconducteur sous contrainte. Dans la deuxième étape nous exprimons les déplacements des minima de la bande de conduction et du niveau de Fermi en termes de potentiels de déformation et de contraintes. Nous proposons ensuite des expressions générales pour les coefficients piezorésistifs fondamentaux linéaires, π_{11} et π_{12}, et non-linéaires, π_{111}, π_{112}, π_{122} et π_{123}. Des représentations graphiques des variations des coefficients non-linéaires permettent de caractériser l'influence du dopage et de la température. Enfin nous fournissons une première pré-estimation des effets

  20. A galerkin/neural-network-based design of guaranteed cost control for nonlinear distributed parameter systems.

    PubMed

    Wu, Huai-Ning; Li, Han-Xiong

    2008-05-01

    This paper presents a Galerkin/neural-network- based guaranteed cost control (GCC) design for a class of parabolic partial differential equation (PDE) systems with unknown nonlinearities. A parabolic PDE system typically involves a spatial differential operator with eigenspectrum that can be partitioned into a finite-dimensional slow one and an infinite-dimensional stable fast complement. Motivated by this, in the proposed control scheme, Galerkin method is initially applied to the PDE system to derive an ordinary differential equation (ODE) system with unknown nonlinearities, which accurately describes the dynamics of the dominant (slow) modes of the PDE system. The resulting nonlinear ODE system is subsequently parameterized by a multilayer neural network (MNN) with one-hidden layer and zero bias terms. Then, based on the neural model and a Lure-type Lyapunov function, a linear modal feedback controller is developed to stabilize the closed-loop PDE system and provide an upper bound for the quadratic cost function associated with the finite-dimensional slow system for all admissible approximation errors of the network. The outcome of the GCC problem is formulated as a linear matrix inequality (LMI) problem. Moreover, by using the existing LMI optimization technique, a suboptimal guaranteed cost controller in the sense of minimizing the cost bound is obtained. Finally, the proposed design method is applied to the control of the temperature profile of a catalytic rod.

  1. Evaluation of nonlinear structural dynamic responses using a fast-running spring-mass formulation

    NASA Astrophysics Data System (ADS)

    Benjamin, A. S.; Altman, B. S.; Gruda, J. D.

    In today's world, accurate finite-element simulations of large nonlinear systems may require meshes composed of hundreds of thousands of degrees of freedom. Even with today's fast computers and the promise of ever-faster ones in the future, central processing unit (CPU) expenditures for such problems could be measured in days. Many contemporary engineering problems, such as those found in risk assessment, probabilistic structural analysis, and structural design optimization, cannot tolerate the cost or turnaround time for such CPU-intensive analyses, because these applications require a large number of cases to be run with different inputs. For many risk assessment applications, analysts would prefer running times to be measurable in minutes. There is therefore a need for approximation methods which can solve such problems far more efficiently than the very detailed methods and yet maintain an acceptable degree of accuracy. For this purpose, we have been working on two methods of approximation: neural networks and spring-mass models. This paper presents our work and results to date for spring-mass modeling and analysis, since we are further along in this area than in the neural network formulation. It describes the physical and numerical models contained in a code we developed called STRESS, which stands for 'Spring-mass Transient Response Evaluation for structural Systems'. The paper also presents results for a demonstration problem, and compares these with results obtained for the same problem using PRONTO3D, a state-of-the-art finite element code which was also developed at Sandia.

  2. Evaluation of nonlinear structural dynamic responses using a fast-running spring-mass formulation

    SciTech Connect

    Benjamin, A.S.; Altman, B.S.; Gruda, J.D.

    1995-03-01

    In today`s world, accurate finite-element simulations of large nonlinear systems may require meshes composed of hundreds of thousands of degrees of freedom. Even with today`s fast computers and the promise of ever-faster ones in the future, central processing unit (CPU) expenditures for such problems could be measured in days. Many contemporary engineering problems, such as those found in risk assessment, probabilistic structural analysis, and structural design optimization, cannot tolerate the cost or turnaround time for such CPU-intensive analyses, because these applications require a large number of cases to be run with different inputs. For many risk assessment applications, analysts would prefer running times to be measurable in minutes. There is therefore a need for approximation methods which can solve such problems far more efficiently than the very detailed methods and yet maintain an acceptable degree of accuracy. For this purpose, we have been working on two methods of approximation: neural networks and spring-mass models. This paper presents our work and results to date for spring-mass modeling and analysis, since we are further along in this area than in the neural network formulation. It describes the physical and numerical models contained in a code we developed called STRESS, which stands for ``Spring-mass Transient Response Evaluation for structural Systems``. The paper also presents results for a demonstration problem, and compares these with results obtained for the same problem using PRONTO3D, a state-of-the-art finite element code which was also developed at Sandia.

  3. Semi-analytical formulation of modal dispersion parameter of an optical fiber with Kerr nonlinearity and using a novel fundamental modal field approximation

    NASA Astrophysics Data System (ADS)

    Choudhury, Raja Roy; Choudhury, Arundhati Roy; Ghose, Mrinal Kanti

    2013-09-01

    To characterize nonlinear optical fiber, a semi-analytical formulation using variational principle and the Nelder-Mead Simplex method for nonlinear unconstrained minimization is proposed. The number of optimizing parameters in order to optimize core parameter U has been increased to incorporate more flexibility in the formulation of an innovative form of fundamental modal field. This formulation provides accurate analytical expressions for modal dispersion parameter (g) of optical fiber with Kerr nonlinearity. The minimization of core parameter (U), which involves Kerr nonlinearity through the nonstationary expression of propagation constant, is carried out by the Nelder-Mead Simplex method of nonlinear unconstrained minimization, suitable for problems with nonsmooth functions as the method does not require any derivative information. This formulation has less computational burden for calculation of modal parameters than full numerical methods.

  4. Investigation of PDE5/PDE6 and PDE5/PDE11 selective potent tadalafil-like PDE5 inhibitors using combination of molecular modeling approaches, molecular fingerprint-based virtual screening protocols and structure-based pharmacophore development.

    PubMed

    Kayık, Gülru; Tüzün, Nurcan Ş; Durdagi, Serdar

    2017-12-01

    The essential biological function of phosphodiesterase (PDE) type enzymes is to regulate the cytoplasmic levels of intracellular second messengers, 3',5'-cyclic guanosine monophosphate (cGMP) and/or 3',5'-cyclic adenosine monophosphate (cAMP). PDE targets have 11 isoenzymes. Of these enzymes, PDE5 has attracted a special attention over the years after its recognition as being the target enzyme in treating erectile dysfunction. Due to the amino acid sequence and the secondary structural similarity of PDE6 and PDE11 with the catalytic domain of PDE5, first-generation PDE5 inhibitors (i.e. sildenafil and vardenafil) are also competitive inhibitors of PDE6 and PDE11. Since the major challenge of designing novel PDE5 inhibitors is to decrease their cross-reactivity with PDE6 and PDE11, in this study, we attempt to identify potent tadalafil-like PDE5 inhibitors that have PDE5/PDE6 and PDE5/PDE11 selectivity. For this aim, the similarity-based virtual screening protocol is applied for the "clean drug-like subset of ZINC database" that contains more than 20 million small compounds. Moreover, molecular dynamics (MD) simulations of selected hits complexed with PDE5 and off-targets were performed in order to get insights for structural and dynamical behaviors of the selected molecules as selective PDE5 inhibitors. Since tadalafil blocks hERG1 K channels in concentration dependent manner, the cardiotoxicity prediction of the hit molecules was also tested. Results of this study can be useful for designing of novel, safe and selective PDE5 inhibitors.

  5. Is PDE4 too difficult a drug target?

    PubMed

    Higgs, Gerry

    2010-05-01

    The search for selective inhibitors of PDE4 as novel anti-inflammatory drugs has continued for more than 30 years. Although several compounds have demonstrated therapeutic effects in diseases such as asthma, COPD, atopic dermatitis and psoriasis, none have reached the market. A persistent challenge in the development of PDE4 inhibitors has been drug-induced gastrointestinal adverse effects, such as nausea. However, extensive clinical trials with well-tolerated doses of roflumilast (Daxas; Nycomed/Mitsubishi Tanabe Pharma Corp/Forest Laboratories Inc) in COPD, a disease that is generally unresponsive to existing therapies, have demonstrated significant therapeutic improvements. In addition, GlaxoSmithKline plc is developing 256066, an inhaled formulation of a PDE4 inhibitor that has demonstrated efficacy in trials in asthma, and apremilast from Celgene Corp has been reported to be effective for the treatment of psoriasis. Despite the challenges and complications that have been encountered during the development of PDE4 inhibitors, these drugs may provide a genuinely novel class of anti-inflammatory agents, and there are several compounds in development that could fulfill that promise.

  6. PDE11A negatively regulates lithium responsivity

    PubMed Central

    Pathak, G.; Agostino, M.J.; Bishara, K.; Capell, W.R.; Fisher, J.L.; Hegde, S.; Ibrahim, B.A.; Pilarzyk, Kaitlyn; Sabin, C.; Tuczkewycz, Taras; Wilson, Steven; Kelly, M.P.

    2016-01-01

    Lithium responsivity in patients with bipolar disorder has been genetically associated with Phosphodiesterase 11A (PDE11A), and lithium decreases PDE11A mRNA in IPSC-derived hippocampal neurons originating from lithium responsive patients. PDE11 is an enzyme uniquely enriched in the hippocampus that breaks down cAMP and cGMP. Here, we determined if decreasing PDE11A expression is sufficient to increase lithium responsivity in mice. In dorsal hippocampus (DHIPP) and ventral hippocampus (VHIPP), lithium-responsive C57BL/6J and 129S6/SvEvTac mice show decreased PDE11A4 protein expression relative to lithium-unresponsive BALB/cJ mice. In VHIPP, C57BL/6J mice also show differences in PDE11A4 compartmentalization relative to BALB/cJ mice. In contrast, neither PDE2A nor PDE10A expression differ among the strains. The compartment-specific differences in PDE11A4 protein expression are explained by a coding SNP at amino acid 499, which falls within the GAF-B homodimerization domain. Relative to the BALB/cJ 499T, the C57BL/6J 499A decreases PDE11A4 homodimerization, which removes PDE11A4 from the membrane. Consistent with the observation that lower PDE11A4 expression correlates with better lithium responsiveness, we found that Pde11a KO mice given 0.4% lithium chow for 3+ weeks exhibit greater lithium responsivity relative to WT littermates in tail suspension, an antidepressant predictive assay, and amphetamine hyperlocomotion, an anti-manic predictive assay. Reduced PDE11A4 expression may represent a lithium-sensitive pathophysiology, because both C57BL/6J and Pde11a KO mice show increased expression of the pro-inflammatory cytokine IL-6 relative to BALB/cJ and PDE11A WT mice, respectively. Our finding that PDE11A4 negatively regulates lithium responsivity in mice suggests that the PDE11A SNPs identified in patients may be functionally relevant. PMID:27646265

  7. A local PDE model of aggregation formation in bacterial colonies

    NASA Astrophysics Data System (ADS)

    Chavy-Waddy, Paul-Christopher; Kolokolnikov, Theodore

    2016-10-01

    We study pattern formation in a model of cyanobacteria motion recently proposed by Galante, Wisen, Bhaya and Levy. By taking a continuum limit of their model, we derive a novel fourth-order nonlinear parabolic PDE equation that governs the behaviour of the model. This PDE is {{u}t}=-{{u}xx}-{{u}xxxx}+α {{≤ft(\\frac{{{u}x}{{u}xx}}{u}\\right)}x} . We then derive the instability thresholds for the onset of pattern formation. We also compute analytically the spatial profiles of the steady state aggregation density. These profiles are shown to be of the form \\text{sec}{{\\text{h}}p} where the exponent p is related to the parameters of the model. Full numerical simulations give a favorable comparison between the continuum and the underlying discrete system, and show that the aggregation profiles are stable above the critical threshold.

  8. Interaction of Lyapunov vectors in the formulation of the nonlinear extension of the Kalman filter.

    PubMed

    Palatella, Luigi; Trevisan, Anna

    2015-04-01

    When applied to strongly nonlinear chaotic dynamics the extended Kalman filter (EKF) is prone to divergence due to the difficulty of correctly forecasting the forecast error probability density function. In operational forecasting applications ensemble Kalman filters circumvent this problem with empirical procedures such as covariance inflation. This paper presents an extension of the EKF that includes nonlinear terms in the evolution of the forecast error estimate. This is achieved starting from a particular square-root implementation of the EKF with assimilation confined in the unstable subspace (EKF-AUS), that is, the span of the Lyapunov vectors with non-negative exponents. When the error evolution is nonlinear, the space where it is confined is no more restricted to the unstable and neutral subspace causing filter divergence. The algorithm presented here, denominated EKF-AUS-NL, includes the nonlinear terms in the error dynamics: These result from the nonlinear interaction among the leading Lyapunov vectors and account for all directions where the error growth may take place. Numerical results show that with the nonlinear terms included, filter divergence can be avoided. We test the algorithm on the Lorenz96 model, showing very promising results.

  9. Updated Lagrangian finite element formulations of various biological soft tissue non-linear material models: a comprehensive procedure and review.

    PubMed

    Townsend, Molly T; Sarigul-Klijn, Nesrin

    2016-01-01

    Simplified material models are commonly used in computational simulation of biological soft tissue as an approximation of the complicated material response and to minimize computational resources. However, the simulation of complex loadings, such as long-duration tissue swelling, necessitates complex models that are not easy to formulate. This paper strives to offer the updated Lagrangian formulation comprehensive procedure of various non-linear material models for the application of finite element analysis of biological soft tissues including a definition of the Cauchy stress and the spatial tangential stiffness. The relationships between water content, osmotic pressure, ionic concentration and the pore pressure stress of the tissue are discussed with the merits of these models and their applications.

  10. Nonlinear incompressible finite element for simulating loading of cardiac tissue--Part I: Two dimensional formulation for thin myocardial strips.

    PubMed

    Horowitz, A; Sheinman, I; Lanir, Y; Perl, M; Sideman, S

    1988-02-01

    A two-dimensional incompressible plane-stress finite element is formulated for the simulation of the passive-state mechanics of thin myocardial strips. The formulation employs a total Lagrangian and materially nonlinear approach, being based on a recently proposed structural material law, which is derived from the histological composition of the tissue. The ensuing finite element allows to demonstrate the mechanical properties of a single myocardial layer containing uniformly directed fibers by simulating various loading cases such as tension, compression and shear. The results of these cases show that the fiber direction is considerably stiffer than the cross-fiber direction, that there is significant coupling between these two directions, and that the shear stiffness of the tissue is lower than its tensile and compressive stiffness.

  11. A non-linear programming approach to the computer-aided design of regulators using a linear-quadratic formulation

    NASA Technical Reports Server (NTRS)

    Fleming, P.

    1985-01-01

    A design technique is proposed for linear regulators in which a feedback controller of fixed structure is chosen to minimize an integral quadratic objective function subject to the satisfaction of integral quadratic constraint functions. Application of a non-linear programming algorithm to this mathematically tractable formulation results in an efficient and useful computer-aided design tool. Particular attention is paid to computational efficiency and various recommendations are made. Two design examples illustrate the flexibility of the approach and highlight the special insight afforded to the designer.

  12. A mixed finite element formulation for a non-linear, transversely isotropic material model for the cardiac tissue.

    PubMed

    Thorvaldsen, Tom; Osnes, Harald; Sundnes, Joakim

    2005-12-01

    In this paper we present a mixed finite element method for modeling the passive properties of the myocardium. The passive properties are described by a non-linear, transversely isotropic, hyperelastic material model, and the myocardium is assumed to be almost incompressible. Single-field, pure displacement-based formulations are known to cause numerical difficulties when applied to incompressible or slightly compressible material cases. This paper presents an alternative approach in the form of a mixed formulation, where a separately interpolated pressure field is introduced as a primary unknown in addition to the displacement field. Moreover, a constraint term is included in the formulation to enforce (almost) incompressibility. Numerical results presented in the paper demonstrate the difficulties related to employing a pure displacement-based method, applying a set of physically relevant material parameter values for the cardiac tissue. The same problems are not experienced for the proposed mixed method. We show that the mixed formulation provides reasonable numerical results for compressible as well as nearly incompressible cases, also in situations of large fiber stretches. There is good agreement between the numerical results and the underlying analytical models.

  13. Square-root formulation of the SVSF with applications to nonlinear target tracking problems

    NASA Astrophysics Data System (ADS)

    Gadsden, S. A.; Al-Shabi, M.; Kirubarajan, T.

    2015-05-01

    The smooth variable structure filter (SVSF) is a state and parameter estimation strategy based on sliding mode concepts. It has seen significant development and research activity in recent years. In an effort to improve upon the numerical stability of the SVSF, a square-root formulation is derived. The square-root SVSF is based on Potter's algorithm. The proposed formulation is computationally more efficient and reduces the risks of failure due to numerical instability. The new strategy is applied on target tracking scenarios for the purposes of state estimation. The results are compared with the popular Kalman filter.

  14. Structure -activity relationships of PDE5 inhibitors.

    PubMed

    Eros, D; Szántai-Kis, Cs; Kiss, R; Kéri, Gy; Hegymegi-Barakonyi, B; Kövesdi, I; Orfi, L

    2008-01-01

    cGMP has a short-term effect on smooth muscle tone and a longer-term effect on responses to chronic drug treatment or proliferative signals. cGMP-Phosphodiesterase type 5 (PDE5) hydrolizes cGMP, and the result is smooth muscle contraction. PDE5 is a relatively novel therapeutic target of various diseases, such as erectile dysfunction and pulmonary hypertension. The most intensively examined and marketed PDE5 inhibitor was sildenafil (Viagra) but recently vardenafil (Levitra) and tadalafil (Cialis) were launched with beneficial ADME parameters and PDE5 selectivity. The increasing interest in PDE5 inhibition made it reasonable to collect the available inhibitory data from the scientific literature and set up a structure-activity relationship study. Chemical structures of 438 compounds and their cGMP-PDE5 inhibitory data (IC50) were collected from recently published articles. In this paper physiology, regulation and inhibition of PDE5 (and briefly other PDE-s) are discussed and inhibitors are tabulated by the core structures. Finally, a general QSAR model built from these data is presented. All data used in the QSAR study were summarized in a Supplement (for description please see the online version of the article).

  15. From a Nonlinear, Nonconvex Variational Problem to a Linear, Convex Formulation

    SciTech Connect

    Egozcue, J. Meziat, R. Pedregal, P.

    2002-12-19

    We propose a general approach to deal with nonlinear, nonconvex variational problems based on a reformulation of the problem resulting in an optimization problem with linear cost functional and convex constraints. As a first step we explicitly explore these ideas to some one-dimensional variational problems and obtain specific conclusions of an analytical and numerical nature.

  16. The uncertainty principle and a semiclassical nonlinear differential equation formulation for bound states

    NASA Astrophysics Data System (ADS)

    Mukhopadhyay, S.; Bhattacharyya, K.

    2000-10-01

    The kinship of a simple variational scheme involving the uncertainty product with a prevalent semiclassical nonlinear differential equation approach for finding energies of stationary states is established. This leads to a transparent physical interpretation of the embedded parameters in the latter approach, providing additionally a lower bound to the integration constant. The domain of applicability of this strategy is also extended to encompass neighbouring states. Other advantages of the simpler alternative route are stressed. Pilot calculations demonstrate nicely the efficacy of the endeavour.

  17. Wavefront Propagation for Reaction-Diffusion Systems of PDE

    DTIC Science & Technology

    1989-03-01

    scaled reaction- diffusion system: C C 1 (u)in R n X (O,cc)uk = cdkAu + - fn u = gk on Rn x 40k Here the constants dk (15kSm), and the functions n m m...m) 3 is a bounded, smooth subset of R n . Under these assumptions there exists a unique smooth solution u€ of the PDE (1.1) , with C u > 0 in Rn x...the Kolmogorov-Petrovskii- Piskunov nonlinearity, discussed in (6]. Our main result, Theorem 1, asserts that under hypotheses (FI) - (F5) uC (x,t

  18. An asymptotically stable robust controller formulation for a class of MIMO nonlinear systems with uncertain dynamics

    NASA Astrophysics Data System (ADS)

    Bidikli, Baris; Tatlicioglu, Enver; Zergeroglu, Erkan; Bayrak, Alper

    2016-09-01

    In this work, we present a novel continuous robust controller for a class of multi-input/multi-output nonlinear systems that contains unstructured uncertainties in their drift vectors and input matrices. The proposed controller compensates uncertainties in the system dynamics and achieves asymptotic tracking while requiring only the knowledge of the sign of the leading principal minors of the input gain matrix. A Lyapunov-based argument backed up with an integral inequality is applied to prove the asymptotic stability of the closed-loop system. Simulation results are presented to illustrate the viability of the proposed method.

  19. A stabilized complementarity formulation for nonlinear analysis of 3D bimodular materials

    NASA Astrophysics Data System (ADS)

    Zhang, L.; Zhang, H. W.; Wu, J.; Yan, B.

    2016-06-01

    Bi-modulus materials with different mechanical responses in tension and compression are often found in civil, composite, and biological engineering. Numerical analysis of bimodular materials is strongly nonlinear and convergence is usually a problem for traditional iterative schemes. This paper aims to develop a stabilized computational method for nonlinear analysis of 3D bimodular materials. Based on the parametric variational principle, a unified constitutive equation of 3D bimodular materials is proposed, which allows the eight principal stress states to be indicated by three parametric variables introduced in the principal stress directions. The original problem is transformed into a standard linear complementarity problem (LCP) by the parametric virtual work principle and a quadratic programming algorithm is developed by solving the LCP with the classic Lemke's algorithm. Update of elasticity and stiffness matrices is avoided and, thus, the proposed algorithm shows an excellent convergence behavior compared with traditional iterative schemes. Numerical examples show that the proposed method is valid and can accurately analyze mechanical responses of 3D bimodular materials. Also, stability of the algorithm is greatly improved.

  20. A solution procedure for mixed-integer nonlinear programming formulation of supply chain planning with quantity discounts under demand uncertainty

    NASA Astrophysics Data System (ADS)

    Yin, Sisi; Nishi, Tatsushi

    2014-11-01

    Quantity discount policy is decision-making for trade-off prices between suppliers and manufacturers while production is changeable due to demand fluctuations in a real market. In this paper, quantity discount models which consider selection of contract suppliers, production quantity and inventory simultaneously are addressed. The supply chain planning problem with quantity discounts under demand uncertainty is formulated as a mixed-integer nonlinear programming problem (MINLP) with integral terms. We apply an outer-approximation method to solve MINLP problems. In order to improve the efficiency of the proposed method, the problem is reformulated as a stochastic model replacing the integral terms by using a normalisation technique. We present numerical examples to demonstrate the efficiency of the proposed method.

  1. A continuum three-dimensional, fully coupled, dynamic, non-linear finite element formulation for magnetostrictive materials

    NASA Astrophysics Data System (ADS)

    Pérez-Aparicio, José L.; Sosa, Horacio

    2004-06-01

    Magnetostriction is a phenomenon observed in all ferromagnetic materials. It couples elastic, electric, magnetic and in some situations also thermal fields and is of great industrial interest for use in sensors, actuators, adaptive or functional structures, robotics, transducers and MEMS. In this work, the governing equations of the three-field problem (i.e., the interactions of elastic, electric and magnetic effects) are formulated in three dimensions, accounting for non-linear (through magnetic body forces represented by the Maxwell tensor) and dynamic effects, and with constitutive equations resembling those of piezoelectricity. Through manipulation of Maxwell equations it is possible to find suitable expressions for developing the numerical weak, Galerkin and matrix forms in a natural way, including seven residuals (one for each nodal degree of freedom) and non-symmetric tangent, 'capacity' and mass consistent matrices. Simple backward Euler and central difference schemes can be used for the time domain integration. The only assumption made in this work for simplification is that the time variation of electric induction is negligible. This is justified by the relatively low frequencies ({\\ll }1 GHz) under which magnetostrictive materials usually work. The principal feature of the equations is the use of a magnetic potential (without much physical meaning) that allows a complete 'displacement' finite element formulation: all elastic, electric and magnetic nodal unknowns are zero derivatives. This allows the algorithm to be treated in a standard way, and important effects such as eddy currents can be obtained naturally. The formulation is implemented in the research finite element code FEAP. Although seven degrees of freedom per node is computer expensive to solve (especially for 3D problems), the current trend in the performance of computers, even personal ones, makes it worthwhile to build complete finite elements following the well-established (in mechanics

  2. Inhibitors of phosphodiesterases PDE2, PDE3, and PDE4 do not increase the sinoatrial tachycardia of noradrenaline and prostaglandin PGE₁ in mice.

    PubMed

    Galindo-Tovar, Alejandro; Vargas, María Luisa; Kaumann, Alberto J

    2016-02-01

    Phosphodiesterases PDE2, PDE3, and PDE4 are expressed in murine sinoatrial cells. PDE3 and/or PDE4 reduce heart rate but apparently do not influence the tachycardia mediated through sinoatrial β1- and β2-adrenoceptors despite the high content of sinoatrial cAMP. The function of PDE2 is, however, uncertain. Prostaglandin PGE1 elicits sinoatrial tachycardia through EP receptors, but the control by phosphodiesterases is unknown. We investigated on spontaneously beating right atria of mice the effects of the PDE2 inhibitors Bay 60-7550 and EHNA on basal beating and the tachycardia produced by noradrenaline (3 nM) and PGE1 (1 μM). Bay 60-7550 (1 μM), but not EHNA (10 μM), increased basal sinoatrial beating. EHNA also failed to produce tachycardia in the presence of the adenosine deaminase inhibitor 2'-deoxycoformycin (10 μM), remaining inconclusive whether PDE2 reduces basal sinoatrial beating. Rolipram (10 μM) and cilostamide (300 nM) caused moderate tachycardia. The tachycardia evoked by Bay 60-7550 was similar in the absence and presence of rolipram. Noradrenaline elicited stable tachycardia that was not increased by Bay 60-7550. A stable tachycardia caused by PGE1 was not increased by the inhibitors of PDE2, PDE3, and PDE4. Unlike PDE3 and PDE4 which reduce murine basal sinoatrial beating, a possible effect of PDE2 needs further research. The stable tachycardia produced by noradrenaline and PGE1, together with the lack potentiation by the inhibitors of PDE2, PDE3, and PDE4, suggests that cAMP generated at the receptor compartments is hardly hydrolyzed by these phophodiesterases. Evidence from human volunteers is consistent with this proposal.

  3. Dual PDE3/4 and PDE4 inhibitors: novel treatments for COPD and other inflammatory airway diseases.

    PubMed

    Abbott-Banner, Katharine H; Page, Clive P

    2014-05-01

    Selective phosphodiesterase (PDE) 4 and dual PDE3/4 inhibitors have attracted considerable interest as potential therapeutic agents for the treatment of respiratory diseases, largely by virtue of their anti-inflammatory (PDE4) and bifunctional bronchodilator/anti-inflammatory (PDE3/4) effects. Many of these agents have, however, failed in early development for various reasons, including dose-limiting side effects when administered orally and lack of sufficient activity when inhaled. Indeed, only one selective PDE4 inhibitor, the orally active roflumilast-n-oxide, has to date received marketing authorization. The majority of the compounds that have failed were, however, orally administered and non-selective for either PDE3 (A,B) or PDE4 (A,B,C,D) subtypes. Developing an inhaled dual PDE3/4 inhibitor that is rapidly cleared from the systemic circulation, potentially with subtype specificity, may represent one strategy to improve the therapeutic index and also exhibit enhanced efficacy versus inhibition of either PDE3 or PDE4 alone, given the potential positive interactions with regard to anti-inflammatory and bronchodilator effects that have been observed pre-clinically with dual inhibition of PDE3 and PDE4 compared with inhibition of either isozyme alone. This MiniReview will summarize recent clinical data obtained with PDE inhibitors and the potential for these drugs to treat COPD and other inflammatory airways diseases such as asthma and cystic fibrosis.

  4. Spillover, nonlinearity, and flexible structures

    NASA Technical Reports Server (NTRS)

    Bass, Robert W.; Zes, Dean

    1991-01-01

    Many systems whose evolution in time is governed by Partial Differential Equations (PDEs) are linearized around a known equilibrium before Computer Aided Control Engineering (CACE) is considered. In this case, there are infinitely many independent vibrational modes, and it is intuitively evident on physical grounds that infinitely many actuators would be needed in order to control all modes. A more precise, general formulation of this grave difficulty (spillover problem) is due to A.V. Balakrishnan. A possible route to circumvention of this difficulty lies in leaving the PDE in its original nonlinear form, and adding the essentially finite dimensional control action prior to linearization. One possibly applicable technique is the Liapunov Schmidt rigorous reduction of singular infinite dimensional implicit function problems to finite dimensional implicit function problems. Omitting details of Banach space rigor, the formalities of this approach are given.

  5. A geometric nonlinear degenerated shell element using a mixed formulation with independently assumed strain fields. Final Report; Ph.D. Thesis, 1989

    NASA Technical Reports Server (NTRS)

    Graf, Wiley E.

    1991-01-01

    A mixed formulation is chosen to overcome deficiencies of the standard displacement-based shell model. Element development is traced from the incremental variational principle on through to the final set of equilibrium equations. Particular attention is paid to developing specific guidelines for selecting the optimal set of strain parameters. A discussion of constraint index concepts and their predictive capability related to locking is included. Performance characteristics of the elements are assessed in a wide variety of linear and nonlinear plate/shell problems. Despite limiting the study to geometric nonlinear analysis, a substantial amount of additional insight concerning the finite element modeling of thin plate/shell structures is provided. For example, in nonlinear analysis, given the same mesh and load step size, mixed elements converge in fewer iterations than equivalent displacement-based models. It is also demonstrated that, in mixed formulations, lower order elements are preferred. Additionally, meshes used to obtain accurate linear solutions do not necessarily converge to the correct nonlinear solution. Finally, a new form of locking was identified associated with employing elements designed for biaxial bending in uniaxial bending applications.

  6. Challenge of human Jurkat T-cells with the adenylate cyclase activator forskolin elicits major changes in cAMP phosphodiesterase (PDE) expression by up-regulating PDE3 and inducing PDE4D1 and PDE4D2 splice variants as well as down-regulating a novel PDE4A splice variant.

    PubMed Central

    Erdogan, S; Houslay, M D

    1997-01-01

    The cAMP phosphodiesterase (PDE) 3 and PDE4 isoforms provide the major cAMP-hydrolysing PDE activities in Jurkat T-cells, with additional contributions from the PDE1 and PDE2 isoforms. Challenge of cells with the adenylate cyclase activator forskolin led to a rapid, albeit transient, increase in PDE3 activity occurring over the first 45 min, followed by a sustained increase in PDE3 activity which began after approximately 3 h and continued for at least 24 h. Only this second phase of increase in PDE3 activity was blocked by the transcriptional inhibitor actinomycin D. After approximately 3 h of exposure to forskolin, PDE4 activity had increased, via a process that could be inhibited by actinomycin D, and it remained elevated for at least a 24 h period. Such actions of forskolin were mimicked by cholera toxin and 8-bromo-cAMP. Forskolin increased intracellular cAMP concentrations in a time-dependent fashion and its action was enhanced when PDE induction was blocked with actinomycin D. Reverse transcription (RT)-PCR analysis, using generic primers designed to detect transcripts representing enzymically active products of the four PDE4 genes, identified transcripts for PDE4A and PDE4D but not for PDE4B or PDE4C in untreated Jurkat T-cells. Forskolin treatment did not induce transcripts for either PDE4B or PDE4C; however, it reduced the RT-PCR signal for PDE4A transcripts and markedly enhanced that for PDE4D transcripts. Using RT-PCR primers for PDE4 splice variants, a weak signal for PDE4D1 was evident in control cells whereas, in forskolin-treated cells, clear signals for both PDE4D1 and PDE4D2 were detected. RT-PCR analysis of the PDE4A species indicated that it was not the PDE4A isoform PDE-46 (PDE4A4B). Immunoblotting of control cells for PDE4 forms identified a single PDE4A species of approximately 118 kDa, which migrated distinctly from the PDE4A4B isoform PDE-46, with immunoprecipitation analyses showing that it provided all of the PDE4 activity in control

  7. PDE1C deficiency antagonizes pathological cardiac remodeling and dysfunction

    PubMed Central

    Knight, Walter E.; Chen, Si; Zhang, Yishuai; Oikawa, Masayoshi; Wu, Meiping; Zhou, Qian; Miller, Clint L.; Cai, Yujun; Mickelsen, Deanne M.; Moravec, Christine; Small, Eric M.; Abe, Junichi; Yan, Chen

    2016-01-01

    Cyclic nucleotide phosphodiesterase 1C (PDE1C) represents a major phosphodiesterase activity in human myocardium, but its function in the heart remains unknown. Using genetic and pharmacological approaches, we studied the expression, regulation, function, and underlying mechanisms of PDE1C in the pathogenesis of cardiac remodeling and dysfunction. PDE1C expression is up-regulated in mouse and human failing hearts and is highly expressed in cardiac myocytes but not in fibroblasts. In adult mouse cardiac myocytes, PDE1C deficiency or inhibition attenuated myocyte death and apoptosis, which was largely dependent on cyclic AMP/PKA and PI3K/AKT signaling. PDE1C deficiency also attenuated cardiac myocyte hypertrophy in a PKA-dependent manner. Conditioned medium taken from PDE1C-deficient cardiac myocytes attenuated TGF-β–stimulated cardiac fibroblast activation through a mechanism involving the crosstalk between cardiac myocytes and fibroblasts. In vivo, cardiac remodeling and dysfunction induced by transverse aortic constriction, including myocardial hypertrophy, apoptosis, cardiac fibrosis, and loss of contractile function, were significantly attenuated in PDE1C-knockout mice relative to wild-type mice. These results indicate that PDE1C activation plays a causative role in pathological cardiac remodeling and dysfunction. Given the continued development of highly specific PDE1 inhibitors and the high expression level of PDE1C in the human heart, our findings could have considerable therapeutic significance. PMID:27791092

  8. Nonlocality as a function of PDE type

    NASA Astrophysics Data System (ADS)

    Maker, David

    2007-08-01

    Here we postulate a geometrical 2D closed path invariant ds=ds t+ds Φ (geometrical interpretation) with the observer's own 2D ds=ds t+ds Φ then giving a total direct sum 2⊕2=4 degrees of freedom for the resulting (observer translation) Dirac equation pde and its ψ. There are several, more or less technical, ways of stating the consequences of that new "observer interpretation" Dirac equation pde. Two such ways are "wave function collapse," and in a more common sense vein "Bertlmann's socks." Note that wavefunction collapse to ψ then (and experimental nonlocality implications) is the "observables translation" of that fundamental postulate and so not itself postulated. Also that geometrical postulate does not allow a Bohmian hidden variable interpretation because of its fundamental nature (i.e., we cannot go any deeper). For example that postulate states no x or p that we would be certain of in some hidden variable context. Thus we can ignore here the straw man arguments of J.S. Bell that are in response to Bohmian hidden variable theories only. Thus there cannot result Bell's kink at θ=0 in the correlation function between the polarization measurements on the two ends of an EPR experimental apparatus (Bell, 1987). Recall this kink required correlating in a hidden variable, classical statistical mechanical context, with resulting superluminal implications. Also note here the "observer interpretation" boundary condition conservation of angular momentum of the initial singlet state for our 4D Dirac pde results in this being a time independent solution to this pde. Thus wave function collapse to the measured value in no way implies superluminal communication. In laymen terms it is just the Bertlmann's socks common sense fact that we knew before hand about the original singlet state of the central emitter, no superluminal communication between the left and right ends of the Aspect apparatus was required to know about this. Thus our new observer representation

  9. Step-response of a torsional device with multiple discontinuous non-linearities: Formulation of a vibratory experiment

    NASA Astrophysics Data System (ADS)

    Krak, Michael D.; Dreyer, Jason T.; Singh, Rajendra

    2016-03-01

    A vehicle clutch damper is intentionally designed to contain multiple discontinuous non-linearities, such as multi-staged springs, clearances, pre-loads, and multi-staged friction elements. The main purpose of this practical torsional device is to transmit a wide range of torque while isolating torsional vibration between an engine and transmission. Improved understanding of the dynamic behavior of the device could be facilitated by laboratory measurement, and thus a refined vibratory experiment is proposed. The experiment is conceptually described as a single degree of freedom non-linear torsional system that is excited by an external step torque. The single torsional inertia (consisting of a shaft and torsion arm) is coupled to ground through parallel production clutch dampers, which are characterized by quasi-static measurements provided by the manufacturer. Other experimental objectives address physical dimensions, system actuation, flexural modes, instrumentation, and signal processing issues. Typical measurements show that the step response of the device is characterized by three distinct non-linear regimes (double-sided impact, single-sided impact, and no-impact). Each regime is directly related to the non-linear features of the device and can be described by peak angular acceleration values. Predictions of a simplified single degree of freedom non-linear model verify that the experiment performs well and as designed. Accordingly, the benchmark measurements could be utilized to validate non-linear models and simulation codes, as well as characterize dynamic parameters of the device including its dissipative properties.

  10. Nonlinear incompressible finite element for simulating loading of cardiac tissue--Part II: Three dimensional formulation for thick ventricular wall segments.

    PubMed

    Horowitz, A; Sheinman, I; Lanir, Y

    1988-02-01

    A three dimensional incompressible and geometrically as well as materially nonlinear finite element is formulated for future implementation in models of cardiac mechanics. The stress-strain relations in the finite element are derived from a recently proposed constitutive law which is based on the histological composition of the myocardium. The finite element is formulated for large deformations and considers incompressibility by introducing the hydrostatic pressure as an additional variable. The results of passive loading cases simulated by this element allow to analyze the mechanical properties of ventricular wall segments, the main of which are that the circumferential direction is stiffer than the longitudinal one, that its shear stiffness is considerably lower than its tensile and compressive stiffness and that, due to its mechanically prominent role, the collagenous matrix may affect the myocardial perfusion.

  11. Differential Expression and Function of PDE8 and PDE4 in Effector T cells: Implications for PDE8 as a Drug Target in Inflammation.

    PubMed

    Vang, Amanda G; Basole, Chaitali; Dong, Hongli; Nguyen, Rebecca K; Housley, William; Guernsey, Linda; Adami, Alexander J; Thrall, Roger S; Clark, Robert B; Epstein, Paul M; Brocke, Stefan

    2016-01-01

    Abolishing the inhibitory signal of intracellular cAMP is a prerequisite for effector T (Teff) cell function. The regulation of cAMP within leukocytes critically depends on its degradation by cyclic nucleotide phosphodiesterases (PDEs). We have previously shown that PDE8A, a PDE isoform with 40-100-fold greater affinity for cAMP than PDE4, is selectively expressed in Teff vs. regulatory T (Treg) cells and controls CD4(+) Teff cell adhesion and chemotaxis. Here, we determined PDE8A expression and function in CD4(+) Teff cell populations in vivo. Using magnetic bead separation to purify leukocyte populations from the lung draining hilar lymph node (HLN) in a mouse model of ovalbumin-induced allergic airway disease (AAD), we found by Western immunoblot and quantitative (q)RT-PCR that PDE8A protein and gene expression are enhanced in the CD4(+) T cell fraction over the course of the acute inflammatory disease and recede at the late tolerant non-inflammatory stage. To evaluate PDE8A as a potential drug target, we compared the selective and combined effects of the recently characterized highly potent PDE8-selective inhibitor PF-04957325 with the PDE4-selective inhibitor piclamilast (PICL). As previously shown, PF-04957325 suppresses T cell adhesion to endothelial cells. In contrast, we found that PICL alone increased firm T cell adhesion to endothelial cells by ~20% and significantly abrogated the inhibitory effect of PF-04957325 on T cell adhesion by over 50% when cells were co-exposed to PICL and PF-04957325. Despite its robust effect on T cell adhesion, PF-04957325 was over two orders of magnitude less efficient than PICL in suppressing polyclonal Teff cell proliferation, and showed no effect on cytokine gene expression in these cells. More importantly, PDE8 inhibition did not suppress proliferation and cytokine production of myelin-antigen reactive proinflammatory Teff cells in vivo and in vitro. Thus, targeting PDE8 through PF-04957325 selectively regulates Teff

  12. Algebraic coarsening methods for linear and nonlinear PDE and systems

    SciTech Connect

    McWilliams, J C

    2000-11-06

    In [l] Brandt describes a general approach for algebraic coarsening. Given fine-grid equations and a prescribed relaxation method, an approach is presented for defining both the coarse-grid variables and the coarse-grid equations corresponding to these variables. Although, these two tasks are not necessarily related (and, indeed, are often performed independently and with distinct techniques) in the approaches of [1] both revolve around the same underlying observation. To determine whether a given set of coarse-grid variables is appropriate it is suggested that one should employ compatible relaxation. This is a generalization of so-called F-relaxation (e.g., [2]). Suppose that the coarse-grid variables are defined as a subset of the fine-grid variables. Then, F-relaxation simply means relaxing only the F-variables (i.e., fine-grid variables that do not correspond to coarse-grid variables), while leaving the remaining fine-grid variables (C-variables) unchanged. The generalization of compatible relaxation is in allowing the coarse-grid variables to be defined differently, say as linear combinations of fine-grid variables, or even nondeterministically (see examples in [1]). For the present summary it suffices to consider the simple case. The central observation regarding the set of coarse-grid variables is the following [1]: Observation 1--A general measure for the quality of the set of coarse-grid variables is the convergence rate of compatible relaxation. The conclusion is that a necessary condition for efficient multigrid solution (e.g., with convergence rates independent of problem size) is that the compatible-relaxation convergence be bounded away from 1, independently of the number of variables. This is often a sufficient condition, provided that the coarse-grid equations are sufficiently accurate. Therefore, it is suggested in [1] that the convergence rate of compatible relaxation should be used as a criterion for choosing and evaluating the set of coarse-grid variables. Once a coarse grid is chosen for which compatible relaxation converges fast, it follows that the dependence of the coarse-grid variables on each other decays exponentially or faster with the distance between them, measured in mesh-sizes. This implies that highly accurate coarse-grid equations can be constructed locally. A method for doing this by solving local constrained minimization problems is described in [1]. It is also shown how this approach can be applied to devise prolongation operators, which can be used for Galerkin coarsening in the usual way. In the present research we studied and developed methods based, in part, on these ideas. We developed and implemented an AMG approach which employs compatible relaxation to define the prolongation operator (hut is otherwise similar in its structure to classical AMG); we introduced a novel method for direct (i.e., non-Galerkin) algebraic coarsening, which is in the spirit of the approach originally proposed by Brandt in [1], hut is more efficient and well-defined; we investigated an approach for treating systems of equations and other problems where there is no unambiguous correspondence between equations and unknowns.

  13. Lagrangian three-dimensional finite-element formulation for the nonlinear fluid-structural response of reactor components. [LMFBR

    SciTech Connect

    Kulak, R. F.; Fiala, C.

    1980-03-01

    This report presents the formulations used in the NEPTUNE code. Specifically, it describes the finite-element formulation of a three-dimensional hexahedral element for simulating the behavior of either fluid or solid continua. Since the newly developed hexahedral element and the original triangular plate element are finite elements, they are compatible in the sense that they can be combined arbitrarily to simulate complex reactor components in three-dimensional space. Because rate-type constitutive relations are used in conjunction with a velocity-strain tensor, the formulation is applicable to large deformation problems. This development can be used to simulate (1) the fluid adjacent to reactor components and (2) the concrete fill found in large reactor head closures.

  14. The emperor's new clothes: PDE5 and the heart.

    PubMed

    Degen, Chantal V; Bishu, Kalkidan; Zakeri, Rosita; Ogut, Ozgur; Redfield, Margaret M; Brozovich, Frank V

    2015-01-01

    Phosphodiesterase-5 (PDE5) is highly expressed in the pulmonary vasculature, but its expression in the myocardium is controversial. Cyclic guanosine monophosphate (cGMP) activates protein kinase G (PKG), which has been hypothesized to blunt cardiac hypertrophy and negative remodeling in heart failure. Although PDE5 has been suggested to play a significant role in the breakdown of cGMP in cardiomyocytes and hence PKG regulation in the myocardium, the RELAX trial, which tested effect of PDE5 inhibition on exercise capacity in patients with heart failure with preserved ejection fraction (HFpEF) failed to show a beneficial effect. These results highlight the controversy regarding the role and expression of PDE5 in the healthy and failing heart. This study used one- and two-dimensional electrophoresis and Western blotting to examine PDE5 expression in mouse (before and after trans-aortic constriction), dog (control and HFpEF) as well as human (healthy and failing) heart. We were unable to detect PDE5 in any cardiac tissue lysate, whereas PDE5 was present in the murine and bovine lung samples used as positive controls. These results indicate that if PDE5 is expressed in cardiac tissue, it is present in very low quantities, as PDE5 was not detected in either humans or any model of heart failure examined. Therefore in cardiac muscle, it is unlikely that PDE5 is involved the regulation of cGMP-PKG signaling, and hence PDE5 does not represent a suitable drug target for the treatment of cardiac hypertrophy. These results highlight the importance of rigorous investigation prior to clinical trial design.

  15. The Emperor's New Clothes: PDE5 and the Heart

    PubMed Central

    Degen, Chantal V.; Bishu, Kalkidan; Zakeri, Rosita; Ogut, Ozgur; Redfield, Margaret M.; Brozovich, Frank V.

    2015-01-01

    Phosphodiesterase-5 (PDE5) is highly expressed in the pulmonary vasculature, but its expression in the myocardium is controversial. Cyclic guanosine monophosphate (cGMP) activates protein kinase G (PKG), which has been hypothesized to blunt cardiac hypertrophy and negative remodeling in heart failure. Although PDE5 has been suggested to play a significant role in the breakdown of cGMP in cardiomyocytes and hence PKG regulation in the myocardium, the RELAX trial, which tested effect of PDE5 inhibition on exercise capacity in patients with heart failure with preserved ejection fraction (HFpEF) failed to show a beneficial effect. These results highlight the controversy regarding the role and expression of PDE5 in the healthy and failing heart. This study used one- and two-dimensional electrophoresis and Western blotting to examine PDE5 expression in mouse (before and after trans-aortic constriction), dog (control and HFpEF) as well as human (healthy and failing) heart. We were unable to detect PDE5 in any cardiac tissue lysate, whereas PDE5 was present in the murine and bovine lung samples used as positive controls. These results indicate that if PDE5 is expressed in cardiac tissue, it is present in very low quantities, as PDE5 was not detected in either humans or any model of heart failure examined. Therefore in cardiac muscle, it is unlikely that PDE5 is involved the regulation of cGMP-PKG signaling, and hence PDE5 does not represent a suitable drug target for the treatment of cardiac hypertrophy. These results highlight the importance of rigorous investigation prior to clinical trial design. PMID:25747598

  16. State Space Formulation of Nonlinear Vibration Responses Collected from a Dynamic Rotor-Bearing System: An Extension of Bearing Diagnostics to Bearing Prognostics

    PubMed Central

    Tse, Peter W.; Wang, Dong

    2017-01-01

    Bearings are widely used in various industries to support rotating shafts. Their failures accelerate failures of other adjacent components and may cause unexpected machine breakdowns. In recent years, nonlinear vibration responses collected from a dynamic rotor-bearing system have been widely analyzed for bearing diagnostics. Numerous methods have been proposed to identify different bearing faults. However, these methods are unable to predict the future health conditions of bearings. To extend bearing diagnostics to bearing prognostics, this paper reports the design of a state space formulation of nonlinear vibration responses collected from a dynamic rotor-bearing system in order to intelligently predict bearing remaining useful life (RUL). Firstly, analyses of nonlinear vibration responses were conducted to construct a bearing health indicator (BHI) so as to assess the current bearing health condition. Secondly, a state space model of the BHI was developed to mathematically track the health evolution of the BHI. Thirdly, unscented particle filtering was used to predict bearing RUL. Lastly, a new bearing acceleration life testing setup was designed to collect natural bearing degradation data, which were used to validate the effectiveness of the proposed bearing prognostic method. Results show that the prediction accuracy of the proposed bearing prognostic method is promising and the proposed bearing prognostic method is able to reflect future bearing health conditions. PMID:28216586

  17. State Space Formulation of Nonlinear Vibration Responses Collected from a Dynamic Rotor-Bearing System: An Extension of Bearing Diagnostics to Bearing Prognostics.

    PubMed

    Tse, Peter W; Wang, Dong

    2017-02-14

    Bearings are widely used in various industries to support rotating shafts. Their failures accelerate failures of other adjacent components and may cause unexpected machine breakdowns. In recent years, nonlinear vibration responses collected from a dynamic rotor-bearing system have been widely analyzed for bearing diagnostics. Numerous methods have been proposed to identify different bearing faults. However, these methods are unable to predict the future health conditions of bearings. To extend bearing diagnostics to bearing prognostics, this paper reports the design of a state space formulation of nonlinear vibration responses collected from a dynamic rotor-bearing system in order to intelligently predict bearing remaining useful life (RUL). Firstly, analyses of nonlinear vibration responses were conducted to construct a bearing health indicator (BHI) so as to assess the current bearing health condition. Secondly, a state space model of the BHI was developed to mathematically track the health evolution of the BHI. Thirdly, unscented particle filtering was used to predict bearing RUL. Lastly, a new bearing acceleration life testing setup was designed to collect natural bearing degradation data, which were used to validate the effectiveness of the proposed bearing prognostic method. Results show that the prediction accuracy of the proposed bearing prognostic method is promising and the proposed bearing prognostic method is able to reflect future bearing health conditions.

  18. Blow-up of a hyperbolic equation of viscoelasticity with supercritical nonlinearities

    NASA Astrophysics Data System (ADS)

    Guo, Yanqiu; Rammaha, Mohammad A.; Sakuntasathien, Sawanya

    2017-02-01

    We investigate a hyperbolic PDE, modeling wave propagation in viscoelastic media, under the influence of a linear memory term of Boltzmann type, and a nonlinear damping modeling friction, as well as an energy-amplifying supercritical nonlinear source:

  19. Multithreaded Model for Dynamic Load Balancing Parallel Adaptive PDE Computations

    NASA Technical Reports Server (NTRS)

    Chrisochoides, Nikos

    1995-01-01

    We present a multithreaded model for the dynamic load-balancing of numerical, adaptive computations required for the solution of Partial Differential Equations (PDE's) on multiprocessors. Multithreading is used as a means of exploring concurrency in the processor level in order to tolerate synchronization costs inherent to traditional (non-threaded) parallel adaptive PDE solvers. Our preliminary analysis for parallel, adaptive PDE solvers indicates that multithreading can be used an a mechanism to mask overheads required for the dynamic balancing of processor workloads with computations required for the actual numerical solution of the PDE's. Also, multithreading can simplify the implementation of dynamic load-balancing algorithms, a task that is very difficult for traditional data parallel adaptive PDE computations. Unfortunately, multithreading does not always simplify program complexity, often makes code re-usability not an easy task, and increases software complexity.

  20. PDE regularization for Bayesian reconstruction of emission tomography

    NASA Astrophysics Data System (ADS)

    Wang, Zhentian; Zhang, Li; Xing, Yuxiang; Zhao, Ziran

    2008-03-01

    The aim of the present study is to investigate a type of Bayesian reconstruction which utilizes partial differential equations (PDE) image models as regularization. PDE image models are widely used in image restoration and segmentation. In a PDE model, the image can be viewed as the solution of an evolutionary differential equation. The variation of the image can be regard as a descent of an energy function, which entitles us to use PDE models in Bayesian reconstruction. In this paper, two PDE models called anisotropic diffusion are studied. Both of them have the characteristics of edge-preserving and denoising like the popular median root prior (MRP). We use PDE regularization with an Ordered Subsets accelerated Bayesian one step late (OSL) reconstruction algorithm for emission tomography. The OS accelerated OSL algorithm is more practical than a non-accelerated one. The proposed algorithm is called OSEM-PDE. We validated the OSEM-PDE using a Zubal phantom in numerical experiments with attenuation correction and quantum noise considered, and the results are compared with OSEM and an OS version of MRP (OSEM-MRP) reconstruction. OSEM-PDE shows better results both in bias and variance. The reconstruction images are smoother and have sharper edges, thus are more applicable for post processing such as segmentation. We validate this using a k-means segmentation algorithm. The classic OSEM is not convergent especially in noisy condition. However, in our experiment, OSEM-PDE can benefit from OS acceleration and keep stable and convergent while OSEM-MRP failed to converge.

  1. Boundary Control of Linear Uncertain 1-D Parabolic PDE Using Approximate Dynamic Programming.

    PubMed

    Talaei, Behzad; Jagannathan, Sarangapani; Singler, John

    2017-03-02

    This paper develops a near optimal boundary control method for distributed parameter systems governed by uncertain linear 1-D parabolic partial differential equations (PDE) by using approximate dynamic programming. A quadratic surface integral is proposed to express the optimal cost functional for the infinite-dimensional state space. Accordingly, the Hamilton-Jacobi-Bellman (HJB) equation is formulated in the infinite-dimensional domain without using any model reduction. Subsequently, a neural network identifier is developed to estimate the unknown spatially varying coefficient in PDE dynamics. Novel tuning law is proposed to guarantee the boundedness of identifier approximation error in the PDE domain. A radial basis network (RBN) is subsequently proposed to generate an approximate solution for the optimal surface kernel function online. The tuning law for near optimal RBN weights is created, such that the HJB equation error is minimized while the dynamics are identified and closed-loop system remains stable. Ultimate boundedness (UB) of the closed-loop system is verified by using the Lyapunov theory. The performance of the proposed controller is successfully confirmed by simulation on an unstable diffusion-reaction process.

  2. Adaptive neural control design for nonlinear distributed parameter systems with persistent bounded disturbances.

    PubMed

    Wu, Huai-Ning; Li, Han-Xiong

    2009-10-01

    In this paper, an adaptive neural network (NN) control with a guaranteed L(infinity)-gain performance is proposed for a class of parabolic partial differential equation (PDE) systems with unknown nonlinearities and persistent bounded disturbances. Initially, Galerkin method is applied to the PDE system to derive a low-order ordinary differential equation (ODE) system that accurately describes the dynamics of the dominant (slow) modes of the PDE system. Subsequently, based on the low-order slow model and the Lyapunov technique, an adaptive modal feedback controller is developed such that the closed-loop slow system is semiglobally input-to-state practically stable (ISpS) with an L(infinity)-gain performance. In the proposed control scheme, a radial basis function (RBF) NN is employed to approximate the unknown term in the derivative of the Lyapunov function due to the unknown system nonlinearities. The outcome of the adaptive L(infinity)-gain control problem is formulated as a linear matrix inequality (LMI) problem. Moreover, by using the existing LMI optimization technique, a suboptimal controller is obtained in the sense of minimizing an upper bound of the L(infinity)-gain, while control constraints are respected. Furthermore, it is shown that the proposed controller can ensure the semiglobal input-to-state practical stability and L(infinity)-gain performance of the closed-loop PDE system. Finally, by applying the developed design method to the temperature profile control of a catalytic rod, the achieved simulation results show the effectiveness of the proposed controller.

  3. Formulation of the nonlinear analysis of shell-like structures, subjected to time-dependent mechanical and thermal loading

    NASA Technical Reports Server (NTRS)

    Simitses, George J.; Carlson, Robert L.; Riff, Richard

    1991-01-01

    The object of the research reported herein was to develop a general mathematical model and solution methodologies for analyzing the structural response of thin, metallic shell structures under large transient, cyclic, or static thermomechanical loads. Among the system responses associated with these loads and conditions are thermal buckling, creep buckling, and ratcheting. Thus geometric and material nonlinearities (of high order) can be anticipated and must be considered in developing the mathematical model. The methodology is demonstrated through different problems of extension, shear, and of planar curved beams. Moreover, importance of the inclusion of large strain is clearly demonstrated, through the chosen applications.

  4. PDE Nozzle Optimization Using a Genetic Algorithm

    NASA Technical Reports Server (NTRS)

    Billings, Dana; Turner, James E. (Technical Monitor)

    2000-01-01

    Genetic algorithms, which simulate evolution in natural systems, have been used to find solutions to optimization problems that seem intractable to standard approaches. In this study, the feasibility of using a GA to find an optimum, fixed profile nozzle for a pulse detonation engine (PDE) is demonstrated. The objective was to maximize impulse during the detonation wave passage and blow-down phases of operation. Impulse of each profile variant was obtained by using the CFD code Mozart/2.0 to simulate the transient flow. After 7 generations, the method has identified a nozzle profile that certainly is a candidate for optimum solution. The constraints on the generality of this possible solution remain to be clarified.

  5. PDE5 expression in human thyroid tumors and effects of PDE5 inhibitors on growth and migration of cancer cells.

    PubMed

    Sponziello, Marialuisa; Verrienti, Antonella; Rosignolo, Francesca; De Rose, Roberta Francesca; Pecce, Valeria; Maggisano, Valentina; Durante, Cosimo; Bulotta, Stefania; Damante, Giuseppe; Giacomelli, Laura; Di Gioia, Cira Rosaria Tiziana; Filetti, Sebastiano; Russo, Diego; Celano, Marilena

    2015-11-01

    Recent studies have revealed in normal thyroid tissue the presence of the transcript of several phosphodiesterases (PDEs), enzymes responsible for the hydrolysis of cyclic nucleotides. In this work, we analyzed the expression of PDE5 in a series of human papillary thyroid carcinomas (PTCs) presenting or not BRAF V600E mutation and classified according to ATA risk criteria. Furthermore, we tested the effects of two PDE5 inhibitors (sildenafil, tadalafil) against human thyroid cancer cells. PDE5 gene and protein expression were analyzed in two different cohorts of PTCs by real-time PCR using a TaqMan micro-fluid card system and Western blot. MTT and migration assay were used to evaluate the effects of PDE5 inhibitors on proliferation and migration of TPC-1, BCPAP, and 8505C cells. In a first series of 36 PTCs, we found higher expression levels of PDE5A in tumors versus non-tumor (normal) tissues. PTCs with BRAF mutation showed higher levels of mRNA compared with those without mutation. No significant differences were detected between subgroups with low and intermediate ATA risk. Upregulation of PDE5 was also detected in tumor tissue proteins. Similar results were obtained analyzing the second cohort of 50 PTCs. Moreover, all tumor tissues with high PDE5 levels showed reduction of Thyroglobulin, TSH receptor, Thyroperoxidase, and NIS transcripts. In thyroid cancer cells in vitro, sildenafil and tadalafil determined a reduction of proliferation and cellular migration. Our findings demonstrate for the first time an overexpression of PDE5 in PTCs, and the ability of PDE5 inhibitors to block the proliferation of thyroid cancer cells in culture, therefore, suggesting that specific inhibition of PDE5 may be proposed for the treatment of these tumors.

  6. Contribution of the cyclic nucleotide phosphodiesterases PdeA and PdeB to adaptation of Myxococcus xanthus cells to osmotic or high-temperature stress.

    PubMed

    Kimura, Yoshio; Nakatuma, Hiromi; Sato, Naoko; Ohtani, Mika

    2006-01-01

    A tBLASTn search of the Myxococcus xanthus genome database at The Institute for Genomic Research (TIGR) identified three genes (pdeA, pdeB, and pdeC) that encode proteins homologous to 3',5'-cyclic nucleotide phosphodiesterase. pdeA, pdeB, and pdeC mutants, constructed by replacing a part of the gene with the kanamycin or tetracycline resistance gene, showed normal growth, development, and germination under nonstress conditions. However, the spores of mutants, especially the pdeA and pdeB mutants, placed under osmotic stress germinated earlier than the wild-type spores. The phenotype was the opposite of that of the receptor-type adenylyl cyclase (cyaA or cyaB) mutant. Also, pdeA and pdeB mutants were found to have impaired growth under the condition of high-temperature stress. Intracellular cyclic AMP (cAMP) levels of pdeA or pdeB mutant cells under these stressful conditions were about 1.3-fold to 2.0-fold higher than those of wild-type cells. These results suggest that PdeA and PdeB may be involved in osmotic adaptation during spore germination and temperature adaptation during vegetative growth through the regulation of cAMP levels.

  7. Discretely Conservative Finite-Difference Formulations for Nonlinear Conservation Laws in Split Form: Theory and Boundary Conditions

    NASA Technical Reports Server (NTRS)

    Fisher, Travis C.; Carpenter, Mark H.; Nordstroem, Jan; Yamaleev, Nail K.; Swanson, R. Charles

    2011-01-01

    Simulations of nonlinear conservation laws that admit discontinuous solutions are typically restricted to discretizations of equations that are explicitly written in divergence form. This restriction is, however, unnecessary. Herein, linear combinations of divergence and product rule forms that have been discretized using diagonal-norm skew-symmetric summation-by-parts (SBP) operators, are shown to satisfy the sufficient conditions of the Lax-Wendroff theorem and thus are appropriate for simulations of discontinuous physical phenomena. Furthermore, special treatments are not required at the points that are near physical boundaries (i.e., discrete conservation is achieved throughout the entire computational domain, including the boundaries). Examples are presented of a fourth-order, SBP finite-difference operator with second-order boundary closures. Sixth- and eighth-order constructions are derived, and included in E. Narrow-stencil difference operators for linear viscous terms are also derived; these guarantee the conservative form of the combined operator.

  8. Selective Extraction of Entangled Textures via Adaptive PDE Transform

    PubMed Central

    Wang, Yang; Wei, Guo-Wei; Yang, Siyang

    2012-01-01

    Texture and feature extraction is an important research area with a wide range of applications in science and technology. Selective extraction of entangled textures is a challenging task due to spatial entanglement, orientation mixing, and high-frequency overlapping. The partial differential equation (PDE) transform is an efficient method for functional mode decomposition. The present work introduces adaptive PDE transform algorithm to appropriately threshold the statistical variance of the local variation of functional modes. The proposed adaptive PDE transform is applied to the selective extraction of entangled textures. Successful separations of human face, clothes, background, natural landscape, text, forest, camouflaged sniper and neuron skeletons have validated the proposed method. PMID:22315584

  9. Selective Extraction of Entangled Textures via Adaptive PDE Transform.

    PubMed

    Wang, Yang; Wei, Guo-Wei; Yang, Siyang

    2012-01-01

    Texture and feature extraction is an important research area with a wide range of applications in science and technology. Selective extraction of entangled textures is a challenging task due to spatial entanglement, orientation mixing, and high-frequency overlapping. The partial differential equation (PDE) transform is an efficient method for functional mode decomposition. The present work introduces adaptive PDE transform algorithm to appropriately threshold the statistical variance of the local variation of functional modes. The proposed adaptive PDE transform is applied to the selective extraction of entangled textures. Successful separations of human face, clothes, background, natural landscape, text, forest, camouflaged sniper and neuron skeletons have validated the proposed method.

  10. Mean Field Limit of Interacting Filaments and Vector Valued Non-linear PDEs

    NASA Astrophysics Data System (ADS)

    Bessaih, Hakima; Coghi, Michele; Flandoli, Franco

    2017-01-01

    Families of N interacting curves are considered, with long range, mean field type, interaction. They generalize models based on classical interacting point particles to models based on curves. In this new set-up, a mean field result is proven, as N→ ∞. The limit PDE is vector valued and, in the limit, each curve interacts with a mean field solution of the PDE. This target is reached by a careful formulation of curves and weak solutions of the PDE which makes use of 1-currents and their topologies. The main results are based on the analysis of a nonlinear Lagrangian-type flow equation. Most of the results are deterministic; as a by-product, when the initial conditions are given by families of independent random curves, we prove a propagation of chaos result. The results are local in time for general interaction kernel, global in time under some additional restriction. Our main motivation is the approximation of 3D-inviscid flow dynamics by the interacting dynamics of a large number of vortex filaments, as observed in certain turbulent fluids; in this respect, the present paper is restricted to smoothed interaction kernels, instead of the true Biot-Savart kernel.

  11. Mean Field Limit of Interacting Filaments and Vector Valued Non-linear PDEs

    NASA Astrophysics Data System (ADS)

    Bessaih, Hakima; Coghi, Michele; Flandoli, Franco

    2017-03-01

    Families of N interacting curves are considered, with long range, mean field type, interaction. They generalize models based on classical interacting point particles to models based on curves. In this new set-up, a mean field result is proven, as N→ ∞. The limit PDE is vector valued and, in the limit, each curve interacts with a mean field solution of the PDE. This target is reached by a careful formulation of curves and weak solutions of the PDE which makes use of 1-currents and their topologies. The main results are based on the analysis of a nonlinear Lagrangian-type flow equation. Most of the results are deterministic; as a by-product, when the initial conditions are given by families of independent random curves, we prove a propagation of chaos result. The results are local in time for general interaction kernel, global in time under some additional restriction. Our main motivation is the approximation of 3D-inviscid flow dynamics by the interacting dynamics of a large number of vortex filaments, as observed in certain turbulent fluids; in this respect, the present paper is restricted to smoothed interaction kernels, instead of the true Biot-Savart kernel.

  12. Optimal trajectory design to Halo orbits via pseudo-invariant manifolds using a nonlinear four body formulation

    NASA Astrophysics Data System (ADS)

    Sayanjali, M.; Pourtakdoust, Seid H.

    2015-05-01

    This paper investigates the problem of optimal transfer trajectory design towards the L2 centered Halo orbit of the Sun-Earth three body system, where the initial launch is to start from a low Earth parking orbit (LEO). The proposed optimal transfer trajectory consists of an active part with low-thrust propulsion and a passive coasting part with no thrust or fuel consumption. In this respect a pseudo-stable manifold (SM) is initially determined through backward time integration of the bicircular four body (BCFB) equations of motion, whose initial states are obtained via stable manifolds of the restricted three body problem (R3BP). The optimal transfer trajectories are extracted via a hybrid direct-indirect optimization formulation applied on both R3BP as well as the BCFB models for comparative purposes. The optimal transfer trajectories are designed and analyzed for different Halo injection points (HOI), different Moon's final anomaly (FMA) and also for different locations of the burn-out conditions.

  13. Effect of an experimental design for evaluating the nonlinear optimal formulation of theophylline tablets using a bootstrap resampling technique.

    PubMed

    Arai, Hiroaki; Suzuki, Tatsuya; Kaseda, Chosei; Takayama, Kozo

    2009-06-01

    The optimal solutions of theophylline tablet formulations based on datasets from 4 experimental designs (Box and Behnken design, central composite design, D-optimal design, and full factorial design) were calculated by the response surface method incorporating multivariate spline interpolation (RSM(S)). Reliability of these solutions was evaluated by a bootstrap (BS) resampling technique. The optimal solutions derived from the Box and Behnken design, D-optimal design, and full factorial design dataset were similar. The distributions of the BS optimal solutions calculated for these datasets were symmetrical. Thus, the accuracy and the reproducibility of the optimal solutions enabled quantitative evaluation based on the deviations of these distributions. However, the distribution of the BS optimal solutions calculated for the central composite design dataset were almost unsymmetrical, and the basic statistic of these distributions could not be conducted. The reason for this problem was considered to be the mixing of the global and local optima. Therefore, self-organizing map (SOM) clustering was applied to identify the global optimal solutions. The BS optimal solutions were divided into 4 clusters by SOM clustering, the accuracy and reproducibility of the optimal solutions in each cluster were quantitatively evaluated, and the cluster containing the global optima was identified. Therefore, SOM clustering was considered to reinforce the BS resampling method for the evaluation of the reliability of optimal solutions irrespective of the dataset style.

  14. An alternative local collocation strategy for high-convergence meshless PDE solutions, using radial basis functions

    NASA Astrophysics Data System (ADS)

    Stevens, D.; Power, H.; Meng, C. Y.; Howard, D.; Cliffe, K. A.

    2013-12-01

    This work proposes an alternative decomposition for local scalable meshless RBF collocation. The proposed method operates on a dataset of scattered nodes that are placed within the solution domain and on the solution boundary, forming a small RBF collocation system around each internal node. Unlike other meshless local RBF formulations that are based on a generalised finite difference (RBF-FD) principle, in the proposed "finite collocation" method the solution of the PDE is driven entirely by collocation of PDE governing and boundary operators within the local systems. A sparse global collocation system is obtained not by enforcing the PDE governing operator, but by assembling the value of the field variable in terms of the field value at neighbouring nodes. In analogy to full-domain RBF collocation systems, communication between stencils occurs only over the stencil periphery, allowing the PDE governing operator to be collocated in an uninterrupted manner within the stencil interior. The local collocation of the PDE governing operator allows the method to operate on centred stencils in the presence of strong convective fields; the reconstruction weights assigned to nodes in the stencils being automatically adjusted to represent the flow of information as dictated by the problem physics. This "implicit upwinding" effect mitigates the need for ad-hoc upwinding stencils in convective dominant problems. Boundary conditions are also enforced within the local collocation systems, allowing arbitrary boundary operators to be imposed naturally within the solution construction. The performance of the method is assessed using a large number of numerical examples with two steady PDEs; the convection-diffusion equation, and the Lamé-Navier equations for linear elasticity. The method exhibits high-order convergence in each case tested (greater than sixth order), and the use of centred stencils is demonstrated for convective-dominant problems. In the case of linear elasticity

  15. Parallels between control PDE's (Partial Differential Equations) and systems of ODE's (Ordinary Differential Equations)

    NASA Technical Reports Server (NTRS)

    Hunt, L. R.; Villarreal, Ramiro

    1987-01-01

    System theorists understand that the same mathematical objects which determine controllability for nonlinear control systems of ordinary differential equations (ODEs) also determine hypoellipticity for linear partial differentail equations (PDEs). Moreover, almost any study of ODE systems begins with linear systems. It is remarkable that Hormander's paper on hypoellipticity of second order linear p.d.e.'s starts with equations due to Kolmogorov, which are shown to be analogous to the linear PDEs. Eigenvalue placement by state feedback for a controllable linear system can be paralleled for a Kolmogorov equation if an appropriate type of feedback is introduced. Results concerning transformations of nonlinear systems to linear systems are similar to results for transforming a linear PDE to a Kolmogorov equation.

  16. Comparison of the Pharmacological Profiles of Selective PDE4B and PDE4D Inhibitors in the Central Nervous System

    PubMed Central

    Zhang, Chong; Xu, Ying; Zhang, Han-Ting; Gurney, Mark E.; O’Donnell, James M.

