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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. Bivariate spline solution of time dependent nonlinear PDE for a population density over irregular domains.

    PubMed

    Gutierrez, Juan B; Lai, Ming-Jun; Slavov, George

    2015-12-01

    We study a time dependent partial differential equation (PDE) which arises from classic models in ecology involving logistic growth with Allee effect by introducing a discrete weak solution. Existence, uniqueness and stability of the discrete weak solutions are discussed. We use bivariate splines to approximate the discrete weak solution of the nonlinear PDE. A computational algorithm is designed to solve this PDE. A convergence analysis of the algorithm is presented. We present some simulations of population development over some irregular domains. Finally, we discuss applications in epidemiology and other ecological problems. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. 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.

  5. Sampled-Data Fuzzy Control for Nonlinear Coupled Parabolic PDE-ODE Systems.

    PubMed

    Wang, Zi-Peng; Wu, Huai-Ning; Li, Han-Xiong

    2017-09-01

    In this paper, a sampled-data fuzzy control problem is addressed for a class of nonlinear coupled systems, which are described by a parabolic partial differential equation (PDE) and an ordinary differential equation (ODE). Initially, the nonlinear coupled system is accurately represented by the Takagi-Sugeno (T-S) fuzzy coupled parabolic PDE-ODE model. Then, based on the T-S fuzzy model, a novel time-dependent Lyapunov functional is used to design a sampled-data fuzzy controller such that the closed-loop coupled system is exponentially stable, where the sampled-data fuzzy controller consists of the ODE state feedback and the PDE static output feedback under spatially averaged measurements. The stabilization condition is presented in terms of a set of linear matrix inequalities. Finally, simulation results on the control of a hypersonic rocket car are given to illustrate the effectiveness of the proposed design method.

  6. 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.

  7. Generalised solutions for fully nonlinear PDE systems and existence-uniqueness theorems

    NASA Astrophysics Data System (ADS)

    Katzourakis, Nikos

    2017-07-01

    We introduce a new theory of generalised solutions which applies to fully nonlinear PDE systems of any order and allows for merely measurable maps as solutions. This approach bypasses the standard problems arising by the application of Distributions to PDEs and is not based on either integration by parts or on the maximum principle. Instead, our starting point builds on the probabilistic representation of derivatives via limits of difference quotients in the Young measures over a toric compactification of the space of jets. After developing some basic theory, as a first application we consider the Dirichlet problem and we prove existence-uniqueness-partial regularity of solutions to fully nonlinear degenerate elliptic 2nd order systems and also existence of solutions to the ∞-Laplace system of vectorial Calculus of Variations in L∞.

  8. Pricing index-based catastrophe bonds: Part 1: Formulation and discretization issues using a numerical PDE approach

    NASA Astrophysics Data System (ADS)

    Unger, André J. A.

    2010-02-01

    This work is the first installment in a two-part series, and focuses on the development of a numerical PDE approach to price components of a Bermudan-style callable catastrophe (CAT) bond. The bond is based on two underlying stochastic variables; the PCS index which posts quarterly estimates of industry-wide hurricane losses as well as a single-factor CIR interest rate model for the three-month LIBOR. The aggregate PCS index is analogous to losses claimed under traditional reinsurance in that it is used to specify a reinsurance layer. The proposed CAT bond model contains a Bermudan-style call feature designed to allow the reinsurer to minimize their interest rate risk exposure on making substantial fixed coupon payments using capital from the reinsurance premium. Numerical PDE methods are the fundamental strategy for pricing early-exercise constraints, such as the Bermudan-style call feature, into contingent claim models. Therefore, the objective and unique contribution of this first installment in the two-part series is to develop a formulation and discretization strategy for the proposed CAT bond model utilizing a numerical PDE approach. Object-oriented code design is fundamental to the numerical methods used to aggregate the PCS index, and implement the call feature. Therefore, object-oriented design issues that relate specifically to the development of a numerical PDE approach for the component of the proposed CAT bond model that depends on the PCS index and LIBOR are described here. Formulation, numerical methods and code design issues that relate to aggregating the PCS index and introducing the call option are the subject of the companion paper.

  9. 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.

  10. 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.

  11. 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.

  12. A discrete model for an ill-posed nonlinear parabolic PDE

    NASA Astrophysics Data System (ADS)

    Witelski, Thomas P.; Schaeffer, David G.; Shearer, Michael

    2001-12-01

    We study a finite-difference discretization of an ill-posed nonlinear parabolic partial differential equation. The PDE is the one-dimensional version of a simplified two-dimensional model for the formation of shear bands via anti-plane shear of a granular medium. For the discretized initial value problem, we derive analytically, and observed numerically, a two-stage evolution leading to a steady-state: (i) an initial growth of grid-scale instabilities, and (ii) coarsening dynamics. Elaborating the second phase, at any fixed time the solution has a piecewise linear profile with a finite number of shear bands. In this coarsening phase, one shear band after another collapses until a steady-state with just one jump discontinuity is achieved. The amplitude of this steady-state shear band is derived analytically, but due to the ill-posedness of the underlying problem, its position exhibits sensitive dependence. Analyzing data from the simulations, we observe that the number of shear bands at time t decays like t-1/3. From this scaling law, we show that the time-scale of the coarsening phase in the evolution of this model for granular media critically depends on the discreteness of the model. Our analysis also has implications to related ill-posed nonlinear PDEs for the one-dimensional Perona-Malik equation in image processing and to models for clustering instabilities in granular materials.

  13. Optimal control of a class of nonlinear parabolic PDE systems arising in fusion plasma current profile dynamics

    NASA Astrophysics Data System (ADS)

    Ou, Yongsheng

    control) but also to modify the resistivity of the plasma (diffusivity control). Motivated by the current profile control problem in nuclear fusion reactors, we study in this thesis a particular class of nonlinear parabolic PDEs that admit interior, boundary and diffusivity actuation. We make in this way theoretical and practical contributions to control systems and nuclear fusion respectively. First, a simplified dynamic PDE model describing the evolution of the poloidal flux, and therefore the q profile, during the inductive phase of the discharge is introduced. Simulation results show qualitative agreement with experiments. Then, a multi-parameter, extremum-seeking, non-model-based, open-loop, optimal controller is designed, successfully tested in simulations, and implemented experimentally in the DIII-D tokamak, to match a desired q profile within a predefined time window during the flattop phase of the tokamak discharge. The controller is shown to be effective to deal with an optimal control problem defined for a nonlinear PDE system subject to many constraints in its actuators. Next, using the Proper Orthogonal Decomposition (POD) and Galerkin Projection techniques, we derive a finite dimensional ODE (Ordinary Differential Equation) dynamical system that preserves the dominant dynamics of the original infinite dimensional PDE system. This low dimensional model is used to design several closed-loop controllers, which have been tested successfully in simulations and are being implemented in the DIII-D tokamak: (i) we propose a convergent successive scheme based on the quasi-linear approximation to compute an optimal tracking control for the reduced order system; (ii) we formulate the problem as an abstract bilinear-quadratic regulator (BQR) problem. A receding horizon control (RHC) algorithm to solve the problem based on the infinite-dimensional system is proposed and stability of the algorithm for the solution of the BQR problem is studied; (iii) we present a robust

  14. 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.

  15. 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.

  16. 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.

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

    DTIC Science & Technology

    2001-02-23

    analysis also has implications to related ill posed nonlinear PDEs for the one- dimensional Perona - Malik equation in image processing and to models for clustering instabilities in granular materials.

  18. 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.

  19. 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.

  20. 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.

  1. 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.

  2. 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.

  3. Comparison of PDE-based nonlinear diffusion approaches for image enhancement and denoising in optical coherence tomography.

    PubMed

    Salinas, Harry M; Fernández, Delia Cabrera

    2007-06-01

    A comparison between two nonlinear diffusion methods for denoising OCT images is performed. Specifically, we compare and contrast the performance of the traditional nonlinear Perona-Malik filter with a complex diffusion filter that has been recently introduced by Gilboa et al.. The complex diffusion approach based on the generalization of the nonlinear scale space to the complex domain by combining the diffusion and the free Schridinger equation is evaluated on synthetic images and also on representative OCT images at various noise levels. The performance improvement over the traditional nonlinear Perona-Malik filter is quantified in terms of noise suppression, image structural preservation and visual quality. An average signal-to-noise ratio (SNR) improvement of about 2.5 times and an average contrast to noise ratio (CNR) improvement of 49% was obtained while mean structure similarity (MSSIM) was practically not degraded after denoising. The nonlinear complex diffusion filtering can be applied with success to many OCT imaging applications. In summary, the numerical values of the image quality metrics along with the qualitative analysis results indicated the good feature preservation performance of the complex diffusion process, as desired for better diagnosis in medical imaging processing.

  4. 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.

  5. Implications of a wavepacket formulation for the nonlinear parabolized stability equations to hypersonic boundary layers

    NASA Astrophysics Data System (ADS)

    Kuehl, Joseph

    2016-11-01

    The parabolized stability equations (PSE) have been developed as an efficient and powerful tool for studying the stability of advection-dominated laminar flows. In this work, a new "wavepacket" formulation of the PSE 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 saturation amplitudes consistent with experiment. A Mach 6 flared-cone example is presented. Support from the AFOSR Young Investigator Program via Grant FA9550-15-1-0129 is gratefully acknowledges.

  6. 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.

  7. Entropic and gradient flow formulations for nonlinear diffusion

    SciTech Connect

    Dirr, Nicolas; Stamatakis, Marios Zimmer, Johannes

    2016-08-15

    Nonlinear diffusion ∂{sub t}ρ = Δ(Φ(ρ)) is considered for a class of nonlinearities Φ. It is shown that for suitable choices of Φ, an associated Lyapunov functional can be interpreted as thermodynamic entropy. This information is used to derive an associated metric, here called thermodynamic metric. The analysis is confined to nonlinear diffusion obtainable as hydrodynamic limit of a zero range process. The thermodynamic setting is linked to a large deviation principle for the underlying zero range process and the corresponding equation of fluctuating hydrodynamics. For the latter connections, the thermodynamic metric plays a central role.

  8. Quantum geometry of PDE's

    NASA Astrophysics Data System (ADS)

    Prástaro, Agostino

    1991-12-01

    In this paper we present the formal quantization of PDE's [35-40] in categorial language. Formal quantization results as a canonical functor defined on the category of differential equations. Furthermore, a Dirac-quantization can be interpreted as a covering in the category of differential equations. A quantum (pre-)spectral measure is a functor that can be factorized by means of formal quantization and a (pre-)spectral measure. A relation between canonical Dirac- quantization and singular solutions of PDE's is given. It is also proved that the knowledge of Bäcklund correspondences, as well as the conservation laws, can aid the procedure of canonical quantization of PDE's. Physically interesting examples are considered. In particular, we give the canonical quantization of an anharmonic oscillator. A general theory of quantum tunneling effects in PDE's is given. In particular, quantum cobordism has been related with Leray-Serre spectral sequences of PDE's.

  9. 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.

  10. Integrating gene set analysis and nonlinear predictive modeling of disease phenotypes using a Bayesian multitask formulation.

    PubMed

    Gönen, Mehmet

    2016-12-13

    Identifying molecular signatures of disease phenotypes is studied using two mainstream approaches: (i) Predictive modeling methods such as linear classification and regression algorithms are used to find signatures predictive of phenotypes from genomic data, which may not be robust due to limited sample size or highly correlated nature of genomic data. (ii) Gene set analysis methods are used to find gene sets on which phenotypes are linearly dependent by bringing prior biological knowledge into the analysis, which may not capture more complex nonlinear dependencies. Thus, formulating an integrated model of gene set analysis and nonlinear predictive modeling is of great practical importance. In this study, we propose a Bayesian binary classification framework to integrate gene set analysis and nonlinear predictive modeling. We then generalize this formulation to multitask learning setting to model multiple related datasets conjointly. Our main novelty is the probabilistic nonlinear formulation that enables us to robustly capture nonlinear dependencies between genomic data and phenotype even with small sample sizes. We demonstrate the performance of our algorithms using repeated random subsampling validation experiments on two cancer and two tuberculosis datasets by predicting important disease phenotypes from genome-wide gene expression data. We are able to obtain comparable or even better predictive performance than a baseline Bayesian nonlinear algorithm and to identify sparse sets of relevant genes and gene sets on all datasets. We also show that our multitask learning formulation enables us to further improve the generalization performance and to better understand biological processes behind disease phenotypes.

  11. 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

  12. 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

  13. 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.

  14. /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.

  15. Use of nonlinear programming to optimize performance response to energy density in broiler feed formulation.

    PubMed

    Guevara, V R

    2004-02-01

    A nonlinear programming optimization model was developed to maximize margin over feed cost in broiler feed formulation and is described in this paper. The model identifies the optimal feed mix that maximizes profit margin. Optimum metabolizable energy level and performance were found by using Excel Solver nonlinear programming. Data from an energy density study with broilers were fitted to quadratic equations to express weight gain, feed consumption, and the objective function income over feed cost in terms of energy density. Nutrient:energy ratio constraints were transformed into equivalent linear constraints. National Research Council nutrient requirements and feeding program were used for examining changes in variables. The nonlinear programming feed formulation method was used to illustrate the effects of changes in different variables on the optimum energy density, performance, and profitability and was compared with conventional linear programming. To demonstrate the capabilities of the model, I determined the impact of variation in prices. Prices for broiler, corn, fish meal, and soybean meal were increased and decreased by 25%. Formulations were identical in all other respects. Energy density, margin, and diet cost changed compared with conventional linear programming formulation. This study suggests that nonlinear programming can be more useful than conventional linear programming to optimize performance response to energy density in broiler feed formulation because an energy level does not need to be set.

  16. 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

  17. 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}.

  18. 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.

  19. 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.

  20. 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.

  1. 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.

  2. 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

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. Nonlinear electromagnetic formulation for particle-in-cell simulation of lower hybrid waves in toroidal geometry

    SciTech Connect

    Bao, J.; Lin, Z. Kuley, A.; Wang, Z. X.

    2016-06-15

    An electromagnetic particle simulation model has been formulated and verified for nonlinear processes of lower hybrid (LH) waves in fusion plasmas. Electron dynamics are described by the drift kinetic equation using either kinetic momentum or canonical momentum. Ion dynamics are treated as the fluid system or by the Vlasov equation. Compressible magnetic perturbation is retained to simulate both the fast and slow LH waves. Numerical properties are greatly improved by using the electron continuity equation to enforce the consistency between electrostatic potential and vector potential, and by using the importance sampling scheme. The simulation model has been implemented in the gyrokinetic toroidal code (GTC), and verified for the dispersion relation and nonlinear particle trapping of the electromagnetic LH waves.

  8. 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.

  9. 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.

  10. On the development of hierarchical solution strategies for nonlinear finite element formulations

    NASA Technical Reports Server (NTRS)

    Padovan, J.; Lackney, J.

    1984-01-01

    This paper develops a hierarchical type solution scheme which can handle the field equations associated with nonlinear finite element simulations. The overall procedure possesses various levels of application namely degree of freedom, nodal, elemental, substructural as well as global. In particular iteration, updating, assembly and solution control occurs at the various hierarchical levels. Due to the manner of formulation, the degree of matrix inversion depends on the size of the various hierarchical partitioned groups. In this context, degree of freedom partitioning requires no inversion. To benchmark the overall scheme, the results of several numerical examples are presented.

  11. 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.

  12. 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.

  13. 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.

  14. A new outer boundary formulation and energy corrections for the nonlinear Poisson-Boltzmann equation.

    PubMed

    Boschitsch, Alexander H; Fenley, Marcia O

    2007-04-15

    The nonlinear Poisson-Boltzmann equation (PBE) has been successfully used for the prediction of numerous electrostatic properties of highly charged biopolyelectrolytes immersed in aqueous salt solutions. While numerous numerical solvers for the 3D PBE have been developed, the formulation of the outer boundary treatments used in these methods has only been loosely addressed, especially in the nonlinear case. The de facto standard in current nonlinear PBE implementations is to either set the potential at the outer boundaries to zero or estimate it using the (linear) Debye-Hückel (DH) approximation. However, an assessment of how these outer boundary treatments affect the overall solution accuracy does not appear to have been previously made. As will be demonstrated here, both approximations can, under certain conditions, produce completely erroneous estimates of the potential and energy salt dependencies. A related concern for calculations carried out on grids of finite extent (e.g., all current finite difference and finite element implementations) is the contribution to the energy and salt dependence from the exterior region outside the computational grid. This too is shown to be significant, especially at low salt concentration where essentially all of the contributions to the excess osmotic pressure and ion stress energies originate from this exterior region. In this paper the authors introduce a new outer boundary treatment that is valid for both the linear and nonlinear PBE. The authors also formulate energy corrections to account for contributions from outside the computational domain. Finally, the authors also consider the effects of general ion exclusion layers upon biomolecular electrostatics. It is shown that while these layers tend to increase the surface electrostatic potential, under physiological salt conditions and high net charges their effect on the excess osmotic pressure term, which is a measure of the salt dependence of the total electrostatic

  15. 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.

  16. 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.

  17. A three-dimensional nonlinear Timoshenko beam based on the core-congruential formulation

    NASA Technical Reports Server (NTRS)

    Crivelli, Luis A.; Felippa, Carlos A.

    1992-01-01

    A three-dimensional, geometrically nonlinear two-node Timoshenkoo beam element based on the total Larangrian description is derived. The element behavior is assumed to be linear elastic, but no restrictions are placed on magnitude of finite rotations. The resulting element has twelve degrees of freedom: six translational components and six rotational-vector components. The formulation uses the Green-Lagrange strains and second Piola-Kirchhoff stresses as energy-conjugate variables and accounts for the bending-stretching and bending-torsional coupling effects without special provisions. The core-congruential formulation (CCF) is used to derived the discrete equations in a staged manner. Core equations involving the internal force vector and tangent stiffness matrix are developed at the particle level. A sequence of matrix transformations carries these equations to beam cross-sections and finally to the element nodal degrees of freedom. The choice of finite rotation measure is made in the next-to-last transformation stage, and the choice of over-the-element interpolation in the last one. The tangent stiffness matrix is found to retain symmetry if the rotational vector is chosen to measure finite rotations. An extensive set of numerical examples is presented to test and validate the present element.

  18. 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

  19. 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.

  20. 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.

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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

  6. Evaluation of PDE5 and PDE9 expression in benign and malignant breast tumors.

    PubMed

    Karami-Tehrani, Fatemeh; Moeinifard, Marzieh; Aghaei, Mahmoud; Atri, Morteza

    2012-08-01

    Phosphodiesterases 5 and 9 (PDE5, PDE9) are enzymes responsible for regulating second messenger signaling by hydrolyzing 3',5' cyclic guanosine monophosphate (cGMP). PDE isoforms are deregulated in some types of human cancer. The present study was carried out to evaluate the expression of phosphodiesterase isoenzymes, PDE5 and PDE9, in benign and malignant breast tumors. The expression levels of PDE5 and PDE9 were assayed in malignant and benign breast tumors and corresponding normal breast tissues using quantitative real-time RT-PCR. Moreover, the correlation between PDE5, PDE9 relative expression and clinicopathological characteristics were analyzed. The relative expressions of PDE5 and PDE9 in malignant tumors were significantly higher than those of respective normal breast tissues and benign tumors (5.5-fold, p <0.001 and 6-fold, p <0.001, respectively). Furthermore, a significant positive correlation was found between PDE5 and PDE9 overexpression and tumor grade, stage, and lymph node involvement. However, a negative correlation was observed with age. Based on the present results, it is concluded that assessment of PDE5 and PDE9 expression may be useful in the differential diagnosis of benign and malignant breast disease and successful treatment of breast cancer. To the best of our knowledge, this is the first study to show that PDE5 and PDE9 expression levels are higher in malignant breast tumors than those of normal and benign breast tissue. Copyright © 2012 IMSS. Published by Elsevier Inc. All rights reserved.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  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. Assessing the performance of formulations for nonlinear feedback of surface gravity waves on ocean currents over coastal waters

    NASA Astrophysics Data System (ADS)

    Wang, Pengcheng; Sheng, Jinyu; Hannah, Charles

    2017-08-01

    This study presents applications of a two-way coupled wave-circulation modelling system over coastal waters, with a special emphasis of performance assessments of two different methods for nonlinear feedback of ocean surface gravity waves on three-dimensional (3D) ocean currents. These two methods are the vortex force (VF) formulation suggested by Bennis et al. (2011) and the latest version of radiation stress (RS) formulation suggested by Mellor (2015). The coupled modelling system is first applied to two idealized test cases of surf-zone scales to validate implementations of these two methods in the coupled wave-circulation system. Model results show that the latest version of RS has difficulties in producing the undertow over the surf zone. The coupled system is then applied to Lunenburg Bay (LB) of Nova Scotia during Hurricane Juan in 2003. The coupled system using both the VF and RS formulations generates much stronger and more realistic 3D circulation in the Bay during Hurricane Juan than the circulation-only model, demonstrating the importance of surface wave forces to the 3D ocean circulation over coastal waters. However, the RS formulation generates some weak unphysical currents outside the wave breaking zone due to a less reasonable representation for the vertical distribution of the RS gradients over a slopping bottom. These weak unphysical currents are significantly magnified in a two-way coupled system when interacting with large surface waves, degrading the model performance in simulating currents at one observation site. Our results demonstrate that the VF formulation with an appropriate parameterization of wave breaking effects is able to produce reasonable results for applications over coastal waters during extreme weather events. The RS formulation requires a complex wave theory rather than the linear wave theory for the approximation of a vertical RS term to improve its performance under both breaking and non-breaking wave conditions.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. Programming finite element method based hysteresis loss computation software using non-linear superconductor resistivity and T - phiv formulation

    NASA Astrophysics Data System (ADS)

    Stenvall, A.; Tarhasaari, T.

    2010-07-01

    Due to the rapid development of personal computers from the beginning of the 1990s, it has become a reality to simulate current penetration, and thus hysteresis losses, in superconductors with other than very simple one-dimensional (1D) Bean model computations or Norris formulae. Even though these older approaches are still usable, they do not consider, for example, multifilamentary conductors, local critical current dependency on magnetic field or varying n-values. Currently, many numerical methods employing different formulations are available. The problem of hysteresis losses can be scrutinized via an eddy current formulation of the classical theory of electromagnetism. The difficulty of the problem lies in the non-linear resistivity of the superconducting region. The steep transition between the superconducting and the normal states often causes convergence problems for the most common finite element method based programs. The integration methods suffer from full system matrices and, thus, restrict the number of elements to a few thousands at most. The so-called T - phiv formulation and the use of edge elements, or more precisely Whitney 1-forms, within the finite element method have proved to be a very suitable method for hysteresis loss simulations of different geometries. In this paper we consider making such finite element method software from first steps, employing differential geometry and forms.

  18. 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).

  19. 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.

  20. A nonlinear, control-oriented model for ionic polymer-metal composite actuators

    NASA Astrophysics Data System (ADS)

    Chen, Zheng; Hedgepeth, Dawn Rochelle; Tan, Xiaobo

    2009-05-01

    Ionic polymer-metal composites (IPMCs) form an important category of electroactive polymers and have many potential applications in biomedical, robotic and micro/nanomanipulation systems. In this paper, a nonlinear, control-oriented model is proposed for IPMC actuators. A key component in the proposed model is the nonlinear capacitance of the IPMC. A nonlinear partial differential equation (PDE), which can capture the fundamental physics in the IPMC, is fully considered in the derivation of nonlinear capacitance. A systems perspective is taken to get the nonlinear mapping from the voltage to the induced charge by analytically solving the nonlinear PDE at the steady state when a step voltage is applied. The nonlinear capacitance is incorporated into a circuit model, which includes additionally the pseudocapacitance due to the electrochemical adsorption process, the ion diffusion resistance, and the nonlinear DC resistance of the polymer, to capture electrical dynamics of the IPMC. With electromechanical coupling, the curvature output is derived based on the circuit model. The proposed model is formulated in the state space, which will be the starting point for nonlinear controller design. Experimental verification shows that the proposed model can capture the major nonlinearities in the electrical response of the IPMC.

  1. 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.

  2. 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

  3. A Mathematical Formulation for the Effects of Nonlinear Chemical Reactions upon Taylor Dispersive Phenomena

    NASA Astrophysics Data System (ADS)

    Wright, E. S.; Aleem, T.

    2003-12-01

    In 1953, G.I.~Taylor published his landmark paper concerning the transport of a contaminant dissolved in a fluid flowing through a pipe of narrow diameter. He demonstrated that an interaction between the transverse variations in the fluid's velocity field and the transverse diffusion of the solute yielded an effective downstream mixing mechanism for the transverse average of the solute. This mechanism has since been dubbed ``Taylor Dispersion.'' Since his original publication, many related studies have surfaced. These include generalizations of channel geometry, generalizations of the velocity field (including turbulent field), applications to sedimentation problems, etc. However, much less attention has been given to the effects of nonlinear chemical reactions upon a system of solutes undergoing Taylor Dispersion. We present a rigorous mathematical model for the evolution of the transverse averages of reacting solutes that travel within a fluid flowing down a pipe of arbitrary cross-section. The technique for deriving this model is a generalization of a multiple scales perturbation approach described by P.C.~Fife for linear (reactionless) problems. The key outcome is that while one still finds an effective mechanism for downstream mixing, but also there is also a effective mechanism for nonlinear advection.

  4. 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.

  5. 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.

  6. 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

  7. 8-Methoxyquinolines as PDE4 inhibitors.

    PubMed

    Billah, Motasim; Buckley, George M; Cooper, Nicola; Dyke, Hazel J; Egan, Robert; Ganguly, Ashit; Gowers, Lewis; Haughan, Alan F; Kendall, Hannah J; Lowe, Christopher; Minnicozzi, Michael; Montana, John G; Oxford, Janet; Peake, Joanna C; Picken, C Louise; Piwinski, John J; Naylor, Robert; Sabin, Verity; Shih, Neng-Yang; Warneck, Julie B H

    2002-06-17

    The synthesis and pharmacological profile of a novel series of 2-substituted 8-methoxyquinolines is described. The 2-trifluoromethyl compound was found to be a potent inhibitor of phosphodiesterase type 4 (PDE4).

  8. Biomolecular surface construction by PDE transform.

    PubMed

    Zheng, Qiong; Yang, Siyang; Wei, Guo-Wei

    2012-03-01

    This work proposes a new framework for the surface generation based on the partial differential equation (PDE) transform. The PDE transform has recently been introduced as a general approach for the mode decomposition of images, signals, and data. It relies on the use of arbitrarily high-order PDEs to achieve the time-frequency localization, control the spectral distribution, and regulate the spatial resolution. The present work provides a new variational derivation of high-order PDE transforms. The fast Fourier transform is utilized to accomplish the PDE transform so as to avoid stringent stability constraints in solving high-order PDEs. As a consequence, the time integration of high-order PDEs can be done efficiently with the fast Fourier transform. The present approach is validated with a variety of test examples in two-dimensional and three-dimensional settings. We explore the impact of the PDE transform parameters, such as the PDE order and propagation time, on the quality of resulting surfaces. Additionally, we utilize a set of 10 proteins to compare the computational efficiency of the present surface generation method and a standard approach in Cartesian meshes. Moreover, we analyze the present method by examining some benchmark indicators of biomolecular surface, that is, surface area, surface-enclosed volume, solvation free energy, and surface electrostatic potential. A test set of 13 protein molecules is used in the present investigation. The electrostatic analysis is carried out via the Poisson-Boltzmann equation model. To further demonstrate the utility of the present PDE transform-based surface method, we solve the Poisson-Nernst-Planck equations with a PDE transform surface of a protein. Second-order convergence is observed for the electrostatic potential and concentrations. Finally, to test the capability and efficiency of the present PDE transform-based surface generation method, we apply it to the construction of an excessively large biomolecule, a

  9. Biomolecular surface construction by PDE transform

    PubMed Central

    Zheng, Qiong; Yang, Siyang; Wei, Guo-Wei

    2011-01-01

    This work proposes a new framework for the surface generation based on the partial differential equation (PDE) transform. The PDE transform has recently been introduced as a general approach for the mode decomposition of images, signals, and data. It relies on the use of arbitrarily high order PDEs to achieve the time-frequency localization, control the spectral distribution, and regulate the spatial resolution. The present work provides a new variational derivation of high order PDE transforms. The fast Fourier transform is utilized to accomplish the PDE transform so as to avoid stringent stability constraints in solving high order PDEs. As a consequence, the time integration of high order PDEs can be done efficiently with the fast Fourier transform. The present approach is validated with a variety of test examples in two and three-dimensional settings. We explore the impact of the PDE transform parameters, such as the PDE order and propagation time, on the quality of resulting surfaces. Additionally, we utilize a set of 10 proteins to compare the computational efficiency of the present surface generation method and the MSMS approach in Cartesian meshes. Moreover, we analyze the present method by examining some benchmark indicators of biomolecular surface, i.e., surface area, surface enclosed volume, solvation free energy and surface electrostatic potential. A test set of 13 protein molecules is used in the present investigation. The electrostatic analysis is carried out via the Poisson-Boltzmann equation model. To further demonstrate the utility of the present PDE transform based surface method, we solve the Poisson-Nernst-Planck (PNP) equations with a PDE transform surface of a protein. Second order convergence is observed for the electrostatic potential and concentrations. Finally, to test the capability and efficiency of the present PDE transform based surface generation method, we apply it to the construction of an excessively large biomolecule, a virus

  10. 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.

  11. GNGA for general regions: Semilinear elliptic PDE and crossing eigenvalues

    NASA Astrophysics Data System (ADS)

    Hineman, Jay L.; Neuberger, John M.

    2007-07-01

    We consider the semilinear elliptic PDE Δ u + f( λ, u) = 0 with the zero-Dirichlet boundary condition on a family of regions, namely stadions. Linear problems on such regions have been widely studied in the past. We seek to observe the corresponding phenomena in our nonlinear setting. Using the Gradient Newton Galerkin Algorithm (GNGA) of Neuberger and Swift, we document bifurcation, nodal structure, and symmetry of solutions. This paper provides the first published instance where the GNGA is applied to general regions. Our investigation involves both the dimension of the stadions and the value λ as parameters. We find that the so-called crossings and avoided crossings of eigenvalues as the dimension of the stadions vary influences the symmetry and variational structure of nonlinear solutions in a natural way.

  12. A new Bayesian formulation to integrate body-wave polarisation in non-linear probabilistic earthquake location

    NASA Astrophysics Data System (ADS)

    Gaucher, Emmanuel; Gesret, Alexandrine; Noble, Mark; Kohl, Thomas

    2016-04-01

    Earthquake location is most of the time computed using the arrival time of the seismic waves observed on monitoring networks. However, three-component seismometers enable measurement of the seismic wave polarisation which is also hypocentre dependent. This information is necessary when considering single-station locations but may also be applied to local and sparse seismic networks with poor coverage to better constrain the local earthquake hypocentres, as typically seen in hydraulic fracturing or geothermal field monitoring. In this work, we propose a new Bayesian formulation that integrates the information associated with the P-wave polarisation into a probabilistic earthquake location scheme. The approach takes a single 3C-sensor perspective and uses the covariance matrix to quantify the polarisation. This matrix contains all necessary axial information including uncertainties. According to directional statistics, the tri-variate Gaussian distribution represented by the covariance matrix corresponds to an angular central Gaussian distribution when axial data are considered. This property allows us defining a simple probability density function associated with a modelled polarisation vector given the observed covariance matrix. With this approach, the non-linearity of the location problem is kept. Unlike existing least-square misfit functions, this formulation does not reduce the polarisation to a single axis and avoids inexact estimate of a priori angular uncertainties. Furthermore, it replaces the polarisation information in the spherical data space, which yields correct probability density normalisation and prevents from any weighting when combined with e.g. travel-time probability density function. We first present the Bayesian formalism. Then, several synthetic tests on a 1D velocity model are performed to illustrate the technique and to show the effect of integrating the polarisation information. In this synthetic test, we also compare the results with an

  13. Mechanisms of mutant PDE6 proteins underlying retinal diseases.

    PubMed

    Gopalakrishna, Kota N; Boyd, Kimberly; Artemyev, Nikolai O

    2017-09-01

    Mutations in PDE6 genes encoding the effector enzymes in rods and cones underlie severe retinal diseases including retinitis pigmentosa (RP), autosomal dominant congenital stationary night blindness (adCSNB), and achromatopsia (ACHM). Here we examined a spectrum of pathogenic missense mutations in PDE6 using the system based on co-expression of cone PDE6C with its specialized chaperone AIPL1 and the regulatory Pγ subunit as a potent co-chaperone. We uncovered two mechanisms of PDE6C mutations underlying ACHM: (a) folding defects leading to expression of catalytically inactive proteins and (b) markedly diminished ability of Pγ to co-chaperone mutant PDE6C proteins thereby dramatically reducing the levels of functional enzyme. The mechanism of the Rambusch adCSNB associated with the H258N substitution in PDE6B was probed through the analysis of the model mutant PDE6C-H262N. We identified two interrelated deficits of PDE6C-H262N: disruption of the inhibitory interaction of Pγ with mutant PDE6C that markedly reduced the ability of Pγ to augment the enzyme folding. Thus, we conclude that the Rambusch adCSNB is triggered by low levels of the constitutively active PDE6. Finally, we examined PDE6C-L858V, which models PDE6B-L854V, an RP-linked mutation that alters the protein isoprenyl modification. This analysis suggests that the type of prenyl modifications does not impact the folding of PDE6, but it modulates the enzyme affinity for its trafficking partner PDE6D. Hence, the pathogenicity of PDE6B-L854V likely arises from its trafficking deficiency. Taken together, our results demonstrate the effectiveness of the PDE6C expression system to evaluate pathogenicity and elucidate the mechanisms of PDE6 mutations in retinal diseases. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. 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.

  15. An investigation of the beam-column and the finite-element formulations for analyzing geometrically nonlinear thermal response of plane frames

    NASA Astrophysics Data System (ADS)

    Silwal, Baikuntha

    The objective of this study is to investigate the accuracy and computational efficiency of two commonly used formulations for performing the geometrically nonlinear thermal analysis of plane framed structures. The formulations considered are the followings: the Beam-Column formulation and the updated Lagrangian version of the finite element formulation that has been adopted in the commercially well-known software SAP2000. These two formulations are used to generate extensive numerical data for three plane frame configurations, which are then compared to evaluate the performance of the two formulations. The Beam-Column method is based on an Eulerian formulation that incorporates the effects of large joint displacements. In addition, local member force-deformation relationships are based on the Beam-Column approach that includes the axial strain, flexural bowing, and thermal strain. The other formulation, the SAP2000, is based on the updated Lagrangian finite element formulation. The results for nonlinear thermal responses were generated for three plane structures by these formulations. Then, the data were compared for accuracy of deflection responses and for computational efficiency of the Newton-Raphson iteration cycles required for the thermal analysis. The results of this study indicate that the Beam-Column method is quite efficient and powerful for the thermal analysis of plane frames since the method is based on the exact solution of the differential equations. In comparison to the SAP2000 software, the Beam-Column method requires fewer iteration cycles and fewer elements per natural member, even when the structures are subjected to significant curvature effects and to restrained support conditions. The accuracy of the SAP2000 generally depends on the number of steps and/or the number of elements per natural member (especially four or more elements per member may be needed when structure member encounters a significant curvature effect). Succinctly, the Beam

  16. Rod Phosphodiesterase-6 (PDE6) Catalytic Subunits Restore Cone Function in a Mouse Model Lacking Cone PDE6 Catalytic Subunit*

    PubMed Central

    Kolandaivelu, Saravanan; Chang, Bo; Ramamurthy, Visvanathan

    2011-01-01

    Rod and cone photoreceptor neurons utilize discrete PDE6 enzymes that are crucial for phototransduction. Rod PDE6 is composed of heterodimeric catalytic subunits (αβ), while the catalytic core of cone PDE6 (α′) is a homodimer. It is not known if variations between PDE6 subunits preclude rod PDE6 catalytic subunits from coupling to the cone phototransduction pathway. To study this issue, we generated a cone-dominated mouse model lacking cone PDE6 (Nrl−/− cpfl1). In this animal model, using several independent experimental approaches, we demonstrated the expression of rod PDE6 (αβ) and the absence of cone PDE6 (α′) catalytic subunits. The rod PDE6 enzyme expressed in cone cells is active and contributes to the hydrolysis of cGMP in response to light. In addition, rod PDE6 expressed in cone cells couples to the light signaling pathway to produce S-cone responses. However, S-cone responses and light-dependent cGMP hydrolysis were eliminated when the β-subunit of rod PDE6 was removed (Nrl−/− cpfl1 rd). We conclude that either rod or cone PDE6 can effectively couple to the cone phototransduction pathway to mediate visual signaling. Interestingly, we also found that functional PDE6 is required for trafficking of M-opsin to cone outer segments. PMID:21799013

  17. 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.

  18. 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.

  19. 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.

  20. Slow-roll, acceleration, the big rip and the Wentzel-Kramers-Brillouin approximation in the non-linear Schroedinger-type formulation of scalar field cosmology

    SciTech Connect

    Gumjudpai, Burin E-mail: buring@nu.ac.th

    2008-09-15

    Aspects of the non-linear Schroedinger (NLS) type of formulation of scalar (phantom) field cosmology for slow-roll, acceleration, the Wentzel-Kramers-Brillouin (WKB) approximation and the big rip singularity are presented. Slow-roll parameters for the curvature and barotropic density terms are introduced. We re-express all slow-roll parameters, slow-roll conditions and the acceleration condition in NLS form. The WKB approximation in the NLS formulation is also discussed while simplifying to the linear case. Most of the Schroedinger potentials in the NLS formulation are very slowly varying; hence the WKB approximation is valid in some ranges. In the NLS form of the big rip singularity, two quantities are infinite instead of three. We also found that approaching the big rip, w{sub eff}{yields}-1+2/3q (q<0), which is the same as the effective phantom equation of state in the flat case.

  1. 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

  2. Goal oriented adaptivity in the IRGNM for parameter identification in PDEs: II. all-at-once formulations

    NASA Astrophysics Data System (ADS)

    Kaltenbacher, B.; Kirchner, A.; Vexler, B.

    2014-04-01

    In this paper we investigate adaptive discretization of the iteratively regularized Gauss-Newton method IRGNM. All-at-once formulations considering the PDE and the measurement equation simultaneously allow to avoid (approximate) solution of a potentially nonlinear PDE in each Newton step as compared to the reduced form Kaltenbacher et al (2014 Inverse Problems 30 045001). We analyze a least squares and a generalized Gauss-Newton formulation and in both cases prove convergence and convergence rates with a posteriori choice of the regularization parameters in each Newton step and of the stopping index under certain accuracy requirements on four quantities of interest. Estimation of the error in these quantities by means of a weighted dual residual method is discussed, which leads to an algorithm for adaptive mesh refinement. Numerical experiments with an implementation of this algorithm show the numerical efficiency of this approach, which especially for strongly nonlinear PDEs outperforms the nonlinear Tikhonov regularization considered in Kaltenbacher et al (2011 Inverse Problems 27 125008).

  3. Interesting effect of aspect ratio on Kerr nonlinear optical processes in subwavelength diameter single-mode trapezoidal index fiber using Marcuse-type spot-size formulations

    NASA Astrophysics Data System (ADS)

    Sadhu, Arunangshu; Sarkar, Somenath

    2016-08-01

    We investigate the Kerr nonlinear optical processes (NOPs) in the case of a single-mode trapezoidal index fiber based on recently formulated and appropriate Marcuse-type relations for spot size in terms of normalized frequency corresponding to such fiber having various aspect ratios. With the help of these relations, we have analyzed the maximum NOP in these fibers having prospective the merits of tight light confinement in the subwavelength diameter waveguiding region. The comparative investigation reveals that the aspect ratio having a value of 0.7 is the most promising candidate for maximum optical nonlinearity, constructional convenience, and less diffraction. The analysis should be attractive for system users as a ready reference.

  4. 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.

  5. 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.

  6. 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

  7. 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

  8. 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.

  9. 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.

  10. 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

  11. 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.

  12. 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

  13. Mathematical Simulation of the Problem of the Pre-Critical Sandwich Plate Bending in Geometrically Nonlinear One Dimensional Formulation

    NASA Astrophysics Data System (ADS)

    Badriev, I. B.; Banderov, V. V.; Makarov, M. V.

    2017-06-01

    In this paper we consider the geometrically nonlinear problem of determining the equilibrium position of a sandwich plate consisting of two external carrier layers and located between transversely soft core, connected with carrier layer by means of adhesive joint. We investigate the generalized statement of the problem. For its numerical implementation we offer a two-layer iterative process and investigate the convergence of the method. Numerical experiments are carried out for the model problem.

  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. 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:

  17. 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.

  18. 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.

  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. 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.

  3. A combined analytical formulation and genetic algorithm to analyze the nonlinear damage responses of continuous fiber toughened composites

    NASA Astrophysics Data System (ADS)

    Jeon, Haemin; Yu, Jaesang; Lee, Hunsu; Kim, G. M.; Kim, Jae Woo; Jung, Yong Chae; Yang, Cheol-Min; Yang, B. J.

    2017-04-01

    Continuous fiber-reinforced composites are important materials that have the highest commercialized potential in the upcoming future among existing advanced materials. Despite their wide use and value, their theoretical mechanisms have not been fully established due to the complexity of the compositions and their unrevealed failure mechanisms. This study proposes an effective three-dimensional damage modeling of a fibrous composite by combining analytical micromechanics and evolutionary computation. The interface characteristics, debonding damage, and micro-cracks are considered to be the most influential factors on the toughness and failure behaviors of composites, and a constitutive equation considering these factors was explicitly derived in accordance with the micromechanics-based ensemble volume averaged method. The optimal set of various model parameters in the analytical model were found using modified evolutionary computation that considers human-induced error. The effectiveness of the proposed formulation was validated by comparing a series of numerical simulations with experimental data from available studies.

  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. 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.

  7. 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.

  8. 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.

  9. a Non-Linear Adapted Tri-Tree Multigrid Solver for Finite Element Formulation of the Navier-Stokes Equations

    NASA Astrophysics Data System (ADS)

    Wille, S. Ø.

    1996-06-01

    An iterative adaptive equation multigrid solver for solving the implicit Navier-Stokes equations simultaneously with tri-tree grid generation is developed. The tri-tree grid generator builds a hierarchical grid structur e which is mapped to a finite element grid at each hierarchical level. For each hierarchical finite element multigrid the Navier-Stokes equations are solved approximately. The solution at each level is projected onto the next finer grid and used as a start vector for the iterative equation solver at the finer level. When the finest grid is reached, the equation solver is iterated until a tolerated solution is reached. The iterative multigrid equation solver is preconditioned by incomplete LU factorization with coupled node fill-in.The non-linear Navier-Stokes equations are linearized by both the Newton method and grid adaption. The efficiency and behaviour of the present adaptive method are compared with those of the previously developed iterative equation solver which is preconditioned by incomplete LU factorization with coupled node fill-in.

  10. 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.

  11. 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.

  12. 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.

  13. 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

  14. Optimal control of coupled PDE networks with automated code generation

    NASA Astrophysics Data System (ADS)

    Papadopoulos, D.

    2012-09-01

    The purpose of this work is to present a framework for the optimal control of coupled PDE networks. A coupled PDE network is a system of partial differential equations coupled together. Such systems can be represented as a directed graph. A domain specific language (DSL)—an extension of the DOT language—is used for the description of such a coupled PDE network. The adjoint equations and the gradient, required for its optimal control, are computed with the help of a computer algebra system (CAS). Automated code generation techniques have been used for the generation of the PDE systems of both the direct and the adjoint equations. Both the direct and adjoint equations are solved with the standard finite element method. Finally, for the numerical optimization of the system standard optimization techniques are used such as BFGS and Newton conjugate gradient.

  15. 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

  16. 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.

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

    PubMed

    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

    2016-09-27

    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.

  18. PDE8 controls CD4(+) T cell motility through the PDE8A-Raf-1 kinase signaling complex.

    PubMed

    Basole, Chaitali P; Nguyen, Rebecca K; Lamothe, Katie; Vang, Amanda; Clark, Robert; Baillie, George S; Epstein, Paul M; Brocke, Stefan

    2017-08-26

    The levels of cAMP are regulated by phosphodiesterase enzymes (PDEs), which are targets for the treatment of inflammatory disorders. We have previously shown that PDE8 regulates T cell motility. Here, for the first time, we report that PDE8A exerts part of its control of T cell function through the V-raf-1 murine leukemia viral oncogene homolog 1 (Raf-1) kinase signaling pathway. To examine T cell motility under physiologic conditions, we analyzed T cell interactions with endothelial cells and ligands in flow assays. The highly PDE8-selective enzymatic inhibitor PF-04957325 suppresses adhesion of in vivo myelin oligodendrocyte glycoprotein (MOG) activated inflammatory CD4(+) T effector (Teff) cells to brain endothelial cells under shear stress. Recently, PDE8A was shown to associate with Raf-1 creating a compartment of low cAMP levels around Raf-1 thereby protecting it from protein kinase A (PKA) mediated inhibitory phosphorylation. To test the function of this complex in Teff cells, we used a cell permeable peptide that selectively disrupts the PDE8A-Raf-1 interaction. The disruptor peptide inhibits the Teff-endothelial cell interaction more potently than the enzymatic inhibitor. Furthermore, the LFA-1/ICAM-1 interaction was identified as a target of disruptor peptide mediated reduction of adhesion, spreading and locomotion of Teff cells under flow. Mechanistically, we observed that disruption of the PDE8A-Raf-1 complex profoundly alters Raf-1 signaling in Teff cells. Collectively, our studies demonstrate that PDE8A inhibition by enzymatic inhibitors or PDE8A-Raf-1 kinase complex disruptors decreases Teff cell adhesion and migration under flow, and represents a novel approach to target T cells in inflammation. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. 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

  20. 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

  1. 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.

  2. Efficacy and selectivity of phosphodiesterase-targeted drugs to inhibit photoreceptor phosphodiesterase (PDE6) in retinal photoreceptors*

    PubMed Central

    Zhang, Xiujun; Feng, Qing; Cote, Rick H.

    2005-01-01

    Purpose: Phosphodiesterase (PDE) inhibitors are important therapeutic agents, but their effects on photoreceptor PDE (PDE6) and photoreceptor cells are poorly understood. We characterized the potency and selectivity of various classes of PDE inhibitors on purified rod and cone PDE6 and on intact rod outer segments (ROS). Methods: The inhibition constant (KI) of isozyme-selective PDE inhibitors was determined for purified rod and cone PDE6. Perturbations of cGMP levels in isolated ROS suspensions by PDE inhibitors were quantitated by a cGMP enzyme-linked immunoassay. Results: Most PDE5-selective inhibitors are excellent PDE6 inhibitors. Vardenafil, a potent PDE5 inhibitor (KI = 0.2 nM), is the most potent PDE6 inhibitor tested (KI = 0.7 nM). Zaprinast is the only drug that inhibits PDE6 more potently than PDE5. PDE1-selective inhibitors were equally effective in inhibiting PDE6. In intact ROS, PDE inhibitors elevated cGMP levels but none fully inhibited PDE6. Their potency to elevate cGMP levels in ROS was much lower than their ability to inhibit the purified enzyme. Competition between PDE5/6-selective drugs and the inhibitory γ subunit for the active site of PDE6 is proposed to reduce the effectiveness of drugs at the enzyme active site. Conclusions: Several classes of PDE inhibitors equally well inhibit PDE6 as the PDE family to which they are targeted. In intact ROS, high PDE6 concentrations, binding of the γ subunit to the active site, and calcium feedback mechanisms attenuate the effectiveness of PDE inhibitors to inhibit PDE6 and disrupt the cGMP signaling pathway during visual transduction. PMID:16123402

  3. 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.