    2017-01-01

    Inhibition of cyclic AMP (cAMP)-specific phosphodiesterase 4 (PDE4) has been proposed as a potential treatment for a series of neuropsychological conditions such as depression, anxiety and memory loss. However, the specific involvement of each of the PDE4 subtypes (PDE4A, 4B and 4C) in different categories of behavior has yet to be elucidated. In the present study, we compared the possible pharmacological effects of PDE4B and PDE4D selective inhibitors, A-33 and D159687, in mediating neurological function in mice. Both compounds were equally potent in stimulating cAMP signaling in the mouse hippocampal cell line HT-22 leading to an increase in CREB phosphorylation. In contrast, A-33 and D159687 displayed distinct neuropharmacological effects in mouse behavioral tests. A-33 has an antidepressant-like profile as indicated by reduced immobility time in the forced swim and tail suspension tasks, as well as reduced latency to feed in the novelty suppressed feeding test. D159687, on the other hand, had a procognitive profile as it improved memory in the novel object recognition test but had no antidepressant or anxiolytic benefit. The present data suggests that inhibitors targeting specific subtypes of PDE4 may exhibit differential pharmacological effects and aid a more efficient pharmacotherapy towards neuropsychological conditions. PMID:28054669

  17. Anxiogenic-Like Behavioral Phenotype of Mice Deficient in Phosphodiesterase 4B (PDE4B)

    PubMed Central

    Zhang, Han-Ting; Huang, Ying; Masood, Anbrin; Stolinski, Lisa R; Li, Yunfeng; Zhang, Lei; Dlaboga, Daniel; Jin, S-L Catherine; Conti, Marco; O’Donnell, James M

    2009-01-01

    Phosphodiesterase-4 (PDE4), an enzyme that catalyzes the hydrolysis of cyclic AMP and plays a critical role in controlling its intracellular concentration, has been implicated in depression- and anxiety-like behaviors. However, the functions of the four PDE4 subfamilies (PDE4A, PDE4B, PDE4C, and PDE4D) remain largely unknown. In animal tests sensitive to anxiolytics, antidepressants, memory enhancers, or analgesics, we examined the behavioral phenotype of mice deficient in PDE4B (PDE4B−/−). Immunoblot analysis revealed loss of PDE4B expression in the cerebral cortex and amygdala of PDE4B−/− mice. The reduction of PDE4B expression was accompanied by decreases in PDE4 activity in the brain regions of PDE4B−/− mice. Compared to PDE4B + / + littermates, PDE4B−/− mice displayed anxiogenic-like behavior, as evidenced by decreased head-dips and time spent in head-dipping in the holeboard test, reduced transitions and time on the light side in the light–dark transition test, and decreased initial exploration and rears in the open-field test. Consistent with anxiogenic-like behavior, PDE4B−/− mice displayed increased levels of plasma corticosterone. In addition, these mice also showed a modest increase in the proliferation of neuronal cells in the hippocampal dentate gyrus. In the forced-swim test, PDE4B−/− mice exhibited decreased immobility; however, this was not supported by the results from the tail-suspension test. PDE4B−/− mice did not display changes in memory, locomotor activity, or nociceptive responses. Taken together, these results suggest that the PDE4B subfamily is involved in signaling pathways that contribute to anxiogenic-like effects on behavior PMID:17700644

  18. Systemic and metabolic effects of PDE5-inhibitor drugs.

    PubMed

    Aversa, Antonio

    2010-03-15

    Phosphodiesterase type-5 inhibitor (PDE5-i) drugs were first marketed in 1998 (sildenafil) for 'ondemand' treatment of male erectile dysfunction (ED) of any origin. They selectively inhibit intrapenile PDE5 isoenzyme which in turn increases intracellular cyclic guanosine monophosphate levels, thus resulting in prolonged relaxation of cavernosum smooth muscle cells and facilitating the erectile process. Since 2003, two new molecules (tadalafil and vardenafil) have been introduced, resulting in greater interest in these compounds and leading patients to ask for more prescriptions from their doctors. The vast use of PDE5-i in diabetic and cardiovascular ED patients led researchers to investigate their possible extra sexual effects. Several studies investigating their effects on endothelium, coronary and pulmonary circulation, inferior oesophageal sphincter and kidney functions have appeared and, finally, sildenafil was approved for the treatment of pulmonary arterial hypertension. Recent animal studies highlighted a possible interaction between chronic PDE5 inhibition and glucose homeostasis which occurs through a marked improvement of high fat diet induced insulin resistance. If this data is extended to humans, a new scenario will be opened for the chronic use of PDE5-i for sexual rehabilitation along with cardiovascular and metabolic benefits.

  19. Systemic and metabolic effects of PDE5-inhibitor drugs

    PubMed Central

    Aversa, Antonio

    2010-01-01

    Phosphodiesterase type-5 inhibitor (PDE5-i) drugs were first marketed in 1998 (sildenafil) for 'ondemand' treatment of male erectile dysfunction (ED) of any origin. They selectively inhibit intrapenile PDE5 isoenzyme which in turn increases intracellular cyclic guanosine monophosphate levels, thus resulting in prolonged relaxation of cavernosum smooth muscle cells and facilitating the erectile process. Since 2003, two new molecules (tadalafil and vardenafil) have been introduced, resulting in greater interest in these compounds and leading patients to ask for more prescriptions from their doctors. The vast use of PDE5-i in diabetic and cardiovascular ED patients led researchers to investigate their possible extra sexual effects. Several studies investigating their effects on endothelium, coronary and pulmonary circulation, inferior oesophageal sphincter and kidney functions have appeared and, finally, sildenafil was approved for the treatment of pulmonary arterial hypertension. Recent animal studies highlighted a possible interaction between chronic PDE5 inhibition and glucose homeostasis which occurs through a marked improvement of high fat diet induced insulin resistance. If this data is extended to humans, a new scenario will be opened for the chronic use of PDE5-i for sexual rehabilitation along with cardiovascular and metabolic benefits. PMID:21537421

  20. Higher-order nonlinear priors for surface reconstruction.

    PubMed

    Tasdizen, Tolga; Whitaker, Ross

    2004-07-01

    For surface reconstruction problems with noisy and incomplete range data, a Bayesian estimation approach can improve the overall quality of the surfaces. The Bayesian approach to surface estimation relies on a likelihood term, which ties the surface estimate to the input data, and the prior, which ensures surface smoothness or continuity. This paper introduces a new high-order, nonlinear prior for surface reconstruction. The proposed prior can smooth complex, noisy surfaces, while preserving sharp, geometric features, and it is a natural generalization of edge-preserving methods in image processing, such as anisotropic diffusion. An exact solution would require solving a fourth-order partial differential equation (PDE), which can be difficult with conventional numerical techniques. Our approach is to solve a cascade system of two second-order PDEs, which resembles the original fourth-order system. This strategy is based on the observation that the generalization of image processing to surfaces entails filtering the surface normals. We solve one PDE for processing the normals and one for refitting the surface to the normals. Furthermore, we implement the associated surface deformations using level sets. Hence, the algorithm can accommodate very complex shapes with arbitrary and changing topologies. This paper gives the mathematical formulation and describes the numerical algorithms. We also show results using range and medical data.

  1. A Comparison of PETSC Library and HPF Implementations of an Archetypal PDE Computation

    NASA Technical Reports Server (NTRS)

    Hayder, M. Ehtesham; Keyes, David E.; Mehrotra, Piyush

    1997-01-01

    Two paradigms for distributed-memory parallel computation that free the application programmer from the details of message passing are compared for an archetypal structured scientific computation a nonlinear, structured-grid partial differential equation boundary value problem using the same algorithm on the same hardware. Both paradigms, parallel libraries represented by Argonne's PETSC, and parallel languages represented by the Portland Group's HPF, are found to be easy to use for this problem class, and both are reasonably effective in exploiting concurrency after a short learning curve. The level of involvement required by the application programmer under either paradigm includes specification of the data partitioning (corresponding to a geometrically simple decomposition of the domain of the PDE). Programming in SPAM style for the PETSC library requires writing the routines that discretize the PDE and its Jacobian, managing subdomain-to-processor mappings (affine global- to-local index mappings), and interfacing to library solver routines. Programming for HPF requires a complete sequential implementation of the same algorithm, introducing concurrency through subdomain blocking (an effort similar to the index mapping), and modest experimentation with rewriting loops to elucidate to the compiler the latent concurrency. Correctness and scalability are cross-validated on up to 32 nodes of an IBM SP2.

  2. Reversal of neurobehavioral social deficits in dystrophic mice using inhibitors of phosphodiesterases PDE5A and PDE9A

    PubMed Central

    Alexander, M S; Gasperini, M J; Tsai, P T; Gibbs, D E; Spinazzola, J M; Marshall, J L; Feyder, M J; Pletcher, M T; Chekler, E L P; Morris, C A; Sahin, M; Harms, J F; Schmidt, C J; Kleiman, R J; Kunkel, L M

    2016-01-01

    Duchenne muscular dystrophy is caused by mutations in the DYSTROPHIN gene. Although primarily associated with muscle wasting, a significant portion of patients (approximately 25%) are also diagnosed with autism spectrum disorder. We describe social behavioral deficits in dystrophin-deficient mice and present evidence of cerebellar deficits in cGMP production. We demonstrate therapeutic potential for selective inhibitors of the cGMP-specific PDE5A and PDE9A enzymes to restore social behaviors in dystrophin-deficient mice. PMID:27676442

  3. Student's Lab Assignments in PDE Course with MAPLE.

    ERIC Educational Resources Information Center

    Ponidi, B. Alhadi

    Computer-aided software has been used intensively in many mathematics courses, especially in computational subjects, to solve initial value and boundary value problems in Partial Differential Equations (PDE). Many software packages were used in student lab assignments such as FORTRAN, PASCAL, MATLAB, MATHEMATICA, and MAPLE in order to accelerate…

  4. A Galerkin method for linear PDE systems in circular geometries with structural acoustic applications

    NASA Technical Reports Server (NTRS)

    Smith, Ralph C.

    1994-01-01

    A Galerkin method for systems of PDE's in circular geometries is presented with motivating problems being drawn from structural, acoustic, and structural acoustic applications. Depending upon the application under consideration, piecewise splines or Legendre polynomials are used when approximating the system dynamics with modifications included to incorporate the analytic solution decay near the coordinate singularity. This provides an efficient method which retains its accuracy throughout the circular domain without degradation at singularity. Because the problems under consideration are linear or weakly nonlinear with constant or piecewise constant coefficients, transform methods for the problems are not investigated. While the specific method is developed for the two dimensional wave equations on a circular domain and the equation of transverse motion for a thin circular plate, examples demonstrating the extension of the techniques to a fully coupled structural acoustic system are used to illustrate the flexibility of the method when approximating the dynamics of more complex systems.

  5. Tumours with cancer stem cells: A PDE model.

    PubMed

    Fasano, A; Mancini, A; Primicerio, M

    2016-02-01

    The role of cancer stem cells (CSC) in tumour growth has received increasing attention in the recent literature. Here we stem from an integro-differential system describing the evolution of a population of CSC and of ordinary (non-stem) tumour cells formulated and studied in a previous paper, and we investigate an approximation in which the system reduces to a pair of nonlinear coupled parabolic equation. We prove that the new system is well posed and we examine some general properties. Numerical simulations show more on the qualitative behaviour of the solutions, concerning in particular the so-called tumour paradox, according to which an increase of the mortality rate of ordinary (non-stem) tumour cells results asymptotically in a faster growth.

  6. Exploration and Optimization of Substituted Triazolothiadiazines and Triazolopyridazines as PDE4 Inhibitors

    PubMed Central

    Skoumbourdis, Amanda P.; LeClair, Christopher A.; Stefan, Eduard; Turjanski, Adrian G.; Maguire, William; Titus, Steven A.; Huang, Ruili; Auld, Douglas S.; Inglese, James; Austin, Christopher P.; Michnick, Stephen W.; Xia, Menghang; Thomas, Craig J.

    2010-01-01

    An expansion of structure-activity studies on a series of substituted 7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine PDE4 inhibitors and the introduction of a related [1,2,4]triazolo[4,3-b]pyridazine based inhibitor of PDE4 is presented. The development of SAR included strategic incorporation of known substituents on the critical catachol diether moiety of the 6-phenyl appendage on each heterocyclic core. From these studies, (R)-3-(2,5-dimethoxyphenyl)-6-(4-methoxy-3-(tetrahydrofuran-3-yloxy)phenyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine (10) and (R)-3-(2,5-dimethoxyphenyl)-6-(4-methoxy-3-(tetrahydrofuran-3-yloxy)phenyl)-[1,2,4]triazolo[4,3-b]pyridazine (18) were identified as highly potent PDE4A inhibitors. Each of these analogues was submitted across a panel of 21 PDE family members and was shown to be highly selective for PDE4 isoforms (PDE4A, PDE4B, PDE4C, PDE4D). Both 10 and 18 were then evaluated in divergent cell-based assays to assess their relevant use as probes of PDE4 activity. Finally, docking studies with selective ligands (including 10 and 18) were undertaken to better understand this chemotypes ability to bind and inhibit PDE4 selectively. PMID:19464886

  7. Synthesis, biological activities and pharmacokinetic properties of new fluorinated derivatives of selective PDE4D inhibitors.

    PubMed

    Brullo, Chiara; Massa, Matteo; Villa, Carla; Ricciarelli, Roberta; Rivera, Daniela; Pronzato, Maria Adelaide; Fedele, Ernesto; Barocelli, Elisabetta; Bertoni, Simona; Flammini, Lisa; Bruno, Olga

    2015-07-01

    A new series of selective PDE4D inhibitors has been designed and synthesized by replacing 3-methoxy group with 3-difluoromethoxy isoster moiety in our previously reported cathecolic structures. All compounds showed a good PDE4D3 inhibitory activity, most of them being inactive toward other PDE4 isoforms (PDE4A4, PDE4B2 and PDE4C2). Compound 3b, chosen among the synthesized compounds as the most promising in terms of inhibitory activity, selectivity and safety, showed an improved pharmacokinetic profile compared to its non fluorinated analogue. Spontaneous locomotor activity, assessed in an open field apparatus, showed that, differently from rolipram and diazepam, selective PDE4D inhibitors, such as compounds 3b, 5b and 7b, did not affect locomotion, whereas compound 1b showed a tendency to reduce the distance traveled and to prolong the immobility period, possibly due to a poor selectivity.

  8. cAMP-specific PDE4 phosphodiesterases and AIP in the pathogenesis of pituitary tumors.

    PubMed

    Bolger, Graeme B; Bizzi, Mariana F; Pinheiro, Sergio V; Trivellin, Giampaolo; Smoot, Lisa; Accavitti, Mary-Ann; Korbonits, Márta; Ribeiro-Oliveira, Antonio

    2016-05-01

    PDE4 cyclic nucleotide phosphodiesterases regulate cAMP abundance in cells and therefore regulate numerous processes, including cell growth and differentiation. The rat PDE4A5 isoform (human homolog PDE4A4) interacts with the AIP protein (also called XAP2 or ARA-9). Germline mutations in AIP occur in approximately 20% of patients with Familial Isolated Pituitary Adenoma (FIPA) and 20% of childhood-onset simplex somatotroph adenomas. We therefore examined the protein expression of PDE4A4 and the closely related isoform PDE4A8 in normal human pituitary tissue and in pituitary adenomas. PDE4A4 had low expression in normal pituitary but was significantly overexpressed in somatotroph, lactotroph, corticotroph and clinically nonfunctioning gonadotroph adenomas (P<0.0001 for all subtypes). Likewise, PDE4A8 was expressed in normal pituitary and was also significantly overexpressed in the adenoma subtypes (P<0.0001 for all). Among the different adenoma subtypes, corticotroph and lactotroph adenomas were the highest and lowest expressed for PDE4A4, respectively, whereas the opposite was observed for PDE4A8. Naturally occurring oncogenic variants in AIP were shown by a two-hybrid assay to disrupt the ability of AIP to interact with PDE4A5. A reverse two-hybrid screen identified numerous additional variants in the tetratricopeptide repeat (TPR) region of AIP that also disrupted its ability to interact with PDE4A5. The expression of PDE4A4 and PDE4A8 in normal pituitary, their increased expression in adenomatous pituitary cells where AIP is meant to participate, and the disruption of the PDE4A4-AIP interaction by AIP mutants may play a role in pituitary tumorigenesis.

  9. Interactive medical image segmentation using PDE control of active contours.

    PubMed

    Karasev, Peter; Kolesov, Ivan; Fritscher, Karl; Vela, Patricio; Mitchell, Phillip; Tannenbaum, Allen

    2013-11-01

    Segmentation of injured or unusual anatomic structures in medical imagery is a problem that has continued to elude fully automated solutions. In this paper, the goal of easy-to-use and consistent interactive segmentation is transformed into a control synthesis problem. A nominal level set partial differential equation (PDE) is assumed to be given; this open-loop system achieves correct segmentation under ideal conditions, but does not agree with a human expert's ideal boundary for real image data. Perturbing the state and dynamics of a level set PDE via the accumulated user input and an observer-like system leads to desirable closed-loop behavior. The input structure is designed such that a user can stabilize the boundary in some desired state without needing to understand any mathematical parameters. Effectiveness of the technique is illustrated with applications to the challenging segmentations of a patellar tendon in magnetic resonance and a shattered femur in computed tomography.

  10. Interactive Medical Image Segmentation using PDE Control of Active Contours

    PubMed Central

    Karasev, Peter; Kolesov, Ivan; Fritscher, Karl; Vela, Patricio; Mitchell, Phillip; Tannenbaum, Allen

    2014-01-01

    Segmentation of injured or unusual anatomic structures in medical imagery is a problem that has continued to elude fully automated solutions. In this paper, the goal of easy-to-use and consistent interactive segmentation is transformed into a control synthesis problem. A nominal level set PDE is assumed to be given; this open-loop system achieves correct segmentation under ideal conditions, but does not agree with a human expert's ideal boundary for real image data. Perturbing the state and dynamics of a level set PDE via the accumulated user input and an observer-like system leads to desirable closed-loop behavior. The input structure is designed such that a user can stabilize the boundary in some desired state without needing to understand any mathematical parameters. Effectiveness of the technique is illustrated with applications to the challenging segmentations of a patellar tendon in MR and a shattered femur in CT. PMID:23893712

  11. Approximation error in PDE-based modelling of vehicular platoons

    NASA Astrophysics Data System (ADS)

    Hao, He; Barooah, Prabir

    2012-08-01

    We study the problem of how much error is introduced in approximating the dynamics of a large vehicular platoon by using a partial differential equation, as was done in Barooah, Mehta, and Hespanha [Barooah, P., Mehta, P.G., and Hespanha, J.P. (2009), 'Mistuning-based Decentralised Control of Vehicular Platoons for Improved Closed Loop Stability', IEEE Transactions on Automatic Control, 54, 2100-2113], Hao, Barooah, and Mehta [Hao, H., Barooah, P., and Mehta, P.G. (2011), 'Stability Margin Scaling Laws of Distributed Formation Control as a Function of Network Structure', IEEE Transactions on Automatic Control, 56, 923-929]. In particular, we examine the difference between the stability margins of the coupled-ordinary differential equations (ODE) model and its partial differential equation (PDE) approximation, which we call the approximation error. The stability margin is defined as the absolute value of the real part of the least stable pole. The PDE model has proved useful in the design of distributed control schemes (Barooah et al. 2009; Hao et al. 2011); it provides insight into the effect of gains of local controllers on the closed-loop stability margin that is lacking in the coupled-ODE model. Here we show that the ratio of the approximation error to the stability margin is O(1/N), where N is the number of vehicles. Thus, the PDE model is an accurate approximation of the coupled-ODE model when N is large. Numerical computations are provided to corroborate the analysis.

  12. XRF map identification problems based on a PDE electrodeposition model

    NASA Astrophysics Data System (ADS)

    Sgura, Ivonne; Bozzini, Benedetto

    2017-04-01

    In this paper we focus on the following map identification problem (MIP): given a morphochemical reaction–diffusion (RD) PDE system modeling an electrodepostion process, we look for a time t *, belonging to the transient dynamics and a set of parameters \\mathbf{p} , such that the PDE solution, for the morphology h≤ft(x,y,{{t}\\ast};\\mathbf{p}\\right) and for the chemistry θ ≤ft(x,y,{{t}\\ast};\\mathbf{p}\\right) approximates a given experimental map M *. Towards this aim, we introduce a numerical algorithm using singular value decomposition (SVD) and Frobenius norm to give a measure of error distance between experimental maps for h and θ and simulated solutions of the RD-PDE system on a fixed time integration interval. The technique proposed allows quantitative use of microspectroscopy images, such as XRF maps. Specifically, in this work we have modelled the morphology and manganese distributions of nanostructured components of innovative batteries and we have followed their changes resulting from ageing under operating conditions. The availability of quantitative information on space-time evolution of active materials in terms of model parameters will allow dramatic improvements in knowledge-based optimization of battery fabrication and operation.

  13. Mean field spin glasses treated with PDE techniques

    NASA Astrophysics Data System (ADS)

    Barra, Adriano; Del Ferraro, Gino; Tantari, Daniele

    2013-07-01

    Following an original idea of Guerra, in these notes we analyze the Sherrington-Kirkpatrick model from different perspectives, all sharing the underlying approach which consists in linking the resolution of the statistical mechanics of the model (e.g. solving for the free energy) to well-known partial differential equation (PDE) problems (in suitable spaces). The plan is then to solve the related PDE using techniques involved in their native field and lastly bringing back the solution in the proper statistical mechanics framework. Within this strand, after a streamlined test-case on the Curie-Weiss model to highlight the methods more than the physics behind, we solve the SK both at the replica symmetric and at the 1-RSB level, obtaining the correct expression for the free energy via an analogy to a Fourier equation and for the self-consistencies with an analogy to a Burger equation, whose shock wave develops exactly at critical noise level (triggering the phase transition). Our approach, beyond acting as a new alternative method (with respect to the standard routes) for tackling the complexity of spin glasses, links symmetries in PDE theory with constraints in statistical mechanics and, as a novel result from the theoretical physics perspective, we obtain a new class of polynomial identities (namely of Aizenman-Contucci type, but merged within the Guerra's broken replica measures), whose interest lies in understanding, via the recent Panchenko breakthroughs, how to force the overlap organization to the ultrametric tree predicted by Parisi.

  14. Biallelic Mutations in PDE10A Lead to Loss of Striatal PDE10A and a Hyperkinetic Movement Disorder with Onset in Infancy

    PubMed Central

    Diggle, Christine P.; Sukoff Rizzo, Stacey J.; Popiolek, Michael; Hinttala, Reetta; Schülke, Jan-Philip; Kurian, Manju A.; Carr, Ian M.; Markham, Alexander F.; Bonthron, David T.; Watson, Christopher; Sharif, Saghira Malik; Reinhart, Veronica; James, Larry C.; Vanase-Frawley, Michelle A.; Charych, Erik; Allen, Melanie; Harms, John; Schmidt, Christopher J.; Ng, Joanne; Pysden, Karen; Strick, Christine; Vieira, Päivi; Mankinen, Katariina; Kokkonen, Hannaleena; Kallioinen, Matti; Sormunen, Raija; Rinne, Juha O.; Johansson, Jarkko; Alakurtti, Kati; Huilaja, Laura; Hurskainen, Tiina; Tasanen, Kaisa; Anttila, Eija; Marques, Tiago Reis; Howes, Oliver; Politis, Marius; Fahiminiya, Somayyeh; Nguyen, Khanh Q.; Majewski, Jacek; Uusimaa, Johanna; Sheridan, Eamonn; Brandon, Nicholas J.

    2016-01-01

    Deficits in the basal ganglia pathways modulating cortical motor activity underlie both Parkinson disease (PD) and Huntington disease (HD). Phosphodiesterase 10A (PDE10A) is enriched in the striatum, and animal data suggest that it is a key regulator of this circuitry. Here, we report on germline PDE10A mutations in eight individuals from two families affected by a hyperkinetic movement disorder due to homozygous mutations c.320A>G (p.Tyr107Cys) and c.346G>C (p.Ala116Pro). Both mutations lead to a reduction in PDE10A levels in recombinant cellular systems, and critically, positron-emission-tomography (PET) studies with a specific PDE10A ligand confirmed that the p.Tyr107Cys variant also reduced striatal PDE10A levels in one of the affected individuals. A knock-in mouse model carrying the homologous p.Tyr97Cys variant had decreased striatal PDE10A and also displayed motor abnormalities. Striatal preparations from this animal had an impaired capacity to degrade cyclic adenosine monophosphate (cAMP) and a blunted pharmacological response to PDE10A inhibitors. These observations highlight the critical role of PDE10A in motor control across species. PMID:27058446

  15. Biallelic Mutations in PDE10A Lead to Loss of Striatal PDE10A and a Hyperkinetic Movement Disorder with Onset in Infancy.

    PubMed

    Diggle, Christine P; Sukoff Rizzo, Stacey J; Popiolek, Michael; Hinttala, Reetta; Schülke, Jan-Philip; Kurian, Manju A; Carr, Ian M; Markham, Alexander F; Bonthron, David T; Watson, Christopher; Sharif, Saghira Malik; Reinhart, Veronica; James, Larry C; Vanase-Frawley, Michelle A; Charych, Erik; Allen, Melanie; Harms, John; Schmidt, Christopher J; Ng, Joanne; Pysden, Karen; Strick, Christine; Vieira, Päivi; Mankinen, Katariina; Kokkonen, Hannaleena; Kallioinen, Matti; Sormunen, Raija; Rinne, Juha O; Johansson, Jarkko; Alakurtti, Kati; Huilaja, Laura; Hurskainen, Tiina; Tasanen, Kaisa; Anttila, Eija; Marques, Tiago Reis; Howes, Oliver; Politis, Marius; Fahiminiya, Somayyeh; Nguyen, Khanh Q; Majewski, Jacek; Uusimaa, Johanna; Sheridan, Eamonn; Brandon, Nicholas J

    2016-04-07

    Deficits in the basal ganglia pathways modulating cortical motor activity underlie both Parkinson disease (PD) and Huntington disease (HD). Phosphodiesterase 10A (PDE10A) is enriched in the striatum, and animal data suggest that it is a key regulator of this circuitry. Here, we report on germline PDE10A mutations in eight individuals from two families affected by a hyperkinetic movement disorder due to homozygous mutations c.320A>G (p.Tyr107Cys) and c.346G>C (p.Ala116Pro). Both mutations lead to a reduction in PDE10A levels in recombinant cellular systems, and critically, positron-emission-tomography (PET) studies with a specific PDE10A ligand confirmed that the p.Tyr107Cys variant also reduced striatal PDE10A levels in one of the affected individuals. A knock-in mouse model carrying the homologous p.Tyr97Cys variant had decreased striatal PDE10A and also displayed motor abnormalities. Striatal preparations from this animal had an impaired capacity to degrade cyclic adenosine monophosphate (cAMP) and a blunted pharmacological response to PDE10A inhibitors. These observations highlight the critical role of PDE10A in motor control across species.

  16. Isolation and characterization of PDE9A, a novel human cGMP-specific phosphodiesterase.

    PubMed

    Fisher, D A; Smith, J F; Pillar, J S; St Denis, S H; Cheng, J B

    1998-06-19

    We have cloned and characterized the first human isozyme in a new family of cyclic nucleotide phosphodiesterases, PDE9A. By sequence homology in the catalytic domain, PDE9A is almost equidistant from all eight known mammalian PDE families but is most similar to PDE8A (34% amino acid identity) and least like PDE5A (28% amino acid identity). We report the cloning of human cDNA encoding a full-length protein of 593 amino acids, including a 261-amino acid region located near the C terminus that is homologous to the approximately 270-amino acid catalytic domain of other PDEs. PDE9A is expressed in all eight tissues examined as a approximately 2. 0-kilobase mRNA, with highest levels in spleen, small intestine, and brain. The full-length PDE9A was expressed in baculovirus fused to an N-terminal 9-amino acid FLAG tag. Kinetic analysis of the baculovirus-expressed enzyme shows it to be a very high affinity cGMP-specific PDE with a Km of 170 nM for cGMP and 230 microM for cAMP. The Km for cGMP makes PDE9A one of the highest affinity PDEs known. The Vmax for cGMP (4.9 nmol/min/microg recombinant enzyme) is about twice as fast as that of PDE4 for cAMP. The enzyme is about twice as active in vitro in 1-10 mM Mn2+ than in the same concentration of Mg2+ or Ca2+. PDE9A is insensitive (up to 100 microM) to a variety of PDE inhibitors including rolipram, vinpocetine, SKF-94120, dipyridamole, and 3-isobutyl-1-methyl-xanthine but is inhibited (IC50 = 35 microM) by zaprinast, a PDE5 inhibitor. PDE9A lacks a region homologous to the allosteric cGMP-binding regulatory regions found in the cGMP-binding PDEs: PDE2, PDE5, and PDE6.

  17. Comparative assessment of PDE 4 and 7 inhibitors as therapeutic agents in experimental autoimmune encephalomyelitis

    PubMed Central

    González-García, C; Bravo, B; Ballester, A; Gómez-Pérez, R; Eguiluz, C; Redondo, M; Martínez, A; Gil, C; Ballester, S

    2013-01-01

    BACKGROUND AND PURPOSE PDE4 inhibition suppresses experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). However, side effects hinder PDE4 inhibitors clinical use. PDE7 inhibition might constitute an alternative therapeutic strategy, but few data about the anti-inflammatory potential of PDE7 inhibitors are currently available. We have used the EAE model to perform a comparative evaluation of PDE4 and PDE7 inhibition as strategies for MS treatment. EXPERIMENTAL APPROACH Two PDE7 inhibitors, the sulfonamide derivative BRL50481 and the recently described quinazoline compound TC3.6, were assayed to modulate EAE in SJL mice, in comparison with the well-known PDE4 inhibitor Rolipram. We evaluated clinical signs, presence of inflammatory infiltrates in CNS and anti-inflammatory markers. We also analysed the effect of these inhibitors on the inflammatory profile of spleen cells in vitro. KEY RESULTS TC3.6 prevented EAE with efficacy similar to Rolipram, while BRL50481 had no effect on the disease. Differences between both PDE7 inhibitors are discussed. Data from Rolipram and TC3.6 showed that PDE4 and PDE7 inhibition work through both common and distinct pathways. Rolipram administration caused an increase in IL-10 and IL-27 expression which was not found after TC3.6 treatment. On the other hand, both inhibitors reduced IL-17 levels, prevented infiltration in CNS and increased the expression of the T regulator cell marker Foxp3. CONCLUSIONS AND IMPLICATIONS These results provide new information about the effects of Rolipram on EAE, underline PDE7 inhibition as a new therapeutic target for inflammatory diseases and show the value of TC3.6 to prevent EAE, with possible consequences for new therapeutic tools in MS. PMID:23869659

  18. Potential of Targeting PDE1C/2A for Suppressing Metastatic Ovarian Cancers

    DTIC Science & Technology

    2014-07-01

    molecular mechanisms associated with forskolin /PDE2 inhibitor-induced apoptosis of aggressive ovarian cancer cells and 2) to evaluate the translation value...of treating aggressive ovarian cancer cells with forskolin and PDE2 inhibitor in an intraperitoneal xenograft model. In first year of the funding...we showed that knockdown of PDE2A rendered ovarian cancer cells susceptible for forskolin -induced cell growth inhibition/apoptosis. We further showed

  19. Daily rhythm in pineal phosphodiesterase (PDE) activity reflects adrenergic/3',5'-cyclic adenosine 5'-monophosphate induction of the PDE4B2 variant.

    PubMed

    Kim, Jong-So; Bailey, Michael J; Ho, Anthony K; Møller, Morten; Gaildrat, Pascaline; Klein, David C

    2007-04-01

    The pineal gland is a photoneuroendocrine transducer that influences circadian and circannual dynamics of many physiological functions via the daily rhythm in melatonin production and release. Melatonin synthesis is stimulated at night by a photoneural system through which pineal adenylate cyclase is adrenergically activated, resulting in an elevation of cAMP. cAMP enhances melatonin synthesis through actions on several elements of the biosynthetic pathway. cAMP degradation also appears to increase at night due to an increase in phosphodiesterase (PDE) activity, which peaks in the middle of the night. Here, it was found that this nocturnal increase in PDE activity results from an increase in the abundance of PDE4B2 mRNA (approximately 5-fold; doubling time, approximately 2 h). The resulting level is notably higher (>6-fold) than in all other tissues examined, none of which exhibit a robust daily rhythm. The increase in PDE4B2 mRNA is followed by increases in PDE4B2 protein and PDE4 enzyme activity. Results from in vivo and in vitro studies indicate that these changes are due to activation of adrenergic receptors and a cAMP-dependent protein kinase A mechanism. Inhibition of PDE4 activity during the late phase of adrenergic stimulation enhances cAMP and melatonin levels. The evidence that PDE4B2 plays a negative feedback role in adrenergic/cAMP signaling in the pineal gland provides the first proof that cAMP control of PDE4B2 is a physiologically relevant control mechanism in cAMP signaling.

  20. Research in nonlinear structural and solid mechanics

    NASA Technical Reports Server (NTRS)

    Mccomb, H. G., Jr. (Compiler); Noor, A. K. (Compiler)

    1980-01-01

    Nonlinear analysis of building structures and numerical solution of nonlinear algebraic equations and Newton's method are discussed. Other topics include: nonlinear interaction problems; solution procedures for nonlinear problems; crash dynamics and advanced nonlinear applications; material characterization, contact problems, and inelastic response; and formulation aspects and special software for nonlinear analysis.

  1. Domain decomposition in time for PDE-constrained optimization

    SciTech Connect

    Barker, Andrew T.; Stoll, Martin

    2015-08-28

    Here, PDE-constrained optimization problems have a wide range of applications, but they lead to very large and ill-conditioned linear systems, especially if the problems are time dependent. In this paper we outline an approach for dealing with such problems by decomposing them in time and applying an additive Schwarz preconditioner in time, so that we can take advantage of parallel computers to deal with the very large linear systems. We then illustrate the performance of our method on a variety of problems.

  2. alphaPDE: A new multivariate technique for parameter estimation

    SciTech Connect

    Knuteson, B.; Miettinen, H.; Holmstrom, L.

    2002-06-01

    We present alphaPDE, a new multivariate analysis technique for parameter estimation. The method is based on a direct construction of joint probability densities of known variables and the parameters to be estimated. We show how posterior densities and best-value estimates are then obtained for the parameters of interest by a straightforward manipulation of these densities. The method is essentially non-parametric and allows for an intuitive graphical interpretation. We illustrate the method by outlining how it can be used to estimate the mass of the top quark, and we explain how the method is applied to an ensemble of events containing background.

  3. Pyrazolopyridines as potent PDE4B inhibitors: 5-Heterocycle SAR

    SciTech Connect

    Mitchell, Charlotte J.; Ballantine, Stuart P.; Coe, Diane M.; Cook, Caroline M.; Delves, Christopher J.; Dowle, Mike D.; Edlin, Chris D.; Hamblin, J. Nicole; Holman, Stuart; Johnson, Martin R.; Jones, Paul S.; Keeling, Sue E.; Kranz, Michael; Lindvall, Mika; Lucas, Fiona S.; Neu, Margarete; Solanke, Yemisi E.; Somers, Don O.; Trivedi, Naimisha A.; Wiseman, Joanne O.

    2012-05-03

    Following the discovery of 4-(substituted amino)-1-alkyl-pyrazolo[3,4-b]pyridine-5-carboxamides as potent and selective phosphodiesterase 4B inhibitors, [Hamblin, J. N.; Angell, T.; Ballentine, S., et al. Bioorg. Med. Chem. Lett.2008, 18, 4237] the SAR of the 5-position was investigated further. A range of substituted heterocycles showed good potencies against PDE4. Optimisation using X-ray crystallography and computational modelling led to the discovery of 16, with sub-nM inhibition of LPS-induced TNF-{alpha} production from isolated human peripheral blood mononuclear cells.

  4. Simulation of Stochastic Processes by Coupled ODE-PDE

    NASA Technical Reports Server (NTRS)

    Zak, Michail

    2008-01-01

    A document discusses the emergence of randomness in solutions of coupled, fully deterministic ODE-PDE (ordinary differential equations-partial differential equations) due to failure of the Lipschitz condition as a new phenomenon. It is possible to exploit the special properties of ordinary differential equations (represented by an arbitrarily chosen, dynamical system) coupled with the corresponding Liouville equations (used to describe the evolution of initial uncertainties in terms of joint probability distribution) in order to simulate stochastic processes with the proscribed probability distributions. The important advantage of the proposed approach is that the simulation does not require a random-number generator.

  5. Quantum Hasimoto transformation and nonlinear waves on a superfluid vortex filament under the quantum local induction approximation.

    PubMed

    Van Gorder, Robert A

    2015-05-01

    The Hasimoto transformation between the classical LIA (local induction approximation, a model approximating the motion of a thin vortex filament) and the nonlinear Schrödinger equation (NLS) has proven very useful in the past, since it allows one to construct new solutions to the LIA once a solution to the NLS is known. In the present paper, the quantum form of the LIA (which includes mutual friction effects) is put into correspondence with a type of complex nonlinear dispersive partial differential equation (PDE) with cubic nonlinearity (similar in form to a Ginsburg-Landau equation, with additional nonlinear terms). Transforming the quantum LIA in such a way enables one to obtain quantum vortex filament solutions once solutions to this dispersive PDE are known. From our quantum Hasimoto transformation, we determine the form and behavior of Stokes waves, a standing one-soliton, traveling waves, and similarity solutions under normal and binormal friction effects. The quantum Hasimoto transformation is useful when normal fluid velocity is relatively weak, so for the case where the normal fluid velocity is dominant we resort to other approaches. We exhibit a number of solutions that exist only in the presence of the normal fluid velocity and mutual friction terms (which would therefore not exist in the limit taken to obtain the classical LIA, decaying into line filaments under such a limit), examples of which include normal fluid driven helices, stationary and propagating topological solitons, and a vortex ring whose radius varies inversely with the normal fluid magnitude. We show that, while chaos may not be impossible under the quantum LIA, it should not be expected to arise from traveling waves along quantum vortex filaments under the quantum LIA formulation.

  6. Mesh Algorithms for PDE with Sieve I: Mesh Distribution

    DOE PAGES

    Knepley, Matthew G.; Karpeev, Dmitry A.

    2009-01-01

    We have developed a new programming framework, called Sieve, to support parallel numerical partial differential equation(s) (PDE) algorithms operating over distributed meshes. We have also developed a reference implementation of Sieve in C++ as a library of generic algorithms operating on distributed containers conforming to the Sieve interface. Sieve makes instances of the incidence relation, or arrows, the conceptual first-class objects represented in the containers. Further, generic algorithms acting on this arrow container are systematically used to provide natural geometric operations on the topology and also, through duality, on the data. Finally, coverings and duality are used to encode notmore » only individual meshes, but all types of hierarchies underlying PDE data structures, including multigrid and mesh partitions. In order to demonstrate the usefulness of the framework, we show how the mesh partition data can be represented and manipulated using the same fundamental mechanisms used to represent meshes. We present the complete description of an algorithm to encode a mesh partition and then distribute a mesh, which is independent of the mesh dimension, element shape, or embedding. Moreover, data associated with the mesh can be similarly distributed with exactly the same algorithm. The use of a high level of abstraction within the Sieve leads to several benefits in terms of code reuse, simplicity, and extensibility. We discuss these benefits and compare our approach to other existing mesh libraries.« less

  7. Validation and application of an intervertebral disc finite element model utilizing independently constructed tissue-level constitutive formulations that are nonlinear, anisotropic, and time-dependent.

    PubMed

    Jacobs, Nathan T; Cortes, Daniel H; Peloquin, John M; Vresilovic, Edward J; Elliott, Dawn M

    2014-08-22

    Finite element (FE) models are advantageous in the study of intervertebral disc mechanics as the stress-strain distributions can be determined throughout the tissue and the applied loading and material properties can be controlled and modified. However, the complicated nature of the disc presents a challenge in developing an accurate and predictive disc model, which has led to limitations in FE geometry, material constitutive models and properties, and model validation. The objective of this study was to develop a new FE model of the intervertebral disc, to validate the model's nonlinear and time-dependent responses without tuning or calibration, and to evaluate the effect of changes in nucleus pulposus (NP), cartilaginous endplate (CEP), and annulus fibrosus (AF) material properties on the disc mechanical response. The new FE disc model utilized an analytically-based geometry. The model was created from the mean shape of human L4/L5 discs, measured from high-resolution 3D MR images and averaged using signed distance functions. Structural hyperelastic constitutive models were used in conjunction with biphasic-swelling theory to obtain material properties from recent tissue tests in confined compression and uniaxial tension. The FE disc model predictions fit within the experimental range (mean ± 95% confidence interval) of the disc's nonlinear response for compressive slow loading ramp, creep, and stress-relaxation simulations. Changes in NP and CEP properties affected the neutral-zone displacement but had little effect on the final stiffness during slow-ramp compression loading. These results highlight the need to validate FE models using the disc's full nonlinear response in multiple loading scenarios.

  8. Distinct patterns of compartmentalization and proteolytic stability of PDE6C mutants linked to achromatopsia.

    PubMed

    Cheguru, Pallavi; Majumder, Anurima; Artemyev, Nikolai O

    2015-01-01

    Phosphodiesterase-6 (PDE6) is an essential effector enzyme in vertebrate photoreceptor cells. Mutations in rod and cone PDE6 cause recessive retinitis pigmentosa and achromatopsia, respectively. The mechanisms of missense PDE6 mutations underlying severe visual disorders are poorly understood. To probe these mechanisms, we expressed seven known missense mutants of cone PDE6C in rods of transgenic Xenopus laevis and examined their stability and compartmentalization. PDE6C proteins with mutations in the catalytic domain, H602L and E790K, displayed modestly reduced proteolytic stability, but they were properly targeted to the outer segment of photoreceptor cells. Mutations in the regulatory GAF domains, R104W, Y323N, and P391L led to a proteolytic degradation of the proteins involving a cleavage in the GAFb domain. Lastly, the R29W and M455V mutations residing outside the conserved PDE6 domains produced a pattern of subcellular compartmentalization different from that of PDE6C. Thus, our results suggest a spectrum of mechanisms of missense PDE6C mutations in achromatopsia including catalytic defects, protein mislocalization, or a specific sequence of proteolytic degradation.

  9. How Schools and Students Respond to School Improvement Programs: The Case of Brazil's PDE

    ERIC Educational Resources Information Center

    Carnoy, Martin; Gove, Amber K.; Loeb, Susanna; Marshall, Jeffrey H.; Socias, Miguel

    2008-01-01

    This study uses rich empirical data from Brazil to assess how a government program (PDE) that decentralizes school management decisions changes what goes on in schools and how these changes affect student outcomes. It appears that the PDE resulted in some improvements in management and learning materials, but little change in other areas including…

  10. Discovery of oxazole-based PDE4 inhibitors with picomolar potency.

    PubMed

    Kuang, Rongze; Shue, Ho-Jane; Xiao, Li; Blythin, David J; Shih, Neng-Yang; Chen, Xiao; Gu, Danlin; Schwerdt, John; Lin, Ling; Ting, Pauline C; Cao, Jianhua; Aslanian, Robert; Piwinski, John J; Prelusky, Daniel; Wu, Ping; Zhang, Ji; Zhang, Xiang; Celly, Chander S; Billah, Motasim; Wang, Peng

    2012-04-01

    Optimization of oxazole-based PDE4 inhibitors has led to the discovery of a series of quinolyl oxazoles, with 4-benzylcarboxamide and 5-α-aminoethyl groups which exhibit picomolar potency against PDE4. Selectivity profiles and in vivo biological activity are also reported.

  11. Design and Microwave Assisted Synthesis of Coumarin Derivatives as PDE Inhibitors

    PubMed Central

    Kumbar, Mahadev N.; Kamble, Ravindra R.; Kamble, Atulkumar A.; Salian, Sujith Raj; Kumari, Sandhya; Nair, Ramya; Kalthur, Guruprasad; Adiga, Satish Kumar; Prasad, D. Jagadeesh

    2016-01-01

    Coumarins appended to benzimidazole through pyrazole are designed and synthesized using microwave irradiation. These compounds were analyzed for phosphodiesterase (PDE) inhibition indirectly by motility pattern in human spermatozoa. Some of the synthesized compounds, namely, 5d, 5e, 5f, 5g, 5h, and 5k, have exhibited potent inhibitory activity on PDE. PMID:26998358

  12. Highway traffic estimation of improved precision using the derivative-free nonlinear Kalman Filter

    NASA Astrophysics Data System (ADS)

    Rigatos, Gerasimos; Siano, Pierluigi; Zervos, Nikolaos; Melkikh, Alexey

    2015-12-01

    The paper proves that the PDE dynamic model of the highway traffic is a differentially flat one and by applying spatial discretization its shows that the model's transformation into an equivalent linear canonical state-space form is possible. For the latter representation of the traffic's dynamics, state estimation is performed with the use of the Derivative-free nonlinear Kalman Filter. The proposed filter consists of the Kalman Filter recursion applied on the transformed state-space model of the highway traffic. Moreover, it makes use of an inverse transformation, based again on differential flatness theory which enables to obtain estimates of the state variables of the initial nonlinear PDE model. By avoiding approximate linearizations and the truncation of nonlinear terms from the PDE model of the traffic's dynamics the proposed filtering methods outperforms, in terms of accuracy, other nonlinear estimators such as the Extended Kalman Filter. The article's theoretical findings are confirmed through simulation experiments.

  13. Differential Regulation of PDE5 Expression in Left and Right Ventricles of Feline Hypertrophy Models

    PubMed Central

    Shan, Xiaoyin; Margulies, Kenneth B.

    2011-01-01

    Background Though long known to affect smooth muscle biology, recent studies indicate that phosphodiesterase 5 (PDE5) is also expressed in myocardium. Recognizing that the regulation of PDE5 in hypertrophy is not well understood, we assessed the response of PDE5 expression and the level of cGMP-dependent kinase I (cGKI) in the left and right ventricles of feline hypertrophy models. Methodology/Principal Findings Using a cDNA library of feline aortic smooth muscle cells, we identified and cloned PDE5 cDNA for the first time in this species. The sequence shares 98% identity with its human orthologue at the amino acid level. E. coli expression of the cloned allele allowed selection of antibodies with appropriate specificity, facilitating the analysis of PDE5 expression in feline models created by selective proximal aortic (Ao) or pulmonary artery (PA) banding that resulted in hypertrophy of the left ventricle (LV) and right ventricle (RV), respectively. We demonstrated that PDE5 expression responded differentially with a decreased expression in the LV and an increased expression in the RV in the Ao-banded model. Similarly, in the PA-banded model, LV showed reduced expression while the RV expression was unaltered. In addition, the expression of cGKI was significantly decreased in the RV of Ao-banded group, correlating inversely with the increase in PDE5 expression. Conclusions/Significance The differential regulation of PDE5 and cGKI expression suggests that the mechanisms involved in hypertrophy could be different in RV vs. LV. Reciprocal PDE5 and cGKI expression in the RV of Ao-banded model suggests functional significance for PDE5 up-regulation. PMID:21625548

  14. PHLPP2 Downregulation Contributes to Lung Carcinogenesis Following B[a]P/B[a]PDE Exposure

    PubMed Central

    Huang, Haishan; Pan, Xiaofu; Jin, Honglei; Li, Yang; Zhang, Lin; Yang, Caili; Liu, Pei; Liu, Ya; Chen, Lili; Li, Jingxia; Zhu, Junlan; Zeng, Xingruo; Fu, Kai; Chen, Guorong; Gao, Jimin; Huang, Chuanshu

    2015-01-01

    Purpose The carcinogenic capacity of B[a]P/B[a]PDE is supported by epidemiologic studies. However, the molecular mechanisms responsible for B[a]P/B[a]PDE-caused lung cancer have not been well investigated. We evaluated here the role of novel target PHLPP2 in lung inflammation and carcinogenesis upon B[a]P/B[a]PDE exposure. Experimental Design We used the Western blotting, RT-PCR, [35S]methionine pulse and immunohistochemistry staining to determine PHLPP2 downregulation following B[a]P/B[a]PDE exposure. Both B[a]PDE-induced Beas-2B cell transformation model and B[a]P-caused mouse lung cancer model were used to elucidate the mechanisms leading to PHLPP2 downregulation and lung carcinogenesis. The important findings were also extended to in vivo human studies. Results We found that B[a]P/B[a]PDE exposure downregulated PHLPP2 expression in human lung epithelial cells in vitro and in mouse lung tissues in vivo. The ectopic expression of PHLPP2 dramatically inhibited cell transformation upon B[a]PDE exposure. Mechanistic studies showed that miR-205 induction was crucial for inhibition of PHLPP2 protein translation by targeting PHLPP2-3′-UTR. Interestingly, PHLPP2 expression was inversely associated with tumor necrosis factor alpha (TNFα) expression, with low PHLPP2 and high TNFα expression in lung cancer tissues compared with the paired adjacent normal lung tissues. Additional studies revealed that PHLPP2 exhibited its antitumorigenic effect of B[a]P/B[a]PDE through the repression of inflammatory TNFα transcription. Conclusions Our studies not only first time identify PHLPP2 downregulation by lung carcinogen B[a]P/B[a]PDE, but also elucidate a novel molecular mechanisms underlying lung inflammation and carcinogenesis upon B[a]P/B[a]PDE exposure. PMID:25977341

  15. Compartmentalized PDE4A5 Signaling Impairs Hippocampal Synaptic Plasticity and Long-Term Memory

    PubMed Central

    Park, Alan J.; Tolentino, Rosa E.; Bruinenberg, Vibeke M.; Tudor, Jennifer C.; Lee, Yool; Hansen, Rolf T.; Guercio, Leonardo A.; Linton, Edward; Neves-Zaph, Susana R.; Meerlo, Peter; Baillie, George S.; Houslay, Miles D.

    2016-01-01

    Alterations in cAMP signaling are thought to contribute to neurocognitive and neuropsychiatric disorders. Members of the cAMP-specific phosphodiesterase 4 (PDE4) family, which contains >25 different isoforms, play a key role in determining spatial cAMP degradation so as to orchestrate compartmentalized cAMP signaling in cells. Each isoform binds to a different set of protein complexes through its unique N-terminal domain, thereby leading to targeted degradation of cAMP in specific intracellular compartments. However, the functional role of specific compartmentalized PDE4 isoforms has not been examined in vivo. Here, we show that increasing protein levels of the PDE4A5 isoform in mouse hippocampal excitatory neurons impairs a long-lasting form of hippocampal synaptic plasticity and attenuates hippocampus-dependent long-term memories without affecting anxiety. In contrast, viral expression of a truncated version of PDE4A5, which lacks the unique N-terminal targeting domain, does not affect long-term memory. Further, overexpression of the PDE4A1 isoform, which targets a different subset of signalosomes, leaves memory undisturbed. Fluorescence resonance energy transfer sensor-based cAMP measurements reveal that the full-length PDE4A5, in contrast to the truncated form, hampers forskolin-mediated increases in neuronal cAMP levels. Our study indicates that the unique N-terminal localization domain of PDE4A5 is essential for the targeting of specific cAMP-dependent signaling underlying synaptic plasticity and memory. The development of compounds to disrupt the compartmentalization of individual PDE4 isoforms by targeting their unique N-terminal domains may provide a fruitful approach to prevent cognitive deficits in neuropsychiatric and neurocognitive disorders that are associated with alterations in cAMP signaling. SIGNIFICANCE STATEMENT Neurons exhibit localized signaling processes that enable biochemical cascades to be activated selectively in specific subcellular

  16. A regularizing iterative ensemble Kalman method for PDE-constrained inverse problems

    NASA Astrophysics Data System (ADS)

    Iglesias, Marco A.

    2016-02-01

    We introduce a derivative-free computational framework for approximating solutions to nonlinear PDE-constrained inverse problems. The general aim is to merge ideas from iterative regularization with ensemble Kalman methods from Bayesian inference to develop a derivative-free stable method easy to implement in applications where the PDE (forward) model is only accessible as a black box (e.g. with commercial software). The proposed regularizing ensemble Kalman method can be derived as an approximation of the regularizing Levenberg-Marquardt (LM) scheme (Hanke 1997 Inverse Problems 13 79-95) in which the derivative of the forward operator and its adjoint are replaced with empirical covariances from an ensemble of elements from the admissible space of solutions. The resulting ensemble method consists of an update formula that is applied to each ensemble member and that has a regularization parameter selected in a similar fashion to the one in the LM scheme. Moreover, an early termination of the scheme is proposed according to a discrepancy principle-type of criterion. The proposed method can be also viewed as a regularizing version of standard Kalman approaches which are often unstable unless ad hoc fixes, such as covariance localization, are implemented. The aim of this paper is to provide a detailed numerical investigation of the regularizing and convergence properties of the proposed regularizing ensemble Kalman scheme; the proof of these properties is an open problem. By means of numerical experiments, we investigate the conditions under which the proposed method inherits the regularizing properties of the LM scheme of (Hanke 1997 Inverse Problems 13 79-95) and is thus stable and suitable for its application in problems where the computation of the Fréchet derivative is not computationally feasible. More concretely, we study the effect of ensemble size, number of measurements, selection of initial ensemble and tunable parameters on the performance of the method

  17. DISC1, PDE4B, and NDE1 at the centrosome and synapse

    SciTech Connect

    Bradshaw, Nicholas J.; Ogawa, Fumiaki; Antolin-Fontes, Beatriz; Chubb, Jennifer E.; Carlyle, Becky C.; Christie, Sheila; Claessens, Antoine; Porteous, David J.; Millar, J. Kirsty

    2008-12-26

    Disrupted-In-Schizophrenia 1 (DISC1) is a risk factor for schizophrenia and other major mental illnesses. Its protein binding partners include the Nuclear Distribution Factor E Homologs (NDE1 and NDEL1), LIS1, and phosphodiesterases 4B and 4D (PDE4B and PDE4D). We demonstrate that NDE1, NDEL1 and LIS1, together with their binding partner dynein, associate with DISC1, PDE4B and PDE4D within the cell, and provide evidence that this complex is present at the centrosome. LIS1 and NDEL1 have been previously suggested to be synaptic, and we now demonstrate localisation of DISC1, NDE1, and PDE4B at synapses in cultured neurons. NDE1 is phosphorylated by cAMP-dependant Protein Kinase A (PKA), whose activity is, in turn, regulated by the cAMP hydrolysis activity of phosphodiesterases, including PDE4. We propose that DISC1 acts as an assembly scaffold for all of these proteins and that the NDE1/NDEL1/LIS1/dynein complex is modulated by cAMP levels via PKA and PDE4.

  18. Identification of cancer cytotoxic modulators of PDE3A by predictive chemogenomics

    PubMed Central

    de Waal, Luc; Lewis, Timothy A.; Rees, Matthew G.; Tsherniak, Aviad; Wu, Xiaoyun; Choi, Peter S.; Gechijian, Lara; Hartigan, Christina; Faloon, Patrick W.; Hickey, Mark J.; Tolliday, Nicola; Carr, Steven A.; Clemons, Paul A.; Munoz, Benito; Wagner, Bridget K.; Shamji, Alykhan F.; Koehler, Angela N.; Schenone, Monica; Burgin, Alex B.; Schreiber, Stuart L.; Greulich, Heidi; Meyerson, Matthew

    2015-01-01

    High cancer death rates indicate the need for new anti-cancer therapeutic agents. Approaches to discover new cancer drugs include target-based drug discovery and phenotypic screening. Here, we identified phosphodiesterase 3A modulators as cell-selective cancer cytotoxic compounds by phenotypic compound library screening and target deconvolution by predictive chemogenomics. We found that sensitivity to 6-(4-(diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one, or DNMDP, across 766 cancer cell lines correlates with expression of the phosphodiesterase 3A gene, PDE3A. Like DNMDP, a subset of known PDE3A inhibitors kill selected cancer cells while others do not. Furthermore, PDE3A depletion leads to DNMDP resistance. We demonstrated that DNMDP binding to PDE3A promotes an interaction between PDE3A and Schlafen 12 (SLFN12), suggesting a neomorphic activity. Co-expression of SLFN12 with PDE3A correlates with DNMDP sensitivity, while depletion of SLFN12 results in decreased DNMDP sensitivity. Our results implicate PDE3A modulators as candidate cancer therapeutic agents and demonstrate the power of predictive chemogenomics in small-molecule discovery. PMID:26656089

  19. Altered PDE10A expression detectable early before symptomatic onset in Huntington's disease.

    PubMed

    Niccolini, Flavia; Haider, Salman; Reis Marques, Tiago; Muhlert, Nils; Tziortzi, Andri C; Searle, Graham E; Natesan, Sridhar; Piccini, Paola; Kapur, Shitij; Rabiner, Eugenii A; Gunn, Roger N; Tabrizi, Sarah J; Politis, Marios

    2015-10-01

    There is an urgent need for early biomarkers and novel disease-modifying therapies in Huntington's disease. Huntington's disease pathology involves the toxic effect of mutant huntingtin primarily in striatal medium spiny neurons, which highly express phosphodiesterase 10A (PDE10A). PDE10A hydrolyses cAMP/cGMP signalling cascades, thus having a key role in the regulation of striatal output, and in promoting neuronal survival. PDE10A could be a key therapeutic target in Huntington's disease. Here, we used combined positron emission tomography (PET) and multimodal magnetic resonance imaging to assess PDE10A expression in vivo in a unique cohort of 12 early premanifest Huntington's disease gene carriers with a mean estimated 90% probability of 25 years before the predicted onset of clinical symptoms. We show bidirectional changes in PDE10A expression in premanifest Huntington's disease gene carriers, which are associated with the probability of symptomatic onset. PDE10A expression in early premanifest Huntington's disease was decreased in striatum and pallidum and increased in motor thalamic nuclei, compared to a group of matched healthy controls. Connectivity-based analysis revealed prominent PDE10A decreases confined in the sensorimotor-striatum and in striatonigral and striatopallidal projecting segments. The ratio between higher PDE10A expression in motor thalamic nuclei and lower PDE10A expression in striatopallidal projecting striatum was the strongest correlate with higher probability of symptomatic conversion in early premanifest Huntington's disease gene carriers. Our findings demonstrate in vivo, a novel and earliest pathophysiological mechanism underlying Huntington's disease with direct implications for the development of new pharmacological treatments, which can promote neuronal survival and improve outcome in Huntington's disease gene carriers.

  20. Convergence acceleration for time-independent first-order PDE using optimal PNB-approximations

    SciTech Connect

    Holmgren, S.; Branden, H.

    1996-12-31

    We consider solving time-independent (steady-state) flow problems in 2D or 3D governed by hyperbolic or {open_quotes}almost hyperbolic{close_quotes} systems of partial differential equations (PDE). Examples of such PDE are the Euler and the Navier-Stokes equations. The PDE is discretized using a finite difference or finite volume scheme with arbitrary order of accuracy. If the matrix B describes the discretized differential operator and u denotes the approximate solution, the discrete problem is given by a large system of equations.

  1. Parameter identification of aggregated thermostatically controlled loads for smart grids using PDE techniques

    NASA Astrophysics Data System (ADS)

    Moura, Scott; Bendtsen, Jan; Ruiz, Victor

    2014-07-01

    This paper develops methods for model identification of aggregated thermostatically controlled loads (TCLs) in smart grids, via partial differential equation (PDE) techniques. Control of aggregated TCLs provides a promising opportunity to mitigate the mismatch between power generation and demand, thus enhancing grid reliability and enabling renewable energy penetration. To this end, this paper focuses on developing parameter identification algorithms for a PDE-based model of aggregated TCLs. First, a two-state boundary-coupled hyperbolic PDE model for homogenous TCL populations is derived. This model is extended to heterogeneous populations by including a diffusive term, which provides an elegant control-oriented model. Next, a passive parameter identification scheme and a swapping-based identification scheme are derived for the PDE model structure. Simulation results demonstrate the efficacy of each method under various autonomous and non-autonomous scenarios. The proposed models can subsequently be employed to provide system critical information for power system monitoring and control.

  2. Testosterone regulates smooth muscle contractile pathways in the rat prostate: emphasis on PDE5 signaling

    PubMed Central

    Zhang, Xinhua; Zang, Ning; Wei, Yu; Yin, Jin; Teng, Ruobing; Seftel, Allen

    2012-01-01

    Testosterone (T) plays a permissive role in the development of benign prostatic hyperplasia (BPH), and phosphodiesterase 5 inhibitors (PDE5is) have been found to be effective for BPH and lower urinary tract symptoms (LUTS) in clinical trials. This study investigated the effect of T on smooth muscle (SM) contractile and regulatory signaling pathways, including PDE5 expression and functional activity in prostate in male rats (sham-operated, surgically castrated, and castrated with T supplementation). In vitro organ bath studies, real-time RT-PCR, Western blot analysis, and immunohistochemistry were performed. Castration heavily attenuated contractility, including sensitivity to phenylephrine with SM myosin immunostaining revealing a disrupted SM cell arrangement in the stroma. PDE5 was immunolocalized exclusively in the prostate stroma, and orchiectomy signficantly reduced PDE5 immunopositivity, mRNA, and protein expression, along with nNOS and ROKβ mRNA, whereas it increased eNOS plus α1a and α1b adrenoreceptor expression in castrated animals. The PDE5i zaprinast significantly increased prostate strip relaxation to the nitric oxide donor sodium nitroprusside (SNP) in control but not castrated rats. But SNP alone was more effective on castrated rats, comparable with sham treated with SNP plus zaprinast. T supplementation prevented or restored all above changes, including SNP and zaprinast in vitro responsiveness. In conclusion, our data show that T positively regulates PDE5 expression and functional activities in prostate, and T ablation not only suppresses prostate size but also reduces prostatic SM contractility, with several potential SM contraction/relaxation pathways implicated. Zaprinast findings strongly suggest a major role for PDE5/cGMP in this signaling cascade. PDE5 inhibition may represent a novel mechanism for treatment of BPH. PMID:22028410

  3. Rip3 knockdown rescues photoreceptor cell death in blind pde6c zebrafish

    PubMed Central

    Viringipurampeer, I A; Shan, X; Gregory-Evans, K; Zhang, J P; Mohammadi, Z; Gregory-Evans, C Y

    2014-01-01

    Achromatopsia is a progressive autosomal recessive retinal disease characterized by early loss of cone photoreceptors and later rod photoreceptor loss. In most cases, mutations have been identified in CNGA3, CNGB3, GNAT2, PDE6C or PDE6H genes. Owing to this genetic heterogeneity, mutation-independent therapeutic schemes aimed at preventing cone cell death are very attractive treatment strategies. In pde6cw59 mutant zebrafish, cone photoreceptors expressed high levels of receptor-interacting protein kinase 1 (RIP1) and receptor-interacting protein kinase 3 (RIP3) kinases, key regulators of necroptotic cell death. In contrast, rod photoreceptor cells were alternatively immunopositive for caspase-3 indicating activation of caspase-dependent apoptosis in these cells. Morpholino gene knockdown of rip3 in pde6cw59 embryos rescued the dying cone photoreceptors by inhibiting the formation of reactive oxygen species and by inhibiting second-order neuron remodelling in the inner retina. In rip3 morphant larvae, visual function was restored in the cones by upregulation of the rod phosphodiesterase genes (pde6a and pde6b), compensating for the lack of cone pde6c suggesting that cones are able to adapt to their local environment. Furthermore, we demonstrated through pharmacological inhibition of RIP1 and RIP3 activity that cone cell death was also delayed. Collectively, these results demonstrate that the underlying mechanism of cone cell death in the pde6cw59 mutant retina is through necroptosis, whereas rod photoreceptor bystander death occurs through a caspase-dependent mechanism. This suggests that targeting the RIP kinase signalling pathway could be an effective therapeutic intervention in retinal degeneration patients. As bystander cell death is an important feature of many retinal diseases, combinatorial approaches targeting different cell death pathways may evolve as an important general principle in treatment. PMID:24413151

  4. Phosphodiesterase 3B (PDE3B) regulates NLRP3 inflammasome in adipose tissue

    PubMed Central

    Ahmad, Faiyaz; Chung, Youn Wook; Tang, Yan; Hockman, Steven C.; Liu, Shiwei; Khan, Yusuf; Huo, Kevin; Billings, Eric; Amar, Marcelo J.; Remaley, Alan T.; Manganiello, Vincent C.

    2016-01-01

    Activation of inflammation in white adipose tissue (WAT), includes infiltration/expansion of WAT macrophages, contributes pathogenesis of obesity, insulin resistance, and metabolic syndrome. The inflammasome comprises an intracellular sensor (NLR), caspase-1 and the adaptor ASC. Inflammasome activation leads to maturation of caspase-1 and processing of IL1β, contributing to many metabolic disorders and directing adipocytes to a more insulin-resistant phenotype. Ablation of PDE3B in WAT prevents inflammasome activation by reducing expression of NLRP3, caspase-1, ASC, AIM2, TNFα, IL1β and proinflammatory genes. Following IP injection of lipopolysaccharide (LPS), serum levels of IL1β and TNFα were reduced in PDE3B−/−mice compared to WT. Activation of signaling cascades, which mediate inflammasome responses, were modulated in PDE3B−/−mice WAT, including smad, NFAT, NFkB, and MAP kinases. Moreover, expression of chemokine CCL2, MCP-1 and its receptor CCR2, which play an important role in macrophage chemotaxis, were reduced in WAT of PDE3B−/−mice. In addition, atherosclerotic plaque formation was significantly reduced in the aorta of apoE−/−/PDE3B−/−and LDL-R−/−/PDE3B−/−mice compared to apoE−/−and LDL-R−/−mice, respectively. Obesity-induced changes in serum-cholesterol were blocked in PDE3B−/−mice. Collectively, these data establish a role for PDE3B in modulating inflammatory response, which may contribute to a reduced inflammatory state in adipose tissue. PMID:27321128

  5. Discovery of novel 1,4-dihydropyridine-based PDE4 inhibitors.

    PubMed

    Poondra, Rajamohan R; Nallamelli, Ratnam V; Meda, Chandana Lakshmi Teja; Srinivas, B N V; Grover, Anushka; Muttabathula, Jyotsna; Voleti, Sreedhara R; Sridhar, Balasubramanian; Pal, Manojit; Parsa, Kishore V L

    2013-02-15

    Substituted 1,4-dihydropyridines were discovered as a novel and potent series of phosphodiesterase 4 (PDE4) inhibitors. Structure-activity relationships within this series have been carried out and studies revealed that the dihydropyridine core, with indole moiety and 3,4-dimethoxybenzyl group, is a potent analogue for PDE4 inhibition. These novel series of compounds were prepared via a 3-component reaction in a single pot. In vitro biological activity, modeling studies and crystallography data are also reported.

  6. [A HPF application to parallelize a 2-D PDE model].

    PubMed

    Contreras, Xiómara; Hernández, Emilio

    2003-01-01

    Many practical numerical applications would require a parallel implementation in order to obtain a satisfactory response in a reasonable amount of time. In this sense, this work shows a parallel implementation of an explicit scheme of finite difference (FD) proposed by Kelly et. al., to solve the Partial Differential Equation (PDE / EDDP) of the Wave Propagation problem in an elastic, homogeneous or heterogeneous, two-dimensional medium. High-Performance-Fortran (HPF) will be used here for this purpose. This report shows measures of time on a PC-Cluster using 1, 2, and 4 processors with different sizes of data grid. In addition, a comparative test is included in which the cluster was initially connected using a Fast-Ethernet card, and then connected by a Myrinet card, using a grid size of 2500 x 2500 in both cases. The execution time achieved with two processors was highly satisfactory for all cases. In analogous conditions, the performance obtained with a Myrinet interconnection was better than the one obtained with a Fast-Ethernet interconnection. The scheme mentioned above has showed an excellent numerical result as it could be seen on the images included in this work. Key words: Partial differential equation, wave equation, explicite finite differences scheme, parallel scheme.

  7. Zaprinast impairs spatial memory by increasing PDE5 expression in the rat hippocampus.

    PubMed

    Giorgi, Mauro; Pompili, Assunta; Cardarelli, Silvia; Castelli, Valentina; Biagioni, Stefano; Sancesario, Giuseppe; Gasbarri, Antonella

    2015-02-01

    In this work, we report the effect of post-training intraperitoneal administration of zaprinast on rat memory retention in the Morris water maze task that revealed a significant memory impairment at the intermediate dose of 10mg/kg. Zaprinast is capable of inhibiting both striatal and hippocampal PDE activity but to a different extent which is probably due to the different PDE isoforms expressed in these areas. To assess the possible involvement of cyclic nucleotides in rat memory impairment, we compared the effects obtained 30 min after the zaprinast injection with respect to 24h after injection by measuring both cyclic nucleotide levels and PDE activity. As expected, 30 min after the zaprinast administration, we observed an increase of cyclic nucleotides, which returned to a basal level within 24h, with the exception of the hippocampal cGMP which was significantly decreased at the dose of 10mg/kg of zaprinast. This increase in the hippocampal region is the result of a cGMP-specific PDE5 induction, confirmed by sildenafil inhibition, in agreement with literature data that demonstrate transcriptional regulation of PDE5 by cAMP/cGMP intracellular levels. Our results highlight the possible rebound effect of PDE inhibitors.

  8. Engineered stabilization and structural analysis of the autoinhibited conformation of PDE4

    SciTech Connect

    Cedervall, Peder; Aulabaugh, Ann; Geoghegan, Kieran F.; McLellan, Thomas J.; Pandit, Jayvardhan

    2015-03-09

    Phosphodiesterase 4 (PDE4) is an essential contributor to intracellular signaling and an important drug target. The four members of this enzyme family (PDE4A to -D) are functional dimers in which each subunit contains two upstream conserved regions (UCR), UCR1 and -2, which precede the C-terminal catalytic domain. Alternative promoters, transcriptional start sites, and mRNA splicing lead to the existence of over 25 variants of PDE4, broadly classified as long, short, and supershort forms. We report the X-ray crystal structure of long form PDE4B containing UCR1, UCR2, and the catalytic domain, crystallized as a dimer in which a disulfide bond cross-links cysteines engineered into UCR2 and the catalytic domain. Biochemical and mass spectrometric analyses showed that the UCR2-catalytic domain interaction occurs in trans, and established that this interaction regulates the catalytic activity of PDE4. By elucidating the key structural determinants of dimerization, we show that only long forms of PDE4 can be regulated by this mechanism. The results also provide a structural basis for the long-standing observation of high- and low-affinity binding sites for the prototypic inhibitor rolipram.

  9. Engineered stabilization and structural analysis of the autoinhibited conformation of PDE4

    DOE PAGES

    Cedervall, Peder; Aulabaugh, Ann; Geoghegan, Kieran F.; ...

    2015-03-09

    Phosphodiesterase 4 (PDE4) is an essential contributor to intracellular signaling and an important drug target. The four members of this enzyme family (PDE4A to -D) are functional dimers in which each subunit contains two upstream conserved regions (UCR), UCR1 and -2, which precede the C-terminal catalytic domain. Alternative promoters, transcriptional start sites, and mRNA splicing lead to the existence of over 25 variants of PDE4, broadly classified as long, short, and supershort forms. We report the X-ray crystal structure of long form PDE4B containing UCR1, UCR2, and the catalytic domain, crystallized as a dimer in which a disulfide bond cross-linksmore » cysteines engineered into UCR2 and the catalytic domain. Biochemical and mass spectrometric analyses showed that the UCR2-catalytic domain interaction occurs in trans, and established that this interaction regulates the catalytic activity of PDE4. By elucidating the key structural determinants of dimerization, we show that only long forms of PDE4 can be regulated by this mechanism. The results also provide a structural basis for the long-standing observation of high- and low-affinity binding sites for the prototypic inhibitor rolipram.« less

  10. The Role of PDE3B Phosphorylation in the Inhibition of Lipolysis by Insulin

    PubMed Central

    DiPilato, Lisa M.; Ahmad, Faiyaz; Harms, Matthew; Seale, Patrick; Manganiello, Vincent

    2015-01-01

    Inhibition of adipocyte lipolysis by insulin is important for whole-body energy homeostasis; its disruption has been implicated as contributing to the development of insulin resistance and type 2 diabetes mellitus. The main target of the antilipolytic action of insulin is believed to be phosphodiesterase 3B (PDE3B), whose phosphorylation by Akt leads to accelerated degradation of the prolipolytic second messenger cyclic AMP (cAMP). To test this hypothesis genetically, brown adipocytes lacking PDE3B were examined for their regulation of lipolysis. In Pde3b knockout (KO) adipocytes, insulin was unable to suppress β-adrenergic receptor-stimulated glycerol release. Reexpressing wild-type PDE3B in KO adipocytes fully rescued the action of insulin against lipolysis. Surprisingly, a mutant form of PDE3B that ablates the major Akt phosphorylation site, murine S273, also restored the ability of insulin to suppress lipolysis. Taken together, these data suggest that phosphorylation of PDE3B by Akt is not required for insulin to suppress adipocyte lipolysis. PMID:26031333

  11. Novel PDE10A transcript diversity in the human striatum: Insights into gene complexity, conservation and regulation.

    PubMed

    MacMullen, Courtney M; Fallahi, Mohammad; Davis, Ronald L

    2017-03-30

    PDE10A is a cAMP/cGMP phosphodiesterase important in signal transduction within medium spiny neurons of the human striatum. This gene region has been associated with bipolar disorder via case-control and linkage studies. The three most studied human PDE10A isoforms differ in both their N-termini and trafficking within the cell with PDE10A2 found predominantly at the plasma membrane and PDE10A1 and PDE10A19 remaining primarily within the cytosol. RNA-sequencing and 5' RLM-RACE studies of the human putamen and caudate nucleus revealed 16 new exons and 12 novel transcripts of PDE10A, 3 of which are predicted to produce proteins with unique N-termini. The novel first exons of these transcripts are highly conserved in non-human primate species and are rarely found in other mammals. One hundred and eight previously classified intronic SNPs were found within the novel PDE10A exons of which 78% were classified as rare variants. Since most of the rare variants localize to 5' UTR regions, they may influence PDE10A transcription, translation, or mRNA stability. Dysregulation of cAMP signaling has been proposed as a cause of bipolar disorder and PDE10A inhibitors have been investigated as potential therapeutics for schizophrenia. Understanding the mechanisms contributing to PDE10A expression in the human striatum may provide evidence linking this gene to the phenotypes observed in neuropsychiatric disorders.