  4. 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

  5. Finite-Difference Schemes for a Scalar Reaction-Convection PDE.

    NASA Astrophysics Data System (ADS)

    Mickens, R. E.

    1997-04-01

    The scalar reaction-convection partial differential equation (SRCPDE) has been used as a model equation to investigate the properties of various numerical integration schemes.(R. J. LeVeque and H. C. Yee, J. Comput. Phys. 86), 187 (1990). In particular, these studies have provided information on the genesis of numerical instabilities and related issues such as stability and convergence of the solutions, the existence of ``false" fixed-points, bifurcation of solutions as the step-sizes are varied, etc.(H. C. Yee and P. K. Sweby, NASA Technical Memorandum 110398 (April 1996).) We consider a SRCPDE having a symmetric, nonlinear cubic source term in the dependent variable. A non-standard finite-difference scheme(R. E. Mickens, Nonstandard Finite Difference Models of Differential Equations) (World Scientific, 1994); Chapter 6. is constructed and its mathematical properties are studied and compared to those of the original PDE. We are also able to determine an exact scheme for the PDE. This research is supported by grants from ARO, DOE, NASA, and NIH-(MBRS).

  6. 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.

  7. Calmodulin-dependent cyclic nucleotide phosphodiesterase (PDE1).

    PubMed

    Kakkar, R; Raju, R V; Sharma, R K

    1999-07-01

    Ca2+/calmodulin-dependent cyclic nucleotide phosphodiesterase (PDE1) is one of the key enzymes involved in the complex interactions between the cyclic nucleotide and Ca2+ second messenger systems. Currently, three genes encode PDE1, and alternate splicing of these genes gives rise to functionally different isozymes which exhibit distinct catalytic and regulatory properties. Some isozymes have similar kinetic and immunological properties but are differentially regulated by Ca2+ and calmodulin. These isozymes also differ in their mechanism of regulation by phosphorylation. Analysis of various regulatory reactions involving Ca2+ and cyclic adenosine monophosphate (cAMP) has revealed the importance of the time dependence of these reactions during cell activation; however, no measurement is available for the time of occurrence of specific regulatory reactions. cAMP-signalling systems provide a pivotal centre for achieving crosstalk regulation by various signalling pathways. It has been proposed that polypeptide sequences enriched in proline (P), glutamate (E), serine (S) and threonine (T), known as PEST motifs, serve as putative intramolecular signals for rapid proteolytic degradation by calpains. Calpains are Ca(2+)-dependent cysteine proteases that regulate various enzymes, transcription factors and structural proteins through limited proteolysis. Isozyme PDE1A2 has a PEST motif and acts as a substrate for m-calpain. In this paper, we have described PDE1A2 regulation by calpains and its physiological implications. cAMP is an important component of the signal transduction pathway and plays an integral role in various physiological processes such as gene transcription, various neuronal functions, cardiac muscle contraction, vascular relaxation, cell proliferation and a host of other functions. It is important to identify the cellular processes where PDE isoform(s) and cAMP response are altered. This will lead to better understanding of the pathology of disease states

  8. 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

  9. 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.

  10. PDE5 Inhibitors Enhance Celecoxib Killing in Multiple Tumor Types

    PubMed Central

    BOOTH, LAURENCE; ROBERTS, JANE L.; CRUICKSHANKS, NICHOLA; TAVALLAI, SEYEDMEHRAD; WEBB, TIMOTHY; SAMUEL, PETER; CONLEY, ADAM; BINION, BRITTANY; YOUNG, HAROLD F.; POKLEPOVIC, ANDREW; SPIEGEL, SARAH; DENT, PAUL

    2015-01-01

    The present studies determined whether clinically relevant phosphodiesterase 5 (PDE5) inhibitors interacted with a clinically relevant NSAID, celecoxib, to kill tumor cells. Celecoxib and PDE5 inhibitors interacted in a greater than additive fashion to kill multiple tumor cell types. Celecoxib and sildenafil killed ex vivo primary human glioma cells as well as their associated activated microglia. Knock down of PDE5 recapitulated the effects of PDE5 inhibitor treatment; the nitric oxide synthase inhibitor L-NAME suppressed drug combination toxicity. The effects of celecoxib were COX2 independent. Over-expression of c-FLIP-s or knock down of CD95/FADD significantly reduced killing by the drug combination. CD95 activation was dependent on nitric oxide and ceramide signaling. CD95 signaling activated the JNK pathway and inhibition of JNK suppressed cell killing. The drug combination inactivated mTOR and increased the levels of autophagy and knock down of Beclin1 or ATG5 strongly suppressed killing by the drug combination. The drug combination caused an ER stress response; knock down of IRE1α/XBP1 enhanced killing whereas knock down of eIF2α/ATF4/CHOP suppressed killing. Sildenafil and celecoxib treatment suppressed the growth of mammary tumors in vivo. Collectively our data demonstrate that clinically achievable concentrations of celecoxib and sildenafil have the potential to be a new therapeutic approach for cancer. PMID:25303541

  11. 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…

  12. 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.

  13. Coupled nonlinear-diffusion color image sharpening based on the chromaticity-brightness model

    NASA Astrophysics Data System (ADS)

    Saito, Takahiro; Nosaka, Reina; Komatsu, Takashi

    2006-01-01

    Previously we have presented a selective image sharpening method based on the coupled nonlinear diffusion process composed of a nonlinear diffusion term, a fidelity term and an isotropic peaking term, and it can sharpen only blurred edges without increasing the noise visibility. Our previously presented prototypal color-image sharpening methods based on the coupled nonlinear-diffusion process have been formulated on the linear color models, namely, the channel-bychannel model and the 3D vectorial model. Our prototypal methods can sharpen blurred color step edges, but they do not necessarily enhance contrasts of signal variations in complex texture image regions so well as in simple step-edge regions. To remedy the drawback, this paper extends our coupled nonlinear-diffusion color-image sharpening method to the nonlinear non-flat color model, namely, the chromaticity-brightness model, which is known to be closely relating to human color perception. We modify our time-evolution PDE's for the non-flat space of the chromaticity vector and present its digital implementations. Through experimental simulations, we compare our new color-image sharpening method based on the chromaticity-brightness model with our prototypal color-image sharpening methods based on the linear color models.

  14. PDE8 regulates rapid Teff cell adhesion and proliferation independent of ICER.

    PubMed

    Vang, Amanda G; Ben-Sasson, Shlomo Z; Dong, Hongli; Kream, Barbara; DeNinno, Michael P; Claffey, Michelle M; Housley, William; Clark, Robert B; Epstein, Paul M; Brocke, Stefan

    2010-08-09

    Abolishing the inhibitory signal of intracellular cAMP by phosphodiesterases (PDEs) is a prerequisite for effector T (Teff) cell function. While PDE4 plays a prominent role, its control of cAMP levels in Teff cells is not exclusive. T cell activation has been shown to induce PDE8, a PDE isoform with 40- to 100-fold greater affinity for cAMP than PDE4. Thus, we postulated that PDE8 is an important regulator of Teff cell functions. We found that Teff cells express PDE8 in vivo. Inhibition of PDE8 by the PDE inhibitor dipyridamole (DP) activates cAMP signaling and suppresses two major integrins involved in Teff cell adhesion. Accordingly, DP as well as the novel PDE8-selective inhibitor PF-4957325-00 suppress firm attachment of Teff cells to endothelial cells. Analysis of downstream signaling shows that DP suppresses proliferation and cytokine expression of Teff cells from Crem-/- mice lacking the inducible cAMP early repressor (ICER). Importantly, endothelial cells also express PDE8. DP treatment decreases vascular adhesion molecule and chemokine expression, while upregulating the tight junction molecule claudin-5. In vivo, DP reduces CXCL12 gene expression as determined by in situ probing of the mouse microvasculature by cell-selective laser-capture microdissection. Collectively, our data identify PDE8 as a novel target for suppression of Teff cell functions, including adhesion to endothelial cells.

  15. 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

  16. 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.

  17. AKAP3 Selectively Binds PDE4A Isoforms in Bovine Spermatozoa1

    PubMed Central

    Bajpai, Malini; Fiedler, Sarah E.; Huang, Zaohua; Vijayaraghavan, Srinivasan; Olson, Gary E.; Livera, Gabriel; Conti, Marco; Carr, Daniel W.

    2006-01-01

    Cyclic AMP plays an important role in regulating sperm motility and acrosome reaction through activation of cAMP-dependent protein kinase A (PKA). Phosphodiesterases (PDEs) modulate the levels of cyclic nucleotides by catalyzing their degradation. Although PDE inhibitors specific to PDE1 and PDE4 are known to alter sperm motility and capacitation in humans, little is known about the role or subcellular distribution of PDEs in spermatozoa. The localization of PKA is regulated by A-kinase anchoring proteins (AKAPs), which may also control the intracellular distribution of PDE. The present study was undertaken to investigate the role and localization of PDE4 during sperm capacitation. Addition of Rolipram or RS25344, PDE4-specific inhibitors significantly increased the progressive motility of bovine spermatozoa. Immunolocalization techniques detected both PDE4A and AKAP3 (formerly known as AKAP110) in the principal piece of bovine spermatozoa. The PDE4A5 isoform was detected primarily in the Triton X-100-soluble fraction of caudal epididymal spermatozoa. However, in ejaculated spermatozoa it was seen primarily in the SDS-soluble fraction, indicating a shift in PDE4A5 localization into insoluble organelles during sperm capacitation. AKAP3 was detected only in the SDS-soluble fraction of both caudal and ejaculated sperm. Immunoprecipitation experiments using COS cells cotransfected with AKAP3 and either Pde4a5 or Pde4d provide evidence that PDE4A5 but not PDE4D interacts with AKAP3. Pulldown assays using sperm cell lysates confirm this interaction in vitro. These data suggest that AKAP3 binds both PKA and PDE4A and functions as a scaffolding protein in spermatozoa to regulate local cAMP concentrations and modulate sperm functions. PMID:16177223

  18. 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.

  19. 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

  20. 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.

  1. 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.

  2. 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.

  3. 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.

  4. 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. Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  5. 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

  6. Leptin receptor expressing neurons express phosphodiesterase-3B (PDE3B) and leptin induces STAT3 activation in PDE3B neurons in the mouse hypothalamus

    PubMed Central

    Sahu, Maitrayee; Sahu, Abhiram

    2015-01-01

    Leptin signaling in the hypothalamus is critical for normal food intake and body weight regulation. Cumulative evidence suggests that besides the signal transducer and activator of transcription-3 (STAT3) pathway, several non-STAT3 pathways including the phosphodiesterase-3B (PDE3B) pathway mediate leptin signaling in the hypothalamus. We have shown that PDE3B is localized in various hypothalamic sites implicated in the regulation of energy homeostasis and that the anorectic and body weight reducing effects of leptin are mediated by the activation of PDE3B. It is still unknown if PDE3B is expressed in the long form of the leptin-receptor (ObRb)-expressing neurons in the hypothalamus and whether leptin induces STAT3 activation in PDE3B-expressing neurons. In this study, we examined co-localization of PDE3B with ObRb neurons in various hypothalamic nuclei in ObRb-GFP mice that were treated with leptin (5mg/kg, ip) for 2 hr. Results showed that most of the ObRb neurons in the arcuate nucleus (ARC, 93%), ventromedial nucleus (VMN, 94%), dorsomedial nucleus (DMN, 95%), ventral premammillary nucleus (PMv, 97%) and lateral hypothalamus (LH, 97%) co-expressed PDE3B. We next examined co-localization of p-STAT3 and PDE3B in the hypothalamus in C57BL6 mice that were treated with leptin (5mg/kg, ip) for 1 hr. The results showed that almost all p-STAT3 positive neurons in different hypothalamic nuclei including ARC, VMN, DMN, LH and PMv areas expressed PDE3B. These results suggest the possibility for a direct role for the PDE3B pathway in mediating leptin action in the hypothalamus. PMID:26297880

  7. Leptin receptor expressing neurons express phosphodiesterase-3B (PDE3B) and leptin induces STAT3 activation in PDE3B neurons in the mouse hypothalamus.

    PubMed

    Sahu, Maitrayee; Sahu, Abhiram

    2015-11-01

    Leptin signaling in the hypothalamus is critical for normal food intake and body weight regulation. Cumulative evidence suggests that besides the signal transducer and activator of transcription-3 (STAT3) pathway, several non-STAT3 pathways including the phosphodiesterase-3B (PDE3B) pathway mediate leptin signaling in the hypothalamus. We have shown that PDE3B is localized in various hypothalamic sites implicated in the regulation of energy homeostasis and that the anorectic and body weight reducing effects of leptin are mediated by the activation of PDE3B. It is still unknown if PDE3B is expressed in the long form of the leptin-receptor (ObRb)-expressing neurons in the hypothalamus and whether leptin induces STAT3 activation in PDE3B-expressing neurons. In this study, we examined co-localization of PDE3B with ObRb neurons in various hypothalamic nuclei in ObRb-GFP mice that were treated with leptin (5mg/kg, ip) for 2h. Results showed that most of the ObRb neurons in the arcuate nucleus (ARC, 93%), ventromedial nucleus (VMN, 94%), dorsomedial nucleus (DMN, 95%), ventral premammillary nucleus (PMv, 97%) and lateral hypothalamus (LH, 97%) co-expressed PDE3B. We next examined co-localization of p-STAT3 and PDE3B in the hypothalamus in C57BL6 mice that were treated with leptin (5mg/kg, ip) for 1h. The results showed that almost all p-STAT3 positive neurons in different hypothalamic nuclei including ARC, VMN, DMN, LH and PMv areas expressed PDE3B. These results suggest the possibility for a direct role for the PDE3B pathway in mediating leptin action in the hypothalamus. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. 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.

  9. 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.

  10. 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.

  11. 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

  12. 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

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. Thiophene inhibitors of PDE4: crystal structures show a second binding mode at the catalytic domain of PDE4D2.

    PubMed

    Nankervis, Jacob L; Feil, Susanne C; Hancock, Nancy C; Zheng, Zhaohua; Ng, Hooi-Ling; Morton, Craig J; Holien, Jessica K; Ho, Patricia W M; Frazzetto, Mark M; Jennings, Ian G; Manallack, David T; Martin, T John; Thompson, Philip E; Parker, Michael W

    2011-12-01

    PDE4 inhibitors have been identified as therapeutic targets for a variety of conditions, particularly inflammatory diseases. We have serendipitously identified a novel class of phosphodiesterase 4 (PDE4) inhibitor during a study to discover antagonists of the parathyroid hormone receptor. X-ray crystallographic studies of PDE4D2 complexed to four potent inhibitors reveal the atomic details of how they inhibit the enzyme and a notable contrast to another recently reported thiophene-based inhibitor. Copyright © 2011 Elsevier Ltd. All rights reserved.

  19. 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.

  20. 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.

  1. 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

  2. Parallel PDE-Based Simulations Using the Common Component Architecture

    SciTech Connect

    McInnes, Lois C.; Allan, Benjamin A.; Armstrong, Robert; Benson, Steven J.; Bernholdt, David E.; Dahlgren, Tamara L.; Diachin, Lori; Krishnan, Manoj Kumar; Kohl, James A.; Larson, J. Walter; Lefantzi, Sophia; Nieplocha, Jarek; Norris, Boyana; Parker, Steven G.; Ray, Jaideep; Zhou, Shujia

    2006-03-05

    Summary. The complexity of parallel PDE-based simulations continues to increase as multimodel, multiphysics, and multi-institutional projects become widespread. A goal of componentbased software engineering in such large-scale simulations is to help manage this complexity by enabling better interoperability among various codes that have been independently developed by different groups. The Common Component Architecture (CCA) Forum is defining a component architecture specification to address the challenges of high-performance scientific computing. In addition, several execution frameworks, supporting infrastructure, and generalpurpose components are being developed. Furthermore, this group is collaborating with others in the high-performance computing community to design suites of domain-specific component interface specifications and underlying implementations. This chapter discusses recent work on leveraging these CCA efforts in parallel PDE-based simulations involving accelerator design, climate modeling, combustion, and accidental fires and explosions. We explain how component technology helps to address the different challenges posed by each of these applications, and we highlight how component interfaces built on existing parallel toolkits facilitate the reuse of software for parallel mesh manipulation, discretization, linear algebra, integration, optimization, and parallel data redistribution. We also present performance data to demonstrate the suitability of this approach, and we discuss strategies for applying component technologies to both new and existing applications.

  3. Inhibition of PDE5A1 guanosine cyclic monophosphate (cGMP) hydrolysing activity by sildenafil analogues that inhibit cellular cGMP efflux.

    PubMed

    Subbotina, Anna; Ravna, Aina W; Lysaa, Roy A; Abagyan, Ruben; Bugno, Ryszard; Sager, Georg

    2017-06-01

    To determine the ability of 11 sildenafil analogues to discriminate between cyclic nucleotide phosphodiesterases (cnPDEs) and to characterise their inhibitory potencies (Ki values) of PDE5A1-dependent guanosine cyclic monophosphate (cGMP) hydrolysis. Sildenafil analogues were identified by virtual ligand screening (VLS) and screened for their ability to inhibit adenosine cyclic monophosphate (cAMP) hydrolysis by PDE1A1, PDE1B1, PDE2A1, PDE3A, PDE10A1 and PDE10A2, and cGMP hydrolysis by PDE5A, PDE6C, PDE9A2 for a low (1 nm) and high concentration (10 μm). Complete IC50 plots for all analogues were performed for PDE5A-dependent cGMP hydrolysis. Docking studies and scoring were made using the ICM molecular modelling software. The analogues in a low concentration showed no or low inhibition of PDE1A1, PDE1B1, PDE2A1, PDE3A, PDE10A1 and PDE10A2. In contrast, PDE5A and PDE6C were markedly inhibited to a similar extent by the analogues in a low concentration, whereas PDE9A2 was much less inhibited. The analogues showed a relative narrow range of Ki values for PDE5A inhibition (1.2-14 nm). The sildenafil molecule was docked in the structure of PDE5A1 co-crystallised with sildenafil. All the analogues had similar binding poses as sildenafil. Sildenafil analogues that inhibit cellular cGMP efflux are potent inhibitors of PDE5A and PDE6C. © 2017 The Authors. Journal of Pharmacy and Pharmacology published by John Wiley & Sons Ltd on behalf of Royal Pharmaceutical Society.

  4. On the Interface of Probabilistic and PDE Methods in a Multifactor Term Structure Theory

    ERIC Educational Resources Information Center

    Mamon, Rogemar S.

    2004-01-01

    Within the general framework of a multifactor term structure model, the fundamental partial differential equation (PDE) satisfied by a default-free zero-coupon bond price is derived via a martingale-oriented approach. Using this PDE, a result characterizing a model belonging to an exponential affine class is established using only a system of…

  5. 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.

  6. 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.

  7. 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…

  8. PDE5 inhibitors enhance the lethality of standard of care chemotherapy in pediatric CNS tumor cells

    PubMed Central

    Roberts, Jane L; Booth, Laurence; Conley, Adam; Cruickshanks, Nichola; Malkin, Mark; Kukreja, Rakesh C; Grant, Steven; Poklepovic, Andrew; Dent, Paul

    2014-01-01

    We determined whether clinically relevant phosphodiesterase 5 (PDE5) inhibitors interacted with clinically relevant chemotherapies to kill medulloblastoma cells. In medulloblastoma cells PDE5 inhibitors interacted in a greater than additive fashion with vincristine/etoposide/cisplatin to cause cell death. Knockdown of PDE5 expression recapitulated the combination effects of PDE5 inhibitor drugs with chemotherapy drugs. Expression of dominant negative caspase 9 did not significantly inhibit chemotherapy lethality but did significantly reduce enhanced killing in combination with the PDE5 inhibitor sildenafil. Overexpression of BCL-XL and c-FLIP-s suppressed individual and combination drug toxicities. Knockdown of CD95 or FADD suppressed drug combination toxicity. Treatment with PDE5 inhibitors and chemotherapy drugs promoted autophagy which was maximal at ~12 h post-treatment, and in a cell type-dependent manner knockdown of Beclin1 or ATG5 either suppressed or enhanced drug combination lethality. PDE5 inhibitors enhanced the induction of chemotherapy-induced DNA damage in a nitric oxide synthase-dependent fashion. In conclusion, our data demonstrate that the combination of PDE5 inhibitors with standard of care chemotherapy agents for medulloblastoma represents a possible novel modality for future treatment of this disease. PMID:24651037

  9. 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

  10. 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…

  11. Stochastic-convective transport with nonlinear reactions and mixing: finite streamtube ensemble formulation for multicomponent reaction systems with intra-streamtube dispersion.

    PubMed

    Ginn, T R

    2001-01-01

    An effective streamtube ensemble method is developed to upscale convective-dispersive transport with multicomponent nonlinear reactions in steady nonuniform flow. The transport is cast in terms of a finite ensemble of independent discrete streamtubes that approximate convective transport along macroscopically averaged pathlines and dispersive transport longitudinally as microscopic mixing within streamtubes. The representation of fate and transport via a finite ensemble of effective linear streamtubes, allows the treatment of arbitrarily complex reaction systems involving both homogeneous and heterogeneous reactions, and longitudinal dispersive/diffusive mixing within streamtubes. This allows the use of reactive-transport codes designed to solve such problems in an Eulerian framework, as opposed to reliance on closed-form (convolutional or canonical) expressions for reactive transport in exclusively convective streamtubes. The approach requires both reactive-transport solutions for a representative ensemble of one-dimensional convective-dispersive-reactive streamtubes and the distribution of flux over the streamtube ensemble variants, and it does not allow for lateral mixing between streamtubes. Here, the only ensemble variant is travel time. The discussion details the way that the conventional Eulerian fate and transport model is converted first into an ensemble of transports along three-dimensional streamtubes of unknown geometry, and then to approximate one-dimensional streamtubes that are designed to honor the important global properties of the transport. Conditions under which such an 'equivalent' ensemble of one-dimensional streamtubes are described. The breakthrough curve of a nonreactive tracer in the ensemble is expressed as a combined Volterra-Fredholm integral equation, which serves as the basis for estimation of the distribution of flux over the variant of the ensemble, travel time. Transient convective speed and the effects of errors in flux

  12. Strong-continuation, contrast-invariant inpainting with a third-order optimal PDE.

    PubMed

    Bertalmío, Marcelo

    2006-07-01

    PDE-based image inpainting has become a very active area of research after the pioneering works of Masnou and Morel, Bertalmío et al., and Ballester et al. In this paper, we take a different approach, inspired by the excellent work of Caselles et al. We view the inpainting problem as a particular case of image interpolation in which we intend to propagate level lines. Expressing this in terms of local neighborhoods and using a Taylor expansion we derive a third-order PDE that performs inpainting. This PDE is optimal in the sense that it is the most accurate third-order PDE which can ensure continuation of level lines. The continuation is strong, allowing the restoration of thin structures occluded by a wide gap. The result is also contrast invariant. This is a novel PDE, which, in both its accuracy and contrast invariance, outperforms the approaches cited above.

  13. Cyclic nucleotide phosphodiesterases in human spermatozoa and seminal fluid: Presence of an active PDE10A in human spermatozoa.