  12. Coupled nonlinear dynamical systems

    NASA Astrophysics Data System (ADS)

    Sun, Hongyan

    In this dissertation, we study coupled nonlinear dynamical systems that exhibit new types of complex behavior. We numerically and analytically examine a variety of dynamical models, ranging from systems of ordinary differential equations (ODE) with novel elements of feedback to systems of partial differential equations (PDE) that model chemical pattern formation. Chaos, dynamical uncertainty, synchronization, and spatiotemporal pattern formation constitute the primary topics of the dissertation. Following the introduction in Chapter 1, we study chaos and dynamical uncertainty in Chapter 2 with coupled Lorenz systems and demonstrate the existence of extreme complexity in high-dimensional ODE systems. In Chapter 3, we demonstrate that chaos synchronization can be achieved by mutual and multiplicative coupling of dynamical systems. Chapter 4 and 5 focus on pattern formation in reaction-diffusion systems, and we investigate segregation and integration behavior of populations in competitive and cooperative environments, respectively.

  13. A Discrete Model for an Ill-Posed Nonlinear Parabolic PDE

    DTIC Science & Technology

    2001-02-23

    BA9]%J\\^C/CacFGHiSamFIJBXQA`acFIJB\\/_FICM,k� ADHd � PQA`]¢J\\^M,HQ]`U(£�XQ\\/C^A�¤*�,Ut�¥¦XQFG]�F>EGA`@¢idZQ\\t�7AD@BA`HJracMGJB\\^EIFIJB\\/M,H J...ôR°_kV_?TV_kVU[^V_?ex��V_?m�[�Y\\[�hk[�Y\\�Uex¤~h_?��[�Y\\V_�L a@_öµ ߨ��|�z��bu^y÷p uUp?�Í�~p�Soq�c�0oq��|���oq�PrU� ì�g�^ gp |���oq��Søg�?oU

  14. Computer-Aided Closure of the Lie Algebra Associated with a Nonlinear PDE,

    DTIC Science & Technology

    1980-10-01

    wave packets which are slowly varying on the space and time scales of the corresponding wavelengths and periods, yet sufficiently broad in Fourier space ...velocities. The solutions to Eqs. (1) ignoring spatial derivatives ( time -only) are given in standard plasma physic’ texts6. The time -only equations are...commutators. We add one element at a time , substituting all newly determined commutators into the Jacobi identities as we proceed. For the example which

  15. Explicit Solutions for a Class of Nonlinear PDE that Arise in Allocation Problems

    DTIC Science & Technology

    2006-05-12

    approximations for allocation and occupancy problems one must solve a deterministic optimal control problem (or equiv- alently, a calculus of variations...to comply with a collection of information if it does not display a currently valid OMB control number. 1. REPORT DATE 12 MAY 2006 2. REPORT TYPE 3...significant underlying simplification. In the first example it is the fact that the value function for the control problem is expected to be quadratic

  16. Human PDE4D isoform composition is deregulated in primary prostate cancer and indicative for disease progression and development of distant metastases

    PubMed Central

    Böttcher, René; Dulla, Kalyan; van Strijp, Dianne; Dits, Natasja; Verhoef, Esther I.; Baillie, George S.; van Leenders, Geert J.L.H.; Houslay, Miles D.; Jenster, Guido; Hoffmann, Ralf

    2016-01-01

    Phosphodiesterase 4D7 was recently shown to be specifically over-expressed in localized prostate cancer, raising the question as to which regulatory mechanisms are involved and whether other isoforms of this gene family (PDE4D) are affected under the same conditions. We investigated PDE4D isoform composition in prostatic tissues using a total of seven independent expression datasets and also included data on DNA methylation, copy number and AR and ERG binding in PDE4D promoters to gain insight into their effect on PDE4D transcription. We show that expression of PDE4D isoforms is consistently altered in primary human prostate cancer compared to benign tissue, with PDE4D7 being up-regulated while PDE4D5 and PDE4D9 are down-regulated. Disease progression is marked by an overall down-regulation of long PDE4D isoforms, while short isoforms (PDE4D1/2) appear to be relatively unaffected. While these alterations seem to be independent of copy number alterations in the PDE4D locus and driven by AR and ERG binding, we also observed increased DNA methylation in the promoter region of PDE4D5, indicating a long lasting alteration of the isoform composition in prostate cancer tissues. We propose two independent metrics that may serve as diagnostic and prognostic markers for prostate disease: (PDE4D7 - PDE4D5) provides an effective means for distinguishing PCa from normal adjacent prostate, whereas PDE4D1/2 - (PDE4D5 + PDE4D7 + PDE4D9) offers strong prognostic potential to detect aggressive forms of PCa and is associated with metastasis free survival. Overall, our findings highlight the relevance of PDE4D as prostate cancer biomarker and potential drug target. PMID:27683107

  17. A PDE Sensitivity Equation Method for Optimal Aerodynamic Design

    NASA Technical Reports Server (NTRS)

    Borggaard, Jeff; Burns, John

    1996-01-01

    The use of gradient based optimization algorithms in inverse design is well established as a practical approach to aerodynamic design. A typical procedure uses a simulation scheme to evaluate the objective function (from the approximate states) and its gradient, then passes this information to an optimization algorithm. Once the simulation scheme (CFD flow solver) has been selected and used to provide approximate function evaluations, there are several possible approaches to the problem of computing gradients. One popular method is to differentiate the simulation scheme and compute design sensitivities that are then used to obtain gradients. Although this black-box approach has many advantages in shape optimization problems, one must compute mesh sensitivities in order to compute the design sensitivity. In this paper, we present an alternative approach using the PDE sensitivity equation to develop algorithms for computing gradients. This approach has the advantage that mesh sensitivities need not be computed. Moreover, when it is possible to use the CFD scheme for both the forward problem and the sensitivity equation, then there are computational advantages. An apparent disadvantage of this approach is that it does not always produce consistent derivatives. However, for a proper combination of discretization schemes, one can show asymptotic consistency under mesh refinement, which is often sufficient to guarantee convergence of the optimal design algorithm. In particular, we show that when asymptotically consistent schemes are combined with a trust-region optimization algorithm, the resulting optimal design method converges. We denote this approach as the sensitivity equation method. The sensitivity equation method is presented, convergence results are given and the approach is illustrated on two optimal design problems involving shocks.

  18. PDE5 inhibitors as therapeutics for heart disease, diabetes and cancer

    PubMed Central

    Das, Anindita; Durrant, David; Salloum, Fadi N; Xi, Lei; Kukreja, Rakesh C

    2015-01-01

    The phosphodiesterase 5 (PDE5) inhibitors, including sildenafil (Viagra™), vardenafil (Levitra™), and tadalafil (Cialis™) have been developed for treatment of erectile dysfunction. Moreover, sildenafil and tadalafil are used for the management of pulmonary arterial hypertension in patients. Since our first report showing the cardioprotective effect of sildenafil in 2002, there has been tremendous growth of preclinical and clinical studies on the use of PDE5 inhibitors for cardiovascular diseases and cancer. Numerous animal studies have demonstrated that PDE5 inhibitors have powerful protective effect against myocardial ischemia/reperfusion (I/R) injury, doxorubicin cardiotoxicity, ischemic and diabetic cardiomyopathy, cardiac hypertrophy, Duchenne muscular dystrophy and the improvement stem cell efficacy for myocardial repair. Mechanistically, PDE5 inhibitors protect the heart against I/R injury through increased expression of nitric oxide synthases, activation of protein kinase G (PKG), PKG-dependent hydrogen sulfide generation, and phosphorylation of glycogen synthase kinase-3β - a master switch immediately proximal to mitochondrial permeability transition pore and the end effector of cardioprotection. In addition, PDE5 inhibitors enhance the sensitivity of certain types of cancer to standard chemotherapeutic drugs, including doxorubicin. Many clinical trials with PDE5 inhibitors have focused on the potential cardiovascular and cancer benefits. Despite mixed results of these clinical trials, there is continuing strong interest by basic scientists and clinical investigators in exploring their new clinical uses. It is our hope that future new mechanistic investigations and carefully designed clinical trials would help in reaping additional benefits of PDE5 inhibitors for cardiovascular disease and cancer in patients. PMID:25444755

  19. Dissecting the cofactor-dependent and independent bindings of PDE4 inhibitors.

    PubMed

    Liu, S; Laliberté, F; Bobechko, B; Bartlett, A; Lario, P; Gorseth, E; Van Hamme, J; Gresser, M J; Huang, Z

    2001-08-28

    Type 4 phosphodiesterases (PDE4s) are metallohydrolases that catalyze the hydrolysis of cAMP to AMP. At the bottom of its active site lie two divalent metal ions in a binuclear motif which are involved in both cAMP binding and catalysis [(2000) Science 288, 1822-1825; (2000) Biochemistry 39, 6449-6458]. Using a SPA-based equilibrium [(3)H]rolipram binding assay, we have determined that Mg(2+), Mn(2+), and Co(2+) all mediated a high-affinity (K(d) between 3 and 8 nM) and near stoichiometric (R)-rolipram binding to PDE4. In their absence, (R)-rolipram binds stoichiometrically to the metal ion-free apoenzyme with a K(d) of approximately 150 nM. The divalent cation dose responses in mediating the high-affinity rolipram/PDE4 interaction mirror their efficacy in catalysis, suggesting that both metal ions of the holoenzyme are involved in mediating the high-affinity (R)-rolipram/PDE4 interaction. The specific rolipram binding to the apo- and holoenzyme is differentially displaced by cAMP, AMP, and other inhibitors, providing a robust tool to dissect the components of metal ion-dependent and independent PDE4/ligand interactions. cAMP binds to the holoenzyme with a K(s) of 1.9 microM and nonproductively to the apoenzyme with a K(d) of 179 microM. In comparison, AMP binds to the holo- and apoenzyme with K(d) values of 7 and 11 mM, respectively. The diminished Mg(2+)-dependent component of AMP binding to PDE4 suggests that most of the Mg(2+)/phosphate interaction in the cAMP/PDE4 complex is disrupted upon the hydrolysis of the cyclic phosphoester bond, leading to the rapid release of AMP.

  20. PDE 7 Inhibitors: New Potential Drugs for the Therapy of Spinal Cord Injury

    PubMed Central

    Paterniti, Irene; Mazzon, Emanuela; Gil, Carmen; Impellizzeri, Daniela; Palomo, Valle; Redondo, Myriam; Perez, Daniel I.; Esposito, Emanuela; Martinez, Ana; Cuzzocrea, Salvatore

    2011-01-01

    Background Primary traumatic mechanical injury to the spinal cord (SCI) causes the death of a number of neurons that to date can neither be recovered nor regenerated. During the last years our group has been involved in the design, synthesis and evaluation of PDE7 inhibitors as new innovative drugs for several neurological disorders. Our working hypothesis is based on two different facts. Firstly, neuroinflammation is modulated by cAMP levels, thus the key role for phosphodiesterases (PDEs), which hydrolyze cAMP, is undoubtedly demonstrated. On the other hand, PDE7 is expressed simultaneously on leukocytes and on the brain, highlighting the potential crucial role of PDE7 as drug target for neuroinflammation. Methodology/Principal Findings Here we present two chemically diverse families of PDE7 inhibitors, designed using computational techniques such as virtual screening and neuronal networks. We report their biological profile and their efficacy in an experimental SCI model induced by the application of vascular clips (force of 24 g) to the dura via a four-level T5–T8 laminectomy. We have selected two candidates, namely S14 and VP1.15, as PDE7 inhibitors. These compounds increase cAMP production both in macrophage and neuronal cell lines. Regarding drug-like properties, compounds were able to cross the blood brain barrier using parallel artificial membranes (PAMPA) methodology. SCI in mice resulted in severe trauma characterized by edema, neutrophil infiltration, and production of a range of inflammatory mediators, tissue damage, and apoptosis. Treatment of the mice with S14 and VP1.15, two PDE7 inhibitors, significantly reduced the degree of spinal cord inflammation, tissue injury (histological score), and TNF-α, IL-6, COX-2 and iNOS expression. Conclusions/Significance All these data together led us to propose PDE7 inhibitors, and specifically S14 and VP1.15, as potential drug candidates to be further studied for the treatment of SCI. PMID:21297958

  1. Genome-wide Association Analysis Identifies PDE4D as an Asthma-Susceptibility Gene

    PubMed Central

    Himes, Blanca E.; Hunninghake, Gary M.; Baurley, James W.; Rafaels, Nicholas M.; Sleiman, Patrick; Strachan, David P.; Wilk, Jemma B.; Willis-Owen, Saffron A.G.; Klanderman, Barbara; Lasky-Su, Jessica; Lazarus, Ross; Murphy, Amy J.; Soto-Quiros, Manuel E.; Avila, Lydiana; Beaty, Terri; Mathias, Rasika A.; Ruczinski, Ingo; Barnes, Kathleen C.; Celedón, Juan C.; Cookson, William O.C.; Gauderman, W. James; Gilliland, Frank D.; Hakonarson, Hakon; Lange, Christoph; Moffatt, Miriam F.; O'Connor, George T.; Raby, Benjamin A.; Silverman, Edwin K.; Weiss, Scott T.

    2009-01-01

    Asthma, a chronic airway disease with known heritability, affects more than 300 million people around the world. A genome-wide association (GWA) study of asthma with 359 cases from the Childhood Asthma Management Program (CAMP) and 846 genetically matched controls from the Illumina ICONdb public resource was performed. The strongest region of association seen was on chromosome 5q12 in PDE4D. The phosphodiesterase 4D, cAMP-specific (phosphodiesterase E3 dunce homolog, Drosophila) gene (PDE4D) is a regulator of airway smooth-muscle contractility, and PDE4 inhibitors have been developed as medications for asthma. Allelic p values for top SNPs in this region were 4.3 × 10−07 for rs1588265 and 9.7 × 10−07 for rs1544791. Replications were investigated in ten independent populations with different ethnicities, study designs, and definitions of asthma. In seven white and Hispanic replication populations, two PDE4D SNPs had significant results with p values less than 0.05, and five had results in the same direction as the original population but had p values greater than 0.05. Combined p values for 18,891 white and Hispanic individuals (4,342 cases) in our replication populations were 4.1 × 10−04 for rs1588265 and 9.2 × 10−04 for rs1544791. In three black replication populations, which had different linkage disequilibrium patterns than the other populations, original findings were not replicated. Further study of PDE4D variants might lead to improved understanding of the role of PDE4D in asthma pathophysiology and the efficacy of PDE4 inhibitor medications. PMID:19426955

  2. A framework for the construction of preconditioners for systems of PDE

    SciTech Connect

    Holmgren, S.; Otto, K.

    1994-12-31

    The authors consider the solution of systems of partial differential equations (PDE) in 2D or 3D using preconditioned CG-like iterative methods. The PDE is discretized using a finite difference scheme with arbitrary order of accuracy. The arising sparse and highly structured system of equations is preconditioned using a discretization of a modified PDE, possibly exploiting a different discretization stencil. The preconditioner corresponds to a separable problem, and the discretization in one space direction is constructed so that the corresponding matrix is diagonalized by a unitary transformation. If this transformation is computable using a fast O(n log{sub 2} n) algorithm, the resulting preconditioner solve is of the same complexity. Also, since the preconditioner solves are based on a dimensional splitting, the intrinsic parallelism is good. Different choices of the unitary transformation are considered, e.g., the discrete Fourier transform, sine transform, and modified sine transform. The preconditioners fully exploit the structure of the original problem, and it is shown how to compute the parameters describing them subject to different optimality constraints. Some of these results recover results derived by e.g. R. Chan, T. Chan, and E. Tyrtyshnikov, but here they are stated in a {open_quotes}PDE context{close_quotes}. Numerical experiments where different preconditioners are exploited are presented. Primarily, high-order accurate discretizations for first-order PDE problems are studied, but also second-order derivatives are considered. The results indicate that utilizing preconditioners based on fast solvers for modified PDE problems yields good solution algorithms. These results extend previously derived theoretical and numerical results for second-order approximations for first-order PDE, exploiting preconditioners based on fast Fourier transforms.

  3. Reliability of Complex Nonlinear Numerical Simulations

    NASA Technical Reports Server (NTRS)

    Yee, H. C.

    2004-01-01

    This work describes some of the procedure to ensure a higher level of confidence in the predictability and reliability (PAR) of numerical simulation of multiscale complex nonlinear problems. The focus is on relating PAR of numerical simulations with complex nonlinear phenomena of numerics. To isolate sources of numerical uncertainties, the possible discrepancy between the chosen partial differential equation (PDE) model and the real physics and/or experimental data is set aside. The discussion is restricted to how well numerical schemes can mimic the solution behavior of the underlying PDE model for finite time steps and grid spacings. The situation is complicated by the fact that the available theory for the understanding of nonlinear behavior of numerics is not at a stage to fully analyze the nonlinear Euler and Navier-Stokes equations. The discussion is based on the knowledge gained for nonlinear model problems with known analytical solutions to identify and explain the possible sources and remedies of numerical uncertainties in practical computations. Examples relevant to turbulent flow computations are included.

  4. Continuum Modeling and Control of Large Nonuniform Wireless Networks via Nonlinear Partial Differential Equations

    DOE PAGES

    Zhang, Yang; Chong, Edwin K. P.; Hannig, Jan; ...

    2013-01-01

    We inmore » troduce a continuum modeling method to approximate a class of large wireless networks by nonlinear partial differential equations (PDEs). This method is based on the convergence of a sequence of underlying Markov chains of the network indexed by N , the number of nodes in the network. As N goes to infinity, the sequence converges to a continuum limit, which is the solution of a certain nonlinear PDE. We first describe PDE models for networks with uniformly located nodes and then generalize to networks with nonuniformly located, and possibly mobile, nodes. Based on the PDE models, we develop a method to control the transmissions in nonuniform networks so that the continuum limit is invariant under perturbations in node locations. This enables the networks to maintain stable global characteristics in the presence of varying node locations.« less

  5. PDE12 removes mitochondrial RNA poly(A) tails and controls translation in human mitochondria.

    PubMed

    Rorbach, Joanna; Nicholls, Thomas J J; Minczuk, Michal

    2011-09-01

    Polyadenylation of mRNA in human mitochondria is crucial for gene expression and perturbation of poly(A) tail length has been linked to a human neurodegenerative disease. Here we show that 2'-phosphodiesterase (2'-PDE), (hereafter PDE12), is a mitochondrial protein that specifically removes poly(A) extensions from mitochondrial mRNAs both in vitro and in mitochondria of cultured cells. In eukaryotes, poly(A) tails generally stabilize mature mRNAs, whereas in bacteria they increase mRNA turnover. In human mitochondria, the effects of increased PDE12 expression were transcript dependent. An excess of PDE12 led to an increase in the level of three mt-mRNAs (ND1, ND2 and CytB) and two (CO1 and CO2) were less abundant than in mitochondria of control cells and there was no appreciable effect on the steady-state level of the remainder of the mitochondrial transcripts. The alterations in poly(A) tail length accompanying elevated PDE12 expression were associated with severe inhibition of mitochondrial protein synthesis, and consequently respiratory incompetence. Therefore, we propose that mRNA poly(A) tails are important in regulating protein synthesis in human mitochondria, as it is the case for nuclear-encoded eukaryotic mRNA.

  6. Integration based profile likelihood calculation for PDE constrained parameter estimation problems

    NASA Astrophysics Data System (ADS)

    Boiger, R.; Hasenauer, J.; Hroß, S.; Kaltenbacher, B.

    2016-12-01

    Partial differential equation (PDE) models are widely used in engineering and natural sciences to describe spatio-temporal processes. The parameters of the considered processes are often unknown and have to be estimated from experimental data. Due to partial observations and measurement noise, these parameter estimates are subject to uncertainty. This uncertainty can be assessed using profile likelihoods, a reliable but computationally intensive approach. In this paper, we present the integration based approach for the profile likelihood calculation developed by (Chen and Jennrich 2002 J. Comput. Graph. Stat. 11 714-32) and adapt it to inverse problems with PDE constraints. While existing methods for profile likelihood calculation in parameter estimation problems with PDE constraints rely on repeated optimization, the proposed approach exploits a dynamical system evolving along the likelihood profile. We derive the dynamical system for the unreduced estimation problem, prove convergence and study the properties of the integration based approach for the PDE case. To evaluate the proposed method, we compare it with state-of-the-art algorithms for a simple reaction-diffusion model for a cellular patterning process. We observe a good accuracy of the method as well as a significant speed up as compared to established methods. Integration based profile calculation facilitates rigorous uncertainty analysis for computationally demanding parameter estimation problems with PDE constraints.

  7. Characterization of a canine model of autosomal recessive retinitis pigmentosa due to a PDE6A mutation

    PubMed Central

    Tuntivanich, Nalinee; Pittler, Steven J.; Fischer, Andy J.; Omar, Ghezal; Kiupel, Matti; Weber, Arthur; Yao, Suxia; Steibel, Juan Pedro; Khan, Naheed Wali; Petersen-Jones, Simon M.

    2013-01-01

    Purpose To characterize a canine model of autosomal recessive RP due to a PDE6A gene mutation. Methods Affected and breed- and age-matched control puppies were studied by electroretinography (ERG), light and electron microscopy, immunohistochemistry and by assay for retinal PDE6 levels and enzymatic activity. Results The mutant puppies failed to develop normal rod-mediated ERG responses and had reduced light-adapted a-wave amplitudes from an early age. The residual ERG waveforms originated primarily from cone-driven responses. Development of photoreceptor outer segments was halted and rod cells were lost by apoptosis. Immunohistochemistry demonstrated a marked reduction in rod-opsin immunostaining outer segments and relative preservation of cones early in the disease process. With exception of rod bipolar cells that appeared to be reduced in number relatively early in the disease process other inner retinal cells were preserved in the early stages of the disease although there was marked and early activation of Müller glia. Western blotting showed that the PDE6A mutation not only resulted in a lack of PDE6A protein but the affected retinas also lacked the other PDE6 subunits, suggesting expression of PDE6A is required for normal expression of PDE6B and PDE6G. Affected retinas lacked PDE6 enzymatic activity. Conclusions This represents the first characterization of a PDE6A model of autosomal recessive retinitis pigmentosa and the PDE6A mutant dog shows promise as a large animal model for investigation of therapies to rescue mutant rod photoreceptors and to preserve cone photoreceptors in the face a rapid loss of rod cells. PMID:18775863

  8. A PDE Pricing Framework for Cross-Currency Interest Rate Derivatives with Target Redemption Features

    NASA Astrophysics Data System (ADS)

    Christara, Christina C.; Minh Dang, Duy; Jackson, Kenneth R.; Lakhany, Asif

    2010-09-01

    We propose a general framework for efficient pricing via a partial differential equation (PDE) approach for exotic cross-currency interest rate (IR) derivatives, with strong emphasis on long-dated foreign exchange (FX) IR hybrids, namely Power Reverse Dual Currency (PRDC) swaps with a FX Target Redemption (FX-TARN) provision. The FX-TARN provision provides a cap on the FX-linked PRDC coupon amounts, and once the accumulated coupon amount reaches this cap, the underlying PRDC swap terminates. Our PDE pricing framework is based on an auxiliary state variable to keep track of the total accumulated PRDC coupon amount. Finite differences on uniform grids and the Alternating Direction Implicit (ADI) method are used for the spatial and time discretizations, respectively, of the model-dependent PDE corresponding to each discretized value of the auxiliary variable. Numerical examples illustrating the convergence properties of the numerical methods are provided.

  9. PDE5 Inhibitors as Potential Tools in the Treatment of Cystic Fibrosis.

    PubMed

    Noel, Sabrina; Dhooghe, Barbara; Leal, Teresinha

    2012-01-01

    Despite great advances in the understanding of the genetics and pathophysiology of cystic fibrosis (CF), there is still no cure for the disease. Using phosphodiesterase type 5 (PDE5) inhibitors, we and others have provided evidence of rescued F508del-CFTR trafficking and corrected deficient chloride transport activity. Studies using PDE5 inhibitors in mice homozygous for the clinically relevant F508del mutation have been conducted with the aim of restoring F508del-CFTR protein function. We demonstrated, by measuring transepithelial nasal potential difference in F508del mice following intraperitoneal injection of sildenafil, vardenafil, or taladafil at clinical doses are able to restore the decreased CFTR-dependent chloride transport across the nasal mucosa. Moreover, vardenafil, but not sildenafil, stimulates chloride transport through the normal CFTR protein. We developed a specific nebulizer setup for mice, with which we demonstrated, through a single inhalation of PDE5 inhibitors, local activation of CFTR protein in CF. Significant potential advantages of inhalation drug therapy over oral or intravenous routes include rapid onset of pharmacological action, reduced systemic secondary effects, and reduced effective drug doses compared to the drug delivered orally; this underlines the relevance and impact of our work for translational science. More recently, we analyzed the bronchoalveolar lavage of CF and wild-type mice for cell infiltrates and expression of pro-inflammatory cytokines and chemokines; we found that the CFTR activating effect of vardenafil, selected as a representative long-lasting PDE5 inhibitor, breaks the vicious circle of lung inflammation which plays a major role in morbi-mortality in CF. Our data highlight the potential use of PDE5 inhibitors in CF. Therapeutic approaches using clinically approved PDE5 inhibitors to address F508del-CFTR defects could speed up the development of new therapies for CF.

  10. PDE5 Inhibitors as Potential Tools in the Treatment of Cystic Fibrosis

    PubMed Central

    Noel, Sabrina; Dhooghe, Barbara; Leal, Teresinha

    2012-01-01

    Despite great advances in the understanding of the genetics and pathophysiology of cystic fibrosis (CF), there is still no cure for the disease. Using phosphodiesterase type 5 (PDE5) inhibitors, we and others have provided evidence of rescued F508del-CFTR trafficking and corrected deficient chloride transport activity. Studies using PDE5 inhibitors in mice homozygous for the clinically relevant F508del mutation have been conducted with the aim of restoring F508del-CFTR protein function. We demonstrated, by measuring transepithelial nasal potential difference in F508del mice following intraperitoneal injection of sildenafil, vardenafil, or taladafil at clinical doses are able to restore the decreased CFTR-dependent chloride transport across the nasal mucosa. Moreover, vardenafil, but not sildenafil, stimulates chloride transport through the normal CFTR protein. We developed a specific nebulizer setup for mice, with which we demonstrated, through a single inhalation of PDE5 inhibitors, local activation of CFTR protein in CF. Significant potential advantages of inhalation drug therapy over oral or intravenous routes include rapid onset of pharmacological action, reduced systemic secondary effects, and reduced effective drug doses compared to the drug delivered orally; this underlines the relevance and impact of our work for translational science. More recently, we analyzed the bronchoalveolar lavage of CF and wild-type mice for cell infiltrates and expression of pro-inflammatory cytokines and chemokines; we found that the CFTR activating effect of vardenafil, selected as a representative long-lasting PDE5 inhibitor, breaks the vicious circle of lung inflammation which plays a major role in morbi-mortality in CF. Our data highlight the potential use of PDE5 inhibitors in CF. Therapeutic approaches using clinically approved PDE5 inhibitors to address F508del-CFTR defects could speed up the development of new therapies for CF. PMID:23024633

  11. Pulmonary Hypertension Therapy and a Systematic Review of Efficacy and Safety of PDE-5 Inhibitors.

    PubMed

    Unegbu, Chinwe; Noje, Corina; Coulson, John D; Segal, Jodi B; Romer, Lewis

    2017-03-01

    Pulmonary hypertension (PH) is a syndrome that is of growing concern to pediatricians worldwide. Recent data led to concerns about the safety of phosphodiesterase type 5 (PDE5) inhibitors in children and a US Food and Drug Administration safety advisory. Our objective is to provide insight into therapies for PH in children and to systematically review the comparative effectiveness and safety of PDE5 inhibitors in the management of pediatric patients with PH. We searched the following databases through February 2015: Medline, Embase, SCOPUS, and the Cochrane Central Register of Controlled Trials. We included studies that examined PDE5 inhibitor use in children with PH. Allowed comparators were either no medication or other classes of medication for management of PH. Study inclusion was via a 2-stage process with 2 reviewers and a predesigned form. Of 1270 papers identified by the literature search, 21 were included: 8 randomized controlled trials and 13 observational studies (9 retrospective, 4 prospective). There is strong evidence that PDE5 inhibitor use improves echocardiography measurements, cardiac catheterization parameters, and oxygenation compared with baseline or placebo in pediatric patients with PH. Evidence suggests that low- and moderate-dose sildenafil are safe regimens for children. There are a relatively small number of randomized controlled trials that address use of PDE5 inhibitors in pediatric patients with PH. PDE5 inhibitors are effective agents for cardiovascular and oxygenation end points in pediatric PH and important components of a multimodal pharmacotherapeutic approach to this growing challenge. Additional studies are needed to define optimal PH therapy in childhood.

  12. Transport-theory based multispectral imaging with PDE-constrained optimization

    NASA Astrophysics Data System (ADS)

    Kim, Hyun K.; Flexman, Molly; Yamashiro, Darrell J.; Kandel, Jessica J.; Hielscher, Andreas H.

    2011-02-01

    We introduce here a transport-theory-based PDE-constrained multispectral imaging algorithm for direct reconstruction of the spatial distribution of chromophores in tissue. The method solves the forward and inverse problems simultaneously in the framework of a reduced Hessian sequential quadratic programming method. The performance of the new algorithm is evaluated using numerical and experimental studies involving tumor bearing mice. The results show that the PDE-constrained multispectral method leads to 15-fold acceleration in the image reconstruction of tissue chromophores when compared to the unconstrained multispectral approach and also gives more accurate results when compared to the traditional two-step method.

  13. N Termini of apPDE4 Isoforms Are Responsible for Targeting the Isoforms to Different Cellular Membranes

    ERIC Educational Resources Information Center

    Jang, Deok-Jin; Park, Soo-Won; Lee, Jin-A; Lee, Changhoon; Chae, Yeon-Su; Park, Hyungju; Kim, Min-Jeong; Choi, Sun-Lim; Lee, Nuribalhae; Kim, Hyoung; Kaang, Bong-Kiun

    2010-01-01

    Phosphodiesterases (PDEs) are known to play a key role in the compartmentalization of cAMP signaling; however, the molecular mechanisms underlying intracellular localization of different PDE isoforms are not understood. In this study, we have found that each of the supershort, short, and long forms of apPDE4 showed distinct localization in the…

  14. Further Insights in the Binding Mode of Selective Inhibitors to Human PDE4D Enzyme Combining Docking and Molecular Dynamics

    PubMed Central

    D'Ursi, Pasqualina; Guariento, Sara; Trombetti, Gabriele; Orro, Alessandro; Cichero, Elena; Milanesi, Luciano; Bruno, Olga

    2016-01-01

    Abstract Alzheimer′s disease has recently emerged as a possible field of application for PDE4D inhibitors (PDE4DIs). The great structure similarity among the various PDE4 isoforms and, furthermore, the lack of the full length crystal structure of the enzyme, impaired the rational design of new selective PDE4DIs. In this paper, with the aim of exploring new insights into the PDE4D binding, we tackled the problem by performing a computational study based on docking simulations combined with molecular dynamics (D‐MD). Our work uniquely identified the binding mode and the key residues involved in the interaction with a number of in‐house catechol iminoether derivatives, acting as PDE4DIs. Moreover, the new binding mode was tested using a series of analogues previously reported by us and it was used to confirm their key structural features to allow PDE4D inhibition. The binding model disclosed within the current computational study may prove to be useful to further advance the design and synthesis of novel, more potent and selective, PDE4D inhibitors. PMID:27546041

  15. Design and Synthesis of Novel and Selective Phosphodiesterase 2 (PDE2a) Inhibitors for the Treatment of Memory Disorders.

    PubMed

    Gomez, Laurent; Massari, Mark Eben; Vickers, Troy; Freestone, Graeme; Vernier, William; Ly, Kiev; Xu, Rui; McCarrick, Margaret; Marrone, Tami; Metz, Markus; Yan, Yingzhou G; Yoder, Zachary W; Lemus, Robert; Broadbent, Nicola J; Barido, Richard; Warren, Noelle; Schmelzer, Kara; Neul, David; Lee, Dong; Andersen, Carsten B; Sebring, Kristen; Aertgeerts, Kathleen; Zhou, Xianbo; Tabatabaei, Ali; Peters, Marco; Breitenbucher, J Guy

    2017-03-09

    A series of potent and selective [1,2,4]triazolo[1,5-a]pyrimidine PDE2a inhibitors is reported. The design and improvement of the binding properties of this series was achieved using X-ray crystal structures in conjunction with careful analysis of electronic and structural requirements for the PDE2a enzyme. One of the lead compounds, compound 27 (DNS-8254), was identified as a potent and highly selective PDE2a enzyme inhibitor with favorable rat pharmacokinetic properties. Interestingly, the increased potency of compound 27 was facilitated by the formation of a halogen bond with the oxygen of Tyr827 present in the PDE2a active site. In vivo, compound 27 demonstrated significant memory enhancing effects in a rat model of novel object recognition. Taken together, these data suggest that compound 27 may be a useful tool to explore the pharmacology of selective PDE2a inhibition.

  16. PDE-based geophysical modelling using finite elements: examples from 3D resistivity and 2D magnetotellurics

    NASA Astrophysics Data System (ADS)

    Schaa, R.; Gross, L.; du Plessis, J.

    2016-04-01

    We present a general finite-element solver, escript, tailored to solve geophysical forward and inverse modeling problems in terms of partial differential equations (PDEs) with suitable boundary conditions. Escript’s abstract interface allows geoscientists to focus on solving the actual problem without being experts in numerical modeling. General-purpose finite element solvers have found wide use especially in engineering fields and find increasing application in the geophysical disciplines as these offer a single interface to tackle different geophysical problems. These solvers are useful for data interpretation and for research, but can also be a useful tool in educational settings. This paper serves as an introduction into PDE-based modeling with escript where we demonstrate in detail how escript is used to solve two different forward modeling problems from applied geophysics (3D DC resistivity and 2D magnetotellurics). Based on these two different cases, other geophysical modeling work can easily be realized. The escript package is implemented as a Python library and allows the solution of coupled, linear or non-linear, time-dependent PDEs. Parallel execution for both shared and distributed memory architectures is supported and can be used without modifications to the scripts.

  17. A Tensor B-Spline Approach for Solving the Diffusion PDE With Application to Optical Diffusion Tomography.

    PubMed

    Shulga, Dmytro; Morozov, Oleksii; Hunziker, Patrick

    2016-12-19

    Optical Diffusion Tomography (ODT) is a modern non-invasive medical imaging modality which requires mathematical modelling of near-infrared light propagation in tissue. Solving the ODT forward problem equation accurately and efficiently is crucial. Typically, the forward problem is represented by a Diffusion PDE and is solved using the Finite Element Method (FEM) on a mesh, which is often unstructured. Tensor B-spline signal processing has the attractive features of excellent interpolation and approximation properties, multiscale properties, fast algorithms and does not require meshing. This paper introduces Tensor B-spline methodology with arbitrary spline degree tailored to solve the ODT forward problem in an accurate and efficient manner. We show that our Tensor B-spline formulation induces efficient and highly parallelizable computational algorithms. Exploitation of B-spline properties for integration over irregular domains proved valuable. The Tensor B-spline solver was tested on standard problems and on synthetic medical data and compared to FEM, including state-ofthe art ODT forward solvers. Results show that 1) a significantly higher accuracy can be achieved with the same number of nodes, 2) fewer nodes are required to achieve a prespecified accuracy, 3) the algorithm converges in significantly fewer iterations to a given error. These findings support the value of Tensor Bspline methodology for high-performance ODT implementations. This may translate into advances in ODT imaging for biomedical research and clinical application.

  18. Research on odor interaction between aldehyde compounds via a partial differential equation (PDE) model.

    PubMed

    Yan, Luchun; Liu, Jiemin; Qu, Chen; Gu, Xingye; Zhao, Xia

    2015-01-28

    In order to explore the odor interaction of binary odor mixtures, a series of odor intensity evaluation tests were performed using both individual components and binary mixtures of aldehydes. Based on the linear relation between the logarithm of odor activity value and odor intensity of individual substances, the relationship between concentrations of individual constituents and their joint odor intensity was investigated by employing a partial differential equation (PDE) model. The obtained results showed that the binary odor interaction was mainly influenced by the mixing ratio of two constituents, but not the concentration level of an odor sample. Besides, an extended PDE model was also proposed on the basis of the above experiments. Through a series of odor intensity matching tests for several different binary odor mixtures, the extended PDE model was proved effective at odor intensity prediction. Furthermore, odorants of the same chemical group and similar odor type exhibited similar characteristics in the binary odor interaction. The overall results suggested that the PDE model is a more interpretable way of demonstrating the odor interactions of binary odor mixtures.

  19. Interaction between integrin α5 and PDE4D regulates endothelial inflammatory signalling

    PubMed Central

    Yun, Sanguk; Budatha, Madhusudhan; Dahlman, James E.; Coon, Brian G.; Cameron, Ryan T.; Langer, Robert; Anderson, Daniel G.; Baillie, George; Schwartz, Martin A.

    2016-01-01

    Atherosclerosis is primarily a disease of lipid metabolism and inflammation; however, it is also closely associated with endothelial extracellular matrix (ECM) remodelling, with fibronectin accumulating in the laminin–collagen basement membrane. To investigate how fibronectin modulates inflammation in arteries, we replaced the cytoplasmic tail of the fibronectin receptor integrin α5 with that of the collagen/laminin receptor integrin α2. This chimaera suppressed inflammatory signalling in endothelial cells on fibronectin and in knock-in mice. Fibronectin promoted inflammation by suppressing anti-inflammatory cAMP. cAMP was activated through endothelial prostacyclin secretion; however, this was ECM-independent. Instead, cells on fibronectin suppressed cAMP via enhanced phosphodiesterase (PDE) activity, through direct binding of integrin α5 to phosphodiesterase-4D5 (PDE4D5), which induced PP2A-dependent dephosphorylation of PDE4D5 on the inhibitory site Ser651. In vivo knockdown of PDE4D5 inhibited inflammation at athero-prone sites. These data elucidate a molecular mechanism linking ECM remodelling and inflammation, thereby identifying a new class of therapeutic targets. PMID:27595237

  20. 5'-Phosphodiesterase (5'-PDE) from germinated barley for hydrolysis of RNA to produce flavour nucleotides.

    PubMed

    Deoda, Anand J; Singhal, Rekha S

    2003-07-01

    5'-Phosphodiesterase (5'-PDE) is an enzyme that hydrolyses RNA to a mixture of ribonucleotides, from which the flavour enhancers, 5'-guanosine monophosphate (5'-GMP) and 5'-inosine monophosphate (5'-IMP) can be isolated. In the present work, 5'-PDE was extracted and partially purified from germinated barley seeds. 5'-PDE activity was monitored using bis-p-nitrophenyl phosphate as the substrate. The enzyme acts on the substrate and releases the p-nitrophenol, which is measured at 420 nm. Ultrafiltration using a polysulfone membrane having molecular weight cut off (MWCO) of 20 kDa gave 12-fold concentration. Further purification using ammonium sulphate gave 18-fold concentration. Heat shock for 15 min at 60 degrees C after the ultrafiltration enhanced the concentration of 5'-PDE 9.10 fold, while a similar treatment after ammonium sulphate treatment enhanced it by 17.83-fold. The enzyme had a pH optimum of 5, and was stable at 0 degrees C. This partially purified enzyme could be used for hydrolysis of RNA to produce 5'-GMP and 5' adenosine monophosphate, a precursor of 5'-IMP.

  1. PDE-4 inhibition rescues aberrant synaptic plasticity in Drosophila and mouse models of fragile X syndrome.

    PubMed

    Choi, Catherine H; Schoenfeld, Brian P; Weisz, Eliana D; Bell, Aaron J; Chambers, Daniel B; Hinchey, Joseph; Choi, Richard J; Hinchey, Paul; Kollaros, Maria; Gertner, Michael J; Ferrick, Neal J; Terlizzi, Allison M; Yohn, Nicole; Koenigsberg, Eric; Liebelt, David A; Zukin, R Suzanne; Woo, Newton H; Tranfaglia, Michael R; Louneva, Natalia; Arnold, Steven E; Siegel, Steven J; Bolduc, Francois V; McDonald, Thomas V; Jongens, Thomas A; McBride, Sean M J

    2015-01-07

    Fragile X syndrome (FXS) is the leading cause of both intellectual disability and autism resulting from a single gene mutation. Previously, we characterized cognitive impairments and brain structural defects in a Drosophila model of FXS and demonstrated that these impairments were rescued by treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium. A well-documented biochemical defect observed in fly and mouse FXS models and FXS patients is low cAMP levels. cAMP levels can be regulated by mGluR signaling. Herein, we demonstrate PDE-4 inhibition as a therapeutic strategy to ameliorate memory impairments and brain structural defects in the Drosophila model of fragile X. Furthermore, we examine the effects of PDE-4 inhibition by pharmacologic treatment in the fragile X mouse model. We demonstrate that acute inhibition of PDE-4 by pharmacologic treatment in hippocampal slices rescues the enhanced mGluR-dependent LTD phenotype observed in FXS mice. Additionally, we find that chronic treatment of FXS model mice, in adulthood, also restores the level of mGluR-dependent LTD to that observed in wild-type animals. Translating the findings of successful pharmacologic intervention from the Drosophila model into the mouse model of FXS is an important advance, in that this identifies and validates PDE-4 inhibition as potential therapeutic intervention for the treatment of individuals afflicted with FXS.

  2. PDE-4 Inhibition Rescues Aberrant Synaptic Plasticity in Drosophila and Mouse Models of Fragile X Syndrome

    PubMed Central

    Choi, Catherine H.; Schoenfeld, Brian P.; Weisz, Eliana D.; Bell, Aaron J.; Chambers, Daniel B.; Hinchey, Joseph; Choi, Richard J.; Hinchey, Paul; Kollaros, Maria; Gertner, Michael J.; Ferrick, Neal J.; Terlizzi, Allison M.; Yohn, Nicole; Koenigsberg, Eric; Liebelt, David A.; Zukin, R. Suzanne; Woo, Newton H.; Tranfaglia, Michael R.; Louneva, Natalia; Arnold, Steven E.; Siegel, Steven J.

    2015-01-01

    Fragile X syndrome (FXS) is the leading cause of both intellectual disability and autism resulting from a single gene mutation. Previously, we characterized cognitive impairments and brain structural defects in a Drosophila model of FXS and demonstrated that these impairments were rescued by treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium. A well-documented biochemical defect observed in fly and mouse FXS models and FXS patients is low cAMP levels. cAMP levels can be regulated by mGluR signaling. Herein, we demonstrate PDE-4 inhibition as a therapeutic strategy to ameliorate memory impairments and brain structural defects in the Drosophila model of fragile X. Furthermore, we examine the effects of PDE-4 inhibition by pharmacologic treatment in the fragile X mouse model. We demonstrate that acute inhibition of PDE-4 by pharmacologic treatment in hippocampal slices rescues the enhanced mGluR-dependent LTD phenotype observed in FXS mice. Additionally, we find that chronic treatment of FXS model mice, in adulthood, also restores the level of mGluR-dependent LTD to that observed in wild-type animals. Translating the findings of successful pharmacologic intervention from the Drosophila model into the mouse model of FXS is an important advance, in that this identifies and validates PDE-4 inhibition as potential therapeutic intervention for the treatment of individuals afflicted with FXS. PMID:25568131

  3. The synthesis and biological evaluation of a novel series of phthalazine PDE4 inhibitors I.

    PubMed

    Napoletano, M; Norcini, G; Pellacini, F; Marchini, F; Morazzoni, G; Ferlenga, P; Pradella, L

    2000-10-02

    This communication describes the synthesis and in vitro evaluation of a novel and potent series of phosphodiesterase type IV (PDE4) inhibitors. The compounds described represent conformationally constrained analogues of RP 73401, Piclamilast. Preliminary evidences of reduced side effects of II compared to standards are also reported.

  4. Synthesis and bioactivity of pyrazole and triazole derivatives as potential PDE4 inhibitors.

    PubMed

    Li, Ya-Sheng; Tian, Hao; Zhao, Dong-Sheng; Hu, De-Kun; Liu, Xing-Yu; Jin, Hong-Wei; Song, Gao-Peng; Cui, Zi-Ning

    2016-08-01

    A series of pyrazole and triazole derivatives containing 5-phenyl-2-furan functionality were designed and synthesized as phosphodiesterase type 4 (PDE4) inhibitors. The bioassay results showed that title compounds exhibited considerable inhibitory activity against PDE4B and blockade of LPS-induced TNFα release. Meanwhile, the activity of compounds containing 1,2,4-triazole (series II) was higher than that of pyrazole-attached derivatives (series I). The primary structure-activity relationship study and docking results showed that the 1,2,4-triazole moiety of compound IIk played a key role to form integral hydrogen bonds and π-π stacking interaction with PDE4B protein while the rest part of the molecule extended into the catalytic domain to block the access of cAMP and formed the foundation for inhibition of PDE4. Compound IIk would be great promise as a hit compound for further study based on the preliminary structure-activity relationship and molecular modeling studies.

  5. The Phosphodiesterase 5-Inhibitors (PDE-5i) for ERECTILE DYSFUNCTION (ED): A Therapeutic Challenge For Psychiatrists.

    PubMed

    Koon, Chong Siew; Sidi, Hatta; Kumar, Jaya; Das, Srijit; Xi, Ong Wan; Hatta, Muhammad Hizri; Alfonso, Cesar

    2017-02-15

    Erectile function (EF) is a prerequisite for satisfactory sexual intercourse (SI) and central to male sexual functioning. Satisfactory SI eventually leads to orgasm - a biopsychophysiological state of euphoria - leading to a sense of bliss, enjoyment and positive mental well being. For a psychiatrist, treating ED is self-propelled to harmonize these pleasurable experiences alongside with encouragement of physical wellness and sensuality. Hence, the role of PDE-5i is pivotal in the context of treating ED constitutes a therapeutic challenge. PDE-5i work via the dopaminergic-oxytocin-nitric oxide pathway by increasing the availability of endothelial's guanosine monophosphate (GMP), immediately causing relaxation of the penile smooth muscle and an erection. The PDE-5i, like sildenafil, vardenafil and tadalafil, are effective in the treatment of ED with some benefits and disadvantages compared to other treatment modalities. Prescribed PDE-5i exclusively improve EF, fostering male's self-confidence and self-esteem. Treatment failures are associated with factors such as absent (or insufficient) sexual stimulation, psychosexual conflicts and the co-existence of medical disorders. Managing ED requires dealing with underlying medical diseases, addressing other co-morbid sexual dysfunctions like premature ejaculation (PE), and educating the patient on healthy life-styles beside being cautious with the potential side-effects and drug-drug interactions. Furthermore, by dealing with interpersonal dynamics within the couple and embracing adequate lifestyles (managing stress and revising one's sexual scripts), PDE-5i treatment benefits may be enhanced. In this review, we propose a holistic conceptual framework approach for psychiatric management of patients with ED.

  6. The PDE4 inhibitor roflumilast improves memory in rodents at non-emetic doses.

    PubMed

    Vanmierlo, Tim; Creemers, Pim; Akkerman, Sven; van Duinen, Marlies; Sambeth, Anke; De Vry, Jochen; Uz, Tolga; Blokland, Arjan; Prickaerts, Jos

    2016-04-15

    Enhancement of central availability of the second messenger cAMP is a promising approach to improve cognitive function. Pharmacological inhibition of phosphodiesterase type 4 (PDE4), a group of cAMP hydrolyzing enzymes in the brain, has been shown to improve cognitive performances in rodents and monkeys. However, inhibition of PDE4 is generally associated with severe emetic side-effects. Roflumilast, an FDA-approved PDE4 inhibitor for treatment of chronic obstructive pulmonary disease (COPD), is yielding only mild emetic side effects. In the present study we investigate the potential of roflumilast as a cognition enhancer and to determine the potential coinciding emetic response in comparison to rolipram, a classic PDE4 inhibitor with pronounced emetic effects. Cognition enhancement was evaluated in mice and it was found that both roflumilast and rolipram enhanced memory in an object location task (0.03mg/kg), whereas only roflumilast was effective in a spatial Y-maze (0.1mg/kg). Emetic potential was measured using competition of PDE4 inhibition for α2-adrenergic receptor antagonism in which recovery from xylazine/ketamine-mediated anesthesia is used as a surrogate marker. While rolipram displayed emetic properties at a dose 10 times the memory-enhancing dose, roflumilast only showed increased emetic-like properties at a dose 100 times the memory-enhancing dose. Moreover, combining sub-efficacious doses of the approved cognition-enhancer donepezil and roflumilast, which did not improve memory when given alone, fully restored object recognition memory deficit in rats induced by the muscarinic receptor antagonist scopolamine. These findings suggest that roflumilast offers a more favorable window for treatment of cognitive deficits compared to rolipram.

  7. De Novo Mutations in PDE10A Cause Childhood-Onset Chorea with Bilateral Striatal Lesions.

    PubMed

    Mencacci, Niccolò E; Kamsteeg, Erik-Jan; Nakashima, Kosuke; R'Bibo, Lea; Lynch, David S; Balint, Bettina; Willemsen, Michèl A A P; Adams, Matthew E; Wiethoff, Sarah; Suzuki, Kazunori; Davies, Ceri H; Ng, Joanne; Meyer, Esther; Veneziano, Liana; Giunti, Paola; Hughes, Deborah; Raymond, F Lucy; Carecchio, Miryam; Zorzi, Giovanna; Nardocci, Nardo; Barzaghi, Chiara; Garavaglia, Barbara; Salpietro, Vincenzo; Hardy, John; Pittman, Alan M; Houlden, Henry; Kurian, Manju A; Kimura, Haruhide; Vissers, Lisenka E L M; Wood, Nicholas W; Bhatia, Kailash P

    2016-04-07

    Chorea is a hyperkinetic movement disorder resulting from dysfunction of striatal medium spiny neurons (MSNs), which form the main output projections from the basal ganglia. Here, we used whole-exome sequencing to unravel the underlying genetic cause in three unrelated individuals with a very similar and unique clinical presentation of childhood-onset chorea and characteristic brain MRI showing symmetrical bilateral striatal lesions. All individuals were identified to carry a de novo heterozygous mutation in PDE10A (c.898T>C [p.Phe300Leu] in two individuals and c.1000T>C [p.Phe334Leu] in one individual), encoding a phosphodiesterase highly and selectively present in MSNs. PDE10A contributes to the regulation of the intracellular levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Both substitutions affect highly conserved amino acids located in the regulatory GAF-B domain, which, by binding to cAMP, stimulates the activity of the PDE10A catalytic domain. In silico modeling showed that the altered residues are located deep in the binding pocket, where they are likely to alter cAMP binding properties. In vitro functional studies showed that neither substitution affects the basal PDE10A activity, but they severely disrupt the stimulatory effect mediated by cAMP binding to the GAF-B domain. The identification of PDE10A mutations as a cause of chorea further motivates the study of cAMP signaling in MSNs and highlights the crucial role of striatal cAMP signaling in the regulation of basal ganglia circuitry. Pharmacological modulation of this pathway could offer promising etiologically targeted treatments for chorea and other hyperkinetic movement disorders.

  8. A new efficient formulation of the HLLEM Riemann solver for general conservative and non-conservative hyperbolic systems

    SciTech Connect

    Dumbser, Michael; Balsara, Dinshaw S.

    2016-01-01

    In this paper a new, simple and universal formulation of the HLLEM Riemann solver (RS) is proposed that works for general conservative and non-conservative systems of hyperbolic equations. For non-conservative PDE, a path-conservative formulation of the HLLEM RS is presented for the first time in this paper. The HLLEM Riemann solver is built on top of a novel and very robust path-conservative HLL method. It thus naturally inherits the positivity properties and the entropy enforcement of the underlying HLL scheme. However, with just the slight additional cost of evaluating eigenvectors and eigenvalues of intermediate characteristic fields, we can represent linearly degenerate intermediate waves with a minimum of smearing. For conservative systems, our paper provides the easiest and most seamless path for taking a pre-existing HLL RS and quickly and effortlessly converting it to a RS that provides improved results, comparable with those of an HLLC, HLLD, Osher or Roe-type RS. This is done with minimal additional computational complexity, making our variant of the HLLEM RS also a very fast RS that can accurately represent linearly degenerate discontinuities. Our present HLLEM RS also transparently extends these advantages to non-conservative systems. For shallow water-type systems, the resulting method is proven to be well-balanced. Several test problems are presented for shallow water-type equations and two-phase flow models, as well as for gas dynamics with real equation of state, magnetohydrodynamics (MHD & RMHD), and nonlinear elasticity. Since our new formulation accommodates multiple intermediate waves and has a broader applicability than the original HLLEM method, it could alternatively be called the HLLI Riemann solver, where the “I” stands for the intermediate characteristic fields that can be accounted for. -- Highlights: •New simple and general path-conservative formulation of the HLLEM Riemann solver. •Application to general conservative and non

  9. Preventing Blow up by Convective Terms in Dissipative PDE's

    NASA Astrophysics Data System (ADS)

    Bilgin, Bilgesu; Kalantarov, Varga; Zelik, Sergey

    2016-09-01

    We study the impact of the convective terms on the global solvability or finite time blow up of solutions of dissipative PDEs. We consider the model examples of 1D Burger's type equations, convective Cahn-Hilliard equation, generalized Kuramoto-Sivashinsky equation and KdV type equations. The following common scenario is established: adding sufficiently strong (in comparison with the destabilizing nonlinearity) convective terms to equation prevents the solutions from blowing up in a finite time and makes the considered system globally well-posed and dissipative and for weak enough convective terms the finite time blow up may occur similar to the case, when the equation does not involve convective term. This kind of result has been previously known for the case of Burger's type equations and has been strongly based on maximum principle. In contrast to this, our results are based on the weighted energy estimates which do not require the maximum principle for the considered problem.

  10. Reasons and predictive factors for discontinuation of PDE-5 inhibitors despite successful intercourse in erectile dysfunction patients.

    PubMed

    Kim, S-C; Lee, Y-S; Seo, K-K; Jung, G-W; Kim, T-H

    2014-01-01

    This study was aimed to identify characteristics of ED patients who discontinued PDE5i despite successful intercourse. Data were collected using a questionnaire from 34 urologic clinics regardless of the effect (success or failure) of PDE5i treatment by visiting the clinics (717), e-mail (64) or post (101) for 882 ED patients who had previously taken any kind of PDE5i on demand four or more times. Discontinuation of PDE5i was defined if the patient had never taken PDE5i for the previous 1 year despite successful intercourse. Of the 882 patients, 485 were included in the final analysis. Difference in the socio-demographic, ED- and partner-related data between the continuation and discontinuation group and factors influencing discontinuation of the PDE5i were analyzed. Among 485 respondents (mean age, 53.6), 116 (23.9%) had discontinued PDE5i use despite successful intercourse. Most common reasons for the discontinuation were 'reluctant medication-dependent intercourse' (31.0%), 'spontaneous recovery of erectile function without further treatment' (30.2%), and 'high cost' (26.7%). In multiple logistic regression analysis, independent factors influencing discontinuation of the drug were cause of ED (psychogenic), short duration of ED, low education (⩽ middle school), and religion (Catholic). In partner-related compliance, only partner's religion (Catholic) was a significant factor.

  11. Sildenafil and analogous phosphodiesterase type 5 (PDE-5) inhibitors in herbal food supplements sampled on the Dutch market.

    PubMed

    Reeuwijk, N M; Venhuis, B J; de Kaste, D; Hoogenboom, L A P; Rietjens, I M C M; Martena, M J

    2013-01-01

    Herbal food supplements, claiming to enhance sexual potency, may contain deliberately added active pharmacological ingredients (APIs) that can be used for the treatment of erectile dysfunction (ED). The aim of this study was to determine whether herbal food supplements on the Dutch market indeed contain APIs that inhibit phosphodiesterase type 5 (PDE-5) inhibitors, such as sildenafil and analogous PDE-5 inhibitors. Herbal food supplements intended to enhance sexual potency (n = 71), and two soft drinks, were sampled from 2003 up to and including 2012. In 23 herbal supplements, nine different PDE-5 inhibitors were identified; in a few cases (n = 3), more than one inhibitor was indentified. The presence of these APIs was however not stated on the label. The concentrations of PDE-5 inhibitors per dose unit were analysed. Furthermore, the potential pharmacologically active properties of the detected PDE-5 inhibitors were estimated by using data from the scientific and patent literature regarding (1) in vitro PDE-5 activity, (2) reported effective doses of registered drugs with PDE-5 inhibitor activity and (3) similarity to other structural analogues. It was concluded that 18 of the 23 herbal food supplements, when used as recommended, would have significant pharmacological effects due to added APIs. Adequate use of existing regulation and control measures seems necessary to protect consumers against the adverse effects of these products.

  12. Anchored PDE4 regulates chloride conductance in wild-type and ΔF508-CFTR human airway epithelia.

    PubMed

    Blanchard, Elise; Zlock, Lorna; Lao, Anna; Mika, Delphine; Namkung, Wan; Xie, Moses; Scheitrum, Colleen; Gruenert, Dieter C; Verkman, Alan S; Finkbeiner, Walter E; Conti, Marco; Richter, Wito

    2014-02-01

    Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) that impair its expression and/or chloride channel function. Here, we provide evidence that type 4 cyclic nucleotide phosphodiesterases (PDE4s) are critical regulators of the cAMP/PKA-dependent activation of CFTR in primary human bronchial epithelial cells. In non-CF cells, PDE4 inhibition increased CFTR activity under basal conditions (ΔISC 7.1 μA/cm(2)) and after isoproterenol stimulation (increased ΔISC from 13.9 to 21.0 μA/cm(2)) and slowed the return of stimulated CFTR activity to basal levels by >3-fold. In cells homozygous for ΔF508-CFTR, the most common mutation found in CF, PDE4 inhibition alone produced minimal channel activation. However, PDE4 inhibition strongly amplified the effects of CFTR correctors, drugs that increase expression and membrane localization of CFTR, and/or CFTR potentiators, drugs that increase channel gating, to reach ∼ 25% of the chloride conductance observed in non-CF cells. Biochemical studies indicate that PDE4s are anchored to CFTR and mediate a local regulation of channel function. Taken together, our results implicate PDE4 as an important determinant of CFTR activity in airway epithelia, and support the use of PDE4 inhibitors to potentiate the therapeutic benefits of CFTR correctors and potentiators.

  13. Role of AKAP 149-PKA-PDE4A complex in cell survival and cell differentiation processes.

    PubMed

    Fernández-Araujo, A; Tobío, A; Alfonso, A; Botana, L M

    2014-08-01

    The cellular localization of A-kinase anchoring proteins (AKAPs), protein kinase A (PKAs) and phosphodiesterases (PDEs) is a key step to the spatiotemporal regulation of the second messenger adenosine 3',5'-cyclic monophosphate (cAMP). In this paper the cellular distribution of the mitochondrial AKAP 149-PKA-PDE4A complex and its implications in the cell death induced by YTX treatment, a known PDE modulator, was studied. K-562 cell line was incubated with YTX for 24 or 48 h. Under these conditions AKAP 149, PKA and type-4A PDE (PDE4A) levels were measured in the cytosol, in the plasma membrane and in the nucleus. Apoptotic hallmarks were also measured after the same conditions. In addition, YTX effect on cell viability was checked after AKAP 149 and PDE4A silencing. The results obtained show a decrease in AKAP 149-PKA-PDE4A levels in cytosol after YTX exposure. 24h after the toxin addition, the complex expression increased in the plasma membrane and after 48 h in the nucleus domain. Furthermore Bcl-2 levels were decreased and the expression of caspase 3 together with caspase 8 activity were increased after 24h of toxin incubation but not after 48 h. These results suggest apoptotic cell death at 24h and a non-apoptotic cell death after 48 h. When AKAP 149 and PDE4A were silenced YTX did not induce cellular death. In summary, AKAP 149-PKA-PDE4A complex localization is related with YTX effect in K-562 cell line. When this complex is mainly located in the plasma membrane apoptosis is activated while when the complex is in the nuclear domain non-apoptotic cellular death or cellular differentiation is activated. Therefore AKAP 149-PKA-PDE4A distribution and integrity have a key role in cellular survival.

  14. Sub-acute hemolysis in sickle cell mice causes priapism secondary to NO imbalance and PDE5 dysregulation

    PubMed Central

    Sopko, Nikolai A.; Matsui, Hotaka; Hannan, Johanna L.; Berkowitz, Dan; Champion, Hunter C.; Hsu, Lewis L.; Musicki, Biljana; Burnett, Arthur L.; Bivalacqua, Trinity J.

    2015-01-01

    Introduction Recent research suggests that priapism in Sickle Cell Disease (SCD) is due to dysregulation of penile erection homeostasis including alteration of nitric oxide synthase (NOS) and phosphodiesterase 5 (PDE5) activities by excessive levels of reactive oxygen species (ROS) released during hemolysis. It is unknown if sub-acute exposure to hemolysis is sufficient or if chronic reconditioning of erectile tissues is required for perturbation of homeostatic pathways and whether PDE5 inhibitor (PDE5I) treatment can restore erectile homeostasis in the sub-acute setting. Aims To investigate the effects of sub-acute hemolysis (3 month exposure) on priapism and NO pathway regulation. Methods Mice underwent bone marrow transplantation with either SCD (BM-SS) or wild type (WT) bone marrow. BM-SS mice were treated with sildenafil 100mg/kg/day. We measured intracavernous pressure (ICP) measurements with or without cavernosal nerve stimulation (CNS) following bone marrow transplantation to assess for priapism. Main Outcome Measures ICP and frequency of erections were assessed. Penile tissues were analyzed for NOS, PKG, PDE5, and ROS activities. Results BM-SS mice demonstrated a priapism phenotype. PDE5I treatment reduced the frequency of erections in BM-SS mice (1.7 ± 1.1 vs. 5.5 ± 2.8 erections/hour, p<0.05). Penile tissues from BM-SS mice demonstrated decreased NOS, PKG, PDE5 and elevated ROS activities compared to that of control mice. PDE5I treatment increased NOS (11.6 ± 1.3% vs. 7.8 ± 2.3%, p<0.05) and PDE5 (76.3 ± 9.8% vs. 52.3 ± 11.1%, p<0.05) activities and decreased ROS activity (137.8 ± 12.1% vs. 199.1 ± 11.3%, p<0.05) compared to non-PDE5I treated BM-SS mice. PKG activity was increased beyond control levels with PDE5I treatment (158.4 ± 10.3%, p<0.05). Conclusion Short-term hemolysis is sufficient to establish a priapism phenotype and results in loss of erectile function. PDE5I treatment ameliorates priapism, in part, due to restored NO balance with

  15. New 2-(2-Phenylethyl)chromone Derivatives and Inhibitors of Phosphodiesterase (PDE) 3A from Agarwood.

    PubMed

    Sugiyama, Takuji; Narukawa, Yuji; Shibata, Shunsuke; Masui, Ryo; Kiuchia, Fumiyuki

    2016-06-01

    The MeOH extract of agarwood showed inhibitory activity against phosphodiesterase (PDE) 3A. Fractionation of the extract led to the isolation of two new 2-(2-phenylethyl)chromones, 6,8-dihydroxy-2-[2-(4'-methoxyphenyl)ethyl]chromone (6), and 6,7-dihydroxy-2-(2-phenylethyl)chromone (8), together with six known compounds. All isolated compounds were tested for their PDE 3A inhibitory activity using fluorescence polarization method. Compound 7 showed PDE 3A inhibitory activity with IC50 of 4.83 μM.

  16. Phosphodiesterase 11A (PDE11A), Enriched in Ventral Hippocampus Neurons, is Required for Consolidation of Social but not Nonsocial Memories in Mice

    PubMed Central

    Hegde, Shweta; Capell, Will R; Ibrahim, Baher A; Klett, Jennifer; Patel, Neema S; Sougiannis, Alexander T; Kelly, Michy P

    2016-01-01

    The capacity to form long-lasting social memories is critical to our health and survival. cAMP signaling in the ventral hippocampal formation (VHIPP) appears to be required for social memory formation, but the phosphodiesterase (PDE) involved remains unknown. Previously, we showed that PDE11A, which degrades cAMP and cGMP, is preferentially expressed in CA1 and subiculum of the VHIPP. Here, we determine whether PDE11A is expressed in neurons where it could directly influence synaptic plasticity and whether expression is required for the consolidation and/or retrieval of social memories. In CA1, and possibly CA2, PDE11A4 is expressed throughout neuronal cell bodies, dendrites (stratum radiatum), and axons (fimbria), but not astrocytes. Unlike PDE2A, PDE9A, or PDE10A, PDE11A4 expression begins very low at postnatal day 7 (P7) and dramatically increases until P28, at which time it stabilizes to young adult levels. This expression pattern is consistent with the fact that PDE11A is required for social long-term memory (LTM) formation during adolescence and adulthood. Male and female PDE11 knockout (KO) mice show normal short-term memory (STM) for social odor recognition (SOR) and social transmission of food preference (STFP), but no LTM 24 h post training. Importantly, PDE11A KO mice show normal LTM for nonsocial odor recognition. Deletion of PDE11A may impair memory consolidation by impairing requisite protein translation in the VHIPP. Relative to WT littermates, PDE11A KO mice show reduced expression of RSK2 and lowered phosphorylation of S6 (pS6–235/236). Together, these data suggest PDE11A is selectively required for the proper consolidation of recognition and associative social memories. PMID:27339393

  17. Novel, primate-specific PDE10A isoform highlights gene expression complexity in human striatum with implications on the molecular pathology of bipolar disorder.

    PubMed

    MacMullen, C M; Vick, K; Pacifico, R; Fallahi-Sichani, M; Davis, R L

    2016-02-23

    Bipolar disorder is a highly heritable neuropsychiatric disorder affecting nearly 2.5% of the population. Prior genetic studies identified a panel of common and rare single-nucleotide polymorphisms associated with the disease that map to the first intron of the PDE10A gene. RNA sequencing of striatal brain tissue from bipolar and healthy control subjects identified a novel transcript of PDE10A, named PDE10A19, that codes for a PDE10A isoform with a unique N terminus. Genomic sequences that can encode the novel N terminus were conserved in other primates but not rodents. The RNA transcript was expressed at equal or greater levels in the human striatum compared with the two annotated transcripts, PDE10A1 and PDE10A2. The PDE10A19 transcript was detected in polysomal fractions; western blotting experiments confirmed that the RNA transcript is translated into protein. Immunocytochemistry studies using transfected mouse striatal and cortical neurons demonstrated that the PDE10A19 protein distributes to the cytosol, like PDE10A1, and unlike PDE10A2, which is associated with plasma membranes. Immunoprecipitation and immunocytochemical experiments revealed that the PDE10A19 isoform interacts physically with PDE10A2 and, when expressed at elevated levels, interferes with the plasma membrane localization of PDE10A2. These studies illustrate the complexity of PDE10A gene expression in the human brain and highlight the need to unravel the gene's complex and complete coding capabilities along with its transcriptional and translational regulation to guide the development of therapeutic agents that target the protein for the treatment of neuropsychiatric illness.

  18. Design and synthesis of potent and selective pyridazin-4(1H)-one-based PDE10A inhibitors interacting with Tyr683 in the PDE10A selectivity pocket.

    PubMed

    Yoshikawa, Masato; Hitaka, Takenori; Hasui, Tomoaki; Fushimi, Makoto; Kunitomo, Jun; Kokubo, Hironori; Oki, Hideyuki; Nakashima, Kosuke; Taniguchi, Takahiko

    2016-08-15

    Utilizing structure-based drug design techniques, we designed and synthesized phosphodiesterase 10A (PDE10A) inhibitors based on pyridazin-4(1H)-one. These compounds can interact with Tyr683 in the PDE10A selectivity pocket. Pyridazin-4(1H)-one derivative 1 was linked with a benzimidazole group through an alkyl spacer to interact with the OH of Tyr683 and fill the PDE10A selectivity pocket. After optimizing the linker length, we identified 1-(cyclopropylmethyl)-5-[3-(1-methyl-1H-benzimidazol-2-yl)propoxy]-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (16f) as having highly potent PDE10A inhibitory activity (IC50=0.76nM) and perfect selectivity against other PDEs (>13,000-fold, IC50=>10,000nM). The crystal structure of 16f bound to PDE10A revealed that the benzimidazole moiety was located deep within the PDE10A selectivity pocket and interacted with Tyr683. Additionally, a bidentate interaction existed between the 5-alkoxypyridazin-4(1H)-one moiety and the conserved Gln716 present in all PDEs.

  19. Toward Interoperable Mesh, Geometry and Field Components for PDE Simulation Development

    SciTech Connect

    Chand, K K; Diachin, L F; Li, X; Ollivier-Gooch, C; Seol, E S; Shephard, M; Tautges, T; Trease, H

    2005-07-11

    Mesh-based PDE simulation codes are becoming increasingly sophisticated and rely on advanced meshing and discretization tools. Unfortunately, it is still difficult to interchange or interoperate tools developed by different communities to experiment with various technologies or to develop new capabilities. To address these difficulties, we have developed component interfaces designed to support the information flow of mesh-based PDE simulations. We describe this information flow and discuss typical roles and services provided by the geometry, mesh, and field components of the simulation. Based on this delineation for the roles of each component, we give a high-level description of the abstract data model and set of interfaces developed by the Department of Energy's Interoperable Tools for Advanced Petascale Simulation (ITAPS) center. These common interfaces are critical to our interoperability goal, and we give examples of several services based upon these interfaces including mesh adaptation and mesh improvement.

  20. The estimation of material and patch parameters in a PDE-based circular plate model

    NASA Technical Reports Server (NTRS)

    Banks, H. T.; Smith, Ralph C.; Brown, D. E.; Metcalf, Vern L.; Silcox, R. J.

    1995-01-01

    The estimation of material and patch parameters for a system involving a circular plate, to which piezoceramic patches are bonded, is considered. A partial differential equation (PDE) model for the thin circular plate is used with the passive and active contributions form the patches included in the internal and external bending moments. This model contains piecewise constant parameters describing the density, flexural rigidity, Poisson ratio, and Kelvin-Voigt damping for the system as well as patch constants and a coefficient for viscous air damping. Examples demonstrating the estimation of these parameters with experimental acceleration data and a variety of inputs to the experimental plate are presented. By using a physically-derived PDE model to describe the system, parameter sets consistent across experiments are obtained, even when phenomena such as damping due to electric circuits affect the system dynamics.

  1. PDE-constrained multispectral imaging of tissue chromophores with the equation of radiative transfer

    PubMed Central

    Kim, Hyun Keol; Flexman, Molly; Yamashiro, Darrell J.; Kandel, Jessica J.; Hielscher, Andreas H.

    2010-01-01

    We introduce a transport-theory-based PDE-constrained multispectral model for direct imaging of the spatial distributions of chromophores concentrations in biological tissue. The method solves the forward problem (boundary radiance at each wavelength) and the inverse problem (spatial distribution of chromophores concentrations), in an all-at-once manner in the framework of a reduced Hessian sequential quadratic programming method. To illustrate the code’s performance, we present numerical and experimental studies involving tumor bearing mice. It is shown that the PDE-constrained multispectral method accelerates the reconstruction process by up to 15 times compared to unconstrained reconstruction algorithms and provides more accurate results as compared to the so-called two-step approach to multi-wavelength imaging. PMID:21258511

  2. Isoflavones from Maclura pomifera: structural elucidation and in silico evaluation of their interaction with PDE5.

    PubMed

    Ribaudo, Giovanni; Vendrame, Tiziano; Bova, Sergio

    2016-12-27

    While osajin and pomiferin are known for their anticancer, antibacterial and antidiabetic properties, scandenone and auriculasin have been proposed as anti-inflammatory and antinociceptive agents. Curiously, these two couples of molecules are, from a chemical point of view, structural isomers which can all be extracted from Maclura pomifera. Although previous works described, separately, the isolation in reasonable amounts of the sole osajin/pomiferin couple or of scandenone/auriculasin, we report the extraction and characterization using direct spectral and chromatographical comparison of the four compounds. 2D NMR allowed to unambiguously assign the correct structures to the isomers. The compounds were screened in silico against PDE5 and their interaction pattern with the protein was compared with that of icarisid II, a natural PDE5 inhibitor.

  3. PDE-constrained multispectral imaging of tissue chromophores with the equation of radiative transfer.

    PubMed

    Kim, Hyun Keol; Flexman, Molly; Yamashiro, Darrell J; Kandel, Jessica J; Hielscher, Andreas H

    2010-09-08

    We introduce a transport-theory-based PDE-constrained multispectral model for direct imaging of the spatial distributions of chromophores concentrations in biological tissue. The method solves the forward problem (boundary radiance at each wavelength) and the inverse problem (spatial distribution of chromophores concentrations), in an all-at-once manner in the framework of a reduced Hessian sequential quadratic programming method. To illustrate the code's performance, we present numerical and experimental studies involving tumor bearing mice. It is shown that the PDE-constrained multispectral method accelerates the reconstruction process by up to 15 times compared to unconstrained reconstruction algorithms and provides more accurate results as compared to the so-called two-step approach to multi-wavelength imaging.

  4. Investigation of Thrust Augmentation and Acoustic Performance by Ejectors on PDE

    NASA Astrophysics Data System (ADS)

    Xu, Gui-yang; Weng, Chun-sheng; Li, Ning; Huang, Xiao-long

    2016-04-01

    Thrust augmentation and acoustic performance of a Pulse Detonation Engine (PDE) with ejector system is experimentally investigated. For these tests the LEjector/DEjector is varied from 1.18 to 4 and the axial placement of the ejector relative to the PDE exhaust is varied from an x/DPDE of -3 to 3. Results from the tests show that the optimum LEjector/DEjector based on thrust augmentation and Overall Sound Pressure Level (OASPL) is found to be 2.61. The divergent ejector performed the best based on thrust augmentation, while the reduction effect for OASPL and Peak Sound Pressure Level (PSPL) at 60° is most prominent for the convergent ejector. The optimum axial position based on thrust augmentation is determined to be x/DPDE = 2, while, x/DPDE = 0 based on OASPL and PSPL.

  5. Algorithmic Perspectives on Problem Formulations in MDO

    NASA Technical Reports Server (NTRS)

    Alexandrov, Natalia M.; Lewis, Robert Michael

    2000-01-01

    This work is concerned with an approach to formulating the multidisciplinary optimization (MDO) problem that reflects an algorithmic perspective on MDO problem solution. The algorithmic perspective focuses on formulating the problem in light of the abilities and inabilities of optimization algorithms, so that the resulting nonlinear programming problem can be solved reliably and efficiently by conventional optimization techniques. We propose a modular approach to formulating MDO problems that takes advantage of the problem structure, maximizes the autonomy of implementation, and allows for multiple easily interchangeable problem statements to be used depending on the available resources and the characteristics of the application problem.

  6. Optimality conditions for the numerical solution of optimization problems with PDE constraints :

    SciTech Connect

    Aguilo Valentin, Miguel Alejandro; Ridzal, Denis

    2014-03-01

    A theoretical framework for the numerical solution of partial di erential equation (PDE) constrained optimization problems is presented in this report. This theoretical framework embodies the fundamental infrastructure required to e ciently implement and solve this class of problems. Detail derivations of the optimality conditions required to accurately solve several parameter identi cation and optimal control problems are also provided in this report. This will allow the reader to further understand how the theoretical abstraction presented in this report translates to the application.

  7. Improving Fiber Alignment in HARDI by Combining Contextual PDE Flow with Constrained Spherical Deconvolution

    PubMed Central

    Portegies, J. M.; Fick, R. H. J.; Sanguinetti, G. R.; Meesters, S. P. L.; Girard, G.; Duits, R.

    2015-01-01

    We propose two strategies to improve the quality of tractography results computed from diffusion weighted magnetic resonance imaging (DW-MRI) data. Both methods are based on the same PDE framework, defined in the coupled space of positions and orientations, associated with a stochastic process describing the enhancement of elongated structures while preserving crossing structures. In the first method we use the enhancement PDE for contextual regularization of a fiber orientation distribution (FOD) that is obtained on individual voxels from high angular resolution diffusion imaging (HARDI) data via constrained spherical deconvolution (CSD). Thereby we improve the FOD as input for subsequent tractography. Secondly, we introduce the fiber to bundle coherence (FBC), a measure for quantification of fiber alignment. The FBC is computed from a tractography result using the same PDE framework and provides a criterion for removing the spurious fibers. We validate the proposed combination of CSD and enhancement on phantom data and on human data, acquired with different scanning protocols. On the phantom data we find that PDE enhancements improve both local metrics and global metrics of tractography results, compared to CSD without enhancements. On the human data we show that the enhancements allow for a better reconstruction of crossing fiber bundles and they reduce the variability of the tractography output with respect to the acquisition parameters. Finally, we show that both the enhancement of the FODs and the use of the FBC measure on the tractography improve the stability with respect to different stochastic realizations of probabilistic tractography. This is shown in a clinical application: the reconstruction of the optic radiation for epilepsy surgery planning. PMID:26465600

  8. Positive association of phencyclidine-responsive genes, PDE4A and PLAT, with schizophrenia.

    PubMed

    Deng, Xiangdong; Takaki, Hiromi; Wang, Lixiang; Kuroki, Tosihide; Nakahara, Tatsuo; Hashimoto, Kijiro; Ninomiya, Hideaki; Arinami, Tadao; Inada, Toshiya; Ujike, Hiroshi; Itokawa, Masanari; Tochigi, Mamoru; Watanabe, Yuichiro; Someya, Toshiyuki; Kunugi, Hiroshi; Iwata, Nakao; Ozaki, Norio; Shibata, Hiroki; Fukumaki, Yasuyuki

    2011-12-01

    As schizophrenia-like symptoms are produced by administration of phencyclidine (PCP), a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors, PCP-responsive genes could be involved in the pathophysiology of schizophrenia. We injected PCP to Wistar rats and isolated five different parts of the brain in 1 and 4 hr after the injection. We analyzed the gene expression induced by the PCP treatment of these tissues using the AGILENT rat cDNA microarray system. We observed changes in expression level in 90 genes and 21 ESTs after the treatment. Out of the 10 genes showing >2-fold expressional change evaluated by qRT-PCR, we selected 7 genes as subjects for the locus-wide association study to identify susceptibility genes for schizophrenia in the Japanese population. In haplotype analysis, significant associations were detected in combinations of two SNPs of BTG2 (P = 1.4 × 10(-6) ), PDE4A (P = 1.4 × 10(-6) ), and PLAT (P = 1 × 10(-3) ), after false discovery rate (FDR) correction. Additionally, we not only successfully replicated the haplotype associations in PDE4A (P = 6.8 × 10(-12) ) and PLAT (P = 0.015), but also detected single-point associations of one SNP in PDE4A (P = 0.0068) and two SNPs in PLAT (P = 0.0260 and 0.0104) in another larger sample set consisting of 2,224 cases and 2,250 controls. These results indicate that PDE4A and PLAT may be susceptibility genes for schizophrenia in the Japanese population.

  9. Colon tumor cell growth inhibitory activity of sulindac sulfide and other NSAIDs is associated with PDE5 inhibition

    PubMed Central

    Tinsley, Heather N.; Gary, Bernard D.; Thaiparambil, Jose; Li, Nan; Lu, Wenyan; Li, Yonghe; Maxuitenko, Yulia Y.; Keeton, Adam B.; Piazza, Gary A.

    2010-01-01

    In experimental studies, nonsteroidal anti-inflammatory drugs (NSAIDs) display promising antineoplastic activity, but toxicity resulting from cyclooxygenase (COX) inhibition limits their clinical use for chemoprevention. Studies suggest that the mechanism may be COX independent, although alternative targets have not been well defined. Here we show that the NSAID, sulindac sulfide (SS) inhibits cGMP phosphodiesterase (PDE) activity in colon tumor cell lysates at concentrations that inhibit colon tumor cell growth in vitro and in vivo. A series of chemically diverse NSAIDs inhibited cGMP hydrolysis at concentrations that correlate with their potency to inhibit colon tumor cell growth, while no correlation was observed with COX-2 inhibition. Consistent with its selectivity for inhibiting cGMP hydrolysis compared with cAMP hydrolysis, SS inhibited the cGMP specific PDE5 isozyme and increased cGMP levels in colon tumor cells. Of numerous PDE isozyme specific inhibitors evaluated, only the PDE5 selective inhibitor MY5445 inhibited colon tumor cell growth. The effects of SS and MY5445 on cell growth were associated with inhibition of β-catenin mediated transcriptional activity to suppress the synthesis of cyclin D and survivin, which regulate tumor cell proliferation and apoptosis, respectively. SS had minimal effects on cGMP PDE activity in normal colonocytes, which displayed reduced sensitivity to SS and did not express PDE5. PDE5 was found to be overexpressed in colon tumor cell lines as well as in colon adenomas and adenocarcinomas compared to normal colonic mucosa. These results suggest that PDE5 inhibition, cGMP elevation, and inhibition of β-catenin transcriptional activity may contribute to the chemopreventive properties of certain NSAIDs. PMID:20876730

  10. Low-complexity PDE-based approach for automatic microarray image processing.

    PubMed

    Belean, Bogdan; Terebes, Romulus; Bot, Adrian

    2015-02-01

    Microarray image processing is known as a valuable tool for gene expression estimation, a crucial step in understanding biological processes within living organisms. Automation and reliability are open subjects in microarray image processing, where grid alignment and spot segmentation are essential processes that can influence the quality of gene expression information. The paper proposes a novel partial differential equation (PDE)-based approach for fully automatic grid alignment in case of microarray images. Our approach can handle image distortions and performs grid alignment using the vertical and horizontal luminance function profiles. These profiles are evolved using a hyperbolic shock filter PDE and then refined using the autocorrelation function. The results are compared with the ones delivered by state-of-the-art approaches for grid alignment in terms of accuracy and computational complexity. Using the same PDE formalism and curve fitting, automatic spot segmentation is achieved and visual results are presented. Considering microarray images with different spots layouts, reliable results in terms of accuracy and reduced computational complexity are achieved, compared with existing software platforms and state-of-the-art methods for microarray image processing.

  11. Mutations in the PDE6B gene in autosomal recessive retinitis pigmentosa

    SciTech Connect

    Danciger, M.; Blaney, J.; Gao, Y.Q.; Zhao, D.Y.

    1995-11-01

    We have studied 24 small families with presumed autosomal recessive inheritance of retinitis pigmentosa by a combination of haplotype analysis and exon screening. Initial analysis of the families was made with a dinucleotide repeat polymorphism adjacent to the gene for rod cGMP-phosphodiesterase (PDE6B). This was followed by denaturing gradient gel electrophoresis (DGGE) and single-strand conformation polymorphism electrophoresis (SSCPE) of the 22 exons and a portion of the 5{prime} untranslated region of the PDE6B gene in the probands of each family in which the PDE6B locus could not be ruled out from segregating with disease. Two probands were found with compound heterozygous mutations: Gly576Asp and His620(1-bp del) mutations were present in one proband, and a Lys706X null mutation and an AG to AT splice acceptor site mutation in intron 2 were present in the other. Only the affecteds of each of the two families carried both corresponding mutations. 29 refs., 3 figs., 1 tab.

  12. Mitotic activation of the DISC1-inducible cyclic AMP phosphodiesterase-4D9 (PDE4D9), through multi-site phosphorylation, influences cell cycle progression.

    PubMed

    Sheppard, Catherine L; Lee, Louisa C Y; Hill, Elaine V; Henderson, David J P; Anthony, Diana F; Houslay, Daniel M; Yalla, Krishna C; Cairns, Lynne S; Dunlop, Allan J; Baillie, George S; Huston, Elaine; Houslay, Miles D

    2014-09-01

    In Rat-1 cells, the dramatic decrease in the levels of both intracellular cyclic 3'5' adenosine monophosphate (cyclic AMP; cAMP) and in the activity of cAMP-activated protein kinase A (PKA) observed in mitosis was paralleled by a profound increase in cAMP hydrolyzing phosphodiesterase-4 (PDE4) activity. The decrease in PKA activity, which occurs during mitosis, was attributable to PDE4 activation as the PDE4 selective inhibitor, rolipram, but not the phosphodiesterase-3 (PDE3) inhibitor, cilostamide, specifically ablated this cell cycle-dependent effect. PDE4 inhibition caused Rat-1 cells to move from S phase into G2/M more rapidly, to transit through G2/M more quickly and to remain in G1 for a longer period. Inhibition of PDE3 elicited no observable effects on cell cycle dynamics. Selective immunopurification of each of the four PDE4 sub-families identified PDE4D as being selectively activated in mitosis. Subsequent analysis uncovered PDE4D9, an isoform whose expression can be regulated by Disrupted-In-Schizophrenia 1 (DISC1)/activating transcription factor 4 (ATF4) complex, as the sole PDE4 species activated during mitosis in Rat-1 cells. PDE4D9 becomes activated in mitosis through dual phosphorylation at Ser585 and Ser245, involving the combined action of ERK and an unidentified 'switch' kinase that has previously been shown to be activated by H2O2. Additionally, in mitosis, PDE4D9 also becomes phosphorylated at Ser67 and Ser81, through the action of MK2 (MAPKAPK2) and AMP kinase (AMPK), respectively. The multisite phosphorylation of PDE4D9 by all four of these protein kinases leads to decreased mobility (band-shift) of PDE4D9 on SDS-PAGE. PDE4D9 is predominantly concentrated in the perinuclear region of Rat-1 cells but with a fraction distributed asymmetrically at the cell margins. Our investigations demonstrate that the diminished levels of cAMP and PKA activity that characterise mitosis are due to enhanced cAMP degradation by PDE4D9. PDE4D9, was found to

  13. Linear stability analysis for travelling waves of second order in time PDE's

    NASA Astrophysics Data System (ADS)

    Stanislavova, Milena; Stefanov, Atanas

    2012-09-01

    We study travelling waves φc of second order in time PDE's u_{tt}+{ L} u+N(u)=0 . The linear stability analysis for these models is reduced to the question of the stability of quadratic pencils in the form \\lambda^2Id+2c\\lambda \\partial_x+{ H}_c , where { H}_c=c^2 \\partial_{xx}+{ L}+N'(\\varphi_c) . If { H}_c is a self-adjoint operator, with a simple negative eigenvalue and a simple eigenvalue at zero, then we completely characterize the linear stability of φc. More precisely, we introduce an explicitly computable index \\omega^*({ H}_c)\\in (0, \\infty] , so that the wave φc is stable if and only if |c|\\geq \\omega^*({ H}_c) . The results are applicable both in the periodic case and in the whole line case. The method of proof involves a delicate analysis of a function { G} , associated with { H} , whose positive zeros are exactly the positive (unstable) eigenvalues of the pencil \\lambda^2Id+2c\\lambda \\partial_x+{ H} . We would like to emphasize that the function { G} is not the Evans function for the problem, but rather a new object that we define herein, which fits the situation rather well. As an application, we consider three classical models—the ‘good’ Boussinesq equation, the Klein-Gordon-Zakharov (KGZ) system and the fourth order beam equation. In the whole line case, for the Boussinesq case and the KGZ system (and as a direct application of the main results), we compute explicitly the set of speeds which give rise to linearly stable travelling waves (and for all powers of p in the case of Boussinesq). This result is new for the KGZ system, while it generalizes the results of Alexander et al (2012, personal communication) and Alexander and Sachs (1995 Nonlinear World 2 471-507), which apply to the case p = 2. For the beam equation, we provide an implicit formula (depending only on the function \\|\\varphi_c'\\|_{L^2}) , which works for all p and for both the periodic and the whole line cases. Our results complement (and exactly match

  14. Pharmacophore modeling and virtual screening for the discovery of new type 4 cAMP phosphodiesterase (PDE4) inhibitors.

    PubMed

    Niu, Miaomiao; Dong, Fenggong; Tang, Shi; Fida, Guissi; Qin, Jingyi; Qiu, Jiadan; Liu, Kangbo; Gao, Weidong; Gu, Yueqing

    2013-01-01

    Type 4 cAMP phosphodiesterase (PDE4) inhibitors show a broad spectrum of anti-inflammatory effects in almost all kinds of inflamed cells, by an increase in cAMP levels which is a pivotal second messenger responsible for various biological processes. These inhibitors are now considered as the potential drugs for treatment of chronic inflammatory diseases. However, some recently marketed inhibitors e.g., roflumilast, have shown adverse effects such as nausea and emesis, thus restricting its use. In order to identify novel PDE4 inhibitors with improved therapeutic indexes, a highly correlating (r = 0.963930) pharmacophore model (Hypo1) was established on the basis of known PDE4 inhibitors. Validated Hypo1 was used in database screening to identify chemical with required pharmacophoric features. These compounds are further screened by using the rule of five, ADMET and molecular docking. Finally, twelve hits which showed good results with respect to following properties such as estimated activity, calculated drug-like properties and scores were proposed as potential leads to inhibit the PDE4 activity. Therefore, this study will not only assist in the development of new potent hits for PDE4 inhibitors, but also give a better understanding of their interaction with PDE4. On a wider scope, this will be helpful for the rational design of novel potent enzyme inhibitors.

  15. UCR1C is a novel activator of phosphodiesterase 4 (PDE4) long isoforms and attenuates cardiomyocyte hypertrophy

    PubMed Central

    Wang, Li; Burmeister, Brian T.; Johnson, Keven R.; Baillie, George S.; Karginov, Andrei V.; Skidgel, Randal A.; O’Bryan, John P.; Carnegie, Graeme K.

    2015-01-01

    Hypertrophy increases the risk of heart failure and arrhythmia. Prevention or reversal of the maladaptive hypertrophic phenotype has thus been proposed to treat heart failure. Chronic β-adrenergic receptor (β-AR) stimulation induces cardiomyocyte hypertrophy by elevating 3′, 5′-cyclic adenosine monophosphate (cAMP) levels and activating downstream effectors such protein kinase A (PKA). Conversely, hydrolysis of cAMP by phosphodiesterases (PDEs) spatiotemporally restricts cAMP signaling. Here, we demonstrate that PDE4, but not PDE3, is critical in regulating cardiomyocyte hypertrophy, and may represent a potential target for preventing maladaptive hypertrophy. We identify a sequence within the upstream conserved region 1 of PDE4D, termed UCR1C, as a novel activator of PDE4 long isoforms. UCR1C activates PDE4 in complex with A-Kinase anchoring protein (AKAP)-Lbc resulting in decreased PKA signaling facilitated by AKAP-Lbc. Expression of UCR1C in cardiomyocytes inhibits hypertrophy in response to chronic β-AR stimulation. This effect is partially due to inhibition of nuclear PKA activity, which decreases phosphorylation of the transcription factor cAMP response element-binding protein (CREB). In conclusion, PDE4 activation by UCR1C attenuates cardiomyocyte hypertrophy by specifically inhibiting nuclear PKA activity. PMID:25683917

  16. Building Blocks for Reliable Complex Nonlinear Numerical Simulations. Chapter 2

    NASA Technical Reports Server (NTRS)

    Yee, H. C.; Mansour, Nagi N. (Technical Monitor)

    2001-01-01

    This chapter describes some of the building blocks to ensure a higher level of confidence in the predictability and reliability (PAR) of numerical simulation of multiscale complex nonlinear problems. The focus is on relating PAR of numerical simulations with complex nonlinear phenomena of numerics. To isolate sources of numerical uncertainties, the possible discrepancy between the chosen partial differential equation (PDE) model and the real physics and/or experimental data is set aside. The discussion is restricted to how well numerical schemes can mimic the solution behavior of the underlying PDE model for finite time steps and grid spacings. The situation is complicated by the fact that the available theory for the understanding of nonlinear behavior of numerics is not at a stage to fully analyze the nonlinear Euler and Navier-Stokes equations. The discussion is based on the knowledge gained for nonlinear model problems with known analytical solutions to identify and explain the possible sources and remedies of numerical uncertainties in practical computations. Examples relevant to turbulent flow computations are included.

  17. Building Blocks for Reliable Complex Nonlinear Numerical Simulations

    NASA Technical Reports Server (NTRS)

    Yee, H. C.

    2005-01-01

    This chapter describes some of the building blocks to ensure a higher level of confidence in the predictability and reliability (PAR) of numerical simulation of multiscale complex nonlinear problems. The focus is on relating PAR of numerical simulations with complex nonlinear phenomena of numerics. To isolate sources of numerical uncertainties, the possible discrepancy between the chosen partial differential equation (PDE) model and the real physics and/or experimental data is set aside. The discussion is restricted to how well numerical schemes can mimic the solution behavior of the underlying PDE model for finite time steps and grid spacings. The situation is complicated by the fact that the available theory for the understanding of nonlinear behavior of numerics is not at a stage to fully analyze the nonlinear Euler and Navier-Stokes equations. The discussion is based on the knowledge gained for nonlinear model problems with known analytical solutions to identify and explain the possible sources and remedies of numerical uncertainties in practical computations.

  18. Building Blocks for Reliable Complex Nonlinear Numerical Simulations

    NASA Technical Reports Server (NTRS)

    Yee, H. C.; Mansour, Nagi N. (Technical Monitor)

    2002-01-01

    This talk describes some of the building blocks to ensure a higher level of confidence in the predictability and reliability (PAR) of numerical simulation of multiscale complex nonlinear problems. The focus is on relating PAR of numerical simulations with complex nonlinear phenomena of numerics. To isolate sources of numerical uncertainties, the possible discrepancy between the chosen partial differential equation (PDE) model and the real physics and/or experimental data is set aside. The discussion is restricted to how well numerical schemes can mimic the solution behavior of the underlying PDE model for finite time steps and grid spacings. The situation is complicated by the fact that the available theory for the understanding of nonlinear behavior of numerics is not at a stage to fully analyze the nonlinear Euler and Navier-Stokes equations. The discussion is based on the knowledge gained for nonlinear model problems with known analytical solutions to identify and explain the possible sources and remedies of numerical uncertainties in practical computations. Examples relevant to turbulent flow computations are included.

  19. Firing properties of a stochastic PDE model of a rat sensory cortex layer 2/3 pyramidal cell.

    PubMed

    Iannella, Nicolangelo; Tuckwell, Henry C; Tanaka, Shigeru

    2004-01-01

    We have developed a non-linear stochastic PDE (partial differential equation) model of a rat layer 2/3 somatosensory pyramidal neuron which approximates several of the dynamical properties of these cells. The model distinguishes telodendrites, a myelinated axon, initial segment, hillock, soma and a simplified dendritic tree. Distributions and properties of excitatory and inhibitory synapses were included, in accordance with recent anatomical and physiological findings. Using simulation methods, we aim to show that the spatial separation between regions of spatially distributed randomly activated excitatory and inhibitory synaptic inputs may be an important parameter which can influence neuronal firing properties. Due to the complexity of the problem, with respect to configurations of spatially and temporally activated excitatory and inhibitory synaptic inputs, we consider two simple configurations in which the spatial region of activated excitatory and inhibitory synaptic inputs overlap and when they are far from each. In the first, denoted configuration A, activated excitatory and inhibitory synapses were located close to the soma. In the second, denoted configuration B, active inhibitory synapses were close the soma, while active excitatory synapses were located on distal regions of the dendrite. For the first configuration, we find that increases in the mean rate of inhibition results in an increase in the width of the firing rate tuning curves, and that for particular mean input frequencies of excitation, increasing the mean input rate of inhibition does not always imply that the neuron fires at a slower rate. Furthermore, we observed for mean input frequencies of excitation between 15 and 60 (Hz), that increasing the mean rate of inhibition resulted in the linearization of the firing rate over this interval. For configuration B, no increase in width nor a linearization effect via inhibition was observed. These differences indicate that the distance between

  20. Synergistic interactions between PDE4B and GSK-3: DISC1 mutant mice.

    PubMed

    Lipina, Tatiana V; Wang, Min; Liu, Fang; Roder, John C

    2012-03-01

    Disrupted-In-Schizophrenia-1 (DISC1) is a strong genetic risk factor associated with psychiatric disorders. Two distinct mutations in the second exon of the DISC1 gene (Q31L and L100P) lead to either depression- or schizophrenia-like behavior in mice. Both phosphodiesterase-4B (PDE4B) and glycogen synthase kinase-3 (GSK-3) have common binding sites on N-terminal region of DISC1 and are implicated into etiology of schizophrenia and depression. It is not known if PDE4B and GSK-3 could converge signals in the cell via DISC1 at the same time. The purpose of the present study was to assess whether rolipram (PDE4 inhibitor) might synergize with TDZD-8 (GSK-3 blocker) to produce antipsychotic effects at low doses on the DISC1-L100P genetic model. Indeed, combined treatment of DISC1-L100P mice with rolipram (0.1 mg/kg) and TDZD-8 (2.5 mg/kg) in sub-threshold doses corrected their Pre-Pulse Inhibition (PPI) deficit and hyperactivity, without any side effects at these doses. We have suggested that rolipram-induced increase of cAMP level might influence GSK-3 function and, hence the efficacy of TDZD-8. Our second goal was to estimate how DISC1-Q31L with reduced PDE4B activity, and therefore mimicking rolipram-induced conditions, could alter pharmacological response to TDZD-8, GSK-3 activity and its interaction with DISC1. DISC1-Q31L mutants showed increased sensitivity to GSK-3 inhibitor compare to DISC1-L100P mice. TDZD-8 (2.5 mg/kg) was able to correct PPI deficit, reduce immobility in the forced swim test (FST) and increased social motivation/novelty. In parallel, biochemical analysis revealed significantly reduced binding of GSK-3 to the mutated DISC1-Q31L and increased enzymatic activity of GSK-3. Taken together, genetic variations in DISC1 influence formation of biochemical complex with PDE4 and GSK-3 and strength the possibility of synergistic interactions between these proteins.

  1. Practical aspects of variable reduction formulations and reduced basis algorithms in multidisciplinary design optimization

    NASA Technical Reports Server (NTRS)

    Lewis, Robert Michael

    1995-01-01

    This paper discusses certain connections between nonlinear programming algorithms and the formulation of optimization problems for systems governed by state constraints. The major points of this paper are the detailed calculation of the sensitivities associated with different formulations of optimization problems and the identification of some useful relationships between different formulations. These relationships have practical consequences; if one uses a reduced basis nonlinear programming algorithm, then the implementations for the different formulations need only differ in a single step.

  2. Nonlinear Wave Propagation

    DTIC Science & Technology

    1983-12-30

    Equation * Discrete IST and numerical simulations * Long time asymptotic solutions of nonlinear evolution equations * Painlevf equations . Focussing...larger class of solutions io KdV than does the Gel’fand-’Levitan equation . Specifically we have shown by direct calculation that if 0(k;x,t) solves oV...Investigation of the full generality of the solutions of KdV via this new formulation. (b) Developnent of similar types - integral equations for

  3. Effects of PDE5 Inhibitors and sGC Stimulators in a Rat Model of Artificial Ureteral Calculosis

    PubMed Central

    Sandner, Peter; Tinel, Hanna; Affaitati, Giannapia; Costantini, Raffaele; Giamberardino, Maria Adele

    2015-01-01

    Urinary colics from calculosis are frequent and intense forms of pain whose current pharmacological treatment remains unsatisfactory. New and more effective drugs are needed to control symptoms and improve stone expulsion. Recent evidence suggested that the Nitric Oxide (NO) / cyclic guanosine monophosphate (cGMP) / phosphodiesterase type 5 (PDE5) system may contribute to ureteral motility influencing stone expulsion. We investigated if PDE5 inhibitors and sGC stimulators influence ureteral contractility, pain behaviour and stone expulsion in a rat model of ureteral calculosis. We investigated: a)the sex-specific PDE5 distribution in the rat ureter; b)the functional in vitro effects of vardenafil and sildenafil (PDE5 inhibitors) and BAY41-2272 (sGC stimulator) on induced ureteral contractility in rats and c)the in vivo effectiveness of vardenafil and BAY41-2272, alone and combined with ketoprofen, vs hyoscine-N-butylbromide alone or combined with ketoprofen, on behavioural pain indicators and stone expulsion in rats with artificial calculosis in one ureter. PDE5 was abundantly expressed in male and female rats’ ureter. In vitro, both vardenafil and BAY41-2272 significantly relaxed pre-contracted ureteral strips. In vivo, all compounds significantly reduced number and global duration of “ureteral crises” and post-stone lumbar muscle hyperalgesia in calculosis rats. The highest level of reduction of the pain behaviour was observed with BAY41-2272 among all spasmolytics administered alone, and with the combination of ketoprofen with BAY41-2272. The percentage of stone expulsion was maximal in the ketoprofen+BAY41-2272 group. The NO/cGMP/PDE5 pathway is involved in the regulation of ureteral contractility and pain behaviour in urinary calculosis. PDE5 inhibitors and sGC stimulators could become a potent new option for treatment of urinary colic pain. PMID:26509272

  4. Changes in NMDA receptor-induced cyclic nucleotide synthesis regulate the age-dependent increase in PDE4A expression in primary cortical cultures

    PubMed Central

    Hajjhussein, Hassan; Suvarna, Neesha U.; Gremillion, Carmen; Judson Chandler, L.; O’Donnell, James M.

    2007-01-01

    NMDA receptor-induced cAMP and cGMP are selectively hydrolyzed by PDE4 and PDE2, respectively, in rat primary cerebral cortical and hippocampal cultures. Because cAMP levels regulate the expression of PDE4 in rat primary cortical cultures, we examined the manner in which NMDA receptor activity regulates the age-dependent increase in the expression of PDE4A observed in vivo and in vitro. Inhibiting the activity of NR2B subunit with ifenprodil blocked NMDA receptor-induced cGMP synthesis and increased NMDA receptor-induced cAMP levels in a manner that reduced PDE4 activity. Therefore, NR1/NR2B receptor-induced cGMP signaling is involved in an acute cross-talk regulation of NR1/NR2A receptor-induced cAMP levels, mediated by PDE4. Chronic inhibition of NMDA receptor activity with MK-801 reduced PDE4A1 and PDE4A5 expression and activity in a time-dependent manner; this effect was reversed by adding the PKA activator dbr-cAMP. Inhibiting GABA receptors with bicuculline increased NMDA receptor-induced cAMP synthesis and PDE4A expression in cultures treated between DIV 16 and DIV 21 but not in cultures treated between DIV 8 and DIV 13. This effect was due to a high tone of NMDA receptor-induced cGMP in younger cultures, which negatively regulated the expression of PDE4A by a PKG-mediated process. The present results are consistent with behavioral data showing that both PDE4 and PDE2 are involved in NMDA receptor-mediated memory processes. PMID:17407767

  5. Synthesis of Fluorine-Containing Phosphodiesterase 10A (PDE10A) Inhibitors and the In Vivo Evaluation of F-18 Labeled PDE10A PET Tracers in Rodent and Nonhuman Primate

    PubMed Central

    Li, Junfeng; Zhang, Xiang; Jin, Hongjun; Fan, Jinda; Flores, Hubert; Perlmutter, Joel S.; Tu, Zhude

    2015-01-01

    A series of fluorine-containing PDE10A inhibitors were designed and synthesized to improve the metabolic stability of [11C]MP-10. Twenty of the 22 new analogues had high potency and selectivity for PDE10A: 18a–j, 19d–j, 20a–b, and 21b had IC50 values <5 nM for PDE10A. Seven F-18 labeled compounds [18F]18a–e, [18F]18g, and [18F]20a were radiosynthesized by 18F-introduction onto the quinoline rather than the pyrazole moiety of the MP-10 pharmacophore and performed in vivo evaluation. Biodistribution studies in rats showed ~2-fold higher activity in the PDE10A-enriched striatum than nontarget brain regions; this ratio increased from 5 to 30 min postinjection, particularly for [18F]18a–d and [18F]20a. Micro-PET studies of [18F]18d and [18F]20a in nonhuman primates provided clear visualization of striatum with suitable equilibrium kinetics and favorable metabolic stability. These results suggest this strategy may identify a 18F-labeled PET tracer for quantifying the levels of PDE10A in patients with CNS disorders including Huntington’s disease and schizophrenia. PMID:26430878

  6. Compartmentalized Cyclic Adenosine 3′,5′-Monophosphate at the Plasma Membrane Clusters PDE3A and Cystic Fibrosis Transmembrane Conductance Regulator into Microdomains

    PubMed Central

    Penmatsa, Himabindu; Zhang, Weiqiang; Yarlagadda, Sunitha; Li, Chunying; Conoley, Veronica G.; Yue, Junming; Bahouth, Suleiman W.; Buddington, Randal K.; Zhang, Guangping; Nelson, Deborah J.; Sonecha, Monal D.; Manganiello, Vincent; Wine, Jeffrey J.

    2010-01-01

    Formation of multiple-protein macromolecular complexes at specialized subcellular microdomains increases the specificity and efficiency of signaling in cells. In this study, we demonstrate that phosphodiesterase type 3A (PDE3A) physically and functionally interacts with cystic fibrosis transmembrane conductance regulator (CFTR) channel. PDE3A inhibition generates compartmentalized cyclic adenosine 3′,5′-monophosphate (cAMP), which further clusters PDE3A and CFTR into microdomains at the plasma membrane and potentiates CFTR channel function. Actin skeleton disruption reduces PDE3A–CFTR interaction and segregates PDE3A from its interacting partners, thus compromising the integrity of the CFTR-PDE3A–containing macromolecular complex. Consequently, compartmentalized cAMP signaling is lost. PDE3A inhibition no longer activates CFTR channel function in a compartmentalized manner. The physiological relevance of PDE3A–CFTR interaction was investigated using pig trachea submucosal gland secretion model. Our data show that PDE3A inhibition augments CFTR-dependent submucosal gland secretion and actin skeleton disruption decreases secretion. PMID:20089840

  7. Exploring pyrazolo[3,4-d]pyrimidine phosphodiesterase 1 (PDE1) inhibitors: a predictive approach combining comparative validated multiple molecular modelling techniques.

    PubMed

    Amin, Sk Abdul; Bhargava, Sonam; Adhikari, Nilanjan; Gayen, Shovanlal; Jha, Tarun

    2017-02-13

    Phosphodiesterase 1 (PDE1) is a potential target for a number of neurodegenerative disorders such as Schizophrenia, Parkinson's and Alzheimer's diseases. A number of pyrazolo[3,4-d]pyrimidine PDE1 inhibitors were subjected to different molecular modelling techniques [such as regression-based quantitative structure-activity relationship (QSAR): multiple linear regression, support vector machine and artificial neural network; classification-based QSAR: Bayesian modelling and Recursive partitioning; Monte Carlo based QSAR; Open3DQSAR; pharmacophore mapping and molecular docking analyses] to get a detailed knowledge about the physicochemical and structural requirements for higher inhibitory activity. The planarity of the pyrimidinone ring plays an important role for PDE1 inhibition. The N-methylated function at the 5th position of the pyrazolo[3,4-d]pyrimidine core is required for interacting with the PDE1 enzyme. The cyclopentyl ring fused with the parent scaffold is necessary for PDE1 binding potency. The phenylamino substitution at 3rd position is crucial for PDE1 inhibition. The N2-substitution at the pyrazole moiety is important for PDE1 inhibition compared to the N1-substituted analogues. Moreover, the p-substituted benzyl side chain at N2-position helps to enhance the PDE1 inhibitory profile. Depending on these observations, some new molecules are predicted that may possess better PDE1 inhibition.

  8. Exploring equivalence domain in nonlinear inverse problems using Covariance Matrix Adaption Evolution Strategy (CMAES) and random sampling

    NASA Astrophysics Data System (ADS)

    Grayver, Alexander V.; Kuvshinov, Alexey V.

    2016-05-01

    This paper presents a methodology to sample equivalence domain (ED) in nonlinear partial differential equation (PDE)-constrained inverse problems. For this purpose, we first applied state-of-the-art stochastic optimization algorithm called Covariance Matrix Adaptation Evolution Strategy (CMAES) to identify low-misfit regions of the model space. These regions were then randomly sampled to create an ensemble of equivalent models and quantify uncertainty. CMAES is aimed at exploring model space globally and is robust on very ill-conditioned problems. We show that the number of iterations required to converge grows at a moderate rate with respect to number of unknowns and the algorithm is embarrassingly parallel. We formulated the problem by using the generalized Gaussian distribution. This enabled us to seamlessly use arbitrary norms for residual and regularization terms. We show that various regularization norms facilitate studying different classes of equivalent solutions. We further show how performance of the standard Metropolis-Hastings Markov chain Monte Carlo algorithm can be substantially improved by using information CMAES provides. This methodology was tested by using individual and joint inversions of magneotelluric, controlled-source electromagnetic (EM) and global EM induction data.

  9. Program Code Generator for Cardiac Electrophysiology Simulation with Automatic PDE Boundary Condition Handling

    PubMed Central

    Punzalan, Florencio Rusty; Kunieda, Yoshitoshi; Amano, Akira

    2015-01-01

    Clinical and experimental studies involving human hearts can have certain limitations. Methods such as computer simulations can be an important alternative or supplemental tool. Physiological simulation at the tissue or organ level typically involves the handling of partial differential equations (PDEs). Boundary conditions and distributed parameters, such as those used in pharmacokinetics simulation, add to the complexity of the PDE solution. These factors can tailor PDE solutions and their corresponding program code to specific problems. Boundary condition and parameter changes in the customized code are usually prone to errors and time-consuming. We propose a general approach for handling PDEs and boundary conditions in computational models using a replacement scheme for discretization. This study is an extension of a program generator that we introduced in a previous publication. The program generator can generate code for multi-cell simulations of cardiac electrophysiology. Improvements to the system allow it to handle simultaneous equations in the biological function model as well as implicit PDE numerical schemes. The replacement scheme involves substituting all partial differential terms with numerical solution equations. Once the model and boundary equations are discretized with the numerical solution scheme, instances of the equations are generated to undergo dependency analysis. The result of the dependency analysis is then used to generate the program code. The resulting program code are in Java or C programming language. To validate the automatic handling of boundary conditions in the program code generator, we generated simulation code using the FHN, Luo-Rudy 1, and Hund-Rudy cell models and run cell-to-cell coupling and action potential propagation simulations. One of the simulations is based on a published experiment and simulation results are compared with the experimental data. We conclude that the proposed program code generator can be used to

  10. Program Code Generator for Cardiac Electrophysiology Simulation with Automatic PDE Boundary Condition Handling.

    PubMed

    Punzalan, Florencio Rusty; Kunieda, Yoshitoshi; Amano, Akira

    2015-01-01

    Clinical and experimental studies involving human hearts can have certain limitations. Methods such as computer simulations can be an important alternative or supplemental tool. Physiological simulation at the tissue or organ level typically involves the handling of partial differential equations (PDEs). Boundary conditions and distributed parameters, such as those used in pharmacokinetics simulation, add to the complexity of the PDE solution. These factors can tailor PDE solutions and their corresponding program code to specific problems. Boundary condition and parameter changes in the customized code are usually prone to errors and time-consuming. We propose a general approach for handling PDEs and boundary conditions in computational models using a replacement scheme for discretization. This study is an extension of a program generator that we introduced in a previous publication. The program generator can generate code for multi-cell simulations of cardiac electrophysiology. Improvements to the system allow it to handle simultaneous equations in the biological function model as well as implicit PDE numerical schemes. The replacement scheme involves substituting all partial differential terms with numerical solution equations. Once the model and boundary equations are discretized with the numerical solution scheme, instances of the equations are generated to undergo dependency analysis. The result of the dependency analysis is then used to generate the program code. The resulting program code are in Java or C programming language. To validate the automatic handling of boundary conditions in the program code generator, we generated simulation code using the FHN, Luo-Rudy 1, and Hund-Rudy cell models and run cell-to-cell coupling and action potential propagation simulations. One of the simulations is based on a published experiment and simulation results are compared with the experimental data. We conclude that the proposed program code generator can be used to

  11. Development of a New Radiofluorinated Quinoline Analog for PET Imaging of Phosphodiesterase 5 (PDE5) in Brain

    PubMed Central

    Liu, Jianrong; Wenzel, Barbara; Dukic-Stefanovic, Sladjana; Teodoro, Rodrigo; Ludwig, Friedrich-Alexander; Deuther-Conrad, Winnie; Schröder, Susann; Chezal, Jean-Michel; Moreau, Emmanuel; Brust, Peter; Maisonial-Besset, Aurélie

    2016-01-01

    Phosphodiesterases (PDEs) are enzymes that play a major role in cell signalling by hydrolysing the secondary messengers cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP) throughout the body and brain. Altered cyclic nucleotide-mediated signalling has been associated with a wide array of disorders, including neurodegenerative disorders. Recently, PDE5 has been shown to be involved in neurodegenerative disorders such as Alzheimer’s disease, but its precise role has not been elucidated yet. To visualize and quantify the expression of this enzyme in brain, we developed a radiotracer for specific PET imaging of PDE5. A quinoline-based lead compound has been structurally modified resulting in the fluoroethoxymethyl derivative ICF24027 with high inhibitory activity towards PDE5 (IC50 = 1.86 nM). Radiolabelling with fluorine-18 was performed by a one-step nucleophilic substitution reaction using a tosylate precursor (RCY(EOB) = 12.9% ± 1.8%; RCP > 99%; SA(EOS) = 70–126 GBq/μmol). In vitro autoradiographic studies of [18F]ICF24027 on different mouse tissue as well as on porcine brain slices demonstrated a moderate specific binding to PDE5. In vivo studies in mice revealed that [18F]ICF24027 was metabolized under formation of brain penetrable radiometabolites making the radiotracer unsuitable for PET imaging of PDE5 in brain. PMID:27110797

  12. A homotopy analysis method for the option pricing PDE in illiquid markets

    NASA Astrophysics Data System (ADS)

    E-Khatib, Youssef

    2012-09-01

    One of the shortcomings of the Black and Scholes model on option pricing is the assumption that trading the underlying asset does not affect the underlying asset price. This can happen in perfectly liquid markets and it is evidently not viable in markets with imperfect liquidity (illiquid markets). It is well-known that markets with imperfect liquidity are more realistic. Thus, the presence of price impact while studying options is very important. This paper investigates a solution for the option pricing PDE in illiquid markets using the homotopy analysis method.

  13. A discontinuous Galerkin method for two-dimensional PDE models of Asian options

    NASA Astrophysics Data System (ADS)

    Hozman, J.; Tichý, T.; Cvejnová, D.

    2016-06-01

    In our previous research we have focused on the problem of plain vanilla option valuation using discontinuous Galerkin method for numerical PDE solution. Here we extend a simple one-dimensional problem into two-dimensional one and design a scheme for valuation of Asian options, i.e. options with payoff depending on the average of prices collected over prespecified horizon. The algorithm is based on the approach combining the advantages of the finite element methods together with the piecewise polynomial generally discontinuous approximations. Finally, an illustrative example using DAX option market data is provided.

  14. Nonlinear Waves

    DTIC Science & Technology

    1989-06-15

    following surprising situation. Namely associated with the integrable nonlinear Schrodinger equations are standard numerical schemes which exhibit at...36. An Initial Boundary Value Problem for the Nonlinear Schrodinger Equations , A.S. Fokas, Physica D March 1989. 37. Evolution Theory, Periodic... gravity waves and wave excitation phenomena related to moving pressure distributions; numerical approximation and computation; nonlinear optics; and

  15. Prediction of nonlinear soil effects

    USGS Publications Warehouse

    Hartzell, S.; Bonilla, L.F.; Williams, R.A.

    2004-01-01

    Mathematical models of soil nonlinearity in common use and recently developed nonlinear codes compared to investigate the range of their predictions. We consider equivalent linear formulations with and without frequency-dependent moduli and damping ratios and nonlinear formulations for total and effective stress. Average velocity profiles to 150 m depth with midrange National Earthquake Hazards Reduction Program site classifications (B, BC, C, D, and E) in the top 30 m are used to compare the response of a wide range of site conditions from rock to soft soil. Nonlinear soil models are compared using the amplification spectrum, calculated as the ratio of surface ground motion to the input motion at the base of the velocity profile. Peak input motions from 0.1g to 0.9g are considered. For site class B, no significant differences exist between the models considered in this article. For site classes BC and C, differences are small at low input motions (0.1g to 0.2g), but become significant at higher input levels. For site classes D and E the overdamping of frequencies above about 4 Hz by the equivalent linear solution with frequency-independent parameters is apparent for the entire range of input motions considered. The equivalent linear formulation with frequency-dependent moduli and damping ratios under damps relative to the nonlinear models considered for site class C with larger input motions and most input levels for site classes D and E. At larger input motions the underdamping for site classes D and E is not as severe as the overdamping with the frequency-independent formulation, but there are still significant differences in the time domain. A nonlinear formulation is recommended for site classes D and E and for site classes BC and C with input motions greater than a few tenths of the acceleration of gravity. The type of nonlinear formulation to use is driven by considerations of the importance of water content and the availability of laboratory soils data. Our

  16. Identification, characterization and subcellular localization of TcPDE1, a novel cAMP-specific phosphodiesterase from Trypanosoma cruzi.

    PubMed Central

    D'Angelo, Maximiliano A; Sanguineti, Santiago; Reece, Jeffrey M; Birnbaumer, Lutz; Torres, Héctor N; Flawiá, Mirtha M

    2004-01-01

    Compartmentalization of cAMP phosphodiesterases plays a key role in the regulation of cAMP signalling in mammals. In the present paper, we report the characterization and subcellular localization of TcPDE1, the first cAMP-specific phosphodiesterase to be identified from Trypanosoma cruzi. TcPDE1 is part of a small gene family and encodes a 929-amino-acid protein that can complement a heat-shock-sensitive yeast mutant deficient in phospho-diesterase genes. Recombinant TcPDE1 strongly associates with membranes and cannot be released with NaCl or sodium cholate, suggesting that it is an integral membrane protein. This enzyme is specific for cAMP and its activity is not affected by cGMP, Ca2+, calmodulin or fenotiazinic inhibitors. TcPDE1 is sensitive to the phosphodiesterase inhibitor dipyridamole but is resistant to 3-isobutyl-1-methylxanthine, theophylline, rolipram and zaprinast. Papaverine, erythro-9-(2-hydroxy-3-nonyl)-adenine hydrochloride, and vinpocetine are poor inhibitors of this enzyme. Confocal laser scanning of T. cruzi epimastigotes showed that TcPDE1 is associated with the plasma membrane and concentrated in the flagellum of the parasite. The association of TcPDE1 with this organelle was confirmed by subcellular fractionation and cell-disruption treatments. The localization of this enzyme is a unique feature that distinguishes it from all the trypanosomatid phosphodiesterases described so far and indicates that compartmentalization of cAMP phosphodiesterases could also be important in these parasites. PMID:14556647

  17. Radiosynthesis and biological evaluation of the new PDE10A radioligand [(18) F]AQ28A.

    PubMed

    Wagner, Sally; Teodoro, Rodrigo; Deuther-Conrad, Winnie; Kranz, Mathias; Scheunemann, Matthias; Fischer, Steffen; Wenzel, Barbara; Egerland, Ute; Hoefgen, Norbert; Steinbach, Jörg; Brust, Peter

    2017-01-01

    Cyclic nucleotide phosphodiesterase 10A (PDE10A) regulates the level of the second messengers cAMP and cGMP in particular in brain regions assumed to be associated with neurodegenerative and psychiatric diseases. A better understanding of the pathophysiological role of the expression of PDE10A could be obtained by quantitative imaging of the enzyme by positron emission tomography (PET). Thus, in this study we developed, radiolabeled, and evaluated a new PDE10A radioligand, 8-bromo-1-(6-[(18) F]fluoropyridin-3-yl)-3,4-dimethylimidazo[1,5-a]quinoxaline ([(18) F]AQ28A). [(18) F]AQ28A was radiolabeled by both nucleophilic bromo-to-fluoro or nitro-to-fluoro exchange using K[(18) F]F-K2.2.2 -carbonate complex with different yields. Using the superior nitro precursor, we developed an automated synthesis on a Tracerlab FX F-N module and obtained [(18) F]AQ28A with high radiochemical yields (33 ± 6%) and specific activities (96-145 GBq·μmol(-1) ) for further evaluation. Initially, we investigated the binding of [(18) F]AQ28A to the brain of different species by autoradiography and observed the highest density of binding sites in striatum, the brain region with the highest PDE10A expression. Subsequent dynamic PET studies in mice revealed a region-specific accumulation of [(18) F]AQ28A in this region, which could be blocked by preinjection of the selective PDE10A ligand MP-10. In conclusion, the data suggest [(18) F]AQ28A is a suitable candidate for imaging of PDE10A in rodent brain by PET.

  18. A Novel Access to Arylated and Heteroarylated Beta-Carboline Based PDE5 Inhibitors

    PubMed Central

    Ahmed, Nermin S.; Gary, Bernard D.; Piazza, Gary A.; Tinsley, Heather N.; Laufer, Stefan; Abadi, Ashraf H.

    2016-01-01

    Starting from a previously reported lead compound GR30040X (a hydantoin tetrahydro-β-carboline derivative with a 4- pyridinyl ring at C- 5), a series of structurally related tetrahydro-β-carboline derivatives were prepared. The tet-rahydro-β-carboline skeleton was fused either to a hydantoin or to a piperazindione ring, the pendant aryl group attached to C-5 or C-6 was changed to a 3, 4-dimethoxyphenyl or a 3-pyridinyl ring; different N-substituents on the terminal ring were introduced, a straight chain ethyl group, a branched tert. butyl and P-chlorophenyl group rather than n-butyl group of the lead compound. All four possible diastereomers of target tetrahydro-β-carboline derivatives were prepared, separated by column chromatography and the significance of these stereochemical manipulations was studied. Synthesized compounds were evaluated for their inhibitory effect versus PDE5. Seven hits were obtained with appreciable inhibitory activity versus PDE5 with IC50s 0.14 - 4.99 μM. PMID:21054274

  19. Bioactive triterpenoids from the leaves of Eriobotrya japonica as the natural PDE4 inhibitors.

    PubMed

    Tan, Bing-Xin; Yang, Lu; Huang, Yi-You; Chen, Yun-Yun; Peng, Guang-Tian; Yu, Si; Wu, Yi-Nuo; Luo, Hai-Bin; He, Xi-Xin

    2017-03-10

    The ethanolic extract of the leaves of Eriobotrya japonica exhibited inhibitory activity against phosphodiesterase-4D (PDE4D), which is a therapeutic target of inflammatory disease. Subsequent bioassay-guided fractionation led to the isolation of a new triterpene (1), together with seven known triterpenoids, methyl corosolate (2), ursolic acid (3), oleanolic acid (4), methyl maslinate (5), α-amyin (6), 3β,19α,23-trihydroxy-urs-12-ene (7) and uvaol (8). The structure of compound 1 was established as 3β-hydroxyl-21β-acetoxyl-urs-12-en-28-carboxylate on the basis of interpretation of its 1D and 2D NMR and HR-ESI-MS spectroscopic data. The bioassay results verified compounds 2, 3 and 8 inhibited PDE4D2 effectively with the IC50 values of 3.06, 2.18 and 5.17 μM, respectively, which may provide a novel mechanism for the anti-inflammatory activity of the leaves of E. japonica.

  20. Phosphatidic Acid Induces Ligand-independent Epidermal Growth Factor Receptor Endocytic Traffic through PDE4 Activation

    PubMed Central

    Norambuena, Andrés; Metz, Claudia; Jung, Juan E.; Silva, Antonia; Otero, Carolina; Cancino, Jorge; Retamal, Claudio; Valenzuela, Juan C.; Soza, Andrea

    2010-01-01

    Endocytosis modulates EGFR function by compartmentalizing and attenuating or enhancing its ligand-induced signaling. Here we show that it can also control the cell surface versus intracellular distribution of empty/inactive EGFR. Our previous observation that PKA inhibitors induce EGFR internalization prompted us to test phosphatidic acid (PA) generated by phospholipase D (PLD) as an endogenous down-regulator of PKA activity, which activates rolipram-sensitive type 4 phosphodiesterases (PDE4) that degrade cAMP. We found that inhibition of PA hydrolysis by propranolol, in the absence of ligand, provokes internalization of inactive (neither tyrosine-phosphorylated nor ubiquitinated) EGFR, accompanied by a transient increase in PA levels and PDE4s activity. This EGFR internalization is mimicked by PA micelles and is strongly counteracted by PLD2 silencing, rolipram or forskolin treatment, and PKA overexpression. Accelerated EGFR endocytosis seems to be mediated by clathrin-dependent and -independent pathways, leading to receptor accumulation in juxtanuclear recycling endosomes, also due to a decreased recycling. Internalized EGFR can remain intracellular without degradation for several hours or return rapidly to the cell surface upon discontinuation of the stimulus. This novel regulatory mechanism of EGFR, also novel function of signaling PA, can transmodulate receptor accessibility in response to heterologous stimuli. PMID:20554760

  1. Comparison of PDE based and other techniques for speckle reduction from digitally reconstructed holographic images

    NASA Astrophysics Data System (ADS)

    Srivastava, Rajeev; Gupta, JRP; Parthasarthy, Harish

    2010-05-01

    In this paper, the partial differential equation (PDE) based homomorphic filtering technique is proposed for speckle reduction from digitally reconstructed holographic images based on the concepts of complex diffusion processes. For digital implementations, the proposed scheme was discretized using finite differences scheme. Further, the performance of the proposed PDE-based technique is compared with other speckle reduction techniques such as homomorphic anisotropic diffusion filter based on extended concept of Perona and Malik (1990) [2], homomorphic Weiner filter, Lee filter, Frost filter, Kuan filter, speckle reducing anisotropic diffusion (SRAD) filter and hybrid filter in the context of digital holography. For the comparison of various speckle reduction techniques, the performance is evaluated quantitatively in terms of all possible parameters that justify the applicability of a scheme for a specific application. The chosen parameters are mean-square-error (MSE), normalized mean-square-error (NMSE), peak signal-to-noise ratio (PSNR), speckle index, average signal-to-noise ratio (SNR), effective number of looks (ENL), correlation parameter (CP), mean structure similarity index map (MSSIM) and execution time in seconds. For experimentation and computer simulation MATLAB 7.0 has been used and the performance is evaluated and tested for various sample holographic images for varying amount of speckle variance. The results obtained justify the applicability of proposed schemes.

  2. Effective viscosity of bacterial suspensions: a three-dimensional PDE model with stochastic torque.

    SciTech Connect

    Haines, B. M.; Aranson, I. S.; Berlyand, L.; Karpeev, D. A.

    2012-01-01

    We present a PDE model for dilute suspensions of swimming bacteria in a three-dimensional Stokesian fluid. This model is used to calculate the statistically-stationary bulk deviatoric stress and effective viscosity of the suspension from the microscopic details of the interaction of an elongated body with the background flow. A bacterium is modeled as an impenetrable prolate spheroid with self-propulsion provided by a point force, which appears in the model as an inhomogeneous delta function in the PDE. The bacterium is also subject to a stochastic torque in order to model tumbling (random reorientation). Due to a bacterium's asymmetric shape, interactions with prescribed generic planar background flows, such as a pure straining or planar shear flow, cause the bacterium to preferentially align in certain directions. Due to the stochastic torque, the steady-state distribution of orientations is unique for a given background flow. Under this distribution of orientations, self-propulsion produces a reduction in the effective viscosity. For sufficiently weak background flows, the effect of self-propulsion on the effective viscosity dominates all other contributions, leading to an effective viscosity of the suspension that is lower than the viscosity of the ambient fluid. This is in qualitative agreement with recent experiments on suspensions of Bacillus subtilis.

  3. Phthalazine PDE IV inhibitors: conformational study of some 6-methoxy-1,4-disubstituted derivatives.

    PubMed

    Haack, Thomas; Fattori, Raimondo; Napoletano, Mauro; Pellacini, Franco; Fronza, Giovanni; Raffaini, Giuseppina; Ganazzoli, Fabio

    2005-07-15

    This report describes the detailed conformational analysis and synthesis of a series of phthalazine phosphodiesterase-type (IV) (PDE IV) inhibitors bearing either mono- or dichloro 4-methylenepyridine at the 'down' position of the phthalazine nucleus or different heterocycles at the 'top' position 4 of the phthalazine moiety. Both the mono- and dichloro 4-methylenepyridine units linked at carbon C1 of the phthalazine nucleus show identical conformational behaviour with the substituent preferentially oriented towards the external part of the molecule and the pyridine plane almost orthogonal to that of phthalazine ring. The heterocyclic five-membered rings linked at carbon C4 of phthalazine show quite different conformational behaviour. The 1,3-thiazole ring exists in a well-defined conformation almost coplanar with respect to the phthalazine nucleus while the 1,2,4-triazole and the 1,3-diazole heterocycles show a great conformational freedom with large torsion angles. Compound 3 bearing the thiazole ring at C4 displays the major biological activity, thus suggesting that a planar and rather rigid conformation of the pentacycle should favour the PDE IV inhibition capacity of this class of compounds.

  4. A Cell-based PDE4 Assay in 1536-well Plate format for High Throughput Screening

    PubMed Central

    Titus, Steven A.; Li, Xiao; Southall, Noel; Lu, Jianming; Inglese, James; Brasch, Michael; Austin, Christopher P.; Zheng, Wei

    2009-01-01

    The cyclic nucleotide phosphodiesterases (PDEs) are intracellular enzymes that catalyze the hydrolysis of 3', 5'-cyclic nucleotides, such as cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), to their corresponding 5'-nucleotide monophosphates. These enzymes play an important role in controlling cellular concentrations of cyclic nucleotides and thus regulate a variety of cellular signaling events. PDEs are emerging as drug targets for several diseases including asthma, cardiovascular disease, ADHD, Parkinson’s disease, and Alzheimer’s disease. Though biochemical assays with purified recombinant PDE enzymes and cAMP or cGMP substrate are commonly used for compound screening, cell-based assays would provide a better assessment of compound activity in a more physiological context. Here we report the development and validation of a new cell-based PDE4 assay using a constitutively active GPCR as a driving force for cAMP production and a cyclic nucleotide gated (CNG) cation channel as a biosensor in 1536-well plates. PMID:18591513

  5. Nonlinear supratransmission

    NASA Astrophysics Data System (ADS)

    Geniet, F.; Leon, J.

    2003-05-01

    A nonlinear system possessing a natural forbidden band gap can transmit energy of a signal with a frequency in the gap, as recently shown for a nonlinear chain of coupled pendulums (Geniet and Leon 2002 Phys. Rev. Lett. 89 134102). This process of nonlinear supratransmission, occurring at a threshold that is exactly predictable in many cases, is shown to have a simple experimental realization with a mechanical chain of pendulums coupled by a coil spring. It is then analysed in more detail. First we go to different (nonintegrable) systems which do sustain nonlinear supratransmission. Then a Josephson transmission line (a one-dimensional array of short Josephson junctions coupled through superconducting wires) is shown to also sustain nonlinear supratransmission, though being related to a different class of boundary conditions, and despite the presence of damping, finiteness, and discreteness. Finally, the mechanism at the origin of nonlinear supratransmission is found to be a nonlinear instability, and this is briefly discussed here.

  6. 3-D zebrafish embryo image filtering by nonlinear partial differential equations.

    PubMed

    Rizzi, Barbara; Campana, Matteo; Zanella, Cecilia; Melani, Camilo; Cunderlik, Robert; Krivá, Zuzana; Bourgine, Paul; Mikula, Karol; Peyriéras, Nadine; Sarti, Alessandro

    2007-01-01

    We discuss application of nonlinear PDE based methods to filtering of 3-D confocal images of embryogenesis. We focus on the mean curvature driven and the regularized Perona-Malik equations, where standard as well as newly suggested edge detectors are used. After presenting the related mathematical models, the practical results are given and discussed by visual inspection and quantitatively using the mean Hausdorff distance.

  7. Montmorillonite K-10 catalyzed green synthesis of 2,6-unsubstituted dihydropyridines as potential inhibitors of PDE4.

    PubMed

    Reddy, T Ram; Reddy, G Rajeshwar; Reddy, L Srinivasula; Meda, Chandana Lakshmi T; Parsa, Kishore V L; Kumar, K Shiva; Lingappa, Y; Pal, Manojit

    2013-04-01

    Montmorillonite K-10 mediated MCR of anilines, arylaldehydes and ethyl-3,3-diethoxypropionate in water afforded 2,6-unsubstituted dihydropyridines depending on the nature of anilines employed. A variety of dihydropyridines were prepared by using this green methodology in good yields and montmorillonite K-10 was found to be an inexpensive and reusable catalyst. The structure elaboration of a representative compound was carried out under Heck conditions. Some of the compounds synthesized showed significant inhibition of PDE4B when tested in vitro. Docking studies indicated that one of the ester moieties of these compounds played a key role in their interactions with the PDE4B protein.

  8. Constrained optimization for image restoration using nonlinear programming

    NASA Technical Reports Server (NTRS)

    Yeh, C.-L.; Chin, R. T.

    1985-01-01

    The constrained optimization problem for image restoration, utilizing incomplete information and partial constraints, is formulated using nonlinear proramming techniques. This method restores a distorted image by optimizing a chosen object function subject to available constraints. The penalty function method of nonlinear programming is used. Both linear or nonlinear object function, and linear or nonlinear constraint functions can be incorporated in the formulation. This formulation provides a generalized approach to solve constrained optimization problems for image restoration. Experiments using this scheme have been performed. The results are compared with those obtained from other restoration methods and the comparative study is presented.

  9. High order ADER schemes for a unified first order hyperbolic formulation of continuum mechanics: Viscous heat-conducting fluids and elastic solids

    SciTech Connect

    Dumbser, Michael; Peshkov, Ilya; Romenski, Evgeniy; Zanotti, Olindo

    2016-06-01

    Highlights: • High order schemes for a unified first order hyperbolic formulation of continuum mechanics. • The mathematical model applies simultaneously to fluid mechanics and solid mechanics. • Viscous fluids are treated in the frame of hyper-elasticity as generalized visco-plastic solids. • Formal asymptotic analysis reveals the connection with the Navier–Stokes equations. • The distortion tensor A in the model appears to be well-suited for flow visualization. - Abstract: This paper is concerned with the numerical solution of the unified first order hyperbolic formulation of continuum mechanics recently proposed by Peshkov and Romenski [110], further denoted as HPR model. In that framework, the viscous stresses are computed from the so-called distortion tensor A, which is one of the primary state variables in the proposed first order system. A very important key feature of the HPR model is its ability to describe at the same time the behavior of inviscid and viscous compressible Newtonian and non-Newtonian fluids with heat conduction, as well as the behavior of elastic and visco-plastic solids. Actually, the model treats viscous and inviscid fluids as generalized visco-plastic solids. This is achieved via a stiff source term that accounts for strain relaxation in the evolution equations of A. Also heat conduction is included via a first order hyperbolic system for the thermal impulse, from which the heat flux is computed. The governing PDE system is hyperbolic and fully consistent with the first and the second principle of thermodynamics. It is also fundamentally different from first order Maxwell–Cattaneo-type relaxation models based on extended irreversible thermodynamics. The HPR model represents therefore a novel and unified description of continuum mechanics, which applies at the same time to fluid mechanics and solid mechanics. In this paper, the direct connection between the HPR model and the classical hyperbolic–parabolic Navier

  10. 1-(2-(2,2,2-trifluoroethoxy)ethyl-1H-pyrazolo[4,3-d]pyrimidines as potent phosphodiesterase 5 (PDE5) inhibitors.

    PubMed

    Tollefson, Michael B; Acker, Brad A; Jacobsen, E J; Hughes, Robert O; Walker, John K; Fox, David N A; Palmer, Michael J; Freeman, Sandra K; Yu, Ying; Bond, Brian R

    2010-05-15

    1H-Pyrazolo[4,3-d]pyrimidines were previously disclosed as a potent second generation class of phosphodiesterase 5 (PDE5) inhibitors. This work explores the advancement of more selective and potent PDE5 inhibitors resulting from the substitution of 2-(2,2,2-trifluoroethoxy)ethyl at the 1 position in the so-called alkoxy pocket.

  11. 1-(2-Ethoxyethyl)-1H-pyrazolo[4,3-d]pyrimidines as potent phosphodiesterase 5 (PDE5) inhibitors.

    PubMed

    Tollefson, Michael B; Acker, Brad A; Jacobsen, E J; Hughes, Robert O; Walker, John K; Fox, David N A; Palmer, Michael J; Freeman, Sandra K; Yu, Ying; Bond, Brian R

    2010-05-15

    1H-Pyrazolo[4,3-d]pyrimidines are a class of potent and selective second generation phosphodiesterase 5 (PDE5) inhibitors. This work explores the potency, selectivity and efficacy of 1-(2-ethoxyethyl)-1H-pyrazolo[4,5-d]pyrimidines as PDE5 inhibitors resulting in the advancement of a clinical candidate.

  12. Identification of a multifunctional docking site on the catalytic unit of phosphodiesterase-4 (PDE4) that is utilised by multiple interaction partners

    PubMed Central

    Houslay, Kirsty F.; Christian, Frank; MacLeod, Ruth; Adams, David R.; Houslay, Miles D.

    2017-01-01

    Cyclic AMP (cAMP)-specific phosphodiesterase-4 (PDE4) enzymes underpin compartmentalised cAMP signalling by localising to distinct signalling complexes. PDE4 long isoforms can be phosphorylated by mitogen-activated protein kinase-activated protein kinase 2 (MK2), which attenuates activation of such enzymes through their phosphorylation by protein kinase A. Here we show that MK2 interacts directly with PDE4 long isoforms and define the sites of interaction. One is a unique site that locates within the regulatory upstream conserved region 1 (UCR1) domain and contains a core Phe141, Leu142 and Tyr143 (FLY) cluster (PDE4A5 numbering). Located with the second site is a critical core Phe693, Glu694, Phe695 (FQF) motif that is also employed in the sequestering of PDE4 long forms by an array of other signalling proteins, including the signalling scaffold β-arrestin, the tyrosyl kinase Lyn, the SUMOylation E2 ligase UBC9, the dynein regulator Lis1 (PAFAH1B1) and the protein kinase Erk. We propose that the FQF motif lies at the heart of a multifunctional docking (MFD) site located within the PDE4 catalytic unit. It is clear from our data that, as well as aiding fidelity of interaction, the MFD site confers exclusivity of binding between PDE4 and a single specific partner protein from the cohort of signalling proteins whose interaction with PDE4 involves the FQF motif. PMID:27993970

  13. Lagrangian averaging, nonlinear waves, and shock regularization

    NASA Astrophysics Data System (ADS)

    Bhat, Harish S.

    In this thesis, we explore various models for the flow of a compressible fluid as well as model equations for shock formation, one of the main features of compressible fluid flows. We begin by reviewing the variational structure of compressible fluid mechanics. We derive the barotropic compressible Euler equations from a variational principle in both material and spatial frames. Writing the resulting equations of motion requires certain Lie-algebraic calculations that we carry out in detail for expository purposes. Next, we extend the derivation of the Lagrangian averaged Euler (LAE-alpha) equations to the case of barotropic compressible flows. The derivation in this thesis involves averaging over a tube of trajectories etaepsilon centered around a given Lagrangian flow eta. With this tube framework, the LAE-alpha equations are derived by following a simple procedure: start with a given action, expand via Taylor series in terms of small-scale fluid fluctuations xi, truncate, average, and then model those terms that are nonlinear functions of xi. We then analyze a one-dimensional subcase of the general models derived above. We prove the existence of a large family of traveling wave solutions. Computing the dispersion relation for this model, we find it is nonlinear, implying that the equation is dispersive. We carry out numerical experiments that show that the model possesses smooth, bounded solutions that display interesting pattern formation. Finally, we examine a Hamiltonian partial differential equation (PDE) that regularizes the inviscid Burgers equation without the addition of standard viscosity. Here alpha is a small parameter that controls a nonlinear smoothing term that we have added to the inviscid Burgers equation. We show the existence of a large family of traveling front solutions. We analyze the initial-value problem and prove well-posedness for a certain class of initial data. We prove that in the zero-alpha limit, without any standard viscosity

  14. Adaptive optimal control of highly dissipative nonlinear spatially distributed processes with neuro-dynamic programming.

    PubMed

    Luo, Biao; Wu, Huai-Ning; Li, Han-Xiong

    2015-04-01

    Highly dissipative nonlinear partial differential equations (PDEs) are widely employed to describe the system dynamics of industrial spatially distributed processes (SDPs). In this paper, we consider the optimal control problem of the general highly dissipative SDPs, and propose an adaptive optimal control approach based on neuro-dynamic programming (NDP). Initially, Karhunen-Loève decomposition is employed to compute empirical eigenfunctions (EEFs) of the SDP based on the method of snapshots. These EEFs together with singular perturbation technique are then used to obtain a finite-dimensional slow subsystem of ordinary differential equations that accurately describes the dominant dynamics of the PDE system. Subsequently, the optimal control problem is reformulated on the basis of the slow subsystem, which is further converted to solve a Hamilton-Jacobi-Bellman (HJB) equation. HJB equation is a nonlinear PDE that has proven to be impossible to solve analytically. Thus, an adaptive optimal control method is developed via NDP that solves the HJB equation online using neural network (NN) for approximating the value function; and an online NN weight tuning law is proposed without requiring an initial stabilizing control policy. Moreover, by involving the NN estimation error, we prove that the original closed-loop PDE system with the adaptive optimal control policy is semiglobally uniformly ultimately bounded. Finally, the developed method is tested on a nonlinear diffusion-convection-reaction process and applied to a temperature cooling fin of high-speed aerospace vehicle, and the achieved results show its effectiveness.

  15. A thermal model for nonlinear panel flutter

    NASA Astrophysics Data System (ADS)

    Gee, David John

    The subject of this research is the nonlinear panel flutter behavior for high Mach number, viscous compressible flow over one side of an isotropic, elastic panel. The fluid/structure interaction is treated as an aerothermoelastic problem in the sense that in addition to aeroelastic coupling, we consider thermal coupling between the fluid and structure. Specifically, at least two distinct heat transfer mechanisms for thermal interaction between the fluid and structure may be important in the panel flutter problem considered here. The primary contribution to thermal stress in the panel is aerodynamic heating. The temperature rise is obtained from a known solution of the compressible Navier-Stokes equations for flow over a flat plate. A secondary source of thermal heating may be due to the panel profile shape and/or any fluttering motion. An unsteady temperature component is obtained by assuming that the unsteady pressure and temperature above the panel are related through an isentropic flow relation. The equation of motion for the panel transverse deflection is based on von Karman large deflection plate theory. The unsteady pressure is computed using aerodynamic piston theory. The PDE is reduced to a system of nonlinear, coupled ordinary differential equations via Galerkin's method and is solved numerically using the 4th-order Runge-Kutta method. However, due to large variation in magnitude of the thermal compressive stress, the stepsize requirement for the numerical integrations is critical and, in fact, limits the usefulness of this procedure. Therefore, bifurcation diagrams are traced out using the pseudo-arclength continuation method (AUTO94). Representative results are given for several combinations of cruise Mach number and altitude. Several stable attractors are found as functions of the in-plane load and dynamic pressure parameters. These two parameters are coupled to the flight conditions and are, therefore, not wholly independent. A direct consequence of

  16. Inhibitory effects of furoquinoline alkaloids from Melicope confusa and Dictamnus albus against human phosphodiesterase 5 (hPDE5A) in vitro.