    PubMed

    Maréchal, Loïze; Guillemette, Christine; Goupil, Serge; Blondin, Patrick; Leclerc, Pierre; Richard, François J

    2017-02-01

    Cyclic adenosine monophosphate (cAMP) plays a crucial role as a signaling molecule for sperm functions such as capacitation, motility and acrosome reaction. It is well known that cAMP degradation by phosphodiesterase (PDE) enzyme has a major impact on sperm functions. The present study was undertaken to characterize cAMP-PDE activity in human semen. cAMP-PDE activity was measured in human sperm and seminal plasma using family specific PDE inhibitors. Three sperm fractionation methods were applied to assess cAMP-PDE activity in spermatozoa. Western blots were used to validate the presence of specific family in sperm and seminal plasma. Using three sperm fractionation methods, we demonstrated that in human sperm, the major cAMP-PDE activity is papaverine-sensitive and thus ascribed to PDE10. In seminal plasma, total cAMP-PDE activity was 1.14±0.39fmol of cAMP hydrolyzed per minute per μg of protein. Using specific inhibitors, we showed that the major cAMP-PDE activity found in human seminal plasma is ascribed to PDE4 and PDE11. Western blot analysis, immunoprecipitation with a specific monoclonal antibody, and mass spectrometry confirmed the presence of PDE10 in human spermatozoa. This study provides the first demonstration of the presence of functional PDE10 in human spermatozoa and functional PDE4 and PDE11 in human seminal plasma. Since the contribution of cyclic nucleotides in several sperm functions is well known, the finding that PDE10 is an active enzyme in human spermatozoa is novel and may lead to new insight into fertility. Copyright © 2016 Elsevier B.V. All rights reserved.

  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. 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

  16. A-optimal encoding weights for nonlinear inverse problems, with application to the Helmholtz inverse problem

    NASA Astrophysics Data System (ADS)

    Crestel, Benjamin; Alexanderian, Alen; Stadler, Georg; Ghattas, Omar

    2017-07-01

    The computational cost of solving an inverse problem governed by PDEs, using multiple experiments, increases linearly with the number of experiments. A recently proposed method to decrease this cost uses only a small number of random linear combinations of all experiments for solving the inverse problem. This approach applies to inverse problems where the PDE solution depends linearly on the right-hand side function that models the experiment. As this method is stochastic in essence, the quality of the obtained reconstructions can vary, in particular when only a small number of combinations are used. We develop a Bayesian formulation for the definition and computation of encoding weights that lead to a parameter reconstruction with the least uncertainty. We call these weights A-optimal encoding weights. Our framework applies to inverse problems where the governing PDE is nonlinear with respect to the inversion parameter field. We formulate the problem in infinite dimensions and follow the optimize-then-discretize approach, devoting special attention to the discretization and the choice of numerical methods in order to achieve a computational cost that is independent of the parameter discretization. We elaborate our method for a Helmholtz inverse problem, and derive the adjoint-based expressions for the gradient of the objective function of the optimization problem for finding the A-optimal encoding weights. The proposed method is potentially attractive for real-time monitoring applications, where one can invest the effort to compute optimal weights offline, to later solve an inverse problem repeatedly, over time, at a fraction of the initial cost.

  17. 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

  18. 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

  19. Identification of cancer-cytotoxic modulators of PDE3A by predictive chemogenomics.

    PubMed

    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

    2016-02-01

    High cancer death rates indicate the need for new anticancer therapeutic agents. Approaches to discovering new cancer drugs include target-based drug discovery and phenotypic screening. Here, we identified phosphodiesterase 3A modulators as cell-selective cancer cytotoxic compounds through 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 gene PDE3A, encoding phosphodiesterase 3A. Like DNMDP, a subset of known PDE3A inhibitors kill selected cancer cells, whereas 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), suggestive of a neomorphic activity. Coexpression of SLFN12 with PDE3A correlates with DNMDP sensitivity, whereas 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.

  20. 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.

  1. 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

  2. A meta-analysis of PDE-gene polymorphism and cerebral infarction risk

    PubMed Central

    Wu, Wei-Lin; Feng, Xue-Wen; Qiu, Chen-Feng; Lin, Jing; Bao, Xian-Jun

    2017-01-01

    Previous studies identified that phosphodiesterase 4D (PDE4D) gene polymorphism might be associated with cerebral infarction or ischemic stroke, and hemorrhagic stroke in human populations. However, as yet, no meta-analysis has revealed any detailed association. We retrospectively reviewed studies regarding the relationship of PDE4D gene polymorphism with ischemic stroke (IS) published during the period January 2003 to September 2012. According to the inclusion criteria, 9 of 105 initial studies were included in the subsequent analysis. The PubMed, Embase and CNKI of China were searched to identify the relevant studies. A total of 186 young patients with IS were included for the meta-analysis and 232 matched control subjects were enrolled and results were presented. The association of PDE4D gene polymorphism with IS in various populations was examined. The results suggested that single nucleotide polymorphism (SNP), SNP 83 in PDE4D gene was significantly related with susceptibility to IS. The meta-analysis also showed that PDE4D gene was associated with an enhanced risk of IS. The meta-analysis suggested that PDE4D SNP 87 constitutes an independent risk factor for IS development. To the best of our knowledge, the present meta-analysis reveals a number of possible associations between PDE4D gene polymorphism and IS. PMID:28587358

  3. Ischemic preconditioning inhibits mitochondrial permeability transition pore opening through the PTEN/PDE4 signaling pathway.

    PubMed

    Zheng, Xiaoxu; Zu, Lingyun; Becker, Lewis; Cai, Zheqing P

    2014-01-01

    Ischemic preconditioning (IPC) induces cardioprotection against ischemia-reperfusion (IR) injury by inhibiting the mitochondrial permeability transition pore (mPTP). Here, we tested the hypothesis that IPC-induced cardioprotection is mediated by the phosphatase PTEN and PDE4 (phosphodiesterase 4). Isolated hearts from wild-type mice (WT, n = 110) and myocyte-specific PTEN-knockout mice (PKO, n = 94) were exposed to IPC or control conditions followed by IR. Subcellular fractionation was performed by sucrose gradient ultracentrifugation. IPC limited myocardial infarct size (IS) in WT mice. The PDE4 inhibitor rolipram abolished the protective effect of IPC. However, small IS was found in PKO hearts after IR, and IPC did not decrease IS but enlarged it in PKO hearts. IPC promoted PDE4D localization to caveolin-3-enriched fractions in WT mice by increasing Akt levels at the caveolae. In PKO hearts, basal PDE4D levels were elevated at the caveolae, and IPC decreased PDE4D levels. Consistent with the subcellular PDE4D protein levels and its activity, elevation in intracellular Ca(2+) levels in the ischemic heart and opening of mPTP after IR were inhibited by IPC in WT mice, but not by IPC in PKO mice. IPC inhibits mPTP opening by regulating the PTEN/PDE4 signaling pathway. © 2014 S. Karger AG, Basel.

  4. 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.

  5. 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.

  6. 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.

  7. Effect of Operating Frequency and Fill Time on PDE-Ejector Thrust Performance

    NASA Technical Reports Server (NTRS)

    Landry, K.; Santoro, Robert J.; Pal, Sibtosh; Shehadeh, R.; Bouvet, N.; Lee, S.-Y.

    2005-01-01

    Thrust measurements for a pulse detonation engine (PDE)-ejector system were determined for a range of operating frequencies. Various length tubular ejectors were utilized. The results were compared to the measurements of the thrust output of the PDE alone to determine the enhancement provided by each ejector configuration at the specified frequencies. Ethylene was chosen as the fuel, with an equi-molar mixture of nitrogen and oxygen acting as the oxidizer. The propellant was kept at an equivalence ratio of one during all the experiments. The system was operated for frequencies between 20 and 50 Hz. The parameter space of the study included PDE operation frequency, ejector length, overlap percentage, the radius of curvature for the ejector inlets, and duration of the time allowed between cycles. The results of the experiments showed a maximum thrust augmentation of 120% for a PDE-ejector configuration at a frequency of 40Hz with a fill time of 10 ms.

  8. 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.

  9. Nonlinear traveling waves in a compressible Mooney-Rivlin rod I. Long finite-amplitude waves

    NASA Astrophysics Data System (ADS)

    Huihui, Dai; Zengrong, Liu

    2004-08-01

    In literature, nonlinear traveling waves in elastic circular rods have only been studied based on single partial differential equation (pde) models, and here we consider such a problem by using a more accurate coupled-pde model. We derive the Hamiltonian from the model equations for the long finite-amplitude wave approximation, analyze how the number of singular points of the system changes with the parameters, and study the features of these singular points qualitatively. Various physically acceptable nonlinear traveling waves are also discussed, and corresponding examples are given. In particular, we find that certain waves, which cannot be counted by the single-equation model, can arise.

  10. 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

  11. 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

  12. 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

  13. ADI Finite Difference Discretization of the Heston-Hull-White PDE

    NASA Astrophysics Data System (ADS)

    Haentjens, Tinne; Hout, Karel in't.

    2010-09-01

    This paper concerns the efficient numerical solution of the time-dependent, three-dimensional Heston-Hull-White PDE for the fair prices of European call options. The numerical solution method described in this paper consists of a finite difference discretization on non-uniform spatial grids followed by an Alternating Direction Implicit scheme for the time discretization and extends the method recently proved effective by In't Hout & Foulon (2010) for the simpler, two-dimensional Heston PDE.

  14. Retinitis pigmentosa: impact of different Pde6a point mutations on the disease phenotype.

    PubMed

    Sothilingam, Vithiyanjali; Garcia Garrido, Marina; Jiao, Kangwei; Buena-Atienza, Elena; Sahaboglu, Ayse; Trifunović, Dragana; Balendran, Sukirthini; Koepfli, Tanja; Mühlfriedel, Regine; Schön, Christian; Biel, Martin; Heckmann, Angelique; Beck, Susanne C; Michalakis, Stylianos; Wissinger, Bernd; Seeliger, Mathias W; Paquet-Durand, François

    2015-10-01

    Mutations in the PDE6A gene can cause rod photoreceptors degeneration and the blinding disease retinitis pigmentosa (RP). While a number of pathogenic PDE6A mutations have been described, little is known about their impact on compound heterozygous situations and potential interactions of different disease-causing alleles. Here, we used a novel mouse model for the Pde6a R562W mutation in combination with an existing line carrying the V685M mutation to generate compound heterozygous Pde6a V685M/R562W animals, exactly homologous to a case of human RP. We compared the progression of photoreceptor degeneration in these compound heterozygous mice with the homozygous V685M and R562W mutants, and additionally with the D670G line that is known for a relatively mild phenotype. We investigated PDE6A expression, cyclic guanosine mono-phosphate accumulation, calpain and caspase activity, in vivo retinal function and morphology, as well as photoreceptor cell death and survival. This analysis confirms the severity of different Pde6a mutations and indicates that compound heterozygous mutants behave like intermediates of the respective homozygous situations. Specifically, the severity of the four different Pde6a situations may be categorized by the pace of photoreceptor degeneration: V685M (fastest) > V685M/R562W > R562W > D670G (slowest). While calpain activity was strongly increased in all four mutants, caspase activity was not. This points to the execution of non-apoptotic cell death and may lead to the identification of new targets for therapeutic interventions. For individual RP patients, our study may help to predict time-courses for Pde6a-related retinal degeneration and thereby facilitate the definition of a window-of-opportunity for clinical interventions. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  15. 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.

  16. [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.

  17. Inertial Manifold and Large Deviations Approach to Reduced PDE Dynamics

    NASA Astrophysics Data System (ADS)

    Cardin, Franco; Favretti, Marco; Lovison, Alberto

    2017-07-01

    In this paper a certain type of reaction-diffusion equation—similar to the Allen-Cahn equation—is the starting point for setting up a genuine thermodynamic reduction i.e. involving a finite number of parameters or collective variables of the initial system. We firstly operate a finite Lyapunov-Schmidt reduction of the cited reaction-diffusion equation when reformulated as a variational problem. In this way we gain a finite-dimensional ODE description of the initial system which preserves the gradient structure of the original one and that is exact for the static case and only approximate for the dynamic case. Our main concern is how to deal with this approximate reduced description of the initial PDE. To start with, we note that our approximate reduced ODE is similar to the approximate inertial manifold introduced by Temam and coworkers for Navier-Stokes equations. As a second approach, we take into account the uncertainty (loss of information) introduced with the above mentioned approximate reduction by considering the stochastic version of the ODE. We study this reduced stochastic system using classical tools from large deviations, viscosity solutions and weak KAM Hamilton-Jacobi theory. In the last part we suggest a possible use of a result of our approach in the comprehensive treatment non equilibrium thermodynamics given by Macroscopic Fluctuation Theory.

  18. Inertial Manifold and Large Deviations Approach to Reduced PDE Dynamics

    NASA Astrophysics Data System (ADS)

    Cardin, Franco; Favretti, Marco; Lovison, Alberto

    2017-09-01

    In this paper a certain type of reaction-diffusion equation—similar to the Allen-Cahn equation—is the starting point for setting up a genuine thermodynamic reduction i.e. involving a finite number of parameters or collective variables of the initial system. We firstly operate a finite Lyapunov-Schmidt reduction of the cited reaction-diffusion equation when reformulated as a variational problem. In this way we gain a finite-dimensional ODE description of the initial system which preserves the gradient structure of the original one and that is exact for the static case and only approximate for the dynamic case. Our main concern is how to deal with this approximate reduced description of the initial PDE. To start with, we note that our approximate reduced ODE is similar to the approximate inertial manifold introduced by Temam and coworkers for Navier-Stokes equations. As a second approach, we take into account the uncertainty (loss of information) introduced with the above mentioned approximate reduction by considering the stochastic version of the ODE. We study this reduced stochastic system using classical tools from large deviations, viscosity solutions and weak KAM Hamilton-Jacobi theory. In the last part we suggest a possible use of a result of our approach in the comprehensive treatment non equilibrium thermodynamics given by Macroscopic Fluctuation Theory.

  19. 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

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

    PubMed

    DiPilato, Lisa M; Ahmad, Faiyaz; Harms, Matthew; Seale, Patrick; Manganiello, Vincent; Birnbaum, Morris J

    2015-08-01

    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. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  1. 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.

  2. Inhibition of PDE4B suppresses inflammation by increasing expression of the deubiquitinase CYLD

    PubMed Central

    Komatsu, Kensei; Lee, Ji-Yun; Miyata, Masanori; Hyang Lim, Jae; Jono, Hirofumi; Koga, Tomoaki; Xu, Haidong; Yan, Chen; Kai, Hirofumi; Li, Jian-Dong

    2013-01-01

    The deubiquitinase CYLD acts as a key negative regulator to tightly control overactive inflammation. Most anti-inflammatory strategies have focused on directly targeting the positive regulator, which often results in significant side effects such as suppression of the host defence response. Here, we show that inhibition of phosphodiesterase 4B (PDE4B) markedly enhances upregulation of CYLD expression in response to bacteria, thereby suggesting that PDE4B acts as a negative regulator for CYLD. Interestingly, in Cyld-deficient mice, inhibition of PDE4B no longer suppresses inflammation. Moreover, PDE4B negatively regulates CYLD via specific activation of JNK2 but not JNK1. Importantly, ototopical post-inoculation administration of a PDE4 inhibitor suppresses inflammation in this animal model, thus demonstrating the therapeutic potential of targeting PDE4. These studies provide insights into how inflammation is tightly regulated via the inhibition of its negative regulator and may also lead to the development of new anti-inflammatory therapeutics that upregulate CYLD expression. PMID:23575688

  3. 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.

  4. 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

  5. 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.

  6. 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

  7. 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

  8. PDE11A regulates social behaviors and is a key mechanism by which social experience sculpts the brain.

    PubMed

    Hegde, Shweta; Ji, Hao; Oliver, David; Patel, Neema S; Poupore, Nicolas; Shtutman, Michael; Kelly, Michy P

    2016-10-29

    Despite the fact that appropriate social behaviors are vital to thriving in one's environment, little is understood of the molecular mechanisms controlling social behaviors or how social experience sculpts these signaling pathways. Here, we determine if Phosphodiesterase 11A (PDE11A), an enzyme that is enriched in the ventral hippocampal formation (VHIPP) and that breaks down cAMP and cGMP, regulates social behaviors. PDE11 wild-type (WT), heterozygous (HT), and knockout (KO) mice were tested in various social approach assays and gene expression differences were measured by RNA sequencing. The effect of social isolation on PDE11A4 compartmentalization and subsequent social interactions and social memory was also assessed. Deletion of PDE11A triggered age- and sex-dependent deficits in social approach in specific social contexts but not others. Mice appear to detect altered social behaviors of PDE11A KO mice, because C57BL/6J mice prefer to spend time with a sex-matched PDE11A WT vs. its KO littermate; whereas, a PDE11A KO prefers to spend time with a novel PDE11A KO vs. its WT littermate. Not only is PDE11A required for intact social interactions, we found that 1month of social isolation vs. group housing decreased PDE11A4 protein expression specifically within the membrane fraction of VHIPP. This isolation-induced decrease in PDE11A4 expression appears functional because social isolation impairs subsequent social approach behavior and social memory in a PDE11A genotype-dependent manner. Pathway analyses following RNA sequencing suggests PDE11A is a key regulator of the oxytocin pathway and membrane signaling, consistent with its pivotal role in regulating social behavior. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  9. 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.

  10. 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

  11. 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.

  12. Identification and characterization of a new human type 9 cGMP-specific phosphodiesterase splice variant (PDE9A5). Differential tissue distribution and subcellular localization of PDE9A variants.

    PubMed

    Wang, Peng; Wu, Ping; Egan, Robert W; Billah, M Motasim

    2003-09-18

    Previously, four splice variants of human cGMP-specific phosphodiesterase (PDE) 9A (PDEs 9A1, 9A2, 9A3 and 9A4) have been identified. In this study, we have cloned a cDNA representing a new human PDE9A variant (PDE9A5). PDE9A5 encodes a protein of 492 amino acids, smaller than PDEs 9A1 and 9A2 but larger than PDEs 9A3 and 9A4. The exon structure of PDE9A5 is different from those of PDEs 9A1, 9A2, 9A3 and 9A4 in that, of the 20 exons of PDE9A gene, it lacks exons 2 and 5. PDE9A5 has been characterized in comparison with PDE9A1, the longest PDE9A variant. PDEs 9A5 and 9A1 have similar enzymatic properties. They both have a high affinity for cGMP with similar Km values (0.39 and 0.25 microM, respectively), although they have slightly different Vmax values (2.55 and 0.96 micromol/min/mg, respectively). They exhibit very similar divalent metal ion dependency and inhibitor sensitivity. Real-time quantitative PCR analysis shows that PDEs 9A5 and 9A1 exhibit differential tissue distribution. They are highly expressed in immune tissues (spleen, lymph node and thymus) and are more abundant in T cells than in B cells, neutrophils and monocytes. When transiently expressed in HEK293 cells, PDEs 9A5 and 9A1 proteins exhibit differential subcellular localization. PDE9A5 localizes exclusively in the cytoplasm, whereas PDE9A1 localizes in the nucleus only. The nuclear localization of PDE9A1 is dependent on a unique pat7 motif. By Western blot analysis, native PDE9A1 is detectable in the nucleus but not in the cytoplasm of T cells. Thus, to our knowledge, PDE9A1 is the only PDE isoform found to localize exclusively in the nucleus. We speculate that the physiological role of the PDE9A diversity may be imparting cGMP-metabolizing ability to specific cellular compartments in appropriate tissues.

  13. 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.

  14. 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

  15. 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

  16. Development of a series of novel carbon-11 labeled PDE10A inhibitors.

    PubMed

    Stepanov, Vladimir; Miura, Shotaro; Takano, Akihiro; Amini, Nahid; Nakao, Ryuji; Hasui, Tomoaki; Nakashima, Kosuke; Taniguchi, Takahiko; Kimura, Haruhide; Kuroita, Takanobu; Halldin, Christer

    2015-05-15

    Phosphodiesterase 10A (PDE10A) is a member of the PDE family of enzymes that degrades cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Our aim was to label a series of structurally related PDE10A inhibitors with carbon-11 and evaluate them as potential positron emission tomography (PET) radioligands for PDE10A using nonhuman primates. The series consisted of seven compounds based on the 3-(1H-pyrazol-5-yl)pyridazin-4(1H)-one backbone. These compounds were selected from the initial larger library based on a number of parameters such as affinity, selectivity for hPDE10A in in vitro tests, lipophilicity, and on the results of multidrug resistance protein 1 (MDR1)-LLCPK1 and the parallel artificial membrane permeability assays. Seven radioligands (KIT-1, 3, 5, 6, 7, 9, and 12) were radiolabeled with carbon-11 employing O-methylation on the hydroxyl moiety using [(11)C]methyl triflate. In vivo examination of each radioligand was performed using PET in rhesus monkeys; analysis of radiometabolites in plasma also was conducted using HPLC. All seven radioligands were labeled with high (>90%) incorporation of [(11)C]methyl triflate into their appropriate precursors and with high specific radioactivity. Carbon-11 labeled KIT-5 and KIT-6 showed high accumulation in the striatum, consistent with the known anatomical distribution of PDE10A in brain, accompanied by fast washout and high specific binding ratio. In particular [(11)C]KIT-6, named [(11)C]T-773, is a promising PET tool for further examination of PDE10A in human brain. Copyright © 2015 John Wiley & Sons, Ltd.

  17. 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

  18. 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.

  19. 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

  20. Phosphodiesterase-5A (PDE5A) is localized to the endothelial caveolae and modulates NOS3 activity

    PubMed Central

    Gebska, Milena A.; Stevenson, Blake K.; Hemnes, Anna R.; Bivalacqua, Trinity J.; Haile, Azeb; Hesketh, Geoffrey G.; Murray, Christopher I.; Zaiman, Ari L.; Halushka, Marc K.; Krongkaew, Nispa; Strong, Travis D.; Cooke, Carol A.; El-Haddad, Hazim; Tuder, Rubin M.; Berkowitz, Dan E.; Champion, Hunter C.

    2011-01-01

    Aims It has been well demonstrated that phosphodiesterase-5A (PDE5A) is expressed in smooth muscle cells and plays an important role in regulation of vascular tone. The role of endothelial PDE5A, however, has not been yet characterized. The present study was undertaken to determine the presence, localization, and potential physiologic significance of PDE5A within vascular endothelial cells. Methods and results We demonstrate primary location of human, mouse, and bovine endothelial PDE5A at or near caveolae. We found that the spatial localization of PDE5A at the level of caveolin-rich lipid rafts allows for a feedback loop between endothelial PDE5A and nitric oxide synthase (NOS3). Treatment of human endothelium with PDE5A inhibitors resulted in a significant increase in NOS3 activity, whereas overexpression of PDE5A using an adenoviral vector, both in vivo and in cell culture, resulted in decreased NOS3 activity and endothelium-dependent vasodilation. The molecular mechanism responsible for these interactions is primarily regulated by cGMP-dependent second messenger. PDE5A overexpression also resulted in a significant decrease in protein kinase 1 (PKG1) activity. Overexpression of PKG1 rapidly activated NOS3, whereas silencing of the PKG1 gene with siRNA inhibited both NOS3 phosphorylation (S1179) and activity, indicating a novel role for PKG1 in direct regulation of NOS3. Conclusion Our data collectively suggest another target for PDE5A inhibition in endothelial dysfunction and provide another physiologic significance for PDE5A in the modulation of endothelial-dependent flow-mediated vasodilation. Using both in vitro and in vivo models, as well as human data, we show that inhibition of endothelial PDE5A improves endothelial function. PMID:21421555

  1. Phosphodiesterase-5A (PDE5A) is localized to the endothelial caveolae and modulates NOS3 activity.

    PubMed

    Gebska, Milena A; Stevenson, Blake K; Hemnes, Anna R; Bivalacqua, Trinity J; Haile, Azeb; Hesketh, Geoffrey G; Murray, Christopher I; Zaiman, Ari L; Halushka, Marc K; Krongkaew, Nispa; Strong, Travis D; Cooke, Carol A; El-Haddad, Hazim; Tuder, Rubin M; Berkowitz, Dan E; Champion, Hunter C

    2011-05-01

    It has been well demonstrated that phosphodiesterase-5A (PDE5A) is expressed in smooth muscle cells and plays an important role in regulation of vascular tone. The role of endothelial PDE5A, however, has not been yet characterized. The present study was undertaken to determine the presence, localization, and potential physiologic significance of PDE5A within vascular endothelial cells. We demonstrate primary location of human, mouse, and bovine endothelial PDE5A at or near caveolae. We found that the spatial localization of PDE5A at the level of caveolin-rich lipid rafts allows for a feedback loop between endothelial PDE5A and nitric oxide synthase (NOS3). Treatment of human endothelium with PDE5A inhibitors resulted in a significant increase in NOS3 activity, whereas overexpression of PDE5A using an adenoviral vector, both in vivo and in cell culture, resulted in decreased NOS3 activity and endothelium-dependent vasodilation. The molecular mechanism responsible for these interactions is primarily regulated by cGMP-dependent second messenger. PDE5A overexpression also resulted in a significant decrease in protein kinase 1 (PKG1) activity. Overexpression of PKG1 rapidly activated NOS3, whereas silencing of the PKG1 gene with siRNA inhibited both NOS3 phosphorylation (S1179) and activity, indicating a novel role for PKG1 in direct regulation of NOS3. Our data collectively suggest another target for PDE5A inhibition in endothelial dysfunction and provide another physiologic significance for PDE5A in the modulation of endothelial-dependent flow-mediated vasodilation. Using both in vitro and in vivo models, as well as human data, we show that inhibition of endothelial PDE5A improves endothelial function.

  2. Inactivation of Pde8b enhances memory, motor performance, and protects against age-induced motor coordination decay

    PubMed Central

    Tsai, Li-Chun Lisa; Chan, Guy Chiu-Kai; Nangle, Shannon N.; Shimizu-Albergine, Masami; Jones, Graham; Storm, Daniel R.; Beavo, Joseph A.; Zweifel, Larry S.

    2012-01-01

    Phosphodiesterases (PDEs) are critical regulatory enzymes in cyclic nucleotide signaling. PDEs have diverse expression patterns within the central nervous system (CNS), show differing affinities for cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), and regulate a vast array of behaviors. Here, we investigated the expression profile of the PDE8 gene family members Pde8a and Pde8b in the mouse brain. We find that Pde8a expression is largely absent in the CNS; by contrast, Pde8b is expressed in select regions of the hippocampus, ventral striatum, and cerebellum. Behavioral analysis of mice with Pde8b gene inactivation (PDE8B KO) demonstrate an enhancement in contextual fear, spatial memory, performance in an appetitive instrumental conditioning task, motor-coordination, and have an attenuation of age-induced motor coordination decline. In addition to improvements observed in select behaviors, we find basal anxiety levels to be increased in PDE8B KO mice. These findings indicate that selective antagonism of PDE8B may be an attractive target for enhancement of cognitive and motor functions; however, possible alterations in affective state will need to be weighed against potential therapeutic value. PMID:22925203

  3. Targeting PDE10A GAF Domain with Small Molecules: A Way for Allosteric Modulation with Anti-Inflammatory Effects.

    PubMed

    García, Ana M; Brea, José; González-García, Alejandro; Pérez, Concepción; Cadavid, María Isabel; Loza, María Isabel; Martinez, Ana; Gil, Carmen

    2017-09-04

    Phosphodiesterase (PDE) enzymes regulate the levels of cyclic nucleotides, cAMP, and/or cGMP, being attractive therapeutic targets. In order to modulate PDE activity in a selective way, we focused our efforts on the search of allosteric modulators. Based on the crystal structure of the PDE10A GAF-B domain, a virtual screening study allowed the discovery of new hits that were also tested experimentally, showing inhibitory activities in the micromolar range. Moreover, these new PDE10A inhibitors were able to decrease the nitrite production in LPS-stimulated cells, thus demonstrating their potential as anti-inflammatory agents.

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

    PubMed

    Havekes, Robbert; 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; Abel, Ted

    2016-08-24

    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. Neurons exhibit localized signaling processes that enable biochemical cascades to be activated selectively in specific subcellular compartments. The

  5. 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.

  6. 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.

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

    PubMed Central

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

    2011-01-01

    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. PMID:21666256

  8. PDE based scheme for multi-modal medical image watermarking.

    PubMed

    Aherrahrou, N; Tairi, H

    2015-11-25

    This work deals with copyright protection of digital images, an issue that needs protection of intellectual property rights. It is an important issue with a large number of medical images interchanged on the Internet every day. So, it is a challenging task to ensure the integrity of received images as well as authenticity. Digital watermarking techniques have been proposed as valid solution for this problem. It is worth mentioning that the Region Of Interest (ROI)/Region Of Non Interest (RONI) selection can be seen as a significant limitation from which suffers most of ROI/RONI based watermarking schemes and that in turn affects and limit their applicability in an effective way. Generally, the ROI/RONI is defined by a radiologist or a computer-aided selection tool. And thus, this will not be efficient for an institute or health care system, where one has to process a large number of images. Therefore, developing an automatic ROI/RONI selection is a challenge task. The major aim of this work is to develop an automatic selection algorithm of embedding region based on the so called Partial Differential Equation (PDE) method. Thus avoiding ROI/RONI selection problems including: (1) computational overhead, (2) time consuming, and (3) modality dependent selection. The algorithm is evaluated in terms of imperceptibility, robustness, tamper localization and recovery using MRI, Ultrasound, CT and X-ray grey scale medical images. From experimental results that we have conducted on a database of 100 medical images of four modalities, it can be inferred that our method can achieve high imperceptibility, while showing good robustness against attacks. Furthermore, the experiment results confirm the effectiveness of the proposed algorithm in detecting and recovering the various types of tampering. The highest PSNR value reached over the 100 images is 94,746 dB, while the lowest PSNR value is 60,1272 dB, which demonstrates the higher imperceptibility nature of the proposed

  9. Increased Cardiac Myocyte PDE5 Levels in Human and Murine Pressure Overload Hypertrophy Contribute to Adverse LV Remodeling

    PubMed Central

    Vandenwijngaert, Sara; Pokreisz, Peter; Hermans, Hadewich; Gillijns, Hilde; Pellens, Marijke; Bax, Noortje A. M.; Coppiello, Giulia; Oosterlinck, Wouter; Balogh, Agnes; Papp, Zoltan; Bouten, Carlijn V. C.; Bartunek, Jozef; D'hooge, Jan; Luttun, Aernout; Verbeken, Erik; Herregods, Marie Christine; Herijgers, Paul; Bloch, Kenneth D.; Janssens, Stefan

    2013-01-01

    Background The intracellular second messenger cGMP protects the heart under pathological conditions. We examined expression of phosphodiesterase 5 (PDE5), an enzyme that hydrolyzes cGMP, in human and mouse hearts subjected to sustained left ventricular (LV) pressure overload. We also determined the role of cardiac myocyte-specific PDE5 expression in adverse LV remodeling in mice after transverse aortic constriction (TAC). Methodology/Principal Findings In patients with severe aortic stenosis (AS) undergoing valve replacement, we detected greater myocardial PDE5 expression than in control hearts. We observed robust expression in scattered cardiac myocytes of those AS patients with higher LV filling pressures and BNP serum levels. Following TAC, we detected similar, focal PDE5 expression in cardiac myocytes of C57BL/6NTac mice exhibiting the most pronounced LV remodeling. To examine the effect of cell-specific PDE5 expression, we subjected transgenic mice with cardiac myocyte-specific PDE5 overexpression (PDE5-TG) to TAC. LV hypertrophy and fibrosis were similar as in WT, but PDE5-TG had increased cardiac dimensions, and decreased dP/dtmax and dP/dtmin with prolonged tau (P<0.05 for all). Greater cardiac dysfunction in PDE5-TG was associated with reduced myocardial cGMP and SERCA2 levels, and higher passive force in cardiac myocytes in vitro. Conclusions/Significance Myocardial PDE5 expression is increased in the hearts of humans and mice with chronic pressure overload. Increased cardiac myocyte-specific PDE5 expression is a molecular hallmark in hypertrophic hearts with contractile failure, and represents an important therapeutic target. PMID:23527037

  10. 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

  11. Advantages of multigrid methods for certifying the accuracy of PDE modeling

    NASA Technical Reports Server (NTRS)

    Forester, C. K.

    1981-01-01

    Numerical techniques for assessing and certifying the accuracy of the modeling of partial differential equations (PDE) to the user's specifications are analyzed. Examples of the certification process with conventional techniques are summarized for the three dimensional steady state full potential and the two dimensional steady Navier-Stokes equations using fixed grid methods (FG). The advantages of the Full Approximation Storage (FAS) scheme of the multigrid technique of A. Brandt compared with the conventional certification process of modeling PDE are illustrated in one dimension with the transformed potential equation. Inferences are drawn for how MG will improve the certification process of the numerical modeling of two and three dimensional PDE systems. Elements of the error assessment process that are common to FG and MG are analyzed.

  12. 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.

  13. Advantages of multigrid methods for certifying the accuracy of PDE modeling

    NASA Technical Reports Server (NTRS)

    Forester, C. K.

    1981-01-01

    Numerical techniques for assessing and certifying the accuracy of the modeling of partial differential equations (PDE) to the user's specifications are analyzed. Examples of the certification process with conventional techniques are summarized for the three dimensional steady state full potential and the two dimensional steady Navier-Stokes equations using fixed grid methods (FG). The advantages of the Full Approximation Storage (FAS) scheme of the multigrid technique of A. Brandt compared with the conventional certification process of modeling PDE are illustrated in one dimension with the transformed potential equation. Inferences are drawn for how MG will improve the certification process of the numerical modeling of two and three dimensional PDE systems. Elements of the error assessment process that are common to FG and MG are analyzed.

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

    NASA Astrophysics Data System (ADS)

    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.

  15. 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

  16. 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.

  17. New achievement and novel therapeutic applications of PDE5 inhibithors in older males.

    PubMed

    Frajese, G V; Pozzi, F

    2005-01-01

    Erectile dysfunction (ED) increases in prevalence and severity because of aging processes and related organic, iatrogenic and social problems. Decline of testosterone (T) levels is observed with age and also in illnesses with a common basis of endothelial damage. The T deficiency may lead to decreased energy, mood depression, reduction of sexual desire, but no correlation has been reported between T level and severity of ED, which is mainly a neurovascular disease. In facts, inhibition of phosphodiesterase type 5 (PDE5) isoenzyme with sildenafil, tadalafil and vardenafil enhances vasodilatation in the corpus cavernosum and subsequent penile erection. Absolute pharmacological potency of PDE5 inhibitors is similar and non-selectivity defines the side-effects profile, while their elimination half-life explains not only the different duration of action, but also short and long-term tolerability. Efficacy of PDE5 inhibitors in younger patients is greater in respect to older subjects because of associated pathologies and the decline in hypothalamic-pituitary-gonadal function. T is essential in erectile function, controlling the expression and activity of PDE5 and therefore, androgen supplementation improves therapeutic response to PDE5 inhibitors in hypogonadal subjects. Since sexual behavior is a complex interplay of physical, psychological, and social factors, the possible effect of these drugs on androgen levels and brain function need to be deeply investigated. The ubiquitarious distribution of PDE5 and the availability of selective inhibitory molecules foster newer studies in the treatment of heart failure, pulmonary hypertension, inflammation, and depression. This new progress is certainly contributing to a better medical approach to sexuality and quality of life in aging people.

  18. 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.

  19. 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…

  20. 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

  1. 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…

  2. Frequent phosphodiesterase 11A gene (PDE11A) defects in patients with Carney complex (CNC) caused by PRKAR1A mutations: PDE11A may contribute to adrenal and testicular tumors in CNC as a modifier of the phenotype.

    PubMed

    Libé, Rossella; Horvath, Anelia; Vezzosi, Delphine; Fratticci, Amato; Coste, Joel; Perlemoine, Karine; Ragazzon, Bruno; Guillaud-Bataille, Marine; Groussin, Lionel; Clauser, Eric; Raffin-Sanson, Marie-Laure; Siegel, Jennifer; Moran, Jason; Drori-Herishanu, Limor; Faucz, Fabio Rueda; Lodish, Maya; Nesterova, Maria; Bertagna, Xavier; Bertherat, Jerome; Stratakis, Constantine A

    2011-01-01

    Carney complex (CNC) is an autosomal dominant multiple neoplasia, caused mostly by inactivating mutations of the regulatory subunit 1A of the protein kinase A (PRKAR1A). Primary pigmented nodular adrenocortical disease (PPNAD) is the most frequent endocrine manifestation of CNC with a great inter-individual variability. Germline, protein-truncating mutations of phosphodiesterase type 11A (PDE11A) have been described to predispose to a variety of endocrine tumors, including adrenal and testicular tumors. Our objective was to investigate the role of PDE11A as a possible gene modifier of the phenotype in a series of 150 patients with CNC. A higher frequency of PDE11A variants in patients with CNC compared with healthy controls was found (25.3 vs. 6.8%, P < 0.0001). Among CNC patients, those with PPNAD were significantly more frequently carriers of PDE11A variants compared with patients without PPNAD (30.8 vs. 13%, P = 0.025). Furthermore, men with PPNAD were significantly more frequently carriers of PDE11A sequence variants (40.7%) than women with PPNAD (27.3%) (P < 0.001). A higher frequency of PDE11A sequence variants was also found in patients with large-cell calcifying Sertoli cell tumors (LCCSCT) compared with those without LCCSCT (50 vs. 10%, P = 0.0056). PDE11A variants were significantly associated with the copresence of PPNAD and LCCSCT in men: 81 vs. 20%, P < 0.004). The simultaneous inactivation of PRKAR1A and PDE11A by small inhibitory RNA led to an increase in cAMP-regulatory element-mediated transcriptional activity under basal conditions and after stimulation by forskolin. We demonstrate, in a large cohort of CNC patients, a high frequency of PDE11A variants, suggesting that PDE11A is a genetic modifying factor for the development of testicular and adrenal tumors in patients with germline PRKAR1A mutation.

  3. 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.

  4. 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.

  5. Targeted ablation of the Pde6h gene in mice reveals cross-species differences in cone and rod phototransduction protein isoform inventory.

    PubMed

    Brennenstuhl, Christina; Tanimoto, Naoyuki; Burkard, Markus; Wagner, Rebecca; Bolz, Sylvia; Trifunovic, Dragana; Kabagema-Bilan, Clement; Paquet-Durand, Francois; Beck, Susanne C; Huber, Gesine; Seeliger, Mathias W; Ruth, Peter; Wissinger, Bernd; Lukowski, Robert

    2015-04-17

    Phosphodiesterase-6 (PDE6) is a multisubunit enzyme that plays a key role in the visual transduction cascade in rod and cone photoreceptors. Each type of photoreceptor utilizes discrete catalytic and inhibitory PDE6 subunits to fulfill its physiological tasks, i.e. the degradation of cyclic guanosine-3',5'-monophosphate at specifically tuned rates and kinetics. Recently, the human PDE6H gene was identified as a novel locus for autosomal recessive (incomplete) color blindness. However, the three different classes of cones were not affected to the same extent. Short wave cone function was more preserved than middle and long wave cone function indicating that some basic regulation of the PDE6 multisubunit enzyme was maintained albeit by a unknown mechanism. To study normal and disease-related functions of cone Pde6h in vivo, we generated Pde6h knock-out (Pde6h(-/-)) mice. Expression of PDE6H in murine eyes was restricted to both outer segments and synaptic terminals of short and long/middle cone photoreceptors, whereas Pde6h(-/-) retinae remained PDE6H-negative. Combined in vivo assessment of retinal morphology with histomorphological analyses revealed a normal overall integrity of the retinal organization and an unaltered distribution of the different cone photoreceptor subtypes upon Pde6h ablation. In contrast to human patients, our electroretinographic examinations of Pde6h(-/-) mice suggest no defects in cone/rod-driven retinal signaling and therefore preserved visual functions. To this end, we were able to demonstrate the presence of rod PDE6G in cones indicating functional substitution of PDE6. The disparities between human and murine phenotypes caused by mutant Pde6h/PDE6H suggest species-to-species differences in the vulnerability of biochemical and neurosensory pathways of the visual signal transduction system. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  6. Targeted Ablation of the Pde6h Gene in Mice Reveals Cross-species Differences in Cone and Rod Phototransduction Protein Isoform Inventory*

    PubMed Central

    Brennenstuhl, Christina; Tanimoto, Naoyuki; Burkard, Markus; Wagner, Rebecca; Bolz, Sylvia; Trifunovic, Dragana; Kabagema-Bilan, Clement; Paquet-Durand, Francois; Beck, Susanne C.; Huber, Gesine; Seeliger, Mathias W.; Ruth, Peter; Wissinger, Bernd; Lukowski, Robert

    2015-01-01

    Phosphodiesterase-6 (PDE6) is a multisubunit enzyme that plays a key role in the visual transduction cascade in rod and cone photoreceptors. Each type of photoreceptor utilizes discrete catalytic and inhibitory PDE6 subunits to fulfill its physiological tasks, i.e. the degradation of cyclic guanosine-3′,5′-monophosphate at specifically tuned rates and kinetics. Recently, the human PDE6H gene was identified as a novel locus for autosomal recessive (incomplete) color blindness. However, the three different classes of cones were not affected to the same extent. Short wave cone function was more preserved than middle and long wave cone function indicating that some basic regulation of the PDE6 multisubunit enzyme was maintained albeit by a unknown mechanism. To study normal and disease-related functions of cone Pde6h in vivo, we generated Pde6h knock-out (Pde6h−/−) mice. Expression of PDE6H in murine eyes was restricted to both outer segments and synaptic terminals of short and long/middle cone photoreceptors, whereas Pde6h−/− retinae remained PDE6H-negative. Combined in vivo assessment of retinal morphology with histomorphological analyses revealed a normal overall integrity of the retinal organization and an unaltered distribution of the different cone photoreceptor subtypes upon Pde6h ablation. In contrast to human patients, our electroretinographic examinations of Pde6h−/− mice suggest no defects in cone/rod-driven retinal signaling and therefore preserved visual functions. To this end, we were able to demonstrate the presence of rod PDE6G in cones indicating functional substitution of PDE6. The disparities between human and murine phenotypes caused by mutant Pde6h/PDE6H suggest species-to-species differences in the vulnerability of biochemical and neurosensory pathways of the visual signal transduction system. PMID:25739440

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

    NASA Astrophysics Data System (ADS)

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

    2016-06-01

    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-Stokes-Fourier theory is established for the first time via a formal asymptotic analysis in the stiff relaxation limit. From a numerical point of view, the governing partial differential equations are very challenging, since they form a large nonlinear hyperbolic PDE system that includes stiff source terms and non-conservative products. We apply the successful family of one-step ADER-WENO finite volume (FV) and ADER discontinuous Galerkin (DG) finite element schemes to the HPR model in the stiff

  8. 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.

  9. 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

  10. 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.

  11. 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

  12. 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.

  13. 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.

  14. PDE-based random-valued impulse noise removal based on new class of controlling functions.

    PubMed

    Wu, Jian; Tang, Chen

    2011-09-01

    This paper is concerned with partial differential equation (PDE)-based image denoising for random-valued impulse noise. We introduce the notion of ENI (the abbreviation for "edge pixels, noisy pixels, and interior pixels") that denotes the number of homogeneous pixels in a local neighborhood and is significantly different for edge pixels, noisy pixels, and interior pixels. We redefine the controlling speed function and the controlling fidelity function to depend on ENI. According to our two controlling functions, the diffusion and fidelity process at edge pixels, noisy pixels, and interior pixels can be selectively carried out. Furthermore, a class of second-order improved and edge-preserving PDE denoising models is proposed based on the two new controlling functions in order to deal with random-valued impulse noise reliably. We demonstrate the performance of the proposed PDEs via application to five standard test images, corrupted by random-valued impulse noise with various noise levels and comparison with the related second-order PDE models and the other special filtering methods for random-valued impulse noise. Our two controlling functions are extended to automatically other PDE models.

  15. 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.

  16. Research on Odor Interaction between Aldehyde Compounds via a Partial Differential Equation (PDE) Model

    PubMed Central

    LuchunYan; Liu, Jiemin; Qu, Chen; Gu, Xingye; Zhao, Xia

    2015-01-01

    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. PMID:25635413

  17. 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.

  18. 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

  19. 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.

  20. 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.

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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

  9. 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.

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

    PubMed

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

    2016-11-01

    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.

  11. Kaempferia parviflora, a plant used in traditional medicine to enhance sexual performance contains large amounts of low affinity PDE5 inhibitors.

    PubMed

    Temkitthawon, Prapapan; Hinds, Thomas R; Beavo, Joseph A; Viyoch, Jarupa; Suwanborirux, Khanit; Pongamornkul, Wittaya; Sawasdee, Pattara; Ingkaninan, Kornkanok

    2011-10-11

    A number of medicinal plants are used in traditional medicine to treat erectile dysfunction. Since cyclic nucleotide PDEs inhibitors underlie several current treatments for this condition, we sought to show whether these plants might contain substantial amounts of PDE5 inhibitors. Forty one plant extracts and eight 7-methoxyflavones from Kaempferia parviflora Wall. ex Baker were screened for PDE5 and PDE6 inhibitory activities using the two-step radioactive assay. The PDE5 and PDE6 were prepared from mice lung and chicken retinas, respectively. All plant extracts were tested at 50 μg/ml whereas the pure compounds were tested at 10 μM. From forty one plant extracts tested, four showed the PDE5 inhibitory effect. The chemical constituents isolated from rhizomes of Kaempferia parviflora were further investigated on inhibitory activity against PDE5 and PDE6. The results showed that 7-methoxyflavones from this plant showed inhibition toward both enzymes. The most potent PDE5 inhibitor was 5,7-dimethoxyflavone (IC(50) = 10.64 ± 2.09 μM, selectivity on PDE5 over PDE6 = 3.71). Structure activity relationship showed that the methoxyl group at C-5 position of 7-methoxyflavones was necessary for PDE5 inhibition. Kaempferia parviflora rhizome extract and its 7-methoxyflavone constituents had moderate inhibitory activity against PDE5. This finding provides an explanation for enhancing sexual performance in the traditional use of Kaempferia parviflora. Moreover, 5,7-dimethoxyflavones should make a useful lead compound to further develop clinically efficacious PDE5 inhibitors. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  12. Kaempferia parviflora, a plant used in traditional medicine to enhance sexual performance contains large amounts of low affinity PDE5 inhibitors

    PubMed Central

    Temkitthawon, Prapapan; Hinds, Thomas R.; Beavo, Joseph A.; Viyoch, Jarupa; Suwanborirux, Khanit; Pongamornkul, Wittaya; Sawasdee, Pattara; Ingkaninan, Kornkanok

    2014-01-01

    Aim of the study A number of medicinal plants are used in traditional medicine to treat erectile dysfunction. Since cyclic nucleotide PDEs inhibitors underlie several current treatments for this condition, we sought to show whether these plants might contain substantial amounts of PDE5 inhibitors. Materials and methods Forty one plant extracts and eight 7-methoxyflavones from Kaempferia parviflora Wall. ex Baker were screened for PDE5 and PDE6 inhibitory activities using the two-step radioactive assay. The PDE5 and PDE6 were prepared from mice lung and chicken retinas, respectively. All plant extracts were tested at 50 μg/ml whereas the pure compounds were tested at 10 μM. Results From forty one plant extracts tested, four showed the PDE5 inhibitory effect. The chemical constituents isolated from rhizomes of Kaempferia parviflora were further investigated on inhibitory activity against PDE5 and PDE6. The results showed that 7-methoxyflavones from this plant showed inhibition toward both enzymes. The most potent PDE5 inhibitor was 5,7-dimethoxyflavone (IC50 = 10.64 ± 2.09 μM, selectivity on PDE5 over PDE6 = 3.71). Structure activity relationship showed that the methoxyl group at C-5 position of 7-methoxyflavones was necessary for PDE5 inhibition. Conclusions Kaempferia parviflora rhizome extract and its 7-methoxyflavone constituents had moderate inhibitory activity against PDE5. This finding provides an explanation for enhancing sexual performance in the traditional use of Kaempferia parviflora. Moreover, 5,7-dimethoxyflavones should make a useful lead compound to further develop clinically efficacious PDE5 inhibitors. PMID:21884777

  13. 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

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  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. The Discovery of a Novel Phosphodiesterase (PDE) 4B-preferring Radioligand for Positron Emission Tomography (PET) Imaging.