    PubMed

    Nam, Kung-Woo; Je, Kang-Hoon; Shin, Young-Jun; Kang, Sam Sik; Mar, Woongchon

    2005-06-01

    Eight furoquinoline alkaloids were purified from two plants belonging to the Rutaceae family. Kokusaginine, skimmianine, evolitrine, and confusameline were purified from Melicope confusa, and haplopine, robustine, dictamine, and gamma-fagarine from Dictamnus albus. In this study, the eight furoquinoline alkaloids were examined for inhibitory potency against human phosphodiesterase 5 (hPDE5A) in vitro. DNA encoding the catalytic domain of human PDE5A was amplified from the mRNA of T24 cells by RT-PCR and was fused to GST in an expression vector. GST-tagged PDE5A was then purified by glutathione affinity chromatography and used in inhibition assays. Of the eight alkaloids, gamma-fagarine was the most potent inhibitor of PDE5A, and its single methoxy group at the C-8 position was shown to be critical for inhibitory activity. These results clearly illustrate the relationship between PDE5A inhibition and the methoxy group position in furoquinoline alkaloids.

  17. On the dynamics of approximating schemes for dissipative nonlinear equations

    NASA Technical Reports Server (NTRS)

    Jones, Donald A.

    1993-01-01

    Since one can rarely write down the analytical solutions to nonlinear dissipative partial differential equations (PDE's), it is important to understand whether, and in what sense, the behavior of approximating schemes to these equations reflects the true dynamics of the original equations. Further, because standard error estimates between approximations of the true solutions coming from spectral methods - finite difference or finite element schemes, for example - and the exact solutions grow exponentially in time, this analysis provides little value in understanding the infinite time behavior of a given approximating scheme. The notion of the global attractor has been useful in quantifying the infinite time behavior of dissipative PDEs, such as the Navier-Stokes equations. Loosely speaking, the global attractor is all that remains of a sufficiently large bounded set in phase space mapped infinitely forward in time under the evolution of the PDE. Though the attractor has been shown to have some nice properties - it is compact, connected, and finite dimensional, for example - it is in general quite complicated. Nevertheless, the global attractor gives a way to understand how the infinite time behavior of approximating schemes such as the ones coming from a finite difference, finite element, or spectral method relates to that of the original PDE. Indeed, one can often show that such approximations also have a global attractor. We therefore only need to understand how the structure of the attractor for the PDE behaves under approximation. This is by no means a trivial task. Several interesting results have been obtained in this direction. However, we will not go into the details. We mention here that approximations generally lose information about the system no matter how accurate they are. There are examples that show certain parts of the attractor may be lost by arbitrary small perturbations of the original equations.

  18. Inhibition of PDE5 by sulindac sulfide selectively induces apoptosis and attenuates oncogenic Wnt/β-catenin mediated transcription in human breast tumor cells

    PubMed Central

    Tinsley, Heather N.; Gary, Bernard D.; Keeton, Adam B.; Lu, Wenyan; Li, Yonghe; Piazza, Gary A.

    2011-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) such as sulindac sulfide (SS) display promising antineoplastic properties, but toxicities resulting from cyclooxygenase (COX) inhibition limit their clinical use. While COX inhibition is responsible for the anti-inflammatory activity of SS, recent studies suggest that phosphodiesterase (PDE) 5 inhibition and activation of cGMP signaling are closely associated with its ability to induce apoptosis of tumor cells. However, the underlying mechanisms responsible for apoptosis induction, factors that influence sensitivity of tumor cells to SS, and the importance of PDE5 for breast tumor cell growth have not been established. Here we show that SS can induce apoptosis of breast tumor cells, which predominantly rely on PDE5 for cGMP hydrolysis, but not normal mammary epithelial cells, which rely on PDE isozymes other than PDE5 for cGMP hydrolysis. Inhibition of PDE5 and activation of PKG by SS was associated with increased β-catenin phosphorylation, decreased β-catenin mRNA and protein levels, reduced β-catenin nuclear localization, decreased Tcf/Lef promoter activity, and decreased expression of Wnt/β-catenin regulated proteins. Suppression of PDE5 with siRNA or known PDE5 inhibitors was sufficient to selectively induce apoptosis and attenuate β-catenin mediated transcription in breast tumor cells with minimal effects on normal mammary epithelial cells. These findings provide evidence that SS induces apoptosis of breast tumor cells through a mechanism involving inhibition of PDE5 and attenuation of oncogenic Wnt/β-catenin mediated transcription. We conclude that PDE5 represents a novel molecular target for the discovery of safer and more efficacious drugs for breast cancer chemoprevention. PMID:21505183

  19. Inhibition of PDE5 by sulindac sulfide selectively induces apoptosis and attenuates oncogenic Wnt/β-catenin-mediated transcription in human breast tumor cells.

    PubMed

    Tinsley, Heather N; Gary, Bernard D; Keeton, Adam B; Lu, Wenyan; Li, Yonghe; Piazza, Gary A

    2011-08-01

    Nonsteroidal anti-inflammatory drugs (NSAID) such as sulindac sulfide (SS) display promising antineoplastic properties, but toxicities resulting from COX inhibition limit their clinical use. Although COX inhibition is responsible for the anti-inflammatory activity of SS, recent studies suggest that phosphodiesterase (PDE) 5 inhibition and activation of cyclic guanosine monophosphate (cGMP) signaling are closely associated with its ability to induce apoptosis of tumor cells. However, the underlying mechanisms responsible for apoptosis induction, factors that influence sensitivity of tumor cells to SS, and the importance of PDE5 for breast tumor cell growth have not been established. Here we show that SS can induce apoptosis of breast tumor cells, which predominantly rely on PDE5 for cGMP hydrolysis but not normal mammary epithelial cells, which rely on PDE isozymes other than PDE5 for cGMP hydrolysis. Inhibition of PDE5 and activation of protein kinase G (PKG) by SS was associated with increased β-catenin phosphorylation, decreased β-catenin mRNA and protein levels, reduced β-catenin nuclear localization, decreased T-cell factor/lymphoid enhancer factor (Tcf/Lef) promoter activity, and decreased expression of Wnt/β-catenin-regulated proteins. Suppression of PDE5 with siRNA or known PDE5 inhibitors was sufficient to selectively induce apoptosis and attenuate β-catenin-mediated transcription in breast tumor cells with minimal effects on normal mammary epithelial cells. These findings provide evidence that SS induces apoptosis of breast tumor cells through a mechanism involving inhibition of PDE5 and attenuation of oncogenic Wnt/β-catenin-mediated transcription. We conclude that PDE5 represents a novel molecular target for the discovery of safer and more efficacious drugs for breast cancer chemoprevention.

  20. β-catenin nuclear translocation in colorectal cancer cells is suppressed by PDE10A inhibition, cGMP elevation, and activation of PKG

    PubMed Central

    Lee, Kevin; Lindsey, Ashley S.; Li, Nan; Gary, Bernard; Andrews, Joel; Keeton, Adam B.; Piazza, Gary A.

    2016-01-01

    Phosphodiesterase 10A (PDE10) is a cGMP and cAMP degrading PDE isozyme that is highly expressed in the brain striatum where it appears to play an important role in cognition and psychomotor activity. PDE10 inhibitors are being developed for the treatment of schizophrenia and Huntington's disease and are generally well tolerated, possibly because of low expression levels in most peripheral tissues. We recently reported high levels of PDE10 in colon tumors and that genetic silencing of PDE10 by siRNA or inhibition with small molecule inhibitors can suppress colon tumor cell growth with a high degree of selectivity over normal colonocytes (Li et al., Oncogene 2015). These observations suggest PDE10 may have an unrecognized role in tumorigenesis. Here we report that the concentration range by which the highly specific PDE10 inhibitor, Pf-2545920 (MP-10), inhibits colon tumor cell growth parallels the concentration range required to increase cGMP and cAMP levels, and activates PKG and PKA, respectively. Moreover, PDE10 knockdown by shRNA reduces the sensitivity of colon tumor cells to the growth inhibitory activity of Pf-2545920. Pf-2545920 also inhibits the translocation of β-catenin to the nucleus, thereby reducing β-catenin mediated transcription of survivin, resulting in caspase activation and apoptosis. PDE10 mRNA was also found to be elevated in colon tumors compared with normal tissues. These findings suggest that PDE10 can be targeted for cancer therapy or prevention whereby inhibition results in cGMP elevation and PKG activation to reduce β-catenin-mediated transcription of survival proteins leading to the selective apoptosis of cancer cells. PMID:26713600

  1. β-catenin nuclear translocation in colorectal cancer cells is suppressed by PDE10A inhibition, cGMP elevation, and activation of PKG.

    PubMed

    Lee, Kevin; Lindsey, Ashley S; Li, Nan; Gary, Bernard; Andrews, Joel; Keeton, Adam B; Piazza, Gary A

    2016-02-02

    Phosphodiesterase 10A (PDE10) is a cGMP and cAMP degrading PDE isozyme that is highly expressed in the brain striatum where it appears to play an important role in cognition and psychomotor activity. PDE10 inhibitors are being developed for the treatment of schizophrenia and Huntington's disease and are generally well tolerated, possibly because of low expression levels in most peripheral tissues. We recently reported high levels of PDE10 in colon tumors and that genetic silencing of PDE10 by siRNA or inhibition with small molecule inhibitors can suppress colon tumor cell growth with a high degree of selectivity over normal colonocytes (Li et al., Oncogene 2015). These observations suggest PDE10 may have an unrecognized role in tumorigenesis. Here we report that the concentration range by which the highly specific PDE10 inhibitor, Pf-2545920 (MP-10), inhibits colon tumor cell growth parallels the concentration range required to increase cGMP and cAMP levels, and activates PKG and PKA, respectively. Moreover, PDE10 knockdown by shRNA reduces the sensitivity of colon tumor cells to the growth inhibitory activity of Pf-2545920. Pf-2545920 also inhibits the translocation of β-catenin to the nucleus, thereby reducing β-catenin mediated transcription of survivin, resulting in caspase activation and apoptosis. PDE10 mRNA was also found to be elevated in colon tumors compared with normal tissues. These findings suggest that PDE10 can be targeted for cancer therapy or prevention whereby inhibition results in cGMP elevation and PKG activation to reduce β-catenin-mediated transcription of survival proteins leading to the selective apoptosis of cancer cells.

  2. Characterization of the shape stability for nonlinear elliptic problems

    NASA Astrophysics Data System (ADS)

    Bucur, Dorin

    We characterize all geometric perturbations of an open set, for which the solution of a nonlinear elliptic PDE of p-Laplacian type with Dirichlet boundary condition is stable in the L-norm. The necessary and sufficient conditions are jointly expressed by a geometric property associated to the γ-convergence. If the dimension N of the space satisfies N-1

  3. Use of minipig skin biopsy model as an innovative tool to design topical formulation to achieve desired pharmacokinetics in humans.

    PubMed

    Mitra, Amitava; Leyes, Aquiles; Manser, Kimberly; Roadcap, Brad; Mestre, Christine; Tatosian, Daniel; Jin, Lan; Uemura, Naoto

    2015-05-01

    In vitro cadaver skin permeation studies are often conducted to characterize the permeation profile of compounds for dermal delivery. However, its utility could be limited in the case of topical products because of lack of reliable prediction of in vivo skin kinetics. In this paper, the use of in vivo skin biopsy data to guide topical formulation development is described. A formulation was developed by compounding MK-0873, a phosphodiesterase 4 (PDE4) inhibitor, into a commercially available cream base. The cream was characterized by skin pharmacokinetic studies in minipigs, which demonstrated that MK-0873 concentrations in the epidermis and dermis were substantially higher than the IC80 for human whole blood PDE4 inhibition of ∼200 nM, suggesting that cream should provide sufficient skin exposure to assess clinical efficacy. In toxicological studies, after 1 month repeat application in minipigs minor dermal irritation and minimal systemic exposure were observed. Based on these preclinical data, the cream formulation was chosen for single rising dose clinical studies, where plasma levels of MK-0873 were mostly below the LOQ, whereas skin biopsy concentrations ranged from 6.5 to 25.1 μM. These data suggested that minipig skin biopsy model can be a valuable tool to assess performance of topical formulations and guide formulation development.

  4. Psychiatrists' use of formulation

    PubMed Central

    Hughes, Patricia M.

    2016-01-01

    Both psychologists and psychiatrists are trained to write formulations of their patients' illnesses, with some differences in how they do this. Psychologists focus on psychological understanding, while psychiatrists' formulation brings together aetiology, functioning and a management plan. Mohtashemi et al's study records how some psychiatrists understand formulation and its usefulness. Time pressure was an important barrier to making a full formulation, and some believed the medical role of the psychiatrist was a priority. The study illustrates some of the challenges facing psychiatrists working in the NHS in terms of maintaining high clinical standards and a holistic approach to patient care. PMID:27512593

  5. [Lipid formulations of amphotericin].

    PubMed

    Botero, Martha C; Puentes-Herrera, Marcela; Cortés, Jorge A

    2014-10-01

    Amphotericin B deoxycholate use has increased during the past years in parallel with the increase in the number of immunosuppressed patients suffering invasive fungal infections. This drug is associated with a high rate of side effects, especially renal toxicity. Lipid formulations (liposomal, lipid complex, colloidal suspension and the Indian liposomal formulation) have been developed, which share the same antifungal spectrum but differ in efficacy and toxicity. A review of amphotericin lipid formulations is presented, focusing on differences in efficacy and, especially renal toxicity. The main problem for use of these formulations in Latin America is their highcost.

  6. HEAT.PRO - THERMAL IMBALANCE FORCE SIMULATION AND ANALYSIS USING PDE2D

    NASA Technical Reports Server (NTRS)

    Vigue, Y.

    1994-01-01

    HEAT.PRO calculates the thermal imbalance force resulting from satellite surface heating. The heated body of a satellite re-radiates energy at a rate that is proportional to its temperature, losing the energy in the form of photons. By conservation of momentum, this momentum flux out of the body creates a reaction force against the radiation surface, and the net thermal force can be observed as a small perturbation that affects long term orbital behavior of the satellite. HEAT.PRO calculates this thermal imbalance force and then determines its effects on satellite orbits, especially where the Earth's shadowing of an orbiting satellite causes periodic changes in the spacecraft's thermal environment. HEAT.PRO implements a finite element method routine called PDE2D which incorporates material properties to determine the solar panel surface temperatures. The nodal temperatures are computed at specified time steps and are used to determine the magnitude and direction of the thermal force on the spacecraft. These calculations are based on the solar panel orientation and satellite's position with respect to the earth and sun. It is necessary to have accurate, current knowledge of surface emissivity, thermal conductivity, heat capacity, and material density. These parameters, which may change due to degradation of materials in the environment of space, influence the nodal temperatures that are computed and thus the thermal force calculations. HEAT.PRO was written in FORTRAN 77 for Cray series computers running UNICOS. The source code contains directives for and is used as input to the required partial differential equation solver, PDE2D. HEAT.PRO is available on a 9-track 1600 BPI magnetic tape in UNIX tar format (standard distribution medium) or a .25 inch streaming magnetic tape cartridge in UNIX tar format. An electronic copy of the documentation in Macintosh Microsoft Word format is included on the distribution tape. HEAT.PRO was developed in 1991. Cray and UNICOS are

  7. Solving large-scale PDE-constrained Bayesian inverse problems with Riemann manifold Hamiltonian Monte Carlo

    NASA Astrophysics Data System (ADS)

    Bui-Thanh, T.; Girolami, M.

    2014-11-01

    We consider the Riemann manifold Hamiltonian Monte Carlo (RMHMC) method for solving statistical inverse problems governed by partial differential equations (PDEs). The Bayesian framework is employed to cast the inverse problem into the task of statistical inference whose solution is the posterior distribution in infinite dimensional parameter space conditional upon observation data and Gaussian prior measure. We discretize both the likelihood and the prior using the H1-conforming finite element method together with a matrix transfer technique. The power of the RMHMC method is that it exploits the geometric structure induced by the PDE constraints of the underlying inverse problem. Consequently, each RMHMC posterior sample is almost uncorrelated/independent from the others providing statistically efficient Markov chain simulation. However this statistical efficiency comes at a computational cost. This motivates us to consider computationally more efficient strategies for RMHMC. At the heart of our construction is the fact that for Gaussian error structures the Fisher information matrix coincides with the Gauss-Newton Hessian. We exploit this fact in considering a computationally simplified RMHMC method combining state-of-the-art adjoint techniques and the superiority of the RMHMC method. Specifically, we first form the Gauss-Newton Hessian at the maximum a posteriori point and then use it as a fixed constant metric tensor throughout RMHMC simulation. This eliminates the need for the computationally costly differential geometric Christoffel symbols, which in turn greatly reduces computational effort at a corresponding loss of sampling efficiency. We further reduce the cost of forming the Fisher information matrix by using a low rank approximation via a randomized singular value decomposition technique. This is efficient since a small number of Hessian-vector products are required. The Hessian-vector product in turn requires only two extra PDE solves using the adjoint

  8. HIGH-LEVEL WASTE GLASS FORMULATION MODEL SENSITIVITY STUDY 2009 GLASS FORMULATION MODEL VERSUS 1996 GLASS FORMULATION MODEL

    SciTech Connect

    BELSHER JD; MEINERT FL

    2009-12-07

    This document presents the differences between two HLW glass formulation models (GFM): The 1996 GFM and 2009 GFM. A glass formulation model is a collection of glass property correlations and associated limits, as well as model validity and solubility constraints; it uses the pretreated HLW feed composition to predict the amount and composition of glass forming additives necessary to produce acceptable HLW glass. The 2009 GFM presented in this report was constructed as a nonlinear optimization calculation based on updated glass property data and solubility limits described in PNNL-18501 (2009). Key mission drivers such as the total mass of HLW glass and waste oxide loading are compared between the two glass formulation models. In addition, a sensitivity study was performed within the 2009 GFM to determine the effect of relaxing various constraints on the predicted mass of the HLW glass.

  9. Enabling Predictive Simulation and UQ of Complex Multiphysics PDE Systems by the Development of Goal-Oriented Variational Sensitivity Analysis and A Posteriori Error Estimation Methods

    SciTech Connect

    Ginting, Victor

    2014-03-15

    it was demonstrated that a posteriori analyses in general and in particular one that uses adjoint methods can accurately and efficiently compute numerical error estimates and sensitivity for critical Quantities of Interest (QoIs) that depend on a large number of parameters. Activities include: analysis and implementation of several time integration techniques for solving system of ODEs as typically obtained from spatial discretization of PDE systems; multirate integration methods for ordinary differential equations; formulation and analysis of an iterative multi-discretization Galerkin finite element method for multi-scale reaction-diffusion equations; investigation of an inexpensive postprocessing technique to estimate the error of finite element solution of the second-order quasi-linear elliptic problems measured in some global metrics; investigation of an application of the residual-based a posteriori error estimates to symmetric interior penalty discontinuous Galerkin method for solving a class of second order quasi-linear elliptic problems; a posteriori analysis of explicit time integrations for system of linear ordinary differential equations; derivation of accurate a posteriori goal oriented error estimates for a user-defined quantity of interest for two classes of first and second order IMEX schemes for advection-diffusion-reaction problems; Postprocessing finite element solution; and A Bayesian Framework for Uncertain Quantification of Porous Media Flows.

  10. PDE6δ-mediated sorting of INPP5E into the cilium is determined by cargo-carrier affinity.

    PubMed

    Fansa, Eyad Kalawy; Kösling, Stefanie Kristine; Zent, Eldar; Wittinghofer, Alfred; Ismail, Shehab

    2016-04-11

    The phosphodiesterase 6 delta subunit (PDE6δ) shuttles several farnesylated cargos between membranes. The cargo sorting mechanism between cilia and other compartments is not understood. Here we show using the inositol polyphosphate 5'-phosphatase E (INPP5E) and the GTP-binding protein (Rheb) that cargo sorting depends on the affinity towards PDE6δ and the specificity of cargo release. High-affinity cargo is exclusively released by the ciliary transport regulator Arl3, while low-affinity cargo is released by Arl3 and its non-ciliary homologue Arl2. Structures of PDE6δ/cargo complexes reveal the molecular basis of the sorting signal which depends on the residues at the -1 and -3 positions relative to farnesylated cysteine. Structure-guided mutation allows the generation of a low-affinity INPP5E mutant which loses exclusive ciliary localization. We postulate that the affinity to PDE6δ and the release by Arl2/3 in addition to a retention signal are the determinants for cargo sorting and enrichment at its destination.

  11. Noninvasive aortic bloodflow by Pulsed Doppler Echocardiography (PDE) compared to cardiac output by the direct Fick procedure

    NASA Technical Reports Server (NTRS)

    1980-01-01

    Left ventricular stroke volume was estimated from the systolic velocity integral in the ascending aorta by pulsed Doppler Echocardiography (PDE) and the cross sectional area of the aorta estimated by M mode echocardiography on 15 patients with coronary disease undergoing right catheterization for diagnostic purposes. Cardiac output was calculated from stroke volume and heart volume using the PDE method as well as the Fick procedure for comparison. The mean value for the cardiac output via the PDE method (4.42 L/min) was only 6% lower than for the cardiac output obtained from the Fick procedure (4.69 L/min) and the correlation between the two methods was excellent (r=0.967, p less than .01). The good agreement between the two methods demonstrates that the PDE technique offers a reliable noninvasive alternative for estimating cardiac output, requiring no active cooperation by the subject. It was concluded that the Doppler method is superior to the Fick method in that it provides beat by beat information on cardiac performance.

  12. Pulmonary hemodynamic responses to inhaled NO in chronic heart failure depend on PDE5 G(-1142)T polymorphism.

    PubMed

    Damy, Thibaud; Lesault, Pierre-François; Guendouz, Soulef; Eddahibi, Saadia; Tu, Ly; Marcos, Elisabeth; Guellich, Aziz; Dubois-Randé, Jean-Luc; Teiger, Emmanuel; Hittinger, Luc; Adnot, Serge

    2011-01-01

    To evaluate the vasoconstrictor component of PH in CHF by investigating the hemodynamic response to inhaled nitric oxide (iNO) and to determine whether this response was influenced by the phosphodiesterase 5 gene (PDE5) G(1142)T polymorphism. CHF patients underwent right heart catheterization at rest and after 20 ppm of iNO and plasma cGMP and PDE5 G(1142)T polymorphism determinations. Of the 72 included CHF patients (mean age, 53±1 years; mean left ventricular ejection fraction, 29±1%; and mean pulmonary artery pressure, 25.5±1.3 mmHg), 54% had ischemic heart disease. Proportions of patients with the TT, GT, and GG genotypes were 39%, 42% and 19% respectively. Baseline hemodynamic characteristics were not significantly different across PDE5 genotype groups, although pulmonary capillary wedge pressure (PCWP) tended to be lower in the TT group (P=0.09). Baseline plasma cGMP levels were significantly lower in the TT than in the GG and GT patients. With iNO, PVR diminished in TT (-33%) but not GG (-1.6%) or GT (0%) patients (P=0.002); and PCWP increased more in TT than in GT (P<0.05) or GG (P<0.003) patients. The PDE5 G(-1142) polymorphism is therefore a major contributor to the iNO-induced PVR decrease in CHF.

  13. Phthalazine PDE4 inhibitors. Part 3: the synthesis and in vitro evaluation of derivatives with a hydrogen bond acceptor.

    PubMed

    Napoletano, Mauro; Norcini, Gabriele; Pellacini, Franco; Marchini, Francesco; Morazzoni, Gabriele; Fattori, Raimondo; Ferlenga, Pierpaolo; Pradella, Lorenzo

    2002-01-07

    This communication describes the synthesis and in vitro evaluation of a novel and potent series of phthalazine phosphodiesterase type (IV) (PDE4) inhibitors. The interaction with two distinct polar binding sites allowed us to eliminate the cyclopentyloxy substitution from rolipram-like analogues.

  14. Phthalazine PDE4 inhibitors. Part 2: the synthesis and biological evaluation of 6-methoxy-1,4-disubstituted derivatives.

    PubMed

    Napoletano, M; Norcini, G; Pellacini, F; Marchini, F; Morazzoni, G; Ferlenga, P; Pradella, L

    2001-01-08

    This communication describes the synthesis and in vitro evaluation of a novel and potent series of phosphodiesterase type IV (PDE4) inhibitors. The compounds described present substituents in position 4 of the phthalazine ring to replace the commonly observed cyclopentyloxy moiety of rolipram analogues. Preliminary evidences of reduced side effects compared to standards and improved pharmacokinetic properties for selected derivatives are also reported.

  15. Spectroscopic Observation of Comet P/de Vico: Comparison with P/Halley and P/Brorsen-Metcalf

    NASA Astrophysics Data System (ADS)

    Kawakita, Hideyo; Ayani, Kazuya; Matsubara, Keiji

    1998-06-01

    A spectroscopic observation of Comet P/de Vico in the visible region was made at Bisei Astronomical Observatory on 1995 October 11. The obtained spectrum covers the wavelengths from 5200 to 7200 Angstroms, and includes several emissions, such as C_2, NH_2, and [O I]. The ratios of the gas-production rates of C_2 and NH_2 relative to that of H_2O, Q(C_2)/Q(H_2O), and Q(NH_2)/Q(H_2O), were determined from our observation based on the Haser model. The production-rate ratio and gas-to-dust ratio were: Q(C_2)/Q(H_2O) = 0.25%, Q(NH_2)/Q(H_2O) = 0.14%, and log_ {10}[ Q(H_2O)/Af rho ] = 26.9 at the time of observation. Comet P/de Vico was similar to P/Halley from the viewpoint of the chemical composition (C_2 and NH_2 relative to the H_2O), and P/de Vico was comparable to P/Brorsen-Metcalf concerning the gas-to-dust ratio. P/de Vico was one of the most gas-rich comets ever known.

  16. Design, synthesis and biological evaluation of 2,4-disubstituted oxazole derivatives as potential PDE4 inhibitors.

    PubMed

    Li, Ya-Sheng; Hu, De-Kun; Zhao, Dong-Sheng; Liu, Xing-Yu; Jin, Hong-Wei; Song, Gao-Peng; Cui, Zi-Ning; Zhang, Lian-Hui

    2017-03-15

    In this study, a series of pyrazole derivatives containing 4-phenyl-2-oxazole moiety were designed and synthesized in a concise way, some of which exhibited considerable inhibitory activity against PDE4B and blockade of LPS-induced TNF-α release. Compound 4c displayed the strongest inhibition activity (IC50=1.6±0.4μM) and good selectivity against PDE4B. Meanwhile, compound 4c showed good in vivo activity in animal models of asthma/COPD and sepsis induced by LPS. The primary structure-activity relationship study showed the 3,5-dimethylpyrazole residue was essential for the bioactivity, and the substituted group R1 at the benzene ring also affected the activity. Docking results showed that compound 4c played a key role to form integral hydrogen bonds and a π-π stacking interaction, using hydrazide scaffold (CONN) and pyrazole ring respectively, with PDE4B protein. While the rest part of the molecule extended into the catalytic domain to block the access of cAMP and formed the foundation for inhibition of PDE4B. Compound 4c would be great promise as a lead compound for further study based on the preliminary structure-activity relationship and molecular modeling studies.

  17. White to beige conversion in PDE3B KO adipose tissue through activation of AMPK signaling and mitochondrial function

    PubMed Central

    Chung, Youn Wook; Ahmad, Faiyaz; Tang, Yan; Hockman, Steven C.; Kee, Hyun Jung; Berger, Karin; Guirguis, Emilia; Choi, Young Hun; Schimel, Dan M.; Aponte, Angel M.; Park, Sunhee; Degerman, Eva; Manganiello, Vincent C.

    2017-01-01

    Understanding mechanisms by which a population of beige adipocytes is increased in white adipose tissue (WAT) reflects a potential strategy in the fight against obesity and diabetes. Cyclic adenosine monophosphate (cAMP) is very important in the development of the beige phenotype and activation of its thermogenic program. To study effects of cyclic nucleotides on energy homeostatic mechanisms, mice were generated by targeted inactivation of cyclic nucleotide phosphodiesterase 3b (Pde3b) gene, which encodes PDE3B, an enzyme that catalyzes hydrolysis of cAMP and cGMP and is highly expressed in tissues that regulate energy homeostasis, including adipose tissue, liver, and pancreas. In epididymal white adipose tissue (eWAT) of PDE3B KO mice on a SvJ129 background, cAMP/protein kinase A (PKA) and AMP-activated protein kinase (AMPK) signaling pathways are activated, resulting in “browning” phenotype, with a smaller increases in body weight under high-fat diet, smaller fat deposits, increased β-oxidation of fatty acids (FAO) and oxygen consumption. Results reported here suggest that PDE3B and/or its downstream signaling partners might be important regulators of energy metabolism in adipose tissue, and potential therapeutic targets for treating obesity, diabetes and their associated metabolic disorders. PMID:28084425

  18. PREFACE Integrability and nonlinear phenomena Integrability and nonlinear phenomena

    NASA Astrophysics Data System (ADS)

    Gómez-Ullate, David; Lombardo, Sara; Mañas, Manuel; Mazzocco, Marta; Nijhoff, Frank; Sommacal, Matteo

    2010-10-01

    according to the standards of the journal. The selection of papers in this issue aims to bring together recent developments and findings, even though it consists of only a fraction of the impressive developments in recent years which have affected a broad range of fields, including the theory of special functions, quantum integrable systems, numerical analysis, cellular automata, representations of quantum groups, symmetries of difference equations, discrete geometry, among others. The special issue begins with four review papers: Integrable models in nonlinear optics and soliton solutions Degasperis [1] reviews integrable models in nonlinear optics. He presents a number of approximate models which are integrable and illustrates the links between the mathematical and applicative aspects of the theory of integrable dynamical systems. In particular he discusses the recent impact of boomeronic-type wave equations on applications arising in the context of the resonant interaction of three waves. Hamiltonian PDEs: deformations, integrability, solutions Dubrovin [2] presents classification results for systems of nonlinear Hamiltonian partial differential equations (PDEs) in one spatial dimension. In particular he uses a perturbative approach to the theory of integrability of these systems and discusses their solutions. He conjectures universality of the critical behaviour for the solutions, where the notion of universality refers to asymptotic independence of the structure of solutions (at the point of gradient catastrophe) from the choice of generic initial data as well as from the choice of a generic PDE. KP solitons in shallow water Kodama [3] presents a survey of recent studies on soliton solutions of the Kadomtsev-Petviashvili (KP) equation. A large variety of exact soliton solutions of the KP equation are presented and classified. The study includes numerical analysis of the stability of the found solution as well as numerical simulations of the initial value problems which

  19. Electronic speckle pattern interferometry for fracture expansion in nuclear graphite based on PDE image processing methods

    NASA Astrophysics Data System (ADS)

    Tang, Chen; Zhang, Junjiang; Sun, Chen; Su, Yonggang; Su, Kai Leung

    2015-05-01

    Nuclear graphite has been widely used as moderating and reflecting materials. However, due to severe neutron irradiation under high temperature, nuclear graphite is prone to deteriorate, resulting in massive microscopic flaws and even cracks under large stress in the later period of its service life. It is indispensable, therefore, to understand the fracture behavior of nuclear graphite to provide reference to structural integrity and safety analysis of nuclear graphite members in reactors. In this paper, we investigated the fracture expansion in nuclear graphite based on PDE image processing methods. We used the second-order oriented partial differential equations filtering model (SOOPDE) to denoise speckle noise, then used the oriented gradient vector fields for to obtain skeletons. The full-field displacement of fractured nuclear graphite and the location of the crack tip were lastly measured under various loading conditions.

  20. A curvature filter and PDE based non-uniformity correction algorithm

    NASA Astrophysics Data System (ADS)

    Cheng, Kuanhong; Zhou, Huixin; Qin, Hanlin; Zhao, Dong; Qian, Kun; Rong, Shenghui; Yin, Shimin

    2016-10-01

    In this paper, a curvature filter and PDE based non-uniformity correction algorithm is proposed, the key point of this algorithm is the way to estimate FPN. We use anisotropic diffusion to smooth noise and Gaussian curvature filter to extract the details of original image. Then combine these two parts together by guided image filter and subtract the result from original image to get the crude approximation of FPN. After that, a Temporal Low Pass Filter (TLPF) is utilized to filter out random noise and get the accurate FPN. Finally, subtract the FPN from original image to achieve non-uniformity correction. The performance of this algorithm is tested with two infrared image sequences, and the experimental results show that the proposed method achieves a better non-uniformity correction performance.

  1. Experimental confirmation of a PDE-based approach to design of feedback controls

    NASA Technical Reports Server (NTRS)

    Banks, H. T.; Smith, Ralph C.; Brown, D. E.; Silcox, R. J.; Metcalf, Vern L.

    1995-01-01

    Issues regarding the experimental implementation of partial differential equation based controllers are discussed in this work. While the motivating application involves the reduction of vibration levels for a circular plate through excitation of surface-mounted piezoceramic patches, the general techniques described here will extend to a variety of applications. The initial step is the development of a PDE model which accurately captures the physics of the underlying process. This model is then discretized to yield a vector-valued initial value problem. Optimal control theory is used to determine continuous-time voltages to the patches, and the approximations needed to facilitate discrete time implementation are addressed. Finally, experimental results demonstrating the control of both transient and steady state vibrations through these techniques are presented.

  2. Muscle MRS detects elevated PDE/ATP ratios prior to fatty infiltration in Becker muscular dystrophy.

    PubMed

    Wokke, B H; Hooijmans, M T; van den Bergen, J C; Webb, A G; Verschuuren, J J; Kan, H E

    2014-11-01

    Becker muscular dystrophy (BMD) is characterized by progressive muscle weakness. Muscles show structural changes (fatty infiltration, fibrosis) and metabolic changes, both of which can be assessed using MRI and MRS. It is unknown at what stage of the disease process metabolic changes arise and how this might vary for different metabolites. In this study we assessed metabolic changes in skeletal muscles of Becker patients, both with and without fatty infiltration, quantified via Dixon MRI and (31) P MRS. MRI and (31) P MRS scans were obtained from 25 Becker patients and 14 healthy controls using a 7 T MR scanner. Five lower-leg muscles were individually assessed for fat and muscle metabolite levels. In the peroneus, soleus and anterior tibialis muscles with non-increased fat levels, PDE/ATP ratios were higher (P < 0.02) compared with controls, whereas in all muscles with increased fat levels PDE/ATP ratios were higher compared with healthy controls (P ≤ 0.05). The Pi /ATP ratio in the peroneus muscles was higher in muscles with increased fat fractions (P = 0.005), and the PCr/ATP ratio was lower in the anterior tibialis muscles with increased fat fractions (P = 0.005). There were no other significant changes in metabolites, but an increase in tissue pH was found in all muscles of the total group of BMD patients in comparison with healthy controls (P < 0.05). These findings suggest that (31) P MRS can be used to detect early changes in individual muscles of BMD patients, which are present before the onset of fatty infiltration.

  3. Molecular inotropy mediated by cardiac miR-based PDE4D/PRKAR1α/phosphoprotein signaling

    PubMed Central

    Bedada, Fikru B.; Martindale, Joshua J.; Arden, Erik; Metzger, Joseph M.

    2016-01-01

    Molecular inotropy refers to cardiac contractility that can be modified to affect overall heart pump performance. Here we show evidence of a new molecular pathway for positive inotropy by a cardiac-restricted microRNA (miR). We report enhanced cardiac myocyte performance by acute titration of cardiac myosin-embedded miR-208a. The observed positive effect was independent of host gene myosin effects with evidence of negative regulation of cAMP-specific 3′,5′-cyclic phosphodiesterase 4D (PDE4D) and the regulatory subunit of PKA (PRKAR1α) content culminating in PKA-site dependent phosphorylation of cardiac troponin I (cTnI) and phospholamban (PLN). Further, acute inhibition of miR-208a in adult myocytes in vitro increased PDE4D expression causing reduced isoproterenol-mediated phosphorylation of cTnI and PLN. Next, rAAV-mediated miR-208a gene delivery enhanced heart contractility and relaxation parameters in vivo. Finally, acute inducible increases in cardiac miR-208a in vivo reduced PDE4D and PRKAR1α, with evidence of increased content of several complementary miRs harboring the PDE4D recognition sequence. Physiologically, this resulted in significant cardiac cTnI and PLN phosphorylation and improved heart performance in vivo. As phosphorylation of cTnI and PLN is critical to myocyte function, titration of miR-208a represents a potential new mechanism to enhance myocardial performance via the PDE4D/PRKAR1α/PKA phosphoprotein signaling pathway. PMID:27833092

  4. Solution of the scalar wave equation over very long distances using nonlinear solitary waves: Relation to finite difference methods

    NASA Astrophysics Data System (ADS)

    Steinhoff, John; Chitta, Subhashini

    2012-08-01

    The linear wave equation represents the basis of many linear electromagnetic and acoustic propagation problems. Features that a computational model must have, to capture large scale realistic effects (for over the horizon or "OTH" radar communication, for example), include propagation of short waves with scattering and partial absorption by complex topography. For these reasons, it is not feasible to use Green's Function or any simple integral method, which neglects these intermediate effects and requires a known propagation function between source and observer. In this paper, we describe a new method for propagating such short waves over long distances, including intersecting scattered waves. The new method appears to be much simpler than conventional high frequency schemes: Lagrangian "particle" based approaches, such as "ray tracing" become very complex in 3-D, especially for waves that may be expanding, or even intersecting. The other high frequency scheme in common use, the Eikonal, also has difficulty with intersecting waves. Our approach, based on nonlinear solitary waves concentrated about centroid surfaces of physical wave features, is related to that of Whitham [1], which involves solving wave fronts propagating on characteristics. Then, the evolving electromagnetic (or acoustic) field can be approximated as a collection of propagating co-dimension one surfaces (for example, 2-D surfaces in three dimensions). This approach involves solving propagation equations discretely on an Eulerian grid to approximate the linear wave equation. However, to propagate short waves over long distances, conventional Eulerian numerical methods, which attempt to resolve the structure of each wave, require far too many grid cells and are not feasible on current or foreseeable computers. Instead, we employ an "extended" wave equation that captures the important features of the propagating waves. This method is first formulated at the partial differential equation (PDE) level

  5. A Nonlinear Physics-Based Optimal Control Method for Magnetostrictive Actuators

    NASA Technical Reports Server (NTRS)

    Smith, Ralph C.

    1998-01-01

    This paper addresses the development of a nonlinear optimal control methodology for magnetostrictive actuators. At moderate to high drive levels, the output from these actuators is highly nonlinear and contains significant magnetic and magnetomechanical hysteresis. These dynamics must be accommodated by models and control laws to utilize the full capabilities of the actuators. A characterization based upon ferromagnetic mean field theory provides a model which accurately quantifies both transient and steady state actuator dynamics under a variety of operating conditions. The control method consists of a linear perturbation feedback law used in combination with an optimal open loop nonlinear control. The nonlinear control incorporates the hysteresis and nonlinearities inherent to the transducer and can be computed offline. The feedback control is constructed through linearization of the perturbed system about the optimal system and is efficient for online implementation. As demonstrated through numerical examples, the combined hybrid control is robust and can be readily implemented in linear PDE-based structural models.

  6. Design, optimization, and biological evaluation of novel keto-benzimidazoles as potent and selective inhibitors of phosphodiesterase 10A (PDE10A).

    PubMed

    Hu, Essa; Kunz, Roxanne K; Chen, Ning; Rumfelt, Shannon; Siegmund, Aaron; Andrews, Kristin; Chmait, Samer; Zhao, Sharon; Davis, Carl; Chen, Hang; Lester-Zeiner, Dianna; Ma, Ji; Biorn, Christopher; Shi, Jianxia; Porter, Amy; Treanor, James; Allen, Jennifer R

    2013-11-14

    Our development of PDE10A inhibitors began with an HTS screening hit (1) that exhibited both high p-glycoprotein (P-gp) efflux ratios in rat and human and poor metabolic stability. On the basis of cocrystal structure of 1 in human PDE10A enzyme, we designed a novel keto-benzimidazole 26 with comparable PDE10A potency devoid of efflux liabilities. On target in vivo coverage of PDE10A in rat brain was assessed using our previously reported LC-MS/MS receptor occupancy (RO) technology. Compound 26 achieved 55% RO of PDE10A at 30 mg/kg po and covered PDE10A receptors in rat brain in a dose-dependent manner. Cocrystal structure of 26 in PDE10A confirmed the binding mode of the novel scaffold. Further optimization resulted in the identification of keto-benzimidazole 34, which showed an increased in vivo efficacy of 57% RO in rats at 10 mg/kg po and an improved in vivo rat clearance and oral bioavailability.

  7. Suppression of β-catenin/TCF transcriptional activity and colon tumor cell growth by dual inhibition of PDE5 and 10.

    PubMed

    Li, Nan; Chen, Xi; Zhu, Bing; Ramírez-Alcántara, Verónica; Canzoneri, Joshua C; Lee, Kevin; Sigler, Sara; Gary, Bernard; Li, Yonghe; Zhang, Wei; Moyer, Mary P; Salter, E Alan; Wierzbicki, Andrzej; Keeton, Adam B; Piazza, Gary A

    2015-09-29

    Previous studies suggest the anti-inflammatory drug, sulindac inhibits tumorigenesis by a COX independent mechanism involving cGMP PDE inhibition. Here we report that the cGMP PDE isozymes, PDE5 and 10, are elevated in colon tumor cells compared with normal colonocytes, and that inhibitors and siRNAs can selectively suppress colon tumor cell growth. Combined treatment with inhibitors or dual knockdown suppresses tumor cell growth to a greater extent than inhibition from either isozyme alone. A novel sulindac derivative, ADT-094 was designed to lack COX-1/-2 inhibitory activity but have improved potency to inhibit PDE5 and 10. ADT-094 displayed >500 fold higher potency to inhibit colon tumor cell growth compared with sulindac by activating cGMP/PKG signaling to suppress proliferation and induce apoptosis. Combined inhibition of PDE5 and 10 by treatment with ADT-094, PDE isozyme-selective inhibitors, or by siRNA knockdown also suppresses β-catenin, TCF transcriptional activity, and the levels of downstream targets, cyclin D1 and survivin. These results suggest that dual inhibition of PDE5 and 10 represents novel strategy for developing potent and selective anticancer drugs.

  8. Suppression of β-catenin/TCF transcriptional activity and colon tumor cell growth by dual inhibition of PDE5 and 10

    PubMed Central

    Li, Nan; Chen, Xi; Zhu, Bing; Ramírez-Alcántara, Verónica; Canzoneri, Joshua C.; Lee, Kevin; Sigler, Sara; Gary, Bernard; Li, Yonghe; Zhang, Wei; Moyer, Mary P.; Salter, E. Alan; Wierzbicki, Andrzej; Keeton, Adam B.; Piazza, Gary A.

    2015-01-01

    Previous studies suggest the anti-inflammatory drug, sulindac inhibits tumorigenesis by a COX independent mechanism involving cGMP PDE inhibition. Here we report that the cGMP PDE isozymes, PDE5 and 10, are elevated in colon tumor cells compared with normal colonocytes, and that inhibitors and siRNAs can selectively suppress colon tumor cell growth. Combined treatment with inhibitors or dual knockdown suppresses tumor cell growth to a greater extent than inhibition from either isozyme alone. A novel sulindac derivative, ADT-094 was designed to lack COX-1/-2 inhibitory activity but have improved potency to inhibit PDE5 and 10. ADT-094 displayed >500 fold higher potency to inhibit colon tumor cell growth compared with sulindac by activating cGMP/PKG signaling to suppress proliferation and induce apoptosis. Combined inhibition of PDE5 and 10 by treatment with ADT-094, PDE isozyme-selective inhibitors, or by siRNA knockdown also suppresses β-catenin, TCF transcriptional activity, and the levels of downstream targets, cyclin D1 and survivin. These results suggest that dual inhibition of PDE5 and 10 represents novel strategy for developing potent and selective anticancer drugs. PMID:26299804

  9. Reactive decontamination formulation

    DOEpatents

    Giletto, Anthony; White, William; Cisar, Alan J.; Hitchens, G. Duncan; Fyffe, James

    2003-05-27

    The present invention provides a universal decontamination formulation and method for detoxifying chemical warfare agents (CWA's) and biological warfare agents (BWA's) without producing any toxic by-products, as well as, decontaminating surfaces that have come into contact with these agents. The formulation includes a sorbent material or gel, a peroxide source, a peroxide activator, and a compound containing a mixture of KHSO.sub.5, KHSO.sub.4 and K.sub.2 SO.sub.4. The formulation is self-decontaminating and once dried can easily be wiped from the surface being decontaminated. A method for decontaminating a surface exposed to chemical or biological agents is also disclosed.

  10. Formulation techniques for nanofluids.

    PubMed

    Rivera-Solorio, Carlos I; Payán-Rodríguez, Luis A; García-Cuéllar, Alejandro J; Ramón-Raygoza, E D; L Cadena-de-la-Peña, Natalia; Medina-Carreón, David

    2013-11-01

    Fluids with suspended nanoparticles, commonly known as nanofluids, may be formulated to improve the thermal performance of industrial heat transfer systems and applications. Nanofluids may show enhanced thermal and electrical properties such as thermal conductivity, viscosity, heat transfer coefficient, dielectric strength, etc. However, stability problems may arise as nanoparticles usually have the tendency to agglomerate and sediment producing deterioration in the increment of these properties. In this review, we discuss patents that report advances in the formulation of nanofluids including: production methods, selection of components (nanoparticles, base fluid and surfactants), their chemical compositions and morphologies, and characterization techniques. Finally, current and future directions in the development of nanofluid formulation are discussed.

  11. Ferulic acid prevents LPS-induced up-regulation of PDE4B and stimulates the cAMP/CREB signaling pathway in PC12 cells

    PubMed Central

    Huang, Hao; Hong, Qian; Tan, Hong-ling; Xiao, Cheng-rong; Gao, Yue

    2016-01-01

    Aim: Phosphodiesterase 4 (PDE4) isozymes are involved in different functions, depending on their patterns of distribution in the brain. The PDE4 subtypes are distributed in different inflammatory cells, and appear to be important regulators of inflammatory processes. In this study we examined the effects of ferulic acid (FA), a plant component with strong anti-oxidant and anti-inflammatory activities, on lipopolysaccharide (LPS)-induced up-regulation of phosphodiesterase 4B (PDE4B) in PC12 cells, which in turn regulated cellular cAMP levels and the cAMP/cAMP response element binding protein (CREB) pathway in the cells. Methods: PC12 cells were treated with LPS (1 μg/mL) for 8 h, and the changes of F-actin were detected using laser scanning confocal microscopy. The levels of pro-inflammatory cytokines were measured suing ELISA kits, and PDE4B-specific enzymatic activity was assessed with a PDE4B assay kit. The mRNA levels of PDE4B were analyzed with Q-PCR, and the protein levels of CREB and phosphorylated CREB (pCREB) were determined using immunoblotting. Furthermore, molecular docking was used to identify the interaction between PDE4B2 and FA. Results: Treatment of PC12 cells with LPS induced thick bundles of actin filaments appearing in the F-actin cytoskeleton, which were ameliorated by pretreatment with FA (10–40 μmol/L) or with a PDE4B inhibitor rolipram (30 μmol/L). Pretreatment with FA dose-dependently inhibited the LPS-induced production of TNF-α and IL-1β in PC12 cells. Furthermore, pretreatment with FA dose-dependently attenuated the LPS-induced up-regulation of PDE4 activity in PC12 cells. Moreover, pretreatment with FA decreased LPS-induced up-regulation of the PDE4B mRNA, and reversed LPS-induced down-regulation of CREB and pCREB in PC12 cells. The molecular docking results revealed electrostatic and hydrophobic interactions between FA and PDE4B2. Conclusion: The beneficial effects of FA in PC12 cells might be conferred through inhibition of LPS

  12. Short-term or long-term treatments with a phosphodiesterase-4 (PDE4) inhibitor result in opposing agonist-induced Ca2+ responses in endothelial cells

    PubMed Central

    Campos-Toimil, M; Keravis, T; Orallo, F; Takeda, K; Lugnier, C

    2008-01-01

    Background and purpose: We previously reported that agonist-induced rises in cytoplasmic Ca2+ concentration ([Ca2+]i) in human umbilical vein endothelial cells (HUVEC) were inhibited after a short-term (2 min) pre-treatment with cAMP-elevating agents. The aim of this work was to study the effects of longer term (8 h) pre-treatment with dibutyryl-cAMP (db-cAMP) or rolipram, a specific inhibitor of phosphodiesterase-4 (PDE4), on [Ca2+]i, cAMP levels and PDE activity and expression in HUVEC. Experimental approach: [Ca2+]i changes were measured in isolated HUVEC by Fura-2 imaging. Intracellular cAMP levels and PDE4 activity were assessed by enzyme-immunoassay and radio-enzymatic assay, respectively. PDE expression was measured by northern and western blot analysis. Key results: Long-term pre-treatment of HUVEC with rolipram or db-cAMP significantly increased ATP-, histamine- and thrombin-induced [Ca2+]i rises. Short-term pre-treatment with rolipram was associated with an increase in cAMP, whereas long-term pre-treatment was associated with a decrease in cAMP. Long-term pre-treatment with rolipram or db-cAMP induced a significant increase in PDE4 activity and the expression of 74 kDa-PDE4A and 73 kDa-PDE4B was specifically enhanced. All these effects were suppressed by cycloheximide. Conclusions and implications: Our data suggest that sustained inhibition of PDE4 by rolipram induced an increase in PDE4 activity, possibly as a compensatory mechanism to accelerate cAMP degradation and that PDE4A and PDE4B were implicated in the regulation of [Ca2+]i. Thus, isozyme-specific PDE4 inhibitors might be useful as therapeutic agents in diseases where [Ca2+]i handling is altered, such as atherosclerosis, hypertension and tolerance to β-adrenoceptor agonists. PMID:18311187

  13. Inversion of geothermal heat flux in a thermomechanically coupled nonlinear Stokes ice sheet model

    NASA Astrophysics Data System (ADS)

    Zhu, Hongyu; Petra, Noemi; Stadler, Georg; Isaac, Tobin; Hughes, Thomas J. R.; Ghattas, Omar

    2016-07-01

    We address the inverse problem of inferring the basal geothermal heat flux from surface velocity observations using a steady-state thermomechanically coupled nonlinear Stokes ice flow model. This is a challenging inverse problem since the map from basal heat flux to surface velocity observables is indirect: the heat flux is a boundary condition for the thermal advection-diffusion equation, which couples to the nonlinear Stokes ice flow equations; together they determine the surface ice flow velocity. This multiphysics inverse problem is formulated as a nonlinear least-squares optimization problem with a cost functional that includes the data misfit between surface velocity observations and model predictions. A Tikhonov regularization term is added to render the problem well posed. We derive adjoint-based gradient and Hessian expressions for the resulting partial differential equation (PDE)-constrained optimization problem and propose an inexact Newton method for its solution. As a consequence of the Petrov-Galerkin discretization of the energy equation, we show that discretization and differentiation do not commute; that is, the order in which we discretize the cost functional and differentiate it affects the correctness of the gradient. Using two- and three-dimensional model problems, we study the prospects for and limitations of the inference of the geothermal heat flux field from surface velocity observations. The results show that the reconstruction improves as the noise level in the observations decreases and that short-wavelength variations in the geothermal heat flux are difficult to recover. We analyze the ill-posedness of the inverse problem as a function of the number of observations by examining the spectrum of the Hessian of the cost functional. Motivated by the popularity of operator-split or staggered solvers for forward multiphysics problems - i.e., those that drop two-way coupling terms to yield a one-way coupled forward Jacobian - we study the

  14. Finite-dimensional constrained fuzzy control for a class of nonlinear distributed process systems.

    PubMed

    Wu, Huai-Ning; Li, Han-Xiong

    2007-10-01

    This correspondence studies the problem of finite-dimensional constrained fuzzy control for a class of systems described by nonlinear parabolic partial differential equations (PDEs). Initially, Galerkin's method is applied to the PDE system to derive a nonlinear ordinary differential equation (ODE) system that accurately describes the dynamics of the dominant (slow) modes of the PDE system. Subsequently, a systematic modeling procedure is given to construct exactly a Takagi-Sugeno (T-S) fuzzy model for the finite-dimensional ODE system under state constraints. Then, based on the T-S fuzzy model, a sufficient condition for the existence of a stabilizing fuzzy controller is derived, which guarantees that the state constraints are satisfied and provides an upper bound on the quadratic performance function for the finite-dimensional slow system. The resulting fuzzy controllers can also guarantee the exponential stability of the closed-loop PDE system. Moreover, a local optimization algorithm based on the linear matrix inequalities is proposed to compute the feedback gain matrices of a suboptimal fuzzy controller in the sense of minimizing the quadratic performance bound. Finally, the proposed design method is applied to the control of the temperature profile of a catalytic rod.

  15. Spatially dependent parameter estimation and nonlinear data assimilation by autosynchronization of a system of partial differential equations

    NASA Astrophysics Data System (ADS)

    Kramer, Sean; Bollt, Erik M.

    2013-09-01

    Given multiple images that describe chaotic reaction-diffusion dynamics, parameters of a partial differential equation (PDE) model are estimated using autosynchronization, where parameters are controlled by synchronization of the model to the observed data. A two-component system of predator-prey reaction-diffusion PDEs is used with spatially dependent parameters to benchmark the methods described. Applications to modeling the ecological habitat of marine plankton blooms by nonlinear data assimilation through remote sensing are discussed.

  16. Spatially dependent parameter estimation and nonlinear data assimilation by autosynchronization of a system of partial differential equations.

    PubMed

    Kramer, Sean; Bollt, Erik M

    2013-09-01

    Given multiple images that describe chaotic reaction-diffusion dynamics, parameters of a partial differential equation (PDE) model are estimated using autosynchronization, where parameters are controlled by synchronization of the model to the observed data. A two-component system of predator-prey reaction-diffusion PDEs is used with spatially dependent parameters to benchmark the methods described. Applications to modeling the ecological habitat of marine plankton blooms by nonlinear data assimilation through remote sensing are discussed.

  17. Edge detection by nonlinear dynamics

    SciTech Connect

    Wong, Yiu-fai

    1994-07-01

    We demonstrate how the formulation of a nonlinear scale-space filter can be used for edge detection and junction analysis. By casting edge-preserving filtering in terms of maximizing information content subject to an average cost function, the computed cost at each pixel location becomes a local measure of edgeness. This computation depends on a single scale parameter and the given image data. Unlike previous approaches which require careful tuning of the filter kernels for various types of edges, our scheme is general enough to be able to handle different edges, such as lines, step-edges, corners and junctions. Anisotropy in the data is handled automatically by the nonlinear dynamics.

  18. Receptor-mediated stimulation of lipid signalling pathways in CHO cells elicits the rapid transient induction of the PDE1B isoform of Ca2+/calmodulin-stimulated cAMP phosphodiesterase.

    PubMed

    Spence, S; Rena, G; Sullivan, M; Erdogan, S; Houslay, M D

    1997-01-01

    Chinese hamster ovary cells (CHO cells) do not exhibit any Ca2+/calmodulin-stimulated cAMP phosphodiesterase (PDE1) activity. Challenge of CHO cells with agonists for endogenous P2-purinoceptors, lysophosphatidic acid receptors and thrombin receptors caused a similar rapid transient induction of PDE1 activity in each instance. This was also evident on noradrenaline challenge of a cloned CHO cell line transfected so as to overexpress alpha 1B-adrenoceptors. This novel PDE1 activity appeared within about 15 min of exposure to ligands, rose to a maximum value within 30 min to 1 h and then rapidly decreased. In each case, the expression of novel PDE1 activity was blocked by the transcriptional inhibitor actinomycin D. Challenge with insulin of either native CHO cells or a CHO cell line transfected so as to overexpress the human insulin receptor failed to induce PDE1 activity. Reverse transcriptase-PCR analyses, using degenerate primers able to detect the PDE1C isoform, did not amplify any fragment from RNA preparations of CHO cells expressing PDE1 activity, although they did so from the human thyroid carcinoma FTC133 cell line. Reverse transcriptase-PCR analyses, using degenerate primers able to detect the PDE1A and PDE1B isoforms, successfully amplified a fragment of the predicted size from RNA preparations of both CHO cells expressing PDE1 activity and human Jurkat T-cells. Sequencing of the PCR products, generated using the PDE1A/B primers, yielded a novel sequence which, by analogy with sequences reported for bovine and murine PDE1B forms, suggests that the PDE1 species induced in CHO cells through protein kinase C activation and that expressed in Jurkat T-cells are PDE1B forms.

  19. Ca2+-activated K+ channel (KCa) stimulation improves relaxant capacity of PDE5 inhibitors in human penile arteries and recovers the reduced efficacy of PDE5 inhibition in diabetic erectile dysfunction

    PubMed Central

    González-Corrochano, R; La Fuente, JM; Cuevas, P; Fernández, A; Chen, MX; Sáenz de Tejada, I; Angulo, J

    2013-01-01

    Background and Purpose We have evaluated the influence of calcium-activated potassium channels (KCa) activation on cGMP-mediated relaxation in human penile tissues from non-diabetic and diabetic patients, and on the effects of PDE5 inhibitors on erectile responses in control and diabetic rats. Experimental Approach Cavernosal tissues were collected from organ donors and from patients with erectile dysfunction (ED). Relaxations of corpus cavernosum strips (HCC) and penile resistance arteries (HPRA) obtained from these specimens were evaluated. Intracavernosal pressure (ICP) increases to cavernosal nerve electrical stimulation were determined in anaesthetized diabetic and non-diabetic rats. Key Results Concentration-dependent vasodilation to the PDE5 inhibitor, sildenafil, in HPRA was sensitive to endothelium removal, NO/cGMP pathway inhibition and KCa blockade. Accordingly, activation of KCa with NS-8 (10 μM) significantly potentiated sildenafil-induced relaxations in HPRA (EC50 0.49 ± 0.22 vs. 5.21 ± 0.63 μM). In HCC, sildenafil-induced relaxation was unaffected by KCa blockade or activation. Potentiating effects in HPRA were reproduced with an alternative PDE5 inhibitor (tadalafil) and KCa activator (NS1619) and prevented by removing the endothelium. Large-conductance KCa (BK) and intermediate-conductance KCa (IK) contribute to NS-8-induced effects and were immunodetected in human and rat penile arteries. NS-8 potentiated sildenafil-induced enhancement of erectile responses in rats. Activation of KCa recovered the impaired relaxation to sildenafil in diabetic HPRA while sildenafil completely reversed diabetes-induced ED in rats only when combined with KCa activation. Conclusions and Implications Activation of KCa improves vasodilatory capacity of PDE5 inhibitors in diabetic and non-diabetic HPRA, resulting in the recovery of erectile function in diabetic rats. These results suggest a therapeutic potential for KCa activation in diabetic ED. PMID:23441682

  20. Nonstandard Finite Difference Schemes: Relations Between Time and Space Step-Sizes in Numerical Schemes for PDE's That Follow from Positivity Condition

    NASA Technical Reports Server (NTRS)

    Mickens, Ronald E.

    1996-01-01

    A large class of physical phenomena can be modeled by evolution and wave type Partial Differential Equations (PDE). Few of these equations have known explicit exact solutions. Finite-difference techniques are a popular method for constructing discrete representations of these equations for the purpose of numerical integration. However, the solutions to the difference equations often contain so called numerical instabilities; these are solutions to the difference equations that do not correspond to any solution of the PDE's. For explicit schemes, the elimination of this behavior requires functional relations to exist between the time and space steps-sizes. We show that such functional relations can be obtained for certain PDE's by use of a positivity condition. The PDE's studied are the Burgers, Fisher, and linearized Euler equations.

  1. Synthesis and biochemical evaluation of the CBI-PDE-I-dimer, a benzannelated analog of (+)-CC-1065 that also produces delayed toxicity in mice.

    PubMed

    Aristoff, P A; Johnson, P D; Sun, D; Hurley, L H

    1993-07-09

    A practical synthesis of CBI (2) was developed and applied to the synthesis of benzannelated analogs of CC-1065, including CBI-PDE-I-dimer (13) and CBI-bis-indole [(+)-A'BC]. The CBI-PDE-I-dimer was shown to have similar DNA sequence selectivity and structural effects on DNA as (+)-CC-1065. Of particular importance was the observed duplex winding effect that has been associated with the pyrrolidine ring of the nonalkylated subunits of (+)-CC-1065 and possibly correlated with its delayed toxicity effects. The effect of CBI-PDE-I-dimer was also compared to (+)-CC-1065 in the inhibition of duplex unwinding by helicase II and nick sealing by T4 ligase and found to be quantitatively similar. The in vitro and in vivo potencies of the CBI compounds corresponded very closely to the corresponding CPI derivatives. Finally, CBI-PDE-I-dimer was like (+)-CC-1065 in causing delayed toxicity in mice.

  2. The role of the PDE4D cAMP phosphodiesterase in the regulation of glucagon-like peptide-1 release

    PubMed Central

    Ong, WK; Gribble, FM; Reimann, F; Lynch, MJ; Houslay, MD; Baillie, GS; Furman, BL; Pyne, NJ

    2009-01-01

    Background and purpose: Increases in intracellular cyclic AMP (cAMP) augment the release/secretion of glucagon-like peptide-1 (GLP-1). As cAMP is hydrolysed by cAMP phosphodiesterases (PDEs), we determined the role of PDEs and particularly PDE4 in regulating GLP-1 release. Experimental approach: GLP-1 release, PDE expression and activity were investigated using rats and GLUTag cells, a GLP-1-releasing cell line. The effects of rolipram, a selective PDE4 inhibitor both in vivo and in vitro and stably overexpressed catalytically inactive PDE4D5 (D556A-PDE4D5) mutant in vitro on GLP-1 release were investigated. Key results: Rolipram (1.5 mg·kg−1 i.v.) increased plasma GLP-1 concentrations approximately twofold above controls in anaesthetized rats and enhanced glucose-induced GLP-1 release in GLUTag cells (EC50∼1.2 nmol·L−1). PDE4D mRNA transcript and protein were detected in GLUTag cells using RT-PCR with gene-specific primers and Western blotting with a specific PDE4D antibody respectively. Moreover, significant PDE activity was inhibited by rolipram in GLUTag cells. A GLUTag cell clone (C1) stably overexpressing the D556A-PDE4D5 mutant, exhibited elevated intracellular cAMP levels and increased basal and glucose-induced GLP-1 release compared with vector-transfected control cells. A role for intracellular cAMP/PKA in enhancing GLP-1 release in response to overexpression of D556A-PDE4D5 mutant was demonstrated by the finding that the PKA inhibitor H89 reduced both basal and glucose-induced GLP-1 release by 37% and 39%, respectively, from C1 GLUTag cells. Conclusions and implications: PDE4D may play an important role in regulating intracellular cAMP linked to the regulation of GLP-1 release. British Journal of Pharmacology (2009) 157, 633–644; doi:10.1111/j.1476-5381.2009.00194.x; published online 9 April 2009 PMID:19371330

  3. A Galerkin-based formulation of the probability density evolution method for general stochastic finite element systems

    NASA Astrophysics Data System (ADS)

    Papadopoulos, Vissarion; Kalogeris, Ioannis

    2016-05-01

    The present paper proposes a Galerkin finite element projection scheme for the solution of the partial differential equations (pde's) involved in the probability density evolution method, for the linear and nonlinear static analysis of stochastic systems. According to the principle of preservation of probability, the probability density evolution of a stochastic system is expressed by its corresponding Fokker-Planck (FP) stochastic partial differential equation. Direct integration of the FP equation is feasible only for simple systems with a small number of degrees of freedom, due to analytical and/or numerical intractability. However, rewriting the FP equation conditioned to the random event description, a generalized density evolution equation (GDEE) can be obtained, which can be reduced to a one dimensional pde. Two Galerkin finite element method schemes are proposed for the numerical solution of the resulting pde's, namely a time-marching discontinuous Galerkin scheme and the StreamlineUpwind/Petrov Galerkin (SUPG) scheme. In addition, a reformulation of the classical GDEE is proposed, which implements the principle of probability preservation in space instead of time, making this approach suitable for the stochastic analysis of finite element systems. The advantages of the FE Galerkin methods and in particular the SUPG over finite difference schemes, like the modified Lax-Wendroff, which is the most frequently used method for the solution of the GDEE, are illustrated with numerical examples and explored further.

  4. PDE7 inhibitor TC3.6 ameliorates symptomatology in a model of primary progressive multiple sclerosis

    PubMed Central

    Mestre, L; Redondo, M; Carrillo-Salinas, F J; Morales-García, J A; Alonso-Gil, S; Pérez-Castillo, A; Gil, C; Martínez, A; Guaza, C

    2015-01-01

    Background and Purpose cAMP plays an important role in the transduction of signalling pathways involved in neuroprotection and immune regulation. Control of the levels of this nucleotide by inhibition of cAMP-specific PDEs such as PDE7 may affect the pathological processes of neuroinflammatory diseases like multiple sclerosis (MS). In the present study, we evaluated the therapeutic potential of the selective PDE7 inhibitor, TC3.6, in a model of primary progressive multiple sclerosis (PPMS), a rare and severe variant of MS. Experimental Approach Theiler’s murine encephalomyelitis virus-induced demyelinated disease (TMEV-IDD) is one of the models used to validate the therapeutic efficacy of new drugs in MS. As recent studies have analysed the effect of PDE7 inhibitors in the EAE model of MS, here the TMEV-IDD model was used to test their efficacy in a progressive variant of MS. Mice were subjected to two protocols of TC3.6 administration: on the pre-symptomatic phase and once the disease was established. Key Results Treatment with TC3.6 ameliorated the disease course and improved motor deficits of infected mice. This was associated with down-regulation of microglial activation and reduced cellular infiltrates. Decreased expression of pro-inflammatory mediators such as COX-2 and the cytokines, IL-1β, TNF-α, IFN-γ and IL-6 in the spinal cord of TMEV-infected mice was also observed after TC3.6 administration. Conclusion These findings support the importance of PDE7 inhibitors, and specifically TC3.6, as a novel class of agents with therapeutic potential for PPMS. Preclinical studies are needed to determine whether their effects translate into durable clinical benefits. PMID:25994655

  5. Increase of Intracellular Cyclic AMP by PDE4 Inhibitors Affects HepG2 Cell Cycle Progression and Survival.

    PubMed

    Massimi, Mara; Cardarelli, Silvia; Galli, Francesca; Giardi, Maria Federica; Ragusa, Federica; Panera, Nadia; Cinque, Benedetta; Cifone, Maria Grazia; Biagioni, Stefano; Giorgi, Mauro

    2017-06-01

    Type 4 cyclic nucleotide phosphodiesterases (PDE4) are major members of a superfamily of enzymes (PDE) involved in modulation of intracellular signaling mediated by cAMP. Broadly expressed in most human tissues and present in large amounts in the liver, PDEs have in the last decade been key therapeutic targets for several inflammatory diseases. Recently, a significant body of work has underscored their involvement in different kinds of cancer, but with no attention paid to liver cancer. The present study investigated the effects of two PDE4 inhibitors, rolipram and DC-TA-46, on the growth of human hepatoma HepG2 cells. Treatment with these inhibitors caused a marked increase of intracellular cAMP level and a dose- and time-dependent effect on cell growth. The concentrations of inhibitors that halved cell proliferation to about 50% were used for cell cycle experiments. Rolipram (10 μM) and DC-TA-46 (0.5 μM) produced a decrease of cyclin expression, in particular of cyclin A, as well as an increase in p21, p27 and p53, as evaluated by Western blot analysis. Changes in the intracellular localization of cyclin D1 were also observed after treatments. In addition, both inhibitors caused apoptosis, as demonstrated by an Annexin-V cytofluorimetric assay and analysis of caspase-3/7 activity. Results demonstrated that treatment with PDE4 inhibitors affected HepG2 cell cycle and survival, suggesting that they might be useful as potential adjuvant, chemotherapeutic or chemopreventive agents in hepatocellular carcinoma. J. Cell. Biochem. 118: 1401-1411, 2017. © 2016 Wiley Periodicals, Inc.

  6. ADI FD schemes for the numerical solution of the three-dimensional Heston-Cox-Ingersoll-Ross PDE

    NASA Astrophysics Data System (ADS)

    Haentjens, Tinne

    2012-09-01

    This paper deals with the numerical solution of the time-dependent, three-dimensional Heston-Cox-Ingersoll- Ross PDE, with all correlations nonzero, for the fair pricing of European call options. We apply a finite difference dis-cretization on non-uniform spatial grids and then numerically solve the semi-discrete system in time by using an Alternating Direction Implicit scheme. We show that this leads to a highly efficient and stable numerical solution method.

  7. A Naturally-Derived Compound Schisandrin B Enhanced Light Sensation in the pde6c Zebrafish Model of Retinal Degeneration

    PubMed Central

    Zhang, Liyun; Xiang, Lue; Liu, Yiwen; Venkatraman, Prahatha; Chong, Leelyn; Cho, Jin; Bonilla, Sylvia; Jin, Zi-Bing; Pang, Chi Pui; Ko, Kam Ming; Ma, Ping

    2016-01-01

    Retinal degeneration is often progressive. This feature has provided a therapeutic window for intervention that may extend functional vision in patients. Even though this approach is feasible, few promising drug candidates are available. The scarcity of new drugs has motivated research to discover novel compounds through different sources. One such example is Schisandrin B (SchB), an active component isolated from the five-flavor fruit (Fructus Schisandrae) that is postulated in traditional Chinese medicines to exert prophylactic visual benefit. This SchB benefit was investigated in this study in pde6cw59, a zebrafish retinal-degeneration model. In this model, the pde6c gene (phosphodiesterase 6C, cGMP-specific, cone, alpha prime) carried a mutation which caused cone degeneration. This altered the local environment and caused the bystander rods to degenerate too. To test SchB on the pde6cw59 mutants, a treatment concentration was first determined that would not cause morphological defects, and would initiate known physiological response. Then, the mutants were treated with the optimized SchB concentration before the appearance of retinal degeneration at 3 days postfertilization (dpf). The light sensation of animals was evaluated at 6 dpf by the visual motor response (VMR), a visual startle that could be initiated by drastic light onset and offset. The results show that the VMR of pde6cw59 mutants towards light onset was enhanced by the SchB treatment, and that the initial phase of the enhancement was primarily mediated through the mutants’ eyes. Further immunostaining analysis indicates that the treatment specifically reduced the size of the abnormally large rods. These observations implicate an interesting hypothesis: that the morphologically-improved rods drive the observed VMR enhancement. Together, these investigations have identified a possible visual benefit of SchB on retinal degeneration, a benefit that can potentially be further developed to extend

  8. Mouse lysine catabolism to aminoadipate occurs primarily through the saccharopine pathway; implications for pyridoxine dependent epilepsy (PDE).

    PubMed

    Pena, Izabella Agostinho; Marques, Lygia Azevedo; Laranjeira, Ângelo B A; Yunes, José A; Eberlin, Marcos N; MacKenzie, Alex; Arruda, Paulo

    2017-01-01

    Lysine is catabolized in mammals through the saccharopine and pipecolate pathways - the former is mainly hepatic and renal, and the latter is believed to play a role in the cerebral lysine oxidation. Both pathways lead to the formation of aminoadipic semialdehyde (AASA) that is then oxidized to aminoadipate (AAA) by antiquitin (ALDH7A1). Mutations in the ALDH7A1 gene result in the accumulation of AASA and its cyclic form, piperideine-6-carboxylate (P6C), which causes pyridoxine-dependent epilepsy (PDE). P6C reacts with pyridoxal 5'-phosphate (PLP) causing its inactivation. Here, we used liquid chromatography-mass spectrometry to investigate lysine catabolism in mice injected with lysine labelled at either its nitrogen epsilon (ε-(15)N) or nitrogen alpha (α-(15)N). Analysis of ε-(15)N and α-(15)N lysine catabolites in plasma, liver and brain suggested the saccharopine as the main pathway for AAA biosynthesis. Although there was evidence for upstream cerebral pipecolate pathway activity, the resulting pipecolate does not appear to be further oxidized into AASA/P6C/AAA. By far the bulk of lysine degradation and therefore, the primary source of lysine catabolites are hepatic and renal. The results indicate that the saccharopine pathway is primarily responsible for body's production of AASA/P6C. The centrality of the saccharopine pathway in whole body lysine catabolism opens new possibilities of therapeutic targets for PDE. We suggest that inhibition of this pathway upstream of AASA/P6C synthesis may be used to prevent its accumulation benefiting PDE patients. Inhibition of the enzyme aminoadipic semialdehyde synthase, for example, could constitute a new strategy to treat PDE and other inherited diseases of lysine catabolism.

  9. PDE10A inhibitors stimulate or suppress motor behavior dependent on the relative activation state of the direct and indirect striatal output pathways

    PubMed Central

    Megens, Anton A H P; Hendrickx, Herman M R; Mahieu, Michel M A; Wellens, Annemie L Y; de Boer, Peter; Vanhoof, Greet

    2014-01-01

    The enzyme phosphodiesterase 10A (PDE10A) regulates the activity of striatal, medium spiny neurons (MSNs), which are divided into a behaviorally stimulating, Gs-coupled D1 receptor-expressing “direct” pathway and a behaviorally suppressant, Gi-coupled D2 receptor-expressing “indirect” pathway. Activating both pathways, PDE10A inhibitors (PDE10AIs) combine functional characteristics of D2 antagonists and D1 agonists. While the effects of PDE10AIs on spontaneous and stimulated behavior have been extensively reported, the present study investigates their effects on suppressed behavior under various conditions of reduced dopaminergic neurotransmission: blockade of D1 receptors with SCH-23390, blockade of D2 receptors with haloperidol, or depletion of dopamine with RO-4-1284 or reserpine. In rats, PDE10AIs displayed relatively low cataleptic activity per se. After blocking D1 receptors, however, they induced pronounced catalepsy at low doses close to those required for inhibition of apomorphine-induced behavior; slightly higher doses resulted in behavioral stimulant effects, counteracting the catalepsy. PDE10AIs also counteracted catalepsy and related behaviors induced by D2 receptor blockade or dopamine depletion; catalepsy was replaced by behavioral stimulant effects under the latter but not the former condition. Similar interactions were observed at the level of locomotion in mice. At doses close to those inhibiting d-amphetamine-induced hyperlocomotion, PDE10AIs reversed hypolocomotion induced by D1 receptor blockade or dopamine depletion but not hypolocomotion induced by D2 receptor blockade. It is concluded that PDE10AIs stimulate or inhibit motor behavior dependent on the relative activation state of the direct and indirect striatal output pathways. PMID:25505601

  10. Formulations and nebulizer performance.

    PubMed

    O'Riordan, Thomas G

    2002-11-01

    To deliver a drug by nebulization, the drug must first be dispersed in a liquid (usually aqueous) medium. After application of a dispersing force (either a jet of gas or ultrasonic waves), the drug particles are contained within the aerosol droplets, which are then inhaled. Some drugs readily dissolve in water, whereas others need a cosolvent such as ethanol or propylene glycol. Some drugs are delivered as suspensions, and the efficiency of nebulizers can be different for solutions and suspensions. Solutions are delivered more efficiently with most devices. In general, conventional ultrasonic nebulizers should not be used to aerosolize suspensions, because of low efficiency. Newer strategies to improve the delivery of non-water-soluble drugs include the use of liposomes and the milling of the drug into very small "nanoparticles." In addition to the active therapeutic ingredient and solvents, drug formulations may include buffers (the solubility of some medications is influenced by pH), stabilizers, and, in the case of multi-dose preparations, antibacterial agents. Though formulations are designed to optimize drug solubility and stability, changes in formulation can also affect inhaled mass, particle size, and treatment time, though the differences between nebulizer brands probably have a greater impact than differences in formulation. Ultrasonic and jet nebulizers may damage protein and other complex agents through heat or shear stress. Additives to multi-dose formulations, especially antimicrobial and chelating agents, may cause adverse events, so there is a trend towards single-use, preservative-free vials.

  11. Current drug therapy of patients with BPH-LUTS with the special emphasis on PDE5 inhibitors

    PubMed Central

    Govorov, Alexander; Kasyan, George; Priymak, Diana; Pushkar, Dmitry

    2016-01-01

    Introduction Benign prostatic hyperplasia (BPH) is the most common cause of lower urinary tract symptom (LUTS) development in men [1]. The intensity of the symptoms may vary from mild to severe, significantly affecting the quality of life. Erectile dysfunction (ED) is one of the most challenging issues in modern urology that significantly influences the quality of life in men worldwide. The objective of this literature review was to analyze the current drug therapies of patients with BPH-LUTS, with the special emphasis on PDE5 inhibitors. Material and methods The authors searched the literature for the period from 2000 until 2015 in MEDLINE and PubMed. Results Twenty-three articles were selected based on their reliability. A detailed analysis of the selected papers was performed. Primary attention was given to articles describing the use of PDE5. Works describing the use of different groups of drugs in patients with BPH-LUTS were also selected. Conclusions The current literature analysis suggests that the introduction of PDE5 inhibitors in clinical practice for the treatment of patients with BPH-LUTS will allow for significant expansion of the therapeutic options for the treatment of this disease. PMID:28127458

  12. Fragment-based screening for inhibitors of PDE4A using enthalpy arrays and X-ray crystallography

    PubMed Central

    Recht, Michael I.; Sridhar, Vandana; Badger, John; Hernandez, Leslie; Chie-Leon, Barbara; Nienaber, Vicki; Torres, Francisco E.

    2013-01-01

    Fragment-based screening has typically relied on X-ray or NMR methods to identify low affinity ligands that bind to therapeutic targets. These techniques are expensive in terms of material and time, so it useful to have a higher-throughput method to reliably pre-screen a fragment library to identify a subset of compounds for structural analysis. Calorimetry provides a label-free method to assay binding and enzymatic activity that is unaffected by the spectroscopic properties of the sample. Conventional microcalorimetry is hampered by requiring large quantities of reagents and long measurement times. Nanocalorimeters can overcome these limitations of conventional ITC. Here we have used enthalpy arrays, which are arrays of nanocalorimeters, to perform an enzyme activity based fragment screen for competitive inhibitors of phosphodiesterase 4A (PDE4A). Several inhibitors with KI<2 mM were identified and moved to X-ray crystallization trials. Although the co-crystals did not yield high-resolution data, evidence of binding was observed and the chemical structures of the hits were consistent with motifs of known PDE4 inhibitors. This study shows how array calorimetry can be used as a pre-screening method for fragment-based lead discovery with enzyme targets, and it provides a list of candidate fragments for inhibition of PDE4A. PMID:22223051

  13. Efficacy of selective PDE4D negative allosteric modulators in the object retrieval task in female cynomolgus monkeys (Macaca fascicularis).

    PubMed

    Sutcliffe, Jane S; Beaumont, Vahri; Watson, James M; Chew, Chang Sing; Beconi, Maria; Hutcheson, Daniel M; Dominguez, Celia; Munoz-Sanjuan, Ignacio

    2014-01-01

    Cyclic adenosine monophosphate (cAMP) signalling plays an important role in synaptic plasticity and information processing in the hippocampal and basal ganglia systems. The augmentation of cAMP signalling through the selective inhibition of phosphodiesterases represents a viable strategy to treat disorders associated with dysfunction of these circuits. The phosphodiesterase (PDE) type 4 inhibitor rolipram has shown significant pro-cognitive effects in neurological disease models, both in rodents and primates. However, competitive non-isoform selective PDE4 inhibitors have a low therapeutic index which has stalled their clinical development. Here, we demonstrate the pro-cognitive effects of selective negative allosteric modulators (NAMs) of PDE4D, D159687 and D159797 in female Cynomolgous macaques, in the object retrieval detour task. The efficacy displayed by these NAMs in a primate cognitive task which engages the corticostriatal circuitry, together with their suitable pharmacokinetic properties and safety profiles, suggests that clinical development of these allosteric modulators should be considered for the treatment of a variety of brain disorders associated with cognitive decline.

  14. Efficacy of Selective PDE4D Negative Allosteric Modulators in the Object Retrieval Task in Female Cynomolgus Monkeys (Macaca fascicularis)

    PubMed Central

    Sutcliffe, Jane S.; Beaumont, Vahri; Watson, James M.; Chew, Chang Sing; Beconi, Maria; Hutcheson, Daniel M.; Dominguez, Celia; Munoz-Sanjuan, Ignacio

    2014-01-01

    Cyclic adenosine monophosphate (cAMP) signalling plays an important role in synaptic plasticity and information processing in the hippocampal and basal ganglia systems. The augmentation of cAMP signalling through the selective inhibition of phosphodiesterases represents a viable strategy to treat disorders associated with dysfunction of these circuits. The phosphodiesterase (PDE) type 4 inhibitor rolipram has shown significant pro-cognitive effects in neurological disease models, both in rodents and primates. However, competitive non-isoform selective PDE4 inhibitors have a low therapeutic index which has stalled their clinical development. Here, we demonstrate the pro-cognitive effects of selective negative allosteric modulators (NAMs) of PDE4D, D159687 and D159797 in female Cynomolgous macaques, in the object retrieval detour task. The efficacy displayed by these NAMs in a primate cognitive task which engages the corticostriatal circuitry, together with their suitable pharmacokinetic properties and safety profiles, suggests that clinical development of these allosteric modulators should be considered for the treatment of a variety of brain disorders associated with cognitive decline. PMID:25050979

  15. Fragment-based screening for inhibitors of PDE4A using enthalpy arrays and X-ray crystallography.

    PubMed

    Recht, Michael I; Sridhar, Vandana; Badger, John; Hernandez, Leslie; Chie-Leon, Barbara; Nienaber, Vicki; Torres, Francisco E

    2012-04-01

    Fragment-based screening has typically relied on X-ray or nuclear magnetic resonance methods to identify low-affinity ligands that bind to therapeutic targets. These techniques are expensive in terms of material and time, so it useful to have a higher throughput method to reliably prescreen a fragment library to identify a subset of compounds for structural analysis. Calorimetry provides a label-free method to assay binding and enzymatic activity that is unaffected by the spectroscopic properties of the sample. Conventional microcalorimetry is hampered by requiring large quantities of reagents and long measurement times. Nanocalorimeters can overcome these limitations of conventional isothermal titration calorimetry. Here we have used enthalpy arrays, which are arrays of nanocalorimeters, to perform an enzyme activity-based fragment screen for competitive inhibitors of phosphodiesterase 4A (PDE4A). Several inhibitors with K ( I ) <2 mM were identified and moved to X-ray crystallization trials. Although the co-crystals did not yield high-resolution data, evidence of binding was observed, and the chemical structures of the hits were consistent with motifs of known PDE4 inhibitors. This study shows how array calorimetry can be used as a prescreening method for fragment-based lead discovery with enzyme targets and provides a list of candidate fragments for inhibition of PDE4A.

  16. Nonlinear channelizer.

    PubMed

    In, Visarath; Longhini, Patrick; Kho, Andy; Neff, Joseph D; Leung, Daniel; Liu, Norman; Meadows, Brian K; Gordon, Frank; Bulsara, Adi R; Palacios, Antonio

    2012-12-01

    The nonlinear channelizer is an integrated circuit made up of large parallel arrays of analog nonlinear oscillators, which, collectively, serve as a broad-spectrum analyzer with the ability to receive complex signals containing multiple frequencies and instantaneously lock-on or respond to a received signal in a few oscillation cycles. The concept is based on the generation of internal oscillations in coupled nonlinear systems that do not normally oscillate in the absence of coupling. In particular, the system consists of unidirectionally coupled bistable nonlinear elements, where the frequency and other dynamical characteristics of the emergent oscillations depend on the system's internal parameters and the received signal. These properties and characteristics are being employed to develop a system capable of locking onto any arbitrary input radio frequency signal. The system is efficient by eliminating the need for high-speed, high-accuracy analog-to-digital converters, and compact by making use of nonlinear coupled systems to act as a channelizer (frequency binning and channeling), a low noise amplifier, and a frequency down-converter in a single step which, in turn, will reduce the size, weight, power, and cost of the entire communication system. This paper covers the theory, numerical simulations, and some engineering details that validate the concept at the frequency band of 1-4 GHz.

  17. Instantaneous stroke volume by PDE during and after constant LBNP (-50 torr)

    NASA Technical Reports Server (NTRS)

    1980-01-01

    Six male subjects were exposed to -50 torr lower body negative pressure (LBNP) for 10 min while stroke volume was recorded beat by beat at regular intervals before, during and after release of LBNP. Stroke volume was calculated from the systolic velocity integral in the ascending aorta by pulsed Doppler echocardiography (PDE) and the cross sectional area of the vessel by M mode echocardiography. Changes in leg volume were recorded continuously and blood pressure was taken every minute. Stroke volume dropped by 51% of the control in the first 33 sec of LBNP and continued to decline slowly to -62% toward the end. Heart rate increased by 15% in the first 10 sec and was 22% above control at the end of exposure. The resulting cardiac output closely followed the course of stroke volume (-47% at 33 sec, -53% at 8 min) showing that the modest increase in heart rate did little to offset the drop in stroke volume. Leg volume increased markedly within the first 10 sec with a more gradual rise reaching +3.5% at the end. Upon sudden release of LBNP, leg volume dropped significantly during the first 3 sec simultaneously with an increase in stroke volume followed by a substantial decline in heart rate below the baseline.

  18. Pseudo-time methods for constrained optimization problems governed by PDE

    NASA Technical Reports Server (NTRS)

    Taasan, Shlomo

    1995-01-01

    In this paper we present a novel method for solving optimization problems governed by partial differential equations. Existing methods are gradient information in marching toward the minimum, where the constrained PDE is solved once (sometimes only approximately) per each optimization step. Such methods can be viewed as a marching techniques on the intersection of the state and costate hypersurfaces while improving the residuals of the design equations per each iteration. In contrast, the method presented here march on the design hypersurface and at each iteration improve the residuals of the state and costate equations. The new method is usually much less expensive per iteration step since, in most problems of practical interest, the design equation involves much less unknowns that that of either the state or costate equations. Convergence is shown using energy estimates for the evolution equations governing the iterative process. Numerical tests show that the new method allows the solution of the optimization problem in a cost of solving the analysis problems just a few times, independent of the number of design parameters. The method can be applied using single grid iterations as well as with multigrid solvers.

  19. Modelling of platelet-fibrin clot formation in flow with a DPD-PDE method.

    PubMed

    Tosenberger, A; Ataullakhanov, F; Bessonov, N; Panteleev, M; Tokarev, A; Volpert, V

    2016-02-01

    The paper is devoted to mathematical modelling of clot growth in blood flow. Great complexity of the hemostatic system dictates the need of usage of the mathematical models to understand its functioning in the normal and especially in pathological situations. In this work we investigate the interaction of blood flow, platelet aggregation and plasma coagulation. We develop a hybrid DPD-PDE model where dissipative particle dynamics (DPD) is used to model plasma flow and platelets, while the regulatory network of plasma coagulation is described by a system of partial differential equations. Modelling results confirm the potency of the scenario of clot growth where at the first stage of clot formation platelets form an aggregate due to weak inter-platelet connections and then due to their activation. This enables the formation of the fibrin net in the centre of the platelet aggregate where the flow velocity is significantly reduced. The fibrin net reinforces the clot and allows its further growth. When the clot becomes sufficiently large, it stops growing due to the narrowed vessel and the increase of flow shear rate at the surface of the clot. Its outer part is detached by the flow revealing the inner part covered by fibrin. This fibrin cap does not allow new platelets to attach at the high shear rate, and the clot stops growing. Dependence of the final clot size on wall shear rate and on other parameters is studied.

  20. Modelling of thrombus growth in flow with a DPD-PDE method.

    PubMed

    Tosenberger, A; Ataullakhanov, F; Bessonov, N; Panteleev, M; Tokarev, A; Volpert, V

    2013-11-21

    Hemostatic plug covering the injury site (or a thrombus in the pathological case) is formed due to the complex interaction of aggregating platelets with biochemical reactions in plasma that participate in blood coagulation. The mechanisms that control clot growth and which lead to growth arrest are not yet completely understood. We model them with numerical simulations based on a hybrid DPD-PDE model. Dissipative particle dynamics (DPD) is used to model plasma flow with platelets while fibrin concentration is described by a simplified reaction-diffusion-advection equation. The model takes into account consecutive stages of clot growth. First, a platelet is weakly connected to the clot and after some time this connection becomes stronger due to other surface receptors involved in platelet adhesion. At the same time, the fibrin mesh is formed inside the clot. This becomes possible because flow does not penetrate the clot and cannot wash out the reactants participating in blood coagulation. Platelets covered by the fibrin mesh cannot attach new platelets. Modelling shows that the growth of a hemostatic plug can stop as a result of its exterior part being removed by the flow thus exposing its non-adhesive core to the flow.

  1. AAV-mediated Gene Therapy Halts Retinal Degeneration in PDE6β-deficient Dogs.

    PubMed

    Pichard, Virginie; Provost, Nathalie; Mendes-Madeira, Alexandra; Libeau, Lyse; Hulin, Philippe; Tshilenge, Kizito-Tshitoko; Biget, Marine; Ameline, Baptiste; Deschamps, Jack-Yves; Weber, Michel; Le Meur, Guylène; Colle, Marie-Anne; Moullier, Philippe; Rolling, Fabienne

    2016-05-01

    We previously reported that subretinal injection of AAV2/5 RK.cpde6β allowed long-term preservation of photoreceptor function and vision in the rod-cone dysplasia type 1 (rcd1) dog, a large animal model of naturally occurring PDE6β deficiency. The present study builds on these earlier findings to provide a detailed assessment of the long-term effects of gene therapy on the spatiotemporal pattern of retinal degeneration in rcd1 dogs treated at 20 days of age. We analyzed the density distribution of the retinal layers and of particular photoreceptor cells in 3.5-year-old treated and untreated rcd1 dogs. Whereas no rods were observed outside the bleb or in untreated eyes, gene transfer halted rod degeneration in all vector-exposed regions. Moreover, while gene therapy resulted in the preservation of cones, glial cells and both the inner nuclear and ganglion cell layers, no cells remained in vector-unexposed retinas, except in the visual streak. Finally, the retinal structure of treated 3.5-year-old rcd1 dogs was identical to that of unaffected 4-month-old rcd1 dogs, indicating near complete preservation. Our findings indicate that gene therapy arrests the degenerative process even if intervention is initiated after the onset of photoreceptor degeneration, and point to significant potential of this therapeutic approach in future clinical trials.

  2. Modulation of signaling through GPCR-cAMP-PKA pathways by PDE4 depends on stimulus intensity: Possible implications for the pathogenesis of acrodysostosis without hormone resistance.

    PubMed

    Motte, Emmanuelle; Le Stunff, Catherine; Briet, Claire; Dumaz, Nicolas; Silve, Caroline

    2017-02-15

    In acrodysostosis without hormone resistance, a disease caused by phosphodiesterase (PDE)-4D mutations, increased PDE activity leads to bone developmental defects but with normal renal responses to PTH. To identify potential mechanisms for these disparate responses, we compared the effect of PDE activity on hormone signaling through the GPCR-Gsα-cAMP-PKA pathway in cells from two lineages, HEK-293 cells stably overexpressing PTH1R (HEKpthr) and human dermal fibroblasts, including studies evaluating cAMP levels using an Epac-based BRET-sensor for cAMP (CAMYEL). For ligand-induced responses inducing strong cAMP accumulation, the inhibition of PDE4 activity resulted in relatively small further increases. In contrast, when ligand-induced cAMP accumulation was of lesser intensity, the inhibition of PDE4 had a more pronounced effect. Similar results were obtained evaluating downstream events (cellular CREB phosphorylation and CRE-luciferase activity). Thus, the ability of PDE4 to modulate signaling through GPCR-cAMP-PKA pathways can depend on the cell type and stimulus intensity.

  3. Excess adenosine A2B receptor signaling contributes to priapism through HIF-1α mediated reduction of PDE5 gene expression.

    PubMed

    Ning, Chen; Wen, Jiaming; Zhang, Yujin; Dai, Yingbo; Wang, Wei; Zhang, Weiru; Qi, Lin; Grenz, Almut; Eltzschig, Holger K; Blackburn, Michael R; Kellems, Rodney E; Xia, Yang

    2014-06-01

    Priapism is featured with prolonged and painful penile erection and is prevalent among males with sickle cell disease (SCD). The disorder is a dangerous urological and hematological emergency since it is associated with ischemic tissue damage and erectile disability. Here we report that phosphodiesterase-5 (PDE5) gene expression and PDE activity is significantly reduced in penile tissues of two independent priapic models: SCD mice and adenosine deaminase (ADA)-deficient mice. Moreover, using ADA enzyme therapy to reduce adenosine or a specific antagonist to block A(2B) adenosine receptor (ADORA2B) signaling, we successfully attenuated priapism in both ADA(-/-) and SCD mice by restoring penile PDE5 gene expression to normal levels. This finding led us to further discover that excess adenosine signaling via ADORA2B activation directly reduces PDE5 gene expression in a hypoxia-inducible factor-1α (HIF-1α)-dependent manner. Overall, we reveal that excess adenosine-mediated ADORA2B signaling underlies reduced penile PDE activity by decreasing PDE5 gene expression in a HIF-1α-dependent manner and provide new insight for the pathogenesis of priapism and novel therapies for the disease.

  4. Aipl1 is required for cone photoreceptor function and survival through the stability of Pde6c and Gc3 in zebrafish

    PubMed Central

    Iribarne, Maria; Nishiwaki, Yuko; Nakamura, Shohei; Araragi, Masato; Oguri, Eri; Masai, Ichiro

    2017-01-01

    Genetic mutations in aryl hydrocarbon receptor interacting protein-like 1 (AIPL1) cause photoreceptor degeneration associated with Leber congenital amaurosis 4 (LCA4) in human patients. Here we report retinal phenotypes of a zebrafish aipl1 mutant, gold rush (gosh). In zebrafish, there are two aipl1 genes, aipl1a and aipl1b, which are expressed mainly in rods and cones, respectively. The gosh mutant gene encodes cone-specific aipl1, aipl1b. Cone photoreceptors undergo progressive degeneration in the gosh mutant, indicating that aipl1b is required for cone survival. Furthermore, the cone-specific subunit of cGMP phosphodiesterase 6 (Pde6c) is markedly decreased in the gosh mutant, and the gosh mutation genetically interacts with zebrafish pde6c mutation eclipse (els). These data suggest that Aipl1 is required for Pde6c stability and function. In addition to Pde6c, we found that zebrafish cone-specific guanylate cyclase, zGc3, is also decreased in the gosh and els mutants. Furthermore, zGc3 knockdown embryos showed a marked reduction in Pde6c. These observations illustrate the interdependence of cGMP metabolism regulators between Aipl1, Pde6c, and Gc3 in photoreceptors. PMID:28378769

  5. Epac and the high affinity rolipram binding conformer of PDE4 modulate neurite outgrowth and myelination using an in vitro spinal cord injury model

    PubMed Central

    Boomkamp, S D; McGrath, M A; Houslay, M D; Barnett, S C

    2014-01-01

    Background and Purpose cAMP and pharmacological inhibition of PDE4, which degrades it, are promising therapeutic targets for the treatment of spinal cord injury (SCI). Using our previously described in vitro SCI model, we studied the mechanisms by which cAMP modulators promote neurite outgrowth and myelination using enantiomers of the PDE4-specific inhibitor rolipram and other modulators of downstream signalling effectors. Experimental Approach Rat mixed neural cell myelinating cultures were cut with a scalpel and treated with enantiomers of the PDE4-specific inhibitor rolipram, Epac agonists and PKA antagonists. Neurite outgrowth, density and myelination were assessed by immunocytochemistry and cytokine levels analysed by qPCR. Key Results Inhibition of the high-affinity rolipram-binding state (HARBS), rather than the low-affinity rolipram binding state (LARBS) PDE4 conformer promoted neurite outgrowth and myelination. These effects were mediated through the activation of Epac and not through PKA. Expression of the chemokine CXCL10, known to inhibit myelination, was markedly elevated in astrocytes after Rho inhibition and this was blocked by inhibition of Rho kinase or PDE4. Conclusions and Implications PDE4 inhibitors targeted at the HARBS conformer or Epac agonists may provide promising novel targets for the treatment of SCI. Our study demonstrates the differential mechanisms of action of these compounds, as well as the benefit of a combined pharmacological approach and highlighting potential promising targets for the treatment of SCI. These findings need to be confirmed in vivo. PMID:24467222

  6. Advanced protein formulations

    PubMed Central

    Wang, Wei

    2015-01-01

    It is well recognized that protein product development is far more challenging than that for small-molecule drugs. The major challenges include inherent sensitivity to different types of stresses during the drug product manufacturing process, high rate of physical and chemical degradation during long-term storage, and enhanced aggregation and/or viscosity at high protein concentrations. In the past decade, many novel formulation concepts and technologies have been or are being developed to address these product development challenges for proteins. These concepts and technologies include use of uncommon/combination of formulation stabilizers, conjugation or fusion with potential stabilizers, site-specific mutagenesis, and preparation of nontraditional types of dosage forms—semiaqueous solutions, nonfreeze-dried solid formulations, suspensions, and other emerging concepts. No one technology appears to be mature, ideal, and/or adequate to address all the challenges. These gaps will likely remain in the foreseeable future and need significant efforts for ultimate resolution. PMID:25858529

  7. Sunscreen product formulation.

    PubMed

    Tanner, Paul R

    2006-01-01

    On the surface, sunscreen products are pretty simple. They consist of a delivery vehicle containing one or more sunscreen active ingredients. When applied to the skin, these sunscreen actives intercept solar ultraviolet (UV) rays before they can damage the underlying skin. However, while conceptually simple, a detailed analysis reveals that sunscreen formulations are quite complex, requiring careful selection of sunscreen active and vehicle components to control multiple performance and in-use parameters.Thus, to enable a better understanding and appreciation of sunscreen products, the typical steps in formulating a sunscreen product are described. Throughout this process, the key is to apply scientific principles together with a bit of formulation art to holistically create the best sunscreen product that meets the design targets--a sunscreen product that people will use regularly and properly.

  8. Granulated decontamination formulations

    DOEpatents

    Tucker, Mark D.

    2007-10-02

    A decontamination formulation and method of making that neutralizes the adverse health effects of both chemical and biological compounds, especially chemical warfare (CW) and biological warfare (BW) agents, and toxic industrial chemicals. The formulation provides solubilizing compounds that serve to effectively render the chemical and biological compounds, particularly CW and BW compounds, susceptible to attack, and at least one reactive compound that serves to attack (and detoxify or kill) the compound. The formulation includes at least one solubilizing agent, a reactive compound, a sorbent additive, and water. A highly adsorbent sorbent additive (e.g., amorphous silica, sorbitol, mannitol, etc.) is used to "dry out" one or more liquid ingredients into a dry, free-flowing powder that has an extended shelf life, and is more convenient to handle and mix in the field.

  9. An analytical formulation for phase noise in MEMS oscillators.

    PubMed

    Agrawal, Deepak; Seshia, Ashwin

    2014-12-01

    In recent years, there has been much interest in the design of low-noise MEMS oscillators. This paper presents a new analytical formulation for noise in a MEMS oscillator encompassing essential resonator and amplifier nonlinearities. The analytical expression for oscillator noise is derived by solving a second-order nonlinear stochastic differential equation. This approach is applied to noise modeling of an electrostatically addressed MEMS resonator-based square-wave oscillator in which the resonator and oscillator circuit nonlinearities are integrated into a single modeling framework. By considering the resulting amplitude and phase relations, we derive additional noise terms resulting from resonator nonlinearities. The phase diffusion of an oscillator is studied and the phase diffusion coefficient is proposed as a metric for noise optimization. The proposed nonlinear phase noise model provides analytical insight into the underlying physics and a pathway toward the design optimization for low-noise MEMS oscillators.

  10. Nonlinear feedback control of multiple robot arms

    NASA Technical Reports Server (NTRS)

    Tarn, T. J.; Yun, X.; Bejczy, A. K.

    1987-01-01

    Multiple coordinated robot arms are modeled by considering the arms: (1) as closed kinematic chains, and (2) as a force constrained mechanical system working on the same object simultaneously. In both formulations a new dynamic control method is discussed. It is based on a feedback linearization and simultaneous output decoupling technique. Applying a nonlinear feedback and a nonlinear coordinate transformation, the complicated model of the multiple robot arms in either formulation is converted into a linear and output decoupled system. The linear system control theory and optimal control theory are used to design robust controllers in the task space. The first formulation has the advantage of automatically handling the coordination and load distribution among the robot arms. In the second formulation, by choosing a general output equation, researchers can superimpose the position and velocity error feedback with the force-torque error feedback in the task space simultaneously.

  11. Lubrication in tablet formulations.

    PubMed

    Wang, Jennifer; Wen, Hong; Desai, Divyakant

    2010-05-01

    Theoretical aspects and practical considerations of lubrication in tablet compression are reviewed in this paper. Properties of the materials that are often used as lubricants, such as magnesium stearate, in tablet dosage form are summarized. The manufacturing process factors that may affect tablet lubrication are discussed. As important as the lubricants in tablet formulations are, their presence can cause some changes to the tablet physical and chemical properties. Furthermore, a detailed review is provided on the methodologies used to characterize lubrication process during tablet compression with relevant process analytical technologies. Finally, the Quality-by-Design considerations for tablet formulation and process development in terms of lubrication are discussed.

  12. Computer aided nonlinear electrical networks analysis

    NASA Technical Reports Server (NTRS)

    Slapnicar, P.

    1977-01-01

    Techniques used in simulating an electrical circuit with nonlinear elements for use in computer-aided circuit analysis programs are described. Elements of the circuit include capacitors, resistors, inductors, transistors, diodes, and voltage and current sources (constant or time varying). Simulation features are discussed for dc, ac, and/or transient circuit analysis. Calculations are based on the model approach of formulating the circuit equations. A particular solution of transient analysis for nonlinear storage elements is described.

  13. Nonlinear transient analysis via energy minimization

    NASA Technical Reports Server (NTRS)

    Kamat, M. P.; Knight, N. F., Jr.

    1978-01-01

    The formulation basis for nonlinear transient analysis of finite element models of structures using energy minimization is provided. Geometric and material nonlinearities are included. The development is restricted to simple one and two dimensional finite elements which are regarded as being the basic elements for modeling full aircraft-like structures under crash conditions. The results indicate the effectiveness of the technique as a viable tool for this purpose.

  14. Association of PDE4B Polymorphisms with Susceptibility to Schizophrenia: A Meta-Analysis of Case-Control Studies

    PubMed Central

    Feng, Yanguo; Cheng, Dejun; Zhang, Chaofeng; Li, Yuchun; Zhang, Zhiying; Wang, Juan; Shi, Yuzhong

    2016-01-01

    Background The PDE4B single nucleotide polymorphisms (SNPs) have been reported to be associated with schizophrenia risk. However, current findings are ambiguous or even conflicting. To better facilitate the understanding the genetic role played by PDE4B in susceptibility to schizophrenia, we collected currently available data and conducted this meta-analysis. Methods A comprehensive electronic literature searching of PubMed, Embase, Web of Science and Cochrane Library was performed. The association between PDE4B SNPs and schizophrenia was evaluated by odds ratios (ORs) and 95% confidence intervals (CIs) under allelic, dominant and recessive genetic models. The random effects model was utilized when high between-study heterogeneity (I2 > 50%) existed, otherwise the fixed effects model was used. Results Five studies comprising 2376 schizophrenia patients and 3093 controls were finally included for meta-analysis. The rs1040716 was statistically significantly associated with schizophrenia risk in Asian and Caucasian populations under dominant model (OR = 0.87, 95% CI: 0.76–0.99, P = 0.04). The rs2180335 was significantly related with schizophrenia risk in Asian populations under allelic (OR = 0.82, 95% CI: 0.72–0.93, P = 0.003) and dominant (OR = 0.75, 95% CI: 0.64–0.88, P < 0.001) models. A significant association was also observed between rs4320761 and schizophrenia in Asian populations under allelic model (OR = 0.87, 95% CI: 0.75–1.00, P = 0.048). In addition, a strong association tendency was found between rs6588190 and schizophrenia in Asian populations under allelic model (OR = 0.87, 95% CI: 0.76–1.00, P = 0.055). Conclusion This meta-analysis suggests that PDE4B SNPs are genetically associated with susceptibility to schizophrenia. However, due to limited sample size, more large-scale, multi-racial association studies are needed to further clarify the genetic association between various PDE4B variants and schizophrenia. PMID:26756575

  15. Mixed formulation for frictionless contact problems

    NASA Technical Reports Server (NTRS)

    Noor, Ahmed K.; Kim, Kyun O.

    1989-01-01

    Simple mixed finite element models and a computational precedure are presented for the solution of frictionless contact problems. The analytical formulation is based on a form of Reissner's large rotation theory of the structure with the effects of transverse shear deformation included. The contact conditions are incorporated into the formulation by using a perturbed Lagrangian approach with the fundamental unknowns consisting of the internal forces (stress resultants), the generalized displacements, and the Lagrange multipliers associated with the contact conditions. The element characteristic array are obtained by using a modified form of the two-field Hellinger-Reissner mixed variational principle. The internal forces and the Lagrange multipliers are allowed to be discontinuous at interelement boundaries. The Newton-Raphson iterative scheme is used for the solution of the nonlinear algebraic equations, and the determination of the contact area and the contact pressures.

  16. Formulation and Application of the Generalized Multilevel Facets Model

    ERIC Educational Resources Information Center

    Wang, Wen-Chung; Liu, Chih-Yu

    2007-01-01

    In this study, the authors develop a generalized multilevel facets model, which is not only a multilevel and two-parameter generalization of the facets model, but also a multilevel and facet generalization of the generalized partial credit model. Because the new model is formulated within a framework of nonlinear mixed models, no efforts are…

  17. Parallelized solvers for heat conduction formulations

    NASA Technical Reports Server (NTRS)

    Padovan, Joe; Kwang, Abel

    1991-01-01

    Based on multilevel partitioning, this paper develops a structural parallelizable solution methodology that enables a significant reduction in computational effort and memory requirements for very large scale linear and nonlinear steady and transient thermal (heat conduction) models. Due to the generality of the formulation of the scheme, both finite element and finite difference simulations can be treated. Diverse model topologies can thus be handled, including both simply and multiply connected (branched/perforated) geometries. To verify the methodology, analytical and numerical benchmark trends are verified in both sequential and parallel computer environments.

  18. Modeling of Viscoelastic Shear: A Nonlinear Stick-Slip Formulation

    DTIC Science & Technology

    2006-02-20

    t 0 e− 416 672τ (t−s)vy(s, b)ds + G(0+)e− 416 672τ t = G(t). (7.6) We next consider the Sturm - Liouville problem −Z ′′ − λZ = 0 Z(a)− h0Z ′(a) = 0...t, b) = 0. Let us now consider the Sturm - Liouville problem −Z ′′ − λZ = 0 Z(0) = 0 (8.12) Z ′ (b) = 0. The eigenvalue problem (8.12) has a system of...for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington VA 22202-4302. Respondents should be aware that

  19. Nonlinear Systems.

    ERIC Educational Resources Information Center

    Seider, Warren D.; Ungar, Lyle H.

    1987-01-01

    Describes a course in nonlinear mathematics courses offered at the University of Pennsylvania which provides an opportunity for students to examine the complex solution spaces that chemical engineers encounter. Topics include modeling many chemical processes, especially those involving reaction and diffusion, auto catalytic reactions, phase…

  20. Nonlinear Acoustics

    DTIC Science & Technology

    1974-02-14

    Wester- velt. [60] Streaming. In 1831, Michael Faraday [61] noted that currents of air were set up in the neighborhood of vibrating plates-the first... ducei in the case of a paramettc amy (from Berktay an Leahy 141). C’ "". k•, SEC 10.1 NONLINEAR ACOUSTICS 345 The principal results of their analysis

  1. Nonlinear resonance

    NASA Astrophysics Data System (ADS)

    Kevorkian, J.

    This report discusses research in the area of slowly varying nonlinear oscillatory systems. Some of the topics discussed are as follows: adiabatic invariants and transient resonance in very slowly varying Hamiltonian systems; sustained resonance in very slowly varying Hamiltonian systems; free-electron lasers with very slow wiggler taper; and bursting oscillators.

  2. Allosteric-Site and Catalytic-Site Ligand Effects on PDE5 Functions are Associated with Distinct Changes in Physical Form of the Enzyme

    PubMed Central

    Corbin, Jackie D.; Zoraghi, Roya; Francis, Sharron H.

    2009-01-01

    Native phosphodiesterase-5 (PDE5) homodimer contains distinct non-catalytic cGMP allosteric sites and catalytic sites for cGMP hydrolysis. Purified recombinant PDE5 was activated by pre-incubation with cGMP. Relatively low concentrations of cGMP produced a Native PAGE gel-shift of PDE5 from a single band position (lower band) to a band with decreased mobility (upper band); higher concentrations of cGMP produced a band of intermediate mobility (middle band) in addition to the upper band. Two point mutations (G659A and G659P) near the catalytic site that reduced affinity for cGMP substrate retained allosteric cGMP-binding affinity like that of WT PDE5 but displayed cGMP-induced gel-shift only to the middle-band position. The upper band could represent a form produced by cGMP binding to the catalytic site, while the middle band could represent a form produced by cGMP binding to the allosteric site. Millimolar cGMP was required for gel-shift of PDE5 when added to the pre-incubation before native PAGE, presumably due to removal of most of the cGMP during electrophoresis, but micromolar cGMP was sufficient for this effect if cGMP was included in the native gel buffer. cGMP-induced gel-shift was associated with stimulation of PDE5 catalytic activity, and the rates of onset and reversibility of this effect suggested that it was due to cGMP binding to the allosteric site. Incubation of PDE5 with non-hydrolyzable, catalytic site-specific, substrate analogs such as the inhibitors sildenafil and tadalafil, followed by dilution, did not produce activation of catalytic activity like that obtained with cGMP, although both inhibitors produced a similar gel-shift to the upper band as that obtained with cGMP. This implied that occupation of the catalytic site alone can produce a gel-shift to the upper band. PDE5 activation or gel-shift was reversed by lowering cGMP with dilution followed by at least one hour of incubation. Such slow reversibility could prolong effects of cGMP on PDE

  3. Activated G-protein releases cGMP from high affinity binding sites on PDE from toad rod outer segments (ROS)

    SciTech Connect

    Yuen, P.S.T.; Walseth, T.F.; Panter, S.S.; Sundby, S.R.; Graeff, R.M.; Goldberg, N.D.

    1987-05-01

    cGMP binding proteins in toad ROS were identified by direct photoaffinity labeling (PAL) with /sup 32/P-cGMP and quantified by retention of complexes on nitrocellulose filters. By PAL, high affinity sites were present on the ..cap alpha.. and ..beta.. subunits of the cGMP-specific phosphodiesterase (PDE) which have MW/sub app/ of 94 and 90 kDa. A doublet was deduced from its photolabeling properties to represent PDE/sub ..gamma../ photocrosslinked with PDE/sub ..cap alpha../ or PDE/sub ..beta../, respectively. cGMP prebound to these high affinity sites was released by light-activated G-protein or its ..cap alpha.. subunit complexed with GTP..gamma..S; this inhibition of cGMP binding to PDE did not result from decreased cGMP availability due to enhanced hydrolysis. A low affinity cGMP binding component identified by PAL is tightly associated with ROS membranes. Apparent ATP/light-dependent stimulation of cGMP binding was shown to result from light activated cGMP hydrolysis in conjunction with ATP-promoted conversion of GMP to GDP/GTP and increased GDP/GTP binding. These findings coincide with a model for light-related regulation of cGMP binding and metabolism predicted from intact and cellfree kinetic measurements: in the dark state the cGMP hydrolic rate is constrained by the availability of cGMP because of its binding to high affinity sites on PDE. Light activated G-protein releases cGMP from these sites and allows for its redistribution to lower affinity sites represented by PDE catalytic site(s) and possible cGMP-dependent membrane cation channels.

  4. The Role of Phosphodiesterase 12 (PDE12) as a Negative Regulator of the Innate Immune Response and the Discovery of Antiviral Inhibitors*

    PubMed Central

    Wood, Edgar R.; Bledsoe, Randy; Chai, Jing; Daka, Philias; Deng, Hongfeng; Ding, Yun; Harris-Gurley, Sarah; Kryn, Luz Helena; Nartey, Eldridge; Nichols, James; Nolte, Robert T.; Prabhu, Ninad; Rise, Cecil; Sheahan, Timothy; Shotwell, J. Brad; Smith, Danielle; Tai, Vince; Taylor, J. David; Tomberlin, Ginger; Wang, Liping; Wisely, Bruce; You, Shihyun; Xia, Bing; Dickson, Hamilton

    2015-01-01

    2′,5′-Oligoadenylate synthetase (OAS) enzymes and RNase-L constitute a major effector arm of interferon (IFN)-mediated antiviral defense. OAS produces a unique oligonucleotide second messenger, 2′,5′-oligoadenylate (2–5A), that binds and activates RNase-L. This pathway is down-regulated by virus- and host-encoded enzymes that degrade 2–5A. Phosphodiesterase 12 (PDE12) was the first cellular 2–5A- degrading enzyme to be purified and described at a molecular level. Inhibition of PDE12 may up-regulate the OAS/RNase-L pathway in response to viral infection resulting in increased resistance to a variety of viral pathogens. We generated a PDE12-null cell line, HeLaΔPDE12, using transcription activator-like effector nuclease-mediated gene inactivation. This cell line has increased 2–5A levels in response to IFN and poly(I-C), a double-stranded RNA mimic compared with the parental cell line. Moreover, HeLaΔPDE12 cells were resistant to viral pathogens, including encephalomyocarditis virus, human rhinovirus, and respiratory syncytial virus. Based on these results, we used DNA-encoded chemical library screening to identify starting points for inhibitor lead optimization. Compounds derived from this effort raise 2–5A levels and exhibit antiviral activity comparable with the effects observed with PDE12 gene inactivation. The crystal structure of PDE12 complexed with an inhibitor was solved providing insights into the structure-activity relationships of inhibitor potency and selectivity. PMID:26055709

  5. A Fast and Scalable Method for A-Optimal Design of Experiments for Infinite-dimensional Bayesian Nonlinear Inverse Problems with Application to Porous Medium Flow

    NASA Astrophysics Data System (ADS)

    Petra, N.; Alexanderian, A.; Stadler, G.; Ghattas, O.

    2015-12-01

    We address the problem of optimal experimental design (OED) for Bayesian nonlinear inverse problems governed by partial differential equations (PDEs). The inverse problem seeks to infer a parameter field (e.g., the log permeability field in a porous medium flow model problem) from synthetic observations at a set of sensor locations and from the governing PDEs. The goal of the OED problem is to find an optimal placement of sensors so as to minimize the uncertainty in the inferred parameter field. We formulate the OED objective function by generalizing the classical A-optimal experimental design criterion using the expected value of the trace of the posterior covariance. This expected value is computed through sample averaging over the set of likely experimental data. Due to the infinite-dimensional character of the parameter field, we seek an optimization method that solves the OED problem at a cost (measured in the number of forward PDE solves) that is independent of both the parameter and the sensor dimension. To facilitate this goal, we construct a Gaussian approximation to the posterior at the maximum a posteriori probability (MAP) point, and use the resulting covariance operator to define the OED objective function. We use randomized trace estimation to compute the trace of this covariance operator. The resulting OED problem includes as constraints the system of PDEs characterizing the MAP point, and the PDEs describing the action of the covariance (of the Gaussian approximation to the posterior) to vectors. We control the sparsity of the sensor configurations using sparsifying penalty functions, and solve the resulting penalized bilevel optimization problem via an interior-point quasi-Newton method, where gradient information is computed via adjoints. We elaborate our OED method for the problem of determining the optimal sensor configuration to best infer the log permeability field in a porous medium flow problem. Numerical results show that the number of PDE

  6. In resting COS1 cells a dominant negative approach shows that specific, anchored PDE4 cAMP phosphodiesterase isoforms gate the activation, by basal cyclic AMP production, of AKAP-tethered protein kinase A type II located in the centrosomal region.

    PubMed

    McCahill, Angela; McSorley, Theresa; Huston, Elaine; Hill, Elaine V; Lynch, Martin J; Gall, Irene; Keryer, Guy; Lygren, Birgitte; Tasken, Kjetil; van Heeke, Gino; Houslay, Miles D

    2005-09-01

    We employ a novel, dominant negative approach to identify a key role for certain tethered cyclic AMP specific phosphodiesterase-4 (PDE4) isoforms in regulating cyclic AMP dependent protein kinase A (PKA) sub-populations in resting COS1 cells. A fraction of PKA is clearly active in resting COS1 cells and this activity increases when cells are treated with the selective PDE4 inhibitor, rolipram. Point mutation of a critical, conserved aspartate residue in the catalytic site of long PDE4A4, PDE4B1, PDE4C2 and PDE4D3 isoforms renders them catalytically inactive. Overexpressed in resting COS1 cells, catalytically inactive forms of PDE4C2 and PDE4D3, but not PDE4A4 and PDE4B1, are constitutively PKA phosphorylated while overexpressed active versions of all these isoforms are not. Inactive and active versions of all these isoforms are PKA phosphorylated in cells where protein kinase A is maximally activated with forskolin and IBMX. By contrast, rolipram challenge of COS1 cells selectively triggers the PKA phosphorylation of recombinant, active PDE4D3 and PDE4C2 but not recombinant, active PDE4A4 and PDE4B1. Purified, recombinant PDE4D3 and PDE4A4 show a similar dose-dependency for in vitro phosphorylation by PKA. Disruption of the tethering of PKA type-II to PKA anchor proteins (AKAPs), achieved using the peptide Ht31, prevents inactive forms of PDE4C2 and PDE4D3 being constitutively PKA phosphorylated in resting cells as does siRNA-mediated knockdown of PKA-RII, but not PKA-RI. PDE4C2 and PDE4D3 co-immunoprecipitate from COS1 cell lysates with 250 kDa and 450 kDa AKAPs that tether PKA type-II and not PKA type-I. PKA type-II co-localises with AKAP450 in the centrosomal region of COS1 cells. The perinuclear distribution of recombinant, inactive PDE4D3, but not inactive PDE4A4, overlaps with AKAP450 and PKA type-II. The distribution of PKA phosphorylated inactive PDE4D3 also overlaps with that of AKAP450 in the centrosomal region of COS1 cells. We propose that a novel role

  7. Development of solution techniques for nonlinear structural analysis

    NASA Technical Reports Server (NTRS)

    Vos, R. G.; Andrews, J. S.

    1974-01-01

    Nonlinear structural solution methods in the current research literature are classified according to order of the solution scheme, and it is shown that the analytical tools for these methods are uniformly derivable by perturbation techniques. A new perturbation formulation is developed for treating an arbitrary nonlinear material, in terms of a finite-difference generated stress-strain expansion. Nonlinear geometric effects are included in an explicit manner by appropriate definition of an applicable strain tensor. A new finite-element pilot computer program PANES (Program for Analysis of Nonlinear Equilibrium and Stability) is presented for treatment of problems involving material and geometric nonlinearities, as well as certain forms on nonconservative loading.

  8. Liposomal paclitaxel formulations.

    PubMed

    Koudelka, Stěpán; Turánek, Jaroslav

    2012-11-10

    Over the past three decades, taxanes represent one of the most important new classes of drugs approved in oncology. Paclitaxel (PTX), the prototype of this class, is an anti-cancer drug approved for the treatment of breast and ovarian cancer. However, notwithstanding a suitable premedication, present-day chemotherapy employing a commercial preparation of PTX (Taxol®) is associated with serious side effects and hypersensitivity reactions. Liposomes represent advanced and versatile delivery systems for drugs. Generally, both in vivo mice tumor models and human clinical trials demonstrated that liposomal PTX formulations significantly increase a maximum tolerated dose (MTD) of PTX which outperform that for Taxol®. Liposomal PTX formulations are in various stages of clinical trials. LEP-ETU (NeoPharm) and EndoTAG®-1 (Medigene) have reached the phase II of the clinical trials; Lipusu® (Luye Pharma Group) has already been commercialized. Present achievements in the preparation of various liposomal formulations of PTX, the development of targeted liposomal PTX systems and the progress in clinical testing of liposomal PTX are discussed in this review summarizing about 30 years of liposomal PTX development.

  9. A note on the generation of phase plane plots on a digital computer. [for solution of nonlinear differential equations

    NASA Technical Reports Server (NTRS)

    Simon, M. K.

    1980-01-01

    A technique is presented for generating phase plane plots on a digital computer which circumvents the difficulties associated with more traditional methods of numerical solving nonlinear differential equations. In particular, the nonlinear differential equation of operation is formulated.

  10. The localization and concentration of the PDE2-encoded high-affinity cAMP phosphodiesterase is regulated by cAMP-dependent protein kinase A in the yeast Saccharomyces cerevisiae.

    PubMed

    Hu, Yun; Liu, Enkai; Bai, Xiaojia; Zhang, Aili

    2010-03-01

    The genome of the yeast Saccharomyces cerevisiae encodes two cyclic AMP (cAMP) phosphodiesterases, a low-affinity one, Pde1, and a high-affinity one, Pde2. Pde1 has been ascribed a function for downregulating agonist-induced cAMP accumulation in a protein kinase A (PKA)-governed negative feedback loop, whereas Pde2 controls the basal cAMP level in the cell. Here we show that PKA regulates the localization and protein concentration of Pde2. Pde2 is accumulated in the nucleus in wild-type cells growing on glucose, or in strains with hyperactive PKA. In contrast, in derepressed wild-type cells or cells with attenuated PKA activity, Pde2 is distributed over the nucleus and cytoplasm. We also show evidence indicating that the Pde2 protein level is positively correlated with PKA activity. The increase in the Pde2 protein level in high-PKA strains and in cells growing on glucose was due to its increased half-life. These results suggest that, like its low-affinity counterpart, the high-affinity phosphodiesterase may also play an important role in the PKA-controlled feedback inhibition of intracellular cAMP.

  11. Micosoft Excel Sensitivity Analysis for Linear and Stochastic Program Feed Formulation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Sensitivity analysis is a part of mathematical programming solutions and is used in making nutritional and economic decisions for a given feed formulation problem. The terms, shadow price and reduced cost, are familiar linear program (LP) terms to feed formulators. Because of the nonlinear nature of...

  12. Bayesian Estimation of Graded Response Multilevel Models Using Gibbs Sampling: Formulation and Illustration

    ERIC Educational Resources Information Center

    Natesan, Prathiba; Limbers, Christine; Varni, James W.

    2010-01-01

    The present study presents the formulation of graded response models in the multilevel framework (as nonlinear mixed models) and demonstrates their use in estimating item parameters and investigating the group-level effects for specific covariates using Bayesian estimation. The graded response multilevel model (GRMM) combines the formulation of…

  13. Negative inotropic action of denbufylline through interfering with the calcium channel independently of its PDE IV inhibitory activity in guinea pig ventricle papillary muscles.

    PubMed

    Sanae, F; Ohmae, S; Kobayashi, D; Takag, K; Miyamoto, K

    1996-04-01

    The inotropic actions of xanthine derivatives with long alkyl chains were investigated in guinea pig ventricular papillary muscle. A potent and nonselective phosphodiesterase (PDE) inhibitor, 3-isobutyl-1-methylxanthine, elicited a positive inotropy and inhibited the negative inotropic effects of calcium channel inhibitors, as did a selective PDE III inhibitor, amrinone, and these effects were canceled by a protein kinase inhibitor, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89). However, 1,3-di-n-butyl-7-(2'oxopropyl)xanthine (denbufylline) and 1-n-butyl-3-n-propylxanthine (XT-044), which have potent and selective PDE IV-inhibitory activities, showed negative inotropic actions that became more potent in the presence of H-89. Denbufylline abolished the late restoration phase induced by ryanodine. This xanthine derivative attenuated the effects of both the calcium channel acting agents Bay K 8644 and verapamil, without interaction with caffeine and dihydropyridine calcium channel inhibitors, and denbufylline had little direct influence on the specific binding of [(3)H]azidopine and [(3)H]desmethoxyverapamil to cardiac membranes. A nonxanthine PDE IV inhibitor, Ro 20-1724, did not affect the inotropic actions of calcium channel inhibitors. The attenuation by denbufylline or XT-044 of the negative inotropic action of verapamil was not influenced by treatment with H-89. These results suggest that in the ventricular papillary muscle, these xanthine derivatives elicit negative inotropy by acting on a verapamil-sensitive site of the calcium channel without involving their PDE-inhibitory activity.

  14. Formulations of entomopathogens as bioinsecticides

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Developing a proper formulation is a necessary component for commercialization of entomopathogenic microbes as biological insecticides. The objective of this chapter is to present broad-ranging information about formulations to foster research toward developing commercial microbial-based insecticide...

  15. Evaluation and applicability of transfinite element formulations with particular reference to radiation

    NASA Technical Reports Server (NTRS)

    Tamma, Kumar K.; Railkar, Sudhir B.

    1988-01-01

    The evaluation and applicability of hybrid transfinite element formulations are described for transient nonlinear thermal models with particular reference to account for radiation effects. The formulations are developed from basic concepts and evaluated for both one- and two-dimensional thermal models. The methodology presented is a hybrid approach as it combines finite elements, classical Galerkin schemes, and transform methods. Basic features of the hybrid formulations and the associated solution scheme used are first described. Therein, numerical test models are presented to evaluate the applicability for predicting the nonlinear transient response in one- and two-dimensional thermal models influenced due to radiation effects.

  16. How to characterize the nonlinear amplifier?

    NASA Technical Reports Server (NTRS)

    Kallistratova, Dmitri Kouznetsov; Cotera, Carlos Flores

    1994-01-01

    The conception of the amplification of the coherent field is formulated. The definition of the coefficient of the amplification as the relation between the mean value of the field at the output to the value at the input and the definition of the noise as the difference between the number of photons in the output mode and square of the modulus of the mean value of the output amplitude are considered. Using a simple example it is shown that by these definitions the noise of the nonlinear amplifier may be less than the noise of the ideal linear amplifier of the same amplification coefficient. Proposals to search another definition of basic parameters of the nonlinear amplifiers are discussed. This definition should enable us to formulate the universal fundamental lower limit of the noise which should be valid for linear quantum amplifiers as for nonlinear ones.

  17. A truncated form of rod photoreceptor PDE6 β-subunit causes autosomal dominant congenital stationary night blindness by interfering with the inhibitory activity of the γ-subunit.

    PubMed

    Manes, Gaël; Cheguru, Pallavi; Majumder, Anurima; Bocquet, Béatrice; Sénéchal, Audrey; Artemyev, Nikolai O; Hamel, Christian P; Brabet, Philippe

    2014-01-01

    Autosomal dominant congenital stationary night blindness (adCSNB) is caused by mutations in three genes of the rod phototransduction cascade, rhodopsin (RHO), transducin α-subunit (GNAT1), and cGMP phosphodiesterase type 6 β-subunit (PDE6B). In most cases, the constitutive activation of the phototransduction cascade is a prerequisite to cause adCSNB. The unique adCSNB-associated PDE6B mutation found in the Rambusch pedigree, the substitution p.His258Asn, leads to rod photoreceptors desensitization. Here, we report a three-generation French family with adCSNB harboring a novel PDE6B mutation, the duplication, c.928-9_940dup resulting in a tyrosine to cysteine substitution at codon 314, a frameshift, and a premature termination (p.Tyr314Cysfs*50). To understand the mechanism of the PDE6β1-314fs*50 mutant, we examined the properties of its PDE6-specific portion, PDE6β1-313. We found that PDE6β1-313 maintains the ability to bind noncatalytic cGMP and the inhibitory γ-subunit (Pγ), and interferes with the inhibition of normal PDE6αβ catalytic subunits by Pγ. Moreover, both truncated forms of the PDE6β protein, PDE6β1-313 and PDE6β1-314fs*50 expressed in rods of transgenic X. laevis are targeted to the phototransduction compartment. We hypothesize that in affected family members the p.Tyr314Cysfs*50 change results in the production of the truncated protein, which binds Pγ and causes constitutive activation of the phototransduction thus leading to the absence of rod adaptation.

  18. Nonlinear mechanical behavior of thermoplastic matrix materials for advanced composites

    NASA Technical Reports Server (NTRS)

    Arenz, R. J.; Landel, R. F.

    1989-01-01

    Two recent theories of nonlinear mechanical response are quantitatively compared and related to experimental data. Computer techniques are formulated to handle the numerical integration and iterative procedures needed to solve the associated sets of coupled nonlinear differential equations. Problems encountered during these formulations are discussed and some open questions described. Bearing in mind these cautions, the consequences of changing parameters that appear in the formulations on the resulting engineering properties are discussed. Hence, engineering approaches to the analysis of thermoplastic matrix material can be suggested.

  19. Nonlinear Waves.

    DTIC Science & Technology

    1982-09-23

    potentiel u(x, t)=21x2 est une solution de l’Ejuation (de Korteweg de Vries): Dans [11, on a construit une famille de solutions de l’&quation I1). Ces...decroissent comme d (d+ 1) /x2 quand Ix I tend vers l’infini. Lorsque d - 1. on retrouve les potentiels de ( 1]. Si d n’est pas eigal i I1. le potentiel ...281 La v~ricazion de (10), (11), (12) dans los cus d w 1, dmw2 est tri viale. Dams le cas do potentiels periodiques, des formules analogues i (11) et

  20. Extended Painlevé Expansion, Nonstandard Truncation and Special Reductions of Nonlinear Evolution Equations

    NASA Astrophysics Data System (ADS)

    Lou, Sen-yue

    1998-05-01

    To study a nonlinear partial differential equation (PDE), the Painleve expansion developed by Weiss, Tabor and Carnevale (WTC) is one of the most powerful methods. In this paper, using any singular manifold, the expansion series in the usual Painleve analysis is shown to be resummable in some different ways. A simple nonstandard truncated expansion with a quite universal reduction function is used for many nonlinear integrable and nonintegrable PDEs such as the Burgers, Korteweg de-Vries (KdV), Kadomtsev-Petviashvli (KP), Caudrey-Dodd-Gibbon-Sawada-Kortera (CDGSK), Nonlinear Schrödinger (NLS), Davey-Stewartson (DS), Broer-Kaup (BK), KdV-Burgers (KdVB), λf4 , sine-Gordon (sG) etc.

  1. Computation of traveling wave fronts for a nonlinear diffusion-advection model.

    PubMed

    Mansour, M B A

    2009-01-01

    This paper utilizes a nonlinear reaction-diffusion-advection model for describing the spatiotemporal evolution of bacterial growth. The traveling wave solutions of the corresponding system of partial differential equations are analyzed. Using two methods, we then find such solutions numerically. One of the methods involves the traveling wave equations and solving an initial-value problem, which leads to accurate computations of the wave profiles and speeds. The second method is to construct time-dependent solutions by solving an initial-moving boundary-value problem for the PDE system, showing another approximation for such wave solutions.

  2. Toxicity of agrochemical formulations.

    PubMed

    Carmichael, Neil G

    2005-01-01

    Most agrochemicals have physicochemical properties that make it impractical to apply them directly to crops and other targets. It is necessary to provide a concentrate of the active ingredient, to which formulation agents have been added to allow dilution with water for spraying. These ingredients perform several functions, including emulsifying, solubilizing, antifoaming, and the like. The properties of these materials are not intended to include pesticidal activity. However, some of these materials may have intrinsic toxicologic properties that should be taken into account in an overall evaluation of the safety of the product. In agriculture, exposure to these materials is sporadic and seasonal. The testing of the complete formulation is based on the evaluation of this risk, and it is concentrated on the evaluation of the short-term exposure to the concentrated product. Many of these substances are rather banal and are generally regarded as safe. Exceptions to this rule do exist, particularly concerning solvents; in such cases a fuller data package is necessary to perform risk assessment.

  3. Effects of a selective PDE4 inhibitor, D-22888, on human airways and eosinophils in vitro and late phase allergic pulmonary eosinophilia in guinea pigs.

    PubMed

    Dent, G; Poppe, H; Egerland, J; Marx, D; Szelenyi, I; Branscheid, D; Magnussen, H; Rabe, K F

    1998-02-01

    The actions of a novel selective inhibitor of type 4 cyclic nucleotide phosphodiesterase (PDE4), D-22888, on human airway smooth muscle tone and human eosinophil respiratory burst in vitro and bronchoalveolar eosinophilia in allergen-challenged sensitized guinea pigs in vivo were assessed. D-22888 was a selective inhibitor of PDE4, exhibiting an IC50 against human neutrophil PDE4 of 0.15 microM, compared to IC 50 values of 4.4 microM and 1.1 microM for human platelet PDE3 and PDE5, respectively. D-22888 relaxed inherent tone in human bronchial rings in a concentration-dependent manner with an IC50 of 5.0 microM (geometric mean, 95% ci 3.0-8.4 microM) and also caused a concentration-dependent inhibition of opsonized zymosan-induced superoxide anion generation by human eosinophils with an IC50 of 3.1 microM (1.0-9.2 microM). Treatment of actively sensitized guinea pigs with single oral doses of D-22888 2 h before or 4 h after challenge reduced bronchoalveolar lavage (BAL) eosinophil numbers, 24 h after aerosol allergen challenge, by 48% and 73% at 10 mg/kg and 30 mg/kg, respectively, 2 h pre-challenge and 68% at 30 mg/kg 4 h post-challenge. Chronic twice-daily oral dosing with D-22888 for three days caused inhibition of 24 h post-challenge BAL eosinophilia, amounting to 88% at 30 mg/kg. These in vivo actions were comparable with those achieved with other selective PDE4 inhibitors and with the corticosteroid, dexamethasone. We conclude that D-22888 exerts actions on airway smooth muscle and eosinophil recruitment and activation that suggest that D-22888 may be a promising new drug for use in the treatment of allergic obstructive airways> diseases such as bronchial asthma.

  4. Nonlinear flight control design using backstepping methodology

    NASA Astrophysics Data System (ADS)

    Tran, Thanh Trung

    The subject of nonlinear flight control design using backstepping control methodology is investigated in the dissertation research presented here. Control design methods based on nonlinear models of the dynamic system provide higher utility and versatility because the design model more closely matches the physical system behavior. Obtaining requisite model fidelity is only half of the overall design process, however. Design of the nonlinear control loops can lessen the effects of nonlinearity, or even exploit nonlinearity, to achieve higher levels of closed-loop stability, performance, and robustness. The goal of the research is to improve control quality for a general class of strict-feedback dynamic systems and provide flight control architectures to augment the aircraft motion. The research is divided into two parts: theoretical control development for the strict-feedback form of nonlinear dynamic systems and application of the proposed theory for nonlinear flight dynamics. In the first part, the research is built on two components: transforming the nonlinear dynamic model to a canonical strict-feedback form and then applying backstepping control theory to the canonical model. The research considers a process to determine when this transformation is possible, and when it is possible, a systematic process to transfer the model is also considered when practical. When this is not the case, certain modeling assumptions are explored to facilitate the transformation. After achieving the canonical form, a systematic design procedure for formulating a backstepping control law is explored in the research. Starting with the simplest subsystem and ending with the full system, pseudo control concepts based on Lyapunov control functions are used to control each successive subsystem. Typically each pseudo control must be solved from a nonlinear algebraic equation. At the end of this process, the physical control input must be re-expressed in terms of the physical states by

  5. Vardenafil reduces macrophage pro-inflammatory overresponses in Cystic Fibrosis through PDE5- and CFTR-dependent mechanisms.

    PubMed

    Noel, Sabrina; Panin, Nadtha; Beka, Mathilde; Dhooghe, Barbara; Huaux, Francois; Leal, Teresinha

    2017-02-14

    Chronic inflammation that progressively disrupts the lung tissue is a hallmark of Cystic Fibrosis (CF). In mice, vardenafil, an inhibitor of phosphodiesterase type 5 (PDE5), restores transepithelial ion transport and corrects mislocalization of the most common CF mutation, F508del-CFTR. It also reduces lung pro-inflammatory responses in mice and in patients with CF. To test the hypothesis that macrophages are target effector cells of the immunomodulatory effect of vardenafil, we isolated lung macrophages from mice homozygous for the F508del mutation or invalidated for the cftr gene and from their corresponding wild-type littermates. We then evaluated the effect of vardenafil on the classical M1 polarization, mirroring release of pro-inflammatory cytokines. We confirmed that macrophages from different body compartments express CFTR and showed that vardenafil targets the cells through PDE5- and CFTR-dependent mechanisms. In the presence of the F508del mutation, vardenafil downregulated overresponses of the M1 markers, tumor necrosis factor (TNF)-α and inducible nitric oxide synthase (NOS)-2. Our study identifies lung macrophages as target cells of the anti-inflammatory effect of vardenafil in CF and supports the view that the drug is potentially beneficial for treating CF as it combines rescue of CFTR protein and anti-inflammatory properties.

  6. Pharmacophore modeling, 3D-QSAR and docking study of 2-phenylpyrimidine analogues as selective PDE4B inhibitors.

    PubMed

    Tripuraneni, Naga Srinivas; Azam, Mohammed Afzal

    2016-04-07

    Pharmacophore modeling, molecular docking, and molecular dynamics (MD) simulation studies have been performed, to explore the putative binding modes of 2-phenylpyrimidine series as PDE4B selective inhibitors. A five point pharmacophore model was developed using 87 molecules having pIC50 ranging from 8.52 to 5.07. The pharmacophore hypothesis yielded a statistically significant 3D-QSAR model, with a high correlation coefficient (R(2)=0.918), cross validation coefficient (Q(2)=0.852), and F value (175) at 4 component PLS factor. The external validation indicated that our QSAR model possessed high predictive power (R(2)=0.70). The generated model was further validated by enrichment studies using the decoy test. To evaluate the effectiveness of docking protocol in flexible docking, we have selected crystallographic bound compound to validate our docking procedure as evident from root mean square deviation. A 10ns molecular dynamics simulation confirmed the docking results of both stability of the 1XMU-ligand complex and the presumed active conformation. Further, similar orientation was observed between the superposition of the conformations of 85 after MD simulation and best XP-docking pose; MD simulation and 3D-QSAR pose; best XP-docking and 3D-QSAR poses. Outcomes of the present study provide insight in designing novel molecules with better PDE4B selective inhibitory activity.

  7. Genomewide Association Study of African Children Identifies Association of SCHIP1 and PDE8A with Facial Size and Shape

    PubMed Central

    Manyama, Mange; Kimwaga, Emmanuel; Mathayo, Joshua; Larson, Jacinda R.; Liberton, Denise K.; Lukowiak, Ken; Riccardi, Sheri L.; Li, Mao; Williams, Trevor; Li, Hong; Jones, Kenneth L.; Klein, Ophir D.; Santorico, Stephanie A.; Hallgrimsson, Benedikt; Spritz, Richard A.

    2016-01-01

    The human face is a complex assemblage of highly variable yet clearly heritable anatomic structures that together make each of us unique, distinguishable, and recognizable. Relatively little is known about the genetic underpinnings of normal human facial variation. To address this, we carried out a large genomewide association study and two independent replication studies of Bantu African children and adolescents from Mwanza, Tanzania, a region that is both genetically and environmentally relatively homogeneous. We tested for genetic association of facial shape and size phenotypes derived from 3D imaging and automated landmarking of standard facial morphometric points. SNPs within genes SCHIP1 and PDE8A were associated with measures of facial size in both the GWAS and replication cohorts and passed a stringent genomewide significance threshold adjusted for multiple testing of 34 correlated traits. For both SCHIP1 and PDE8A, we demonstrated clear expression in the developing mouse face by both whole-mount in situ hybridization and RNA-seq, supporting their involvement in facial morphogenesis. Ten additional loci demonstrated suggestive association with various measures of facial shape. Our findings, which differ from those in previous studies of European-derived whites, augment understanding of the genetic basis of normal facial development, and provide insights relevant to both human disease and forensics. PMID:27560698

  8. A PDE-based Regularization Algorithm toward Reducing Speckle Tracking Noise: A Feasibility Study for Ultrasound Breast Elastography

    PubMed Central

    Guo, Li; Xu, Yan; Xu, Zhengfu; Jiang, Jingfeng

    2015-01-01

    Obtaining accurate ultrasonically-estimated displacements along both axial (parallel to the acoustic beam) and lateral (perpendicular to the beam) directions is an important task for various clinical elastography applications (e.g. modulus reconstruction and temperature imaging). In this study, a partial differential equation (PDE)-based regularization algorithm was proposed to enhance motion tracking accuracy. More specifically, the proposed PDE-based algorithm, utilizing two-dimensional displacement estimates from a conventional elastography system, attempted to iteratively reduce noise contained in the original displacement estimates by mathematical regularization. In this study, the physical constraint used by the above-mentioned mathematical regularization was tissue incompressibility. This proposed algorithm was tested using computer-simulated data, a tissue-mimicking phantom and in vivo breast lesion data. Computer simulation results showed that the method significantly improved the accuracy of lateral tracking (e.g. 17X at 0.5% compression). From in vivo breast lesion data investigated, we have found that, as compared to the conventional method, higher quality axial and lateral strain images (e.g. at least 78% improvements among the estimated contrast-to-noise ratios of lateral strain images) were obtained. Our initial results demonstrated that this conceptually and computationally simple method could be useful to improve the image quality for ultrasound elastography with current clinical equipment as a post-processing tool. PMID:25452434

  9. Autonomous selection of PDE inpainting techniques vs. exemplar inpainting techniques for void fill of high resolution digital surface models

    NASA Astrophysics Data System (ADS)

    Rahmes, Mark; Yates, J. Harlan; Allen, Josef DeVaughn; Kelley, Patrick

    2007-04-01

    High resolution Digital Surface Models (DSMs) may contain voids (missing data) due to the data collection process used to obtain the DSM, inclement weather conditions, low returns, system errors/malfunctions for various collection platforms, and other factors. DSM voids are also created during bare earth processing where culture and vegetation features have been extracted. The Harris LiteSite TM Toolkit handles these void regions in DSMs via two novel techniques. We use both partial differential equations (PDEs) and exemplar based inpainting techniques to accurately fill voids. The PDE technique has its origin in fluid dynamics and heat equations (a particular subset of partial differential equations). The exemplar technique has its origin in texture analysis and image processing. Each technique is optimally suited for different input conditions. The PDE technique works better where the area to be void filled does not have disproportionately high frequency data in the neighborhood of the boundary of the void. Conversely, the exemplar based technique is better suited for high frequency areas. Both are autonomous with respect to detecting and repairing void regions. We describe a cohesive autonomous solution that dynamically selects the best technique as each void is being repaired.

  10. Investigation of a Putative Estrogen-Imprinting Gene, Phosphodiesterase Type IV Variant (Pde4d4), in Determining Prostate Cancer Risk

    DTIC Science & Technology

    2008-04-01

    Jin S-LC, Bushnik T, Lan L, Conti M. Subcellular localization of rolipram-sensitive, cAMP-specific phos- phodiesterases. J Biol Chem 1998;273:19672–8...technique of immunohistochemistry, localization of PDE4D4 in normal or tumor epithelial cells of rat prostate can be examined so as to understand whether...used 5’ Rapid amplification of cDNA ends (5’RACE) to characterize/ localize the promoter region of PDE4D4. Transcription Start Site (TSS) was found at

  11. Investigation of a Putative Estrogen-Imprinting Gene, Phosphodiesterase Type IV Variant (PDE4D4), in Determining Prostate Cancer Risk

    DTIC Science & Technology

    2007-04-01

    Fimia GM, Sassone-Corsi P. Cyclic AMP signalling. J Cell Sci 2001;114:1971–2. 46. Jin S-LC, Bushnik T, Lan L, Conti M. Subcellular localization of...technique of immunohistochemistry, localization of PDE4D4 in normal or tumor epithelial cells of rat prostate can be examined so as to understand whether... localize the promoter region of PDE4D4. Transcription Start Site (TSS) was found at -251 away from the translation start site (ATG). Next, I used

  12. Nonlinear dynamic vibration absorbers with a saturation

    NASA Astrophysics Data System (ADS)

    Febbo, M.; Machado, S. P.