    PubMed

    Zhang, Lei; Chen, Laigao; Beck, Elizabeth M; Chappie, Thomas A; Coelho, Richard V; Doran, Shawn D; Fan, Kuo-Hsien; Humphrey, John M; Hughes, Zoe; Kuszpit, Kyle; Lachapelle, Erik A; Lazzaro, John T; Mather, Robert J; Patel, Nandini C; Skaddan, Marc B; Sciabola, Simone; Verhoest, Patrick R; Young, Joseph Michael; Zasadny, Kenneth; Villalobos, Anabella

    2017-09-28

    As part of our effort in identifying PDE4B-preferring inhibitors for the treatment of central nervous system (CNS) disorders, we sought to identify a positron emission tomography (PET) ligand to enable target occupancy measurement in vivo. Through a systematic and cost-effective PET discovery process, involving expression level (Bmax) and bio-distribution determination, a PET-specific structure-activity relationship (SAR) effort, and specific binding assessment using a LC-MS/MS "cold tracer" method, we have identified 8 (PF-06445974) as a promising PET lead. Compound 8 has exquisite potency at PDE4B, good selectivity over PDE4D, excellent brain permeability, and a high level of specific binding in the "cold tracer" study. In subsequent non-human primate (NHP) PET imaging studies, [18F]8 showed rapid brain uptake and high target specificity, indicating that [18F]8 is a promising PDE4B-preferring radioligand for clinical PET imaging.

  20. 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

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

    PubMed

    Ribaudo, Giovanni; Vendrame, Tiziano; Bova, Sergio

    2017-09-01

    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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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

  7. 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.

  8. Synthesis and biological activities of novel beta-carbolines as PDE5 inhibitors.

    PubMed

    Sui, Zhihua; Guan, Jihua; Macielag, Mark J; Jiang, Weiqin; Qiu, Yuhong; Kraft, Patricia; Bhattacharjee, Sheela; John, T Matthew; Craig, Elizabeth; Haynes-Johnson, Donna; Clancy, Joanna

    2003-02-24

    A series of N(2)-furoyl and N(2)pyrimidinyl beta-carbolines was discovered to possess potent inhibitory activity against PDE5. During the synthesis we developed a tandem resin quenching protocol, which allowed us to synthesize large number of target compounds in a rapid fashion. Representative compounds exhibit superior selectivity to sildenafil versus other isozymes of PDEs, and demonstrated in vivo efficacy in increasing introcavernosal pressure in dogs.

  9. 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.

  10. 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

  11. Nonlinear knowledge-based classification.

    PubMed

    Mangasarian, Olvi L; Wild, Edward W

    2008-10-01

    In this brief, prior knowledge over general nonlinear sets is incorporated into nonlinear kernel classification problems as linear constraints in a linear program. These linear constraints are imposed at arbitrary points, not necessarily where the prior knowledge is given. The key tool in this incorporation is a theorem of the alternative for convex functions that converts nonlinear prior knowledge implications into linear inequalities without the need to kernelize these implications. Effectiveness of the proposed formulation is demonstrated on publicly available classification data sets, including a cancer prognosis data set. Nonlinear kernel classifiers for these data sets exhibit marked improvements upon the introduction of nonlinear prior knowledge compared to nonlinear kernel classifiers that do not utilize such knowledge.

  12. 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

  13. 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.

  14. [Cardiovascular repercussion of lodenafil carbonate, a new PDE5 inhibitor, with and without alcohol consumption].

    PubMed

    Silva, Adauto Carvalho; Toffoletto, Odaly; Lucio, Luiz Antonio Galvão; Santos, Paula Ferreira Dos; Afiune, Jorge Barros; Massud Filho, João; Tufik, Sergio

    2010-02-01

    Millions of men around the world suffer from erectile dysfunction, for which phosphodiesterase 5 inhibitors (PDE-5 inhibitors) are currently the first treatment option. Sexual activity and alcohol consumption are closely related, and the simultaneous use of alcohol and PDE-5 inhibitors can happen. Lodenafil carbonate is a new PDE-5 inhibitor, developed by a Brazilian pharmaceutical company. This work aimed at evaluating the cardiovascular safety of lodenafil carbonate, with and without simultaneous alcohol consumption. Fifteen male volunteers received 160 mg lodenafil carbonate (LC), in three different moments. Participants were assigned to three groups, treated with LC in fasting condition, with alcohol or receiving only placebo. The volunteers were continuously monitored during 24 hours for physical impairment, blood pressure, heart rate, QT interval and lodenafil's pharmacokinetic parameters. Lodenafil carbonate alone or with alcohol did not induce clinically relevant modifications in arterial blood pressure or heart rate. A statistically significant decrease in blood pressure was seen four hours after LC and alcohol intake, and an increase in heart rate six hours after intake of lodenafil carbonate alone. The QTc interval was not significantly modified. Lodenafil carbonate bioavailability was increased in 74% when drug intake was associated with alcohol. These results show that the use of lodenafil carbonate did not have clinically relevant effects on blood pressure or heart rate, and was not associated with QT interval prolongation. The association of lodenafil carbonate and alcohol affected its pharmacokinetic properties, increasing the bioavailability of the drug.

  15. 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.

  16. 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

  17. 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.

  18. 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

  19. The cAMP-specific phosphodiesterase TbPDE2C is an essential enzyme in bloodstream form Trypanosoma brucei

    PubMed Central

    Zoraghi, Roya; Seebeck, Thomas

    2002-01-01

    Chemotherapy of human sleeping sickness, a fatal disease caused by the protozoan parasite Trypanosoma brucei, is in a dismal state, and the identification and characterization of new drug targets is an urgent prerequisite for an improvement of the dramatic situation in the field. Over the last several years, inhibitors of cyclic nucleotide-specific phosphodiesterases have proven to be highly successful drug candidates for an assortment of clinical conditions. Their potential as antiparasitic drugs has not been explored so far. This study reports the characterization of a cAMP-specific phosphodiesterase from T. brucei, TbPDE2C. This enzyme is a class I phosphodiesterase, and it is a member of a small enzyme family in T. brucei, TbPDE2. Inhibitors of this enzyme block the proliferation of bloodstream form trypanosomes in culture. RNA interference experiments demonstrated that the TbPDE2 family, and in particular TbPDE2C, are essential for maintaining intracellular cAMP concentrations within a physiological range. Bloodstream form trypanosomes are exquisitely sensitive to elevated concentrations of intracellular cAMP, and a disruption of TbPDE2C function quickly leads to the disruption of nuclear and cellular cell division, and to cell death. TbPDE2C might represent a novel drug target for the development of new and effective trypanocidal drugs. PMID:11930001

  20. 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

  1. On the removal of boundary errors caused by Runge-Kutta integration of non-linear partial differential equations

    NASA Technical Reports Server (NTRS)

    Abarbanel, Saul; Gottlieb, David; Carpenter, Mark H.

    1994-01-01

    It has been previously shown that the temporal integration of hyperbolic partial differential equations (PDE's) may, because of boundary conditions, lead to deterioration of accuracy of the solution. A procedure for removal of this error in the linear case has been established previously. In the present paper we consider hyperbolic (PDE's) (linear and non-linear) whose boundary treatment is done via the SAT-procedure. A methodology is present for recovery of the full order of accuracy, and has been applied to the case of a 4th order explicit finite difference scheme.

  2. Expression and distribution of key enzymes of the cyclic GMP signaling in the human clitoris: relation to phosphodiesterase type 5 (PDE5).

    PubMed

    Ückert, S; Oelke, M; Albrecht, K; Breitmeier, D; Kuczyk, M A; Hedlund, P

    2011-01-01

    The clitoris contributes to the normal female sexual response cycle. A significance of cyclic guanosine monophosphate (GMP) has been assumed in the control of clitoral vascular smooth muscle. As only a few investigations on the physiology of the vascular and non-vascular clitoral tissue have been carried out, knowledge on the mechanisms controlling this particular female genital organ is still vague. It has been suggested that human clitoral corpus cavernosum smooth muscle is regulated by nitric oxide (NO)/cyclic GMP and related key enzymes, such as NO synthases (NOSs) and the phosphodiesterase type 5 (PDE5). The present study evaluated in the human clitoris, by means of immunohistochemistry, the expression and distribution of key enzymes of the cyclic GMP pathway, such as the endothelial NOS, PDE2, PDE11 and cyclic GMP-dependent protein kinase type I (cGKI) in relation to the PDE5. Immunohistochemistry revealed the presence of PDE2, PDE5 and cGKI in the smooth muscle wall of blood vessels transversing the supepithelial and stromal space. Immunosignals specific for PDE2 were also identified in interstitial-like cells located in the basal epithelial layer. Staining for PDE11A was observed in single nerve trunks located in the clitoral stroma. The results are in favor of a role of the cyclic GMP signaling in the control of clitoral blood flow. It seems likely that PDE2 and PDE11 are also involved in the mechanism of local (neuro)transmission in the clitoris.

  3. 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

  4. 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.

  5. Application of Quasi-Steady-State Methods to Nonlinear Models of Intracellular Transport by Molecular Motors.

    PubMed

    Zmurchok, Cole; Small, Tim; Ward, Michael J; Edelstein-Keshet, Leah

    2017-07-13

    Molecular motors such as kinesin and dynein are responsible for transporting material along microtubule networks in cells. In many contexts, motor dynamics can be modelled by a system of reaction-advection-diffusion partial differential equations (PDEs). Recently, quasi-steady-state (QSS) methods have been applied to models with linear reactions to approximate the behaviour of the full PDE system. Here, we extend this QSS reduction methodology to certain nonlinear reaction models. The QSS method relies on the assumption that the nonlinear binding and unbinding interactions of the cellular motors occur on a faster timescale than the spatial diffusion and advection processes. The full system dynamics are shown to be well approximated by the dynamics on the slow manifold. The slow manifold is parametrized by a single scalar quantity that satisfies a scalar nonlinear PDE, called the QSS PDE. We apply the QSS method to several specific nonlinear models for the binding and unbinding of molecular motors, and we use the resulting approximations to draw conclusions regarding the parameter dependence of the spatial distribution of motors for these models.

  6. Nonlinear optics

    SciTech Connect

    Boyd, R.W. . Inst. of Optics)

    1992-01-01

    Nonlinear optics is the study of the interaction of intense laser light with matter. This book is a textbook on nonlinear optics at the level of a beginning graduate student. The intent of the book is to provide an introduction to the field of nonlinear optics that stresses fundamental concepts and that enables the student to go on to perform independent research in this field. This book covers the areas of nonlinear optics, quantum optics, quantum electronics, laser physics, electrooptics, and modern optics.

  7. 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

  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. Selective Effects of PDE10A Inhibitors on Striatopallidal Neurons Require Phosphatase Inhibition by DARPP-321,2,3

    PubMed Central

    Polito, Marina; Guiot, Elvire; Gangarossa, Giuseppe; Longueville, Sophie; Doulazmi, Mohamed; Valjent, Emmanuel; Hervé, Denis; Girault, Jean-Antoine; Paupardin-Tritsch, Danièle; Castro, Liliana R. V.

    2015-01-01

    Abstract Type 10A phosphodiesterase (PDE10A) is highly expressed in the striatum, in striatonigral and striatopallidal medium-sized spiny neurons (MSNs), which express D1 and D2 dopamine receptors, respectively. PDE10A inhibitors have pharmacological and behavioral effects suggesting an antipsychotic profile, but the cellular bases of these effects are unclear. We analyzed the effects of PDE10A inhibition in vivo by immunohistochemistry, and imaged cAMP, cAMP-dependent protein kinase A (PKA), and cGMP signals with biosensors in mouse brain slices. PDE10A inhibition in mouse striatal slices produced a steady-state increase in intracellular cAMP concentration in D1 and D2 MSNs, demonstrating that PDE10A regulates basal cAMP levels. Surprisingly, the PKA-dependent AKAR3 phosphorylation signal was strong in D2 MSNs, whereas D1 MSNs remained unresponsive. This effect was also observed in adult mice in vivo since PDE10A inhibition increased phospho-histone H3 immunoreactivity selectively in D2 MSNs in the dorsomedial striatum. The PKA-dependent effects in D2 MSNs were prevented in brain slices and in vivo by mutation of the PKA-regulated phosphorylation site of 32 kDa dopamine- and cAMP-regulated phosphoprotein (DARPP-32), which is required for protein phosphatase-1 inhibition. These data highlight differences in the integration of the cAMP signal in D1 and D2 MSNs, resulting from stronger inhibition of protein phosphatase-1 by DARPP-32 in D2 MSNs than in D1 MSNs. This study shows that PDE10A inhibitors share with antipsychotic medications the property of activating preferentially PKA-dependent signaling in D2 MSNs. PMID:26465004

  10. PDE2 at the crossway between cAMP and cGMP signalling in the heart.

    PubMed

    Weber, Silvio; Zeller, Miriam; Guan, Kaomei; Wunder, Frank; Wagner, Michael; El-Armouche, Ali

    2017-10-01

    The cyclic nucleotides cAMP and cGMP are central second messengers in cardiac cells and critical regulators of cardiac physiology as well as pathophysiology. Consequently, subcellular compartmentalization allows for spatiotemporal control of cAMP/cGMP metabolism and subsequent regulation of their respective effector kinases PKA or PKG is most important for cardiac function in health and disease. While acute cAMP-mediated signalling is a mandatory prerequisite for the physiological fight-or-flight response, sustained activation of this pathway may lead to the progression of heart failure. In contrast, acute as well as sustained cGMP-mediated signalling can foster beneficial features, e.g. anti-hypertrophic and vasodilatory effects. These two signalling pathways seem to be intuitively counteracting and there is increasing evidence for a functionally relevant crosstalk between cAMP and cGMP signalling pathways on the level of cyclic nucleotide hydrolysing phosphodiesterases (PDEs). Among this diverse group of enzymes, PDE2 may fulfill a unique integrator role. Equipped with dual substrate specificity for cAMP as well as for cGMP, it is the only cAMP hydrolysing PDE, which is allosterically activated by cGMP. Recent studies have revealed strongly remodelled cAMP/cGMP microdomains and subcellular concentration profiles in different cardiac pathologies, leading to a putatively enhanced involvement of PDE2 in cAMP/cGMP breakdown and crosstalk compared to the other cardiac PDEs. This review sums up the current knowledge about molecular properties and regulation of PDE2 and explains the complex signalling network encompassing PDE2 in order to better understand the functional role of PDE2 in distinct cell types in cardiac health and disease. Moreover, this review gives an outlook in which way PDE2 may serve as a therapeutic target to treat cardiac disease. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. 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

  12. Phosphodiesterase 4 in inflammatory diseases: Effects of apremilast in psoriatic blood and in dermal myofibroblasts through the PDE4/CD271 complex.

    PubMed

    Schafer, Peter H; Truzzi, Francesca; Parton, Anastasia; Wu, Lei; Kosek, Jolanta; Zhang, Ling-Hua; Horan, Gerald; Saltari, Annalisa; Quadri, Marika; Lotti, Roberta; Marconi, Alessandra; Pincelli, Carlo

    2016-07-01

    Phosphodiesterases 4 (PDE4) act as proinflammatory enzymes via degradation of cAMP, whereas PDE4 inhibitors play an anti-inflammatory role in vitro and in vivo. In particular, apremilast has been recently approved for the treatment of psoriasis and psoriatic arthritis. However, little is known on the expression pattern of PDE4 in psoriasis. We report that PDE4B and PDE4D mRNA are overexpressed in peripheral blood mononuclear cells (PBMC) from psoriasis, as compared with normal controls, while apremilast reduces PBMC production of a number of pro-inflammatory cytokines and increases the levels of anti-inflammatory mediators. PDE4 expression is up-regulated in psoriatic dermis as compared with normal skin, with particular regard to fibroblasts. This is confirmed in vitro, where both dermal fibroblasts (DF) and, to a greater extent, myofibroblasts (DM) express all PDE4 isoforms at the mRNA and protein level. Because PDE4 interacts with the nerve growth factor (NGF) receptor CD271 in lung fibroblasts, we evaluated the relationship and function of PDE4 and CD271 in normal human skin fibroblasts. All PDE4 isoforms co-immunoprecipitate with CD271 in DM, while apremilast inhibits apoptosis induced by β-amyloid, a CD271 ligand, in DM. Furthermore, apremilast significantly reduces NGF- and transforming growth factor-β1 (TGF-β1)-induced fibroblast migration, and inhibits DF differentiation into DM mediated by NGF or TGF-β1. Finally, in DM, apremilast significantly reduces cAMP degradation induced by treatment with β-amyloid. Taken together, these results indicate that PDE4 play an important role in psoriasis. In addition, the study reveals that the PDE4/CD271 complex could be important in modulating fibroblast functions. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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.

  18. Role of PDE3A in regulation of cell cycle progression in mouse vascular smooth muscle cells and oocytes: implications in cardiovascular diseases and infertility.

    PubMed

    Begum, Najma; Shen, Weixing; Manganiello, Vincent

    2011-12-01

    Phosphodiesterase-3 (PDE3) is a major cAMP-hydrolyzing PDE in vascular smooth muscle cells (VSMCs) and oocytes. The exact role and contribution of the two PDE3 isoforms, PDE3A and PDE3B, in VSMC growth regulation and oocyte maturation was examined using PDE3A (3A) and PDE3B (3B) knockout (KO) mouse models. PDE3A-deficient VSMCs exhibit marked reduction in mitogen-induced cell growth due to cell cycle arrest at G₀-G₁ phase, which resulted from dysregulation of cAMP/protein kinase A (PKA)-activated and mitogen-activated protein kinase (MAPK)-signaling pathways, as well as from alterations in key cell cycle regulatory proteins. Similarly, PDE3A-deficient oocytes exhibit cell cycle arrest at G₂/M phase because increased cAMP/PKA signaling in KO oocytes most likely inhibits Cdc25B-catalyzed dephosphorylation/activation of Cdc2 (maturation promoting factor (MPF)), a key regulator of G₂/M transition. Copyright © 2011 Elsevier Ltd. All rights reserved.

  19. 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.

  20. Characteristic formulation for metric f (R ) gravity

    NASA Astrophysics Data System (ADS)

    Mongwane, Bishop

    2017-07-01

    In recent years, the characteristic formulation of numerical relativity has found increasing use in the extraction of gravitational radiation from numerically generated spacetimes. In this paper, we formulate the characteristic initial value problem for f (R ) gravity. We consider, in particular, the vacuum field equations of Metric f (R ) gravity in the Jordan frame, without utilizing the dynamical equivalence with scalar-tensor theories. We present the full hierarchy of nonlinear hypersurface and evolution equations necessary for numerical implementation in both tensorial and eth forms. Furthermore, we specialize the resulting equations to situations where the spacetime is almost Minkowski and almost Schwarszchild using standard linearization techniques. We obtain analytic solutions for the dominant ℓ=2 mode and show that they satisfy the concomitant constraints. These results are ideally suited as testbed solutions for numerical codes. Finally, we point out that the characteristic formulation can be used as a complementary analytic tool to the 1 +1 +2 semitetrad formulation.

  1. 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

  2. Screening of synthetic PDE-5 inhibitors and their analogues as adulterants: analytical techniques and challenges.

    PubMed

    Patel, Dhavalkumar Narendrabhai; Li, Lin; Kee, Chee-Leong; Ge, Xiaowei; Low, Min-Yong; Koh, Hwee-Ling

    2014-01-01

    The popularity of phosphodiesterase type 5 (PDE-5) enzyme inhibitors for the treatment of erectile dysfunction has led to the increase in prevalence of illicit sexual performance enhancement products. PDE-5 inhibitors, namely sildenafil, tadalafil and vardenafil, and their unapproved designer analogues are being increasingly used as adulterants in the herbal products and health supplements marketed for sexual performance enhancement. To date, more than 50 unapproved analogues of prescription PDE-5 inhibitors were found as adulterants in the literature. To avoid detection of such adulteration by standard screening protocols, the perpetrators of such illegal products are investing time and resources to synthesize exotic analogues and devise novel means for adulteration. A comprehensive review of conventional and advance analytical techniques to detect and characterize the adulterants is presented. The rapid identification and structural elucidation of unknown analogues as adulterants is greatly enhanced by the wide myriad of analytical techniques employed, including high performance liquid chromatography (HPLC), gas chromatography-mass spectrometry (GC-MS), liquid chromatography mass-spectrometry (LC-MS), nuclear magnetic resonance (NMR) spectroscopy, vibrational spectroscopy, liquid chromatography-Fourier transform ion cyclotron resonance-mass spectrometry (LC-FT-ICR-MS), liquid chromatograph-hybrid triple quadrupole linear ion trap mass spectrometer with information dependent acquisition, ultra high performance liquid chromatography-time of flight-mass spectrometry (UHPLC-TOF-MS), ion mobility spectroscopy (IMS) and immunoassay methods. The many challenges in detecting and characterizing such adulterants, and the need for concerted effort to curb adulteration in order to safe guard public safety and interest are discussed. Copyright © 2013 Elsevier B.V. All rights reserved.

  3. 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

  4. Comparison of efficacy and satisfaction profile, between penile prosthesis implantation and oral PDE5 inhibitor tadalafil therapy, in men with nerve-sparing radical prostatectomy erectile dysfunction.

    PubMed

    Megas, Georgios; Papadopoulos, Georgios; Stathouros, Georgios; Moschonas, Dimitrios; Gkialas, Ioannis; Ntoumas, Konstantinos

    2013-07-01

    WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Erectile dysfunction after nerve-sparing radical retropubic prostatectomy constitutes a challenge to the urologist. The mainstay of medical treatment after radical prostatectomy to restore spontaneous erectile function remains phosphodiesterase (PDE5) inhibitors, despite the fact that data from animal studies suggesting that PDE5 inhibitors can prevent smooth muscle apoptosis and fibrosis have not yet been extrapolated to humans because of a lack of standardized protocols. If the above treatment fails, second-line therapies such as intraurethral prostaglandins, penile injection therapy and vacuum devices are offered. When less invasive therapies are ineffective, interventions that preserve sexual function such as penile prosthesis implantation become the treatment of choice. Our study reveals the alternative of penile prosthesis implantation as first-line treatment in erectile dysfunction after nerve-sparing radical prostatectomy. It also highlights its superiority to the oral PDE5 inhibitor treatment, regarding the erection, frequency, firmness, maintenance and penetration ability. This suggests that a concept of an early penile intervention in the future would be promising for those patients who wish to remain sexually active without depending on oral formulations with doubtful and delayed results. To evaluate the outcome of penile prosthesis surgery in comparison to oral phosphodiesterase type 5 (PDE5) inhibitor administration, in men with erectile dysfunction after nerve-sparing radical prostatectomy, as early penile intervention therapy. A total of 174 patients treated by nerve-sparing retropubic radical prostatectomy (RRP) for clinically localized prostate cancer, between January 2006 and September 2009 enrolled in the study, 153 patients fulfilled the inclusion criteria, and 69 (45%) patients presented with post-RRP erectile dysfunction 6 months after primary surgery. Fifty-four patients were disease

  5. Genetic deletion of PDE10A selectively impairs incentive salience attribution and decreases medium spiny neuron excitability.