    2013-03-01

    The behavior of a new type of nonlinear dynamic vibration absorber is studied. A distinctive characteristic of the proposed absorber is the impossibility to extend the system to infinity. The mathematical formulation is based on a finite extensibility nonlinear elastic potential to model the saturable nonlinearity. The absorber is attached to a single degree-of-freedom linear/nonlinear oscillator subjected to a periodic external excitation. In order to solve the equations of motion and to analyze the frequency-response curves, the method of averaging is used. The performance of the FENE absorber is evaluated considering a variation of the nonlinearity of the primary system, the damping and the linearized frequency of the absorber and the mass ratio. The numerical results show that the proposed absorber has a very good efficiency when the nonlinearity of the primary system increases. When compared with a cubic nonlinear absorber, for a large nonlinearity of the primary system, the FENE absorber shows a better effectiveness for the whole studied frequency range. A complete absence of quasi-periodic oscillations is also found for an appropriate selection of the parameters of the absorber. Finally, direct integrations of the equations of motion are performed to verify the accuracy of the proposed method.

  13. A general formulation for compositional reservoir simulation

    SciTech Connect

    Rodriguez, F.; Guzman, J.; Galindo-Nava, A. |

    1994-12-31

    In this paper the authors present a general formulation to solve the non-linear difference equations that arise in compositional reservoir simulation. The general approach here presented is based on newton`s method and provides a systematic approach to generate several formulations to solve the compositional problem, each possessing a different degree of implicitness and stability characteristics. The Fully-Implicit method is at the higher end of the implicitness spectrum while the IMPECS method, implicit in pressure-explicit in composition and saturation, is at the lower end. They show that all methods may be obtained as particular cases of the fully-implicit method. Regarding the matrix problem, all methods have a similar matrix structure; the composition of the Jacobian matrix is however unique in each case, being in some instances amenable to reductions for optimal solution of the matrix problem. Based on this, a different approach to derive IMPECS type methods is proposed; in this case, the whole set of 2nc + 6 equations, that apply in each gridblock, is reduced to a single pressure equation through matrix reduction operations; this provides a more stable numerical scheme, compared to other published IMPCS methods, in which the subset of thermodynamic equilibrium equations is arbitrarily decoupled form the set of gridblock equations to perform such reduction. The authors discuss how the general formulation here presented can be used to formulate and construct an adaptive-implicit compositional simulators. They also present results on the numerical performance of FI, IMPSEC and IMPECS methods on some test problems.

  14. Multilevel algorithms for nonlinear optimization

    NASA Technical Reports Server (NTRS)

    Alexandrov, Natalia; Dennis, J. E., Jr.

    1994-01-01

    Multidisciplinary design optimization (MDO) gives rise to nonlinear optimization problems characterized by a large number of constraints that naturally occur in blocks. We propose a class of multilevel optimization methods motivated by the structure and number of constraints and by the expense of the derivative computations for MDO. The algorithms are an extension to the nonlinear programming problem of the successful class of local Brown-Brent algorithms for nonlinear equations. Our extensions allow the user to partition constraints into arbitrary blocks to fit the application, and they separately process each block and the objective function, restricted to certain subspaces. The methods use trust regions as a globalization strategy, and they have been shown to be globally convergent under reasonable assumptions. The multilevel algorithms can be applied to all classes of MDO formulations. Multilevel algorithms for solving nonlinear systems of equations are a special case of the multilevel optimization methods. In this case, they can be viewed as a trust-region globalization of the Brown-Brent class.

  15. Nonlinear drainage of some non-Newtonian free films

    NASA Astrophysics Data System (ADS)

    Tabakova, S.

    2015-10-01

    In the present work we apply the generalized lubrication approach (including inertial, viscous, capillary and van-der-Waals forces) to study the dynamics of a free thin film of a non-Newtonian fluid, whose viscosity is described by the Power law and Carreau models. For planar films with fully mobile surfaces, this approach leads to a system of two nonlinear PDE for the film thickness and lateral velocity. This system is solved numerically in the case of laterally bounded free films. The calculations of the film shape and velocity are presented using data of some real liquids: blood and aqueous solution of 0.5% hydroxyethylcellulose. It is shown that the Power law model predicts a very different viscosity to the Carreau model viscosity, although that the film profiles are not very different for all film wetting angles.

  16. Nonrecursive formulations of multibody dynamics and concurrent multiprocessing

    NASA Technical Reports Server (NTRS)

    Kurdila, Andrew J.; Menon, Ramesh

    1993-01-01

    Since the late 1980's, research in recursive formulations of multibody dynamics has flourished. Historically, much of this research can be traced to applications of low dimensionality in mechanism and vehicle dynamics. Indeed, there is little doubt that recursive order N methods are the method of choice for this class of systems. This approach has the advantage that a minimal number of coordinates are utilized, parallelism can be induced for certain system topologies, and the method is of order N computational cost for systems of N rigid bodies. Despite the fact that many authors have dismissed redundant coordinate formulations as being of order N(exp 3), and hence less attractive than recursive formulations, we present recent research that demonstrates that at least three distinct classes of redundant, nonrecursive multibody formulations consistently achieve order N computational cost for systems of rigid and/or flexible bodies. These formulations are as follows: (1) the preconditioned range space formulation; (2) penalty methods; and (3) augmented Lagrangian methods for nonlinear multibody dynamics. The first method can be traced to its foundation in equality constrained quadratic optimization, while the last two methods have been studied extensively in the context of coercive variational boundary value problems in computational mechanics. Until recently, however, they have not been investigated in the context of multibody simulation, and present theoretical questions unique to nonlinear dynamics. All of these nonrecursive methods have additional advantages with respect to recursive order N methods: (1) the formalisms retain the highly desirable order N computational cost; (2) the techniques are amenable to concurrent simulation strategies; (3) the approaches do not depend upon system topology to induce concurrency; and (4) the methods can be derived to balance the computational load automatically on concurrent multiprocessors. In addition to the presentation of

  17. Nonlinear Dynamics of Structures with Material Degradation

    NASA Astrophysics Data System (ADS)

    Soltani, P.; Wagg, D. J.; Pinna, C.; Whear, R.; Briody, C.

    2016-09-01

    Structures usually experience deterioration during their working life. Oxidation, corrosion, UV exposure, and thermo-mechanical fatigue are some of the most well-known mechanisms that cause degradation. The phenomenon gradually changes structural properties and dynamic behaviour over their lifetime, and can be more problematic and challenging in the presence of nonlinearity. In this paper, we study how the dynamic behaviour of a nonlinear system changes as the thermal environment causes certain parameters to vary. To this end, a nonlinear lumped mass modal model is considered and defined under harmonic external force. Temperature dependent material functions, formulated from empirical test data, are added into the model. Using these functions, bifurcation parameters are defined and the corresponding nonlinear responses are observed by numerical continuation. A comparison between the results gives a preliminary insight into how temperature induced properties affects the dynamic response and highlights changes in stability conditions of the structure.

  18. Electromagnetic nonlinear gyrokinetics with polarization drift

    SciTech Connect

    Duthoit, F.-X.; Hahm, T. S.; Wang, Lu

    2014-08-15

    A set of new nonlinear electromagnetic gyrokinetic Vlasov equation with polarization drift and gyrokinetic Maxwell equations is systematically derived by using the Lie-transform perturbation method in toroidal geometry. For the first time, we recover the drift-kinetic expression for parallel acceleration [R. M. Kulsrud, in Basic Plasma Physics, edited by A. A. Galeev and R. N. Sudan (North-Holland, Amsterdam, 1983)] from the nonlinear gyrokinetic equations, thereby bridging a gap between the two formulations. This formalism should be useful in addressing nonlinear ion Compton scattering of intermediate-mode-number toroidal Alfvén eigenmodes for which the polarization current nonlinearity [T. S. Hahm and L. Chen, Phys. Rev. Lett. 74, 266 (1995)] and the usual finite Larmor radius effects should compete.

  19. Electromagnetic nonlinear gyrokinetics with polarization drift

    NASA Astrophysics Data System (ADS)

    Duthoit, F.-X.; Hahm, T. S.; Wang, Lu

    2014-08-01

    A set of new nonlinear electromagnetic gyrokinetic Vlasov equation with polarization drift and gyrokinetic Maxwell equations is systematically derived by using the Lie-transform perturbation method in toroidal geometry. For the first time, we recover the drift-kinetic expression for parallel acceleration [R. M. Kulsrud, in Basic Plasma Physics, edited by A. A. Galeev and R. N. Sudan (North-Holland, Amsterdam, 1983)] from the nonlinear gyrokinetic equations, thereby bridging a gap between the two formulations. This formalism should be useful in addressing nonlinear ion Compton scattering of intermediate-mode-number toroidal Alfvén eigenmodes for which the polarization current nonlinearity [T. S. Hahm and L. Chen, Phys. Rev. Lett. 74, 266 (1995)] and the usual finite Larmor radius effects should compete.

  20. New Nonlinear Multigrid Analysis

    NASA Technical Reports Server (NTRS)

    Xie, Dexuan

    1996-01-01

    The nonlinear multigrid is an efficient algorithm for solving the system of nonlinear equations arising from the numerical discretization of nonlinear elliptic boundary problems. In this paper, we present a new nonlinear multigrid analysis as an extension of the linear multigrid theory presented by Bramble. In particular, we prove the convergence of the nonlinear V-cycle method for a class of mildly nonlinear second order elliptic boundary value problems which do not have full elliptic regularity.

  1. Highly nonlinear stress-relaxation response of articular cartilage in indentation: Importance of collagen nonlinearity.

    PubMed

    Mäkelä, J T A; Korhonen, R K

    2016-06-14

    Modern fibril-reinforced computational models of articular cartilage can include inhomogeneous tissue composition and structure, and nonlinear mechanical behavior of collagen, proteoglycans and fluid. These models can capture well experimental single step creep and stress-relaxation tests or measurements under small strains in unconfined and confined compression. Yet, it is known that in indentation, especially at high strain velocities, cartilage can express highly nonlinear response. Different fibril reinforced poroelastic and poroviscoelastic models were used to assess measured highly nonlinear stress-relaxation response of rabbit articular cartilage in indentation. Experimentally measured depth-dependent volume fractions of different tissue constituents and their mechanical nonlinearities were taken into account in the models. In particular, the collagen fibril network was modeled using eight separate models that implemented five different constitutive equations to describe the nonlinearity. These consisted of linear elastic, nonlinear viscoelastic and multiple nonlinear elastic representations. The model incorporating the most nonlinearly increasing Young׳s modulus of collagen fibrils as a function of strain captured best the experimental data. Relative difference between the model and experiment was ~3%. Surprisingly, the difference in the peak forces between the experiment and the model with viscoelastic collagen fibrils was almost 20%. Implementation of the measured volume fractions did not improve the ability of the model to capture the measured mechanical data. These results suggest that a highly nonlinear formulation for collagen fibrils is needed to replicate multi-step stress-relaxation response of rabbit articular cartilage in indentation with high strain rates.

  2. Plutonium Immobilization Project Baseline Formulation

    SciTech Connect

    Ebbinghaus, B.

    1999-02-01

    A key milestone for the Immobilization Project (AOP Milestone 3.2a) in Fiscal Year 1998 (FY98) is the definition of the baseline composition or formulation for the plutonium ceramic form. The baseline formulation for the plutonium ceramic product must be finalized before the repository- and plant-related process specifications can be determined. The baseline formulation that is currently specified is given in Table 1.1. In addition to the baseline formulation specification, this report provides specifications for two alternative formulations, related compositional specifications (e.g., precursor compositions and mixing recipes), and other preliminary form and process specifications that are linked to the baseline formulation. The preliminary specifications, when finalized, are not expected to vary tremendously from the preliminary values given.

  3. Mathematical programming formulations for satellite synthesis

    NASA Technical Reports Server (NTRS)

    Bhasin, Puneet; Reilly, Charles H.

    1987-01-01

    The problem of satellite synthesis can be described as optimally allotting locations and sometimes frequencies and polarizations, to communication satellites so that interference from unwanted satellite signals does not exceed a specified threshold. In this report, mathematical programming models and optimization methods are used to solve satellite synthesis problems. A nonlinear programming formulation which is solved using Zoutendijk's method and a gradient search method is described. Nine mixed integer programming models are considered. Results of computer runs with these nine models and five geographically compatible scenarios are presented and evaluated. A heuristic solution procedure is also used to solve two of the models studied. Heuristic solutions to three large synthesis problems are presented. The results of our analysis show that the heuristic performs very well, both in terms of solution quality and solution time, on the two models to which it was applied. It is concluded that the heuristic procedure is the best of the methods considered for solving satellite synthesis problems.

  4. Explosive Formulation Code Naming SOP

    SciTech Connect

    Martz, H. E.

    2014-09-19

    The purpose of this SOP is to provide a procedure for giving individual HME formulations code names. A code name for an individual HME formulation consists of an explosive family code, given by the classified guide, followed by a dash, -, and a number. If the formulation requires preparation such as packing or aging, these add additional groups of symbols to the X-ray specimen name.

  5. Discrete- and finite-bandwidth-frequency distributions in nonlinear stability applications

    NASA Astrophysics Data System (ADS)

    Kuehl, Joseph J.

    2017-02-01

    A new "wave packet" formulation of the parabolized stability equations method is presented. This method accounts for the influence of finite-bandwidth-frequency distributions on nonlinear stability calculations. The methodology is motivated by convolution integrals and is found to appropriately represent nonlinear energy transfer between primary modes and harmonics, in particular nonlinear feedback, via a "nonlinear coupling coefficient." It is found that traditional discrete mode formulations overestimate nonlinear feedback by approximately 70%. This results in smaller maximum disturbance amplitudes than those observed experimentally. The new formulation corrects this overestimation, accounts for the generation of side lobes responsible for spectral broadening, and results in disturbance representation more consistent with the experiment than traditional formulations. A Mach 6 flared-cone example is presented.

  6. Lithography overlay controller formulation

    NASA Astrophysics Data System (ADS)

    Bode, Christopher A.; Toprac, Anthony J.; Edwards, Richard D.; Edgar, Thomas F.

    2000-08-01

    Lithography overlay refers to the measurement of the alignment of successive patterns within the manufacture of semiconductor devices. Control of overlay has become of great importance in semiconductor manufacturing, as the tolerance for overlay error is continually shrinking in order to manufacture next-generation semiconductor products. Run-to-run control has become an attractive solution to many control problems within the industry, including overlay. The term run-to-run control refers to any automated procedure whereby recipe settings are updated between successive process runs in order to keep the process under control. The following discussion will present the formulation of such a controller by examining control of overlay. A brief introduction of overlay will be given, highlighting the control challenge overlay presents. A data management methodology that groups like processes together in order to improve controllability, referred to as control threads, will then be presented. Finally, a discussion of linear model predictive control will show its utility in feedback run-to-run control.

  7. Baseline LAW Glass Formulation Testing

    SciTech Connect

    Kruger, Albert A.; Mooers, Cavin; Bazemore, Gina; Pegg, Ian L.; Hight, Kenneth; Lai, Shan Tao; Buechele, Andrew; Rielley, Elizabeth; Gan, Hao; Muller, Isabelle S.; Cecil, Richard

    2013-06-13

    The major objective of the baseline glass formulation work was to develop and select glass formulations that are compliant with contractual and processing requirements for each of the LAW waste streams. Other objectives of the work included preparation and characterization of glasses with respect to the properties of interest, optimization of sulfate loading in the glasses, evaluation of ability to achieve waste loading limits, testing to demonstrate compatibility of glass melts with melter materials of construction, development of glass formulations to support ILAW qualification activities, and identification of glass formulation issues with respect to contract specifications and processing requirements.

  8. Evaluation of single nucleotide polymorphisms in the phosphodiesterase 4D gene (PDE4D) and their association with ischaemic stroke in a large German cohort.

    PubMed

    Kuhlenbäumer, G; Berger, K; Huge, A; Lange, E; Kessler, C; John, U; Funke, H; Nabavi, D G; Stögbauer, F; Ringelstein, E B; Stoll, M

    2006-04-01

    Genetic fine mapping of the first locus identified for genetically complex forms of stroke, STRK1 (which has been mapped to chromosome 5q12 in Icelandic families), has identified the phosphodiesterase 4D gene (PDE4D) gene as a good candidate gene. Association analysis of single nucleotide polymorphisms (SNPs) in the PDE4D gene in an Icelandic stroke cohort demonstrated genetic association between six SNPs in the 5' region of PDE4D and ischaemic stroke. The present study aimed to test whether the same six SNPs in PDE4D were also associated with stroke in a large stroke cohort from northern Germany (stroke patients with acute completed ischaemic stroke: n = 1181; population based controls: n = 1569). None of the six SNPs showed significant association with ischaemic stroke in the whole stroke sample before and after adjustment for conventional stroke risk factors (age, sex, hypertension, diabetes, and hypercholesterolaemia). Haplotype analysis did also not reveal any significant association. Marginally positive statistical measures of association in the subgroup with cardioembolic stroke did not remain significant after correction for multiple testing. In conclusion, this study was unable to demonstrate an association between the six SNPs which had showed significant single marker association with stroke in the Icelandic stroke cohort and ischaemic stroke in a large German cohort.

  9. Synthesis and biological evaluation of nimesulide based new class of triazole derivatives as potential PDE4B inhibitors against cancer cells.

    PubMed

    Mareddy, Jyoti; Nallapati, Suresh Babu; Anireddy, Jayasree; Devi, Yumnam Priyadarshini; Mangamoori, Lakshmi Narasu; Kapavarapu, Ravikumar; Pal, Sarbani

    2013-12-15

    A new class of 1,2,3-triazol derivatives derived from nimesulide was designed as potential inhibitors of PDE4B. Synthesis of these compounds was carried out via a multi-step sequence consisting of copper-catalyzed azide-alkyne cycloaddition (CuAAC) as a key step in aqueous media. The required azide was prepared via the reaction of aryl amine (obtained from nimesulide) with α-chloroacetyl chloride followed by displacing the α-chloro group by an azide. Some of the synthesized compounds showed encouraging PDE4B inhibitory properties in vitro that is >50% inhibition at 30 μM that were supported by the docking studies of these compounds at the active site of PDE4B enzyme (dock scores ~ -28.6 for a representative compound). Two of these PDE4 inhibitors showed promising cytotoxic properties against HCT-15 human colon cancer cells in vitro with IC50 ~ 21-22 μg/mL.

  10. Segregation of Incomplete Achromatopsia and Alopecia Due to PDE6H and LPAR6 Variants in a Consanguineous Family from Pakistan

    PubMed Central

    Pedurupillay, Christeen Ramane J.; Landsend, Erlend Christoffer Sommer; Vigeland, Magnus Dehli; Ansar, Muhammad; Frengen, Eirik; Misceo, Doriana; Strømme, Petter

    2016-01-01

    We report on two brothers with visual impairment, and non-syndromic alopecia in the elder proband. The parents were first-degree Pakistani cousins. Whole exome sequencing of the elder brother and parents, followed by Sanger sequencing of all four family members, led to the identification of the variants responsible for the two phenotypes. One variant was a homozygous nonsense variant in the inhibitory subunit of the cone-specific cGMP phosphodiesterase gene, PDE6H:c.35C>G (p.Ser12*). PDE6H is expressed in the cones of the retina, which are involved in perception of color vision. This is the second report of a homozygous PDE6H:c.35C>G variant causing incomplete achromatopsia (OMIM 610024), thus strongly supporting the hypothesis that loss-of-function variants in PDE6H cause this visual deficiency phenotype. The second variant was a homozygous missense substitution in the lysophosphatidic acid receptor 6, LPAR6:c.188A>T (p.Asp63Val). LPAR6 acts as a G-protein-coupled receptor involved in hair growth. Biallelic loss-of-function variants in LPAR6 cause hypotrichosis type 8 (OMIM 278150), with or without woolly hair, a form of non-syndromic alopecia. Biallelic LPAR6:c.188A>T was previously described in five families from Pakistan. PMID:27472364

  11. cGMP-PDE3-cAMP signal pathway involved in the inhibitory effect of CNP on gastric motility in rat.

    PubMed

    Cai, Ying-Lan; Sun, Qian; Huang, Xu; Jiang, Jing-Zhi; Zhang, Mo-Han; Piao, Li-Hua; Jin, Zheng; Xu, Wen-Xie

    2013-01-10

    In the present study, we investigated the mechanism of C-type natriuretic peptide (CNP)-induced inhibitory effect on spontaneous contraction of gastric antral smooth muscle to clarify CNP-NPR-B/pGC-cGMP downstream signal transduction pathway using organ bath and ELISA methods in rat. CNP significantly reduced the amplitude of the spontaneous contraction and increased the contents of cGMP and cAMP in the gastric antral smooth muscle tissue. In the presence of IBMX, a non-selective phosphodiesterase (PDE) inhibitor, the inhibitory effect of CNP on spontaneous contraction was significantly suppressed; however, the production of cGMP but not cAMP was still increased by CNP. EHNA, a PDE2 inhibitor, did not affect both CNP-induced inhibition of the contraction and CNP-induced increase of cGMP and cAMP generations in gastric smooth muscle tissue, while milrinone, a PDE3 inhibitor, similar to IBMX, attenuated the CNP-induced inhibitory effect on spontaneous contraction and increased the content of cGMP but not cAMP. The results suggest that cGMP-PDE3-cAMP signal pathway is also involved in the CNP-induced inhibition of gastric motility in rat.

  12. Memory-enhancing effects of GEBR-32a, a new PDE4D inhibitor holding promise for the treatment of Alzheimer's disease.

    PubMed

    Ricciarelli, Roberta; Brullo, Chiara; Prickaerts, Jos; Arancio, Ottavio; Villa, Carla; Rebosio, Claudia; Calcagno, Elisa; Balbi, Matilde; van Hagen, Britt T J; Argyrousi, Elentina K; Zhang, Hong; Pronzato, Maria Adelaide; Bruno, Olga; Fedele, Ernesto

    2017-04-12

    Memory loss characterizes several neurodegenerative disorders, including Alzheimer's disease (AD). Inhibition of type 4 phosphodiesterase (PDE4) and elevation of cyclic adenosine monophosphate (cAMP) has emerged as a promising therapeutic approach to treat cognitive deficits. However, PDE4 exists in several isoforms and pan inhibitors cannot be used in humans due to severe emesis. Here, we present GEBR-32a, a new PDE4D full inhibitor that has been characterized both in vitro and in vivo using biochemical, electrophysiological and behavioural analyses. GEBR-32a efficiently enhances cAMP in neuronal cultures and hippocampal slices. In vivo pharmacokinetic analysis shows that GEBR-32a is rapidly distributed within the central nervous system with a very favourable brain/blood ratio. Specific behavioural tests (object location and Y-maze continuous alternation tasks) demonstrate that this PDE4D inhibitor is able to enhance memory in AD transgenic mice and concomitantly rescues their hippocampal long-term potentiation deficit. Of great relevance, our preliminary toxicological analysis indicates that GEBR-32a is not cytotoxic and genotoxic, and does not seem to possess emetic-like side effects. In conclusion, GEBR-32a could represent a very promising cognitive-enhancing drug with a great potential for the treatment of Alzheimer's disease.

  13. NCX-911, a novel nitric oxide-releasing PDE5 inhibitor relaxes rabbit corpus cavernosum in the absence of endogenous nitric oxide.

    PubMed

    Kalsi, J S; Kell, P D; Cellek, S; Ralph, D J

    2004-04-01

    Phosphodiesterase type 5 (PDE5) inhibitors have reduced efficacy in treating erectile dysfunction (ED) in conditions where there is a lack of endogenous nitric oxide (NO). Therefore, NO-releasing PDE5 inhibitors have been developed. Here we report the effect of such a compound, NCX-911, on the tone and nitrergic relaxations of rabbit corpus cavernosum in the absence or presence of a NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME; 500 microM). NCX-911 was found to be as potent as sildenafil at inducing relaxation of rabbit cavernosum (EC(50) values 997.8+/-195.7 and 1000.5+/-140.8 nM, respectively). The potency of NCX-911 was not altered, but that of sildenafil decreased five-fold in the presence of L-NAME (EC(50) values 1281.2+/-268.3 and 4959.1+/-882.1, nM respectively, P<0.001 for sildenafil). Both compounds potentiated nitrergic relaxations with similar potencies. These results suggest that NO-releasing PDE5 inhibitors could potentially be more useful than PDE5 inhibitors in the treatment of ED in conditions where there is a lack of endogenous NO.

  14. Aminoalkyl Derivatives of 8-Alkoxypurine-2,6-diones: Multifunctional 5-HT1A /5-HT7 Receptor Ligands and PDE Inhibitors with Antidepressant Activity.

    PubMed

    Chłoń-Rzepa, Grażyna; Zagórska, Agnieszka; Żmudzki, Paweł; Bucki, Adam; Kołaczkowski, Marcin; Partyka, Anna; Wesołowska, Anna; Kazek, Grzegorz; Głuch-Lutwin, Monika; Siwek, Agata; Starowicz, Gabriela; Pawłowski, Maciej

    2016-12-01

    In the search for potential psychotropic agents, a new series of 3,7-dimethyl- and 1,3-dimethyl-8-alkoxypurine-2,6-dione derivatives of arylpiperazines, perhydroisoquinolines, or tetrahydroisoquinolines with flexible alkylene spacers (5-16 and 21-32) were synthesized and evaluated for 5-HT1A /5-HT7 receptor affinities as well as PDE4B1 and PDE10A inhibitory properties. The 1-(4-(4-(2-hydroxyphenyl)piperazin-1-yl)butyl)-3,7-dimethyl-8-propoxypurine-2,6-dione (16) and 7-(2-hydroxyphenyl)piperazinylalkyl-1,3-dimethyl-8-ethoxypurine-2,6-diones (31 and 32) as potent dual 5-HT1A /5-HT7 receptor ligands with antagonistic activity produced an antidepressant-like effect in the forced swim test in mice. This effect was similar to that produced by citalopram. All the tested compounds were stronger phosphodiesterase isoenzyme inhibitors than theophylline and theobromine. The most potent compounds, 15 and 16, were characterized by 51 and 52% inhibition, respectively, of PDE4B1 activity at a concentration of 10(-5)  M. Concerning the above findings, it may be assumed that the inhibition of PDE4B1 may impact on the signal strength and specificity resulting from antagonism toward the 5-HT1 and 5-HT7 receptors, especially in the case of compounds 15 and 16. This dual receptor and enzyme binding mode was analyzed and explained via molecular modeling studies.

  15. Discovery of novel PDE9 inhibitors capable of inhibiting Aβ aggregation as potential candidates for the treatment of Alzheimer’s disease

    NASA Astrophysics Data System (ADS)

    Su, Tao; Zhang, Tianhua; Xie, Shishun; Yan, Jun; Wu, Yinuo; Li, Xingshu; Huang, Ling; Luo, Hai-Bin

    2016-02-01

    Recently, phosphodiesterase-9 (PDE9) inhibitors and biometal-chelators have received much attention as potential therapeutics for the treatment of Alzheimer’s disease (AD). Here, we designed, synthesized, and evaluated a novel series of PDE9 inhibitors with the ability to chelate metal ions. The bioassay results showed that most of these molecules strongly inhibited PDE9 activity. Compound 16 showed an IC50 of 34 nM against PDE9 and more than 55-fold selectivity against other PDEs. In addition, this compound displayed remarkable metal-chelating capacity and a considerable ability to halt copper redox cycling. Notably, in comparison to the reference compound clioquinol, it inhibited metal-induced Aβ1-42 aggregation more effectively and promoted greater disassembly of the highly structured Aβ fibrils generated through Cu2+-induced Aβ aggregation. These activities of 16, together with its favorable blood-brain barrier permeability, suggest that 16 may be a promising compound for treatment of AD.

  16. PDE5 Inhibitors-Loaded Nanovesicles: Physico-Chemical Properties and In Vitro Antiproliferative Activity

    PubMed Central

    De Rose, Roberta F.; Cristiano, Maria Chiara; Celano, Marilena; Maggisano, Valentina; Vero, Ada; Lombardo, Giovanni Enrico; Di Francesco, Martina; Paolino, Donatella; Russo, Diego; Cosco, Donato

    2016-01-01

    Novel therapeutic approaches are required for the less differentiated thyroid cancers which are non-responsive to the current treatment. In this study we tested an innovative formulation of nanoliposomes containing sildenafil citrate or tadalafil, phosphodiesterase-5 inhibitors, on two human thyroid cancer cell lines (TPC-1 and BCPAP). Nanoliposomes were prepared by the thin layer evaporation and extrusion methods, solubilizing the hydrophilic compound sildenafil citrate in the aqueous phase during the hydration step and dissolving the lipophilic tadalafil in the organic phase. Nanoliposomes, made up of 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine monohydrate (DPPC), cholesterol, and N-(carbonyl-methoxypolyethylene glycol-2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE-mPEG2000) (6:3:1 molar ratio), were characterized by a mean diameter of ~100 nm, a very low polydispersity index (~0.1) and a negative surface charge. The drugs did not influence the physico-chemical properties of the systems and were efficiently retained in the colloidal structure. By using cell count and MTT assay, we found a significant reduction of the viability in both cell lines following 24 h treatment with both nanoliposomal-encapsulated drugs, notably greater than the effect of the free drugs. Our findings demonstrate that nanoliposomes increase the antiproliferative activity of phosphodiesterase-5 inhibitors, providing a useful novel formulation for the treatment of thyroid carcinoma.

  17. A PDE-based methodology for modeling, parameter estimation and feedback control in structural and structural acoustic systems

    NASA Technical Reports Server (NTRS)

    Banks, H. T.; Brown, D. E.; Metcalf, Vern L.; Silcox, R. J.; Smith, Ralph C.; Wang, Yun

    1994-01-01

    A problem of continued interest concerns the control of vibrations in a flexible structure and the related problem of reducing structure-borne noise in structural acoustic systems. In both cases, piezoceramic patches bonded to the structures have been successfully used as control actuators. Through the application of a controlling voltage, the patches can be used to reduce structural vibrations which in turn lead to methods for reducing structure-borne noise. A PDE-based methodology for modeling, estimating physical parameters, and implementing a feedback control scheme for problems of this type is discussed. While the illustrating example is a circular plate, the methodology is sufficiently general so as to be applicable in a variety of structural and structural acoustic systems.

  18. The dynamics of p53 in single cells: physiologically based ODE and reaction-diffusion PDE models

    NASA Astrophysics Data System (ADS)

    Eliaš, Ján; Dimitrio, Luna; Clairambault, Jean; Natalini, Roberto

    2014-08-01

    The intracellular signalling network of the p53 protein plays important roles in genome protection and the control of cell cycle phase transitions. Recently observed oscillatory behaviour in single cells under stress conditions has inspired several research groups to simulate and study the dynamics of the protein with the aim of gaining a proper understanding of the physiological meanings of the oscillations. We propose compartmental ODE and PDE models of p53 activation and regulation in single cells following DNA damage and we show that the p53 oscillations can be retrieved by plainly involving p53-Mdm2 and ATM-p53-Wip1 negative feedbacks, which are sufficient for oscillations experimentally, with no further need to introduce any delays into the protein responses and without considering additional positive feedback.

  19. Geometrically nonlinear behavior of piezoelectric laminated plates

    NASA Astrophysics Data System (ADS)

    Rabinovitch, Oded

    2005-08-01

    The geometrically nonlinear behavior of piezo-laminated plates actuated with isotropic or anisotropic piezoelectric layers is analytically investigated. The analytical model is derived using the variational principle of virtual work along with the lamination and plate theories, the von Karman large displacement and moderate rotation kinematic relations, and the anisotropic piezoelectric constitutive laws. A solution strategy that combines the approach of the method of lines, the advantages of the finite element concept, and the variational formulation is developed. This approach yields a set of nonlinear ordinary differential equations with nonlinear boundary conditions, which are solved using the multiple-shooting method. Convergence and verification of the model are examined through comparison with linear and nonlinear results of other approximation methods. The nonlinear response of two active plate structures is investigated numerically. The first plate is actuated in bending using monolithic piezoceramic layers and the second one is actuated in twist using macro-fiber composites. The results quantitatively reveal the complicated in-plane stress state associated with the piezoelectric actuation and the geometrically nonlinear coupling of the in-plane and out-of-plane responses of the plate. The influence of the nonlinear effects ranges from significant stiffening in certain combinations of electrical loads and boundary conditions to amplifications of the induced deflections in others. The paper closes with a summary and conclusions.

  20. First-in-Human Assessment of the Novel PDE2A PET Radiotracer 18F-PF-05270430

    PubMed Central

    Waterhouse, Rikki N.; Nabulsi, Nabeel; Lin, Shu-Fei; Labaree, David; Ropchan, Jim; Tarabar, Sanela; DeMartinis, Nicholas; Ogden, Adam; Banerjee, Anindita; Huang, Yiyun; Carson, Richard E.

    2016-01-01

    This was a first-in-human study of the novel phosphodiesterase-2A (PDE2A) PET ligand 18F-PF-05270430. The primary goals were to determine the appropriate tracer kinetic model to quantify brain uptake and to examine the within-subject test–retest variability. Methods: In advance of human studies, radiation dosimetry was determined in nonhuman primates. Six healthy male subjects participated in a test–retest protocol with dynamic scans and metabolite-corrected input functions. Nine brain regions of interest were studied, including the striatum, white matter, neocortical regions, and cerebellum. Multiple modeling methods were applied to calculate volume of distribution (VT) and binding potentials relative to the nondisplaceable tracer in tissue (BPND), concentration of tracer in plasma (BPP), and free tracer in tissue (BPF). The cerebellum was selected as a reference region to calculate binding potentials. Results: The dosimetry study provided an effective dose of less than 0.30 mSv/MBq, with the gallbladder as the critical organ; the human target dose was 185 MBq. There were no adverse events or clinically detectable pharmacologic effects reported. Tracer uptake was highest in the striatum, followed by neocortical regions and white matter, and lowest in the cerebellum. Regional time–activity curves were well fit by multilinear analysis-1, and a 70-min scan duration was sufficient to quantify VT and the binding potentials. BPND, with mean values ranging from 0.3 to 0.8, showed the best intrasubject and intersubject variability and reliability. Test–retest variability in the whole brain (excluding the cerebellum) of VT, BPND, and BPP were 8%, 16%, and 17%, respectively. Conclusion: 18F-PF-05270430 shows promise as a PDE2A PET ligand, albeit with low binding potential values. PMID:27103022

  1. Restoration of Vision in the pde6β-deficient Dog, a Large Animal Model of Rod-cone Dystrophy

    PubMed Central

    Petit, Lolita; Lhériteau, Elsa; Weber, Michel; Le Meur, Guylène; Deschamps, Jack-Yves; Provost, Nathalie; Mendes-Madeira, Alexandra; Libeau, Lyse; Guihal, Caroline; Colle, Marie-Anne; Moullier, Philippe; Rolling, Fabienne

    2012-01-01

    Defects in the β subunit of rod cGMP phosphodiesterase 6 (PDE6β) are associated with autosomal recessive retinitis pigmentosa (RP), a childhood blinding disease with early retinal degeneration and vision loss. To date, there is no treatment for this pathology. The aim of this preclinical study was to test recombinant adeno-associated virus (AAV)-mediated gene addition therapy in the rod-cone dysplasia type 1 (rcd1) dog, a large animal model of naturally occurring PDE6β deficiency that strongly resembles the human pathology. A total of eight rcd1 dogs were injected subretinally with AAV2/5RK.cpde6β (n = 4) or AAV2/8RK.cpde6β (n = 4). In vivo and post-mortem morphological analysis showed a significant preservation of the retinal structure in transduced areas of both AAV2/5RK.cpde6β- and AAV2/8RK.cpde6β-treated retinas. Moreover, substantial rod-derived electroretinography (ERG) signals were recorded as soon as 1 month postinjection (35% of normal eyes) and remained stable for at least 18 months (the duration of the study) in treated eyes. Rod-responses were undetectable in untreated contralateral eyes. Most importantly, dim-light vision was restored in all treated rcd1 dogs. These results demonstrate for the first time that gene therapy effectively restores long-term retinal function and vision in a large animal model of autosomal recessive rod-cone dystrophy, and provide great promise for human treatment. PMID:22828504

  2. Saltstone Clean Cap Formulation

    SciTech Connect

    Langton, C

    2005-04-22

    The current operation strategy for using Saltstone Vault 4 to receive 0.2 Ci/gallon salt solution waste involves pouring a clean grout layer over the radioactive grout prior to initiating pour into another cell. This will minimize the radiating surface area and reduce the dose rate at the vault and surrounding area. The Clean Cap will be used to shield about four feet of Saltstone poured into a Z-Area vault cell prior to moving to another cell. The minimum thickness of the Clean Cap layer will be determined by the cesium concentration and resulting dose levels and it is expected to be about one foot thick based on current calculations for 0.1 Ci Saltstone that is produced in the Saltstone process by stabilization of 0.2 Ci salt solution. This report documents experiments performed to identify a formulation for the Clean Cap. Thermal transient calculations, adiabatic temperature rise measurements, pour height, time between pour calculations and shielding calculations were beyond the scope and time limitations of this study. However, data required for shielding calculations (composition and specific gravity) are provided for shielding calculations. The approach used to design a Clean Cap formulation was to produce a slurry from the reference premix (10/45/45 weight percent cement/slag/fly ash) and domestic water that resembled as closely as possible the properties of the Saltstone slurry. In addition, options were investigated that may offer advantages such as less bleed water and less heat generation. The options with less bleed water required addition of dispersants. The options with lower heat contained more fly ash and less slag. A mix containing 10/45/45 weight percent cement/slag/fly ash with a water to premix ratio of 0.60 is recommended for the Clean Cap. Although this mix may generate more than 3 volume percent standing water (bleed water), it has rheological, mixing and flow properties that are similar to previously processed Saltstone. The recommended

  3. Robustness of self-organizing chemoattractant field arising from precise pulse induction of its breakdown enzyme: a single-cell level analysis of PDE expression in Dictyostelium.

    PubMed

    Masaki, Noritaka; Fujimoto, Koichi; Honda-Kitahara, Mai; Hada, Emi; Sawai, Satoshi

    2013-03-05

    The oscillation of chemoattractant cyclic AMP (cAMP) in Dictyostelium discoideum is a collective phenomenon that occurs when the basal level of extracellular cAMP exceeds a threshold and invokes cooperative mutual excitation of cAMP synthesis and secretion. For pulses to be relayed from cell to cell repetitively, secreted cAMP must be cleared and brought down to the subthreshold level. One of the main determinants of the oscillatory behavior is thus how much extracellular cAMP is degraded by extracellular phosphodiesterase (PDE). To date, the exact nature of PDE gene regulation remains elusive. Here, we performed live imaging analysis of mRNA transcripts for pdsA--the gene encoding extracellular PDE. Our analysis revealed that pdsA is upregulated during the rising phase of cAMP oscillations. Furthermore, by analyzing isolated cells, we show that expression of pdsA is strictly dependent on the presence of extracellular cAMP. pdsA is induced only at ∼1 nM extracellular cAMP, which is almost identical to the threshold concentration for the cAMP relay response. The observed precise regulation of PDE expression together with degradation of extracellular cAMP by PDE form a dual positive and negative feedback circuit, and model analysis shows that this sets the cAMP level near the threshold concentration for the cAMP relay response for a wide range of adenylyl cyclase activity. The overlap of the thresholds could allow oscillations of chemoattractant cAMP to self-organize at various starving conditions, making its development robust to fluctuations in its environment.

  4. t(4;8)(q27;q24) in Hodgkin lymphoma cells targets phosphodiesterase PDE5A and homeobox gene ZHX2.

    PubMed

    Nagel, Stefan; Schneider, Björn; Rosenwald, Andreas; Meyer, Corinna; Kaufmann, Maren; Drexler, Hans G; MacLeod, Roderick A F

    2011-12-01

    Hodgkin/Reed-Sternberg (HRS) cells represent the malignant fraction of infiltrated lymph nodes in Hodgkin lymphoma (HL). Although HRS cells display multiple chromosomal aberrations, few are recurrent and the targeted genes unknown. However, understanding the pathology of HL and developing rational therapies may well require identifying putative deregulated genes. Here, we analyzed the karyotype of the well-defined HL cell line L-1236 by spectral karyotyping and identified multiple abnormalities, therein, notably t(4;8)(q27;q24) which includes two breakpoint regions previously highlighted in HL. Target genes at 4q27 and 8q24 were shortlisted by high density genomic arrays and fluorescence in situ hybridization. Expression analysis of candidate target genes revealed conspicuous activation of phosphodiesterase PDE5A at 4q27 and inhibition of homeobox gene ZHX2 at 8q24. Treatment of L-1236 with PDE5A-inhibitor sildenafil or with siRNA directed against PDE5A and concomitant stimulation with cyclic guanosine monophosphate (cGMP) resulted in enhanced apoptosis, indicating PDE5A as an oncogene. Expression profiling of L-1236 cells following siRNA-mediated knockdown of ZHX2 showed inhibition of genes regulating differentiation and apoptosis, suggesting tumor suppressor activity of ZHX2. Downstream genes included STAT1 and several STAT1-target genes, indicating activation of STAT1-signaling by ZHX2 as analyzed by RQ-PCR and western blot. Taken together, we have identified a novel aberration with recurrent breakpoints in HL, t(4;8)(q27;q24), which activate PDE5A and repress ZHX2, deregulating apoptosis, differentiation, and STAT1-signaling in HL cells.

  5. Evaluation of a novel PDE10A PET radioligand, [(11) C]T-773, in nonhuman primates: brain and whole body PET and brain autoradiography.

    PubMed

    Takano, Akihiro; Stepanov, Vladimir; Gulyás, Balázs; Nakao, Ryuji; Amini, Nahid; Miura, Shotaro; Kimura, Haruhide; Taniguchi, Takahiko; Halldin, Christer

    2015-07-01

    Phosphodiesterase 10A (PDE10A) is considered to be a key target for the treatment of several neuropsychiatric diseases. The characteristics of [(11) C]T-773, a novel positron emission tomography (PET) radioligand with high binding affinity and selectivity for PDE10A, were evaluated in autoradiography and in nonhuman primate (NHP) PET. Brain PET measurements were performed under baseline conditions and after administration of a selective PDE10A inhibitor, MP-10. Total distribution volume (VT ) and binding potential (BPND ) were calculated using various kinetic models. Whole body PET measurements were performed to calculate the effective dose of [(11) C]T-773. Autoradiography studies in postmortem human and monkey brain sections showed high accumulation of [(11) C]T-773 in the striatum and substantia nigra which was blocked by MP-10. Brain PET showed high accumulation of [(11) C]T-773 in the striatum, and the data could be fitted using a two tissue compartment model. BPND was approximately 1.8 in the putamen when the cerebellum was used as the reference region. Approximately 70% of PDE10A binding was occupied by 1.8 mg/kg of MP-10. Whole body PET showed high accumulation of [(11) C]T-773 in the liver, kidney, heart, and brain in the initial phase. The radioligand was partly excreted via bile and the gastrointestinal tract, and partly excreted through the urinary tract. The calculated effective dose was 0.007 mSv/MBq. In conclusion, [(11) C]T-773 was demonstrated to be a promising PET radioligand for PDE10A with favorable brain kinetics. Dosimetry results support multiple PET measurements per person in human studies. Further research is required with [(11) C]T-773 in order to test the radioligand's potential clinical applications.

  6. Viscous Nonlinear Dynamics of Twist and Writhe

    NASA Astrophysics Data System (ADS)

    Goldstein, Raymond E.; Powers, Thomas R.; Wiggins, Chris H.

    1998-06-01

    Exploiting the ``natural'' frame of space curves, we formulate an intrinsic dynamics of a twisted elastic filament in a viscous fluid. Coupled nonlinear equations describing the temporal evolution of the filament's complex curvature and twist density capture the dynamic interplay of twist and writhe. These equations are used to illustrate a remarkable nonlinear phenomenon: geometric untwisting of open filaments, whereby twisting strains relax through a transient writhing instability without axial rotation. Experimentally observed writhing motions of fibers of the bacterium B. subtilis [N. H. Mendelson et al., J. Bacteriol. 177, 7060 (1995)] may be examples of this untwisting process.

  7. Biopsychosocial Formulation: Recognizing Educational Shortcomings

    ERIC Educational Resources Information Center

    McClain, Tina; O'Sullivan, Patricia S.; Clardy, James A.

    2004-01-01

    Objective: Since Engel introduced the biopsychosocial model, it has been extensively examined. The authors expect psychiatrists to formulate cases using the biopsychosocial model. However, resident psychiatrists' ability to generate formulations using this model has received little attention. Methods: The authors evaluated resident biopsychosocial…

  8. Operator Formulation of Classical Mechanics.

    ERIC Educational Resources Information Center

    Cohn, Jack

    1980-01-01

    Discusses the construction of an operator formulation of classical mechanics which is directly concerned with wave packets in configuration space and is more similar to that of convential quantum theory than other extant operator formulations of classical mechanics. (Author/HM)

  9. Filtering by nonlinear systems.

    PubMed

    Campos Cantón, E; González Salas, J S; Urías, J

    2008-12-01

    Synchronization of nonlinear systems forced by external signals is formalized as the response of a nonlinear filter. Sufficient conditions for a nonlinear system to behave as a filter are given. Some examples of generalized chaos synchronization are shown to actually be special cases of nonlinear filtering.

  10. MGGHAT: Elliptic PDE software with adaptive refinement, multigrid and high order finite elements

    NASA Technical Reports Server (NTRS)

    Mitchell, William F.

    1993-01-01

    MGGHAT (MultiGrid Galerkin Hierarchical Adaptive Triangles) is a program for the solution of linear second order elliptic partial differential equations in two dimensional polygonal domains. This program is now available for public use. It is a finite element method with linear, quadratic or cubic elements over triangles. The adaptive refinement via newest vertex bisection and the multigrid iteration are both based on a hierarchical basis formulation. Visualization is available at run time through an X Window display, and a posteriori through output files that can be used as GNUPLOT input. In this paper, we describe the methods used by MGGHAT, define the problem domain for which it is appropriate, illustrate use of the program, show numerical and graphical examples, and explain how to obtain the software.

  11. Element-specific modal formulations for large-displacement multibody dynamics

    NASA Technical Reports Server (NTRS)

    Ryan, R. R.; Yoo, H. H.

    1989-01-01

    Large dispacement assumed-mode modeling techniques are examined in the context of multibody elastodynamics. The range of both general and element-specific approaches are studied with the aid of examples involving beams, plates, and shells. For systems undergoing primarily structural bending and twisting with little or no membrane distortion, it is found that fully-linear, element-specific, modal formulations provide the most accurate time history solutions at the least expense. When membrane effects become dominant in structural problems due to loading and boundary conditions, one must naturally resort to a formulation involving a nonlinear stress-strain relationship in addition to nonlinear terms associated with large overall system motion. Such nonlinear models were investigated using assumed modes and found to lead to modal convergence difficulties when standard free-free structural modes are employed. A constrained mode formulation aimed at addressing the convergence problem is proposed.

  12. Novel Formulations for Antimicrobial Peptides

    PubMed Central

    Carmona-Ribeiro, Ana Maria; Carrasco, Letícia Dias de Melo

    2014-01-01

    Peptides in general hold much promise as a major ingredient in novel supramolecular assemblies. They may become essential in vaccine design, antimicrobial chemotherapy, cancer immunotherapy, food preservation, organs transplants, design of novel materials for dentistry, formulations against diabetes and other important strategical applications. This review discusses how novel formulations may improve the therapeutic index of antimicrobial peptides by protecting their activity and improving their bioavailability. The diversity of novel formulations using lipids, liposomes, nanoparticles, polymers, micelles, etc., within the limits of nanotechnology may also provide novel applications going beyond antimicrobial chemotherapy. PMID:25302615

  13. Novel formulations for antimicrobial peptides.

    PubMed

    Carmona-Ribeiro, Ana Maria; de Melo Carrasco, Letícia Dias

    2014-10-09

    Peptides in general hold much promise as a major ingredient in novel supramolecular assemblies. They may become essential in vaccine design, antimicrobial chemotherapy, cancer immunotherapy, food preservation, organs transplants, design of novel materials for dentistry, formulations against diabetes and other important strategical applications. This review discusses how novel formulations may improve the therapeutic index of antimicrobial peptides by protecting their activity and improving their bioavailability. The diversity of novel formulations using lipids, liposomes, nanoparticles, polymers, micelles, etc., within the limits of nanotechnology may also provide novel applications going beyond antimicrobial chemotherapy.

  14. A Dependency-Driven Formulation of Parareal: Parallel-in-Time Solution of PDEs as a Many-Task Application

    SciTech Connect

    Elwasif, Wael R; Foley, Samantha S; Bernholdt, David E; Berry, Lee A; Samaddar, D.; Newman, David E; Sanchez, R.

    2011-01-01

    Parareal is a novel algorithm that allows the solution of time-dependent systems of differential or partial differential equations (PDE) to be parallelized in the temporal domain. Parareal-based implementations of PDE problems can take advantage of this parallelism to significantly reduce the time to solution for a simulation (though at an increased total cost) while making effective use of the much larger processor counts available on current high-end systems. In this paper, we present a dynamic, dependency-driven version of the parareal algorithm which breaks the final sequential bottleneck remaining in the original formulation, making it amenable to a "many-task" treatment. We further improve the cost and execution time of the algorithm by introducing a moving window for time slices, which avoids the execution of tasks which contribute little to the final global solution. We describe how this approach has been realized in the Integrated Plasma Simulator (IPS), a framework for coupled multiphysics simulations, and examine the trade-offs among time-to-solution, total cost, and resource utilization efficiency as a function of the compute resources applied to the problem.

  15. Pesticide formulations and application systems

    SciTech Connect

    Kaneko; Spicer

    1985-01-01

    This book discusses pesticide formulations; spraying techniques and/or low and ultra low volume applications employing oil carriers, including subsurface drip irrigation and plant growth regulators; and granule technology.

  16. Nonlinear Wave-Packet Dynamics in a Disordered Medium

    SciTech Connect

    Schwiete, G.; Finkel'stein, A. M.

    2010-03-12

    We develop an effective theory of pulse propagation in a nonlinear and disordered medium in two dimensions. The theory is formulated in terms of a nonlinear diffusion equation. Despite its apparent simplicity this equation describes novel phenomena which we refer to as 'locked explosion' and diffusive collapse. The equation can be applied to such distinct physical systems as laser beams propagating in disordered photonic crystals or Bose-Einstein condensates expanding in a disordered environment.

  17. Valuation of financial models with non-linear state spaces

    NASA Astrophysics Data System (ADS)

    Webber, Nick

    2001-02-01

    A common assumption in valuation models for derivative securities is that the underlying state variables take values in a linear state space. We discuss numerical implementation issues in an interest rate model with a simple non-linear state space, formulating and comparing Monte Carlo, finite difference and lattice numerical solution methods. We conclude that, at least in low dimensional spaces, non-linear interest rate models may be viable.

  18. Bioavailability of cefuroxime axetil formulations.

    PubMed

    Donn, K H; James, N C; Powell, J R

    1994-06-01

    Cefuroxime axetil tablets have proved effective for the treatment of a variety of community-acquired infections. A suspension formulation has been developed for use in children. Two studies have been conducted to determine if the cefuroxime axetil formulations are bioequivalent. In the initial randomized, two-period crossover study, 24 healthy men received 250-mg doses of suspension and tablet formulations of cefuroxime axetil every 12 h after eating for seven doses. Each treatment period was separated by 4 days. Comparisons of serum and urine pharmacokinetic parameters indicated that the suspension and tablet formulations of cefuroxime axetil are not bioequivalent. Following the initial bioequivalency study, 0.1 % sodium lauryl sulfate (SLS) was added to the suspension to assure the homogeneity of the granules during the manufacturing process. In the subsequent randomized, three-period crossover study, 24 healthy men received single 250-mg doses of three cefuroxime axetil formulations: suspension without SLS, suspension with SLS, and tablet. Again each treatment period was separated by 4 days. Pharmacokinetic analyses demonstrated that while the suspension with SLS and suspension without SLS are bioequivalent, bioequivalence between the suspension with SLS and the tablet was not observed. Thus, the addition of the SLS surfactant to the suspension did not alter the bioavailability of the formulation.

  19. Nonlinear theory of a plasma Cherenkov maser

    SciTech Connect

    Choi, J.S.; Heo, E.G.; Choi, D.I.

    1995-12-31

    The nonlinear saturation state in a plasma Cherenkov maser (PCM) propagating the intense relativistic electron beam through a circular waveguide partially filled with a dense annular plasma, is analyzed from the nonlinear formulation based on the cold fluid-Maxwell equations. We obtain the nonlinear efficiency and the final operation frequency under consideration of the effects of the beam current, the beam energy and the slow wave structure. We show that the saturation mechanism of a PCM instablity is a close correspondence in that of the relativistic two stream instability by the coherent trapping of electrons in a single most-ustable wave. And the optimal conditions in PCM operation are also obtained from performing our nonliear analysis together with computer simulations.

  20. Dynamic analysis of nonlinear rotor-housing systems

    NASA Technical Reports Server (NTRS)

    Noah, Sherif T.

    1988-01-01

    Nonlinear analysis methods are developed which will enable the reliable prediction of the dynamic behavior of the space shuttle main engine (SSME) turbopumps in the presence of bearing clearances and other local nonlinearities. A computationally efficient convolution method, based on discretized Duhamel and transition matrix integral formulations, is developed for the transient analysis. In the formulation, the coupling forces due to the nonlinearities are treated as external forces acting on the coupled subsystems. Iteration is utilized to determine their magnitudes at each time increment. The method is applied to a nonlinear generic model of the high pressure oxygen turbopump (HPOTP). As compared to the fourth order Runge-Kutta numerical integration methods, the convolution approach proved to be more accurate and more highly efficient. For determining the nonlinear, steady-state periodic responses, an incremental harmonic balance method was also developed. The method was successfully used to determine dominantly harmonic and subharmonic responses fo the HPOTP generic model with bearing clearances. A reduction method similar to the impedance formulation utilized with linear systems is used to reduce the housing-rotor models to their coordinates at the bearing clearances. Recommendations are included for further development of the method, for extending the analysis to aperiodic and chaotic regimes and for conducting critical parameteric studies of the nonlinear response of the current SSME turbopumps.

  1. Nonlinear Hysteretic Torsional Waves

    NASA Astrophysics Data System (ADS)

    Cabaret, J.; Béquin, P.; Theocharis, G.; Andreev, V.; Gusev, V. E.; Tournat, V.

    2015-07-01

    We theoretically study and experimentally report the propagation of nonlinear hysteretic torsional pulses in a vertical granular chain made of cm-scale, self-hanged magnetic beads. As predicted by contact mechanics, the torsional coupling between two beads is found to be nonlinear hysteretic. This results in a nonlinear pulse distortion essentially different from the distortion predicted by classical nonlinearities and in a complex dynamic response depending on the history of the wave particle angular velocity. Both are consistent with the predictions of purely hysteretic nonlinear elasticity and the Preisach-Mayergoyz hysteresis model, providing the opportunity to study the phenomenon of nonlinear dynamic hysteresis in the absence of other types of material nonlinearities. The proposed configuration reveals a plethora of interesting phenomena including giant amplitude-dependent attenuation, short-term memory, as well as dispersive properties. Thus, it could find interesting applications in nonlinear wave control devices such as strong amplitude-dependent filters.

  2. Nonlinear Hysteretic Torsional Waves.

    PubMed

    Cabaret, J; Béquin, P; Theocharis, G; Andreev, V; Gusev, V E; Tournat, V

    2015-07-31

    We theoretically study and experimentally report the propagation of nonlinear hysteretic torsional pulses in a vertical granular chain made of cm-scale, self-hanged magnetic beads. As predicted by contact mechanics, the torsional coupling between two beads is found to be nonlinear hysteretic. This results in a nonlinear pulse distortion essentially different from the distortion predicted by classical nonlinearities and in a complex dynamic response depending on the history of the wave particle angular velocity. Both are consistent with the predictions of purely hysteretic nonlinear elasticity and the Preisach-Mayergoyz hysteresis model, providing the opportunity to study the phenomenon of nonlinear dynamic hysteresis in the absence of other types of material nonlinearities. The proposed configuration reveals a plethora of interesting phenomena including giant amplitude-dependent attenuation, short-term memory, as well as dispersive properties. Thus, it could find interesting applications in nonlinear wave control devices such as strong amplitude-dependent filters.

  3. Thermodynamic and structural characterization of halogen bonding in protein-ligand interactions: a case study of PDE5 and its inhibitors.

    PubMed

    Ren, Jing; He, Yang; Chen, Wuyan; Chen, Tiantian; Wang, Guan; Wang, Zhen; Xu, Zhijian; Luo, Xiaomin; Zhu, Weiliang; Jiang, Hualiang; Shen, Jingshan; Xu, Yechun

    2014-04-24

    The significance of halogen bonding in protein-ligand interactions has been recognized recently. We present here the first comprehensive thermodynamic and structural characterization of halogen bonding in PDE5-inhibitor interactions. ITC studies reveal that binding strength of the halogen bonding between chlorine, bromine, and iodine of inhibitor and the protein is -1.57, -3.09, and -5.59 kJ/mol, respectively. The halogens interact with the designed residue Y612 and an unexpected buried water molecule.

  4. Increased PDE5 activity and decreased Rho kinase and PKC activities in colonic muscle from caveolin-1-/- mice impair the peristaltic reflex and propulsion.

    PubMed

    Mahavadi, Sunila; Bhattacharya, Sayak; Kumar, Divya P; Clay, Chereena; Ross, Gracious; Akbarali, Hamid I; Grider, John R; Murthy, Karnam S

    2013-12-01

    Caveolae are specialized regions of the plasma membrane that concentrate receptors and associated signaling molecules critical in regulation of cellular response to transmitters and hormones. We have determined the effects of caveolin-1 (Cav-1) deletion, caveolin-1 siRNA, and caveolar disruption in mice on the signaling pathways that mediate contraction and relaxation in colonic smooth muscle and on the components of the peristaltic reflex in isolated tissue and propulsion in intact colonic segments. In Cav-1-/- mice, both relaxation and contraction were decreased in smooth muscle cells and muscle strips, as well as during both phases of the peristaltic reflex and colonic propulsion. The decrease in relaxation in response to the nitric oxide (NO) donor was accompanied by a decrease in cGMP levels and an increase in phosphodiesterase 5 (PDE5) activity. Relaxation by a PDE5-resistant cGMP analog was not affected in smooth muscle of Cav-1-/- mice, suggesting that inhibition of relaxation was due to augmentation of PDE5 activity. Similar effects on relaxation, PDE5 and cGMP were obtained in muscle cells upon disruption of caveolae by methyl-β-cyclodextrin or suppression of Cav-1. Sustained contraction mediated via inhibition of myosin light chain phosphatase (MLCP) activity is regulated by Rho kinase and PKC via phosphorylation of two endogenous inhibitors of MLCP: myosin phosphatase-targeting subunit (MYPT1) and 17-kDa PKC-potentiated protein phosphatase 1 inhibitor protein (CPI-17), respectively. The activity of both enzymes and phosphorylation of MYPT1 and CPI-17 were decreased in smooth muscle from Cav-1-/- mice. We conclude that the integrity of caveolae is essential for contractile and relaxant activity in colonic smooth muscle and the maintenance of neuromuscular function at organ level.

  5. Differential effects of black raspberry and strawberry extracts on BaPDE-induced activation of transcription factors and their target genes.

    PubMed

    Li, Jingxia; Zhang, Dongyun; Stoner, Gary D; Huang, Chuanshu

    2008-04-01

    The chemopreventive properties of edible berries have been demonstrated both in vitro and in vivo, however, the specific molecular mechanisms underlying their anti-cancer effects are largely unknown. Our previous studies have shown that a methanol extract fraction of freeze-dried black raspberries inhibits benzoapyrene (BaP)-induced transformation of Syrian hamster embryo cells. This fraction also blocks activation of activator protein-1 (AP-1) and nuclear factor kappaB (NF-kappaB) induced by benzoapyrene diol-epoxide (BaPDE) in mouse epidermal JB6 Cl 41 cells. To determine if different berry types exhibit specific mechanisms for their anti-cancer effects, we compared the effects of extract fractions from both black raspberries and strawberries on BaPDE-induced activation of various signaling pathways in Cl 41 cells. Black raspberry fractions inhibited the activation of AP-1, NF-kappaB, and nuclear factor of activated T cells (NFAT) by BaPDE as well as their upstream PI-3K/Akt-p70(S6K) and mitogen-activated protein kinase pathways. In contrast, strawberry fractions inhibited NFAT activation, but did not inhibit the activation of AP-1, NF-kappaB or the PI-3K/Akt-p70(S6K) and mitogen-activated protein kinase pathways. Consistent with the effects on NFAT activation, tumor necrosis factor-alpha (TNF-alpha) induction by BaPDE was blocked by extract fractions of both black raspberries and strawberries, whereas vascular endothelial growth factor (VEGF) expression, which depends on AP-1 activation, was suppressed by black raspberry fractions but not strawberry fractions. These results suggest that black raspberry and strawberry components may target different signaling pathways in exerting their anti-carcinogenic effects.

  6. Intracellular localization of the PDE4A cAMP-specific phosphodiesterase splice variant RD1 (RNPDE4A1A) in stably transfected human thyroid carcinoma FTC cell lines.

    PubMed Central

    Pooley, L; Shakur, Y; Rena, G; Houslay, M D

    1997-01-01

    Cells of two human follicular thyroid carcinoma cell lines (FTC133, FTC236) were stably transfected with a cDNA encoding the PDE4A cAMP-specific phosphodiesterase (PDE) splice variant RD1 (RNPDE4A1A) so as to generate the cloned cell lines, FTC133A and FTC236A. This allowed the expression of a novel rolipram-inhibited cAMP-specific PDE activity in these cells. Unlike the parent cell lines in which Ca2+/calmodulin caused a profound activation (approx. 3-4-fold) of homogenate PDE activity, no such stimulation was evident in the RD1-expressing cell lines, indicating loss of PDE1 activity. Reverse transcriptase-PCR analysis indicated that this was due to the down-regulation of the PDE1C isoform. The novel PDE4 activity in transfected cells was located exclusively in the membrane fraction, as was immunoreactive RD1. Low concentrations of the detergent Triton X-100, but not high NaCl concentrations, allowed RD1 to be solubilized. Laser scanning confocal immunofluorescence analyses identified RD1 immunoreactivity in a discrete perinuclear region of these RD1-expressing transfected cell lines. A similar pattern of labelling was observed using the antiserum Tex1, which specifically identified the Golgi apparatus. Treatment of FTC133A cells with the Golgi-perturbing agents monensin and brefeldin A led to a similar redistribution of immunoreactive species detected using both the Tex1 and anti-RD1 antisera. It is suggested that the PDE4A splice variant RD1 contains a membrane-association signal which allows the targeted expression of RD1 within the Golgi complex of these human follicular thyroid carcinoma cell lines. PMID:9003417

  7. Phosphodiesterase 1B differentially modulates the effects of methamphetamine on locomotor activity and spatial learning through DARPP32-dependent pathways: evidence from PDE1B-DARPP32 double-knockout mice.

    PubMed

    Ehrman, L A; Williams, M T; Schaefer, T L; Gudelsky, G A; Reed, T M; Fienberg, A A; Greengard, P; Vorhees, C V

    2006-10-01

    Mice lacking phosphodiesterase 1B (PDE1B) exhibit an exaggerated locomotor response to D-methamphetamine and increased in vitro phosphorylation of DARPP32 (dopamine- and cAMP-regulated phosphoprotein, M r 32 kDa) at Thr34 in striatal brain slices treated with the D1 receptor agonist, SKF81297. These results indicated a possible regulatory role for PDE1B in pathways involving DARPP32. Here, we generated PDE1B x DARPP32 double-knockout (double-KO) mice to test the role of PDE1B in DARPP32-dependent pathways in vivo. Analysis of the response to d-methamphetamine on locomotor activity showed that the hyperactivity experienced by PDE1B mutant mice was blocked in PDE1B-/- x DARPP32-/- double-KO mice, consistent with participation of PDE1B and DARPP32 in the same pathway. Further behavioral testing in the elevated zero-maze revealed that DARPP32-/- mice showed a less anxious phenotype that was nullified in double-mutant mice. In contrast, in the Morris water maze, double-KO mice showed deficits in spatial reversal learning not observed in either single mutant compared with wild-type mice. The data suggest a role for PDE1B in locomotor responses to psychostimulants through modulation of DARPP32-dependent pathways; however, this modulation does not necessarily impact other behaviors, such as anxiety or learning. Instead, the phenotype of double-KOs observed in these latter tasks may be mediated through independent pathways.

  8. Interaction with receptor for activated C-kinase 1 (RACK1) sensitizes the phosphodiesterase PDE4D5 towards hydrolysis of cAMP and activation by protein kinase C

    PubMed Central

    Bird, Rebecca J.; Baillie, George S.; Yarwood, Stephen J.

    2010-01-01

    We have previously identified the PKC (protein kinase C)-anchoring protein RACK1 (receptor for activated C-kinase 1), as a specific binding partner for the cAMP-specific phosphodiesterase PDE4D5, suggesting a potential site for cross-talk between the PKC and cAMP signalling pathways. In the present study we found that elevation of intracellular cAMP, with the β2-adrenoceptor agonist isoproterenol (isoprenaline), led to activation of PDE4 enzymes in the particulate and soluble fractions of HEK (human embryonic kidney)-293 cells. In contrast activation of PDE4D5, with isoproterenol and the PKC activator PMA, was restricted to the particulate fraction, where it interacts with RACK1; however, RACK1 is dispensable for anchoring PDE4D5 to the particulate fraction. Kinetic studies demonstrated that RACK1 alters the conformation of particulate-associated PDE4D5 so that it more readily interacts with its substrate cAMP and with rolipram, a PDE4 inhibitor that specifically targets the active site of the enzyme. Interaction with RACK1 was also essential for PKC-dependent and ERK (extracellular-signal-regulated kinase)-independent phosphorylation (on Ser126), and activation of PDE4D5 in response to PMA and isoproterenol, both of which trigger the recruitment of PKCα to RACK1. Together these results reveal novel signalling cross-talk, whereby RACK1 mediates PKC-dependent activation of PDE4D5 in the particulate fraction of HEK-293 cells in response to elevations in intracellular cAMP. PMID:20819076

  9. Conformationally restricted novel pyrazole derivatives: synthesis of 1,8-disubstituted 5,5-dimethyl-4,5-dihydro-1H-benzo[g]indazoles as a new class of PDE4 inhibitors.

    PubMed

    Reddy, T Shyamsunder; Kumar, K Shiva; Meda, Chandana L T; Kandale, Ajit; Rambabu, D; Krishna, G Rama; Hariprasad, C; Rao, V Venugopala; Venkataiah, S; Reddy, C Malla; Naidu, A; Dubey, P K; Parsa, Kishore V L; Pal, Manojit

    2012-05-01

    A number of novel 1,8-disubstituted 5,5-dimethyl-4,5-dihydro-1H-benzo[g]indazoles based on a conformationally restricted pyrazole framework have been designed as potential inhibitors of PDE4. All these compounds were readily prepared by using simple chemistry strategy. The in vitro PDE4B inhibitory properties and molecular modeling studies of some of the compounds synthesized along with the X-ray single crystal data of a representative compound is presented.

  10. Selective inhibition of PDE4 in Wistar rats can lead to dilatation in testis, efferent ducts, and epididymis and subsequent formation of sperm granulomas.

    PubMed

    Heuser, Anke; Mecklenburg, Lars; Ockert, Deborah; Kohler, Manfred; Kemkowski, Jörg

    2013-01-01

    Testicular tubular dilatation and degeneration and epididymal sperm granulomas were frequently seen in 4-week toxicity studies using different phosphodiesterase-4 (PDE4) inhibitors in Wistar rats, including the prototypic PDE4 inhibitor BYK169171. To investigate the pathogenesis of testicular and epididymal lesions, a time course study with BYK169171 was conducted with sequential necropsies after 7, 14, 21, and 28 days of treatment. After 7 days, a dilatation of efferent ducts and of the initial segment of the epididymis and a subacute interstitial inflammation were seen followed by a diffuse dilatation of seminiferous tubules in the testis. Dilatation and inflammation were most pronounced after 14 days. Single animals also exhibited vascular necrosis in the inflamed interstitium. Although dilatation decreased later in the study, the incidence and severity of tubular degeneration increased from 14 days onward. Sperm granulomas developed in efferent ducts and in the caput and cauda of the epididymis after 14 days. Our results demonstrate a clear time course of PDE4 inhibition-induced lesions, with dilatation preceding sperm granuloma formation. We conclude that the most likely mechanism of toxicity is a disturbance of fluid homeostasis in efferent and epididymal ducts resulting in abnormal luminal fluid and sperm contents, epithelial damage at specific sites of the excurrent duct system, sperm leakage, and granuloma formation.

  11. Curcumin inhibits B[a]PDE-induced procarcinogenic signals in lung cancer cells, and curbs B[a]P-induced mutagenesis and lung carcinogenesis.

    PubMed

    Puliyappadamba, Vineshkumar T; Thulasidasan, Arun Kumar T; Vijayakurup, Vinod; Antony, Jayesh; Bava, Smitha V; Anwar, Shabna; Sundaram, Sankar; Anto, Ruby John

    2015-01-01

    Benzo[a]pyrene is a procarcinogen present in environment and cigarette smoke, which could be bio-transformed in vivo to B[a]PDE, a potent carcinogen known to form DNA adducts and induce mutations. We observed that curcumin, a known chemopreventive, could significantly inhibit the survival of lung cancer cells exposed to B[a]PDE. It also downregulates B[a]PDE-induced nuclear translocation of NF-κB as assessed by Electrophoretic Mobility Shift Assay (EMSA) and NF-κB-dependent reporter gene assay. Ames assay demonstrated its ability to revert the mutagenic property of benzo[a]pyrene. These observations prompted us to evaluate the efficacy of curcumin in preventing B[a]P-induced lung carcinogenesis in vivo and to explore the molecular mechanism associated with it. The average number of tumor nodules present in the lungs of the Swiss albino mice, which received benzo[a]pyrene, was significantly high compared to that received curcumin as 2% diet along with B[a]P. Curcumin treatment significantly reverted histopathological deviations in the lung tissues due to benzo[a]pyrene ingestion. Moreover, curcumin diet reduced benzo[a]pyrene-induced activation of NF-κB and MAPK signaling and Cox-2 transcription in lung tissues of mice. Taken together, this study illustrates multifaceted efficacy of curcumin in preventing lung cancer.

  12. Strategies for time-dependent PDE control with inequality constraints using an integrated modeling and simulation environment

    NASA Astrophysics Data System (ADS)

    Neitzel, Ira; Prüfert, Uwe; Slawig, Thomas

    2009-03-01

    In Neitzel et al. (Strategies for time-dependent PDE control using an integrated modeling and simulation environment. Part one: problems without inequality constraints. Technical Report 408, Matheon, Berlin, 2007) we have shown how time-dependent optimal control for partial differential equations can be realized in a modern high-level modeling and simulation package. In this article we extend our approach to (state) constrained problems. "Pure" state constraints in a function space setting lead to non-regular Lagrange multipliers (if they exist), i.e. the Lagrange multipliers are in general Borel measures. This will be overcome by different regularization techniques. To implement inequality constraints, active set methods and barrier methods are widely in use. We show how these techniques can be realized in a modeling and simulation package. We implement a projection method based on active sets as well as a barrier method and a Moreau Yosida regularization, and compare these methods by a program that optimizes the discrete version of the given problem.

  13. Linear and nonlinear dynamic analysis of redundant load path bearingless rotor systems

    NASA Technical Reports Server (NTRS)

    Murthy, V. R.; Shultz, Louis A.

    1994-01-01

    The goal of this research is to develop the transfer matrix method to treat nonlinear autonomous boundary value problems with multiple branches. The application is the complete nonlinear aeroelastic analysis of multiple-branched rotor blades. Once the development is complete, it can be incorporated into the existing transfer matrix analyses. There are several difficulties to be overcome in reaching this objective. The conventional transfer matrix method is limited in that it is applicable only to linear branch chain-like structures, but consideration of multiple branch modeling is important for bearingless rotors. Also, hingeless and bearingless rotor blade dynamic characteristics (particularly their aeroelasticity problems) are inherently nonlinear. The nonlinear equations of motion and the multiple-branched boundary value problem are treated together using a direct transfer matrix method. First, the formulation is applied to a nonlinear single-branch blade to validate the nonlinear portion of the formulation. The nonlinear system of equations is iteratively solved using a form of Newton-Raphson iteration scheme developed for differential equations of continuous systems. The formulation is then applied to determine the nonlinear steady state trim and aeroelastic stability of a rotor blade in hover with two branches at the root. A comprehensive computer program is developed and is used to obtain numerical results for the (1) free vibration, (2) nonlinearly deformed steady state, (3) free vibration about the nonlinearly deformed steady state, and (4) aeroelastic stability tasks. The numerical results obtained by the present method agree with results from other methods.

  14. Nonlinear Transient Problems Using Structure Compatible Heat Transfer Code

    NASA Technical Reports Server (NTRS)

    Hou, Gene

    2000-01-01

    The report documents the recent effort to enhance a transient linear heat transfer code so as to solve nonlinear problems. The linear heat transfer code was originally developed by Dr. Kim Bey of NASA Largely and called the Structure-Compatible Heat Transfer (SCHT) code. The report includes four parts. The first part outlines the formulation of the heat transfer problem of concern. The second and the third parts give detailed procedures to construct the nonlinear finite element equations and the required Jacobian matrices for the nonlinear iterative method, Newton-Raphson method. The final part summarizes the results of the numerical experiments on the newly enhanced SCHT code.

  15. An adaptive nonlinear solution scheme for reservoir simulation

    SciTech Connect

    Lett, G.S.

    1996-12-31

    Numerical reservoir simulation involves solving large, nonlinear systems of PDE with strongly discontinuous coefficients. Because of the large demands on computer memory and CPU, most users must perform simulations on very coarse grids. The average properties of the fluids and rocks must be estimated on these grids. These coarse grid {open_quotes}effective{close_quotes} properties are costly to determine, and risky to use, since their optimal values depend on the fluid flow being simulated. Thus, they must be found by trial-and-error techniques, and the more coarse the grid, the poorer the results. This paper describes a numerical reservoir simulator which accepts fine scale properties and automatically generates multiple levels of coarse grid rock and fluid properties. The fine grid properties and the coarse grid simulation results are used to estimate discretization errors with multilevel error expansions. These expansions are local, and identify areas requiring local grid refinement. These refinements are added adoptively by the simulator, and the resulting composite grid equations are solved by a nonlinear Fast Adaptive Composite (FAC) Grid method, with a damped Newton algorithm being used on each local grid. The nonsymmetric linear system of equations resulting from Newton`s method are in turn solved by a preconditioned Conjugate Gradients-like algorithm. The scheme is demonstrated by performing fine and coarse grid simulations of several multiphase reservoirs from around the world.

  16. Formulations of Amlodipine: A Review

    PubMed Central

    Ahsan, Syed Furqan; Khan, Marium Fatima

    2016-01-01

    Amlodipine (AD) is a calcium channel blocker that is mainly used in the treatment of hypertension and angina. However, latest findings have revealed that its efficacy is not only limited to the treatment of cardiovascular diseases as it has shown to possess antioxidant activity and plays an important role in apoptosis. Therefore, it is also employed in the treatment of cerebrovascular stroke, neurodegenerative diseases, leukemia, breast cancer, and so forth either alone or in combination with other drugs. AD is a photosensitive drug and requires protection from light. A number of workers have tried to formulate various conventional and nonconventional dosage forms of AD. This review highlights all the formulations that have been developed to achieve maximum stability with the desired therapeutic action for the delivery of AD such as fast dissolving tablets, floating tablets, layered tablets, single-pill combinations, capsules, oral and transdermal films, suspensions, emulsions, mucoadhesive microspheres, gels, transdermal patches, and liposomal formulations. PMID:27822402

  17. Decontamination formulation with sorbent additive

    DOEpatents

    Tucker; Mark D. , Comstock; Robert H.

    2007-10-16

    A decontamination formulation and method of making that neutralizes the adverse health effects of both chemical and biological compounds, especially chemical warfare (CW) and biological warfare (BW) agents, and toxic industrial chemicals. The formulation provides solubilizing compounds that serve to effectively render the chemical and biological compounds, particularly CW and BW compounds, susceptible to attack, and at least one reactive compound that serves to attack (and detoxify or kill) the compound. The formulation includes at least one solubilizing agent, a reactive compound, a bleaching activator, a sorbent additive, and water. The highly adsorbent, water-soluble sorbent additive (e.g., sorbitol or mannitol) is used to "dry out" one or more liquid ingredients, such as the liquid bleaching activator (e.g., propylene glycol diacetate or glycerol diacetate) and convert the activator into a dry, free-flowing powder that has an extended shelf life, and is more convenient to handle and mix in the field.

  18. Augmented nonlinear differentiator design and application to nonlinear uncertain systems.

    PubMed

    Shao, Xingling; Liu, Jun; Li, Jie; Cao, Huiliang; Shen, Chong; Zhang, Xiaoming

    2017-03-01

    In this paper, an augmented nonlinear differentiator (AND) based on sigmoid function is developed to calculate the noise-less time derivative under noisy measurement condition. The essential philosophy of proposed AND in achieving high attenuation of noise effect is established by expanding the signal dynamics with extra state variable representing the integrated noisy measurement, then with the integral of measurement as input, the augmented differentiator is formulated to improve the estimation quality. The prominent advantages of the present differentiation technique are: (i) better noise suppression ability can be achieved without appreciable delay; (ii) the improved methodology can be readily extended to construct augmented high-order differentiator to obtain multiple derivatives. In addition, the convergence property and robustness performance against noises are investigated via singular perturbation theory and describing function method, respectively. Also, comparison with several classical differentiators is given to illustrate the superiority of AND in noise suppression. Finally, the robust control problems of nonlinear uncertain systems, including a numerical example and a mass spring system, are addressed to demonstrate the effectiveness of AND in precisely estimating the disturbance and providing the unavailable differential estimate to implement output feedback based controller.

  19. Nonlinear identification of base-isolated buildings by reverse path method

    NASA Astrophysics Data System (ADS)

    Xie, Liyu; Mita, Akira

    2009-03-01

    The performance of reverse path methods applied to identify the underlying linear model of base-isolated structures is investigated. The nonlinear rubber bearings are considered as nonlinear components attached to an underlying linear model. The advantage of reverse path formulation is that it can separate the linearity and nonlinearity of the structure, extract the nonlinearity and identify the underlying linear structure. The difficulty lies in selecting the nonlinearity function of the hysteretic force due to its multi-valued property and path-dependence. In the thesis, the hysteretic force is approximated by the polynomial series of displacement and velocity. The reverse path formulation is solved by Nonlinear Identification through Feedback of Output (NIFO) methods using least-square solution. Numerical simulation is carried out to investigate the identification performance.

  20. Bayesian Analysis of Structural Equation Models with Nonlinear Covariates and Latent Variables

    ERIC Educational Resources Information Center

    Song, Xin-Yuan; Lee, Sik-Yum

    2006-01-01

    In this article, we formulate a nonlinear structural equation model (SEM) that can accommodate covariates in the measurement equation and nonlinear terms of covariates and exogenous latent variables in the structural equation. The covariates can come from continuous or discrete distributions. A Bayesian approach is developed to analyze the…

  1. A Lagrangian variational formulation for nonequilibrium thermodynamics. Part I: Discrete systems

    NASA Astrophysics Data System (ADS)

    Gay-Balmaz, François; Yoshimura, Hiroaki

    2017-01-01

    In this paper, we present a Lagrangian variational formulation for nonequilibrium thermodynamics. This formulation is an extension of Hamilton's principle of classical mechanics that allows the inclusion of irreversible phenomena. The irreversibility is encoded into a nonlinear phenomenological constraint given by the expression of the entropy production associated to all the irreversible processes involved. From a mathematical point of view, our variational formulation may be regarded as a generalization to nonequilibrium thermodynamics of the Lagrange-d'Alembert principle used in nonlinear nonholonomic mechanics, where the conventional Lagrange-d'Alembert principle cannot be applied since the nonlinear phenomenological constraint and its associated variational constraint must be treated separately. In our approach, to deal with the nonlinear nonholonomic constraint, we introduce a variable called the thermodynamic displacement associated to each irreversible process. This allows us to systematically define the corresponding variational constraint. In Part I, our variational theory is illustrated with various examples of discrete systems such as mechanical systems with friction, matter transfer, electric circuits, chemical reactions, and diffusion across membranes. In Part II of the present paper, we will extend our variational formulation of discrete systems to the case of continuum systems.

  2. A new Lagrangian formulation for laser-plasma interactions

    SciTech Connect

    Brizard, A.J. |

    1998-04-01

    A new Lagrangian structure for cold relativistic plasma electrodynamics is presented. This new formulation uses the fluid velocity {bold v} instead of the canonical-momentum Clebsch potential {psi} [X. L. Chen and R. N. Sudan, Phys. Fluids B {bold 5}, 1336 (1993)]. As a simple application, it is used to derive (through the Noether method) new {ital exact} conservation laws associated with nonlinear laser wake-field equations in the multi-dimensional quasi-static approximation. {copyright} {ital 1998 American Institute of Physics.}

  3. A nonlinear strategy for sensor based vehicle path control

    NASA Technical Reports Server (NTRS)

    Mayr, R.

    1994-01-01

    A method of transverse control which makes use of nonlinear formulations is presented. The strategy is utilized to stabilize a vehicle. The vehicle is autonomously guided and takes its control inputs from an optical sensing system. Additionally, the velocity of the vehicle is dictated by a longitudinal controller, which is also discussed.

  4. Formulating Policy for Summer Schools.

    ERIC Educational Resources Information Center

    Marriot, Helen

    1991-01-01

    Explores issues relating to the formulation of policy for summer programs for language learning, describing one university's experience with student demand, student motivation and progress, course timing and structure, academic staffing, administrative organization, student and staff evaluation, and funding. (three references) (CB)

  5. Covariant Formulation of Hooke's Law.

    ERIC Educational Resources Information Center

    Gron, O.

    1981-01-01

    Introducing a four-vector strain and a four-force stress, Hooke's law is written as a four-vector equation. This formulation is shown to clarify seemingly paradoxical results in connection with uniformly accelerated motion, and rotational motion with angular acceleration. (Author/JN)

  6. General formulation of transverse hydrodynamics

    SciTech Connect

    Ryblewski, Radoslaw; Florkowski, Wojciech

    2008-06-15

    General formulation of hydrodynamics describing transversally thermalized matter created at the early stages of ultrarelativistic heavy-ion collisions is presented. Similarities and differences with the standard three-dimensionally thermalized relativistic hydrodynamics are discussed. The role of the conservation laws as well as the thermodynamic consistency of two-dimensional thermodynamic variables characterizing transversally thermalized matter is emphasized.

  7. Survey and development of finite elements for nonlinear structural analysis. Volume 2: Nonlinear shell finite elements

    NASA Technical Reports Server (NTRS)

    1976-01-01

    The development of two new shell finite elements for applications to large deflection problems is considered. The elements in question are doubly curved and of triangular and quadrilateral planform. They are restricted to small strains of elastic materials, and can accommodate large rotations. The elements described, which are based on relatively simple linear elements, make use of a new displacement function approach specifically designed for strongly nonlinear problems. The displacement function development for nonlinear applications is based on certain beam element formulations, and the strain-displacement equations are of a shallow shell type. Additional terms were included in these equations in an attempt to avoid the large errors characteristic of shallow shell elements in certain types of problems. An incremental nonlinear solution procedure specifically adopted to the element formulation was developed. The solution procedure is of combined incremental and total Lagrangian type, and uses a new updating scheme. A computer program was written to evaluate the developed formulations. This program can accommodate small element groups in arbitrary arrangements. Two simple programs were successfully solved. The results indicate that this new type of element has definite promise and should be a fruitful area for further research.

  8. IQCB1 and PDE6B Mutations Cause Similar Early Onset Retinal Degenerations in Two Closely Related Terrier Dog Breeds

    PubMed Central

    Goldstein, Orly; Mezey, Jason G.; Schweitzer, Peter A.; Boyko, Adam R.; Gao, Chuan; Bustamante, Carlos D.; Jordan, Julie Ann; Aguirre, Gustavo D.; Acland, Gregory M.

    2013-01-01

    Purpose. To identify the causative mutations in two early-onset canine retinal degenerations, crd1 and crd2, segregating in the American Staffordshire terrier and the Pit Bull Terrier breeds, respectively. Methods. Retinal morphology of crd1- and crd2-affected dogs was evaluated by light microscopy. DNA was extracted from affected and related unaffected controls. Association analysis was undertaken using the Illumina Canine SNP array and PLINK (crd1 study), or the Affymetrix Version 2 Canine array, the “MAGIC” genotype algorithm, and Fisher's Exact test for association (crd2 study). Positional candidate genes were evaluated for each disease. Results. Structural photoreceptor abnormalities were observed in crd1-affected dogs as young as 11-weeks old. Rod and cone inner segment (IS) and outer segments (OS) were abnormal in size, shape, and number. In crd2-affected dogs, rod and cone IS and OS were abnormal as early as 3 weeks of age, progressing with age to severe loss of the OS, and thinning of the outer nuclear layer (ONL) by 12 weeks of age. Genome-wide association study (GWAS) identified association at the telomeric end of CFA3 in crd1-affected dogs and on CFA33 in crd2-affected dogs. Candidate gene evaluation identified a three bases deletion in exon 21 of PDE6B in crd1-affected dogs, and a cytosine insertion in exon 10 of IQCB1 in crd2-affected dogs. Conclusions. Identification of the mutations responsible for these two early-onset retinal degenerations provides new large animal models for comparative disease studies and evaluation of potential therapeutic approaches for the homologous human diseases. PMID:24045995

  9. Nonlinear predictive energy management of residential buildings with photovoltaics & batteries

    NASA Astrophysics Data System (ADS)

    Sun, Chao; Sun, Fengchun; Moura, Scott J.

    2016-09-01

    This paper studies a nonlinear predictive energy management strategy for a residential building with a rooftop photovoltaic (PV) system and second-life lithium-ion battery energy storage. A key novelty of this manuscript is closing the gap between building energy management formulations, advanced load forecasting techniques, and nonlinear battery/PV models. Additionally, we focus on the fundamental trade-off between lithium-ion battery aging and economic performance in energy management. The energy management problem is formulated as a model predictive controller (MPC). Simulation results demonstrate that the proposed control scheme achieves 96%-98% of the optimal performance given perfect forecasts over a long-term horizon. Moreover, the rate of battery capacity loss can be reduced by 25% with negligible losses in economic performance, through an appropriate cost function formulation.

  10. Probabilistic finite elements for transient analysis in nonlinear continua

    NASA Technical Reports Server (NTRS)

    Liu, W. K.; Belytschko, T.; Mani, A.

    1985-01-01

    The probabilistic finite element method (PFEM), which is a combination of finite element methods and second-moment analysis, is formulated for linear and nonlinear continua with inhomogeneous random fields. Analogous to the discretization of the displacement field in finite element methods, the random field is also discretized. The formulation is simplified by transforming the correlated variables to a set of uncorrelated variables through an eigenvalue orthogonalization. Furthermore, it is shown that a reduced set of the uncorrelated variables is sufficient for the second-moment analysis. Based on the linear formulation of the PFEM, the method is then extended to transient analysis in nonlinear continua. The accuracy and efficiency of the method is demonstrated by application to a one-dimensional, elastic/plastic wave propagation problem. The moments calculated compare favorably with those obtained by Monte Carlo simulation. Also, the procedure is amenable to implementation in deterministic FEM based computer programs.

  11. Nonlinear rotordynamics analysis

    NASA Technical Reports Server (NTRS)

    Day, W. B.

    1985-01-01

    The special nonlinearities of the Jeffcott equations in rotordynamics are examined. The immediate application of this analysis is directed toward understanding the excessive vibrations recorded in the LOX pump of the SSME during hot firing ground testing. Deadband, side force and rubbing are three possible sources of inducing nonlinearity in the Jeffcott equations. The present analysis initially reduces these problems to the same mathematical description. A special frequency, named the nonlinear natural frequency is defined and used to develop the solutions of the nonlinear Jeffcott equations as asympotic expansions. This nonlinear natural frequency which is the ratio of the cross-stiffness and the damping, plays a major role in determining response frequencies. Numerical solutions are included for comparison with the analysis. Also, nonlinear frequency-response tables are made for a typical range of values.

  12. Characterization and effects of methyl-2- (4-aminophenyl)-1, 2-dihydro-1-oxo-7- (2-pyridinylmethoxy)-4-(3,4, 5-trimethoxyphenyl)-3-isoquinoline carboxylate sulfate (T-1032), a novel potent inhibitor of cGMP-binding cGMP-specific phosphodiesterase (PDE5).

    PubMed

    Kotera, J; Fujishige, K; Michibata, H; Yuasa, K; Kubo, A; Nakamura, Y; Omori, K

    2000-11-01

    An isoquinolone derivative, methyl-2-(4-aminophenyl)-1, 2-dihydro-1-oxo-7-(2-pyridinylmethoxy)-4-(3,4, 5-trimethoxyphenyl)-3-isoquinoline carboxylate sulfate (T-1032), was found to be a novel potent inhibitor of cyclic GMP (cGMP)-binding cGMP-specific phosphodiesterase (PDE5). We investigated the inhibitory effects of T-1032 on six PDE isozymes isolated from canine tissues. T-1032 specifically inhibited the hydrolysis of cGMP by PDE5 partially purified from canine lung, at a low concentration (IC(50) = 1.0 nM, K(i) = 1.2 nM), in a competitive manner. In contrast, the IC(50) values of T-1032 for PDE1, PDE2, PDE3, and PDE4 were more than 1 microM. T-1032 also inhibited PDE6 from canine retina with an IC(50) of 28 nM, which is of the same order of magnitude as the IC(50) of sildenafil. cGMP hydrolytic activities of two alternative splice variants of canine PDE5 expressed in COS-7 cells were inhibited by this compound to a similar extent. T-1032 increased the intracellular concentration of cGMP in cultured rat vascular smooth muscle cells in the presence and absence of C-type natriuretic peptide, an activator of membrane-bound guanylate cyclase, whereas the compound did not change cyclic AMP levels. These data indicated that T-1032, which belongs to a new structural class of PDE5 inhibitors, is a potent and selective PDE5 inhibitor. This compound may be useful in pharmacological studies to examine the role of a cGMP/PDE5 pathway in tissues.

  13. Principles of Nonlinear Optics

    DTIC Science & Technology

    1989-11-01

    Holography 74 6.2 Semiclassical Analysis 77 7. The Nonlinear Schrodinger Equation and Soliton Propagation 81 8. Conclusion Ancession For 86 ETis -GRA...is analyzed through the nonlinear Schrodinger equation , which is first heuristically derived. The distortionless pulses arising out of a balance...Eq. (71) has the same form as the nonlinear Schrodinger equation (2], (4], [17], (20], which is used to explain soliton propagation through fibers (21

  14. Nonlinear Ship Dynamics

    DTIC Science & Technology

    1992-07-07

    mrtegrating the original governing differential equation. 2. A. H. Nayfeh, " Parametric Identification of Nonlinear Dynamic Systems," Computers...Structures, Vol. 20. No. 1-3. 1985, pp. 487-493. A parametric identification technique that exploits nonlinear resonances and comparisons of the behavior of...617-631. Presentations 1. A. H. Vn’.yfeh, " Parametric Identification of Nonlinear Dynamic Systems," Symposium on Advances and Trends in Structures

  15. Nonlinear magnetic metamaterials.

    PubMed

    Shadrivov, Ilya V; Kozyrev, Alexander B; van der Weide, Daniel W; Kivshar, Yuri S

    2008-12-08

    We study experimentally nonlinear tunable magnetic metamaterials operating at microwave frequencies. We fabricate the nonlinear metamaterial composed of double split-ring resonators where a varactor diode is introduced into each resonator so that the magnetic resonance can be tuned dynamically by varying the input power. We demonstrate that at higher powers the transmission of the metamaterial becomes power-dependent and, as a result, such metamaterial can demonstrate various nonlinear properties. In particular, we study experimentally the power-dependent shift of the transmission band and demonstrate nonlinearity-induced enhancement (or suppression) of wave transmission.

  16. Nonlinearity-reduced interferometer

    NASA Astrophysics Data System (ADS)

    Wu, Chien-ming

    2007-12-01

    Periodic nonlinearity is a systematic error limiting the accuracy of displacement measurements at the nanometer level. It results from many causes such as the frequency mixing, polarization mixing, polarization-frequency mixing, and the ghost reflections. An interferometer having accuracy in displacement measurement of less than one-nanometer is necessary in nanometrology. To meet the requirement, the periodic nonlinearity should be less than deep sub-nanometer. In this paper, a nonlinearity-reduced interferometry has been proposed. Both the linear- and straightness-interferometer were tested. The developed interferometer demonstrated of a residual nonlinearity less than 25 pm.

  17. Fourier continuation methods for high-fidelity simulation of nonlinear acoustic beams.

    PubMed

    Albin, Nathan; Bruno, Oscar P; Cheung, Theresa Y; Cleveland, Robin O

    2012-10-01

    On the basis of recently developed Fourier continuation (FC) methods and associated efficient parallelization techniques, this text introduces numerical algorithms that, due to very low dispersive errors, can accurately and efficiently solve the types of nonlinear partial differential equation (PDE) models of nonlinear acoustics in hundred-wavelength domains as arise in the simulation of focused medical ultrasound. As demonstrated in the examples presented in this text, the FC approach can be used to produce solutions to nonlinear acoustics PDEs models with significantly reduced discretization requirements over those associated with finite-difference, finite-element and finite-volume methods, especially in cases involving waves that travel distances that are orders of magnitude longer than their respective wavelengths. In these examples, the FC methodology is shown to lead to improvements in computing times by factors of hundreds and even thousands over those required by the standard approaches. A variety of one-and two-dimensional examples presented in this text demonstrate the power and capabilities of the proposed methodology, including an example containing a number of scattering centers and nonlinear multiple-scattering events.

  18. Nonlinear programming extensions to rational function approximations of unsteady aerodynamics

    NASA Technical Reports Server (NTRS)

    Tiffany, Sherwood H.; Adams, William M., Jr.

    1987-01-01

    This paper deals with approximating unsteady generalized aerodynamic forces in the equations of motion of a flexible aircraft. Two methods of formulating these approximations are extended to include both the same flexibility in constraining them and the same methodology in optimizing nonlinear parameters as another currently used 'extended least-squares' method. Optimal selection of 'nonlinear' parameters is made in each of the three methods by use of the same nonlinear (nongradient) optimizer. The objective of the nonlinear optimization is to obtain rational approximations to the unsteady aerodynamics whose state-space realization is of lower order than that required when no optimization of the nonlinear terms is performed. The free 'linear' parameters are determined using least-squares matrix techniques on a Lagrange multiplier formulation of an objective function which incorporates selected linear equality constraints. State-space mathematical models resulting from the different approaches are described, and results are presented which show comparative evaluations from application of each of the extended methods to a numerical example. The results obtained for the example problem show a significant (up to 63 percent) reduction in the number of differential equations used to represent the unsteady aerodynamic forces in linear time-invariant equations of motion as compared to a conventional method in which nonlinear terms are not optimized.

  19. Formulation and Stability of Solutions.

    PubMed

    Akers, Michael J

    2016-01-01

    Ready-to-use solutions are the most preferable and most common dosage forms for injectable and topical ophthalmic products. Drugs formulated as solution almost always have chemical and physical stability challenges as well as solubility limitations and the need to prevent inadvertent microbial contamination issues. This article, which takes us through a discussion of optimizing the physical stability of solutions, represents the first of a series of articles discussing how these challenges and issues are addressed.

  20. Nonlinear ultrasonic propagation in bubbly liquids: a numerical model.

    PubMed

    Vanhille, Christian; Campos-Pozuelo, Cleofé

    2008-05-01

    In this paper, we investigate the problem of ultrasonic propagation in liquids with bubbles. A new numerical algorithm is constructed to solve the acoustic field-bubbles vibration coupled system. For this purpose, a second-order equation written in a volume formulation is considered for bubbles vibration and coupled with the linear nondissipative wave equation, i.e., attenuation and nonlinear effects are supposed to occur exclusively because of the presence of bubbles. Nonlinear characteristics of the phenomenon are particularly analyzed and illustrated. Plane harmonic waves are first considered in a mixture of air bubbles in water, and conclusions about changes in the wave speed, attenuation, harmonic distortion, effective nonlinearity parameter and nonlinear effects with distance are given. In particular, a law relating the second-harmonic progression with the density of bubbles is found. The propagation of plane pulses is also analyzed to give results on nonlinear attenuation, changes of frequency, and self-demodulation. The influence of the resonance frequency of bubbles on the nonlinear field is then determined. Differences and similarities with nonlinear acoustics in homogeneous fluid are shown and commented. The possibilities and limits of an equivalent nonlinear fluid are then discussed. The propagation of a high-frequency pulsed signal in a bubbly liquid used in a biological application is also the subject of numerical experiments, for frequencies near and beyond the resonance frequency of the bubbles.

  1. Surface dilational rheological properties in the nonlinear domain.

    PubMed

    Bykov, A G; Liggieri, L; Noskov, B A; Pandolfini, P; Ravera, F; Loglio, G

    2015-08-01

    The interfacial tension response to dilational deformation of interfacial area exhibits a (more or less) nonlinear behavior, depending on the amplitude of the deformation. Studies of such observable interfacial properties in the nonlinear domain suggest valuable information about the two-dimensional microstructure of the interfacial layer, as well as about the structure time-evolution. In this article, the emphasis is centered on the available mathematical methods for quantitatively analyzing and describing the magnitude and the characteristics of the nonlinear interfacial viscoelastic properties. Specifically, in periodic oscillation experiments the nonlinear behavior can be represented by the combination of a linear part (the surface dilational modulus), with an additional complementary Fourier analysis parameterizing the nonlinearity. Also asymmetric Lissajous plots, of interfacial tension versus deformation, are useful tools for expanding the response nonlinearity into four distinct components relevant to significant points of the cyclic loop. In connection with the mathematical methods, nonequilibrium thermodynamic formulations provide a powerful theoretical framework for investigating the interfacial dynamic properties of multiphase systems. Experimental results for adsorption layers of complex components, available in the literature, show notable nonlinear interfacial viscoelastic behavior. In particular in this review, data are illustrated for solutions of polymers and of polyelectrolyte/surfactant complexes. The observed nonlinear findings reveal formation of complexes, patches, and other different interfacial structures.

  2. PDE5 Inhibition Improves Object Memory in Standard Housed Rats but Not in Rats Housed in an Enriched Environment: Implications for Memory Models?

    PubMed Central

    Bruder, Ann K.; Wolfs, Kevin H. M.; De Vry, Jochen; Vanmierlo, Tim; Blokland, Arjan

    2014-01-01

    Drug effects are usually evaluated in animals housed under maximally standardized conditions. However, it is assumed that an enriched environment (EE) more closely resembles human conditions as compared to maximally standardized laboratory conditions. In the present study, we examined the acute cognition enhancing effects of vardenafil, a PDE5 inhibitor, which stimulates protein kinase G/CREB signaling in cells, in three different groups of male Wistar rats tested in an object recognition task (ORT). Rats were either housed solitarily (SOL) or socially (SOC) under standard conditions, or socially in an EE. Although EE animals remembered object information longer in the vehicle condition, vardenafil only improved object memory in SOL and SOC animals. While EE animals had a heavier dorsal hippocampus, we found no differences between experimental groups in total cell numbers in the dentate gyrus, CA2–3 or CA1. Neither were there any differences in markers for pre- and postsynaptic density. No changes in PDE5 mRNA- and protein expression levels were observed. Basal pCREB levels were increased in EE rats only, whereas β-catenin was not affected, suggesting specific activation of the MAP kinase signaling pathway and not the AKT pathway. A possible explanation for the inefficacy of vardenafil could be that CREB signaling is already optimally stimulated in the hippocampus of EE rats. Since previous data has shown that acute PDE5 inhibition does not improve memory performance in humans, the use of EE animals could be considered as a more valid model for testing cognition enhancing drugs. PMID:25372140

  3. Modulation of mGlu2 Receptors, but Not PDE10A Inhibition Normalizes Pharmacologically-Induced Deviance in Auditory Evoked Potentials and Oscillations in Conscious Rats

    PubMed Central

    Ahnaou, Abdallah; Biermans, Ria; Drinkenburg, Wilhelmus H.

    2016-01-01

    Improvement of cognitive impairments represents a high medical need in the development of new antipsychotics. Aberrant EEG gamma oscillations and reductions in the P1/N1 complex peak amplitude of the auditory evoked potential (AEP) are neurophysiological biomarkers for schizophrenia that indicate disruption in sensory information processing. Inhibition of phosphodiesterase (i.e. PDE10A) and activation of metabotropic glutamate receptor (mGluR2) signaling are believed to provide antipsychotic efficacy in schizophrenia, but it is unclear whether this occurs with cognition-enhancing potential. The present study used the auditory paired click paradigm in passive awake Sprague Dawley rats to 1) model disruption of AEP waveforms and oscillations as observed in schizophrenia by peripheral administration of amphetamine and the N-methyl-D-aspartate (NMDA) antagonist phencyclidine (PCP); 2) confirm the potential of the antipsychotics risperidone and olanzapine to attenuate these disruptions; 3) evaluate the potential of mGluR2 agonist LY404039 and PDE10 inhibitor PQ-10 to improve AEP deficits in both the amphetamine and PCP models. PCP and amphetamine disrupted auditory information processing to the first click, associated with suppression of the P1/N1 complex peak amplitude, and increased cortical gamma oscillations. Risperidone and olanzapine normalized PCP and amphetamine-induced abnormalities in AEP waveforms and aberrant gamma/alpha oscillations, respectively. LY404039 increased P1/N1 complex peak amplitudes and potently attenuated the disruptive effects of both PCP and amphetamine on AEPs amplitudes and oscillations. However, PQ-10 failed to show such effect in either models. These outcomes indicate that modulation of the mGluR2 results in effective restoration of abnormalities in AEP components in two widely used animal models of psychosis, whereas PDE10A inhibition does not. PMID:26808689

  4. PDE5 inhibitors enhance the lethality of pemetrexed through inhibition of multiple chaperone proteins and via the actions of cyclic GMP and nitric oxide

    PubMed Central

    Booth, Laurence; Roberts, Jane L.; Poklepovic, Andrew; Gordon, Sarah; Dent, Paul

    2017-01-01

    Phosphodiesterase 5 (PDE5) inhibitors prevent the breakdown of cGMP that results in prolonged protein kinase G activation and the generation of nitric oxide. PDE5 inhibitors enhanced the anti-NSCLC cell effects of the NSCLC therapeutic pemetrexed. [Pemetrexed + sildenafil] activated an eIF2α – ATF4 – CHOP – Beclin1 pathway causing formation of toxic autophagosomes; activated a protective IRE1 – XBP-1 – chaperone induction pathway; and activated a toxic eIF2α – CHOP – DR4 / DR5 / CD95 induction pathway. [Pemetrexed + sildenafil] reduced the expression of c-FLIP-s, MCL-1 and BCL-XL that was blocked in a cell-type -dependent fashion by either over-expression of HSP90 / GRP78 / HSP70 / HSP27 or by blockade of eIF2α-CHOP signaling. Knock down of PKGI/II abolished the ability of sildenafil to enhance pemetrexed toxicity whereas pan-inhibition of NOS using L-NAME or knock down of [iNOS + eNOS] only partially reduced the lethal drug interaction. Pemetrexed reduced the ATPase activities of HSP90 and HSP70 in an ATM-AMPK-dependent fashion that was enhanced by sildenafil signaling via PKGI/II. The drug combination activated an ATM-AMPK-TSC2 pathway that was associated with reduced mTOR S2448 and ULK-1 S757 phosphorylation and increased ULK-1 S317 and ATG13 S318 phosphorylation. These effects were prevented by chaperone over-expression or by expression of an activated form of mTOR that prevented autophagosome formation and reduced cell killing. In two models of NSCLC, sildenafil enhanced the ability of pemetrexed to suppress tumor growth. Collectively we argue that the combination of [pemetrexed + PDE5 inhibitor] should be explored in a new NSCLC phase I trial. PMID:27903966

  5. A new nonhydrolyzable reactive cGMP analogue, (Rp)-Guanosine-3′, 5′-cyclic-S-(4-bromo-2, 3-dioxobutyl)monophosphorothioate, which targets the cGMP binding site of human platelet PDE3A

    PubMed Central

    Hung, Su H.; Liu, Andy H.; Pixley, Robin A.; Francis, Penelope; Williams, LaTeeka D.; Matsko, Christopher M.; Barnes, Karine D.; Sivendran, Sharmila; Colman, Roberta F.; Colman, Robert W.

    2008-01-01

    The amino acids involved in substrate (cAMP) binding to human platelet cGMP-inhibited cAMP phosphodiesterase (PDE3A) are identified. Less is known about the inhibitor (cGMP) binding site. We have now synthesized a nonhydrolyzable reactive cGMP analog, Rp-guanosine-3′, 5′-cyclic-S-(4-bromo-2, 3-dioxobutyl)monophosphorothioate (Rp-cGMPS-BDB). Rp-cGMPS-BDB irreversibly inactivates PDE3A (KI = 43.4 ± 7.2 μM and kcart = 0.007 ± 0.0006 min−1). The effectiveness of protectants in decreasing the rate of inactivation by Rp-cGMPS-BDB is: Rp-cGMPS (Kd = 72 μM) > Sp-cGMPS (124), Sp-cAMPS (182) > GMP (1517), Rp-cAMPS (3762), AMP (4370 μM). NAD+, neither a substrate nor an inhibitor of PDE3A, does not protect. Nonhydrolyzable cGMP analogs exhibit greater affinity than the cAMP analogs. These results indicate that Rp-cGMPS-BDB targets favorably the cGMP binding site consistent with a docking model of PDE3A-Rp-cGMPS-BDB active site. We conclude that Rp-cGMPS-BDB is an effective active site-directed affinity label for PDE3A with potential for other cGMP-dependent enzymes. PMID:18394675

  6. The role of intracavernosal injection therapy and the reasons of withdrawal from therapy in patients with erectile dysfunction in the era of PDE5 inhibitors.

    PubMed

    Sung, H H; Ahn, J S; Kim, J J; Choo, S H; Han, D H; Lee, S W

    2014-01-01

    There has been little data regarding the role of intracavernosal injection (ICI) treatment, its discontinuation rate and the reasons of withdrawal in patients with erectile dysfunction (ED) in the era of phosphodiesterase type 5 (PDE5) inhibitors. The aim of this study was to investigate the rate of withdrawal and its associated reasons in patients undergoing ICI therapy. Patients who were prescribed with ICI treatment two times or more were included since the introduction of sildenafil in Korea in 1999. Telephone surveys were performed to evaluate intercourse rates, withdrawal rates and their associated reasons, adverse events and the patients' satisfaction with their sex lives after the ICI treatments. Two hundred and ninety-four men were contacted by telephone. The mean age was 61.8 ± 7.9 years with a follow-up duration of 25.6 ± 32.1 months. At the last follow-up, 79.9% had discontinued the treatment. Most patients had previously failed PDE5 inhibitor treatment prior to the ICI therapy, and more than half had two or more risk factors of ED. Adequate penile rigidity after ICI therapy was restored in 60.2% of patients. The reasons for discontinuation of ICI were poor response (43.1%), inconvenience of use (18.3%), switch to other treatments (10.7%), loss of libido (6.7%), adverse events (5.5%) and return of spontaneous erection (2.8%). Pain was the most common adverse event in the withdrawal group, whereas prolonged erection was most common in the continuing group. Following ICI treatment, PDE5 inhibitors were the most common therapeutic option (63.1%). The overall satisfaction rate regarding sex life was significantly high in the treatment-continuing group. In conclusion, patients on ICI treatment had severe ED and high withdrawal rates in the era of PDE5 inhibitors. The most common reason for treatment discontinuation was poor response. Before initiating ICI treatments, sufficient counselling is necessary.

  7. Chronic vasodilation increases renal medullary PDE5A and α-ENaC through independent renin-angiotensin-aldosterone system pathways.

    PubMed

    West, Crystal A; Shaw, Stefan; Sasser, Jennifer M; Fekete, Andrea; Alexander, Tyler; Cunningham, Mark W; Masilamani, Shyama M E; Baylis, Chris

    2013-11-15

    We have previously observed that many of the renal and hemodynamic adaptations seen in normal pregnancy can be induced in virgin female rats by chronic systemic vasodilation. Fourteen-day vasodilation with sodium nitrite or nifedipine (NIF) produced plasma volume expansion (PVE), hemodilution, and increased renal medullary phosphodiesterase 5A (PDE5A) protein. The present study examined the role of the renin-angiotensin-aldosterone system (RAAS) in this mechanism. Virgin females were treated for 14 days with NIF (10 mg·kg(-1)·day(-1) via diet), NIF with spironolactone [SPR; mineralocorticoid receptor (MR) blocker, 200-300 mg·kg(-1)·day(-1) via diet], NIF with losartan [LOS; angiotensin type 1 (AT1) receptor blocker, 20 mg·kg(-1)·day(-1) via diet], enalapril (ENAL; angiotensin-converting enzyme inhibitor, 62.5 mg/l via water), or vehicle (CON). Mean arterial pressure (MAP) was reduced 7.4 ± 0.5% with NIF, 6.33 ± 0.5% with NIF + SPR, 13.3 ± 0.9% with NIF + LOS, and 12.0 ± 0.4% with ENAL vs. baseline MAP. Compared with CON (3.6 ± 0.3%), plasma volume factored for body weight was increased by NIF (5.2 ± 0.4%) treatment but not by NIF + SPR (4.3 ± 0.3%), NIF + LOS (3.6 ± 0.1%), or ENAL (4.0 ± 0.3%). NIF increased PDE5A protein abundance in the renal inner medulla, and SPR did not prevent this increase (188 ± 16 and 204 ± 22% of CON, respectively). NIF increased the α-subunit of the epithelial sodium channel (α-ENaC) protein in renal outer (365 ± 44%) and inner (526 ± 83%) medulla, and SPR prevented these changes. There was no change in either PDE5A or α-ENaC abundance vs. CON in rats treated with NIF + LOS or ENAL. These data indicate that the PVE and renal medullary adaptations in response to chronic vasodilation result from RAAS signaling, with increases in PDE5A mediated through AT1 receptor and α-ENaC through the MR.

  8. Nonlinear Elasticity in a Deforming Ambient Space

    NASA Astrophysics Data System (ADS)

    Yavari, Arash; Ozakin, Arkadas; Sadik, Souhayl

    2016-12-01

    In this paper, we formulate a nonlinear elasticity theory in which the ambient space is evolving. For a continuum moving in an evolving ambient space, we model time dependency of the metric by a time-dependent embedding of the ambient space in a larger manifold with a fixed background metric. We derive both the tangential and the normal governing equations. We then reduce the standard energy balance written in the larger ambient space to that in the evolving ambient space. We consider quasi-static deformations of the ambient space and show that a quasi-static deformation of the ambient space results in stresses, in general. We linearize the nonlinear theory about a reference motion and show that variation of the spatial metric corresponds to an effective field of body forces.

  9. Nonlinear dynamics of a double bilipid membrane.

    PubMed

    Sample, C; Golovin, A A

    2007-09-01

    The nonlinear dynamics of a biological double membrane that consists of two coupled lipid bilayers, typical of some intracellular organelles such as mitochondria or nuclei, is studied. A phenomenological free-energy functional is formulated in which the curvatures of the two parts of the double membrane and the distance between them are coupled to the lipid chemical composition. The derived nonlinear evolution equations for the double-membrane dynamics are studied analytically and numerically. A linear stability analysis is performed, and the domains of parameters are found in which the double membrane is stable. For the parameter values corresponding to an unstable membrane, numerical simulations are performed that reveal various types of complex dynamics, including the formation of stationary, spatially periodic patterns.

  10. Taming the nonlinearity of the Einstein equation.

    PubMed

    Harte, Abraham I

    2014-12-31

    Many of the technical complications associated with the general theory of relativity ultimately stem from the nonlinearity of Einstein's equation. It is shown here that an appropriate choice of dynamical variables may be used to eliminate all such nonlinearities beyond a particular order: Both Landau-Lifshitz and tetrad formulations of Einstein's equation are obtained that involve only finite products of the unknowns and their derivatives. Considerable additional simplifications arise in physically interesting cases where metrics become approximately Kerr or, e.g., plane waves, suggesting that the variables described here can be used to efficiently reformulate perturbation theory in a variety of contexts. In all cases, these variables are shown to have simple geometrical interpretations that directly relate the local causal structure associated with the metric of interest to the causal structure associated with a prescribed background. A new method to search for exact solutions is outlined as well.

  11. Spacecraft nonlinear control

    NASA Technical Reports Server (NTRS)

    Sheen, Jyh-Jong; Bishop, Robert H.

    1992-01-01

    The feedback linearization technique is applied to the problem of spacecraft attitude control and momentum management with control moment gyros (CMGs). The feedback linearization consists of a coordinate transformation, which transforms the system to a companion form, and a nonlinear feedback control law to cancel the nonlinear dynamics resulting in a linear equivalent model. Pole placement techniques are then used to place the closed-loop poles. The coordinate transformation proposed here evolves from three output functions of relative degree four, three, and two, respectively. The nonlinear feedback control law is presented. Stability in a neighborhood of a controllable torque equilibrium attitude (TEA) is guaranteed and this fact is demonstrated by the simulation results. An investigation of the nonlinear control law shows that singularities exist in the state space outside the neighborhood of the controllable TEA. The nonlinear control law is simplified by a standard linearization technique and it is shown that the linearized nonlinear controller provides a natural way to select control gains for the multiple-input, multiple-output system. Simulation results using the linearized nonlinear controller show good performance relative to the nonlinear controller in the neighborhood of the TEA.

  12. Optically Nonlinear Polymeric Materials.

    DTIC Science & Technology

    1983-01-01

    optical chromophores into the hydrophobic portions of the polymer, second order . ,nonlinear optical effects may be obtained. Experimental 01 0...8217V cinnamaldehyde , giving the polymer shown in Figure 3. This chromophore should have greater optical nonlinearity because of its better electron

  13. Nonlinear Optics and Applications

    NASA Technical Reports Server (NTRS)

    Abdeldayem, Hossin A. (Editor); Frazier, Donald O. (Editor)

    2007-01-01

    Nonlinear optics is the result of laser beam interaction with materials and started with the advent of lasers in the early 1960s. The field is growing daily and plays a major role in emerging photonic technology. Nonlinear optics play a major role in many of the optical applications such as optical signal processing, optical computers, ultrafast switches, ultra-short pulsed lasers, sensors, laser amplifiers, and many others. This special review volume on Nonlinear Optics and Applications is intended for those who want to be aware of the most recent technology. This book presents a survey of the recent advances of nonlinear optical applications. Emphasis will be on novel devices and materials, switching technology, optical computing, and important experimental results. Recent developments in topics which are of historical interest to researchers, and in the same time of potential use in the fields of all-optical communication and computing technologies, are also included. Additionally, a few new related topics which might provoke discussion are presented. The book includes chapters on nonlinear optics and applications; the nonlinear Schrodinger and associated equations that model spatio-temporal propagation; the supercontinuum light source; wideband ultrashort pulse fiber laser sources; lattice fabrication as well as their linear and nonlinear light guiding properties; the second-order EO effect (Pockels), the third-order (Kerr) and thermo-optical effects in optical waveguides and their applications in optical communication; and, the effect of magnetic field and its role in nonlinear optics, among other chapters.

  14. Nonlinear Maneuver Autopilot

    NASA Technical Reports Server (NTRS)

    Menon, P. K. A.; Badgett, M. E.; Walker, R. A.

    1992-01-01

    Trajectory-control laws based on singular-perturbation theory and nonlinear dynamical modeling. Nonlinear maneuver autopilot commands flight-test trajectories of F-15 airplane. Underlying theory of controller enables separation of variables processed in fast and slow control loops, reducing amount of computation required.

  15. Lasers for nonlinear microscopy.

    PubMed

    Wise, Frank

    2013-03-01

    Various versions of nonlinear microscopy are revolutionizing the life sciences, almost all of which are made possible because of the development of ultrafast lasers. In this article, the main properties and technical features of short-pulse lasers used in nonlinear microscopy are summarized. Recent research results on fiber lasers that will impact future instruments are also discussed.

  16. Bounding solutions of geometrically nonlinear viscoelastic problems

    NASA Technical Reports Server (NTRS)

    Stubstad, J. M.; Simitses, G. J.

    1986-01-01

    Integral transform techniques, such as the Laplace transform, provide simple and direct methods for solving viscoelastic problems formulated within a context of linear material response and using linear measures for deformation. Application of the transform operator reduces the governing linear integro-differential equations to a set of algebraic relations between the transforms of the unknown functions, the viscoelastic operators, and the initial and boundary conditions. Inversion either directly or through the use of the appropriate convolution theorem, provides the time domain response once the unknown functions have been expressed in terms of sums, products or ratios of known transforms. When exact inversion is not possible approximate techniques may provide accurate results. The overall problem becomes substantially more complex when nonlinear effects must be included. Situations where a linear material constitutive law can still be productively employed but where the magnitude of the resulting time dependent deformations warrants the use of a nonlinear kinematic analysis are considered. The governing equations will be nonlinear integro-differential equations for this class of problems. Thus traditional as well as approximate techniques, such as cited above, cannot be employed since the transform of a nonlinear function is not explicitly expressible.

  17. Nonlinear large-scale optimization with WORHP

    NASA Astrophysics Data System (ADS)

    Nikolayzik, Tim; Büskens, Christof; Gerdts, Matthias

    Nonlinear optimization has grown to a key technology in many areas of aerospace industry, e.g. satellite control, shape-optimization, aerodynamamics, trajectory planning, reentry prob-lems, interplanetary flights. One of the most extensive areas is the optimization of trajectories for aerospace applications. These problems typically are discretized optimal control problems, which leads to large sparse nonlinear optimization problems. In the end all these different problems from different areas can be described in the general formulation as a nonlinear opti-mization problem. WORHP is designed to solve nonlinear optimization problems with more then one million variables and one million constraints. WORHP uses a lot of different advanced techniques, e.g. reverse communication, to organize the optimization process as efficient and controllable by the user as possible. The solver has nine different interfaces, e.g. to MAT-LAB/SIMULINK and AMPL. Tests of WORHP had shown that WORHP is a very robust and promising solver. Several examples from space applications will be presented.

  18. Geometrically nonlinear analysis of laminated elastic structures

    NASA Technical Reports Server (NTRS)

    Reddy, J. N.; Chandrashekhara, K.; Chao, W. C.

    1993-01-01

    This final technical report contains three parts: Part 1 deals with the 2-D shell theory and its element formulation and applications. Part 2 deals with the 3-D degenerated element. These two parts constitute the two major tasks that were completed under the grant. Another related topic that was initiated during the present investigation is the development of a nonlinear material model. This topic is briefly discussed in Part 3. To make each part self-contained, conclusions and references are included in each part. In the interest of brevity, the discussions presented are relatively brief. The details and additional topics are described in the references cited.

  19. Probabilistic density function method for nonlinear dynamical systems driven by colored noise

    SciTech Connect

    Barajas-Solano, David A.; Tartakovsky, Alexandre M.

    2016-05-01

    We present a probability density function (PDF) method for a system of nonlinear stochastic ordinary differential equations driven by colored noise. The method provides an integro-differential equation for the temporal evolution of the joint PDF of the system's state, which we close by means of a modified Large-Eddy-Diffusivity-type closure. Additionally, we introduce the generalized local linearization (LL) approximation for deriving a computable PDF equation in the form of the second-order partial differential equation (PDE). We demonstrate the proposed closure and localization accurately describe the dynamics of the PDF in phase space for systems driven by noise with arbitrary auto-correlation time. We apply the proposed PDF method to the analysis of a set of Kramers equations driven by exponentially auto-correlated Gaussian colored noise to study the dynamics and stability of a power grid.

  20. Nonlinear saturation characteristics of a dielectric Cherenkov maser

    SciTech Connect

    Choi, J.S.; Heo, E.G.; Choi, D.I.

    1995-12-31

    The nonlinear saturation state in a dielectric Cherenkov maser (DCM) with the TM mode and the intense relativistic electron beam is analyzed from the nonlinear formulation based on the cold fluid-Maxwell equations. We obtain the nonlinear efficiency and the final operation frequency under consideration of the effects of the beam current, the beam energy and the dielectric materials and show that the characteristics of a DCM instablity has a strong resemblance to that of the relativistic two stream instability by the coherent trapping of electrons in a single most-ustable wave. Finally, the nonlinear analysis shows that the Cherenkov maser operation with a lower-energy beam can be more efficient in the higher frequency regime for the case of the high power DCM with a high current.

  1. Minimal formulation of joint motion for biomechanisms

    PubMed Central

    Seth, Ajay; Sherman, Michael; Eastman, Peter; Delp, Scott

    2010-01-01

    Biomechanical systems share many properties with mechanically engineered systems, and researchers have successfully employed mechanical engineering simulation software to investigate the mechanical behavior of diverse biological mechanisms, ranging from biomolecules to human joints. Unlike their man-made counterparts, however, biomechanisms rarely exhibit the simple, uncoupled, pure-axial motion that is engineered into mechanical joints such as sliders, pins, and ball-and-socket joints. Current mechanical modeling software based on internal-coordinate multibody dynamics can formulate engineered joints directly in minimal coordinates, but requires additional coordinates restricted by constraints to model more complex motions. This approach can be inefficient, inaccurate, and difficult for biomechanists to customize. Since complex motion is the rule rather than the exception in biomechanisms, the benefits of minimal coordinate modeling are not fully realized in biomedical research. Here we introduce a practical implementation for empirically-defined internal-coordinate joints, which we call “mobilizers.” A mobilizer encapsulates the observations, measurement frame, and modeling requirements into a hinge specification of the permissible-motion manifold for a minimal set of internal coordinates. Mobilizers support nonlinear mappings that are mathematically equivalent to constraint manifolds but have the advantages of fewer coordinates, no constraints, and exact representation of the biomechanical motion-space—the benefits long enjoyed for internal-coordinate models of mechanical joints. Hinge matrices within the mobilizer are easily specified by user-supplied functions, and provide a direct means of mapping permissible motion derived from empirical data. We present computational results showing substantial performance and accuracy gains for mobilizers versus equivalent joints implemented with constraints. Examples of mobilizers for joints from human biomechanics

  2. A Lagrangian variational formulation for nonequilibrium thermodynamics. Part II: Continuum systems

    NASA Astrophysics Data System (ADS)

    Gay-Balmaz, François; Yoshimura, Hiroaki

    2017-01-01

    Part I of this paper introduced a Lagrangian variational formulation for nonequilibrium thermodynamics of discrete systems. This variational formulation extends Hamilton's principle to allow the inclusion of irreversible processes in the dynamics. The irreversibility is encoded into a nonlinear nonholonomic constraint given by the expression of entropy production associated to all the irreversible processes involved. In Part II, we develop this formulation for the case of continuum systems by extending the setting of Part I to infinite dimensional nonholonomic Lagrangian systems. The variational formulation is naturally expressed in the material representation, while its spatial version is obtained via a nonholonomic Lagrangian reduction by symmetry. The theory is illustrated with the examples of a viscous heat conducting fluid and its multicomponent extension including chemical reactions and mass transfer.

  3. Post-buckling and Large Amplitude Free Vibration Analysis of Composite Beams: Simple Intuitive Formulation

    NASA Astrophysics Data System (ADS)

    Gunda, Jagadish Babu; Venkateswara Rao, Gundabathula

    2016-04-01

    Post-buckling and large amplitude free vibration analysis of composite beams with axially immovable ends is investigated in the present study using a simple intuitive formulation. Geometric nonlinearity of Von-Karman type is considered in the analysis which accounts for mid-plane stretching action of the beam. Intuitive formulation uses only two parameters: the critical bifurcation point and the axial stretching force developed due to membrane stretching action of the beam. Hinged-hinged, clamped-clamped and clamped-hinged boundary conditions are considered. Numerical accuracy of the proposed analytical closed-form solutions obtained from the intuitive formulation are compared to available finite element solutions for symmetric and asymmetric layup schemes of laminated composite beam which indicates the confidence gained on the present formulation.

  4. Efficient formulations of the material identification problem using full-field measurements

    NASA Astrophysics Data System (ADS)

    Pérez Zerpa, Jorge M.; Canelas, Alfredo

    2016-08-01

    The material identification problem addressed consists of determining the constitutive parameters distribution of a linear elastic solid using displacement measurements. This problem has been considered in important applications such as the design of methodologies for breast cancer diagnosis. Since the resolution of real life problems involves high computational costs, there is great interest in the development of efficient methods. In this paper two new efficient formulations of the problem are presented. The first formulation leads to a second-order cone optimization problem, and the second one leads to a quadratic optimization problem, both allowing the resolution of the problem with high efficiency and precision. Numerical examples are solved using synthetic input data with error. A regularization technique is applied using the Morozov criterion along with an automatic selection strategy of the regularization parameter. The proposed formulations present great advantages in terms of efficiency, when compared to other formulations that require the application of general nonlinear optimization algorithms.

  5. Perfume formulation: words and chats.

    PubMed

    Ellena, Céline

    2008-06-01

    What does it mean to create fragrances with materials from chemistry and/or from nature? How are they used to display their characteristic differences, their own personality? Is it easier to create with synthetic raw materials or with essential oils? This review explains why a perfume formulation corresponds in fact to a conversation, an interplay between synthetic and natural perfumery materials. A synthetic raw material carries a single information, and usually is very linear. Its smell is uniform, clear, and faithful. Natural raw materials, on the contrary, provide a strong, complex and generous image. While a synthetic material can be seen as a single word, a natural one such as rose oil could be compared to chatting: cold, warm, sticky, heavy, transparent, pepper, green, metallic, smooth, watery, fruity... full of information. Yet, if a very small amount of the natural material is used, nothing happens, the fragrance will not change. However, if a large amount is used, the rose oil will swallow up everything else. The fragrance will smell of nothing else except rose! To formulate a perfume is not to create a culinary recipe, with only dosing the ingredients in well-balanced amounts. To formulate rather means to flexibly knit materials together with a lively stitch, meeting or repelling each other, building a pleasant form, which is neither fixed, nor solid, nor rigid. A fragrance has an overall structure, which ranges from a clear sound, made up of stable, unique, and linear items, to a background chat, comfortable and reassuring. But that does, of course, not mean that there is only one way of creating a fragrance!

  6. A novel approach to establishing the design space for the oral formulation manufacturing process.

    PubMed

    Norioka, Tadashi; Hayashi, Yoshihiro; Onuki, Yoshinori; Andou, Hirotaka; Tsunashima, Daisuke; Yamashita, Kazunari; Takayama, Kozo

    2013-01-01

    A novel approach to establishing the design space for the oral formulation manufacturing process was investigated. A response surface method incorporating multivariate spline interpolation was applied to overcome the nonlinear problem, which is always problematic in pharmaceutical development studies, and a bootstrap resampling technique, polynomial approximation technique, and 95% confidence intervals based on a nonparametric approach were applied to estimate the reliability of the established design space derived from the nonlinear response surface model. The critical quality attributes (CQAs) of intermediate material rather than the critical process parameters (CPPs) were chosen as the causal factors for the response variables, which were CQAs of the final product to avoid scale-gap and equipment-gap. This enabled the effective use of data sets accumulated during all pharmaceutical development studies. It was confirmed that a conservative border as well as an optimistic border of the design space for practical use was obtained considering the variability of the border of the design spaces on nonlinear response surfaces. Furthermore, the nonlinear response surface model using CQAs of intermediate material derived from data sets of a laboratory scale study and pilot scale studies could predict the CQA of the final product (2.5 h dissolution of commercial-scale study) with high accuracy. Consequently, the proposed novel approach overcame all of the difficulties for the manufacturing process development of oral formulations and this is the first study to demonstrate the effectiveness of the design space using CQA of intermediate material for the oral formulation manufacturing process.

  7. Formulation and Stability of Solutions.

    PubMed

    Akers, Michael J

    2016-01-01

    Ready-to-use solutions are the most preferable and most common dosage forms for injectable and topical ophthalmic products. Drugs formulated as solution almost always have chemical and physical stability challenges as well as solubility limitations and the need to prevent inadvertent microbial contamination issues. The first in this series of articles took us through a discussion of optimizing the physical stability of solutions. This article concludes this series of articles with a discussion on foreign particles, protein aggregation, and immunogenicity; optimizing microbiological activity; and osmolality (tonicity) agents, and discusses how these challenges and issues are addressed.

  8. Controlled release liquid dosage formulation

    DOEpatents

    Benton, Ben F.; Gardner, David L.

    1989-01-01

    A liquid dual coated dosage formulation sustained release pharmaceutic having substantial shelf life prior to ingestion is disclosed. A dual coating is applied over controlled release cores to form dosage forms and the coatings comprise fats melting at less than approximately 101.degree. F. overcoated with cellulose acetate phthalate or zein. The dual coated dosage forms are dispersed in a sugar based acidic liquid carrier such as high fructose corn syrup and display a shelf life of up to approximately at least 45 days while still retaining their release profiles following ingestion. Cellulose acetate phthalate coated dosage form cores can in addition be dispersed in aqueous liquids of pH <5.

  9. Exposing the nonlinear viscoelastic behavior of asphalt-aggregate mixes

    NASA Astrophysics Data System (ADS)

    Levenberg, Eyal; Uzan, Jacob

    2012-05-01

    In this study asphalt-aggregate mixes are treated as both viscoelastic and viscoplastic. Following a damage mechanics approach, a nonlinear viscoelastic constitutive formulation is generated from a linear formulation by replacing `applied stresses' with `effective viscoelastic stresses'. A non-dimensional scalar entity called `relative viscoelastic stiffness' is introduced; it is defined as the ratio of applied to effective viscoelastic stress and encapsulates different types of nonlinearities. The paper proposes a computational scheme for exposing these nonlinearities by uncovering, through direct analysis of any test data, changes experienced by the `relative viscoelastic stiffness'. In general terms, the method is based on simultaneous application of creep and relaxation formulations while preserving the interrelationship between the corresponding time functions. The proposed scheme is demonstrated by analyzing a uniaxial tension test and a uniaxial compression test (separately). Results are presented and discussed, unveiling and contrasting the character of viscoelastic nonlinearities in both cases. A conceptual viewpoint is offered to explain the observations, illustrating the requirements from any candidate constitutive theory.

  10. Formulation, Preparation, and Characterization of Polyurethane Foams

    ERIC Educational Resources Information Center

    Pinto, Moises L.

    2010-01-01

    Preparation of laboratory-scale polyurethane foams is described with formulations that are easy to implement in experiments for undergraduate students. Particular attention is given to formulation aspects that are based on the main chemical reactions occurring in polyurethane production. This allows students to develop alternative formulations to…

  11. ANTI-RHEUMATIC FORMULATIONS FROM AYURVEDA

    PubMed Central

    Raut, A. A.; Joshi, A. D.; Antarkar, D. S.; Joshi, V. R.; Vaidya, A. B.

    1991-01-01

    Rheumatic disorders like Amavata, Sandhivata and Vatarakta are elaborately described in ayurvedic literature. Preliminary survey of literature shows that about 247 formulations are recommended for these rheumatic disorders. These formulations generally include guggulu compounds, compounds of plant powders, decoctions, medicated ghees, oils, electuaries etc. Therapeutic potential of ayurvedic concepts and a brief review of Ayurvedic formulations are also discussed. PMID:22556565

  12. Nonlinear vibrations of thin arbitrarily laminated composite plates subjected to harmonic excitations using DKT elements

    NASA Technical Reports Server (NTRS)

    Chiang, C. K.; Xue, David Y.; Mei, Chuh

    1993-01-01

    A finite element formulation is presented for determining the large-amplitude free and steady-state forced vibration response of arbitrarily laminated anisotropic composite thin plates using the Discrete Kirchhoff Theory (DKT) triangular elements. The nonlinear stiffness and harmonic force matrices of an arbitrarily laminated composite triangular plate element are developed for nonlinear free and forced vibration analyses. The linearized updated-mode method with nonlinear time function approximation is employed for the solution of the system nonlinear eigenvalue equations. The amplitude-frequency relations for convergence with gridwork refinement, triangular plates, different boundary conditions, lamination angles, number of plies, and uniform versus concentrated loads are presented.

  13. Nonlinear cochlear mechanics.

    PubMed

    Zweig, George

    2016-05-01

    An earlier paper characterizing the linear mechanical response of the organ of Corti [J. Acoust. Soc. Am. 138, 1102-1121 (2015)] is extended to the nonlinear domain. Assuming the existence of nonlinear oscillators nonlocally coupled through the pressure they help create, the oscillator equations are derived and examined when the stimuli are modulated tones and clicks. The nonlinearities are constrained by the requirements of oscillator stability and the invariance of zero crossings in the click response to changes in click amplitude. The nonlinear oscillator equations for tones are solved in terms of the fluid pressure that drives them, and its time derivative, presumably a proxy for forces created by outer hair cells. The pressure equation is reduced to quadrature, the integrand depending on the oscillators' responses. The resulting nonlocally coupled nonlinear equations for the pressure, and oscillator amplitudes and phases, are solved numerically in terms of the fluid pressure at the stapes. Methods for determining the nonlinear damping directly from measurements are described. Once the oscillators have been characterized from their tone and click responses, the mechanical response of the cochlea to natural sounds may be computed numerically. Signal processing inspired by cochlear mechanics opens up a new area of nonlocal nonlinear time-frequency analysis.

  14. Influence of the PDE5 inhibitor tadalafil on redox status and antioxidant defense system in C2C12 skeletal muscle cells.

    PubMed

    Duranti, Guglielmo; Ceci, Roberta; Sgrò, Paolo; Sabatini, Stefania; Di Luigi, Luigi

    2017-03-11

    Phosphodiesterase type 5 inhibitors (PDE5Is), widely known for their beneficial effects onto male erectile dysfunction, seem to exert favorable effects onto metabolism as well. Tadalafil exposure increases oxidative metabolism of C2C12 skeletal muscle cells. A rise in fatty acid (FA) metabolism, requiring more oxygen, could induce a larger reactive oxygen species (ROS) release as a byproduct thus leading to a redox imbalance. The aim of this study was to determine how PDE5I tadalafil influences redox status in skeletal muscle cells to match the increasing oxidative metabolism. To this purpose, differentiated C2C12 skeletal muscle cells were treated with tadalafil and analyzed for total antioxidant capacity (TAC) and glutathione levels as marker of redox status; enzyme activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) engaged in antioxidant defense; and lipid peroxidation (TBARS) and protein carbonyls (PrCar) as markers of oxidative damage. Tadalafil increased total intracellular glutathione (tGSH), CAT, SOD, and GPx enzymatic activities while no changes were found in TAC. A perturbation of redox status, as showed by the decrease in the ratio between reduced/oxidized glutathione (GSH/GSSG), was observed. Nevertheless, it did not cause any change in TBARS and PrCar levels probably due to the enhancement in the antioxidant enzymatic network. Taken together, these data indicate that tadalafil, besides improving oxidative metabolism, may be beneficial to skeletal muscle cells by enhancing the enzymatic antioxidant system capacity.

  15. Association of the PDE3A-SLCO1C1 locus with the response to anti-TNF agents in psoriasis.

    PubMed

    Julià, A; Ferrándiz, C; Dauden, E; Fonseca, E; Fernández-López, E; Sanchez-Carazo, J L; Vanaclocha, F; Puig, L; Moreno-Ramírez, D; Lopez-Estebaranz, J L; Herrera, E; de la Cueva, P; Ávila, G; Alonso, A; Tortosa, R; López-Lasanta, M; Marsal, S

    2015-08-01

    Psoriasis is a prevalent autoimmune disease of the skin that causes significant psychological and physical disability. Tumor necrosis factor (TNF)-blocking agents have proven to be highly efficacious in the management of moderate-to-severe psoriasis. However, a significant percentage of patients do not respond to this treatment. Recently, variation at the PDE3A-SLCO1C1 (phosphodiesterase 3A-SoLute Carrier Organic anion transporter family member 1C1) locus has been robustly associated with anti-TNF response in rheumatoid arthritis. Using a cohort of 130 psoriasis patients treated with anti-TNF therapy, we sought to analyze the association of this locus with treatment response in psoriasis. We found a highly significant association between PDE3A-SLCO1C1 and the clinical response to TNF blockers (P=0.0031). Importantly, the allele that was previously associated with the lack of response to rheumatoid arthritis (G allele, single-nucleotide polymorphism rs3794271) was associated with a higher anti-TNF efficacy in psoriasis. The results of this study are an important step in the characterization of the pharmacogenetic profile associated with anti-TNF response in psoriasis.

  16. Acute effects of Sceletium tortuosum (Zembrin), a dual 5-HT reuptake and PDE4 inhibitor, in the human amygdala and its connection to the hypothalamus.

    PubMed

    Terburg, David; Syal, Supriya; Rosenberger, Lisa A; Heany, Sarah; Phillips, Nicole; Gericke, Nigel; Stein, Dan J; van Honk, Jack

    2013-12-01

    The South African endemic plant Sceletium tortuosum has a long history of traditional use as a masticatory and medicine by San and Khoikhoi people and subsequently by European colonial farmers as a psychotropic in tincture form. Over the past decade, the plant has attracted increasing attention for its possible applications in promoting a sense of wellbeing and relieving stress in healthy individuals and for treating clinical anxiety and depression. The pharmacological actions of a standardized extract of the plant (Zembrin) have been reported to be dual PDE4 inhibition and 5-HT reuptake inhibition, a combination that has been argued to offer potential therapeutic advantages. Here we tested the acute effects of Zembrin administration in a pharmaco-fMRI study focused on anxiety-related activity in the amygdala and its connected neurocircuitry. In a double-blind, placebo-controlled, cross-over design, 16 healthy participants were scanned during performance in a perceptual-load and an emotion-matching task. Amygdala reactivity to fearful faces under low perceptual load conditions was attenuated after a single 25 mg dose of Zembrin. Follow-up connectivity analysis on the emotion-matching task showed that amygdala-hypothalamus coupling was also reduced. These results demonstrate, for the first time, the attenuating effects of S. tortuosum on the threat circuitry of the human brain and provide supporting evidence that the dual 5-HT reuptake inhibition and PDE4 inhibition of this extract might have anxiolytic potential by attenuating subcortical threat responsivity.

  17. Comparison of three development approaches for Stationary Phase Optimised Selectivity Liquid Chromatography based screening methods Part II: A group of structural analogues (PDE-5 inhibitors in food supplements).

    PubMed

    Deconinck, E; Ghijs, L; Kamugisha, A; Courselle, P

    2016-02-01

    Three approaches for the development of a screening method to detect adulterated dietary supplements, based on Stationary Phase Optimised Selectivity Liquid Chromatography were compared for their easiness/speed of development and the performance of the optimal method obtained. This comparison was performed for a heterogeneous group of molecules, i.e. slimming agents (Part I) and a group of structural analogues, i.e. PDE-5 inhibitors (Part II). The first approach makes use of primary runs at one isocratic level, the second of primary runs in gradient mode and the third of primary runs at three isocratic levels to calculate the optimal combination of segments of stationary phases. In each approach the selection of the stationary phase was followed by a gradient optimisation. For the PDE-5 inhibitors, the group of structural analogues, only the method obtained with the third approach was able to differentiate between all the molecules in the development set. Although not all molecules are baseline separated, the method allows the identification of the selected adulterants in dietary supplements using only diode array detection. Though, due to the mobile phases used, the method could also be coupled to mass spectrometry. The method was validated for its selectivity following the guidelines as described for the screening of pesticide residues and residues of veterinary medicines in food.

  18. Nonlinear Statistical Modeling of Speech

    NASA Astrophysics Data System (ADS)

    Srinivasan, S.; Ma, T.; May, D.; Lazarou, G.; Picone, J.

    2009-12-01

    Contemporary approaches to speech and speaker recognition decompose the problem into four components: feature extraction, acoustic modeling, language modeling and search. Statistical signal processing is an integral part of each of these components, and Bayes Rule is used to merge these components into a single optimal choice. Acoustic models typically use hidden Markov models based on Gaussian mixture models for state output probabilities. This popular approach suffers from an inherent assumption of linearity in speech signal dynamics. Language models often employ a variety of maximum entropy techniques, but can employ many of the same statistical techniques used for acoustic models. In this paper, we focus on introducing nonlinear statistical models to the feature extraction and acoustic modeling problems as a first step towards speech and speaker recognition systems based on notions of chaos and strange attractors. Our goal in this work is to improve the generalization and robustness properties of a speech recognition system. Three nonlinear invariants are proposed for feature extraction: Lyapunov exponents, correlation fractal dimension, and correlation entropy. We demonstrate an 11% relative improvement on speech recorded under noise-free conditions, but show a comparable degradation occurs for mismatched training conditions on noisy speech. We conjecture that the degradation is due to difficulties in estimating invariants reliably from noisy data. To circumvent these problems, we introduce two dynamic models to the acoustic modeling problem: (1) a linear dynamic model (LDM) that uses a state space-like formulation to explicitly model the evolution of hidden states using an autoregressive process, and (2) a data-dependent mixture of autoregressive (MixAR) models. Results show that LDM and MixAR models can achieve comparable performance with HMM systems while using significantly fewer parameters. Currently we are developing Bayesian parameter estimation and

  19. NLINEAR - NONLINEAR CURVE FITTING PROGRAM

    NASA Technical Reports Server (NTRS)

    Everhart, J. L.

    1994-01-01

    A common method for fitting data is a least-squares fit. In the least-squares method, a user-specified fitting function is utilized in such a way as to minimize the sum of the squares of distances between the data points and the fitting curve. The Nonlinear Curve Fitting Program, NLINEAR, is an interactive curve fitting routine based on a description of the quadratic expansion of the chi-squared statistic. NLINEAR utilizes a nonlinear optimization algorithm that calculates the best statistically weighted values of the parameters of the fitting function and the chi-square that is to be minimized. The inputs to the program are the mathematical form of the fitting function and the initial values of the parameters to be estimated. This approach provides the user with statistical information such as goodness of fit and estimated values of parameters that produce the highest degree of correlation between the experimental data and the mathematical model. In the mathematical formulation of the algorithm, the Taylor expansion of chi-square is first introduced, and justification for retaining only the first term are presented. From the expansion, a set of n simultaneous linear equations are derived, which are solved by matrix algebra. To achieve convergence, the algorithm requires meaningful initial estimates for the parameters of the fitting function. NLINEAR is written in Fortran 77 for execution on a CDC Cyber 750 under NOS 2.3. It has a central memory requirement of 5K 60 bit words. Optionally, graphical output of the fitting function can be plotted. Tektronix PLOT-10 routines are required for graphics. NLINEAR was developed in 1987.

  20. Metamaterials with conformational nonlinearity

    PubMed Central

    Lapine, Mikhail; Shadrivov, Ilya V.; Powell, David A.; Kivshar, Yuri S.

    2011-01-01

    Within a decade of fruitful development, metamaterials became a prominent area of research, bridging theoretical and applied electrodynamics, electrical engineering and material science. Being man-made structures, metamaterials offer a particularly useful playground to develop interdisciplinary concepts. Here we demonstrate a novel principle in metamaterial assembly which integrates electromagnetic, mechanical, and thermal responses within their elements. Through these mechanisms, the conformation of the meta-molecules changes, providing a dual mechanism for nonlinearity and offering nonlinear chirality. Our proposal opens a wide road towards further developments of nonlinear metamaterials and photonic structures, adding extra flexibility to their design and control. PMID:22355655