    PubMed

    Piccart, Elisabeth; De Backer, Jean-François; Gall, David; Lambot, Laurie; Raes, Adam; Vanhoof, Greet; Schiffmann, Serge; D'Hooge, Rudi

    2014-07-15

    The striatum is the main input structure to the basal ganglia and consists mainly out of medium spiny neurons. The numerous spines on their dendrites render them capable of integrating cortical glutamatergic inputs with a motivational dopaminergic signal that originates in the midbrain. This integrative function is thought to underly attribution of incentive salience, a process that is severely disrupted in schizophrenic patients. Phosphodiesterase 10A (PDE10A) is located mainly to the striatal medium spiny neurons and hydrolyses cAMP and cGMP, key determinants of MSN signaling. We show here that genetic depletion of PDE10A critically mediates attribution of salience to reward-predicting cues, evident in impaired performance in PDE10A knockout mice in an instrumentally conditioned reinforcement task. We furthermore report modest impairment of latent inhibition in PDE10A knockout mice, and unaltered prepulse inhibition. We suggest that the lack of effect on PPI is due to the pre-attentional nature of this task. Finally, we performed whole-cell patch clamp recordings and confirm suggested changes in intrinsic membrane excitability. A decrease in spontaneous firing in striatal medium spiny neurons was found. These data show that PDE10A plays a pivotal role in striatal signaling and striatum-mediated salience attribution.

  6. 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

  7. Formulation of Nematodes.

    PubMed

    Peters, Arne

    2016-01-01

    The enduring stages of entomopathogenic nematodes of the genera Steinernema and Heterorhabditis are infective juveniles, which require a high humidity and sufficient ventilation for survival. Formulations must account for these requirements. Nematodes may be formulated inside the insects in which they reproduced or they need to be cleaned and mixed with a suitable binder to maintain humidity but allowing for gas exchange. Another method for formulation is the encapsulation in beads of Ca-alginate. Generic procedures for these formulation techniques are described.

  8. A Fast PDE Algorithm Using Adaptive Scan and Search for Video Coding

    NASA Astrophysics Data System (ADS)

    Kim, Jong-Nam

    In this paper, we propose an algorithm that reduces unnecessary computations, while keeping the same prediction quality as that of the full search algorithm. In the proposed algorithm, we can reduce unnecessary computations efficiently by calculating initial matching error point from first 1/N partial errors. We can increase the probability that hits minimum error point as soon as possible. Our algorithm decreases the computational amount by about 20% of the conventional PDE algorithm without any degradation of prediction quality. Our algorithm would be useful in real-time video coding applications using MPEG-2/4 AVC standards.

  9. 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.

  10. PDE Based Unsharp Masking, Crispening and High Boost Filtering of Digital Images

    NASA Astrophysics Data System (ADS)

    Srivastava, Rajeev; Gupta, J. R. P.; Parthasarthy, Harish; Srivastava, Subodh

    A partial differential equation (PDE) based technique is proposed and implemented to perform unsharp masking, crispening and high boost filtering of digital images. The traditional concept of unsharp masking and crispening of edges which uses Laplacian as intermediate step for smoothening the image has been extended and modified using the idea of Perona and Malik [1] which overcomes the disadvantages of Laplacian method. For descretization, finite differences scheme has been used. The scheme has been implemented using MATLAB 7.0 and performance is tested for various gray images of different resolutions and the obtained results justify the applicability of proposed scheme.

  11. Prediction of meteor shower associated with Comet 122P/de Vico

    NASA Astrophysics Data System (ADS)

    Tomko, Dusan; Neslusan, Lubos

    2013-01-01

    We model, for a far past, a theoretical stream associated with Comet 122P/de Vico and follow its dynamical evolution until present. Selecting the modeled particles approaching the Earth's orbit at the present, we predict the characteristics of a potential meteor shower and try to identify these particles with the meteors in three databases (photo, radar, and video). Our overall prediction is, however, negative because only the particles released from the comet nucleus before approximately 37 000 years ago are found to evolve into a collision course with the Earth and, therefore, form a possible shower. Meteoroids are known to survive a much shorter time in interplanetary space, unfortunately.

  12. 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.

  13. 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.

  14. 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.

  15. Artificial neural network as an alternative to multiple regression analysis in optimizing formulation parameters of cytarabine liposomes.

    PubMed

    Subramanian, Narayanaswamy; Yajnik, Archit; Murthy, Rayasa S Ramachandra

    2004-02-02

    The objective of the study was to optimize the formulation parameters of cytarabine liposomes by using artificial neural networks (ANN) and multiple regression analysis using 3(3) factorial design (FD). As model formulations, 27 formulations were prepared. The formulation variables, drug (cytarabine)/lipid (phosphatidyl choline [PC] and cholesterol [Chol]) molar ratio (X1), PC/Chol in percentage ratio of total lipids (X2), and the volume of hydration medium (X3) were selected as the independent variables; and the percentage drug entrapment (PDE) was selected as the dependent variable. A set of causal factors was used as tutorial data for ANN and fed into a computer. The optimization was performed by minimizing the generalized distance between the predicted values of each response and the optimized one that was obtained individually. In case of 3(3) factorial design, a second-order full-model polynomial equation and a reduced model were established by subjecting the transformed values of independent variables to multiple regression analysis, and contour plots were drawn using the equation. The optimization methods developed by both ANN and FD were validated by preparing another 5 liposomal formulations. The predetermined PDE and the experimental data were compared with predicted data by paired t test, no statistically significant difference was observed. ANN showed less error compared with multiple regression analysis. These findings demonstrate that ANN provides more accurate prediction and is quite useful in the optimization of pharmaceutical formulations when compared with the multiple regression analysis method.

  16. 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.

  17. The Glutamic Acid-rich Protein-2 (GARP2) Is a High Affinity Rod Photoreceptor Phosphodiesterase (PDE6)-binding Protein That Modulates Its Catalytic Properties*

    PubMed Central

    Pentia, Dana C.; Hosier, Suzanne; Cote, Rick H.

    2010-01-01

    The glutamic acid-rich protein-2 (GARP2) is a splice variant of the β-subunit of the cGMP-gated ion channel of rod photoreceptors. GARP2 is believed to interact with several membrane-associated phototransduction proteins in rod photoreceptors. In this study, we demonstrated that GARP2 is a high affinity PDE6-binding protein and that PDE6 co-purifies with GARP2 during several stages of chromatographic purification. We found that hydrophobic interaction chromatography succeeds in quantitatively separating GARP2 from the PDE6 holoenzyme. Furthermore, the 17-kDa prenyl-binding protein, abundant in retinal cells, selectively released PDE6 (but not GARP2) from rod outer segment membranes, demonstrating the specificity of the interaction between GARP2 and PDE6. Purified GARP2 was able to suppress 80% of the basal activity of the nonactivated, membrane-bound PDE6 holoenzyme at concentrations equivalent to its endogenous concentration in rod outer segment membranes. However, GARP2 was unable to reverse the transducin activation of PDE6 (in contrast to a previous study) nor did it significantly alter catalysis of the fully activated PDE6 catalytic dimer. The high binding affinity of GARP2 for PDE6 and its ability to regulate PDE6 activity in its dark-adapted state suggest a novel role for GARP2 as a regulator of spontaneous activation of rod PDE6, thereby serving to lower rod photoreceptor “dark noise” and allowing these sensory cells to operate at the single photon detection limit. PMID:16407240

  18. 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

  19. 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

  20. 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.

  1. 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

  2. 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.

  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. 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

  5. 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.

  6. PDE4 inhibition suppresses IL-17-associated immunity in dry eye disease.

    PubMed

    Sadrai, Zahra; Stevenson, William; Okanobo, Andre; Chen, Yihe; Dohlman, Thomas H; Hua, Jing; Amparo, Francisco; Chauhan, Sunil K; Dana, Reza

    2012-06-14

    To determine the effect of phosphodiesterase type-4 (PDE4) inhibition on IL-17-associated immunity in experimental dry eye disease (DED). Murine DED was induced, after which a PDE4 inhibitor (cilomilast), dexamethasone, cyclosporine, or a relevant vehicle was administered topically. Real-time PCR, immunohistochemical staining, and flow cytometry were employed to evaluate the immuno-inflammatory parameters of DED with a focus on IL-17-associated immunity. Corneal fluorescein staining (CFS) was performed to evaluate clinical disease progression. DED induction increased proinflammatory cytokine expression, pathogenic immune cell infiltration, and CFS scores. Cilomilast significantly decreased the expression of TNF-α in the cornea (P ≤ 0.05) and IL-1α, IL-1β, and TNF-α in the conjunctiva (P ≤ 0.05) as compared with vehicle control. Cilomilast treatment markedly decreased the presence of CD11b+ antigen-presenting cells in the central and peripheral cornea (P ≤ 0.05), and led to decreased conjunctival expression of cytokines IL-6, IL-23, and IL-17 (P ≤ 0.05). Moreover, cilomilast decreased the expression of IL-17 and IL-23 in the draining lymph nodes (P ≤ 0.05). Topical cilomilast was significantly more effective than vehicle at reducing CFS scores (P ≤ 0.05). The therapeutic efficacy of cilomilast was comparable or superior to that of dexamethasone and cyclosporine in all tested measures. Topical cilomilast suppresses the generation of IL-17-associated immunity in experimental DED.

  7. Assessing protein-ligand binding modes with computational tools: the case of PDE4B

    NASA Astrophysics Data System (ADS)

    Çifci, Gülşah; Aviyente, Viktorya; Akten, E. Demet; Monard, Gerald

    2017-06-01

    In a first step in the discovery of novel potent inhibitor structures for the PDE4B family with limited side effects, we present a protocol to rank newly designed molecules through the estimation of their IC_{50} values. Our protocol is based on reproducing the linear relationship between the logarithm of experimental IC_{50} values [log(IC_{50})] and their calculated binding free energies (Δ G_binding). From 13 known PDE4B inhibitors, we show here that (1) binding free energies obtained after a docking process by AutoDock are not accurate enough to reproduce this linear relationship; (2) MM-GB/SA post-processing of molecular dynamics (MD) trajectories of the top ranked AutoDock pose improves the linear relationship; (3) by taking into account all representative structures obtained by AutoDock and by averaging MM-GB/SA computations on a series of 40 independent MD trajectories, a linear relationship between log(IC_{50}) and the lowest Δ G_binding is achieved with R^2=0.944.

  8. 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.

  9. 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

  10. 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

  11. 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.

  12. 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

  13. 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.

  14. 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.

  15. 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

  16. 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

  17. 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.

  18. 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.

  19. 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

  20. 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.

  1. 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.

  2. 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. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

  3. 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

  4. [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.

  5. 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

  6. 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.

  7. 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

  8. 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.

  9. 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

  10. 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

  11. 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

  12. 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.

  13. 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

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. New PDE-based methods for image enhancement using SOM and Bayesian inference in various discretization schemes

    NASA Astrophysics Data System (ADS)

    Karras, D. A.; Mertzios, G. B.

    2009-10-01

    A novel approach is presented in this paper for improving anisotropic diffusion PDE models, based on the Perona-Malik equation. A solution is proposed from an engineering perspective to adaptively estimate the parameters of the regularizing function in this equation. The goal of such a new adaptive diffusion scheme is to better preserve edges when the anisotropic diffusion PDE models are applied to image enhancement tasks. The proposed adaptive parameter estimation in the anisotropic diffusion PDE model involves self-organizing maps and Bayesian inference to define edge probabilities accurately. The proposed modifications attempt to capture not only simple edges but also difficult textural edges and incorporate their probability in the anisotropic diffusion model. In the context of the application of PDE models to image processing such adaptive schemes are closely related to the discrete image representation problem and the investigation of more suitable discretization algorithms using constraints derived from image processing theory. The proposed adaptive anisotropic diffusion model illustrates these concepts when it is numerically approximated by various discretization schemes in a database of magnetic resonance images (MRI), where it is shown to be efficient in image filtering and restoration applications.

  20. 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.

  1. 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.

  2. 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

  3. 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.

  4. Insulin inhibits human erythrocyte cAMP accumulation and ATP release: role of PDE3 and PI3K

    PubMed Central

    Hanson, Madelyn S.; Stephenson, Alan H.; Bowles, Elizabeth A.; Sprague, Randy S.

    2010-01-01

    In non – erythroid cells, insulin stimulates a signal transduction pathway that results in the activation of phosphoinositide 3 – kinase (PI3K) and phosphorylation of phosphodiesterase 3 (PDE3). Erythrocytes possess insulin receptors, PI3K, and PDE3B. These cells release ATP via a signaling pathway that requires activation of the G protein, Gi, as well as increases in cAMP. Although insulin inhibits ATP release from human erythrocytes in response to Gi activation with mastoparan 7 (Mas 7), no effect on cAMP was described. Here, we investigated the hypothesis that insulin activates PDE3 in human erythrocytes via a PI3K – mediated mechanism resulting in cAMP hydrolysis and inhibition of ATP release. We show that insulin attenuates Mas 7 – induced increases in cAMP and that selective inhibitors of PDE3 (cilostazol) or PI3K (LY294002) rescue this effect of insulin. In addition, we demonstrated that both cilostazol and LY294002 prevent insulin – induced attenuation of Mas 7 – induced ATP release. These results provide support for the hypothesis that insulin activates PDE3 in erythrocytes via a PI3K – dependent mechanism. Once activated, PDE3 limits Mas 7 – induced increases in intracellular cAMP. This effect of insulin leads, ultimately, to decreased ATP release in response to Mas 7. Since the activation of Gi is required for reduced O2 tension – induced ATP release from erythrocytes, and insulin has been shown to inhibit that release, these results suggest a novel mechanism by which supraphysiological levels of plasma insulin, such as those reported in humans with prediabetes, could inhibit ATP release from erythrocytes. Erythrocyte – derived ATP has been shown to participate in the matching of O2 supply with demand in skeletal muscle. Thus, pathological increases in circulating insulin could, via activation of PDE3, inhibit ATP release from erythrocytes depriving the peripheral circulation of a mechanism that regulates delivery of O2 to meet tissue

  5. 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.

  6. ERAP1 and PDE8A Are Downregulated in Cattle Protected against Bovine Tuberculosis.

    PubMed

    Blanco, Federico Carlos; Soria, Marcelo Abel; Klepp, Laura Inés; Bigi, Fabiana

    2017-09-14

    Bovine tuberculosis (bTB) is a zoonotic disease caused by Mycobacterium bovis that is responsible for significant economic losses worldwide. In spite of its relevance, the limited knowledge about the host immune responses that provide effective protection against the disease has long hampered the development of an effective vaccine. The identification of host proteins with an expression that correlates with protection against bTB would contribute to the understanding of the cattle defence mechanisms against M. bovis infection. In this study, we found that ERAP1 and PDE8A were downregulated in vaccinated cattle that were protected from experimental M. bovis challenge. Remarkably, both genes encode proteins that have been negatively associated with immune protection against bTB. © 2017 S. Karger AG, Basel.

  7. Prediction of evolution of meteor shower associated with comet 122P/de Vico

    NASA Astrophysics Data System (ADS)

    Tomko, D.

    2014-04-01

    We deal with a theoretical meteoroid stream of the comet 122P/de Vico. For five perihelion passages in the distant past, we model a theoretical stream and follow its dynamical evolution until the present. We predict the characteristics of potential a meteor shower approaching the Earth's orbit and we make also the identification of the particles of the predicted shower with the real meteors in three databases (photo, radar, and video). Our overall prediction is, however, negative because only the particles released from the comet nucleus before approximately 37 000 years are found to evolve into a collision course with the Earth and, therefore, form a possible shower. Many meteoroids do not survive such a long time in interplanetary space.

  8. 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.

  9. PdeH, a High-Affinity cAMP Phosphodiesterase, Is a Key Regulator of Asexual and Pathogenic Differentiation in Magnaporthe oryzae

    PubMed Central

    Ramanujam, Ravikrishna; Naqvi, Naweed I.

    2010-01-01

    Cyclic AMP-dependent pathways mediate the communication between external stimuli and the intracellular signaling machinery, thereby influencing important aspects of cellular growth, morphogenesis and differentiation. Crucial to proper function and robustness of these signaling cascades is the strict regulation and maintenance of intracellular levels of cAMP through a fine balance between biosynthesis (by adenylate cyclases) and hydrolysis (by cAMP phosphodiesterases). We functionally characterized gene-deletion mutants of a high-affinity (PdeH) and a low-affinity (PdeL) cAMP phosphodiesterase in order to gain insights into the spatial and temporal regulation of cAMP signaling in the rice-blast fungus Magnaporthe oryzae. In contrast to the expendable PdeL function, the PdeH activity was found to be a key regulator of asexual and pathogenic development in M. oryzae. Loss of PdeH led to increased accumulation of intracellular cAMP during vegetative and infectious growth. Furthermore, the pdeHΔ showed enhanced conidiation (2–3 fold), precocious appressorial development, loss of surface dependency during pathogenesis, and highly reduced in planta growth and host colonization. A pdepdeLΔ mutant showed reduced conidiation, exhibited dramatically increased (∼10 fold) cAMP levels relative to the wild type, and was completely defective in virulence. Exogenous addition of 8-Br-cAMP to the wild type simulated the pdeHΔ defects in conidiation as well as in planta growth and development. While a fully functional GFP-PdeH was cytosolic but associated dynamically with the plasma membrane and vesicular compartments, the GFP-PdeL localized predominantly to the nucleus. Based on data from cAMP measurements and Real-Time RTPCR, we uncover a PdeH-dependent biphasic regulation of cAMP levels during early and late stages of appressorial development in M. oryzae. We propose that PdeH-mediated sustenance and dynamic regulation of cAMP signaling during M. oryzae development is

  10. In cardiac myocytes, cAMP elevation triggers the down-regulation of transcripts and promoter activity for cyclic AMP phosphodiesterase-4A10 (PDE4A10).

    PubMed

    McCahill, Angela; Campbell, Lachlan; McSorley, Theresa; Sood, Arvind; Lynch, Martin J; Li, Xiang; Yan, Chen; Baillie, George S; Houslay, Miles D

    2008-11-01

    Transcripts for the PDE4A10 cyclic AMP phosphodiesterase isoform are present in a wide variety of rat tissues including the heart. Sequence comparisons between the putative human and mouse promoters revealed a number of conserved regions including both an Sp1 and a CREB-binding site. The putative mouse PDE4A10 promoter was amplified from genomic DNA and sub-cloned into a luciferase reporter vector for investigation of activity in neonatal cardiac myocytes. Transfection with this construct identified a high level of luciferase expression in neonatal cardiac myocytes. Surprisingly, this activity was down-regulated by elevation of intracellular cAMP through a process involving PKA, but not EPAC, signalling. Such inhibition of the rodent PDE4A10 promoter activity in response to elevated cAMP levels is in contrast to the PDE4 promoters so far described. Site-directed mutagenesis revealed that the Sp1 binding site at promoter position -348 to -336 is responsible for the basal constitutive expression of murine PDE4A10. The conserved CREB-binding motif at position -370 to -363 also contributes to basal promoter activity but does not in itself confer cAMP inhibition upon the PDE4A10 promoter. EMSA analysis confirmed the authenticity of CREB and Sp1 binding sites. The transcriptional start site was identified to be an adenine residue at position -55 in the mouse PDE4A10 promoter. We present evidence that this novel down-regulation of PDE4A10 is mediated by the transcription factor ICER in a PKA dependent manner. The pool of cAMP in cardiac myocytes that down-regulates PDE4A10 is regulated by beta-adrenoceptor coupled adenylyl cyclase activity and via hydrolysis determined predominantly by the action of PDE4 (cAMP phosphodiesterase-4) and not PDE3 (cAMP phosphodiesterase-3). We suggest that increased cAMP may remodel cAMP-mediated signalling events by not only increasing the expression of specific PDE4 cAMP phosphodiesterases but also by down-regulating specific isoforms

  11. 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.

  12. PDE4 Inhibition Suppresses IL-17–Associated Immunity in Dry Eye Disease

    PubMed Central

    Sadrai, Zahra; Stevenson, William; Okanobo, Andre; Chen, Yihe; Dohlamn, Thomas H.; Hua, Jing; Amparo, Francisco; Chauhan, Sunil K.; Dana, Reza

    2012-01-01

    Purpose. To determine the effect of phosphodiesterase type-4 (PDE4) inhibition on IL-17–associated immunity in experimental dry eye disease (DED). Methods. Murine DED was induced, after which a PDE4 inhibitor (cilomilast), dexamethasone, cyclosporine, or a relevant vehicle was administered topically. Real-time PCR, immunohistochemical staining, and flow cytometry were employed to evaluate the immuno-inflammatory parameters of DED with a focus on IL-17–associated immunity. Corneal fluorescein staining (CFS) was performed to evaluate clinical disease progression. Results. DED induction increased proinflammatory cytokine expression, pathogenic immune cell infiltration, and CFS scores. Cilomilast significantly decreased the expression of TNF-α in the cornea (P ≤ 0.05) and IL-1α, IL-1β, and TNF-α in the conjunctiva (P ≤ 0.05) as compared with vehicle control. Cilomilast treatment markedly decreased the presence of CD11b+ antigen-presenting cells in the central and peripheral cornea (P ≤ 0.05), and led to decreased conjunctival expression of cytokines IL-6, IL-23, and IL-17 (P ≤ 0.05). Moreover, cilomilast decreased the expression of IL-17 and IL-23 in the draining lymph nodes (P ≤ 0.05). Topical cilomilast was significantly more effective than vehicle at reducing CFS scores (P ≤ 0.05). The therapeutic efficacy of cilomilast was comparable or superior to that of dexamethasone and cyclosporine in all tested measures. Conclusions. Topical cilomilast suppresses the generation of IL-17–associated immunity in experimental DED. PMID:22577075

  13. Haemodynamic changes in pulmonary hypertension in patients with interstitial lung disease treated with PDE-5 inhibitors.

    PubMed

    Zimmermann, Gregor S; von Wulffen, Werner; Huppmann, Patrick; Meis, Tobias; Ihle, Franziska; Geiseler, Jens; Leuchte, Hanno H; Tufman, Amanda; Behr, Juergen; Neurohr, Claus

    2014-07-01

    Interstitial lung diseases (ILD) are often associated with pulmonary hypertension (PH). This study aimed to evaluate the therapeutic benefit of phosphodiesterase-5 (PDE-5) inhibitors in pulmonary hypertension secondary to ILD. Patients with ILD and PH were treated with sildenafil or tadalafil. Right heart catheterization was performed before and after a minimum of 3-month treatment. In addition, lung function, 6-min walk distance (6MWD) and plasma brain natriuretic peptide (BNP) concentration were assessed. Ten ILD patients (three female, mean age 64.4 ± 9.0 years, six with idiopathic pulmonary fibrosis (IPF), four with hypersensitivity pneumonitis, (HP)) with significant precapillary PH (mean pulmonary artery pressure (PAPm) ≥ 25 mmHg, pulmonary vascular resistance (PVR) > 280 dyn*s*cm(-5) ; pulmonary artery wedge pressure (PAWPm) ≤ 15 mmHg) were treated with either sildenafil (n = 5) or tadalafil (n = 5). Pulmonary haemodynamics were severely impaired at baseline (PAPm 42.9 ± 5.4 mmHg; cardiac index (CI) 2.7 ± 0.6 L/min/m2; PVR 519 ± 131 dyn × sec × cm(-5)). After mean follow-up of 6.9 ± 5.8 months an increase in CI (2.9 ± 0.7 L/min/m2 , P = 0.04) and a decrease in PVR (403 ± 190 dyn × sec × cm(-5) , P = 0.03) were observed. 6MWD and BNP did not change significantly. Our data suggest that treatment with PDE-5 inhibitors improves pulmonary haemodynamic patients with PH secondary to ILD. © 2014 Asian Pacific Society of Respirology.

  14. 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

  15. PdeB, a cyclic Di-GMP-specific phosphodiesterase that regulates Shewanella oneidensis MR-1 motility and biofilm formation.

    PubMed

    Chao, Lily; Rakshe, Shauna; Leff, Maija; Spormann, Alfred M

    2013-09-01

    Shewanella oneidensis MR-1, a gammaproteobacterium with respiratory versatility, forms biofilms on mineral surfaces through a process controlled by the cyclic dinucleotide messenger c-di-GMP. Cellular concentrations of c-di-GMP are maintained by proteins containing GGDEF and EAL domains, which encode diguanylate cyclases for c-di-GMP synthesis and phosphodiesterases for c-di-GMP hydrolysis, respectively. The S. oneidensis MR-1 genome encodes several GGDEF and EAL domain proteins (50 and 31, respectively), with a significant fraction (∼10) predicted to be multidomain (e.g., GGDEF-EAL) enzymes containing an additional Per-Arnt-Sim (PAS) sensor domain. However, the biochemical activities and physiological functions of these multidomain enzymes remain largely unknown. Here, we present genetic and biochemical analyses of a predicted PAS-GGDEF-EAL domain-containing protein, SO0437, here named PdeB. A pdeB deletion mutant exhibited decreased swimming motility and increased biofilm formation under rich growth medium conditions, which was consistent with an increase in intracellular c-di-GMP. A mutation inactivating the EAL domain also produced similar swimming and biofilm phenotypes, indicating that the increase in c-di-GMP was likely due to a loss in phosphodiesterase activity. Therefore, we also examined the enzymatic activity of purified PdeB and found that the protein exhibited phosphodiesterase activity via the EAL domain. No diguanylate cyclase activity was observed. In addition to the motility and biofilm phenotypes, transcriptional profiling by DNA microarray analysis of biofilms of pdeB (in-frame deletion and EAL) mutant cells revealed that expression of genes involved in sulfate uptake and assimilation were repressed. Addition of sulfate to the growth medium resulted in significantly less motile pdeB mutants. Together, these results indicate a link between c-di-GMP metabolism, S. oneidensis MR-1 biofilm development, and sulfate uptake/assimilation.

  16. Semi-synthetic derivatives of natural isoflavones from Maclura pomifera as a novel class of PDE-5A inhibitors.

    PubMed

    Ribaudo, Giovanni; Pagano, Mario Angelo; Pavan, Valeria; Redaelli, Marco; Zorzan, Maira; Pezzani, Raffaele; Mucignat-Caretta, Carla; Vendrame, Tiziano; Bova, Sergio; Zagotto, Giuseppe

    2015-09-01

    Natural (iso)flavonoids have been recently reported to inhibit cyclic nucleotide phosphodiesterases (PDEs) and induce vasorelaxation, albeit the results described in the literature are discordant. The cGMP-selective isoform PDE-5A, in particular, represents the target of sildenafil and its analogues in the treatment of erectile dysfunction (ED) and pulmonary hypertension by promoting relaxation in vascular smooth muscle through the activation of the NO/cGMP pathway. We undertook this study to verify if osajin and pomiferin, two natural prenylated isoflavones and major constituents of Maclura pomifera extracts previously investigated for their anticancer, antibacterial and antidiabetic properties, show inhibitory activity on PDE-5A. These two isoflavones were isolated from the plant extracts and then synthetically modified to obtain a set of semi-synthetic derivatives with slight and focused modifications on the natural scaffold. The compounds were at first screened against PDE-5A in vitro and, based on the encouraging results, further tested for their relaxant effect on isolated rat artery rings. Computational docking studies were also carried out to explore the mode of interaction with the target protein. The obtained data were compared to the behaviour of the well-known PDE-5A inhibitor sildenafil. Our results demonstrate that semi-synthetic derivatives of osajin and pomiferin show an inhibitory effect on the isolated enzyme that, for some of the compounds, is accompanied by a vasorelaxant activity. Based on our findings, we propose the here described isoflavones as potential lead compounds for the development, starting from natural scaffolds, of a new class of PDE-5A inhibitors with vasorelaxant properties. Copyright © 2015 Elsevier B.V. All rights reserved.

  17. 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

  18. 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.

  19. 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.

  20. 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

  1. 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.

  2. Excess adenosine A2B receptor signaling contributes to priapism through HIF-1α mediated reduction of PDE5 gene expression

    PubMed Central

    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

    2014-01-01

    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 A2B 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.—Ning, C., Wen, J., Zhang, Y., Dai, Y., Wang, W., Zhang, W., Qi, L., Grenz, A., Eltzschig, H. K., Blackburn, M. R., Kellems, R. E., Xia, Y. Excess adenosine A2B receptor signaling contributes to priapism through HIF-1α mediated reduction of PDE5 gene expression. PMID:24614760

  3. Audits of radiopharmaceutical formulations

    SciTech Connect

    Castronovo, F.P. Jr. )

    1992-03-01

    A procedure for auditing radiopharmaceutical formulations is described. To meet FDA guidelines regarding the quality of radiopharmaceuticals, institutional radioactive drug research committees perform audits when such drugs are formulated away from an institutional pharmacy. All principal investigators who formulate drugs outside institutional pharmacies must pass these audits before they can obtain a radiopharmaceutical investigation permit. The audit team meets with the individual who performs the formulation at the site of drug preparation to verify that drug formulations meet identity, strength, quality, and purity standards; are uniform and reproducible; and are sterile and pyrogen free. This team must contain an expert knowledgeable in the preparation of radioactive drugs; a radiopharmacist is the most qualified person for this role. Problems that have been identified by audits include lack of sterility and apyrogenicity testing, formulations that are open to the laboratory environment, failure to use pharmaceutical-grade chemicals, inadequate quality control methods or records, inadequate training of the person preparing the drug, and improper unit dose preparation. Investigational radiopharmaceutical formulations, including nonradiolabeled drugs, must be audited before they are administered to humans. A properly trained pharmacist should be a member of the audit team.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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

  10. 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

  11. Forward model nonlinearity versus inverse model nonlinearity

    USGS Publications Warehouse

    Mehl, S.

    2007-01-01

    The issue of concern is the impact of forward model nonlinearity on the nonlinearity of the inverse model. The question posed is, "Does increased nonlinearity in the head solution (forward model) always result in increased nonlinearity in the inverse solution (estimation of hydraulic conductivity)?" It is shown that the two nonlinearities are separate, and it is not universally true that increased forward model nonlinearity increases inverse model nonlinearity. ?? 2007 National Ground Water Association.

  12. 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.

  13. Nonlinear channelizer

    NASA Astrophysics Data System (ADS)

    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.

  14. C33(S), a novel PDE9A inhibitor, protects against rat cardiac hypertrophy through upregulating cGMP signaling.

    PubMed

    Wang, Pan-Xia; Li, Zhuo-Ming; Cai, Si-Dong; Li, Jing-Yan; He, Ping; Huang, Yi; Feng, Guo-Shuai; Luo, Hai-Bin; Chen, Shao-Rui; Liu, Pei-Qing

    2017-09-01

    Phosphodiesterase-9A (PDE9A) expression is upregulated during cardiac hypertrophy and heart failure. Accumulating evidence suggests that PDE9A might be a promising therapeutic target for heart diseases. The present study sought to investigate the effects and underlying mechanisms of C33(S), a novel selective PDE9A inhibitor, on cardiac hypertrophy in vitro and in vivo. Treatment of neonatal rat cardiomyocytes (NRCMs) with PE (100 μmol/L) or ISO (1 μmol/L) induced cardiac hypertrophy characterized by significantly increased cell surface areas and increased expression of fetal genes (ANF and BNP). Furthermore, PE or ISO significantly increased the expression of PDE9A in the cells; whereas knockdown of PDE9A significantly alleviated PE-induced hypertrophic responses. Moreover, pretreatment with PDE9A inhibitor C33(S) (50 and 500 nmol/L) or PF-7943 (2 μmol/L) also alleviated the cardiac hypertrophic responses in PE-treated NRCMs. Abdominal aortic constriction (AAC)-induced cardiac hypertrophy and ISO-induced heart failure were established in SD rats. In ISO-treated rats, oral administration of C33(S) (9, 3, and 1 mg·kg(-1)·d(-1), for 3 consecutive weeks) significantly increased fractional shortening (43.55%±3.98%, 54.79%±1.95%, 43.98%±7.96% vs 32.18%±6.28%), ejection fraction (72.97%±4.64%, 84.29%±1.56%, 73.41%±9.37% vs 49.17%±4.20%) and cardiac output (60.01±9.11, 69.40±11.63, 58.08±8.47 mL/min vs 48.97±2.11 mL/min) but decreased the left ventricular internal diameter, suggesting that the transition to heart failure was postponed by C33(S). We further revealed that C33(S) significantly elevated intracellular cGMP levels, phosphorylation of phospholamban (PLB) and expression of SERCA2a in PE-treated NRCMs in vitro and in ISO-induced heart failure model in vivo. Our results demonstrate that C33(S) effectively protects against cardiac hypertrophy and postpones the transition to heart failure, suggesting that it is a promising agent in the treatment of

  15. The Therapeutic Profile of Rolipram, PDE Target and Mechanism of Action as a Neuroprotectant following Spinal Cord Injury

    PubMed Central

    Schaal, Sandra Marie; Garg, Maneesh Sen; Ghosh, Mousumi; Lovera, Lilie; Lopez, Michael; Patel, Monal; Louro, Jack; Patel, Samik; Tuesta, Luis; Chan, Wai-Man; Pearse, Damien Daniel

    2012-01-01

    The extent of damage following spinal cord injury (SCI) can be reduced by various neuroprotective regimens that include maintaining levels of cyclic adenosine monophosphate (cyclic AMP), via administration of the phosphodiesterase 4 (PDE4) inhibitor Rolipram. The current study sought to determine the optimal neuroprotective dose, route and therapeutic window for Rolipram following contusive SCI in rat as well as its prominent PDE target and putative mechanism of protection. Rolipram or vehicle control (10% ethanol) was given subcutaneously (s.c.) daily for 2 wk post-injury (PI) after which the preservation of oligodendrocytes, neurons and central myelinated axons was stereologically assessed. Doses of 0.1 mg/kg to 1.0 mg/kg (given at 1 h PI) increased neuronal survival; 0.5 mg to 1.0 mg/kg protected oligodendrocytes and 1.0 mg/kg produced optimal preservation of central myelinated axons. Ethanol also demonstrated significant neuronal and oligo-protection; though the preservation provided was significantly less than Rolipram. Subsequent use of this optimal Rolipram dose, 1.0 mg/kg, via different routes (i.v., s.c. or oral, 1 h PI), demonstrated that i.v. administration produced the most significant and consistent cyto- and axo- protection, although all routes were effective. Examination of the therapeutic window for i.v. Rolipram (1.0 mg/kg), when initiated between 1 and 48 h after SCI, revealed maximal neuroprotection at 2 h post-SCI, although the protective efficacy of Rolipram could still be observed when administration was delayed for up to 48 h PI. Importantly, use of the optimal Rolipram regimen significantly improved locomotor function after SCI as measured by the BBB score. Lastly we show SCI-induced changes in PDE4A, B and D expression and phosphorylation as well as cytokine expression and immune cell infiltration. We demonstrate that Rolipram abrogates SCI-induced PDE4B1 and PDE4A5 production, PDE4A5 phosphorylation, MCP-1 expression and immune cell

  16. Integrated analysis and design for controlled nonlinear multibody systems

    NASA Technical Reports Server (NTRS)

    Wu, Shih-Chin; Juang, Jer-Nan; Belvin, W. Keith; Woodard, Stanley E.

    1991-01-01

    A hybrid approach for integrated analysis and design of nonlinear multibody systems is proposed. Based on the approach, a general-purpose design tool is developed for nonlinear dynamic systems subjected to nonlinear design constraints. For analysis purposes, second-order nonlinear equations of motion of the system are automatically generated using general-purpose multibody formulations. Once the equations are solved, they are written in first-order form to take advantage of the first-order formulations of design sensitivity analysis for dynamic systems. A nonlinear programming technique is then used to optimize the nonlinear systems, such that a nonlinear cost function is minimized and performance constraints are satisfied. The approach proved to be very general and useful for design and analysis of controlled multibody systems. The approach is applied to the design of passive dynamic controllers for slewing control of multibody systems.

  17. 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.

  18. Replication confirms the association of loci in FOXE1, PDE8B, CAPZB and PDE10A with thyroid traits: a Genetics of Diabetes Audit and Research Tayside study (GoDARTS).

    PubMed

    Soto-Pedre, Enrique; Siddiqui, Moneeza K; Doney, Alex S; Palmer, Colin N A; Pearson, Ewan R; Leese, Graham P

    2017-10-01

    Replication of associations in genome-wide association studies is desirable to ensure that such signals are potentially clinically meaningful. This study aimed to replicate associations of selected single-nucleotide polymorphisms (SNPs) with hypothyroidism and serum thyroid-stimulating hormone (TSH) using electronic medical records (EMRs). A cross-sectional study was carried out among patients of European Caucasian ethnicity from the Genetics of Diabetes Audit and Research Tayside recruited in Tayside (Scotland, UK). EMRs (biochemistry, prescribing, hospital admissions and demographics) were used to ascertain patients with hypothyroidism and their controls as well as average serum TSH concentration, and linked to genetic biobank data. Genetic tests of association were performed using logistic and linear regression models. We analysed 1703 cases of hypothyroidism and 9457 controls. All four SNPs located on chromosome 9 at FOXE1 were associated with hypothyroidism with similar effect estimates (odds ratio=0.75-0.76, P<5e-08). Also, loci on chromosomes 1 (PTPN22), six (HLA-E/HLA-C) and 12 (SH2B3) were replicated. For serum TSH, we confirmed 12 SNPs previously reported at PDE8B, CAPZB, PDE10A, LOC105371356, NR3C2, VEGFA, IGFBP5, INSR, PRDM11, NFIA, ITPK1 and ABO. Overall, these SNPs accounted for 6.8% of the serum TSH variation (P<1e-04). EMRs linked to genomic data in large populations enable validation of genome-wide association studies discoveries without additional genotyping costs. Our replication confirmed at genome-wide significance the association of loci at FOXE1 with hypothyroidism, and PDE8B, CAPZB and PDE10A with serum TSH. A total of 12 SNPs seemed to explain nearly 7% of the serum TSH variation.

  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. 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

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

    2013-05-01

    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. 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. 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. 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. © 2013 The Authors. British Journal of Pharmacology © 2013 The British Pharmacological Society.

  1. 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.

  2. 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.

  3. 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.

  4. A new elastoplastic shell element formulation for DYNA3D

    SciTech Connect

    Engelmann, B.E.; Whirley, R.G.

    1990-08-01

    The analysis of shell structures undergoing dynamic elastoplastic deformation is an important capability of DYNA3D. This paper presents an improved formulation for a 4-node quadrilateral shell element for explicit dynamic analysis. The proposed element is derived from a three-field weak form, and incorporates recently developed assumed strain methods for improved accuracy. In addition, the element is formulated in a large-displacement small-strain setting for minimum cost. Complex nonlinear constitutive models are easily incorporated into this formulation. Numerical examples illustrating the accuracy, robustness, and speed of the new element are shown. 13 refs., 3 tabs.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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…

  10. 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.

  11. 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…

  12. 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

  13. 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.

  14. 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.

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

    PubMed

    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; Zhang, Mingzhi; Leung, Yuk Fai

    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

  16. 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

  17. 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.

  18. 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

  19. 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.

  20. Identification of PDE5A:E90K: a polymorphism in the canine phosphodiesterase 5A gene affecting basal cGMP concentrations of healthy dogs.

    PubMed

    Stern, J A; Reina-Doreste, Y; Chdid, L; Meurs, K M

    2014-01-01

    Cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase (PDE5A) is the target of phosphodiesterase inhibitors such as sildenafil. Polymorphisms in the PDE5A gene that may predict response to therapy with sildenafil and nitric oxide, be linked to disease progression, and aid in risk assessment have been identified in human beings. Identification of polymorphisms in PDE5A could affect the physiologic actions of PDE5A and the effects of phosphodiestrase type 5 inhibitor drugs. Functional polymorphisms exist in the canine PDE5A gene. Specific objectives were to identify PDE5A polymorphisms and evaluate their functional relevance. Seventy healthy dogs. The exonic, splice-site, 3' and 5' untranslated regions of the canine PDE5A gene were sequenced in 15 dogs and aligned with the canine reference sequence. Identified polymorphisms were evaluated in 55 additional, healthy, unrelated dogs of 20 breeds. Plasma was collected from 51 of these dogs and cGMP was measured. An unpaired t-test and one-way ANOVA with Dunnett's test of multiple comparisons were used to evaluate the effect of genotype on cGMP. A common exonic polymorphism was identified that changed glutamic acid to lysine and resulted in significantly lower cGMP concentrations in the group with polymorphism versus the wild type group (P = .014). Additionally, 6 linked single nucleotide polymorphisms in the 3' untranslated region were identified that did not alter cGMP concentrations. A polymorphism exists in the canine PDE5A gene that is associated with variable circulating cGMP concentrations in healthy dogs and warrants investigation in diseases such as pulmonary hypertension. Copyright © 2013 by the American College of Veterinary Internal Medicine.

  1. Nebivolol potentiates the efficacy of PDE5 inhibitors to relax corpus cavernosum and penile arteries from diabetic patients by enhancing the NO/cGMP pathway.

    PubMed

    Martínez-Salamanca, Juan I; La Fuente, José M; Cardoso, José; Fernández, Argentina; Cuevas, Pedro; Wright, Harold M; Angulo, Javier

    2014-05-01

    The efficacy of oral pharmacotherapy for erectile dysfunction (ED) (i.e., type 5 phosphodiesterase[PDE5] inhibitors) is significantly reduced in diabetic patients. Nebivolol is a selective β1-blocker used for treatinghy pertension that has been shown to increase the efficacy of sildenafil to reverse ED in diabetic rats. To evaluate the effects of nebivolol on the efficacy of the PDE5 inhibitors, sildenafil, tadalafil, and vardenafil to relax human corpus cavernosum (HCC) and vasodilate human penile resistance arteries (HPRA) from diabetic patients with ED (DMED). The influence of nebivolol on the capacity of these three PDE5 inhibitors to stimulate cyclic guanosine monophosphate (cGMP) production in HCC was also evaluated. HCC and HPRA were obtained from organ donors without ED (NEND; n = 18) or patients with diabetes undergoing penile prosthesis implantation (DMED; n = 19). Relaxations of HCC strips and HPRA to sildenafil,tadalafil, and vardenafil were evaluated in organ chambers and wire myographs. cGMP content in HCC was determined by ether extraction and quantification by ELISA. Effects of nebivolol on PDE5 inhibitor-induced relaxation of HCC, vasodilation ofHPRA and cGMP accumulation in HCC. Treatment with nebivolol (1 μM) significantly potentiated sildenafil-, tadalafil- and vardenafil-induced relaxations of HCC and vasodilations of HPRA from both NEND and DMED. Enhancement of relaxant capacity by nebivolol resulted in reversion of the impairment of PDE5 inhibition-induced responses in DMED and it was accompanied by enhancing the ability of PDE5 inhibitors to increase cGMP in HCC restoring reduced cGMP levelsin HCC from DMED. Nebivolol potentiated the capacity of PDE5 inhibitors to relax vascular structures of erectile tissue from diabetic patients by enhancing the nitric oxide (NO)/cGMP pathway in these tissues. These effects suggest a potential therapeutic utility of nebivolol as an adjunct to PDE5 inhibitors for the treatment of ED associated with

  2. 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

  3. 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

  4. 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.

  5. 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

  6. Determination and application of the permitted daily exposure (PDE) for topical ocular drugs in multipurpose manufacturing facilities.

    PubMed

    Lovsin Barle, Ester; Bizec, Jean-Claude; Glogovac, Milica; Gromek, Kamila; Winkler, Gian Christian

    2017-04-12

    Limits for the carry-over of product residues should be based on toxicological evaluation such as described in the "Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities". The toxicological evaluation should be performed also for locally administered drugs to ensure patient safety. Currently, there is no guidance on setting PDE for ocular drug substances in particular. The purpose of this investigation was to identify and describe a method for calculating a PDE value for topical ocular drugs (PDEocular). As an alternative method, extrapolation of a PDE for systemically administered drugs to a PDEocular is presented. These methods may be applied in cross-contamination risk assessments for manufacturing of topical ocular drugs. Similarly, the methods apply to systemically administered drugs, if their production precedes manufacturing of a topical ocular drug. We have examined pharmacokinetic (PK) properties of topical ocular drugs and compared them to the PK parameters of systemically administered drugs. Furthermore, we examined possible adverse effects of the carry-over in topical ocular drugs at therapeutic doses.

  7. Evaluation of patients with nasal polyps about the possible association of desmosomal junctions, RORA and PDE4D gene.

    PubMed

    Apuhan, T; Gepdiremen, S; Arslan, A O; Aktas, G

    2013-10-01

    Nasal polyposis is chronic inflammatory disease of the nasal mucosa of the nose and sinuses, often associated with chronic non-allergic rhinitis, aspirin intolerance and non-allergic asthma. The etiology of nasal polyposis is unknown. Multiple factors contribute to the development of nasal polyps including genetic predisposition. This study was conducted on patients applied due to nasal polyps. Blood samples were collected peripheral vein and stored at 4°C until analysis for DNA extraction. Genomic DNA was extracted from peripheral blood by a standard method, samples were studied in real time PCR. All patients were evaluated about the possible association of DSG1 (rs7236477-G, 96 rxn), DSG3 (rs1941184-C, 96 rxn), PDE4D (rs1588265) and RORA (rs11071559) gene. 32 patients (17 male, 15 female) with nasal polyposis were included to the study. The mean age was 34.9 ± 17.7 years, ranging between 18 and 55 years. Control group was consisted with 50 healthy volunteers without a history of nasal polyp. DSG1, DSG3 and RORA values of the study group were not statistically different from control group (p > 0.05). PDE4D values of the study group were significantly different from control group (p < 0.05). Multiple factors contribute to the pathogenesis of nasal polyps including genetic predisposition. The PDE4D family has gained interest in the complex pathogenesis of nasal polyposis. This is likely linked to the mucosal inflammatory response.

  8. HST1 increases replicative lifespan of a sir2Δ mutant in the absence of PDE2 in Saccharomyces cerevisiae.

    PubMed

    Kang, Woo Kyu; Devare, Mayur; Kim, Jeong-Yoon

    2017-02-01

    Silent information regulator 2 (Sir2), which is the founding member of the sirtuin family of proteins, is a pro-longevity factor for replicative lifespan (RLS) in Saccharomyces cerevisiae. Sir2 is required for transcriptional silencing at mating type loci, telomeres, and rDNA loci. Sir2 also represses transcription of highly expressed growth-related genes, such as PMA1 and some ribosomal protein genes. Although the Sir2 paralogues Hst1, Hst2, Hst3, and Hst4 occur in S. cerevisiae, none of them could replace the transcriptional regulation of PMA1 by Sir2 in the wild type. In this study, we demonstrate t